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Extracorporeal membrane oxygenation for respiratory failure in phases of COVID‐19 variants

Abstract Background Adaptive mutations of the severe acute respiratory syndrome‐related coronavirus (SARS‐CoV‐2) virus have emerged throughout the coronavirus disease 2019 (COVID‐19) pandemic. The characterization of outcomes in patients requiring extracorporeal membrane oxygenation (ECMO) for severe respiratory distress from COVID‐19 during the peak prevalence of different variants is not well known. Methods There were 131 patients with laboratory‐confirmed SARS‐CoV‐2 infection supported by ECMO at two referral centers within a large healthcare system. Three predominant variant phase time windows (Pre‐Alpha, Alpha, and Delta) were determined by a change‐point analyzer based on random population sampling and viral genome sequencing. Patient demographics and outcomes were compared. Results The average age of patients was 46.9 ± 10.5 years and 70.2% (92/131) were male. Patients cannulated for ECMO during the Delta variant wave were younger compared to earlier Pre‐Alpha (39.3 ± 7.8 vs. 48.0 ± 11.1 years) and Alpha phases (39.3 ± 7.8 vs. 47.2 ± 7.7 years) (p < .01). The predominantly affected race in the Pre‐Alpha phase was Hispanic (52.2%; 47/90), while in Alpha (61.5%; 16/26) and Delta (40%; 6/15) variant waves, most patients were White (p < .01). Most patients received a tracheostomy (82.4%; 108/131) with a trend toward early intervention in later phases compared to Pre‐Alpha (p < .01). There was no significant difference between the duration of ECMO, mechanical support, intensive care unit (ICU) length of stay (LOS), or hospital LOS over the three variant phases. The in‐hospital mortality was overall 41.5% (54/131) and was also similar. Six‐month survival of patients who survived to discharge was 92.2% (71/77). Conclusions There was no significant difference in survival or time on ECMO support in patients during the peak prevalence of the three variants.

Alpha, Beta, Gamma, and Delta. 1,2 A recent meta-analysis found that Beta and Delta variants are associated with a higher risk of hospitalization, ICU admission, and mortality, with the Delta variant having the highest relative risk of severe illness and mortality. 3 The use of extracorporeal membrane oxygenation (ECMO) for patients with severe acute respiratory distress syndrome (ARDS) from COVID-19 who have failed conventional mechanical ventilatory strategies has been described in multiple studies throughout the course of the pandemic. [4][5][6][7][8][9][10][11] Besides limited reports in Europe that have described conflicting trends of patient outcomes on ECMO for COVID-19 ARDS over the course of the pandemic, [12][13][14] little is known about the characteristics or trends between the eras of SARS-CoV-2 variants at their peak prevalence in the United States. The goal of this study is to describe the outcomes of patients who were placed on ECMO for severe COVID-19 during different variants phases within a single healthcare system.

| Study design
We conducted a retrospective analysis of 131 patients with laboratory-confirmed COVID-19, all of whom were placed on ECMO between April 2020 to November 2021 at two referral centers within a single healthcare system for severe respiratory failure refractory to conventional mechanical ventilatory strategies. Patients still on ECMO at the time of this study were excluded. Patients were further categorized into three predominant variant phases (Pre-Alpha, Alpha, and Delta) based on the date of their first positive COVID-19 test. For the purposes of this study, Pre-Alpha will be defined as viral lineages that were not classified by the WHO as a distinct variant of interest or concern.
Alpha is defined as the B. or concern were present in small proportions as represented in the Supporting Information: Figure. The study was approved by the Institutional Review Board and the requirement for informed consent was waived due to the retrospective nature of this study.

| Outcomes
The in-hospital mortality was overall 41.5% (54/131) and similar between all three variant phases. Six-month survival of patients who were discharged alive to the last follow-up was 92.2% (71/77) ( Figure 1). This was similar between all three groups ( Figure 2

| COMMENT
Two years ago, our center published its early ECMO experience in the COVID-19 ARDS patient population. 10 The pandemic has continued to progress with the evolution of adaptive mutations in the SARS-CoV-2 virus. This study serves as an update to our previous report and contributes to the growing body of evidence in this specific indication for ECMO. We present the outcomes of patients with severe COVID-19 ARDS requiring ECMO support during time frames of different variants of SARS-CoV-2 at their peak prevalence.
There was no significant difference in duration of ECLS or in-hospital mortality within the Pre-Alpha, Alpha, and Delta variant waves; however, patients placed on ECMO were younger in the more recent phases and were more likely to be of White ethnicity. The most recent emergence of the Omicron variant is a sobering reminder of the continued challenges we face with the pandemic. Therefore, the continued evaluation of COVID-19 outcomes remains relevant.
During the initial phase of the pandemic, the genomic diversity of SARS-CoV-2 was reportedly low. 16 In December of 2020, the alpha variant was first detected in the United Kingdom. 17 Preliminary data suggested that this variant was more transmissible than previous variants. 18 The delta variant was designated a variant of concern by the WHO in May 2021. 17 Studies characterizing the clinical implications of this variant remain sparse. A large cohort study from a national database in England showed that compared to alpha, the delta variant was associated with an increased relative risk of hospitalization compared to the alpha variant. 22 Another study based on national surveillance data in Singapore similarly found that the delta variant was associated with increased severity of COVID-19 infection and higher viral load. 23

| Limitations
This study is subject to all limitations inherent to any retrospective observational study. In addition, our study is limited to a single healthcare system, so the generalizability of this data is unknown. As the pandemic progressed, the management of COVID-19 has evolved. Importantly, the cohort size within the three variant phases is variable, with this study being performed at the tail end of the delta wave. There are significantly fewer patients in the alpha and delta wave with significant variances in outcomes making it difficult to conclude that the results are not influenced by the small sample size.
Several patients in our system who were cannulated during the delta predominant phase remained on ECMO and were excluded from this study. Further studies at later time points will be needed to capture complete data throughout the entire time period of delta variant predominance as well as extend the surveillance period into the predominant Omicron phase. Finally, the viral strain of SARS-CoV-2 that patients were affected by is not exactly known as genomic testing was not performed on all patients included in our cohort.
Rather, our study is based on the likelihood of patients being affected by a particular strain based on the correlation of their first positive COVID-19 test to the most prevalent viral lineage at the time based on random population sampling.