In-hospital and Post-discharge Status in COVID-19 Patients With Acute Respiratory Failure Supported With Extracorporeal Membrane Oxygenation

Abstract

Few data from Latin American centers on clinical outcomes in coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome who required extracorporeal membrane oxygenation (ECMO) are published. Moreover, clinical and functional status after hospital discharge remains poorly explored in these patients. We evaluated in-hospital outcomes of severe COVID-19 patients who received ECMO support in two Brazilian hospitals. In one-third of the survivors, post-acute COVID-19 syndrome (PACS), quality of life, anxiety, depression, and return to work were evaluated. Eighty-five patients were included and in-hospital mortality was 47%. Age >65 years (HR: 4.8; 95% confidence interval [CI]: 1.4–16.4), diabetes (HR: 6.0; 95% CI: 1.8–19.6), ECMO support duration (HR: 1.08; 95% CI: 1.05–1.12) and dialysis initiated after ECMO (HR: 3.4; 95% CI: 1.1–10.8) were independently associated with higher in-hospital mortality and mechanical ventilation (MV) duration before ECMO was not (HR: 1.18; 95% CI: 0.71–2.09). PACS-related symptoms were reported by two-thirds and half of patients at 30- and 90-days post-discharge, respectively. The median EQ-5D score was 0.85 (0.70–1.00) and 0.77 (0.66–1.00) at 30 and 90 days. Of the 15 responders, all previously working patients, except one, have returned to work at 90 days. In conclusion, in-hospital mortality in a large Latin American cohort was comparable to the Global extracorporeal life support organization registry.

Patients with severe coronavirus disease 2019 (COVID-19) infection frequently present acute respiratory distress syndrome (ARDS).¹ In addition to the widely used “protective pulmonary ventilation” strategies, the use of extracorporeal membrane oxygenation (ECMO) support has been recommended for those with refractory hypoxemia and hypercapnia.^2–4 Although early reports indicated a mortality rate above 90% in patients with severe COVID-19 infection undergoing ECMO,⁵ a subsequent study with data from more than 1,000 patients from the extracorporeal life support organization (ELSO) registry showed an estimated 90-day mortality of 38%,⁶ which is in line with previous data for ECMO support in patients with ARDS from other causes.^2,7 In a recent meta-analysis that included nearly 2,000 patients with COVID-19 undergoing ECMO support, mortality was 37%, and patient age and time on ECMO were directly associated with worse outcomes.⁸

In Latina America, however, there is a paucity of data on the outcomes of patients supported with ECMO. Additionally, clinical and functional status, including the magnitude of the post-acute COVID-19 syndrome (PACS), quality of life, anxiety, depression, post-traumatic stress disorder, and working status are largely unexplored in COVID-19 patients’ cohorts.

Therefore, we aim to describe in-hospital clinical outcomes in patients hospitalized with the severe form of COVID-19 who received support with ECMO in two private hospitals in Brazil. We also evaluated the burden of symptoms, functional and mental status, and the return to labor activities 30- and 90 days after hospital discharge. We hypothesized that patients with severe ARDS related to COVID-19 infection who needed ECMO support would have significant impairment in clinical and functional status in the posthospital discharge period.

Methods

Study Design and Oversight

This retrospective cohort study was reviewed by an Institutional Review Board (IRB), approved with a waiver of informed consent at each participating site, and deemed exempt from IRB oversight (Instituto de Ensino e Pesquisa, IEP, Hospital Sírio-Libanês, Sao Paulo, Brazil). The data were analyzed in a secure, anonymized database physically separate from the main production server. All data collected was reviewed by the study team to assure data quality.

