Reduced anticoagulation strategy is associated with a lower incidence of intracerebral hemorrhage in COVID-19 patients on extracorporeal membrane oxygenation.

BACKGROUND: Optimal anticoagulation strategies for COVID-19 patients with the acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) remain uncertain. A higher incidence of intracerebral hemorrhage (ICH) during VV ECMO support compared to non-COVID-19 viral ARDS patients has been reported, with increased bleeding rates in COVID-19 attributed to both intensified anticoagulation and a disease-specific endotheliopathy. We hypothesized that lower intensity of anticoagulation during VV ECMO would be associated with a lower risk of ICH. In a retrospective, multicenter study from three academic tertiary intensive care units, we included patients with confirmed COVID-19 ARDS requiring VV ECMO support from March 2020 to January 2022. Patients were grouped by anticoagulation exposure into higher intensity, targeting anti-factor Xa activity (anti-Xa) of 0.3-0.4 U/mL, versus lower intensity, targeting anti-Xa 0.15-0.3 U/mL, cohorts. Mean daily doses of unfractionated heparin (UFH) per kg bodyweight and effectively measured daily anti-factor Xa activities were compared between the groups over the first 7 days on ECMO support. The primary outcome was the rate of ICH during VV ECMO support. RESULTS: 141 critically ill COVID-19 patients were included in the study. Patients with lower anticoagulation targets had consistently lower anti-Xa activity values over the first 7 ECMO days (p < 0.001). ICH incidence was lower in patients in the lower anti-Xa group: 4 (8%) vs 32 (34%) events. Accounting for death as a competing event, the adjusted subhazard ratio for the occurrence of ICH was 0.295 (97.5% CI 0.1-0.9, p = 0.044) for the lower anti-Xa compared to the higher anti-Xa group. 90-day ICU survival was higher in patients in the lower anti-Xa group, and ICH was the strongest risk factor associated with mortality (odds ratio [OR] 6.8 [CI 2.1-22.1], p = 0.001). CONCLUSIONS: For COVID-19 patients on VV ECMO support anticoagulated with heparin, a lower anticoagulation target was associated with a significant reduction in ICH incidence and increased survival.

Microcirculatory alterations in critically ill COVID-19 patients analyzed using artificial intelligence.

BACKGROUND: The sublingual microcirculation presumably exhibits disease-specific changes in function and morphology. Algorithm-based quantification of functional microcirculatory hemodynamic variables in handheld vital microscopy (HVM) has recently allowed identification of hemodynamic alterations in the microcirculation associated with COVID-19. In the present study we hypothesized that supervised deep machine learning could be used to identify previously unknown microcirculatory alterations, and combination with algorithmically quantified functional variables increases the model's performance to differentiate critically ill COVID-19 patients from healthy volunteers. METHODS: Four international, multi-central cohorts of critically ill COVID-19 patients and healthy volunteers (n = 59/n = 40) were used for neuronal network training and internal validation, alongside quantification of functional microcirculatory hemodynamic variables. Independent verification of the models was performed in a second cohort (n = 25/n = 33). RESULTS: Six thousand ninety-two image sequences in 157 individuals were included. Bootstrapped internal validation yielded AUROC(CI) for detection of COVID-19 status of 0.75 (0.69-0.79), 0.74 (0.69-0.79) and 0.84 (0.80-0.89) for the algorithm-based, deep learning-based and combined models. Individual model performance in external validation was 0.73 (0.71-0.76) and 0.61 (0.58-0.63). Combined neuronal network and algorithm-based identification yielded the highest externally validated AUROC of 0.75 (0.73-0.78) (P < 0.0001 versus internal validation and individual models). CONCLUSIONS: We successfully trained a deep learning-based model to differentiate critically ill COVID-19 patients from heathy volunteers in sublingual HVM image sequences. Internally validated, deep learning was superior to the algorithmic approach. However, combining the deep learning method with an algorithm-based approach to quantify the functional state of the microcirculation markedly increased the sensitivity and specificity as compared to either approach alone, and enabled successful external validation of the identification of the presence of microcirculatory alterations associated with COVID-19 status.

Renal Tubular Acidosis in Pregnant Critically Ill COVID-19 Patients: A Secondary Analysis of a Prospective Cohort.

