Preparing for the Most Critically Ill Patients With COVID-19: The Potential Role of Extracorporeal Membrane Oxygenation | Critical Care Medicine | JAMA | JAMA Network
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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

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    2 Comments for this article
    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.
    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.