Extracorporeal Membrane Oxygenation for COVID-19

A Systematic Review and Meta-Analysis

Kollengode Ramanathan; Kiran Shekar; Ryan Ruiyang Ling; Ryan P. Barbaro; Suei Nee Wong; Chuen Seng Tan; Bram Rochwerg; Shannon M. Fernando; Shinhiro Takeda; Graeme MacLaren; Eddy Fan; Daniel Brodie

Disclosures

Crit Care. 2021;25(211)

Abstract and Introduction

Abstract

Background: There are several reports of extracorporeal membrane oxygenation (ECMO) use in patients with coronavirus disease 2019 (COVID-19) who develop severe acute respiratory distress syndrome (ARDS). We conducted a systematic review and meta-analysis to guide clinical decision-making and future research.

Methods: We searched MEDLINE, Embase, Cochrane and Scopus databases from 1 December 2019 to 10 January 2021 for observational studies or randomised clinical trials examining ECMO in adults with COVID-19 ARDS. We performed random-effects meta-analyses and meta-regression, assessed risk of bias using the Joanna Briggs Institute checklist and rated the certainty of evidence using the GRADE approach. Survival outcomes were presented as pooled proportions while continuous outcomes were presented as pooled means, both with corresponding 95% confidence intervals [CIs]. The primary outcome was in-hospital mortality. Secondary outcomes were duration of ECMO therapy and mechanical ventilation, weaning rate from ECMO and complications during ECMO.

Results: We included twenty-two observational studies with 1896 patients in the meta-analysis. Venovenous ECMO was the predominant mode used (98.6%). The pooled in-hospital mortality in COVID-19 patients (22 studies, 1896 patients) supported with ECMO was 37.1% (95% CI 32.3–42.0%, high certainty). Pooled mortality in the venovenous ECMO group was 35.7% (95% CI 30.7–40.7%, high certainty). Meta-regression found that age and ECMO duration were associated with increased mortality. Duration of ECMO support (18 studies, 1844 patients) was 15.1 days (95% CI 13.4–18.7). Weaning from ECMO (17 studies, 1412 patients) was accomplished in 67.6% (95% CI 50.5–82.7%) of patients. There were a total of 1583 ECMO complications reported (18 studies, 1721 patients) and renal complications were the most common.

Conclusion: The majority of patients received venovenous ECMO support for COVID-19-related ARDS. In-hospital mortality in patients receiving ECMO support for COVID-19 was 37.1% during the first year of the pandemic, similar to those with non-COVID-19-related ARDS. Increasing age was a risk factor for death. Venovenous ECMO appears to be an effective intervention in selected patients with COVID-19-related ARDS.

PROSPERO CRD42020192627.

Introduction

The use of extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) during outbreaks of emerging infections was previously reported during the 2009 influenza A(H1N1) pandemic, as well as the Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks.^[1–4] More recently, there are reports on the use of ECMO in patients with coronavirus disease 2019 (COVID-19), who develop severe ARDS.^[5,6] The Extracorporeal Life Support Organisation (ELSO), the World Health Organization and the Surviving Sepsis Campaign (SSC) Guidelines recommend considering ECMO, in specialised centres, for patients with COVID-19 who develop severe ARDS. In addition, venovenous (VV) ECMO is recommended in selected patients who develop hypoxaemia that is refractory to optimal ventilator management and prone positioning, depending on the availability of resources.^[7–11]

Initial case reports and case series on the use of ECMO for COVID-19-related ARDS were disappointing and raised concerns regarding ECMO use in this patient population.^[12,13] However, several reports of ECMO use have subsequently emerged and have reported considerably better outcomes.^[5,6,14,15] The first update of SSC guidelines published recently, suggested that ECMO should be considered only for carefully selected patients with COVID-19 and severe ARDS, with a weak strength of recommendation.^[16] Given the resource implications of providing ECMO in a pandemic and variability in the reported outcomes, we performed a systematic review of the literature to summarise outcome data during the first year of the pandemic and identify risk factors for an unfavourable outcomes in order to guide clinical decision-making and further research.

1 2 3 4 5

Next Section

Crit Care. 2021;25(211) © 2021 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Demographics of the included studies
First author	Country	Number of patients	Male patients n (%)	Age*	VV ECMO	P/F ratio*
Alnababteh	USA	13	8 (61.5)	44.54 ± 9.49	13	97.96 ± 49.87
Akhtar	UK	18	16 (88.9)	47.3 ± 0.9	18	NR
Barbaro	International	1035	764 (73.8)	49 (41–57)	978	72 (59–94)
Charlton	UK	34	27 (79.4)	46.3 ± 7.5	34	64.5 (54.7–74.3)
Cousin	France	30	24 (80)	33.33 ± 7.00	30	69 ± 9.34
Falcoz	France	17	16 (94.1)	56 [30–76]	16	71 [52–134]
Guihaire	France	24	20 (83.3)	48.8 ± 8.9	24	67 [52–78]
Huette	France	12	12 (100)	62 (58–64)	14	76 (66–83)
Jackel	Germany	15	11 (73.3)	60.8 (54.2–67)	15	63.7 (51.9–94.5)
Jang	Korea	19	15 (79)	63 ± 4.81	16	97.7 ± 61.11
Le Breton	France	13	10 (77)	49.31 ± 7.75	13	60.62 ± 15.23
Jozwiak	France	11	7 (63.6)	50 (38–59)	11	68 (58–89)
Masur	USA	12	8 (66.7)	53.83 ± 13.18	NR	NR
Mustafa	USA	40	30 (75)	48.4 ± 1.5	40	68.9 ± 3.1
Roedl	Germany	20	NR	NR	20	NR
Schmidt	France	83	61 (73.5)	48.0 ± 11.0	81	62 ± 18
Shih	USA	37	27 (73.0)	51 (40–59)	37	95 (73–147)
Takeda	Japan	237	196 (82.7)	NR	230	NR
Yang	China	21	12 (57.1)	58.5 (42.75–67.25)	21	60 (55.6–72)
Zayat	Germany	17	11 (64.7)	57 (53–62)	17	NR
Zeng	China	12	11 (91.7)	50.9 ± 13.5	NR	NR
Zhang	UK	43	33 (76.7)	46 (35.5–52.5)	43	67.5 (58.9–77.8)

VV ECMO, venovenous extracorporeal membrane oxygenation; P/F, partial pressure of arterial oxygen to fraction of inspired oxygen ratio [PaO2/FiO2]; NR, not reported
*Age and P/F ratio reported as mean ± SD, median (interquartile range) or median [range]

Table 2. Outcomes of the included studies
First author	Mortality	Survivors	Not discharged	Still on ECMO	Complications on ECMO	Days on ECMO*
Alnababteh	6	4	3	NR	3 mechanical 7 haemorrhagic 6 renal 4 pulmonary 2 infectious 3 metabolic 2 limb	12.85 ± 6.04
Akhtar	4	14	0	0		17.7 ± 9.4
Barbaro	380	588	67	31	295 mechanical 69 neurologic 444 renal	13.9 (7.8–23.3)
Charlton	16	18	0	0
Cousin	16	NR	NR	NR	8 mechanical 27 haemorrhagic 4 neurologic 15 renal 2 pulmonary 4 infectious 3 limb	10.67 ± 5.45
Falcoz	6	10	1	0	7 mechanical 62 haemorrhagic 1 neurologic 12 renal 1 cardiovascular 3 pulmonary 10 infectious 1 others (thrombocytopenia)	9 [0–16]
Guihaire	4	16	4	3	18 mechanical 1 neurologic 10 pulmonary 3 infectious 1 other (mesenteric ischemia)	19.0 ± 10.1
Huette	4	8	0	0	5 mechanical 3 hemorrhagic 8 renal 1 cardiovascular 4 pulmonary 10 infectious 3 others (2 liver failure, 1 HIT)	12 (9–22)
Jackel	8	7	0	0
Jang	10	4	5	2	5 neurologic 9 renal 1 cardiovascular 6 pulmomary	17.27 ± 16.42
Jozwiak	6	5	0	0
Le Breton	2	11	0	0	2 mechanical 3 hemorrhagic 2 infectious	14.53 ± 8.84
Masur	5	1	6	NR	6 neurologic	9.60
Mustafa	6	29	5	2	10 pulmonary	29.9 ± 3.6
Roedl	13	7	0	0
Schmidt	25	38	20	5	25 mechanical 45 hemorrhagic 5 neurologic 38 renal 11 cardiovascular 50 pulmonary 129 infectious 7 others (5 thrombocytopenia, 2 HIT)	20 (10–40)
Shih	16	21	0	0
Takeda	67	NR	20	20	NA	14.42 ± 9.01
Yang	12	6	3	0	3 hemorrhagic 8 renal 8 cardiovascular 6 pulmonary 3 infectious	NR
Zayat	8	9	0	0
Zeng	5	NR	7	4	NA	11.3 ± 7.8
Zhang	14	29	0	0