Patient Population

We retrospectively studied consecutive hospitalized adult patients at Hospital Sírio-Libanês in Sao Paulo and Brasilia, from April 2020 to August 2021. All patients had a confirmed diagnosis of COVID-19 by the presence of related symptoms and a positive result of a SARS-CoV-2 polymerase chain reaction assay for nasal and pharyngeal swab specimens. All patients with severe ARDS related to COVID-19 infection admitted to the intensive care unit (ICU) that presented refractory hypoxemia despite all clinical and mechanical ventilation strategies and who required ECMO support were included. Figure 1, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A978 depicts the flowchart comprising the overall number of confirmed COVID-19 patients admitted to the hospital during the study period.

Variables and Clinical Outcomes Collected at the Hospital

All participants had their data collected until hospital discharge or in-hospital death. We collected data on demographic characteristics, past medical history, Simplified Acute Physiology Score III (SAPS-3) at the ICU admission day, laboratory examinations, cardiopulmonary arrest or previous infection, therapies used before ECMO cannulation (use of neuromuscular blocking agents [NMBA], inhaled nitric oxide [iNO], prone ventilation, vasopressors, corticosteroids, tocilizumab and convalescent plasma, anticoagulation regimen [therapeutic, prophylactic or intermediate-dose]), data on ventilatory settings and respiratory parameters reported for the ELSO database following the rules of Pre-ECLS Assessment (fraction of inspired oxygen [FiO₂], positive end-expiratory pressure, lung compliance, driving pressure, arterial partial pressure of oxygen [PaO₂], arterial partial pressure of carbon dioxide [PaCO₂], PaO₂/FiO₂ ratio), modality of support (veno-venous or veno-arterial), cannulation site (other hospitals for transfer or at the local hospital), relevant time intervals (symptoms onset to hospital admission, ICU admission, invasive mechanical ventilation [MV] start and ECMO cannulation; hospital and ICU admission to ECMO cannulation; MV start to ECMO cannulation; total ECMO duration; total MV duration; and ICU and hospital length of stay [LOS]), major clinical complications (acute kidney injury; need for dialysis; major bleeding; stroke; ECMO-related complications such as thrombosis, hemolysis, gas embolism, limb ischemia and membrane substitution); and institution where the patient was hospitalized. The definitions of anticoagulation regimen, total MV duration, and ECMO-related complications are described in the supplemental material, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A978.

Variables Collected After Hospital Discharge

The clinical outcomes team prospectively applied a standardized questionnaire by phone calls at 30- and 90 days after hospital discharge for survived patients. Members of this team had no access to in-hospital variables. They evaluated the presence of PACS as defined by the WHO,⁹ including the following symptoms: dyspnea, tiredness, cough, thoracic discomfort, anosmia, dysgeusia, headache, arthralgia, myalgia, and diarrhea at both timeframes. In addition, the following questionnaires were applied: European Quality of Life Five Dimension (EQ-5D),¹⁰ Generalized Anxiety Disorder 2-item (GAD-2),⁹ Patient Health Questionnaire-2 (PHQ-2).^11,12 Post-traumatic stress symptoms and the patient’s return to work were also registered. The complete methodological description of these questionnaires can be accessed in the supplementary material, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A978.

Statistical Analysis

Categorical variables were reported as absolute numbers and percentages and continuous variables as mean and standard deviation or median and interquartile range (IQR). The comparisons between in-hospital survivors and nonsurvivors were performed using chi-square or Fischer’s exact tests for categorical variables and Student’s t-test or Mann-Whitney test for continuous variables, according to their distribution.

Multivariable stepwise Cox proportional hazards regression analysis was performed to explore risk factors associated with in-hospital mortality in time-to-event survival analysis and the proportional hazard assumption was tested by using Schoenfeld residuals. We included pre-ECMO variables (age categorized as > or ≤65 years, sex, arterial hypertension, diabetes, history of coronary artery disease, history of cancer, SAPS-3, PaO₂/FiO₂ ratio, MV duration before ECMO cannulation categorized as > or ≤10 days), clinical complications (dialysis initiation after ECMO cannulation and stroke), and relevant time intervals (total ECMO support duration, time from hospital admission to ECMO cannulation and in-hospital LOS). All analyses were performed with the IBM-SPSS Statistics version 25 (Statistical Package for the Social Sciences, SPSS, Inc, Chicago, IL).

