key: cord-0006678-0chi6pae
authors: Salgado, Diamantino R.; Ortiz, Julian Arias; Favory, Raphaël; Creteur, Jacques; Vincent, Jean-Louis; De Backer, Daniel
title: Microcirculatory abnormalities in patients with severe influenza A (H1N1) infection
date: 2010-07-27
journal: Can J Anaesth
DOI: 10.1007/s12630-010-9365-6
sha: dabe30ddb89180c453fc381eb5ce8e683c6fb716
doc_id: 6678
cord_uid: 0chi6pae

PURPOSE: This study was designed to evaluate the degree of microcirculatory abnormalities in patients with severe influenza A (H1N1) infection. METHODS: We assessed the sublingual microcirculation in seven consecutive patients with acute lung injury related to influenza A (H1N1) infection. The evaluation was carried out using sidestream dark field (SDF) imaging within the first 96 hr after the patients were admitted to the intensive care unit. Thenar oxygen saturation (StO(2)) was also measured with near-infrared spectroscopy (NIRS) during a vascular occlusion test. In addition, the Lung Injury Score (LIS) and the APACHE II and SOFA scores were recorded. RESULTS: All patients received invasive mechanical ventilation and at least one of the following adjuvant therapies: inhaled nitric oxide (n = 4), extracorporeal membrane oxygenation (n = 1), prone position (n = 4), recruitment maneuver (n = 3), and hydrocortisone 50 mg·hr(−6) (n = 6). The median time from admission to microcirculatory assessment was 21 hr. Three patients had bacterial superinfection. The median LIS and PaO(2)/F(i)O(2) were 2.5 (2.25-3.25) and 178 (158-212), respectively. Three subjects were treated with norepinephrine. During a vascular occlusion test, the microcirculation was moderately to severely compromised with a NIRS ascending slope of 2.39%·sec(−1) (1.75-2.67%·sec(−1)), 66% (60-86%) of perfused small vessels in the sublingual microcirculation, and a microvascular flow index of 1.9 (1.3-2.6). The degree of microcirculatory abnormalities detected by the NIRS and SDF imaging techniques was correlated with the severity of the disease, as reflected by the SOFA and APACHE II scores. CONCLUSIONS: The microcirculation as assessed by SDF imaging and NIRS techniques was compromised in patients with acute respiratory distress syndrome (ARDS) and influenza A (H1N1) infection.

Purpose This study was designed to evaluate the degree of microcirculatory abnormalities in patients with severe influenza A (H1N1) infection. Methods We assessed the sublingual microcirculation in seven consecutive patients with acute lung injury related to influenza A (H1N1) infection. The evaluation was carried out using sidestream dark field (SDF) imaging within the first 96 hr after the patients were admitted to the intensive care unit. Thenar oxygen saturation (StO 2 ) was also measured with near-infrared spectroscopy (NIRS) during a vascular occlusion test. In addition, the Lung Injury Score (LIS) and the APACHE II and SOFA scores were recorded. Results All patients received invasive mechanical ventilation and at least one of the following adjuvant therapies: inhaled nitric oxide (n = 4), extracorporeal membrane oxygenation (n = 1), prone position (n = 4), recruitment maneuver (n = 3), and hydrocortisone 50 mgÁhr -6 (n = 6). The median time from admission to microcirculatory assessment was 21 hr. Three patients had bacterial superinfection. The median LIS and PaO 2 /F I O 2 were 2.5 (2.25-3.25) and 178 (158-212), respectively. Three subjects were treated with norepinephrine. During a vascular occlusion test, the microcirculation was moderately to severely compromised with a NIRS ascending slope of 2.39%Ásec -1 (1.75-2.67%Ásec -1 ), 66% (60-86%) of perfused small vessels in the sublingual microcirculation, and a microvascular flow index of 1.9 (1.3-2.6). The degree of microcirculatory abnormalities detected by the NIRS and SDF imaging techniques was correlated with the severity of the disease, as reflected by the SOFA and APACHE II scores.

