key: cord-0770088-amyb7s03
authors: Haroun, Magued W.; Patel, Snehal R.; Sims, Daniel; Jorde, Ulrich P.; Goldstein, Daniel J.; Saeed, Omar
title: Characteristics and Outcomes of COVID-19 Patients Supported by Venoarterial or Veno-Arterial-Venous Extracorporeal Membrane Oxygenation
date: 2022-02-04
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2022.01.049
sha: e11043226221156c6eee384c9a4f67b7cb9c7f9c
doc_id: 770088
cord_uid: amyb7s03

Objectives Cardiac injury has been reported in up to 20-30% of COVID-19 patients and severe disease can lead to cardiopulmonary failure. The role of mechanical circulatory support in these cases remains undetermined. We aimed to determine characteristics and outcomes of patients with COVID-19 requiring venoarterial extracorporeal membrane oxygenation (VA-ECMO) or veno-arterial-venous (VAV) ECMO support. Design and Setting A multicenter, retrospective case series. Participants The cohort consisted of adult patients (18 years of age and older) with confirmed COVID-19 requiring VA- or VAV-ECMO support in the period from March 1, 2020 to April 30, 2021. Outcomes were recorded until July 31, 2021. Measurements and Main Results To show factors related to death during hospitalization, patients were grouped as survivors and non-survivors. Kaplan Meier analysis was used to estimate 90-day in-hospital mortality. Overall, 37 patients from 12 centers comprised the study cohort. Patients were 44 (IQR, 35-52) years old, 12 (32%) were female. Duration of ECMO support ranged from 2 to 132 days. At the end of the follow-up period, 13 patients (35%) were discharged or transferred alive, and 24 patients (65%) died during the hospitalization. The cumulative in-hospital mortality at 90-days was 64% (95% CI: 47-81). Time from intubation to VA- or VAV-ECMO initiation (1 IQR 0-7.5 vs. 6 IQR 2.5-14 days, p=0.0383), body mass index (32 IQR 26-36 vs. 37 IQR 33-40, p=0.009) and baseline C-reactive protein (7.15 vs. 38.9 mg/dL, p=0.009) were higher in those that expired. Conclusions Only one-third of the patients with COVID-19 requiring VA- or VAV-ECMO survived to discharge. Close monitoring of at-risk patients with early initiation of ECMO with circulatory support may further improve outcomes.

Coronavirus disease 2019 continues to pose an overwhelming global healthcare challenge with more than 4.5 million deaths attributed to the pandemic worldwide to date. [1] Cardiac injury has been reported in up to 20-30% of COVID-19 patients and severe disease can lead to cardiopulmonary failure. [2] The role of mechanical circulatory support in these cases remains undetermined.

The use of extracorporeal membrane oxygenation (ECMO) has been reported predominately for refractory pulmonary failure from COVID-19 with estimates of 90-day mortality ranging from 37-46%. [3] [4] [5] While these studies show that ECMO use during COVID-19 is promising, its role in cardiopulmonary failure remains largely unknown. In such reports, the proportion of patients receiving venoarterial or veno-arterial-venous extracorporeal membrane oxygenation (VA-or VAV-ECMO) for combined heart and lung failure was only about 4-6% and reports focusing only on VA-ECMO use during COVID-19 are scarce. [6] [7] [8] Proponents of VA-ECMO use propose that early initiation for refractory cardiogenic shock in appropriately selected patients can lead to favorable outcomes. [9] [10] Appropriate patients tend to be younger and have fewer co-morbidities. [10] On the other hand, VA-ECMO support is extremely resource intensive and many COVID-19 patients can have multi-organ dysfunction arguing against VA-ECMO use. [11] Accordingly, we performed a multicenter study to determine the characteristics, outcomes and clinical factors associated with death during hospitalization in patients with COVID-19 supported with VA-or VAV-ECMO.

This study is a multicenter, retrospective case series of patients aged 18 years and older, with COVID-19 confirmed with a positive real-time reverse transcriptase polymerase chain reaction assay, who received VA-or VAV-ECMO support anytime between March 1, 2020, and April 30, 2021. Patients were divided into those that survived to transfer/discharge and those that did not survive the hospitalization.

Investigators at the data coordination site at Montefiore Medical Center invited centers for participation by directly contacting surgical directors of mechanical circulatory programs. A data use agreement was mutually agreed upon between every participating center and the data coordinating institution at Montefiore Medical Center, Albert Einstein College of Medicine. The study was approved by the institutional review board at all the participating centers and informed consent was waived. Institutional review board approval was granted on April 5, 2020, under protocol number 2020-11375. A data capture tool was created using Research Electronic Data Capture (REDCap) for record entry by the participating centers. Data fields included demographic characteristics, laboratory parameters, ECMO characteristics, and patient outcomes. All data were anonymized. Before data entry, sites were individually familiarized with the data capture tool and consistency was ensured by continuous technical support provided by the corresponding author at the data coordination center throughout the data collection period. To maintain accuracy, the data capture fields contained checks for validity such as input masks and range rules for date fields and branching logic. Data consistency was maintained through built-in drop boxes with standardized responses. Records were manually inspected for data entry errors, such as those in date temporality, by the data coordination center and rectified by sites before analysis.