Results

In-hospital Data

Eighty-five COVID-19 critically ill VV-ECMO-supported patients were included during the study period. The mean age was 59 ± 13 years, 36.5% were older than 65 years and 15% were women. Hypertension and obesity were the most common comorbidities and more than 85% of patients had at least one chronic condition. Compared to nonsurvivors, patients who survived were younger, and had a lower Charlson’s Comorbidity Index and a lower SAPS-3 (Table 1). Only two patients (2.4%) initially on VV-ECMO were converted to VA-ECMO.

Table 1. - Baseline Demographic Characteristics, Prevalence of Comorbidities and Prognostic Risk Scores at ICU-admission in the Whole Population, Survivors and Non-survivors

	Total population n = 85	Survivors n = 45	Non-survivors n = 40	p-value
Baseline demographics
Age, mean ± SD, years	59 ± 13	52 ± 11	66 ± 11	<0.001
>65 years, no. (%)	31 (36.5)	5 (11.1)	26 (65.0)	<0.001
>70 years, no. (%)	16 (18.8)	1 (2.2)	15 (37.5)	<0.001
Weight, median (IQR), kg	88 (77–99)	90 (77–101)	86 (74–97)	0.535
BMI, median (IQR), kg/m2	29.4 (25–33)	29.9 (25–34)	28.9 (25–32)	0.613
Female sex, no. (%)	13 (15.3)	9 (20.0)	4 (10.0)	0.240
Comorbidities
Any chronic condition, no. (%)	72 (85.7)	39 (86.7)	33 (84.6)	1.000
Hypertension, no. (%)	44 (52.4)	19 (42.2)	25 (64.1)	0.052
Diabetes, no. (%)	23 (27.4)	9 (20.0)	14 (35.9)	0.142
Dyslipidemia, no. (%)	21 (25.0)	10 (22.2)	11 (28.2)	0.616
Coronary artery disease, no. (%)	9 (10.7)	2 (4.4)	7 (17.9)	0.075
Obesity, no. (%)	35 (41.7)	19 (42.2)	16 (41.0)	1.000
History of cancer, no. (%)	12 (14.3)	4 (8.9)	8 (20.5)	0.210
Prognostic risk scores
SAPS-3, mean, ± SD	54 ± 12	50 ± 10	57 ± 12	0.009
CCI, median (IQR)	2 (1–3)	1 (0–2)	3 (2–4)	<0.001

BMI, body mass index; CCI, Charlson Comorbidity Index; SAPS-3, Simplified Acute Physiology Score III.

As depicted in Table 2, the near totality of patients received NMBA, and 74.1% were submitted to prone position ventilation. More than 40% received rescue therapy with iNO and nearly 90% of patients were on vasopressors before ECMO cannulation. There were no differences in ICU therapies used between survivors and nonsurvivors. (Table 2) As for ventilatory settings and respiratory parameters at the day of ECMO cannulation, compared to nonsurvivors, survivors needed lower FiO₂ and had a higher PaO₂/FiO₂ ratio. The duration of invasive MV before ECMO was the same for survivors and nonsurvivors and the proportion of patients with >10 days and >14 days of invasive MV before ECMO was equal in both groups.

