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The Use of ECMO for COVID-19: Lessons Learned

Published:November 28, 2022DOI:https://doi.org/10.1016/j.ccm.2022.11.016

      Key Words

      Key Points

      • The COVID-19 pandemic has posed challenges on multiple levels in the implementation of ECMO support for patients with severe ARDS around the world
      • Real-time data gathering and new approaches to research have helped evaluate the utility of ECMO during an ongoing pandemic
      • Regional, national and international coordination has been crucial in knowledge sharing, research collaboration and development of guidelines

      Introduction

      The use of extracorporeal membrane oxygenation (ECMO) in the management of severe acute respiratory distress syndrome (ARDS) has been well established in recent years,
      • Combes A.
      • Hajage D.
      • Capellier G.
      • et al.
      Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome.
      • Goligher E.C.
      • 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.
      • Munshi L.
      • Walkey A.
      • Goligher E.
      • Pham T.
      • Uleryk E.M.
      • Fan E.
      Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis.
      • Combes A.
      • Peek G.J.
      • Hajage D.
      • et al.
      ECMO for severe ARDS: systematic review and individual patient data meta-analysis.
      but the ongoing coronavirus disease 2019 (COVID-19) pandemic has presented new limitations in knowledge and has complicated the implementation of ECMO. Severe COVID-19 frequently presents with acute respiratory failure in the form of ARDS, and the pandemic has been characterized by surges in the volume of critically ill patients with ARDS worldwide.
      Episodic surges in patients with COVID-19-related ARDS have been accompanied by strain both on healthcare resources (e.g. beds, staffing, medical supplies) and in the ability to provide equitable access to care, all of which is further exaggerated when considering the application of ECMO, a highly resource-intensive and specialized technology.
      As the pandemic has evolved, the medical community has learned not only about the role of ECMO for COVID-19 from a clinical standpoint, but also how to gather knowledge in real-time about the use of ECMO for a novel disease, the limitations in our ability to equitably deliver healthcare resources across the globe, and how to devise best strategies for care in light of substantial resource constraints. The use of ECMO for cardiac or circulatory failure, including for extracorporeal cardiopulmonary resuscitation (ECPR) has been relatively limited in the setting of COVID-19; we will focus on the use of ECMO for respiratory failure.

      Early Experience

      Registry data and large cohort studies from early in the pandemic suggested patients managed with ECMO for COVID-19-related ARDS had a mortality rate comparable to similar patients with ARDS prior to COVID-19 (Table 1); mortality rates of 31% at 60 days in a large single-center experience from Paris, France,
      • Schmidt M.
      • Hajage D.
      • Lebreton G.
      • et al.
      Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study.
      33.2% at 60-days in a cohort study across 60 hospitals in the US,
      • Shaefi S.
      • Brenner S.K.
      • Gupta S.
      • et al.
      Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19.
      and an estimated 37.4% in-hospital mortality at 90-days from the Extracorporeal Life Support Organization (ELSO) Registry, including 213 hospitals across 36 countries.
      • Barbaro R.P.
      • MacLaren G.
      • Boonstra P.S.
      • et al.
      Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry.
      A meta-analysis of studies spanning December 1, 2019, through January 10, 2021, tallying 1896 patients, reported an in-hospital mortality rate of 37.1%;
      • Ramanathan K.
      • Shekar K.
      • Ling R.R.
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: a systematic review and meta-analysis.
      these analyses were heavily weighted by the aforementioned large cohort studies.
      Table 1Early experience of ECMO for COVID-19-related ARDS
      Data SourceTimeframeNumber of PatientsMortality
      Single-center observational experience from Paris, France
      • Schmidt M.
      • Hajage D.
      • Lebreton G.
      • et al.
      Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study.
      Patients admitted between March 8th-May 2nd, 20208331% at 60 days
      Cohort study across 60 hospitals in the United States
      • Shaefi S.
      • Brenner S.K.
      • Gupta S.
      • et al.
      Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19.
      Patients admitted between March 1st and July 1st, 202019033.2% at 60-days
      Extracorporeal Life Support Organization (ELSO) registry, including 213 hospitals across 36 countries
      • Barbaro R.P.
      • MacLaren G.
      • Boonstra P.S.
      • et al.
      Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry.
      Patients in whom ECMO was initiated between Jan 16th and May 1st, 2020103537.4% in-hospital mortality at 90-days
      Meta-analysis of 22 studies
      • Ramanathan K.
      • Shekar K.
      • Ling R.R.
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: a systematic review and meta-analysis.
      December 1st, 2019, through January 10th, 2021189637.1% in-hospital mortality

