key: cord-0729650-bnzanx3n
authors: Jacobs, Jeffrey P.; Stammers, Alfred H.; St. Louis, James D.; Hayanga, J. W. Awori; Firstenberg, Michael S.; Mongero, Linda B.; Tesdahl, Eric A.; Rajagopal, Keshava; Cheema, Faisal H.; Patel, Kirti; Coley, Tom; Sestokas, Anthony K.; Slepian, Marvin J.; Badhwar, Vinay
title: Multi-institutional Analysis of 200 COVID-19 Patients treated with ECMO:Outcomes and Trends
date: 2021-07-06
journal: Ann Thorac Surg
DOI: 10.1016/j.athoracsur.2021.06.026
sha: a4d30c21af6735e93daca35943b2624d7824f2a6
doc_id: 729650
cord_uid: bnzanx3n

Background The role of ECMO in the management of patients with COVID-19 continues to evolve. The purpose of this manuscript is to review a multi-institutional clinical experience in 200 consecutive patients at 29 hospitals with confirmed COVID-19 supported with ECMO. Methods This analysis includes our first 200 COVID-19 patients with complete data who were supported with and separated from ECMO. These patients were cannulated between March 17 and December 9, 2020. Differences by mortality group were assessed using chi-square tests for categorical variables and Kruskal-Wallis rank sum tests and Welch’s ANOVA for continuous variables. Results Median ECMO time was 15 days (IQR=9-28). All 200 patients have separated from ECMO: 90 patients (45%) survived and 110 patients (55%) died. Survival with veno-venous ECMO was 87 of 188 patients (46.3%), while survival with veno-arterial ECMO was 3 of 12 patients (25%). Of 90 survivors, 77 have been discharged from the hospital and 13 remain hospitalized at the ECMO-providing hospital. Survivors had lower median age (47 versus 56 years, p<0.001) and shorter median time interval from diagnosis to ECMO cannulation (8 days versus 12 days, p=0.003).In the 90 survivors, adjunctive therapies on ECMO included: intravenous steroids (64), Remdesivir (49), convalescent plasma (43), anti-interleukin-6 receptor blockers (39), prostaglandin (33), and hydroxychloroquine (22). Conclusions ECMO facilitates survival of select critically ill patients with COVID-19. Survivors tend to be younger and have a shorter duration from diagnosis to cannulation. Substantial variation exists in drug treatment of COVID-19, but ECMO offers a reasonable rescue strategy.

As of January 28, 2021, 100,986,160 patients around the world have been diagnosed with Coronavirus Disease 2019 (COVID-19), with 2,177,611 associated deaths (2.16% mortality worldwide) [1] . Meanwhile, in the United States of America, as of January 28, 2021, 25,599,961 patients have been diagnosed with confirmed COVID-19, with 429,214 associated deaths to date (1.68% mortality in the USA) [1] . Most deaths in patients with COVID-19 are due to severe respiratory failure, with a small group succumbing to combined pulmonary and cardiac failure [2, 3] .

We previously published an analysis of our initial 32 COVID-19 patients with severe pulmonary compromise supported with extracorporeal membrane oxygenation (ECMO) [4] and concluded that "ECMO may play a useful role in salvaging select critically ill patients with COVID-19. Additional patient experience and associated clinical and laboratory data must be obtained to further define the optimal role of ECMO in patients with COVID-19 and acute respiratory distress syndrome (ARDS).

These initial data may provide useful information to help define the best strategies to care for these challenging patients, and may also provide a framework for much-needed future research about the use of ECMO to treat patients with COVID-19." [4] Several recently published analyses describe cohorts of COVID-19 patients supported with ECMO [4, 5, 6, 7, 8] . Early data from Wuhan, China reported an alarmingly high rate of mortality of 83% (5 out of 6) in COVID-19 patients supported with ECMO [5, 6] . More recent data, however, reveal improved survival of COVID-19 ECMO patients [4, 7, 8] . Both recent individual institutional reports [7] , as well as recent reports from multi-institutional registries [8] , present detailed analyses with promising results. Our previous report from our multi-institutional database [4] corroborates these findings from individual institutions [7] and multi-institutional registries [8] , but additionally provides more granular, detailed information than a largescale registry and more generalizable information than can be garnered from analysis from a single institution. It is a fact that the role of ECMO in the management of severely ill patients with COVID-19 continues to evolve. The purpose of this manuscript is (1) to review our multi-institutional clinical experience based on 200 consecutive patients with confirmed COVID-19 with severe pulmonary compromise who were supported with and separated from ECMO at 29 hospitals and (2) to document outcomes and trends in management over time.

