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Abstract Background Ventilation management may differ between COVID–19 ARDS (COVID–ARDS) patients and patients with pre–COVID ARDS (CLASSIC–ARDS); it is uncertain whether associations of ventilation management with outcomes for CLASSIC–ARDS also exist in COVID–ARDS. Methods Individual patient data analysis of COVID–ARDS and CLASSIC–ARDS patients in six observational studies of ventilation, four in the COVID–19 pandemic and two pre–pandemic. Descriptive statistics were used to compare epidemiology and ventilation characteristics. The primary endpoint were key ventilation parameters; other outcomes included mortality and ventilator–free days and alive (VFD–60) at day 60. Results This analysis included 6702 COVID–ARDS patients and 1415 CLASSIC–ARDS patients. COVID–ARDS patients received lower median VT (6.6 [6.0 to 7.4] vs 7.3 [6.4 to 8.5] ml/kg PBW; p

BACKGROUND:. Patients with acute hypoxemic respiratory failure are at high risk of death and prolonged time on the ventilator. Interventions often aim to reduce both mortality and time on the ventilator. Many methods have been proposed for analyzing these endpoints as a single composite outcome (days alive and free of ventilation), but it is unclear which analytical method provides the best performance. Thus, we aimed to determine the analysis method with the highest statistical power for use in clinical trials. METHODS:. Using statistical simulation, we compared multiple methods for analyzing days alive and free of ventilation: the t, Wilcoxon rank-sum, and Kryger Jensen and Lange tests, as well as the proportional odds, hurdle-Poisson, and competing risk models. We compared 14 scenarios relating to: 1) varying baseline distributions of mortality and duration of ventilation, which were based on data from a registry of patients with acute hypoxemic respiratory failure and 2) the varying effects of treatment on mortality and duration of ventilation. RESULTS AND CONCLUSIONS:. All methods have good control of type 1 error rates (i.e., avoid false positive findings). When data are simulated using a proportional odds model, the t test and ordinal models have the highest relative power (92% and 90%, respectively), followed by competing risk models. When the data are simulated using survival models, the competing risk models have the highest power (100% and 92%), followed by the t test and a ten-category ordinal model. All models struggled to detect the effect of the intervention when the treatment only affected one of mortality and duration of ventilation. Overall, the best performing analytical strategy depends on the respective effects of treatment on survival and duration of ventilation and the underlying distribution of the outcomes. The evaluated models each provide a different interpretation for the treatment effect, which must be considered alongside the statistical power when selecting analysis models.

OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

OBJECTIVES:. We planned to synthesize evidence examining the potential efficacy and safety of performing physical rehabilitation and/or mobilization (PR&M) in adult patients receiving extracorporeal life support (ECLS). DATA SOURCES:. We included any study that compared PR&M to no PR&M or among different PR&M strategies in adult patients receiving any ECLS for any indication and any cannulation. We searched seven electronic databases with no language limitations. STUDY SELECTION AND DATA EXTRACTION:. Two reviewers, independently and in duplicate, screened all citations for eligibility. We used the Cochrane Risk of Bias 2 and Cochrane Risk Of Bias In Non-randomized Studies of Interventions tools to assess individual study risk of bias. Although we had planned for meta-analysis, this was not possible due to insufficient data, so we used narrative and tabular data summaries for presenting results. We assessed the overall certainty of the evidence for each outcome using the Grading of Recommendations Assessment, Development, and Evaluation framework. DATA SYNTHESIS:. We included 17 studies that enrolled 996 patients. Most studies examined venovenous extracorporeal membrane oxygenation (ECMO) and/or venoarterial ECMO as a bridge to recovery in the ICU. We found an uncertain effect of high-intensity/active PR&M on mortality, duration of mechanical ventilation, ICU length of stay, hospital length of stay, or quality of life compared with low-intensity/passive PR&M in patients receiving ECLS (very low certainty due to very serious imprecision). There was similarly an uncertain effect on safety events including clinically important bleeding, spontaneous intracerebral hemorrhage, limb ischemia, accidental decannulation, or ECLS circuit dysfunction (very low certainty due to very serious risk of bias and imprecision). CONCLUSIONS:. Based on the currently available summary of evidence, there is an uncertain effect of high-intensity/active PR&M on patient important outcomes or safety in patients receiving ECLS. Despite indirect data from other populations suggesting potential benefit of high-intensity PR&M in the ICU; further high-quality randomized trials evaluating the benefits and risks of physical therapy and/or mobilization in this population are needed.

