key: cord-0732298-5h37ixwd authors: Laake, Jon H.; Buanes, Eirik A.; Småstuen, Milada C.; Kvåle, Reidar; Olsen, Brita F.; Rustøen, Tone; Strand, Kristian; Sørensen, Vibecke; Hofsø, Kristin title: Characteristics, management and survival of ICU patients with coronavirus disease‐19 in Norway, March‐June 2020. A prospective observational study date: 2021-02-27 journal: Acta Anaesthesiol Scand DOI: 10.1111/aas.13785 sha: 24525231d45008d746a0d81390bff8a950edc96a doc_id: 732298 cord_uid: 5h37ixwd BACKGROUND: Norwegian hospitals have operated within capacity during the COVID‐19 pandemic. We present patient and management characteristics, and outcomes for the entire cohort of adult (>18 years) COVID‐19 patients admitted to Norwegian intensive care units (ICU) from 10 March to 19 June 2020. METHODS: Data were collected from The Norwegian intensive care and pandemic registry (NIPaR). Demographics, co‐morbidities, management characteristics and outcomes are described. ICU length of stay (LOS) was analysed with linear regression, and associations between risk factors and mortality were quantified using Cox regression. RESULTS: In total, 217 patients were included. The male to female ratio was 3:1 and the median age was 63 years. A majority (70%) had one or more co‐morbidities, most frequently cardiovascular disease (39%), chronic lung disease (22%), diabetes mellitus (20%), and obesity (17%). Most patients were admitted for acute hypoxaemic respiratory failure (AHRF) (91%) and invasive mechanical ventilation (MV) was used in 86%, prone ventilation in 38% and 25% of patients received a tracheostomy. Vasoactive drugs were used in 79% and renal replacement therapy in 15%. Median ICU LOS and time of MV was 14.0 and 12.0 days. At end of follow‐up 45 patients (21%) were dead. Age, co‐morbidities and severity of illness at admission were predictive of death. Severity of AHRF and male gender were associated with LOS. CONCLUSIONS: In this national cohort of COVID‐19 patients, mortality was low and attributable to known risk factors. Importantly, prolonged length‐of‐stay must be taken into account when planning for resource allocation for any next surge. Critically ill patients infected with the SARS-CoV-2 virus (COVID-19 patients) typically present with acute hypoxaemic respiratory failure (AHRF) due to viral pneumonia. This may progress to acute respiratory distress syndrome (ARDS), a common but underrecognized cause of admission to the intensive care unit (ICU) that is associated with high mortality rates and significant morbidity in survivors. 1, 2 Such patients are managed in the ICU with generic measures, including invasive mechanical ventilation (MV), in accordance with evidence-based clinical practice guidelines. [3] [4] [5] [6] Mortality rates in ARDS of mixed aetiologies depend on patients' co-morbidities and age, severity of hypoxaemia and co-existing organ failures. 7 In the "large observational study to understand the global impact of severe acute respiratory failure" (LUNG SAFE), overall mortality for patients with ARDS was 40%. 8 The findings have pointed to a need for improved recognition of ARDS at an early stage, strict adherence to evidence-based strategies and attention to modifiable risk factors. 7 Moreover, there is a geo-economic gradient in mortality from high-income regions to low-and middleincome regions. 9 Early reports of the management of critically ill COVID-19 patients were described in the context of health care systems that were initially overwhelmed by large numbers of patients, often exceeding the surge capacity many hospitals had planned for in the event of a pandemic. 10, 11 Reported mortality rates for MV patients with COVID-19 have been high, ranging from 61.5% (China), 12 53.4% (Italy), 13 50% (Seattle), 14 49.4% (UK), 15 43 .6% (New York). 16 This contrasts with outcome data for critically ill patients with non-COVID-19 viral pneumonia, eg, influenza, where mortality has been found to be considerably lower. 15 More recently, data have emerged from healthcare systems where hospital capacity has not been strained, allowing intensive care units to provide care in accordance with established clinical practice. Although case-mix may differ, evidence is emerging that mortality in the critically ill may be lower under such circumstances. [17] [18] [19] [20] The first Norwegian to test positive for SARS-CoV-2 was identified 21 February 2020. This patient was probably infected in China. 21 Following this, a surge of patients (mostly vacationers returning from Northern Italy and Austria) initiated track-and-trace activities and use of quarantine. When routes of transmission could no longer be identified, Norwegian authorities initiated a society-wide lockdown beginning 12 March, including border closures, travel restrictions for health care personnel, closure of universities, schools and kindergartens. The public was barred from participation in nonessential activities (meetings, restaurants and pubs, sports) and the authorities encouraged working from home for whomever this was an option. 