BACKGROUND: Renal tubular acidosis (RTA) is an extremely rare cause of metabolic acidosis (10 in 100,000). RTA has been linked neither to pregnancy nor to severe coronavirus disease 2019 (COVID-19). The purpose of this study was to analyze the prevalence and clinical course of normal anion gap metabolic acidosis in critically ill pregnant COVID-19 patients and to compare them to an age-matched nonpregnant female patient cohort. METHODS: Secondary analysis was conducted on a prospective observational cohort of critically ill patients suffering from COVID-19 consecutively admitted to a tertiary intensive care unit (ICU) between February 2020 and April 2021. RESULTS: A total of 321 COVID-19 patients required admission to the ICU; 95 (30%) were female, and 18 (19%) were of childbearing age. Seven of eight (88%) pregnant women (all in the last trimester) required advanced respiratory support due to COVID-19. The estimated glomerular filtration rate was 135 (123-158) mL/min/m2 body surface area, and six pregnant women (86%) were diagnosed with a normal, respiratory compensated, anion gap metabolic acidosis (pHmin 7.3 (7.18-7.31), HCO3-min 14.8 (12.8-18.6) mmol/L, and paCO2 3.4 (3.3-4.5) kPa). Three (43%) acidotic pregnant women fulfilled diagnostic criteria for RTA. All women recovered spontaneously within less 7 days. CONCLUSIONS: Metabolic acidosis seems to be very common (85%) in pregnant critically ill COVID-19 patients, and the prevalence of RTA might be higher than normal. It remains to be demonstrated if this observation is an indirect epiphenomenon or due to a direct viral effect on the tubular epithelium.

Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry.

BACKGROUND: It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic. METHODS: Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic. RESULTS: Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO2/FiO2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic. CONCLUSION: Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic.

Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome.

BACKGROUND: A higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose-response relationship between ketamine and bilirubin levels. METHODS: Post hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure-effect relationship between ketamine infusion and total bilirubin levels. RESULTS: Two-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9-2.0] mg/kg/h for 9 [4-18] days. The mixed-effects model revealed a positively correlated infusion duration-effect as well as dose-effect relationship between ketamine infusion and rising bilirubin levels (p < 0.0001). In comparison, long-term infusion of propofol and sufentanil, even at high doses, was not associated with increasing bilirubin levels (p = 0.421, p = 0.258). Patients having received ketamine infusion had a multivariable adjusted competing risk hazard of developing a cholestatic liver injury during their ICU stay of 3.2 [95% confidence interval, 1.3-7.8] (p = 0.01). CONCLUSIONS: A causally plausible, dose-effect relationship between long-term infusion of ketamine and rising total bilirubin levels, as well as an augmented, ketamine-associated, hazard of cholestatic liver injury in critically ill COVID-19 patients could be shown. High-dose ketamine should be refrained from whenever possible for the long-term analgosedation of mechanically ventilated COVID-19 patients.

Non-invasive oxygenation support in acutely hypoxemic COVID-19 patients admitted to the ICU: a multicenter observational retrospective study.

BACKGROUND: Non-invasive oxygenation strategies have a prominent role in the treatment of acute hypoxemic respiratory failure during the coronavirus disease 2019 (COVID-19). While the efficacy of these therapies has been studied in hospitalized patients with COVID-19, the clinical outcomes associated with oxygen masks, high-flow oxygen therapy by nasal cannula and non-invasive mechanical ventilation in critically ill intensive care unit (ICU) patients remain unclear. METHODS: In this retrospective study, we used the best of nine covariate balancing algorithms on all baseline covariates in critically ill COVID-19 patients supported with > 10 L of supplemental oxygen at one of the 26 participating ICUs in Catalonia, Spain, between March 14 and April 15, 2020. RESULTS: Of the 1093 non-invasively oxygenated patients at ICU admission treated with one of the three stand-alone non-invasive oxygenation strategies, 897 (82%) required endotracheal intubation and 310 (28%) died during the ICU stay. High-flow oxygen therapy by nasal cannula (n = 439) and non-invasive mechanical ventilation (n = 101) were associated with a lower rate of endotracheal intubation (70% and 88%, respectively) than oxygen masks (n = 553 and 91% intubated), p < 0.001. Compared to oxygen masks, high-flow oxygen therapy by nasal cannula was associated with lower ICU mortality (hazard ratio 0.75 [95% CI 0.58-0.98), and the hazard ratio for ICU mortality was 1.21 [95% CI 0.80-1.83] for non-invasive mechanical ventilation. CONCLUSION: In critically ill COVID-19 ICU patients and, in the absence of conclusive data, high-flow oxygen therapy by nasal cannula may be the approach of choice as the primary non-invasive oxygenation support strategy.

Awake prone position reduces work of breathing in patients with COVID-19 ARDS supported by CPAP.