Abstract Background Percutaneous cannulation is now accepted as the first-line strategy for extracorporeal cardiopulmonary resuscitation (ECPR) in adults. However, previous studies comparing percutaneous cannulation to surgical cannulation have been limited by small sample size and single-center settings. This study aimed to compare in-hospital outcomes in cardiac arrest (CA) patients who received femoro-femoral ECPR with percutaneous vs surgical cannulation. Methods Adults with refractory CA treated with percutaneous (percutaneous group) or surgical (surgical group) femoro-femoral ECPR between January 2008 and December 2019 were extracted from the international Extracorporeal Life Support Organization registry. The primary outcome was severe neurological complication. Multivariable logistic regression analyses were performed to assess the association between percutaneous cannulation and in-hospital outcomes. Results Among 3575 patients meeting study inclusion, 2749 (77%) underwent percutaneous cannulation. The proportion of patients undergoing percutaneous cannulation increased from 18% to 89% over the study period (p

BackgroundExtracorporeal membrane oxygenation (ECMO) represents an important but limited treatment for patients with severe COVID-19. We assessed the effects of an educational intervention on a person's ECMO care preference and examined whether patients and providers had similar ECMO preferences.MethodsIn the Video+Survey group, patients watched an educational video about ECMO's purpose, benefits, and risks followed by an assessment of ECMO knowledge and care preferences in seven scenarios varying by hypothetical patient age, function, and comorbidities. Patients in the Survey Only group and providers didn't watch the video. Logistic regression was used to estimate the probability of agreement for each ECMO scenario between the two patient groups and then between all patients and providers.ResultsVideo+Survey patients were more likely (64% vs. 17%; p = 0.02) to correctly answer all ECMO knowledge questions than Survey Only patients. Patients in both groups agreed that ECMO should be considered across all hypothetical scenarios, with predicted agreement above 65%. In adjusted analyses, patients and providers had similar predicted agreement for ECMO consideration across six of the seven scenarios, but patients showed greater preference (84% vs. 41%, p = 0.003) for the scenario of a functionally dependent 65-year-old with comorbidities than providers.Discussion and conclusionsAn educational video increased a person's ECMO knowledge but did not change their ECMO preferences. Clinicians were less likely than patients to recommend ECMO for older adults, so advanced care planning discussion between patients and providers about treatment options in critically ill patients with COVID-19 is critical.

Introduction Extracorporeal membrane oxygenation (ECMO) is an intervention used in critically ill patients with severe cardiopulmonary failure that is expensive and resource intensive and requires specialised care. There remains a significant practice variation in its application. This systematic review will assess the evidence for key performance indicators (KPIs) in ECMO.Methods and analysis We will search Ovid MEDLINE, Ovid EMBASE, Cumulative Index to Nursing and Allied Health Literature and the Cochrane Library including the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials and databases from the National Information Center of Health Services Research and Health Care Technology, for studies involving KPIs in ECMO. We will rate methodological quality using the Newcastle-Ottawa Quality Assessment Scale. Randomized controlled trials (RCTs) will be evaluated with the Cochrane Risk of Bias tool, and qualitative studies will be evaluated using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN checklist). Grey literature sources will be searched for technical reports, practice guidelines and conference proceedings. We will identify relevant organisations, industry leaders and non-profit organisations that represent key opinion leads in the use of ECMO. We will search the Agency of Healthcare Research and Quality National Quality Measures Clearinghouse for ECMO-related KPIs. Studies will be included if they contain quality measures that occur in critically ill patients and are associated with ECMO. The analysis will be primarily descriptive. Each KPI will be evaluated for importance, scientific acceptability, utility and feasibility using the four criteria proposed by the US Strategic Framework Board for a National Quality Measurement and Reporting System. Finally, KPIs will be evaluated for their potential operational characteristics, their potential to be integrated into electronic medical records and their affordability, if applicable.Ethics and dissemination Ethical approval is not required as no primary data will be collected. Findings will be published in a peer-reviewed journal and presented at academic.PROSPERO registration number 9 August 2022. CRD42022349910.