Follow up began at the time of ECMO placement and was completed until the time of discharge/transfer or in-hospital mortality. In-hospital follow up was until July 30, 2021. We used Kaplan-Meier curves to estimate the probability of in-hospital mortality at 90-days after ECMO placement. Patients were not censored at the time of any changes in ECMO configuration and retained their initial group classification to adhere to principles of original treatment intention. Additional outcomes that were reported include the development of secondary infections, deep venous thrombosis, stroke, limb ischemia and renal failure requiring dialysis after ECMO placement. Causes of death during hospitalization were also reported.

Continuous data are reported as medians and interquartile ranges (IQR) and categorical data are shown as counts and percentages. Mann-Whitney and chi-square tests were used to assess significant differences in quantitative and categorical variables, respectively. No data were imputed. Stata version 16 (Stata Corp, LLC, College Station, Texas) was used for all statistical analyses.

The study cohort included 37 patients from 12 centers who were supported by VA-or VAV-ECMO during the study period. The median age was 44 years old (IQR, 35-52) and 32% were female. Within the cohort, median body mass index (BMI) was 36 (IQR, 31-38). Twenty-five (68%) patients had pre-existing conditions with 12 (32%) having hypertension and 11 (30%) with diabetes mellitus. Twenty-five (68%) were transferred from another center for ECMO placement and 11 (30%) were supported by ECMO after having received cardiopulmonary resuscitation previously during admission. Eighteen patients (49%) had echocardiogram performed prior to ECMO placement; nine (50%) of whom had a left ventricular ejection fraction under 40%. Fourteen patients (38%) were not proned prior to ECMO in our cohort. Of those, 11 were also on vasopressors and presumptively were not proned due to hemodynamic instability. In our cohort, the median time from intubation to initiation of any ECMO modality was 1 day (IQR, 0-5 days) whereas the median time from intubation to VA-or VAV-ECMO was 6 days (IQR, 1-11 days). Duration of ECMO support ranged from 2 to 132 days. Inflammatory markers including ferritin (1024; IQR, 685-2270 ng/mL), C-reactive protein (14.7; IQR, 4.9-88.8 mg/dL), d-dimer (6.1; IQR, 3.5-1112 mg/mL), and lactate dehydrogenase (744; IQR, 316-1317 U/L) were highly elevated before ECMO placement.

By the end of the follow-up period, 24 (65%) had died during the hospitalization and 13 (35%) were discharged or transferred alive. The probability of death during hospitalization at 90-days was 64% (95% CI: 47-81%) (Figure 1) . Table 1 shows a comparison of the differences in baseline demographic characteristics and laboratory parameters of patients who died and those who were discharged or transferred. Patients that expired had higher BMI (37; IQR: 33-40 vs. 32; IQR 26-36, p=0.009), higher baseline C-reactive protein (38.9 vs. 7.15 mg/dL, p=0.009) and longer time from intubation to VA-or VAV-ECMO initiation (6; IQR: 2.5-14 vs. 1; IQR:0-7.5 days, p=0.038).

The most common causes of death were multiorgan failure (8; 33%), cardiac failure (4; 17%), and respiratory failure (2; 8%). For patients who were discharged or transferred alive, 6 (46%) were discharged to a rehabilitation facility, 5 (38%) were transported to another healthcare facility such as long-term acute care or a lower-acuity hospital and only 2 (15%) were discharged to home (Table 2) .

Seventeen (46%) patients were initially cannulated as venovenous (VV-ECMO), 15 (41%) as VA-ECMO and 5 (14%) as VAV-ECMO. Fourteen patients (38%) were eventually switched to VAV-ECMO (Figure 2 ). Patients receiving VA-ECMO support had a mortality rate of 61% while those placed on VAV-ECMO had a mortality rate of 68%. Patients switched from VV-ECMO to VA-or VAV-ECMO had mortality of 82% whereas patients supported by VA-or VAV-ECMO only or switched from VA-or VAV-ECMO to VV-ECMO had mortality of 46% and 57% respectively.

The most common location in the hospital for cannulation was at bedside or in the intensive care unit procedure room (19, 51%), followed by the operating room (14, 38%). Heparin was used for anticoagulation in 27 (73%), argatroban in 5 (14%), and bivalirudin in 5 (14%) cases.