      Evolving Mortality Over Time

      Despite encouraging data early on, additional data gathered as the pandemic continued suggested increasing mortality and duration of ECMO over time. An analysis of a survey from the European chapter of ELSO (EuroELSO) found a mortality of 56% for COVID-19 patients managed with ECMO between September 15th, 2020, and March 8th, 2021, as compared to 47% prior to that time period.
      • Broman L.M.
      • Eksborg S.
      • Lo Coco V.
      • De Piero M.E.
      • Belohlavek J.
      • Lorusso R.
      Extracorporeal membrane oxygenation for COVID-19 during first and second waves.
      Similarly, data from 24 centers in Spain and Portugal suggested a higher in-hospital mortality after June 30th, 2020 (60.1%) than before that date (41.1%).
      • Riera J.
      • Roncon-Albuquerque Jr., R.
      • Fuset M.P.
      • Alcántara S.
      • Blanco-Schweizer P.
      Increased mortality in patients with COVID-19 receiving extracorporeal respiratory support during the second wave of the pandemic.
      The Paris-Sorbonne University Hospital Network found a 90-day mortality of 48% in patients after July 1st, 2020, as compared to 36% prior to July (HR 2.27, 95% CI 1.02-5.07).
      • Schmidt M.
      • Langouet E.
      • Hajage D.
      • et al.
      Evolving outcomes of extracorporeal membrane oxygenation support for severe COVID-19 ARDS in Sorbonne hospitals, Paris.
      Further analysis of the ELSO registry database, encompassing 4,812 patients, also noted a higher 90-day in-hospital mortality for patients after May 1st, 2020 as compared to earlier (51.9% vs 36.9%, RR 0.82, 95% CI 0.7-0.96), with a longer duration of ECMO support in the latter cohort (20 days vs. 14 days).
      • Barbaro R.P.
      • MacLaren G.
      • Boonstra P.S.
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry.
      Data published from Germany demonstrated a high in-hospital mortality (68%) for all patients supported with ECMO (n=3,397) for COVID-19-related ARDS from the start of the pandemic through May 31st, 2021, despite a lack of resource constraints.
      • Karagiannidis C.
      • Slutsky A.S.
      • Bein T.
      • Windisch W.
      • Weber-Carstens S.
      • Brodie D.
      Complete countrywide mortality in COVID patients receiving ECMO in Germany throughout the first three waves of the pandemic.
      An updated meta-analysis of 52 studies (18,211 patients) reporting data between December 1st, 2019, to January 26th, 2022, revealed a pooled mortality rate of 48.8% (95% CI 44.8-52.9%) among patients with COVID-19 receiving ECMO, with increasing mortality in the second half of 2020 (46.4%) compared with the first half (41.2%), and an even higher mortality (62%) in the first half of 2021. Predictors of increased mortality included age, later time of enrollment, higher proportion of patients receiving corticosteroids, and reduced duration of ECMO run.

      Ling R, Ramanathan K, J S, et al. Evolving outcomes of extracorporeal membrane oxygenation during the first 2 years of the COVID-19 pandemic: a systematic review and meta-analysis. Critical care. 2022;26(147).

