key: cord-0941443-0bp5w5v7 authors: Jacobs, Jeffrey P.; Stammers, Alfred H.; St. Louis, James D.; Tesdahl, Eric A.; Hayanga, J. W. Awori; Morris, Rohinton J.; Lee, Raymond C.; Sestokas, Anthony K.; Badhwar, Vinay; Weinstein, Samuel title: Variation in Survival in Patients with COVID-19 Supported with ECMO: A Multi-institutional analysis of 594 consecutive COVID-19 patients supported with ECMO at 49 hospitals within 21 States date: 2022-05-15 journal: J Thorac Cardiovasc Surg DOI: 10.1016/j.jtcvs.2022.05.002 sha: 03325053424bd6eae0e5f6cde509b51e290bb753 doc_id: 941443 cord_uid: 0bp5w5v7 Objectives We reviewed 594 consecutive COVID-19 patients supported with ECMO at 49 hospitals within 21 states and examined patient characteristics, treatments, and variation in outcomes over the course of the pandemic. Methods A multi-institutional database was utilized to assess all COVID-19 patients supported with and separated from ECMO between March 2020 and December 2021, inclusive. Descriptive analysis was stratified by four time categories: Group-A=3/20-6/20, Group-B=7/20-12/20, Group-C=1/21-6/21, Group D=7/21-12/21. A Bayesian mixed-effects logistic regression was used to assess continuous trends in survival where time was operationalized as the number of days between each patient’s cannulation and that of the first patient in March 2020, controlling for multiple variables and risk factors. Results At hospital discharge, of 594 patients: 221 survived (37.2%) and 373 died. Throughout the study: median age [interquartile range] declined (Group-A=51.0[41.0-60.0], Group-D=39.0[32.0-48.0], P<.001); median days between COVID-19 diagnosis and intubation increased Group-A=4.0[1.0-8.5], Group-D=9.0[5.0-14.5], P<.001); use of medications (glucocorticoids, interleukin-6 blockers, anti-virals, anti-malarials) and convalescent plasma fluctuated significantly (all P<.001). Estimated odds of survival varied over the study period with a decline between 1Apr20 and 21Nov20 (OR=0.39, 95% credibility interval (CrI)=[0.8-0.87], probability of reduction in survival=95.7%), improvement between 21Nov20 and 17May21 (OR=1.85, 95% CrI=[0.86-4.09], probability of improvement=93.4%), and decline from 17May21 and 1Dec21 (OR=0.49, 95% Cr=[0.19-1.44], probability of decrease=92.1%). Conclusion Survival for COVID-19 patients supported with ECMO has fluctuated during the stages of the pandemic. Minimizing variability by adherence to best practices may refine the optimal use of ECMO in a pandemic response.Abstract Words=243/250 The evolution of management and outcomes of COVID-19 holds valuable lessons for the role of ECMO in a pandemic response. We reviewed our experience in 594 consecutive patients with COVID-19 who were supported with and separated from ECMO (3/20-12/21, inclusive, 49 hospitals, 21 states) and examined variation in patient characteristics, treatment strategies, and outcomes over the course of the pandemic. Most deaths in COVID-19 patients are due to respiratory failure, with a small group succumbing to combined pulmonary and cardiac failure [2, 3] . The role of ECMO in the management of severely ill patients with COVID-19 continues to be defined [4] [5] [6] [7] . We previously published analyses of our initial 32, 100, 200, and then 505 COVID-19 patients with severe pulmonary compromise supported with ECMO [8] [9] [10] [11] . These prior analyses documented the evolution of the use ECMO to support patients with and supported the concept that "ECMO facilitates survival of select critically ill patients with COVID-19." [8] [9] [10] [11] Although substantial variation exists in drug treatment of COVID-19, ECMO offers a reasonable rescue strategy [9] [10] [11] . Several analyses have described cohorts of COVID-19 patients supported with ECMO [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] . Over the course of the pandemic, as knowledge evolved, multiple changes have occurred in both the strategies for management and the outcomes of treatment. Valuable lessons can be learned from this evolution of treatment and outcomes associated with COVID- 19 . The purpose of this study was to review our clinical experience in 594 consecutive patients with COVID-19 who were supported with and separated from ECMO between March 2020 and December 2021, inclusive, at 49 hospitals within 21 states and examine characteristics of patients, strategies of treatment, and variation in outcomes over the course of the pandemic. A multi-institutional