J o u r n a l P r e -p r o o f A prospective, multi-institutional cohort study was conducted of all patients with confirmed COVID-19 who were supported with ECMO at 29 different hospitals. Supplemental Table 1 documents the regional distribution of these 200 patients in 18 states at 29 hospitals in the United States. A multi-institutional database was created and utilized to assess these patients. This database is prospectively maintained on all patients and has been used for data collection and analysis. The database used is a component of the SpecialtyCare Operative Procedural REgistry, (SCOPE) [https://specialtycareus.com/]. (SpecialtyCare is a United States provider of Allied Health services, and the SCOPE Registry contains data from over 1 million perfusion procedures in over 40 states at more than 300 hospitals. This manuscript describes the ECMO experience treating a subset of these patients with COVID-19.) Data captured included patient characteristics, pre-COVID-19 risk factors and comorbidities, confirmation of COVID-19 diagnosis, features of ECMO support, specific medications utilized in an attempt to treat COVID-19, and short-term outcomes through hospital discharge.

This analysis includes our first 200 patients with complete data who had confirmed COVID-19 and were supported with ECMO, starting with our first COVID-19 patient who was placed on ECMO on March 17, 2020, and ending with a patient placed on ECMO on December 9, 2020. These 200 patients include 188 patients supported with veno-venous ECMO and 12 patients supported with veno-arterial ECMO. The initial cohort included our first 206 patients who had confirmed COVID-19 and were supported with and decannulated from ECMO; six patients (one survivor and four nonsurvivors) were excluded from this analysis because of incomplete data. Inclusion in the analysis required complete data in the following fields: ECMO start date, ECMO end date, outcome (alive or dead), no more than one missing pre-COVID comorbidities (asthma, cancer, chronic renal failure, diabetes, heart disease, hypertension, obesity), and no more than one missing adjunctive therapeutic interventions (anti-viral medications, anti-malarial medications, convalescent plasma, interleukin-6 blockers, prostaglandin, steroids).

Criteria for placement on ECMO were determined by the individual patient care team(s) at each of the contributing 29 hospitals; all patients who were placed on ECMO had the diagnosis of COVID-19 with severe respiratory failure deemed to be refractory to conventional management. The decision to initiate ECMO, the mode of therapy (i.e., veno-venous, veno-arterial, etc.), and the cannulation strategy were each determined by the individual ECMO teams, in keeping with their respective individual institutional protocols and guidelines. Tables 1 and 2 provides P/F ratio, which is J o u r n a l P r e -p r o o f defined as the arterial pO2 of the patient divided by the FIO2 (the fraction of inspired oxygen expressed as a decimal) that the patient is receiving.

Descriptive analysis of the entire cohort was performed using mean, standard deviation, median, and interquartile range (IQR), as appropriate. The primary outcome of interest was mortality during the index hospitalization. Potential differences in categorical variables by mortality group were assessed using chi-square tests, while potential differences in continuous variables by mortality group were assessed using Kruskal-Wallis rank sum tests and Welch's ANOVA.

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 independent Institutional Review Board. Institutional ethics review board approval was obtained for the use of data from the SCOPE TM Database (Protocol #012017, ADVARRA Center for IRB Intelligence, Columbia, Maryland).

Two hundred consecutive patients with COVID-19 were placed on ECMO at 29 different hospitals. All 200 patients have since been separated from ECMO: 90 patients survived (45%) and 110 patients died (55%). Of the 90 survivors, 77 patients have been discharged from the hospital to date. Table 1 provides detailed data about all 200 patients with COVID-19 treated with ECMO. Of note, out of 200 patients, 128 (64%) were obese, 94 (47%) had hypertension, 76 (38%) had diabetes, 33 (16.5%) had asthma, 22 (11%) had heart disease, 12 (6%) had chronic renal failure, and 6 (3%) had cancer. The median time on ECMO was 15 days (IQR=9-28 days). Table 2 provides detailed data comparing the characteristics of 90 survivors with 110 nonsurvivors. Survivors were generally younger, with a lower median age (47 versus 56 years, p<0.001).

Survivors also had a shorter median time interval from the diagnosis of COVID-19 to cannulation for ECMO (8 days versus 12 days, p=0.003). Although duration on ECMO was shorter in survivors than non-survivors, this trend was not statistically significant: median time on ECMO in survivors was 12. concluded that "The early outcomes presented here suggest that the judicious use of ECMO support in severe COVID-19 may be clinically beneficial". [7] In contrast, the use of veno-arterial ECMO in patients with COVID-19 has been associated with poor survival. Indeed, in patients with COVID-19, if the extent of end organ damage necessitates veno-arterial ECMO, then the prognosis is poor in comparison to patients with isolated respiratory dysfunction requiring only veno-venous ECMO. Furthermore, if the disease is so severe that the patient has a cardiac arrest refractory to CPR without ECMO, the patient is unlikely to survive and the use of veno-arterial ECMO is likely to be futile. Barbaro and colleagues reported a cohort study of 1035 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, using data from the ELSO Registry [8] . At the time of publication, of these 1035 patients, 67 (6%) remained hospitalized, 311 (30%) were discharged home or to an acute rehabilitation center, 101 (10%) were discharged to a long-term acute care center 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. In the subset of patients receiving veno-venous ECMO and characterized as having acute respiratory distress syndrome, estimated in-hospital mortality 90 days after the initiation of ECMO was 38·0% (95% CI 34·6-41·5). ECMO for circulatory support was independently associated with higher in-hospital mortality (hazard ratio 1·89, 95% CI 1·20-2·97).