BACKGROUND: The use of awake prone position concomitant to non-invasive mechanical ventilation in acute respiratory distress syndrome (ARDS) secondary to COVID-19 has shown to improve gas exchange, whereas its effect on the work of breathing remain unclear. The objective of this study was to evaluate the effects of awake prone position during helmet continuous positive airway pressure (CPAP) ventilation on inspiratory effort, gas exchange and comfort of breathing. METHODS: Forty consecutive patients presenting with ARDS due to COVID-19 were prospectively enrolled. Gas exchange, esophageal pressure swing (ΔPes), dynamic transpulmonary pressure (dTPP), modified pressure time product (mPTP), work of breathing (WOB) and comfort of breathing, were recorded on supine position and after 3 h on prone position. RESULTS: The median applied PEEP with helmet CPAP was 10 [8-10] cmH2O. The PaO2/FiO2 was higher in prone compared to supine position (Supine: 166 [136-224] mmHg, Prone: 314 [232-398] mmHg, p < 0.001). Respiratory rate and minute ventilation decreased from supine to prone position from 20 [17-24] to 17 [15-19] b/min (p < 0.001) and from 8.6 [7.3-10.6] to 7.7 [6.6-8.6] L/min (p < 0.001), respectively. Prone position did not reduce ΔPes (Supine: - 7 [- 9 to - 5] cmH2O, Prone: - 6 [- 9 to - 5] cmH2O, p = 0.31) and dTPP (Supine: 17 [14-19] cmH2O, Prone: 16 [14-18] cmH2O, p = 0.34). Conversely, mPTP and WOB decreased from 152 [104-197] to 118 [90-150] cmH2O/min (p < 0.001) and from 146 [120-185] to 114 [95-151] cmH2O L/min (p < 0.001), respectively. Twenty-six (65%) patients experienced a reduction in WOB of more than 10%. The overall sensation of dyspnea was lower in prone position (p = 0.005). CONCLUSIONS: Awake prone position with helmet CPAP enables a reduction in the work of breathing and an improvement in oxygenation in COVID-19-associated ARDS.

Machine learning using the extreme gradient boosting (XGBoost) algorithm predicts 5-day delta of SOFA score at ICU admission in COVID-19 patients.

Background: Accurate risk stratification of critically ill patients with coronavirus disease 2019 (COVID-19) is essential for optimizing resource allocation, delivering targeted interventions, and maximizing patient survival probability. Machine learning (ML) techniques are attracting increased interest for the development of prediction models as they excel in the analysis of complex signals in data-rich environments such as critical care. Methods: We retrieved data on patients with COVID-19 admitted to an intensive care unit (ICU) between March and October 2020 from the RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry. We applied the Extreme Gradient Boosting (XGBoost) algorithm to the data to predict as a binary outcome the increase or decrease in patients' Sequential Organ Failure Assessment (SOFA) score on day 5 after ICU admission. The model was iteratively cross-validated in different subsets of the study cohort. Results: The final study population consisted of 675 patients. The XGBoost model correctly predicted a decrease in SOFA score in 320/385 (83%) critically ill COVID-19 patients, and an increase in the score in 210/290 (72%) patients. The area under the mean receiver operating characteristic curve for XGBoost was significantly higher than that for the logistic regression model (0.86 vs. 0.69, P < 0.01 [paired t-test with 95% confidence interval]). Conclusions: The XGBoost model predicted the change in SOFA score in critically ill COVID-19 patients admitted to the ICU and can guide clinical decision support systems (CDSSs) aimed at optimizing available resources.

Near real-time observation reveals increased prevalence of young patients in the ICU during the emerging third SARS-CoV-2 wave in Switzerland.

AIMS OF THE STUDY: During the ongoing COVID-19 pandemic, the launch of a large-scale vaccination campaign and virus mutations have hinted at possible changes in transmissibility and the virulence affecting disease progression up to critical illness, and carry potential for future vaccination failure. To monitor disease development over time with respect to critically ill COVID-19 patients, we report near real-time prospective observational data from the RISC-19-ICU registry that indicate changed characteristics of critically ill patients admitted to Swiss intensive care units (ICUs) at the onset of a third pandemic wave. METHODS: 1829 of 3344 critically ill COVID-19 patients enrolled in the international RISC-19-ICU registry as of 31 May 2021 were treated in Switzerland and were included in the present study. Of these, 1690 patients were admitted to the ICU before 1 February 2021 and were compared with 139 patients admitted during the emerging third pandemic wave RESULTS: Third wave patients were a mean of 5.2 years (95% confidence interval [CI] 3.2–7.1) younger (median 66.0 years, interquartile range [IQR] 57.0–73.0 vs 62.0 years, IQR 54.5–68.0; p <0.0001) and had a higher body mass index than patients admitted in the previous pandemic period. They presented with lower SAPS II and APACHE II scores, less need for circulatory support and lower white blood cell counts at ICU admission. P/F ratio was similar, but a 14% increase in ventilatory ratio was observed over time (p = 0.03) CONCLUSION: Near real-time registry data show that the latest COVID-19 patients admitted to ICUs in Switzerland at the onset of the third wave were on average 5 years younger, had a higher body mass index, and presented with lower physiological risk scores but a trend towards more severe lung failure. These differences may primarily be related to the ongoing nationwide vaccination campaign, but the possibility that changes in virus-host interactions may be a co-factor in the age shift and change in disease characteristics is cause for concern, and should be taken into account in the public health and vaccination strategy during the ongoing pandemic. (ClinicalTrials.gov Identifier: NCT04357275).