Abstract Background Patients with acute respiratory failure caused by cardiogenic pulmonary edema (CPE) may require mechanical ventilation that can cause further lung damage. Our aim was to determine the impact of ventilatory settings on CPE mortality. Methods Patients from the LUNG SAFE cohort, a multicenter prospective cohort study of patients undergoing mechanical ventilation, were studied. Relationships between ventilatory parameters and outcomes (ICU discharge/hospital mortality) were assessed using latent mixture analysis and a marginal structural model. Results From 4499 patients, 391 meeting CPE criteria (median age 70 [interquartile range 59–78], 40% female) were included. ICU and hospital mortality were 34% and 40%, respectively. ICU survivors were younger (67 [57–77] vs 74 [64–80] years, p

IMPORTANCE:. Prone positioning is associated with improved mortality in patients with moderate/severe acute respiratory distress syndrome (ARDS) and has been increasingly used throughout the COVID-19 pandemic. In patients with refractory hypoxemia, transfer to an extracorporeal membrane oxygenation (ECMO) center may improve outcome but may be challenging due to severely compromised gas exchange. Transport of these patients in prone position may be advantageous; however, there is a paucity of data on their outcomes. OBJECTIVES:. The primary objective of this retrospective cohort study was to describe the early outcomes of ARDS patients transported in prone position for evaluation at a regional ECMO center. A secondary objective was to examine the safety of their transport in the prone position. DESIGN:. Retrospective cohort study. SETTING:. This study used patient charts from Ornge and Toronto General Hospital in Ontario, Canada, between February 1, 2020, and November 31, 2021. PARTICIPANTS:. Patient with ARDS transported in the prone position for ECMO evaluation to Toronto General Hospital. MAIN OUTCOMES AND MEASURES:. Descriptive analysis of patients transported in the prone position and their outcomes. RESULTS:. One hundred fifteen patients were included. Seventy-two received ECMO (63%) and 51 died (44%) with ARDS and sepsis as the most common listed causes of death. Patients were transported primarily for COVID-related indications (93%). Few patients required additional analgesia (8%), vasopressors (4%), or experienced clinically relevant desaturation during transport (2%). CONCLUSIONS AND RELEVANCE:. This cohort of patients with severe ARDS transported in prone position had outcomes ranging from similar to better compared with existing literature. Prone transport was performed safely with few complications or escalation in treatments. Prone transport to an ECMO center should be regarded as safe and potentially beneficial for patients with ARDS and refractory hypoxemia.

Abstract Background Insufficient or excessive respiratory effort during acute hypoxemic respiratory failure (AHRF) increases the risk of lung and diaphragm injury. We sought to establish whether respiratory effort can be optimized to achieve lung- and diaphragm-protective (LDP) targets (esophageal pressure swing − 3 to − 8 cm H2O; dynamic transpulmonary driving pressure ≤ 15 cm H2O) during AHRF. Methods In patients with early AHRF, spontaneous breathing was initiated as soon as passive ventilation was not deemed mandatory. Inspiratory pressure, sedation, positive end-expiratory pressure (PEEP), and sweep gas flow (in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO)) were systematically titrated to achieve LDP targets. Additionally, partial neuromuscular blockade (pNMBA) was administered in patients with refractory excessive respiratory effort. Results Of 30 patients enrolled, most had severe AHRF; 16 required VV-ECMO. Respiratory effort was absent in all at enrolment. After initiating spontaneous breathing, most exhibited high respiratory effort and only 6/30 met LDP targets. After titrating ventilation, sedation, and sweep gas flow, LDP targets were achieved in 20/30. LDP targets were more likely to be achieved in patients on VV-ECMO (median OR 10, 95% CrI 2, 81) and at the PEEP level associated with improved dynamic compliance (median OR 33, 95% CrI 5, 898). Administration of pNMBA to patients with refractory excessive effort was well-tolerated and effectively achieved LDP targets. Conclusion Respiratory effort is frequently absent under deep sedation but becomes excessive when spontaneous breathing is permitted in patients with moderate or severe AHRF. Systematically titrating ventilation and sedation can optimize respiratory effort for lung and diaphragm protection in most patients. VV-ECMO can greatly facilitate the delivery of a LDP strategy. Trial registration: This trial was registered in Clinicaltrials.gov in August 2018 (NCT03612583).