Table 2. - Therapies Used Before ECMO Cannulation and Respiratory Parameters at the Cannulation Day

	Total population n = 85	Survivors n = 45	Non-survivors n = 40	p-value
Therapies before ECMO cannulation	No. pts who received therapy/no. pts with data (%)
Neuromuscular blocking agents	80/82 (97.6)	44/44 (100)	36/38 (94.7)	0.212
Prone position	63/82 (74.1)	36/44 (81.8)	27/38 (71.1)	0.299
Inhaled nitric oxide	38/82 (44.7)	20/45 (44.4)	18/37 (48.6)	0.824
Vasopressors	76/85 (89.4)	39/45 (86.7)	37/40 (92.5)	0.491
Corticosteroids	85/85 (100)	45/45 (100)	40/40 (100)	1.000
Tocilizumab	12/85 (14.1)	7/45 (15.6)	5/40 (12.5)	0.762
Convalescent plasma	9/85 (10.6)	7/45 (15.6)	2/40 (5.0)	0.163
Prophylactic anticoagulation	15/77 (19.5)	8/42 (19.0)	7/35 (20.0)	1.000
Therapeutic anticoagulation	60/77 (77.9)	34/42 (81.0)	26/35 (74.3)	0.588
Intermediate-dose anticoagulation	3/77 (3.5)	1/42 (2.4)	2/35 (5.7)	0.584
Patients transferred on ECMO	22/85 (25.9)	10/45 (22.2)	12/40 (30.0)	0.464
Tracheostomy before ECMO	19/71 (26.8)	7/38 (18.4)	12/33 (36.4)	0.111
Ventilatory settings and respiratory parameters before ECMO cannulation *
	Total n = 64	Survivors n = 35	Non-survivors n = 29	p-value
	No. pts with respiratory parameters available
FiO2, median (IQR), %	80 (65–100)	70 (60–80)	90 (70–100)	0.008
PEEP, median (IQR), mmHg	10 (8–10)	8 (6–10)	10 (8–10)	0.667
Lung compliance, median (IQR), mL/cmH2O)	22 (18–27)	22 (17–27)	23 (19–27)	0.494
Driving pressure, median (IQR), cmH2O	15 (13–15)	15 (13–16)	14 (13–15)	0.625
PaO2/ FiO2 ratio, median (IQR)	100 (81–120)	107 (92–129)	85 (70–113)	0.003
PaCO2, median (IQR) mmHg	68 (57–80)	68 (56–83)	68 (59–77)	0.622
MV duration before ECMO, median (IQR), days	7 (1–14)	6 (1–13)	7 (3–14)	0.210
MV>10 days before ECMO, no. (%)	31 (37.3)	15 (34.1)	16 (41.0)	0.515
MV>14 days before ECMO, no. (%)	18 (21.7)	9 (20.5)	9 (23.1)	0.772

^*data reported for the ELSO database following the rules of Pre-ECLS Assessment.

no. pts, number of patients; FiO₂, fraction of inspired oxygen; PEEP, positive end-expiratory pressure; PaO₂, arterial partial pressure of oxygen; PaCO₂, arterial partial pressure of carbon dioxide; MV, mechanical ventilation; ECMO, extracorporeal membrane oxygenation.

Overall median in-hospital LOS was 58 (39–84) days and compared to nonsurvivors, survivors had a significantly higher in-hospital LOS (62 [51–91] vs. 50 [23–72] days; p = 0.016). Other important time intervals during the clinical course of COVID-19 infection, from symptoms onset until hospital discharge or death are shown in Table 3.

Table 3. - Time Intervals During the Clinical Course of COVID-19 Infection, Since Symptoms Onset Until Hospital Discharge or Death

