Originating from China, a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), emerged in December 2019 (1, 2). SARS-CoV-2 was detected as cause of Coronavirus Disease 2019 in lower respiratory tract samples (3) . The virus spread causing an ongoing global pandemic (4) . COVID-19 led to high hospitalization rates worldwide, and confronted the health care systems with an enormous challenge (5, 6) . The clinical spectrum of COVID-19 ranges from asymptomatic to severe illness with development of acute respiratory distress syndrome (ARDS) and multiple organ failure (1-3). About 17% of hospitalized patients with COVID-19 need admission to intensive care unit (ICU). Certain clinical characteristics and risk factors have been previously reported to be associated with worse outcomes, especially patients with pre-existing medical conditions and older patients (7) (8) (9) .
COVID-19 patients treated at the ICU suffer from high mortality, in patients with invasive mechanical ventilation (MV) rates from 50-97% have been reported (6, (10) (11) (12) . However, some studies were preliminary and included patients without completed ICU stay. Furthermore, numerous studies were conducted in regions with overwhelmed health care systems, which possibly led to a resource limitation as cause of higher mortality rates (13) . Furthermore, due to high risk of infection via respiratory aerosols potential aerosol generating procedures like non-invasive ventilation (NIV) or high-flow nasal cannula (HFNC) therapy are a matter of concern (14) . Avoidance of NIV/HFNC and early tracheal intubation has been suggested as a management strategy for COVID-19, however this is controversial due to the worse outcomes reported with tracheal intubation (15, 16) . Data on outcome following critical illness in patients with COVID-19 and outcome of patients requiring MV are limited. . Therefore, the aim of this study was to investigate clinical characteristics and outcome of MV in critically ill patients with COVID-19 in a large cohort in Germany.
We conducted a retrospective multicentre observational study and included all critically ill adult patients with COVID- 19 Due retrospective and de-identified data collection the need for informed consent was waived.
We included all consecutive adult patients (≥ 18 years) with confirmed COVID-19 and COVID-19 associated critical illness admitted to one of the ICU's in the participating hospitals. Confirmed COVID-19 was defined as at least one positive result on reverse transcriptase-polymerase chain reaction obtained from naso-pharyngeal swabs and/or bronchial secretions. Patients with noncompleted ICU stay (ongoing ICU treatment) were excluded.
The data were collected through a pre-defined case report form (CRF) in electronic-or paper-form.
Each hospital enrolled all patients with confirmed COVID-19 and completed ICU stay. The individual patient data were recorded retrospectively after the end of the ICU stay, the deidentified CRFs were collected till June 3, 2020. The collected data included age, gender, comorbidities, reason of admission, length of ICU-stay, treatment modalities and organ support (MV, vasopressor, renal replacement therapy (RRT), blood transfusions, antibiotics, antivirals, etc.), procedures, complications, and laboratory parameters during the ICU-stay. Pre-existing medication was recorded on the basis of known regular medications and medication on admission.
ARDS was defined according to the Berlin definition (17) . Sepsis and septic shock were defined according to the 2016 Third International Consensus Definition for Sepsis and Septic Shock (18) .
Severity of illness was evaluated by sequential organ failure assessment (SOFA) (19) . Charlson J o u r n a l P r e -p r o o f Comorbidity Index (CCI) (20) was calculated in all patients. For management and therapy of critically ill patients with COVID-19 national and international recommendations were followed (21-23).
Data are presented as count and relative frequency or median and interquartile range (IQR). The distribution of variables was graphically assessed with histograms. Binary variables were compared via Chi-Square-Analysis or Fisher's exact, as appropriate. Metric variables were compared via Mann-Whitney-U-Test. Binary logistic regression analysis using and cox regression analysis was performed, factors that were considered clinically relevant and did not fulfil the criteria for multicollinearity were included in the model. We used a hierarchical backward stepwise approach. the initial model was gradually reduced. Variables that caused a change in parameter estimates >10% or were statistically 
Until June 3 rd , 2020 -5,096 people were tested positive for SARS-CoV-2 in the city of Hamburg.
Overall, 996 (20%) patients with COVID-19 were hospitalized and of those 261 (26%) needed intensive care therapy. During the study period we could include 223 patients with completed ICU stay, which illustrates a representative sample (85%) of all ICU treated COVID-19 patients in the city of Hamburg.
Detailed demographic and baseline characteristics are shown in Table 1 . Comorbidities, displayed by CCI, was median 1 (0 -2) point. Arterial hypertension was the leading comorbidity (49%, n = 108).