      A number of potential reasons for increasing mortality over time have been speculated, including: greater selection over time for treatment-refractory disease (those who did not respond to COVID-19-directed therapies that were increasingly used over the course of the pandemic, e.g. corticosteroid therapy),
      • Broman L.M.
      • Eksborg S.
      • Lo Coco V.
      • De Piero M.E.
      • Belohlavek J.
      • Lorusso R.
      Extracorporeal membrane oxygenation for COVID-19 during first and second waves.
      • Riera J.
      • Roncon-Albuquerque Jr., R.
      • Fuset M.P.
      • Alcántara S.
      • Blanco-Schweizer P.
      Increased mortality in patients with COVID-19 receiving extracorporeal respiratory support during the second wave of the pandemic.
      • Schmidt M.
      • Langouet E.
      • Hajage D.
      • et al.
      Evolving outcomes of extracorporeal membrane oxygenation support for severe COVID-19 ARDS in Sorbonne hospitals, Paris.
      • Barbaro R.P.
      • MacLaren G.
      • Boonstra P.S.
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry.
      increased use of non-invasive ventilatory support prior to intubation and ECMO (which may contribute to pre-endotracheal intubation self-inflicted lung injury),
      • Riera J.
      • Roncon-Albuquerque Jr., R.
      • Fuset M.P.
      • Alcántara S.
      • Blanco-Schweizer P.
      Increased mortality in patients with COVID-19 receiving extracorporeal respiratory support during the second wave of the pandemic.
      • Schmidt M.
      • Langouet E.
      • Hajage D.
      • et al.
      Evolving outcomes of extracorporeal membrane oxygenation support for severe COVID-19 ARDS in Sorbonne hospitals, Paris.
      • Barbaro R.P.
      • MacLaren G.
      • Boonstra P.S.
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry.
      a rise in superimposed bacterial pneumonia in the setting of immunosuppressive treatments for COVID-19,10,15,16 emergence of SARS-CoV-2 variants with differential effects on prognosis, increased use of ECMO by less experienced centers,
      • Riera J.
      • Roncon-Albuquerque Jr., R.
      • Fuset M.P.
      • Alcántara S.
      • Blanco-Schweizer P.
      Increased mortality in patients with COVID-19 receiving extracorporeal respiratory support during the second wave of the pandemic.
      ,
      • Barbaro R.P.
      • MacLaren G.
      • Boonstra P.S.
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry.
      and variations in patient selection criteria for ECMO.
      • Riera J.
      • Roncon-Albuquerque Jr., R.
      • Fuset M.P.
      • Alcántara S.
      • Blanco-Schweizer P.
      Increased mortality in patients with COVID-19 receiving extracorporeal respiratory support during the second wave of the pandemic.
      While the mortality of patients managed with ECMO may have increased over the course of the pandemic, ECMO may still benefit selected patients with severe COVID-19-related ARDS.
      • Urner M.
      • Barnett A.G.
      • Bassi G.L.
      • et al.
      Venovenous extracorporeal membrane oxygenation in patients with acute covid-19 associated respiratory failure: comparative effectiveness study.
      • Whebell S.
      • Zhang J.
      • Lewis R.
      • et al.
      Survival benefit of extracorporeal membrane oxygenation in severe COVID-19: a multi-centre-matched cohort study.
      • Gannon W.D.
      • Stokes J.W.
      • Francois S.A.
      • et al.
      Association Between Availability of ECMO and Mortality in COVID-19 Patients Eligible for ECMO: A Natural Experiment.
      A multi-center international emulation trial, which applies principles of randomized controlled trials to the analysis of observational data, including 7,345 patients between January 3rd, 2020, and August 29th, 2021, found a reduction in 60-day in-hospital mortality with a risk ratio of 0.78 (95% CI 0.75-0.82). Adherence adjusted mortality, which accounts for adherence to the treatment assignment, was 26% for patients managed with ECMO as compared to conventional treatment (33.2%). Secondary analyses suggested ECMO was most effective in patients aged <65, those with a PaO2 to FiO2 ratio of <80 mmHg, a driving pressure >15 cmH2O, or during the first 10 days of mechanical ventilation. While this was not a traditional RCT, the emulation design allowed for a more rigorous analysis of real-world effectiveness of ECMO than a traditional observational study.
      • Urner M.
      • Barnett A.G.
      • Bassi G.L.
      • et al.
      Venovenous extracorporeal membrane oxygenation in patients with acute covid-19 associated respiratory failure: comparative effectiveness study.
      Additionally, a study conducted in the UK demonstrated an absolute mortality reduction of 18.2% (44% vs 25.8%; OR 0.44; 95% CI 0.29-0.68, p<0.001) for those receiving ECMO compared to matched controls.
      • Whebell S.
      • Zhang J.
      • Lewis R.
      • et al.
      Survival benefit of extracorporeal membrane oxygenation in severe COVID-19: a multi-centre-matched cohort study.
      These data should be interpreted cautiously, as residual confounding may have accounted for some of the benefit, especially as those receiving ECMO were managed at highly specialized centers, whereas those not offered ECMO remained in their original facilities for ongoing care.
      The true efficacy of ECMO for severe COVID-19-related ARDS remains uncertain in the absence of high-quality, randomized controlled trials (RCTs). The fact that RCTs could not be implemented despite thousands of ECMO cases highlights the challenges faced in conducting research, especially RCTs, during a constantly changing pandemic with substantial limitations in infrastructure and resources, including staffing and time.
      • Granholm A.
      • Alhazzani W.
      • Derde L.P.G.
      • et al.
      Randomised clinical trials in critical care: past, present and future.
      Ongoing evaluation of emerging data will be necessary to help determine optimal patient selection and management strategies; until then, use of conventional inclusion and exclusion criteria based on pre-COVID ECMO data,
      • Combes A.
      • Hajage D.
      • Capellier G.
      • et al.
      Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome.
      ,
      • Abrams D.
      • Ferguson N.D.
      • Brochard L.
      • et al.
      ECMO for ARDS: from salvage to standard of care?.
      modified by factors identified in large registry analyses to be predictive of outcomes, appears to be a reasonable approach.
      • Combes A.
      • Hajage D.
      • Capellier G.
      • et al.
      Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome.
      ,
      • Badulak J.
      • Antonini M.V.
      • Stead C.M.
      • et al.
      Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization.