	Total population n = 85	Survivors n = 45	Non-survivors n = 40	p-value
Symptoms onset - hospital admission, median (IQR), days	8 (5–11)	8 (6–11)	8 (5–11)	0.856
Symptoms onset - ICU admission, median (IQR), days	12 (9–16)	12 (9–15)	12 (9–16)	0.911
Symptoms onset - invasive MV start, median (IQR), days	17 (10–23)	15 (10–23)	17 (11–23)	0.682
Symptoms onset - ECMO, median (IQR), days	25 (21–32)	25 (17–32)	25 (21–34)	0.561
Hospital admission - ECMO, median (IQR), days	17 (10–23)	16 (8–22)	18 (13–32)	0.073
ICU admission - ECMO, median (IQR), days	12 (6–19)	12 (4–17)	13 (7–24)	0.271
ICU admission - ECMO >7 days, no. (%)	51 (65.4)	28 (63.6)	23 (67.3)	0.812
ECMO duration, median (IQR), days	12 (7–18)	10 (8–16)	13 (6–21)	0.724
Total MV duration, median (IQR), days	37 (16–60)	40 (20–59)	37 (14–67)	0.738
ICU LOS, median (IQR), days	39 (23–58)	41 (29–58)	39 (15–61)	0.306
In-hospital LOS, median (IQR), days	58 (39–84)	62 (51–91)	50 (23–72)	0.016

ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; LOS, length of stay; MV, mechanical ventilation; LOS, length of stay.

In-hospital outcomes are depicted in Table 4, with p-values for univariable analysis. Overall in-hospital mortality was 47.1% and 13 nonsurvivors (32.5%) were successfully decannulated from ECMO and stayed alive for at least 48 h after decannulation. None of the patients diagnosed with a stroke during ECMO support survived and only one patient who initiated dialysis after ECMO cannulation survived, an almost 93% in-hospital mortality rate. Fifty-four patients (63.5%) were supported with ECMO during the first COVID-19 wave in Brazil (April/2020 to March/2021) and the remaining during the second COVID-19 wave (April/2021 to August/2021), without any in-hospital mortality difference (48.1% vs. 45.2%, p = 0.791).

Table 4. - In-hospital Outcomes and Clinical Complications

	Total population n = 85	Survivors n = 45	Non-survivors n = 40	p-value
In-hospital death, no. (%)	40 (47.1)
Succcessful decannulation * , no. (%)	59 (69.4)	45 (100)	14 (35.0)	<0.001
Dialysis during hospital stay, no. (%)	30 (35.3)	5 (11.1)	25 (62.5)	<0.001
Dialysis initiation after ECMO, no. (%)	14 (16.5)	1 (2.2)	13 (32.5)	<0.001
Stroke, no. (%)	7 (8.2)	0 (0)	7 (17.5)	0.004
Major bleeding, no. (%)	19 (22.4)	8 (17.8)	11 (27.5)	0.309
Thrombosis, no. (%)	12 (14.3)	7 (15.6)	5 (12.8)	0.765
Hemolysis, no. (%)	6 (7.1)	1 (2.2)	5 (12.5)	0.095
Gas embolism, no. (%)	5 (5.9)	3 (6.7)	2 (5.0)	1.000
Limb ischemia, no. (%)	0 (0)	0 (0)	0 (0)	-
Membrane substitution, no. (%)	3 (3.5)	0 (0)	3 (7.5)	0.100
ECMO modality change, no. (%)	2 (2.4)	0 (0)	2 (5.0)	0.218

^*Patients who were successfully decannulated from ECMO and stayed alive for at least 48h after decannulation.

ECMO, extracorporeal membrane oxygenation.

The association of relevant demographic characteristics, clinical features, respiratory parameters previous to ECMO cannulation, important time intervals and clinical complications during ECMO support with in-hospital mortality evaluated by Cox proportional hazards regression analysis is shown in Table 5. After multivariable stepwise adjustments including all relevant predictors, age >65 years, diabetes, the duration of ECMO support and dialysis initiated after ECMO remained significantly associated with higher in-hospital mortality.

