Expert consensus statement on venovenous extracorporeal membrane oxygenation ECMO for COVID-19 severe ARDS: an international Delphi study

Abstract Background The high-quality evidence on managing COVID-19 patients requiring extracorporeal membrane oxygenation (ECMO) support is insufficient. Furthermore, there is little consensus on allocating ECMO resources when scarce. The paucity of evidence and the need for guidance on controversial topics required an international expert consensus statement to understand the role of ECMO in COVID-19 better. Twenty-two international ECMO experts worldwide work together to interpret the most recent findings of the evolving published research, statement formulation, and voting to achieve consensus. Objectives To guide the next generation of ECMO practitioners during future pandemics on tackling controversial topics pertaining to using ECMO for patients with COVID-19-related severe ARDS. Methods The scientific committee was assembled of five chairpersons with more than 5 years of ECMO experience and a critical care background. Their roles were modifying and restructuring the panel’s questions and, assisting with statement formulation in addition to expert composition and literature review. Experts are identified based on their clinical experience with ECMO (minimum of 5 years) and previous academic activity on a global scale, with a focus on diversity in gender, geography, area of expertise, and level of seniority. We used the modified Delphi technique rounds and the nominal group technique (NGT) through three face-to-face meetings and the voting on the statement was conducted anonymously. The entire process was planned to be carried out in five phases: identifying the gap of knowledge, validation, statement formulation, voting, and drafting, respectively. Results In phase I, the scientific committee obtained 52 questions on controversial topics in ECMO for COVID-19, further reviewed for duplication and redundancy in phase II, resulting in nine domains with 32 questions with a validation rate exceeding 75% (Fig. 1). In phase III, 25 questions were used to formulate 14 statements, and six questions achieved no consensus on the statements. In phase IV, two voting rounds resulted in 14 statements that reached a consensus are included in four domains which are: patient selection, ECMO clinical management, operational and logistics management, and ethics. Conclusion Three years after the onset of COVID-19, our understanding of the role of ECMO has evolved. However, it is incomplete. Tota14 statements achieved consensus; included in four domains discussing patient selection, clinical ECMO management, operational and logistic ECMO management and ethics to guide next-generation ECMO providers during future pandemic situations

Validation of extracorporeal membrane oxygenation mortality prediction and severity of illness scores in an international COVID-19 cohort

Background Veno-venous extracorporeal membrane oxygenation (V-V ECMO) is a lifesaving support modality for severe respiratory failure, but its resource-intensive nature led to significant controversy surrounding its use during the COVID-19 pandemic. We report the performance of several ECMO mortality prediction and severity of illness scores at discriminating survival in a large COVID-19 V-V ECMO cohort. Methods We validated ECMOnet, PRESET (PREdiction of Survival on ECMO Therapy-Score), Roch, SOFA (Sequential Organ Failure Assessment), APACHE II (acute physiology and chronic health evaluation), 4C (Coronavirus Clinical Characterisation Consortium), and CURB-65 (Confusion, Urea nitrogen, Respiratory Rate, Blood Pressure, age >65 years) scores on the ISARIC (International Severe Acute Respiratory and emerging Infection Consortium) database. We report discrimination via Area Under the Receiver Operative Curve (AUROC) and Area under the Precision Recall Curve (AURPC) and calibration via Brier score. Results We included 1147 patients and scores were calculated on patients with sufficient variables. ECMO mortality scores had AUROC (0.58–0.62), AUPRC (0.62–0.74), and Brier score (0.286–0.303). Roch score had the highest accuracy (AUROC 0.62), precision (AUPRC 0.74) yet worst calibration (Brier score of 0.3) despite being calculated on the fewest patients (144). Severity of illness scores had AUROC (0.52–0.57), AURPC (0.59–0.64), and Brier Score (0.265–0.471). APACHE II had the highest accuracy (AUROC 0.58), precision (AUPRC 0.64), and best calibration (Brier score 0.26). Conclusion Within a large international multicenter COVID-19 cohort, the evaluated ECMO mortality prediction and severity of illness scores demonstrated inconsistent discrimination and calibration highlighting the need for better clinically applicable decision support tools