database was utilized to assess all patients with COVID-19 who were supported with ECMO at 49 hospitals located in 21 states in the USA. This database is prospectively maintained on all patients supported with ECMO and has been used for data collection and analysis for quality improvement. This database is a component of the J o u r n a l P r e -p r o o f Descriptive data tabulations were performed by grouping cases into four time categories representing the first and second halves of 2020 and 2021: • Group-A=3/2020-6/2020 • Group-B=7/2020-12/2020 • Group-C=1/2021-6/2021 • Group D=7/2021-12/2021. J o u r n a l P r e -p r o o f Data were missing for less than 10% of cases for all modeled variables except for BMI (22% missing), days between diagnosis and intubation (19% missing), and days from intubation to cannulation (17% missing). In order to limit bias introduced by missing data, regression analysis was performed on 25 multiply-imputed data sets generated using the chained equations method, as implemented by Harrell and colleagues [18] . Institutional Review Board approval and waiver of the need for consent were obtained. The human subjects research protocol for this study was reviewed and approved by an During the twenty-two months of this study, 640 consecutive patients with COVID-19 were supported with and separated from ECMO at 49 different hospitals. Forty-six patients who were cannulated but transferred to other hospitals on ECMO were not included in this analysis. Of 594 remaining consecutive patients included in this study (non-transferred and separated from We previously reported that "Days from COVID Diagnosis to ECMO Cannulation" is inversely related to survival after ECMO for COVID-19 [11] , and in this same publication, we reported that "Days from COVID Diagnosis to Intubation" is a more important predictor of outcome than "Days from Intubation to ECMO Cannulation" [11] . In this prior publication [11] , median "Days from COVID Diagnosis to Intubation" was 7 days in survivors versus 11 days in non-survivors (p=0.001), while median "Days from Intubation to ECMO Cannulation" was 3. not really surprising that the length of time from diagnosis to institution of mechanical ventilation is perhaps even a greater risk factor. Brochard and colleagues [19] argued that "application of a lung-protective ventilation, today best applied with sedation and endotracheal intubation, might be considered a prophylactic therapy, rather than just a supportive therapy, to minimize the progression of lung injury from a form of patient self-inflicted lung injury" [19] . These authors stated: "A major concern in mechanically ventilated patients is the risk of ventilator-induced lung injury, which is partially prevented by lung-protective ventilation. Spontaneously breathing, nonintubated patients with acute respiratory failure may have a high respiratory drive and breathe with large tidal volumes and potentially injurious transpulmonary pressure swings. In patients with existing lung injury, regional forces generated by the respiratory muscles may lead to injurious effects on a regional level. In addition, the increase in transmural pulmonary vascular pressure swings caused by inspiratory effort may worsen vascular leakage. Recent data suggest that these patients may develop lung injury that is similar to the ventilator-induced lung injury observed in mechanically ventilated patients." [19] . This logic potentially explains our finding that "Days from COVID Diagnosis to ECMO Cannulation" is inversely related to survival after ECMO for COVID-19, and that "Days from COVID Diagnosis to Intubation" is a more important predictor of outcome than "Days from Intubation to ECMO Cannulation". Others have also reported an initial time related decrease in survival over time of patients with COVID-19 supported with ECMO [20] . In October 2021, Barbaro • Group A1 was composed of patients with COVID-19 supported with ECMO in whom ECMO was initiated on or before 5/1/2020 at "early-adopting centers", which were defined as centers using ECMO support for patients with COVID-19 throughout 2020. • Group A2 was composed of patients with COVID-19 supported with ECMO in whom ECMO was initiated between 5/2/2020 and 12/31/2020 at "early-adopting centers", J o u r n a l P r e -p r o o f which were defined as centers using ECMO support for patients with COVID-19 throughout 2020. • Group B was composed of patients with COVID-19 supported with