      Clinical Care

      Patient Selection

      Criteria for ECMO initiation in patients with COVID-19-related ARDS remain the same as those recommended prior to the pandemic,
      • Abrams D.
      • Ferguson N.D.
      • Brochard L.
      • et al.
      ECMO for ARDS: from salvage to standard of care?.
      • Badulak J.
      • Antonini M.V.
      • Stead C.M.
      • et al.
      Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization.
      • Brodie D.
      • Slutsky A.S.
      • Combes A.
      Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review.
      • Shekar K.
      • Badulak J.
      • Peek G.
      • et al.
      Extracorporeal Life Support Organization Coronavirus Disease 2019 Interim Guidelines: A Consensus Document from an International Group of Interdisciplinary Extracorporeal Membrane Oxygenation Providers.
      • Tonna J.E.
      • Abrams D.
      • Brodie D.
      • et al.
      Management of Adult Patients Supported with Venovenous Extracorporeal Membrane Oxygenation (VV ECMO): Guideline from the Extracorporeal Life Support Organization (ELSO).
      and fall within the standard approach to ARDS algorithm (Figure 1), as there is no good evidence to support deviation from these preestablished guidelines when resources are available. Outcomes with delayed initiation may in fact be worse and can lead to longer duration of ECMO support, which may in turn offset the benefit of an attempt of conservation of resources. However, resource constraints during the pandemic have overwhelmed the ability to provide ECMO at varying times in different regions of the world. As such, selection criteria may need to be more flexible and potentially stringent at any given time, depending on available resources and coordination locally. Criteria may need to evolve as well, as increasing knowledge arises regarding prognostic factors.
      • Brodie D.
      • Abrams D.
      • MacLaren G.
      • et al.
      ECMO During Respiratory Pandemics: Past, Present, and Future.
      Figure thumbnail gr1
      Figure 1Algorithm flowsheet for management of ARDS including indications for ECMO PEEP=positive end-expiratory pressure. PaO2:FiO2=ratio of partial pressure of oxygen in arterial blood to the fractional concentration of oxygen in inspired air. ECMO=extracorporeal membrane oxygenation. PaCO2=partial pressure of carbon dioxide in arterial blood. With respiratory rate increased to 35 breaths per minute and mechanical ventilation settings adjusted to keep a plateau airway pressure of ≤32 cm of water. †Consider neuromuscular blockade. ‡There are no absolute contraindications that are agreed upon except end-stage respiratory failure when lung transplantation will not be considered; exclusion criteria used in the EOLIA trial
      • Combes A.
      • Hajage D.
      • Capellier G.
      • et al.
      Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome.
       can be taken as a conservative approach to contraindications to ECMO. §Eg, neuromuscular blockade, high PEEP strategy, inhaled pulmonary vasodilators, recruitment maneuvers, high-frequency oscillatory ventilation. ¶Recommend early ECMO as per EOLIA trial criteria; salvage ECMO, which involves deferral of ECMO initiation until further decompensation (as in the crossovers to ECMO in the EOLIA control group), is not supported by the evidence but might be preferable to not initiating ECMO at all in such patients.From Abrams D, Ferguson ND, Brochard L, et al. ECMO for ARDS: from salvage to standard of care? [published correction appears in Lancet Respir Med. 2019 Feb;7(2):e9]. Lancet Respir Med. 2019;7(2):108-110.