Conclusions The microcirculation as assessed by SDF imaging and NIRS techniques was compromised in patients with acute respiratory distress syndrome (ARDS) and influenza A (H1N1) infection.

Objectif Cette e´tude a e´te´conçue afin d'e´valuer le degred 'anomalies microcirculatoires chez des patients souffrant d'une infection grave a`la grippe A (H1N1). Méthode Nous avons examine´la microcirculation sublinguale chez sept patients conse´cutifs souffrant d'une le´sion pulmonaire aigue¨lie´e à une infection a`la grippe A (H1N1). L'e´valuation a e´te´re´alise´e à l'aide d'imagerie en champ noir a`e´pi-illumination late´rale (sidestream dark field -SDF) au cours des premie`res 96 h suivant l'admission des patients a`l'unite´des soins intensifs. La saturation the´narienne en oxyge`ne (StO 2 ) a e´galement e´teḿ esure´e par spectroscopie proche infrarouge (NIRS) pendant un test d'occlusion vasculaire. De plus, un Score de le´sion pulmonaire (LIS) et les scores APACHE II et SOFA ont e´te´enregistre´s. Résultats Tous les patients ont subi une ventilation me´canique invasive et au moins l'une des the´rapies adjuvantes suivantes: monoxyde d'azote inhale´(n = 4), oxyge´nation par membrane extracorporelle (n = 1), position ventrale (n = 4), manoeuvre de recrutement (n = 3), et hydrocortisone 50 mgÁh -6 (n = 6). Le temps moyen entre l'admission et l'e´valuation microcirculatoire e´tait de 2 Although it presented a global mortality rate similar to that of the seasonal influenza virus, this new strain of influenza A (H1N1) virus has some particularities that make it a specific challenge for the intensivist. First, certain groups of patients, who are usually not at risk of complications or death from seasonal influenza, are at special risk with the influenza A (H1N1) virus, including pregnant or postpartum women, asthmatic or obese patients, and young subjects. [3] [4] [5] Second, this virus has a special tropism for the lower airways. Accordingly, acute viral pneumonitis, with or without bacterial superinfection, and airflow limitation occur frequently. 6, 7 For the most part, patients with severe influenza A (H1N1) are admitted to hospital for respiratory failure that progresses rapidly, usually within one day, into severe respiratory failure necessitating admission to the intensive care unit (ICU) and rescue ventilatory strategies. 3, 7, 8 Such patients present with moderate to severe acute respiratory distress syndrome (ARDS) associated with high morbidity and mortality rates (15-40%). 3, 9, 10 These pulmonary and remote alterations present many similarities to ''bacterial'' sepsis, even though they may occur in the absence of bacterial infection. The H1N1 infection is associated with a strong pulmonary inflammatory response with increased production of interleukin (IL)-10, IL-4, and interferon-gamma (IFN-c). 11 This proinflammatory response is not restricted to the lungs. Recently, Bermejo-Martin et al. 12 reported that systemic levels of several pro-inflammatory cytokines were increased in patients hospitalized with H1N1 infection, especially in those who were critically ill. Remote organ dysfunction may also be observed, including elevated liver enzymes, rhabdomyolysis, renal failure, and shock. 9 In sepsis, severe microcirculatory alterations have been observed. 13 These alterations may have important implications, as the microcirculation is the principal site of oxygen exchange between blood and underlying tissues. Additionally, anomalies of the microcirculatory network have been consistently demonstrated as being associated with organ dysfunction and mortality. 14, 15 However, microcirculatory alterations have not yet been reported in patients with viral infections. We hypothesized that microcirculatory abnormalities may be present in patients with severe influenza A (H1N1) infection, participating in local and remote tissue injury. During the H1N1 pandemic in the fall of 2009, we evaluated the microcirculation of critically ill patients admitted to hospital with severe respiratory failure associated with influenza-like syndrome in order to evaluate the degree of microcirculatory dysfunction in patients with severe influenza A (H1N1) infection.