Symptom‐based case definitions for COVID‐19: time and geographical variations for detection at hospital admission among 260,000 patients

Introduction Case definitions are used to guide clinical practice, surveillance and research protocols. However, how they identify COVID-19-hospitalised patients is not fully understood. We analysed the proportion of hospitalised patients with laboratory-confirmed COVID-19, in the ISARIC prospective cohort study database, meeting widely used case definitions. Methods Patients were assessed using the Centers for Disease Control (CDC), European Centre for Disease Prevention and Control (ECDC), World Health Organization (WHO) and UK Health Security Agency (UKHSA) case definitions by age, region and time. Case fatality ratios (CFRs) and symptoms of those who did and who did not meet the case definitions were evaluated. Patients with incomplete data and non-laboratory-confirmed test result were excluded. Results A total of 263,218 of the patients (42%) in the ISARIC database were included. Most patients (90.4%) were from Europe and Central Asia. The proportions of patients meeting the case definitions were 56.8% (WHO), 74.4% (UKHSA), 81.6% (ECDC) and 82.3% (CDC). For each case definition, patients at the extremes of age distribution met the criteria less frequently than those aged 30 to 70 years; geographical and time variations were also observed. Estimated CFRs were similar for the patients who met the case definitions. However, when more patients did not meet the case definition, the CFR increased. Conclusions The performance of case definitions might be different in different regions and may change over time. Similarly concerning is the fact that older patients often did not meet case definitions, risking delayed medical care. While epidemiologists must balance their analytics with field applicability, ongoing revision of case definitions is necessary to improve patient care through early diagnosis and limit potential nosocomial spread

Correction: Epidemiology and outcomes of early-onset AKI in COVID-19-related ARDS in comparison with non-COVID-19-related ARDS: insights from two prospective global cohort studies (Critical Care, (2023), 27, 1, (3), 10.1186/s13054-022-04294-5)

Following publication of the original article [1], the authors identified that the collaborating authors part of the collaborating author group CCCC Consortium was missing. The collaborating author group is available and included as Additional file 1 in this article

Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry

Background: Multiple major health organisations recommend the use of extracorporeal membrane oxygenation (ECMO) support for COVID-19-related acute hypoxaemic respiratory failure. However, initial reports of ECMO use in patients with COVID-19 described very high mortality and there have been no large, international cohort studies of ECMO for COVID-19 reported to date. Methods: We used data from the Extracorporeal Life Support Organization (ELSO) Registry to characterise the epidemiology, hospital course, and outcomes of patients aged 16 years or older with confirmed COVID-19 who had ECMO support initiated between Jan 16 and May 1, 2020, at 213 hospitals in 36 countries. The primary outcome was in-hospital death in a time-to-event analysis assessed at 90 days after ECMO initiation. We applied a multivariable Cox model to examine whether patient and hospital factors were associated with in-hospital mortality. Findings: Data for 1035 patients with COVID-19 who received ECMO support were included in this study. Of these, 67 (6%) remained hospitalised, 311 (30%) were discharged home or to an acute rehabilitation centre, 101 (10%) were discharged to a long-term acute care centre or unspecified location, 176 (17%) were discharged to another hospital, and 380 (37%) died. The estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 37·4% (95% CI 34·4–40·4). Mortality was 39% (380 of 968) in patients with a final disposition of death or hospital discharge. The use of ECMO for circulatory support was independently associated with higher in-hospital mortality (hazard ratio 1·89, 95% CI 1·20–2·97). In the subset of patients with COVID-19 receiving respiratory (venovenous) ECMO and characterised as having acute respiratory distress syndrome, the estimated cumulative incidence of in-hospital mortality 90 days after the initiation of ECMO was 38·0% (95% CI 34·6–41·5). Interpretation: In patients with COVID-19 who received ECMO, both estimated mortality 90 days after ECMO and mortality in those with a final disposition of death or discharge were less than 40%. These data from 213 hospitals worldwide provide a generalisable estimate of ECMO mortality in the setting of COVID-19. Funding: None