Table 5. - Univariable and Multivariable Stepwise Cox Proportional Hazards Regression Analysis With Predictors Associated With In-Hospital Death

	Univariable analysis			Multivariable analysis
	HR	95% CI	p-value	HR	95% CI	p-value
Age >65 years	3.12	1.63–5.98	0.001	4.8	1.4–16.4	0.012
Diabetes	1.68	0.86–3.27	0.127	6.0	1.8–19.6	0.003
ECMO duration (days)	1.01	1.00–1.02	0.053	1.08	1.05–1.12	0.001
Dialysis started after ECMO cannulation	3.21	1.63–6.32	0.001	3.4	1.1–10.8	0.039
Male sex	1.24	0.43–3.56	0.686	0.93	0.15–5.9	0.934
Hypertension	1.98	1.02–3.82	0.043	1.04	0.29–3.80	0.949
Coronary artery disease	3.38	1.43–7.98	0.005	2.57	0.57–11.6	0.220
History of cancer	2.06	0.94–4.51	0.071	0.31	0.05–1.88	0.200
SAPS3	1.03	1.01–1.06	0.015	1.00	0.93–1.07	0.937
PaO2/FiO2 ratio	0.98	0.97–0.99	0.005	0.99	0.97–1.01	0.186
MV >10 days before ECMO	1.18	0.62–2.23	0.618	0.38	0.71–2.09	0.268
Hospital Admission to ECMO cannulation (days)	1.02	1.00–1.05	0.087	0.98	0.92–1.05	0.551
Stroke during ECMO	1.05	0.46–2.45	0.902	5.73	0.18–181.0	0.322
Hospital LOS (days)	1.00	0.99–1.01	0.821	1.02	1.00–1.04	0.118

ECMO, extracorporeal membrane oxygenation; FiO₂, fraction of inspired oxygen; LOS, length of stay; MV, mechanical ventilation; PaO₂, arterial partial pressure of oxygen; SAPS-3, Simplified Acute Physiology Score III.

MV duration before ECMO cannulation was not associated with higher in-hospital mortality, not as a continuous variable (unadjusted: p = 0.230), nor when categorized as greater than or ≤10 days (unadjusted p = 0.618) or greater than or ≤14 days (unadjusted p = 0.564, Table 2). Even after multivariable-adjusted analysis, MV duration before ECMO did not show any association with in-hospital mortality (Table 5).

Post-discharge Data

From the 45 survivors, 15 (33%) responded to both 30- and 90-day post-discharge structured questionnaires. Except for a higher proportion of diabetes in the responders, there were no other differences in clinical features between responders and nonresponders (Table 1S, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A978). Around two-thirds and half of the responders reported the persistence of at least one symptom at the 30- and 90-day landmark, respectively. The median EQ-5D score reported was 0.85 (0.70–1.00) and 0.77 (0.66–1.00) at 30 and 90 days, respectively (p-value of 0.463). The median EQ visual analog scale (EQ VAS) was 80 (70–90) at both time points, p = 0.653. Only one patient scored at least 3 points in the PHQ-2 score at 90 days, suggesting a major depressive disorder and one patient scored 6 points in the GAD-2, compatible with generalized anxiety disorder. No post-traumatic stress disorder symptoms were reported.

From the 15 responders, four were not working before hospitalization, five returned to work without restrictions 30 days after hospital discharge, one returned with some restriction and five have not returned. At 90 days post-discharge, all previously working patients, except one, have returned to their labor activities.

Discussion

Our study described demographic aspects and clinical features, exploring their association with in-hospital outcomes in 85 ECMO-supported patients with severe ARDS related to COVID-19 infection, who were treated in two private hospitals in Brazil. Although the ELSO Registry Dashboard reports over 13,000 ECMO-supported COVID-19 adult patients worldwide, less than 900 of these reports come from Latin American ECMO centers.¹³ In 2021, Diaz et al.¹⁴ published the most relevant study with COVID-19 patients supported with ECMO in a Latin American country, a nationwide study with 85 patients treated in Chile. The population’s median age was 48 (41–55) years and the 90-day mortality of 38.8% was comparable to previous reports. In our study, overall in-hospital mortality was 47.1%, similar to that reported by the ELSO global registry.¹³ However, we should notice that our patients were older and 85.7% of them had at least one previous chronic condition, features strongly associated with poor outcomes in severe forms of COVID-19.¹⁵ The median age in our cohort was 59 (47–69) years, more than 10 years higher compared to the ELSO registry and similar to a nationwide German cohort that reported a 73% in-hospital mortality.¹⁶