All patients with acute respiratory failure associated with influenza-like illness who were admitted to the 35-bed ICU of a teaching hospital from October to December 2009 were screened for inclusion in the study. Influenza-like illness was defined as two or more of the following symptoms: fever, chills, myalgia, arthralgia, headache, and sore throat and/or cough in the absence of another known cause during the epidemic period of H1N1 infection. Acute lung injury (ALI) was defined as PaO 2 /F I O 2 below 300 in the absence of signs of raised left atrial pressure. 16 

On the day of microcirculatory assessment, severity of illness was assessed using the Sequential Organ Failure Assessment (SOFA) score, 18 the Acute Physiology and Chronic Health Evaluation (APACHE II) score, 19 and the Lung Injury Score (LIS). 20 Length of ICU stay, length of hospital stay, ICU mortality, 28-day mortality, and hospital mortality were recorded.

We also recorded global hemodynamic parameters, demographic data, major comorbidities, variables (in terms of respiration, mechanisms, and oxygenation), blood serum markers of organ function, and the presence of bacterial superinfection. In addition, we noted organ support therapy, such as vasopressors, renal replacement therapy, mechanical ventilation, and related adjuvant therapies (nitric oxide inhalation, steroids, prone position, recruitment maneuvers, and extracorporeal membrane oxygenation) received during the ICU stay.

The microcirculation was assessed using sidestream dark field (SDF) imaging (MicroScan, MicroVision Medical, Amsterdam, The Netherlands) and near-infrared spectroscopy (NIRS) (InSpectra 650, Hutchinson, MN, USA).

The SDF imaging technique has been presented elsewhere in detail. 13 In brief, five sequence images of 20 sec each were recorded from the lateral sublingual area by a video camera (5 X objective), stored and analyzed offline. The density, the proportion of perfused vessels, and the microvascular flow index (MFI) of the vessels were quantified using the semi-quantitative method. 21 The NIRS technique has been detailed elsewhere. 22 Briefly, a probe was placed over the skin of the thenar eminence to register the baseline tissue oxygen saturation (StO 2 ) and the total hemoglobin index (THI), i.e., an estimate of the local tissue hemoglobin concentration. A threeminute vascular occlusive test was then performed with an arterial cuff around the arm inflated up to 50 mmHg above the systolic arterial pressure. The rate of tissue oxygen consumption (linear regression of the downslope) and the tissue oxygen consumption at the end of the first minute of ischemia (NirVO 2 ) were measured during the ischemic phase. The vasoreactivity response to hypoxia was measured as the linear regression of the incremental StO 2 upslope that followed the arterial cuff release. Finally, the difference between the maximal StO 2 and THI following the reperfusion and the baseline values of these variables were computed as DStO 2 and DTHI. 23 

Continuous variables are depicted as median (interquartile range, 25-75%) or as mean ± standard deviation (SD), and categorical variables are depicted as number (%). Parametric (Pearson correlation) or non-parametric (Spearman test) linear regression was performed to evaluate the relationships between microcirculation (NIRS and SDF imaging) variables and indices of severity.