22 After a slow lifting of restrictions beginning 27 April, only minor local outbreaks followed until a limited "second wave" occurred in the autumn months of 2020. Norwegian authorities organised several webinars early March, addressing the management and care for COVID-19 patients, urging preparedness in all hospitals for a surge of patients with AHRF, and stressing the importance of evidence based supportive care, including MV. 3 Hospitals were also warned that in a scenario of strained ICU-capacity, most units must be prepared to manage such patients without referral to university clinics. Use of corticosteroids and experimental therapies, including anti-virals, outside of clinical trials was actively discouraged. In this paper we describe characteristics and management of the first wave of critically ill COVID-19 patients admitted to ICUs in Norway (March 10-June 19) and investigate factors associated with survival and length-of-stay in the ICU. We included all adult patients (>18 years) who were admitted to a Norwegian ICU with a diagnosis of COVID-19, between 10 March 2020 and 19 June 2020. This study was approved by the South-East Norway Regional Committee for Medical and Health Research Ethics (reference no. 135310), with a waiver for informed consent. This study was registered at ClinicalTrials.gov (NCT04601090). added. By late March 2020, Norwegian authorities requested that the registry be further expanded to collect national data from any patient admitted to hospital with a positive test for SARS-CoV-2. This dataset for pandemic patients includes demographics, comorbidities, findings at the day of admission, antibiotics and classification of organ system dysfunction. Use of experimental drugs was not recorded. Detailed information regarding the variables is freely available online. 23,25 Data from the intensive care registry and the pandemic dataset was used to conduct this observational study of short-term outcomes of COVID-19 patients admitted to Norwegian ICUs (this paper). We have also collected follow-up data corresponding to a 'core outcome measurement set' developed through an international Delphi-process for ICU patients with acute respiratory failure. 26, 27 This will address the physical, psychological and cognitive health related challenges occurring after ICU treatment commonly described as "post-ICU syndrome". 28,29 The primary cause for ICU-admission and the identification of ARDS in individual patients, were provided at clinicians' discretion. We did not have access to chest x-ray data or ventilator settings except for the ratio of arterial oxygen partial pressure to fractional inspired oxygen (pf-ratio) at the day of admission. For statistical analysis, we therefore classified patients according to the severity of acute hypoxaemic respiratory failure (AHRF) defined as either 'no invasive ventilation' or, in invasively ventilated patients as 'mild' (pfratio > 26.6 kPa), 'moderate' (pf-ratio > 13.3 kPa and ≤26.6 kPa) or 'severe' (pf-ratio ≤ 13.3 kPa) depending on the pf-ratio, on the first day of admission. Data are presented as descriptive statistics and we used time-toevent techniques to analyze survival after ICU admission. Categorical variables are reported as frequencies (percentages) and continuous variables as medians (with interquartile ranges [IQRs]) or means (with SDs). Vital status was determined for all patients from the National Population Registry as of June 27, 2020. Kaplan-Meier survival estimates and Cox proportional hazards models were used to assess association between patient characteristics and mortality. ICU mortality rates were calculated by patient status at ICU discharge. Days from ICU admission to death (event) or June 27, 2020 (censoring), constituted the time of analysis. At the time of censoring, all patients in this dataset were either discharged from, or dead in the ICU. For patients readmitted to the ICU after discharge, the first ICU admission was considered in the analysis. We did not include patient management data in multivariable analysis due to the risk of timedependent bias (immortal time bias) and lack of statistical power to model this with sufficient precision. ICU LOS was log transformed and analysed with multiple linear regression using demographic data, co-morbidities and severity of illness measures as independent variables. All tests were two-sided and P-values < 0.05 were considered statistically significant. As this study was exploratory, no correction for multiple testing was done. Stata/SE ver 15.1, StataCorp, College Station, TX, USA was used for analysis. Patients' baseline characteristics are presented in Table 1 (see also Appendix Table A1 ). Critically ill patients were predominantly male, with a median age of 63 years, and most with one or more comorbidities involving vital organ systems; cardiovascular disorders, lung-and kidney disease, as well as diabetes and obesity. However, in almost one-third of patients no co-morbid disease was registered by clinicians and one-fifth of patients were less than fifty years old. The cause of ICU-admission (as per clinicians' assessment) was in most cases acute respiratory failure (91.2%) ( Table 1) . On the first day of admission 161 patients (74.2%) required MV, with predominantly moderate or severe hypoxemic respiratory failure according to the ratio of arterial oxygen partial pressure to fractional inspired oxygen (pf-ratio) ( Table 1) . Thirty-four patients (15.7%) did