Fourty-five (20%) patients had ongoing treatment with ACE-Inhibitors and 42 (19%) with angiotensinreceptor-blockers. Further common comorbidities were diabetes mellitus (Type II), history of active haematologic or oncologic disease and chronic respiratory disease in 27% (n=59), 20% (n=44) and 18% (n=40), respectively. The majority of patients were admitted to ICU due to respiratory deterioration. Most common symptoms on ICU admission were shortness of breath and fever in 124 patients (56%) each. Further symptoms were productive cough in 55 (25%), fatigue in 49 (22%), nonproductive cough in 34 (15%) and myalgia in 11 (5%) patients. Seventy-five patients (34%) needed vasopressor support on the day of admission to ICU.
Of 223 patients 167 (75%) received MV during the ICU stay. The median time from admission to initiation of invasive MV was 1 (0 -2) day. Eighty-nine (40%) patients required invasive MV within the first day of ICU admission. Further, NIV and NFNC were used in 18 (8%) and 22 (10%) patients respectively within the first day, and in 31 (14%) and 26 (12%) patients during their ICU stay. 
Clinical findings concerning baseline characteristics, interventions and complications are summarized in Table 2 . No differences were observed in age and gender; BMI was significantly higher (p < 0.05) in MV patients. Severity of illness represented by median SOFA score on admission and after 24h were 5 (3 -9) and 9 (4 -12), respectively. SOFA on admission and after 24h was significantly higher in MV patients (both p < 0.001). Vasopressor use within the first 24h after admission was significantly higher in patients with MV (71% vs. 5%, p < 0.001). RRT was initiated in 73 (33%) in the whole cohort and was used more frequently in MV patients (p < 0.001). Therapeutic anticoagulation was used in 121 (54%) patients overall and was distributed equally in both groups. Use of antibiotic, antifungal and antiviral therapy was common in both groups; use of antibiotic therapy was significantly more frequent in MV patients (p < 0.001). Pre-existing obesity (BMI > 30 kg/m²) as well as diabetes mellitus Type II were significantly higher in patients with MV (p = 0.045 and 0.036). Patients with chronic respiratory disease were more frequent among non-MV patients. Laboratory and blood gas analysis are summarized in Supplementary Table 1 
In our cohort of 223 critically ill patients with COVID-19 78 patients died, resulting in an overall ICU mortality rate of 35%. We observed a mortality rate of 44% (n = 74) in patients with MV and 7% (n = 4) in patients without MV. All 4 patients dying in the non MV group had severe hypoxemia and/or multiple organ failure; therapy was limited according existing advance directive. The mortality of patients receiving ECMO was 65% (n = 13). Overall, median length of ICU stay was 13 (5 -24) days. Fig. 1 We hereby report on a large observational cohort study in critically ill patients with COVID-19 from Germany. To our knowledge this is the first reported cohort of critically ill COVID-19 patients investigating clinical characteristics and outcome following MV including only patients with a completed ICU stay. We demonstrated an overall ICU mortality rate of 35% and a mortality rate of 44% among patients who received MV.
In our representative cohort, 75% of patients required invasive MV. Overall, NIV and HFNC was used in 12% and 14%, respectively. Eighty-one per-cent (46 of 57) needed MV after NIV or HFNC therapy.
However, a previous small study reported a rate of 41% HFNC failure in COVID-19 patients (25) .
Recently a meta-analysis compared different forms of respiratory support in Non-COVID-19 patients with respiratory failure encompassed 25 trials. In this analysis NIV was associated with lower mortality than standard oxygen therapy. Furthermore, NIV and HFNC were associated with lower rates of endotracheal intubation (26) . Nevertheless, it is unclear whether the application of HFNC/NIV or early intubation and subsequent MV is preventing COVID-19 progression (15).
In our cohort, we observed that 40% of patients required MV within the first day of ICU admission.