Shih, DiMaio, and colleagues recently reported an analysis of 37 patients with severe COVID-19 ARDS who "were initiated on venovenous VV ECMO support at one of four ECMO referral hospitals within a large healthcare system. Initiation of ECMO occurred on median day 11.5 following admission, and, of the successfully decannulated patients, median time on ECMO was 17 days.

Survival to discharge from ECMO center has occurred in 21/37 patients (56.8%)" [13] . These findings are also consistent with our analysis. Recently, successful transition from the initial intent of bridge to recovery to subsequent bridge to lung transplantation has been described in a small number of patients with COVID-19 [14] .

Our study adds to the body of knowledge and the literature by providing more granular multiinstitutional data about our cohort of 200 patients with COVID-19 supported with ECMO at 29 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 [4, 5, 6, 7, 8] . Our analysis of the SpecialtyCare SCOPE TM Registry adds another dataset of multi-institutional data to the growing body of literature about the use of ECMO in patients with COVID-19 and demonstrates that support with ECMO facilitates salvage and survival of select critically ill patients with COVID-19.

In our analysis, survival of patients supported with only veno-venous ECMO was 46.3% patients (87 out of 188). Survival in patients requiring veno-arterial ECMO was poor (3 out of 12 = 25%). Our finding of higher survival with veno-venous ECMO in comparison to veno-arterial ECMO in patients with COVID-19 is consistent with the published literature, but is not statistically significant (p=0.255). It is likely that if the extent of end organ damage necessitates veno-arterial ECMO in patients with COVID-19, then the prognosis is poor in comparison to patients with isolated respiratory dysfunction requiring only veno-venous ECMO. Our study also reveals that, not surprisingly, survivors were younger than non-survivors (median age = 47 in survivors versus 56 years in non-survivors, p<0.001). This finding is consistent with the study from Barbaro and colleagues [8] , where patients >40 years of age had an increasing risk of mortality compared to those 16-39 years of age. Our study also reveals that survivors had a shorter median time interval from the diagnosis of COVID-19 to J o u r n a l P r e -p r o o f cannulation for ECMO (8 days versus 12 days, p=0.003). This finding supports earlier consideration for use of ECMO in patients with COVID-19 and severe respiratory failure.

Finally, our study also documents that substantial variation exists in the use of adjunctive therapies in the treatment of COVID-19. The use of these various adjunctive medications and treatments has changed over time as more information has been learned regarding the role and potential success of these medications.

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. Survivors tend to be younger and have a shorter duration from diagnosis to cannulation. Meanwhile, the role of multiple medications in the treatment of COVID-19 remains unclear: none of the adjunct therapies appeared to be associated with survival.

It is a fact that COVID-19 patients have faced challenges with thrombosis, and one third of the patients in this series required at least one circuit change. In the more recent era of our series bivalirudin has been used more commonly; however, the impact of the use of bivalirudin versus heparin needs additional investigation.

Multiple factors support the fact that COVID-19 different than other causes of respiratory failure, such as the flu:

No cause of respiratory failure has ever generated such a large utilization of ECMO in the history of medicine.

No cause of respiratory failure has ever generated this level of concern about the risks to health care providers caring for patients on ECMO.

No cause of respiratory failure has ever placed this level of stress and this amount of resource consumption on the health care system.

Nevertheless, we believe that many of the lessons that have been learned by caring for COVID-19 patients supported with ECMO will likely be applicable to a variety of other etiologies of respiratory failure, now and in the future, as exemplified by the following lessons:

1. Earlier initiation of ECMO for patients with COVID-19 and respiratory failure appears to be associated with better outcomes, and this finding is likely true for other forms of respiratory failure as well.

Prolonged VV ECMO runs allow for the recovery of the native lungs in some patients with COVID-19 and facilitate bridge to lung transplantation in others. The use of such prolonged VV ECMO runs to support adults with respiratory failure is likely to become more common secondary to these valuable lessons learned during the COVID-19 pandemic.

This analysis is based on the available data in our database. Potential limitations include patient selection bias, institutional bias, confounding bias, and potentially 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 centers and patients may benefit.

Our experience and analysis of 200 consecutive patients at 29 hospitals reveal that ECMO facilitates salvage and survival of select critically ill patients with COVID-19. Survivors tend to be younger. Survival of patients supported with only veno-venous ECMO is 46.34% in our cohort.

Survivors had a shorter median time interval from the diagnosis of COVID-19 to cannulation for ECMO, supporting earlier consideration for use of ECMO in patients with COVID-19 and severe respiratory failure. 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. Expansion of studies such as the current analysis presented here will provide a means to further define the role of ECMO in the management of severely compromised patients with COVID-19 and will serve to refine the optimal use of ECMO in these patients, with the goal of continuing to enhance survival. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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