      Cannulation and Transport

      Conventional cannulation strategies are generally recommended for patients undergoing ECMO initiation for severe COVID-19-related ARDS as there is a paucity of data to support alternative strategies.
      • Badulak J.
      • Antonini M.V.
      • Stead C.M.
      • et al.
      Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization.
      These include two-site or single-site, dual-lumen venovenous cannulation (VV), with additional arterial support depending on whether there is concomitant cardiogenic shock.
      • Brodie D.
      • Slutsky A.S.
      • Combes A.
      Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review.
      Some centers have utilized a veno-pulmonary artery (V-P) configuration through a single dual-lumen catheter inserted via the internal jugular or subclavian vein in an attempt to provide right ventricular protection,
      • Mustafa A.K.
      • Alexander P.J.
      • Joshi D.J.
      • et al.
      Extracorporeal Membrane Oxygenation for Patients With COVID-19 in Severe Respiratory Failure.
      as some reports suggest a higher incidence of right ventricular dysfunction in patients with COVID-19-related ARDS,
      • Creel-Bulos C.
      • Hockstein M.
      • Amin N.
      • Melhem S.
      • Truong A.
      • Sharifpour M.
      Acute Cor Pulmonale in Critically Ill Patients with Covid-19.
      but more data is needed to support this strategy either with a dual-lumen cannula or with dual-site cannulation with two separate cannulae. Mobile ECMO or ECMO transport with cannulation at the originating hospital and transfer to another institution appears to be safe from a healthcare exposure standpoint when accompanied by protocols incorporating adequate protective measures.
      • Salas de Armas I.A.
      • Akkanti B.H.
      • Janowiak L.
      • et al.
      Inter-hospital COVID ECMO air transportation.
      ,
      • Rafiq M.U.
      • Valchanov K.
      • Vuylsteke A.
      • et al.
      Regional extracorporeal membrane oxygenation retrieval service during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic: an interdisciplinary team approach to maintain service provision despite increased demand.
      However, it is important to note that the coordination and feasibility of ECMO transport varies across regions and, consequently, rates of transport do as well. This may be due in part to differences in practice, training, certification and regulation.

      Ongoing Care while Receiving ECMO

      Management strategies of patients requiring ECMO support for COVID-19-related ARDS remain similar to those recommended prior to the pandemic (Figure 1), but specific factors should be considered (Figure 2).
      • Brodie D.
      • Slutsky A.S.
      • Combes A.
      Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review.
      ,

      Extracorporeal Life Support Organization (ELSO). Resources > Guidelines. Available at: https://www.elso.org/Resources/Guidelines.aspx. Accessed April 1, 2022.