Thirty patients (35.3%) received dialysis during their hospital stay and from the 14 patients (16.5%) who initiated dialysis after ECMO cannulation, only one survived. This strikingly high (nearly 93%) in-hospital mortality rate associated with dialysis initiated after ECMO support initiation should be further evaluated in other databases, but a possible explanation could be that the patients who evolve with kidney failure after ECMO cannulation probably have other organs’ dysfunctions in progress and therefore are at higher mortality risk. And since starting hemodialysis in an ECMO-supported patient is a relatively simple procedure, the ICU teams could have been more permissive on the indication for dialysis therapy. Seven patients presented intracranial hemorrhage, most of them within the first 2 days after ECMO cannulation, and none survived. The poor prognosis of patients with hemorrhagic stroke was also described in two case series reports.^17,18

We also explored the time interval between invasive MV initiation and ECMO cannulation, as this was postulated as an absolute contraindication to ECMO in COVID-19 patients by previously published ELSO guidelines and still remains a potential additional contraindication in the most recent 2021 update version¹⁹ based on a non-COVID patient study.²⁰ In our study, the median invasive MV duration before ECMO cannulation was 7 (1–14) days, much higher than the 3 days reported by the ELSO registry, but similar to a recent publication by Hermann et al.,²¹ who specifically addressed this issue. In our study, this time interval was not associated with higher in-hospital mortality, nor as a continuous variable, nor when categorized as >10 days or >14 days. Even after multivariable-adjusted analysis, invasive MV duration before ECMO did not show any association with in-hospital mortality. This finding has also been recently described by other authors^21–23 and perhaps further updates in ELSO guidelines should re-evaluate the pertinence of invasive MV duration previous to ECMO cannulation as a contraindication in COVID-19 patients.

In our cohort, age >65 years, diabetes, ECMO duration, and hemodialysis initiated during ECMO remained independently associated with higher in-hospital mortality in a time-to-event multivariable analysis. The first three risk factors have been already associated with higher mortality in other studies and are mainly nonmodifiable ones, except for the fact that we could eventually improve our guidelines on parameters for earlier decannulation. However, hemodialysis initiated after ECMO cannulation should be further evaluated in other databases because if this data comes to be confirmed, we should rediscuss and reconsider the indication for dialytic therapy in these patients.

As an exploratory analysis, we also evaluated short-term post-discharge clinical and functional status in one-third of the patients who survived. A major limitation of this analysis is the high rate of missing data. Brazil is a continental-dimension country and since patients from many different parts of the country were medically assisted in our hospitals, the post-discharge contact with these patients became a great challenge. We, however, compared the survivors who responded to the post-discharge questionnaires with the ones that did not regarding every risk factor that could possibly suggest that these patients’ populations were somehow different and that contacting those patients who did not responded would lead us to a completely different result. Except for a higher proportion of diabetes in the responders, there were no other differences in clinical features between responders and non-responders (Table 1S, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A978). Knowing this important limitation, but since, to the best of our knowledge, very few studies evaluated PACS-related symptoms, mood disorders, QoL, and working status in COVID-19 ECMO-supported patients, the results on postdischarge data are briefly discussed.

Besides a high prevalence of PACS-related symptoms, patients had good QoL scores, anxiety disorder, and depression were rare and most patients have returned to their labor activities. In one of the few studies which evaluated some of these important issues, from 10 patients assessed, 40% screened positive for depression, 60% for anxiety, 40% for post-traumatic stress disorder and only 50% have returned to work after 1 year. However, PACS and QoL were not assessed by the authors. In our study, contrary to our hypothesis, anxiety, depression, and post-traumatic stress disorder symptoms were rare.²⁴ These differences may be related to distinct follow-up periods, but further studies are warranted.