Stroke in critically ill patients with respiratory failure due to COVID-19: Disparities between low-middle and high-income countries

Purpose: We aimed to compare the incidence of stroke in low-and middle-income countries (LMICs) versus high-income countries (HICs) in critically ill patients with COVID-19 and its impact on in-hospital mortality. Methods: International observational study conducted in 43 countries. Stroke and mortality incidence rates and rate ratios (IRR) were calculated per admitted days using Poisson regression. Inverse probability weighting (IPW) was used to address the HICs vs. LMICs imbalance for confounders. Results: 23,738 patients [20,511(86.4 %) HICs vs. 3,227(13.6 %) LMICs] were included. The incidence stroke/1000 admitted-days was 35.7 (95 %CI = 28.4–44.9) LMICs and 17.6 (95 %CI = 15.8–19.7) HICs; ischemic 9.47 (95 %CI = 6.57–13.7) LMICs, 1.97 (95 %CI = 1.53, 2.55) HICs; hemorrhagic, 7.18 (95 %CI = 4.73–10.9) LMICs, and 2.52 (95 %CI = 2.00–3.16) HICs; unspecified stroke type 11.6 (95 %CI = 7.75–17.3) LMICs, 8.99 (95 %CI = 7.70–10.5) HICs. In regression with IPW, LMICs vs. HICs had IRR = 1.78 (95 %CI = 1.31–2.42, p < 0.001). Patients from LMICs were more likely to die than those from HICs [43.6% vs 29.2 %; Relative Risk (RR) = 2.59 (95 %CI = 2.29–2.93), p < 0.001)]. Patients with stroke were more likely to die than those without stroke [RR = 1.43 (95 %CI = 1.19–1.72), p < 0.001)]. Conclusions: Stroke incidence was low in HICs and LMICs although the stroke risk was higher in LMICs. Both LMIC status and stroke increased the risk of death. Improving early diagnosis of stroke and redistribution of healthcare resources should be a priority. Trial registration: ACTRN12620000421932 registered on 30/03/2020

Early short course of neuromuscular blocking agents in patients with COVID-19 ARDS: a propensity score analysis

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

Characteristics and outcomes of an international cohort of 600 000 hospitalized patients with COVID-19

Background: We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, one of the world’s largest international, standardized data sets concerning hospitalized patients. Methods: The data set analysed includes COVID-19 patients hospitalized between January 2020 and January 2022 in 52 countries. We investigated how symptoms on admission, co-morbidities, risk factors and treatments varied by age, sex and other characteristics. We used Cox regression models to investigate associations between demographics, symptoms, co-morbidities and other factors with risk of death, admission to an intensive care unit (ICU) and invasive mechanical ventilation (IMV). Results: Data were available for 689 572 patients with laboratory-confirmed (91.1%) or clinically diagnosed (8.9%) SARS-CoV-2 infection from 52 countries. Age [adjusted hazard ratio per 10 years 1.49 (95% CI 1.48, 1.49)] and male sex [1.23 (1.21, 1.24)] were associated with a higher risk of death. Rates of admission to an ICU and use of IMV increased with age up to age 60 years then dropped. Symptoms, co-morbidities and treatments varied by age and had varied associations with clinical outcomes. The case-fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients and was on average 21.5%. Conclusions: Age was the strongest determinant of risk of death, with a ~30-fold difference between the oldest and youngest groups; each of the co-morbidities included was associated with up to an almost 2-fold increase in risk. Smoking and obesity were also associated with a higher risk of death. The size of our international database and the standardized data collection method make this study a comprehensive international description of COVID-19 clinical features. Our findings may inform strategies that involve prioritization of patients hospitalized with COVID-19 who have a higher risk of death