Closed-Loop Versus Conventional Mechanical Ventilation in COVID-19 ARDS.

BACKGROUND: Lung-protective ventilation is key in bridging patients suffering from COVID-19 acute respiratory distress syndrome (ARDS) to recovery. However, resource and personnel limitations during pandemics complicate the implementation of lung-protective protocols. Automated ventilation modes may prove decisive in these settings enabling higher degrees of lung-protective ventilation than conventional modes. METHOD: Prospective study at a Swiss university hospital. Critically ill, mechanically ventilated COVID-19 ARDS patients were allocated, by study-blinded coordinating staff, to either closed-loop or conventional mechanical ventilation, based on mechanical ventilator availability. Primary outcome was the overall achieved percentage of lung-protective ventilation in closed-loop versus conventional mechanical ventilation, assessed minute-by-minute, during the initial 7 days and overall mechanical ventilation time. Lung-protective ventilation was defined as the combined target of tidal volume <8 ml per kg of ideal body weight, dynamic driving pressure <15 cmH2O, peak pressure <30 cmH2O, peripheral oxygen saturation ≥88% and dynamic mechanical power <17 J/min. RESULTS: Forty COVID-19 ARDS patients, accounting for 1,048,630 minutes (728 days) of cumulative mechanical ventilation, allocated to either closed-loop (n = 23) or conventional ventilation (n = 17), presenting with a median paO2/ FiO2 ratio of 92 [72-147] mmHg and a static compliance of 18 [11-25] ml/cmH2O, were mechanically ventilated for 11 [4-25] days and had a 28-day mortality rate of 20%. During the initial 7 days of mechanical ventilation, patients in the closed-loop group were ventilated lung-protectively for 65% of the time versus 38% in the conventional group (Odds Ratio, 1.79; 95% CI, 1.76-1.82; P < 0.001) and for 45% versus 33% of overall mechanical ventilation time (Odds Ratio, 1.22; 95% CI, 1.21-1.23; P < 0.001). CONCLUSION: Among critically ill, mechanically ventilated COVID-19 ARDS patients during an early highpoint of the pandemic, mechanical ventilation using a closed-loop mode was associated with a higher degree of lung-protective ventilation than was conventional mechanical ventilation.

Analysis of anaesthesia services to calculate national need and supply of anaesthetics in Switzerland during the COVID-19 pandemic.

BACKGROUND: In Switzerland, details of current anaesthesia practice are unknown. However, they are urgently needed to manage anaesthesia drug supply in times of drug shortages due to the pandemic. METHODS: We surveyed all Swiss anaesthesia institutions in April 2020 to determine their annual anaesthesia activity. Together with a detailed analysis on anaesthetic drug use of a large, representative Swiss anaesthesia index institution, calculations and projections for the annual need of anaesthetics in Switzerland were made. Only those drugs have been analysed that are either being used very frequently or that have been classified critical with regard to their supply by the pharmacy of the index institution or the Swiss Federal Office of Public Health. RESULTS: The response rate to our questionnaire was 98%. Out of the present 188 Swiss anaesthesia institutions, 185 responded. In Switzerland, the annual number of anaesthesias was 1'071'054 (12'445 per 100'000 inhabitants) with a mean anaesthesia time of 2.03 hours. Teaching hospitals (n = 54) performed more than half (n = 572'231) and non-teaching hospitals (n = 103) provided almost half of all anaesthesias (n = 412'531). Thereby, private hospitals conducted a total of 290'690 anaesthesias. Finally, office-based anaesthesia institutions with mainly outpatients (n = 31) administered 86'292 anaesthesias. Regarding type of anaesthesia provided, two thirds were general anaesthesias (42% total intravenous, 17% inhalation, 8% combined), 20% regional and 12% monitored anaesthesia care. Projecting for example the annual need for propofol in anaesthesia, Switzerland requires 48'573 L of propofol 1% which corresponds to 5'644 L propofol 1% per 100'000 inhabitants every year. CONCLUSIONS: To actively manage anaesthesia drug supply in the context of the current pandemic, it is mandatory to have a detailed understanding of the number and types of anaesthesias provided. On this basis, the Swiss annual consumption of anaesthetics could be projected and the replenishment organized.