Further, NIV was used in 11% and HFNC in 13% within the first day after admission. In spontaneously breathing patients with an indication for HFNC or NIV immediately after admission, time to intubation was median only 1 day. Overall, 75% of admitted patients received MV which is higher compared to other studies recently reported (27, 28) . However, our findings are comparable to two large trials in Germany on mechanical ventilation recently reported (29, 30) . But differences may be explained by different ICU admission strategies and that some of the hospitals are serving as ARDS referring centres specialized in treatment of ARDS and providing ECMO support. The median duration of invasive MV was 15 days comparable to previous reports in patients with ARDS of non-COVID-19 origin (31). Richardson and colleagues demonstrated a rather low mortality of 25%, in COVID-19 patients who received MV but more than 70% of reported patients were under ongoing ICU treatment resulting in a biased outcome regarding mortality (6). One recent study reporting of 165 critically ill mechanically ventilated COVID-19 patients observed a mortality rate of 36%, with only a small number of patients still ventilated (32) . In our cohort we observed a mortality rate of 44% among MV patients. The differences in mortality between studies can be explained by several observations. Firstly, several studies report from cohorts with incomplete outcomes for large proportions of patients when the studies were submitted. This prevents an actual statement on mortality. Secondly, to-date many studies have reported from regions which have seen a rapid rise in SARS-CoV-2 positive patients leading to significant resource limitation. Due to overwhelming number of patients admitted to hospitals in China (Wuhan), Italy (Lombardi Region) and the US (New York) J o u r n a l P r e -p r o o f local healthcare systems were over their maximal capacities possibly leading to intubation avoidance and rationing of medical therapies (3, 6, 7) . Hereby, we report on a region with overall 5,096 cases during the study period, 996 were hospitalized. The total number of ICU beds was increased by 57% in the city of Hamburg. Luckily, the region of northern Germany was not overwhelmed with COVID-19 cases, so we were able to prepare sufficiently and systematically for the pandemic. Patients were likely admitted early to ICU facilities and received early ventilatory support in sufficiently staffed intensive care setting without shortage of ventilators. However, in a setting without resource limitations, we could show that the observed mortality rate is comparable to Non-COVID-19 ARDS patients (31) .
Several studies have reported on use of ECMO in COVID-19 patients. However, the outcome of patients treated with ECMO due to ARDS caused by COVID-19 is unclear. A recent report from China with 21 of 129 (16%) critically ill patients receiving ECMO reported a mortality of 57% (33) . In our study 9% of our patients received ECMO. The mortality among patients with ECMO in our cohort was 65% and considerably higher compared to previous studies in ARDS (34) . This may be explained by different management strategies and reporting of patients with viral induced ARDS only.
In our cohort we observed different parameters potentially associated with mortality. Both older age and comorbidities were associated with mortality as previously reported (7, 8) . Furthermore, as expected patients with more severe ARDS had worse outcomes. Further, we observed no differences in outcome regarding time of initiation of invasive MV. However, mortality was associated with use of adjunctive therapies -glucocorticoid treatment, inhaled vasodilatory treatment -but not prone positioning or neuromuscular blockade for ARDS treatment. Neuromuscular blockade rate in our cohort was rather low, national guidelines suggest the use of neuromuscular blockade in selected cases only. Our study found that higher lactate, lower pH and lower PaO 2 after 24h, were associated with worse outcomes. Procedures and complications during the ICU stay were frequent: necessity of RRT, septic shock and cardiac arrest were significantly associated with mortality. These findings are in line with previous studies (6, 35) . 12% of patients suffered from clinically detected pulmonary embolism, this was also related to mortality in mechanically ventilated patients. Thromboembolic events are frequently observed in autopsy studies, representing yet another potentially lifethreatening complication in critically ill patients with COVID-19 (36) . These findings led to recommendation of, at least, prophylactic anticoagulation in critically ill patients with COVID-19 (37) .
This study has several strengths. First, we exclusively report on patients with a completed ICU stay which allows to draw firm conclusions regarding outcome. Second, we report on a representative sample of critically ill COVID-19 patients treated during the study period. Some limitations should be mentioned. First, data derived from an observational cohort from different hospitals. Different J o u r n a l P r e -p r o o f management and therapy strategies of patients with COVID-19 requiring MV and influence on outcome cannot be entirely excluded. Second, some cases had incomplete documentation according missing laboratory testing. Third, we observed a rather high rate of complications (e.g. septic shock, cardiac arrest), a more detailed analysis could not be performed according retrospective data collection using CRF. Fourth, residual confounding of unmeasured covariates is a matter of concern and cannot be entirely excluded.
In a large multicentre observational cohort study of 223 critically ill patients with COVID-19, we observed an ICU mortality of 35%, an MV rate of 75% and a mortality rate of 44% in patients receiving MV. Septic shock was a common complication in this cohort. Future randomized trials should focus on the impact of non-invasive ventilation strategies and on the application of adjunctive therapies in patients with COVID-19. Ethics approval and consent to participate:
The local ethics committee approved of anonymised data collection and analyses; the requirement for individual patient consent was waived as this study was based on observational data from routine clinical care.
Availability of data and materials:
The datasets supporting the conclusions of this article are included within the article.
No financial support has been received conducting this study. (14) 26 (12) 15 (8 -25) 167 (100) 20 (12) 23 (14) 23 (14) 