QoL scores in our study were very similar to reports on non-COVID-19 ECMO-supported,^7,25–27 and severe COVID-19 non-ECMO-supported patients.²⁸ The CESAR trial⁷ showed comparable EQ VAS scores in ECMO and non-ECMO-supported patients at 6 months and Wang et al²⁶ reported a mean EQ VAS of 81.5 in ECMO and 79.1 in non-ECMO-supported Chinese patients after 1 year. Regarding QoL assessment in patients with severe COVID-19, McPeake et al²⁸ reported an EQ VAS of 70 in 93 Scotland patients. In this cohort, no significant differences in QoL scores were found between COVID-19 and non-COVID-19 patients in a propensity score-matched analysis. Finally, similar to an EQ VAS of 80 reported in our study, Fernandes et al²⁹ reported a median EQ VAS of 75 at 30- and 90-days post-discharge from 45 Portuguese patients with severe COVID-19 who survived (6 of them were supported with ECMO). All these data suggest that the use of ECMO itself does not seem to have an additional impact on reducing QoL. Although no post-traumatic stress disorder symptoms were reported, we must recognize the limitation that we did not use any specific validated questionnaire for the defined diagnosis, and the questions made for this evaluation had only a screening purpose.

In terms of working status, there is scarce data and a wide variation regarding return to work in ECMO-supported patients, ranging from 26 to 80% in different periods of follow-up.^24,25,30,31 In our study, 91% of previously working patients have returned to work at 90 days post-discharge. This can suggest that in COVID-19 patients, the need for ECMO support does not seem to have a high detrimental effect on returning to labor activities, but more data is needed to preclude more assertive conclusions.

Strengths and Limitations

The present study has strengths and limitations to be addressed. Noteworthy in our study is that, although an apparently small sample size, it represents almost 10% of all Latin America’s ELSO-reported cases of ECMO support in COVID-19 patients. Moreover, the post-discharge QoL, clinical, and functional status assessment in this population is hardly found in the literature. On the other side, there is a major limitation in relation to missing data, mainly related to the postdischarge evaluation, but also noteworthy in ventilatory parameters before ECMO cannulation. The 25% of patients with missing respiratory settings before ECMO support is very close to the number of patients who were cannulated outside our hospital and transferred on ECMO. Brazil is a continental-dimension country with many disparities regarding the health care system and the fact that most patients transferred on ECMO came from states and hospitals with very limited resources and poor medical records explains the reason of these missing data. As for the postdischarge evaluation, missing data is even greater, because only one-third of the survivors responded to both the 30- and 90-day questionnaires. This definitely precludes the possibility of any conclusion, even after evaluation of all relevant risk factors which has shown no significant differences between responders and nonresponders. Also worth mentioning, there are great disparities regarding the quality of care between the public and private health systems in Brazil, limiting the generalizability of these data even within our own country. We also faced significant challenges related to postdischarge evaluations, since many patients came from other cities/states making contact not feasible for a high proportion of patients. Finally, since the systematic evaluation of mental disorders was performed only 30- and 90 days post-discharge, it is unclear whether mood disorders were preexisting or a new-onset condition.

Conclusions

Our study described the results from a large Latin American COVID-19 ECMO-supported patients’ cohort showing comparable in-hospital mortality with the ELSO International registry. However, age >65 years, diabetes, and ECMO duration were found as independent predictors of in-hospital mortality as in other previous studies, our data suggest that dialysis initiated after ECMO cannulation could also be associated with worse outcomes and should be further evaluated in other databases, as no previous publication has addressed this matter. Our data on MV duration before ECMO cannulation reinforces recent publications and should prompt a discussion about whether this feature should remain as a contraindication within the ELSO guidelines. All post-discharge data should be viewed and interpreted with caution, knowing that missing data is a major limiting factor.