Among the 30 patients with influenza-like syndrome who were admitted to the ICU during the study period, seven patients were included for microcirculatory evaluation. Twenty-three patients were excluded for use of non-invasive mechanical ventilation (n = 16) precluding investigation of the sublingual microcirculation, age \ 18 yr (n = 2), time from diagnosis [ 96 hr (n = 2), and missed cases (n = 3). Three of the included patients had confirmed H1N1 infection, one probable and three suspected. At the very least, one comorbidity was found in each of the patients: immunosuppression (n = 4), pregnancy (n = 2), diabetes (n = 2), heart disease (n = 2), chronic obstructive pulmonary disease (n = 1), neoplasia (n = 1), chronic renal failure (n = 1), and cirrhosis (n = 1). Three patients had bacterial superinfection. All patients were on antibiotics and six were receiving oseltamivir at the time of the microcirculatory assessment-in the remaining patient, therapy was initiated just after the microcirculatory assessment. The main clinical and laboratory characteristics of the patients are detailed in Table 1 . Three patients were in shock, requiring norepinephrine administration with a mean dose of 0.57 ± 0.55 lgÁkg -1 Ámin -1 . The main hemodynamic data are shown in Table 2 .

All patients received mechanical ventilatory assistance and fulfilled the ALI/ARDS criteria by way of low lung compliance, hypoxemia, and high LIS. Adjuvant therapy for ARDS was frequently applied, particularly steroids, which were reserved for the most severe cases (Table 2 ). At the time of microcirculatory assessment, the median LIS of all patients was 2.50 (2.25-3.25) points.

The microcirculatory assessment was performed 21 (7-45) hr after admission to the ICU. Both SDF imaging and NIRS revealed that the microcirculation was moderately to severely compromised (Table 3 and Figure) . The proportion of perfused small vessels was 66% (60-86%; normal [ 90%) and the MFI was 1.9 points (1.3-2.6 points; normal [ 2.5 points). The NIRS descending slope was -0.19%Ásec -1 (-0.15-0.22%Ásec -1 ; normal range -0.22 ± 0.06%Ásec -1 ), ascending slope 2.39%Ásec -1 (1.75-2.67% Ásec -1 ; normal range 4.8 ± 1.6%Ásec -1 ), and nirVO 2 110.6 U (80.1-120.2 U; normal range 171 ± 57 U).

The proportion of perfused small vessels and the MFI correlated negatively with the SOFA score (R 2 0.67; P = 0.046 and R 2 0.85; P = 0.009, respectively), while the NIRS ascending slope correlated negatively with the APACHE II score (R 2 0.36; P = 0.05).

Data from this series of seven patients demonstrates that patients with severe influenza A (H1N1) infection with ALI/ARDS have clinically significant microcirculatory abnormalities. In particular, both clinical (LIS) and microcirculatory insults were at least as severe in patients with only viral infection as in those with superimposed bacterial infection.

The microcirculation has a central role in the regulation of organ perfusion. 24 In several studies and in different types of shock, the presence of microcirculatory dysfunction has been associated with poor outcomes, including a higher frequency of organ failure and mortality. 14, 15, 25, 26 In our small series of patients, the microcirculation was moderately to severely compromised, in line with previous studies of patients with severe sepsis and septic shock. 14, 22, 23 For example, Creteur et al. 22 reported NIRS ascending slope values of 2.3 ± 1.3%Ásec -1 in patients with septic shock, a value similar to our findings. Skarda et al. 23 found NirVO 2 values of 97 ± 36 U, again in the range seen in our patients. In addition, the proportion of perfused small vessels assessed by SDF imaging was 65% (53.1-68.9%) in patients with septic shock, similar to that reported by Sakr et al. 14 As in sepsis, we observed a significant correlation between the microcirculatory abnormalities detected by the two methods (SDF imaging and NIRS) and the severity of disease as assessed by SOFA and APACHE II scores.

