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Letters to the Editor

Adding Inflammation to the Perfect Cytokine Storm: Concerns Related to Extracorporeal Membrane Oxygenation for COVID-19 Patients

Angouras, Dimitrios C. MD; Kollias, Vasilios D. MD; Dougenis, Dimitrios MD

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doi: 10.1097/MAT.0000000000001233
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The Extracorporeal Life Support Organization (ELSO), in an Initial Guidance Document,1 suggested extracorporeal membrane oxygenation (ECMO) support for coronavirus disease 2019 (COVID-19) patients with severe cardiopulmonary failure. However, it aptly underlined that “overall patient load, staffing, and other resource constraints” may affect the implementation of this therapeutic strategy.1 Similarly, MacLaren et al. have recently advocated that the role of ECMO in this setting will depend on resource availability and data about its clinical effectiveness.2 Data are still sparse.

Li and colleagues presented preliminary results regarding ECMO support in eight patients with severe COVID-19.3 Four patients had died, and four remained on mechanical ventilation (one also on venovenous-ECMO). The authors concluded that “ECMO support in COVID-19 is key to improving clinical outcomes,” which, we think, is somewhat premature and unsubstantiated. Six other reports from China have demonstrated modest results, with an aggregate survival rate of 17.6% for 17 adult COVID-19 patients undergoing ECMO.4

Presumed utility of ECMO in COVID-19 is based on previous pertinent randomized control trials (RCTs) and observational data from severe acute respiratory infections (SARI)-associated pulmonary failure (e.g., influenza).5 Nevertheless, it is doubtful whether this experience can be duplicated in COVID-19. An essential feature of this disease is its potential progression to a disproportionate inflammatory reaction. Whereas a severe immunologic host response commonly underlies fatal cases in other SARIs as well, the intensity of the reaction in advanced COVID-19 is unparalleled. It includes a persistent much lower level of lymphocytes in peripheral blood, extremely high inflammatory markers, and destroyed lymphoid tissue revealed by atrophy of spleen and lymph nodes.6 Vasculitis-like endothelium damage and abnormal coagulation parameters with disseminated intravascular coagulation profile are also frequently detected.6 This is no longer a respiratory illness but rather a catastrophic systemic hyperinflammatory syndrome, potentially resulting in multiorgan dysfunction and failure.

Disastrously, this is when ECMO support may be needed. Extracorporeal circulation (ECC) is known to initiate per se a systemic inflammatory response, with activation of all parameters of the innate, nonspecific immune system, proinflammatory mediators, endothelial cells and the coagulation cascade, thus conducing to morbidity and mortality.7,8 The role and extent of this phenomenon in COVID-19 patients are unknown. Whereas in typical acute respiratory distress syndrome, ECMO may also be expected to somewhat mitigate inflammation by improving oxygen delivery and alleviating ventilator-induced lung trauma, in a state of uncontrolled systemic hyperinflammation, ECC may be the last drop that will make the cup run over.

Based on modest preliminary outcomes,3,4 possible resource allocation issues posing ethical dilemmas, and the above theoretical concerns related to the pathophysiologic peculiarities of the novel virus, we think that ECMO should be employed very cautiously and selectively in patients with COVID-19. The application of an extracorporeal cytokine hemoadsorption device should be considered in this setting.8 However, if overwhelming systemic inflammation is detected early, alternative therapeutic strategies, e.g., convalescent plasma transfusion or cytokine inhibitors,9,10 may be adopted and evaluated, ideally but not necessarily, within the context of an RCT.

References

1. Bartlett RH, Ogino MT, Brodie D, et al. Initial ELSO guidance document: ECMO for COVID-19 patients with severe cardiopulmonary failure. ASAIO J 2020.66: 472–474.
2. Maclaren G, Fisher D, Brodie D. Preparing for the most critically ill patients with COVID-19: the potential role of extracorporeal membrane oxygenation. JAMA 2020.323: 1245–1246.
3. Li X, Guo Z, Li B, et al. Extracorporeal membrane oxygenation for coronavirus disease 2019 in Shanghai, China. ASAIO J 2020.66: 475–481.
4. Ñamendys-Silva SA. ECMO for ARDS due to COVID-19. Heart Lung 2020.49: 348–349.
5. Brodie D, Slutsky AS, Combes A. Extracorporeal life support for adults with respiratory failure and related indications: a review. JAMA 2019.322: 557–568.
6. Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the Perspectives of clinical immunologists from China. Clin Immunol 2020.214: 108393.
7. Al-Fares A, Pettenuzzo T, Del Sorbo L. Extracorporeal life support and systemic inflammation. Intensive Care Med Exp 2019.7(suppl 1): 1–14.
8. Datzmann T, Träger K. Extracorporeal membrane oxygenation and cytokine adsorption. J Thorac Dis 2018.10: S653–S660.
9. Luo P, Liu Y, Qiu L, et al. Tocilizumab treatment in COVID-19: a single center experience. J Med Virol 2020.92: 814–818.
10. Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci USA 2020.117: 9490–9496.
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