Bacterial pulmonary superinfections are associated with longer duration of ventilation in critically ill COVID-19 patients.

The impact of secondary bacterial infections (superinfections) in coronavirus disease 2019 (COVID-19) is not well understood. In this prospective, monocentric cohort study, we aim to investigate the impact of superinfections in COVID-19 patients with acute respiratory distress syndrome. Patients are assessed for concomitant microbial infections by longitudinal analysis of tracheobronchial secretions, bronchoalveolar lavages, and blood cultures. In 45 critically ill patients, we identify 19 patients with superinfections (42.2%). Superinfections are detected on day 10 after intensive care admission. The proportion of participants alive and off invasive mechanical ventilation at study day 28 (ventilator-free days [VFDs] at 28 days) is substantially lower in patients with superinfection (subhazard ratio 0.37; 95% confidence interval [CI] 0.15-0.90; p = 0.028). Patients with pulmonary superinfections have a higher incidence of bacteremia, virus reactivations, yeast colonization, and required intensive care treatment for a longer time. Superinfections are frequent and associated with reduced VFDs at 28 days despite a high rate of empirical antibiotic therapy.

Bacterial but no SARS-CoV-2 contamination after terminal disinfection of tertiary care intensive care units treating COVID-19 patients.

BACKGROUND: In intensive care units (ICUs) treating patients with Coronavirus disease 2019 (COVID-19) invasive ventilation poses a high risk for aerosol and droplet formation. Surface contamination of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) or bacteria can result in nosocomial transmission. METHODS: Two tertiary care COVID-19 intensive care units treating 53 patients for 870 patient days were sampled after terminal cleaning and preparation for regular use to treat non-COVID-19 patients. RESULTS: A total of 176 swabs were sampled of defined locations covering both ICUs. No SARS-CoV-2 ribonucleic acid (RNA) was detected. Gram-negative bacterial contamination was mainly linked to sinks and siphons. Skin flora was isolated from most swabbed areas and Enterococcus faecium was detected on two keyboards. CONCLUSIONS: After basic cleaning with standard disinfection measures no remaining SARS-CoV-2 RNA was detected. Bacterial contamination was low and mainly localised in sinks and siphons.

Prognostic factors associated with mortality risk and disease progression in 639 critically ill patients with COVID-19 in Europe: Initial report of the international RISC-19-ICU prospective observational cohort.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with a high disease burden with 10% of confirmed cases progressing towards critical illness. Nevertheless, the disease course and predictors of mortality in critically ill patients are poorly understood. METHODS: Following the critical developments in ICUs in regions experiencing early inception of the pandemic, the European-based, international RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry was created to provide near real-time assessment of patients developing critical illness due to COVID-19. FINDINGS: As of April 22, 2020, 639 critically ill patients with confirmed SARS-CoV-2 infection were included in the RISC-19-ICU registry. Of these, 398 had deceased or been discharged from the ICU. ICU-mortality was 24%, median length of stay 12 (IQR, 5-21) days. ARDS was diagnosed in 74%, with a minimum P/F-ratio of 110 (IQR, 80-148). Prone positioning, ECCO2R, or ECMO were applied in 57%. Off-label therapies were prescribed in 265 (67%) patients, and 89% of all bloodstream infections were observed in this subgroup (n = 66; RR=3·2, 95% CI [1·7-6·0]). While PCT and IL-6 levels remained similar in ICU survivors and non-survivors throughout the ICU stay (p = 0·35, 0·34), CRP, creatinine, troponin, d-dimer, lactate, neutrophil count, P/F-ratio diverged within the first seven days (p<0·01). On a multivariable Cox proportional-hazard regression model at admission, creatinine, d-dimer, lactate, potassium, P/F-ratio, alveolar-arterial gradient, and ischemic heart disease were independently associated with ICU-mortality. INTERPRETATION: The European RISC-19-ICU cohort demonstrates a moderate mortality of 24% in critically ill patients with COVID-19. Despite high ARDS severity, mechanical ventilation incidence was low and associated with more rescue therapies. In contrast to risk factors in hospitalized patients reported in other studies, the main mortality predictors in these critically ill patients were markers of oxygenation deficit, renal and microvascular dysfunction, and coagulatory activation. Elevated risk of bloodstream infections underscores the need to exercise caution with off-label therapies.