Abstract Background Extracorporeal membrane oxygenation (ECMO) has been used extensively for coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). Reports early in the pandemic suggested that mortality in patients with COVID-19 receiving ECMO was comparable to non-COVID-19-related ARDS. However, subsequent reports suggested that mortality appeared to be increasing over time. Therefore, we conducted an updated systematic review and meta-analysis, to characterise changes in mortality over time and elucidate risk factors for poor outcomes. Methods We conducted a meta-analysis (CRD42021271202), searching MEDLINE, Embase, Cochrane, and Scopus databases, from 1 December 2019 to 26 January 2022, for studies reporting on mortality among adults with COVID-19 receiving ECMO. We also captured hospital and intensive care unit lengths of stay, duration of mechanical ventilation and ECMO, as well as complications of ECMO. We conducted random-effects meta-analyses, assessed risk of bias of included studies using the Joanna Briggs Institute checklist and evaluated certainty of pooled estimates using GRADE methodology. Results Of 4522 citations, we included 52 studies comprising 18,211 patients in the meta-analysis. The pooled mortality rate among patients with COVID-19 requiring ECMO was 48.8% (95% confidence interval 44.8–52.9%, high certainty). Mortality was higher among studies which enrolled patients later in the pandemic as opposed to earlier (1st half 2020: 41.2%, 2nd half 2020: 46.4%, 1st half 2021: 62.0%, 2nd half 2021: 46.5%, interaction p value = 0.0014). Predictors of increased mortality included age, the time of final patient enrolment from 1 January 2020, and the proportion of patients receiving corticosteroids, and reduced duration of ECMO run. Conclusions The mortality rate for patients receiving ECMO for COVID-19-related ARDS has increased as the pandemic has progressed. The reasons for this are likely multifactorial; however, as outcomes for these patients evolve, the decision to initiate ECMO should include the best contextual estimate of mortality at the time of ECMO initiation.

Abstract Background The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. Methods We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. Results Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0–25) and 25 (IQR 7–26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0–87) and 87 (IQR 0–88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07; p = 0.177). Conclusions In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting.

The COVID-19 pandemic has exposed the precarious demand-capacity balance in Canadian hospitals, including critical care where there is an urgent need for trained health care professionals to dramatically increase ICU capacity. The impact of the pandemic on ICUs varied significantly across the country with provinces that implemented public health measures later and relaxed them sooner being impacted more severely. Pediatric ICUs routinely admitted adult patients. Non-ICU areas were converted to ICUs and staff were redeployed from other essential service areas. Faced with a lack of critical care capacity, triage plans for ICU admission were developed and nearly implemented in some provinces. Twenty eight percent of patients in Canadian ICUs who required mechanical ventilation died. Surviving patients have required prolonged ICU admission, hospitalization and extensive ongoing rehabilitation. Family members of patients were not permitted to visit, resulting in additional psychological stresses to patients, families, and healthcare teams. ICU professionals also experienced extreme psychological stresses from caring for such large numbers of critically ill patients, often in sub-standard conditions. This resulted in large numbers of health workers leaving their professions. This pandemic is not yet over, and it is likely that new pandemics will follow. A review and recommendations for the future are provided.