One of the most interesting findings was that bacterial superinfection was not mandatory for microvascular flow impairment to occur, although the small sample size limits the strength of this conclusion. Influenza A (H1N1) virus may induce microvascular alterations either directly or indirectly via the stimulation of host inflammatory factors. Bacterial superinfection (n) 3 Use of antibiotics (n) 7

Use of oseltamivir (n) 6

Use of norepinephrine (n, dose in lgÁkg -1 Ámin Central venous pressure (mmHg) 14 (11) (12) (13) (14) (15) (16) (17) Pulmonary artery occlusive pressure (mmHg*) 26 ± 6

Cardiac output (LÁmin -1# Administration of tumour necrosis factor (TNF), a proinflammatory cytokine, can lead to microcirculatory alterations in animals. 27 This new influenza strain is more virulent than seasonal influenza strains and may, therefore, induce microcirculatory impairment by a direct viral effect. Using different mammalian models, Itoh et al. 11 demonstrated that one of the first influenza A (H1N1) strains to be isolated was more lethal, persisted longer in the lower airways, caused more intense alveolitis, and induced higher concentrations of inflammatory cytokines in the lungs than a regular seasonal influenza strain. Compared with outpatients, the inflammatory response to severe influenza A (H1N1) is more pronounced in patients with severe disease who require hospitalization, and the response can be observed even in patients who do not have bacterial superinfection. 12 The ability of the influenza and other acute respiratory viruses to provoke microvascular alterationscharacterized by sludge of capillary flow associated with hypercoagulability and increased blood viscosity-has been suggested by others. 28 Therefore, significant microcirculatory perfusion deficits could be an important pathophysiological mechanism in severe influenza A (H1N1) infections. Our study has several limitations. First, although we studied most of the severe cases in our institution, the sample size was relatively limited, and we were unable to perform some exploratory analyses of subgroups. Second, no control groups of patients with less severe H1N1 infection or other causes of ARDS were included. Third, although the examinations were performed quite early, it was impossible to standardize their timing, and there were no follow-up tests to study disease progression.

What then are the implications of our data? First, our data suggest that severe viral infections, like bacterial infections, can induce microcirculatory alterations. The study was not designed to evaluate whether the observed microcirculatory alterations are specific to H1N1 infection or whether they simply reflect the fact that critically ill patients with severe sepsis have disturbed microcirculation. Second, the finding of microcirculatory abnormalities and their correlation with disease severity using two different techniques suggests that endothelial dysfunction may play a role in the pathophysiology of severe H1N1 infections. These findings are in line with other studies in sepsis that relate the severity of microcirculatory abnormalities to the severity of disease. 14, 22, 29 In conclusion, these data suggest that microcirculatory abnormalities are present in patients with acute lung injury associated with severe influenza A (H1N1) infection independently of any bacterial co-infection.

Funding Departmental funds only.

Competing interests None declared.

Swine influenza A (H1N1) infection in two children-Southern California

World Health Organization. WHO Pandemic (H1N1) 2009 -update 86

Severe respiratory disease concurrent with the circulation of H1N1 influenza

H1N1 2009 influenza virus infection during pregnancy in the USA

Critical care services and 2009 H1N1 influenza in Australia and New Zealand

Pandemic (H1N1) 2009 influenza (''swine flu'') in Australian and New Zealand intensive care

Intensive care adult patients with severe respiratory failure caused by Influenza A (H1N1)v in Spain

Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome

Critically Ill patients with 2009 influenza A(H1N1) in Mexico

Critically ill patients with 2009 influenza A(H1N1) infection in Canada

In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses

Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza

Microvascular blood flow is altered in patients with sepsis

Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock

Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis

Ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome

The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination

The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/ failure

Problems of the European Society of Intensive Care Medicine

APACHE II: a severity of disease classification system

An expanded definition of the adult respiratory distress syndrome

How to evaluate the microcirculation: report of a round table conference

The prognostic value of muscle StO2 in septic patients

Dynamic near-infrared spectroscopy measurements in patients with severe sepsis

The microcirculation is the motor of sepsis

Microvascular alterations in patients with acute severe heart failure and cardiogenic shock

Trauma-hemorrhagic shock-induced red blood cell damage leads to decreased microcirculatory blood flow

Acute effects of tumor necrosis factor on the microcirculation in rat cremaster muscle

Microcirculation and hemostasis in influenza and acute viral respiratory infections complicated with pneumonia (Russian)

Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival