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February 19, 2020

Preparing for the Most Critically Ill Patients With COVID-19: The Potential Role of Extracorporeal Membrane Oxygenation

Author Affiliations
  • 1Cardiothoracic Intensive Care Unit, National University Health System, Singapore
  • 2Division of Infectious Diseases, University Medicine Cluster, National University Health Systems, Singapore
  • 3Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • 4Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University College of Physicians and Surgeons/New York-Presbyterian Hospital, New York
  • 5Center for Acute Respiratory Failure, New York-Presbyterian Hospital, New York
JAMA. 2020;323(13):1245-1246. doi:10.1001/jama.2020.2342

The novel coronavirus has now infected tens of thousands of people in China and has spread rapidly around the globe.1 The World Health Organization (WHO) has declared the disease, coronavirus disease 2019 (COVID-19), a Public Health Emergency of International Concern and released interim guidelines on patient management.2 Early reports that emerged from Wuhan, the epicenter of the outbreak, demonstrated that the clinical manifestations of infection were fever, cough, and dyspnea, with radiological evidence of viral pneumonia.3,4 Approximately 15% to 30% of these patients developed acute respiratory distress syndrome (ARDS). The WHO interim guidelines made general recommendations for treatment of ARDS in this setting, including that consideration be given to referring patients with refractory hypoxemia to expert centers capable of providing extracorporeal membrane oxygenation (ECMO).2

ECMO is a form of modified cardiopulmonary bypass in which venous blood is removed from the body and pumped through an artificial membrane lung in patients who have refractory respiratory or cardiac failure.5 Oxygen is added, carbon dioxide is removed, and blood is returned to the patient, either via another vein to provide respiratory support or a major artery to provide circulatory support. ECMO is a resource-intensive, highly specialized, and expensive form of life support with the potential for significant complications, in particular hemorrhage and nosocomial infection. Recent evidence suggests that use of ECMO in the most severe cases of ARDS is associated with reduced mortality.6 There is some evidence that outcomes from ECMO are better in higher-volume centers.7

The role of ECMO in the management of COVID-19 is unclear at this point. It has been used in some patients with COVID-19 in China but detailed information is unavailable.3 ECMO may have a role in the management of some patients with COVID-19 who have refractory hypoxemic respiratory failure.6 However, much about the virus is unknown, including the natural history, incidence of late complications, viral persistence, or the prognoses in different subsets of patients. This uncertainty might be compared to the emergence of influenza A(H1N1) in 2009, when it was initially unclear what the role of ECMO should be.8 However, the degree of uncertainty surrounding COVID-19 is much greater. To address this, prompt mobilization of existing registries and clinical research groups should help facilitate the systematic collection of data. For example, the Extracorporeal Life Support Organization (ELSO) Registry is being adapted to acquire new information about COVID-19 and prospective observational studies are under way.

ECMO does not provide direct support for organs other than the lungs or heart beyond increasing systemic oxygen delivery and mitigating ventilator-induced lung injury. A substantial proportion of critically ill patients with COVID-19 appear to have developed cardiac arrhythmias or shock,3 but it is unknown how many have or will develop refractory multiorgan failure, for which ECMO may be of more limited use. To postulate about the potential benefit of ECMO in this infection, more data on the mechanism of death and disease are required. The virus may cause death through progressive hypoxic respiratory failure, septic shock, refractory multiorgan failure, or by precipitating exacerbation of comorbid diseases such as ischemic heart disease or cardiac failure, but the relative proportions of these diseases in large cohorts of patients with COVID-19 infection are unknown.

The global spread of COVID-19, although the number of cases outside of China remains small, will likely occur via many dispersed epicenters where local transmission has become established. If these epicenters occur in sophisticated health care systems with preexisting ECMO programs, this will provide vital information about the utility of ECMO and help anticipate global demand. Should the initial experience be encouraging, it is likely that non-ECMO centers will refer early to ECMO centers in anticipation of impending clinical deterioration. This will disproportionately affect hospitals with ECMO programs, even when ECMO is not required.

Furthermore, with the apparent contagiousness of this virus and the relatively high numbers of patients who require intensive care, this may prove very resource-consumptive. Countries will need to pay specific attention to the considerable investment needed to provide ECMO during this outbreak. Judgment will be needed to decide when ECMO may be worthwhile and when it may not, understanding that the risk-to-benefit ratio of performing ECMO in these circumstances is dynamic and dependent on many factors. If the mechanism of death in COVID-19 ultimately includes a substantial number of patients with septic shock or refractory multiorgan failure, then the shift away from ECMO is likely to occur earlier because the most severely ill patients in this cohort would be less likely to benefit. The higher the all-cause mortality, the less relevant ECMO becomes.

Regardless, ECMO is clearly a finite resource. In a large outbreak, additional limitations to providing ECMO may include a lack of ECMO consoles or disposable equipment, suitably trained staff, or isolation rooms with the requisite infrastructure. Many materials necessary to make ECMO circuitry are manufactured in China and it is conceivable that the outbreak may disrupt supply chains.

A number of different models of ECMO service provision exist worldwide, ranging from a relative lack of regulation and centralization—with many hospitals having ECMO capability but often with very low case volumes (eg, in the US or Japan)—through to regional or national coordination of ECMO referral centers with dedicated interhospital retrieval teams (eg, New Zealand, Australia, Singapore, Qatar, the United Kingdom, or Sweden). In response to influenza A(H1N1) in 2009, some countries such as Italy adopted the latter model and it is possible that COVID-19 could be addressed similarly. The advantages of such an approach include standardization of indications, management, data collection, and containment.5,7 The disadvantage is the potential for hospitals that provide ECMO to be overwhelmed with critically ill patients unless interhospital transfers are centrally coordinated.

With the WHO recommendation for ECMO in place and the tropism of the COVID-19 virus for severe respiratory illness, the number of cases in which ECMO is used may increase over the course of this outbreak. However, there may come a tipping point. Should the case volume in any given region increase beyond the ability to provide routine care, any earlier increase in ECMO use may give way, with utilization later decreasing in proportion to the overwhelming demands on the system as a whole.

Support with ECMO is for the most critically ill patients in regions with the extensive resources required to provide this therapy. ECMO is not a therapy to be rushed to the frontline when all resources are stretched in a pandemic. In less well-resourced countries, many more lives will be saved by ensuring oxygen and pulse oximetry are widely available. Mitigation efforts to slow the outbreak are critical so that health care systems are not overwhelmed and all patients receive the correct management, whether simply confirmation of the diagnosis and appropriate quarantine, oxygen therapy alone, mechanical ventilation or, for those most likely to benefit, ECMO.

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Article Information

Corresponding Author: Graeme MacLaren, MSc, Cardiothoracic Intensive Care Unit, National University Health System, 5 Lower Kent Ridge Rd, Singapore 119074 (gmaclaren@iinet.net.au).

Published Online: February 19, 2020. doi:10.1001/jama.2020.2342

Conflict of Interest Disclosures: Dr Brodie reported receiving grants from Alung Technologies, serving on the medical advisory board for Alung Technologies, Xenios, Breethe, Baxter, and Hemovent. No other disclosures were reported.

References
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Paules  CI, Marston  HD, Fauci  AS.  Coronavirus infections—more than just the common cold.   JAMA. 2020. Published online January 23, 2020. doi:10.1001/jama.2020.0757PubMedGoogle Scholar
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World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected—interim guidance. Published January 28, 2020. Accessed February 11, 2020. https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected
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Wang  D, Hu  B, Hu  C,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.   JAMA. Published online February 7, 2020. doi:10.1001/jama.2020.1585Google Scholar
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Chen  N, Zhou  M, Dong  X,  et al.  Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.   Lancet. Published online January 30, 2020. doi:10.1016/S0140-6736(20)30211-7Google Scholar
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Brodie  D, Slutsky  AS, Combes  A.  Extracorporeal life support for adults with respiratory failure and related indications: a review.   JAMA. 2019;322(6):557-568. doi:10.1001/jama.2019.9302PubMedGoogle ScholarCrossref
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Goligher  EC, Tomlinson  G, Hajage  D,  et al.  Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and posterior probability of mortality benefit in a post hoc bayesian analysis of a randomized clinical trial.   JAMA. 2018;320(21):2251-2259. doi:10.1001/jama.2018.14276PubMedGoogle ScholarCrossref
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    2 Comments for this article
    EXPAND ALL
    ECMO and Outcome of ARDS—Clinical Thought Experiment
    mohamad abdelsalam, Master of Medicine | Suez General Hospital, Critical Care Department, Suez, Egypt
    In this clinical thought experiment, suppose an ECMO study showed that ECMO significantly reduced mortality of ARDS. Then, what might be the mechanism(s) of mortality reduction among ECMO-treated patients. ECMO has three functions: oxygenation, CO2 removal and ultra-protective ventilation, either or all of which may contribute to survival improvement. But, what is the relative contribution of each function of ECMO to the overall survival benefit?
    Oxygenation and Outcome of ARDS: Causation or Association?
    Assume that SaO2 and survival were significantly higher in the ECMO group, does this establish a causal connection between oxygenation and
    survival? Not necessarily so. The relationship between oxygenation and outcome of ARDS is confounded by the fact that patients on ECMO receive low-volume, low-pressure ventilation that can protect the lung and improve outcome, regardless of the degree of oxygenation. Another confounding factor is CO2 elimination that reduces hypercapnic pulmonary vasoconstriction (and RV afterload) and, in conjunction with ultra-protective ventilation, can improve RV function, increase cardiac output and alleviate tissue hypoxia, MOF and death.
    Survival and CO2 Elimination: Do ARDS Patients Die of Hypercapnia?
    In the respiratory ECMO survival prediction (RESP) score, pre-ECMO hypercapnia (but not hypoxemia) was an independent risk factor for death after initiating ECMO. Acute RV failure initiated or exacerbated by hypercapnia may provide physiological explanation of the association between mortality and severe hypercapnia (PaCO2 ≥75 mm Hg). Since ECMO does not only improve oxygenation but also removes CO2, it is logical to assume that at least part of the survival advantage of ECMO is due to CO2 removal.
    Does it Matter How ECMO Works?
    Imagine that improved oxygenation did not significantly contribute to the overall mortality reduction, which was attributable to ultra-protective ventilation and CO2 elimination. For example, if the ECMO study demonstrated that, for patients receiving ECMO, an increase of SaO2 from 75 to 80% decreased mortality, but increasing SaO2 above 80% did not result in further reduction in mortality. If so, extracorporeal CO2 removal, which can also provide ultra-protective ventilation and CO2 elimination, may be considered as alternative to ECMO in patients without life-threatening hypoxemia, keeping in mind that the imaginary ECMO study suggested that moderate hypoxemia (SaO2 = 80-85%) was well tolerated and that further improvement of oxygenation did not confer additional survival benefit.
    From Thought Experiment to Reality
    To evaluate how much does improvement of oxygenation contribute to mortality reduction, the confounding effects of ultra-protective ventilation and CO2 removal on the causal chain between oxygenation and outcome of ARDS should be controlled. To do so, a secondary analysis of data from the CESAR and EOLIA trials could be performed after stratifying patients in the ECMO group according to SaO2 to determine whether or not SaO2—during ECMO support—was an independent predictor of mortality (ideally, patients on ECMO are similar in the degree of lung protection and CO2 elimination with the only difference being in oxygenation). After defining the relationship between oxygenation and survival (causation vs. association), which will require further experimental and clinical studies, the future of ECMO as a measure to improve oxygenation and the role of ECCOR in the management of ARDS (without life-threatening hypoxemia) can be clearly defined.
    CONFLICT OF INTEREST: None Reported
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    Do We Really Need ECMO? Rationalism vs. Empiricism.
    Mohamad Abdelsalam, Master of Medicine | Suez General Hospital, Critical Care Department, Suez, Egypt
    Paraphrasing Rene Descartes "I think, therefore, I am". And hence, I dare to think and ask the conceptual question of whether we really need ECMO. Obviously, ECMO is life saving for severely hypoxic ARDS patients. However, only a minority of patients who die do so because of hypoxemia. Most patients die with hypoxemia rather than from hypoxemia. In the ARDSNet trial, the low VT group was less likely to die despite being more hypoxic than the high VT group. Also, the PRESERVE and RESP trials showed that it was the airway pressures and PEEP (but not P/F ratio) that predicted mortality. Accordingly, I can speculate that what really matters is avoiding VILI and protecting the right heart (ultra-protective ventilation and CO2 elimination) with ECCOR rather than only improving oxygenation (ECMO). Clearly, ECMO does reduce mortality of ARDS (CEASAR and EOLIA trials). But, why did ECMO improve outcome of ARDS - improved oxygenation or cardio-pulmonary protection? We do not know for sure, but there is historical evidence that doing no harm is better than doing good. Certainly, we cannot answer the question of "what matters most - oxygenation improvement or heart-lung protective ventilation?" without conducting a study that compares the efficacy and safety of two oxygenation strategies - Liberal Strategy targeting SaO2 ≥90% (ECMO group) and Restrictive Strategy or Permissive Hypoxemia targeting SaO2 of 80-85% (ECCOR group). Since both ECMO and ECCOR groups already receive ultra-protective ventilation, the only between-group difference is the oxygenation status. It may be unethical, however, to conduct such a clinical trial without first confirming the safety of permissive hypoxemia in cohort study.

    But, let us imagine that we already have the observational and experimental evidence that moderate hypoxemia (SaO2 80-85%) is as safe and as effective as normoxemia (SaO2 ≥90%). How would permissive hypoxemia alter the future of extracorporeal respiratory support? And do we still need ECMO as much as we used to? Could a strategy of ultra-protective ventilation (ECCOR) and permissive hypoxemia largely replace ECMO? If so, how can we make the provision of ECCOR (with permissive hypoxemia) more feasible and more widely available? Can we dream of a day when patients with moderate-to-severe or severe ARDS could be treated with low-flow ECCOR through a double-lumen cannula slightly larger than that used for hemodialysis? Given the advancement of membrane technology, I think it will not be long before highly efficient membranes in CO2 removal become available. Finally, if proven, the concept of permissive hypoxemia may represent a paradigm shift for both clinicians and industrial companies to focus more on decarboxylation than oxygenation.
    CONFLICT OF INTEREST: None Reported
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