ECMO in whom ECMO was initiated between 5/2/2020 and 12/31/2020 at "late-adopting centers", which were defined as centers using ECMO support for patients with COVID-19 only after 5/1/2020. Our study adds to the body of knowledge and the literature by providing more granular multi-institutional data about our cohort of 594 patients with COVID-19 supported with ECMO J o u r n a l P r e -p r o o f at 49 hospitals. As previously described, several published analyses have studied the outcomes of ECMO in patients with COVID-19, and these outcomes have been quite heterogenous [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] . Our The lessons learned from this analysis can inform both the care of patients with and without COVID-19 supported with ECMO as well as the overall and ECMO-specific approach to future pandemics. Much remains to be learned about the role of ECMO in these patients. From our analysis, no specific demographic, clinical, or laboratory data, to date, is predictive of outcome with ECMO in patients with COVID-19, with the exception of younger age and shorter time from diagnosis to intubation. Survivors tend to be younger and have a shorter duration from diagnosis to intubation. Meanwhile, the role of multiple medications in the treatment of COVID-19 remains unclear: none of the adjunct therapies are associated with survival. More information is needed to better determine which patients with COVID-19 will benefit from ECMO and which patients with COVID-19 will benefit from lung transplantation. Lessons learned from the use of ECMO to support patients with COVID-19 will inform the management of other patients with different forms of severe respiratory failure. This analysis is based on the available data in our database. Potential limitations include patient selection bias, institutional bias, confounding bias, and possible under-powering of the analysis. Additional follow-up is required on all surviving patients. Further patient accrual will enhance continued analysis of outcomes. We plan to continue gathering data to provide additional insight as to guideposts for patient selection and predictors of outcomes. It is our hope that by sharing our experience, other hospitals and patients may benefit. Survival for COVID-19 patients supported with ECMO has fluctuated during the stages of the pandemic. Our experience and analysis of 594 consecutive patients at 49 hospitals reveal that ECMO facilitates salvage and survival of select critically ill patients with COVID-19. Highest survival occurred when veno-venous only ECMO was applied with a shorter median time interval from the diagnosis of COVID-19 to ECMO cannulation, driven mostly by the observation that survivors also had a shorter median time interval from COVID-19 diagnosis to intubation for mechanical ventilation. Substantial variation exists in drug treatment of COVID-19, but ECMO offers a reasonable rescue strategy. Additional gathering and analysis of data will inform appropriate selection of patients and provide guidance as to best use of ECMO in terms of timing, implementation, duration of support, and best criteria for discontinuation. Minimizing variability on how ECMO is applied as a rescue strategy by adherence to best practices may lead to improved survival and may aid in guiding the role of ECMO in a future pandemic response. Increased Survival: 52.125% Contrasts for age, BMI, days from diagnosis to intubation, and days from intubation to cannulation are 75th percentile vs. 25th percentile. Contrasts for cannulation date chosen to assess magnitude of differences in estimated survival early and late in the study period, and at major inflection points of estimated survival trend. Figure 1 is a CONSORT Flow Diagram that depicts the distribution of all 640 patients by category of outcome. factors: age, gender, BMI, the presence or absence of one or more pre-ECMO comorbidities (i.e., obesity, asthma, hypertension, heart J o u r n a l P r e -p r o o f disease, diabetes, chronic renal failure, cancer), days from diagnosis of COVID-19 to intubation, days from intubation to cannulation for ECMO, prone positioning, and whether or not a circuit change-out was required, with a random intercept term for variations by hospital, and exhibits variation over time. Annotated dates have been added to key inflection points in the estimated trend to aid interpretation in concert with Table 2 . 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