not require MV during the first day in the ICU. We could not account for the ventilation needs on the day of admission for 22 patients. Fortythree patients (19.8%) had elevated s-urea and systolic blood pressure was lower than 100 mm Hg in 112 patients (51.6%) on the first day of admission. Respiratory failure was categorized as ARDS by clinicians in 91 patients (41.9%). Median SAPS II-score was 33. A majority of patients were admitted between 10 March and 1 May ( Figure 1 ) and 159 (73.3%) were admitted to hospitals in South-East Norway (capital-region) (Appendix Table A2 ). Median LOS in the ICU was 14.0 days (range 0.7-69.0 days) ( Table 2) . Table A4 ). Other adjuncts (ECMO, nitric oxide) were used sparingly and additional data on ventilator management was not collected. Patients were followed for a median of 89 days after ICUadmission. In total, 177 patients (81.6%) were alive at discharge from the ICU and forty patients (18.4%) died in the ICU. At the end of follow-up forty-five patients (20.7%) were dead with a median ICU LOS of 12.1 days and no patient remained in the ICU (Table 3) . Mortality rates varied depending on patient demographics and co-morbidities, management characteristics and severity of illness at admission (Table 3 and Figure 2 ). There were marked differences in mortality in elderly vs younger patients and mortality was higher in patients with co-morbidities. We performed several multivariable analyses to assess the impact of individual patient and disease characteristics on outcomes (Appendix Table A3 ). In a simplified model, we included age, the most frequently reported co-morbidities as well as co-morbidities that were significantly associated with mortality at univariate analysis. Age ≥ 65 years (hazard ratio [HR] 3.01), diabetes (HR 2.41) and chronic kidney disease (HR 2.89) were strongly associated with higher mortality (Table 4A) . Severity of illness at admission and management characteristics were also associated with different mortality rates; Patients presenting with severe acute respiratory failure, signs of kidney injury or circulatory failure, all had higher mortality (Table 3) . In multivariable analysis, signs of kidney injury at admission (elevated s-urea) were independently and statistically significantly associated with death (HR 3.89) ( Figure A1L ). Mortality was higher in patients requiring organ support (mechanical ventilation, renal replacement therapy or vasoactive infusion) at any point during their stay in the ICU (Table 3) . Notably, patients requiring renal replacement therapy had markedly higher mortality (53.1%) than patients who were managed without. Clinicians' identification of ARDS in these patients was of little consequence for mortality but was associated with prolonged ICU LOS (Appendix Figure A1H , Table A5 ). Mean ICU LOS and days of MV were 17.4 and 15.2, respectively ( Figure 3 and Appendix Table A5 ). In Norway, early public health measures resulted in a low burden of disease from COVID-19 during spring 2020. 30 As a consequence, the number of critically ill COVID-19 patients has been low and Norwegian hospitals have with few exceptions been able to remain operative within capacity, allowing management of critically 14 .7% needed RRT (Table 5) . Need for vasoactive drugs in a majority of patients may presumably be explained by use of sedative drugs (and a consequential drop in blood pressure) in most mechanically ventilated patients, rather than manifest circulatory failure. Renal replacement therapy was used in a minority of patients and in only 8.9% of total bed days. This contrasts with reports from other regions (UK: 26%, 15 New York: 34%.) 40 but resonates with data reviewed by Gabarre and co-workers. 41 In patients with ARDS, the development of acute kidney injury (AKI) portends a severe prognosis. 42 In New York, Chan and co-workers found AKI to be prevalent in ICU-patients with COVID-19 and associated with a high risk of death (in-hospital mortality 52%). 40 In a single-centre study in Modena, Italy, Alfano et al found AKI to be significant predictor of all-cause mortality. 43 This is in agreement with an observed ICU-mortality rate of 53.1% in patients requiring RRT in our cohort. This study is limited by the amount of data available for analysis. The cause(s) for admission to the ICU and classification of ARDS were provided without any qualifying criteria. As in other observational studies, we believe ARDS may have been under-recognised in patients with moderate severity of disease and short LOS. 8 The strength of this report is that it is an analysis of a comprehensive and complete national dataset that includes all COVID-19 patients admitted to Norwegian ICUs and therefore describes a cross-section of both patients and their management in Norwegian ICUs during the first phase of the pandemic. In this national cohort of COVID-19 patients admitted to Norwegian ICUs, acute hypoxaemic respiratory failure was the most common cause of admission to the ICU and severity of respiratory failure at admission was predictive of length of stay. Mortality was comparatively low and associated with age and chronic co-morbidities as well as severity of illness at admission. 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