ECMO, extracorporeal membrane oxygenation; NR, not reported
*Days on ECMO reported as mean ± SD, median (interquartile range) or median [range]

Table 3. Results of meta-regression analyses
Covariate	Studies	OR	LCI	UCI	P
ECMO duration	19	0.987	0.979	0.994	0.001
Age	20	1.014	1.003	1.024	0.01
BMI	16	0.977	0.956	0.999	0.04
Male	21	0.566	0.314	1.017	0.06
Smoking	7	0.360	0.105	1.232	0.10
P/F ratio	15	1.003	0.998	1.007	0.25
Sample size	22	1.000	1.000	1.000	0.59
SOFA score	11	0.991	0.951	1.033	0.66
Ventilation-to-ECMO interval	16	0.997	0.945	1.051	0.90
DM	19	1.018	0.645	1.606	0.94
HTN	18	0.987	0.648	1.502	0.95

p-values: p < 0.05 represented in bold
OR, Odds ratio; LCI, lower 95% confidence interval; UCI, upper 95% confidence interval; P, p-value; ECMO, extracorporeal membrane oxygenation; SOFA, Sequential Organ Failure Assessment; BMI, body mass index; DM, diabetes mellitus; P/F, PaO2/FiO2; HTN, hypertension

Authors and Disclosures

Kollengode Ramanathan^1,2*†, Kiran Shekar^3–6†, Ryan Ruiyang Ling¹, Ryan P. Barbaro^7,8, Suei Nee Wong¹, Chuen Seng Tan^1,9, Bram Rochwerg^10,11, Shannon M. Fernando¹², Shinhiro Takeda¹³, Graeme MacLaren^1,2, Eddy Fan¹⁴ and Daniel Brodie^15,16

¹Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. ²Cardiothoracic Intensive Care Unit, National University Heart Centre, National University Hospital, Singapore 119228, Singapore. ³Adult Intensive Care Services, Prince Charles Hospital, Brisbane, QLD, Australia. ⁴Queensland University of Technology, Brisbane, Australia. ⁵University of Queensland, Brisbane, Australia. ⁶Bond University, Gold Coast, QLD, Australia. ⁷ Division of Paediatric Critical Care Medicine, University of Michigan, Ann Arbor, USA. ⁸Child Health Evaluation and Research Center, University of Michigan, Ann Arbor, MI, USA. ⁹Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. ¹⁰Department of Medicine, Division of Critical Care, McMaster University, Hamilton, ON, Canada. ¹¹Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada. ¹²Division of Critical Care, Department of Medicine, University of Ottawa, Ottawa, ON, Canada. ¹³Japan ECMOnet for COVID-19 & President, Kawaguchi Cardiovascular and Respiratory Hospital, Saitama, Japan. ¹⁴Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada. ¹⁵Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA. ¹⁶Center for Acute Respiratory Failure, New York-Presbyterian Hospital, New York, NY, USA.

*Correspondence
ram_ramanathan@nuhs.edu.sg

^†Kollengode Ramanathan and Kiran Shekar have contributed equally to this work

Authors' contributions
The study was designed by KS and KR. RRL and KR screened the articles, assessed the risk of bias and extracted the data. RPB and ST aided with the data from Extracorporeal Life Support Organisation and Japan ECMOnet for COVID-19 registries, respectively. SNW helped with the search criteria. RRL analysed and interpreted the data under the supervision of CST and KR. BR and SF helped with GRADE analysis. Tables and figures were produced by RRL. KR and KS had primary responsibility of writing the manuscript, to which all authors contributed to and revised. DB, EF, RPB and GM critically revised the manuscript for important intellectual content. All authors provided critical conceptual input, interpreted the data analysis, read and approved the final draft.

Competing interests
DB receives research support from ALung Technologies. He has been on the medical advisory boards for Baxter, Abiomed, Xenios and Hemovent, and is the President-elect of ELSO. RPB receives research support unrelated to this project from National Institutes of Health's National Heart, Lung and Blood Institute K12 HL138039 and R01 HL153519 and the National Institute of Child Health and Human Development R01 HD015434. He is the ELSO Registry Chair. EF reports personal fees from ALung Technologies, Baxter, Fresenius Medical Care, Getinge and MC3 Cardiopulmonary outside the submitted work.