Background. Primary graft dysfunction (PGD) is a form of acute respiratory failure that complicates 30% of bilateral lung transplants. Higher grades of PGD correlate with higher severity of respiratory failure and unfavorable outcomes. Immediate PGD determination posttransplant‚ however, is not always predictive of PGD over subsequent days or intensive care unit outcomes. We aimed to evaluate whether extravascular lung water index (ELWI) measured immediately post bilateral lung transplant was associated with higher severity of PGD at 72 h and duration of mechanical ventilation. Methods. We conducted a prospective, observational study of bilateral lung transplant patients admitted to the intensive care unit. ELWI measurements were performed at admission, 6, 12, 24, 36, 48, 60, and 72 h following transplant or until extubation. We evaluated the association between admission ELWI and 72-h PGD grade and duration of mechanical ventilation. Results. Across 56 patients enrolled, 268 transpulmonary thermodilution measurements were conducted. At admission, median ELWI increased with PGD grade (grade 1: 9 mL/kg [interquartile range (IQR), 8–11 mL/kg]‚ grade 2 [10 mL/kg (IQR, 8–12 mL/kg)]‚ and grade 3 [17 mL/kg (IQR, 14–19 mL/kg); P < 0.001]). Using multivariable Poisson regression analysis adjusting for confounders, admission ELWI elevation was associated with higher severity of PGD at 72 h (incidence rate ratio [IRR], 1.06; 95% confidence interval, 1.01-1.12) and duration of mechanical ventilation (IRR, 1.62; 95% confidence interval, 1.23-2.14). The combination of an ELWI of ≥13 mL/kg and partial pressure of oxygen/fraction of inspired oxygen ≤ 100 within 6 h of admission had high sensitivity (75%) and specificity (100%) for grade 3 PGD at 72 h (area under the curve, 0.95) and performed better than ELWI or partial pressure of oxygen/fraction of inspired oxygen alone. Conclusions. Our exploratory study demonstrates an association between admission ELWI and high grades of PGD at 72 h and longer duration of ventilation. These results provide the impetus to study whether goal-directed ELWI algorithms can improve transplant outcomes.

Summary: Background: Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular “recharge”, allowing for multi-day lung preservation. Methods: Donor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP. After a total of 3 days of preservation, a left lung transplant was performed followed by 4h of graft evaluation. As controls, 2 lungs were preserved solely with continuous 10°C preservation for 3 days and transplanted. Findings: For animals receiving lungs preserved using a cyclic EVLP protocol, lung function and histological structures were stable and the recipient systemic partial pressure of oxygen/fraction of inspired oxygen (P/F Ratio) after excluding the contralateral lung was 422 ± 61 mmHg. In contrast, lungs preserved solely in continuous cold static storage at 10°C for 72h developed massive lung failure, resulting in recipient death. Metabolomic analysis revealed that EVLP plays a critical role in the re-vitalization of key central carbon energy metabolites (Glucose, Succinate, N-Acetyl Aspartate) and reducing the expression of the inflammasome activation marker CASP1. Interpretation: In conclusion, we demonstrate for the first time the feasibility of 3-day lung preservation leading to excellent early post-transplant outcomes. The thoughtful combination of cold storage (10°C) and intermittent EVLP can open new opportunities in organ transplantation. Funding: This work was supported by the UHN Foundation (Grant#1013612).