Secondary infections were common and occurred in almost half of the patients (46%). Of these infections, bacteremia (11, 30%) and bacterial pneumonia (10, 27%) occurred most often, followed by urinary tract infections (3, 8%). Deep venous thrombosis was noted in 5 (14%) patients. Hemorrhagic stroke occurred in 3 (8%) and ischemic stroke was noted in 2 (5%) patients. Renal replacement therapy was required in 19 (51%) patients. A lower proportion of survivors required renal replacement therapy (23% vs. 67%, p=0.017). Bleeding requiring transfusion was noted in 24 (65%) patients.

The major findings of this multicenter case series of patients with COVID-19 requiring VA-or VAV-ECMO support are as follows: 1) in-hospital mortality is elevated at nearly 65%, 2) switching from VV-to VA-or VAV-ECMO is associated with the highest mortality and 3) patients that expired were placed on VA-or VAV-ECMO at later time from intubation in comparison to those that survived. Those that survived incurred significant morbidity as only a minority were able to be discharged directly to home.

This report informs that patients with COVID-19 requiring ECMO for circulatory support have a significantly higher 90-day in-hospital mortality of 64% in comparison to 37-46% reported in studies with nearly all patients requiring VV-ECMO for respiratory support. [ 

Although our study lacks a contemporary non-COVID-19 group, prior observational studies in non-COVID-19 patients with myocarditis requiring VA-ECMO have reported lower mortality.

In a meta-analysis of 170 patients, Cheng et al. reported a pooled mortality of 33%, with similar age and sex distributions as those patients within our case series. [15] The indication for VA-ECMO in those studies however was to primarily provide circulatory support whereas COVID-19 patients usually require both respiratory and circulatory support given the primary pulmonary pathophysiology of the disease. Due to lack of invasive hemodynamic monitoring and absence of echocardiograms in most cases, the exact etiology of hemodynamic decompensation in our cohort could not be precisely determined and could be cardiogenic, sepsis, vasoplegia or mixed shock. Notwithstanding additional clinical confounders and patient selection, it is essential to identify methods to reduce mortality in patients with COVID-19 requiring VA-ECMO.

A subgroup of patients that were switched to VA or VAV-ECMO incurred higher mortality than those placed on circulatory support at the onset. Due to limits of data collection, we cannot determine if such patients developed cardiac failure after placement of VV-ECMO or whether there was unrecognized cardiac dysfunction which eventually declared itself and necessitated mechanical circulatory support. Regardless, the higher mortality of this subgroup, indicates that baseline risk stratification of impending cardiac failure with echocardiographic and if needed invasive hemodynamics is critical and may identify appropriate candidates for early arterial cannulation. This is further underscored with survivors showing a lower time to VA or VAV-ECMO in comparison to non-survivors.

Patients that expired were noted to have a higher CRP and higher BMI than patients who survived. While obesity has not been shown to be a negative prognostic factor in cardiogenic shock requiring VA-ECMO, this finding is consistent with literature showing obesity to be associated with increased risk of death from COVID-19 in adults younger than 65 years. [16] [17] Higher CRP has also been associated with mortality in COVID-19 patients. [18] [19] Hematologic and neurologic disturbances occur with both COVID-19 and VA-ECMO.

[20][21] [22] We noted a numerically higher burden of these adverse events during device support in comparison to prior studies of non-COVID-19 patients. The observed prevalence of bleeding (65%) and stroke (13%) were numerically higher in this series of patients in comparison to reported rates of 40% and 6% during VA-ECMO in non-COVID-19 patients, respectively. [22] This elevated burden of adverse events may have also contributed to greater mortality during ECMO support.

There are several limitations in our study. First, our sample size was small. Second, the retrospective study design and the lack of a control non-COVID-19 group limits the interpretation of the findings. Third, outcomes from centers that participated in this study might not be reflective of those from institutions with different resource availability. There were no prespecified criteria for ECMO placement and the decision to initiate mechanical circulatory support was institution specific. Despite these limitations, the study sheds light on a relatively understudied and extremely resource intensive treatment modality in this pandemic.

In conclusion, this report shows that only one-third of patients with COVID-19 that received VA-or VAV-ECMO survived. Methods to improve outcomes may involve close monitoring of at-risk patients with tenuous cardiac function with early initiation of ECMO with circulatory support in appropriate cases.

O.S. is supported by the National Institutes of Health/National Heart, Lung and Blood Institute (K23HL145140). Percentages represent the proportion of reported observations. Continuous variables are displayed as median (IQR). ECMO, Extracorporeal membrane oxygenation; BMI, body mass index; CPR, cardiopulmonary resuscitation; PaO2/FiO2, partial pressure of oxygen/fraction of inspired oxygen; PaCO2, partial pressure of carbon dioxide. Blood gas parameters were measured before ECMO placement; VA, venoarterial, VAV, veno-arterial-venous; *reported in thirty-two cases.

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