Summary: Background: Endothelial cell (EC) activation, endotheliitis, vascular permeability, and thrombosis have been observed in patients with severe coronavirus disease 2019 (COVID-19), indicating that the vasculature is affected during the acute stages of SARS-CoV-2 infection. It remains unknown whether circulating vascular markers are sufficient to predict clinical outcomes, are unique to COVID-19, and if vascular permeability can be therapeutically targeted. Methods: Prospectively evaluating the prevalence of circulating inflammatory, cardiac, and EC activation markers as well as developing a microRNA atlas in 241 unvaccinated patients with suspected SARS-CoV-2 infection allowed for prognostic value assessment using a Random Forest model machine learning approach. Subsequent ex vivo experiments assessed EC permeability responses to patient plasma and were used to uncover modulated gene regulatory networks from which rational therapeutic design was inferred. Findings: Multiple inflammatory and EC activation biomarkers were associated with mortality in COVID-19 patients and in severity-matched SARS-CoV-2-negative patients, while dysregulation of specific microRNAs at presentation was specific for poor COVID-19-related outcomes and revealed disease-relevant pathways. Integrating the datasets using a machine learning approach further enhanced clinical risk prediction for in-hospital mortality. Exposure of ECs to COVID-19 patient plasma resulted in severity-specific gene expression responses and EC barrier dysfunction, which was ameliorated using angiopoietin-1 mimetic or recombinant Slit2-N. Interpretation: Integration of multi-omics data identified microRNA and vascular biomarkers prognostic of in-hospital mortality in COVID-19 patients and revealed that vascular stabilizing therapies should be explored as a treatment for endothelial dysfunction in COVID-19, and other severe diseases where endothelial dysfunction has a central role in pathogenesis. Funding Information: This work was directly supported by grant funding from the Ted Rogers Center for Heart Research, Toronto, Ontario, Canada and the Peter Munk Cardiac Center, Toronto, Ontario, Canada.

IMPORTANCE:. Factors associated with mortality in coronavirus disease 2019 patients on invasive mechanical ventilation are still not fully elucidated. OBJECTIVES:. To identify patient-level parameters, readily available at the bedside, associated with the risk of in-hospital mortality within 28 days from commencement of invasive mechanical ventilation or coronavirus disease 2019. DESIGN, SETTING, AND PARTICIPANTS:. Prospective observational cohort study by the global Coronavirus Disease 2019 Critical Care Consortium. Patients with laboratory-confirmed coronavirus disease 2019 requiring invasive mechanical ventilation from February 2, 2020, to May 15, 2021. MAIN OUTCOMES AND MEASURES:. Patient characteristics and clinical data were assessed upon ICU admission, the commencement of invasive mechanical ventilation and for 28 days thereafter. We primarily aimed to identify time-independent and time-dependent risk factors for 28-day invasive mechanical ventilation mortality. RESULTS:. One-thousand five-hundred eighty-seven patients were included in the survival analysis; 588 patients died in hospital within 28 days of commencing invasive mechanical ventilation (37%). Cox-regression analysis identified associations between the hazard of 28-day invasive mechanical ventilation mortality with age (hazard ratio, 1.26 per 10-yr increase in age; 95% CI, 1.16–1.37; p < 0.001), positive end-expiratory pressure upon commencement of invasive mechanical ventilation (hazard ratio, 0.81 per 5 cm H2O increase; 95% CI, 0.67–0.97; p = 0.02). Time-dependent parameters associated with 28-day invasive mechanical ventilation mortality were serum creatinine (hazard ratio, 1.28 per doubling; 95% CI, 1.15–1.41; p < 0.001), lactate (hazard ratio, 1.22 per doubling; 95% CI, 1.11–1.34; p < 0.001), Paco2 (hazard ratio, 1.63 per doubling; 95% CI, 1.19–2.25; p < 0.001), pH (hazard ratio, 0.89 per 0.1 increase; 95% CI, 0.8–14; p = 0.041), Pao2/Fio2 (hazard ratio, 0.58 per doubling; 95% CI, 0.52–0.66; p < 0.001), and mean arterial pressure (hazard ratio, 0.92 per 10 mm Hg increase; 95% CI, 0.88–0.97; p = 0.003). CONCLUSIONS AND RELEVANCE:. This international study suggests that in patients with coronavirus disease 2019 on invasive mechanical ventilation, older age and clinically relevant variables monitored at baseline or sequentially during the course of invasive mechanical ventilation are associated with 28-day invasive mechanical ventilation mortality hazard. Further investigation is warranted to validate any causative roles these parameters might play in influencing clinical outcomes.