      From a safety and feasibility standpoint, a number of procedures and techniques have been successfully performed during the course of the pandemic. Endotracheal extubation while awake during ECMO has been performed, although data is very limited;
      • Mustafa A.K.
      • Alexander P.J.
      • Joshi D.J.
      • et al.
      Extracorporeal Membrane Oxygenation for Patients With COVID-19 in Severe Respiratory Failure.
      in contrast, awake ECMO without intubation in selected highly patients has been associated with potentially worse outcomes in one small cohort.
      • Mang S.
      • Reyher C.
      • Mutlak H.
      • et al.
      Awake Extracorporeal Membrane Oxygenation for COVID-19-induced Acute Respiratory Distress Syndrome.
      Prone positioning
      • Schmidt M.
      • Hajage D.
      • Lebreton G.
      • et al.
      Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study.
      ,
      • Garcia B.
      • Cousin N.
      • Bourel C.
      • Jourdain M.
      • Poissy J.
      • Duburcq T.
      Prone positioning under VV-ECMO in SARS-CoV-2-induced acute respiratory distress syndrome.
      ,
      • Giani M.
      • Martucci G.
      • Madotto F.
      • et al.
      Prone Positioning during Venovenous Extracorporeal Membrane Oxygenation in Acute Respiratory Distress Syndrome. A Multicenter Cohort Study and Propensity-matched Analysis.
      and early mobilization
      • Mustafa A.K.
      • Alexander P.J.
      • Joshi D.J.
      • et al.
      Extracorporeal Membrane Oxygenation for Patients With COVID-19 in Severe Respiratory Failure.
      appear feasible in patients with COVID-19 requiring ECMO support, however data remains too limited to support specific recommendations. Percutaneous tracheostomy appears to be safe in patients with COVID-19.
      • Rosano A.
      • Martinelli E.
      • Fusina F.
      • et al.
      Early Percutaneous Tracheostomy in Coronavirus Disease 2019: Association With Hospital Mortality and Factors Associated With Removal of Tracheostomy Tube at ICU Discharge. A Cohort Study on 121 Patients.
      From an infection control standpoint, there is no evidence to suggest virions can be expelled through an ECMO circuit.
      • Dres M.
      • Burrel S.
      • Boutolleau D.
      • et al.
      SARS-CoV-2 Does Not Spread Through Extracorporeal Membrane Oxygenation or Dialysis Membranes.
      Cytokine removal devices, which utilize an absorber to remove excess cytokines from whole blood, have been proposed as adjunctive therapies in patients receiving ECMO for COVID-19-related ARDS. However, clinicians should proceed cautiously and consider only using cytokine removal devices in such patients in the setting of research, given that recent evidence suggests possible harm.
      • Supady A.
      • Weber E.
      • Rieder M.
      • et al.
      Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial.
      Figure thumbnail gr2
      Figure 2Specific considerations for ECMO for COVID-19-related ARDS that may differ from ECMO for non-COVID-19 ARDS RV= right ventricular From Brodie D, Abrams D, MacLaren G, et al. Extracorporeal Membrane Oxygenation during Respiratory Pandemics: Past, Present, and Future. Am J Respir Crit Care Med. 2022;205(12):1382-1390.
      COVID-19 has been associated with coagulopathy, including an increase in risk of both significant thrombosis and bleeding.
      • Barnes G.D.
      • Burnett A.
      • Allen A.
      • et al.
      Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum.
      ,
      • Yusuff H.
      • Zochios V.
      • Brodie D.
      Thrombosis and Coagulopathy in COVID-19 Patients Requiring Extracorporeal Membrane Oxygenation.
      Hematological complications – including circuit clotting,
      • Bemtgen X.
      • Zotzmann V.
      • Benk C.
      • et al.
      Thrombotic circuit complications during venovenous extracorporeal membrane oxygenation in COVID-19.
      ,
      • Guo Z.
      • Sun L.
      • Li B.
      • et al.
      Anticoagulation Management in Severe Coronavirus Disease 2019 Patients on Extracorporeal Membrane Oxygenation.
      pulmonary embolism
      • Schmidt M.
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      • Lebreton G.
      • et al.
      Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study.
      and intracranial hemorrhage
      • Masur J.
      • Freeman C.W.
      • Mohan S.
      A Double-Edged Sword: Neurologic Complications and Mortality in Extracorporeal Membrane Oxygenation Therapy for COVID-19-Related Severe Acute Respiratory Distress Syndrome at a Tertiary Care Center.
      • Usman A.A.
      • Han J.
      • Acker A.
      • et al.
      A Case Series of Devastating Intracranial Hemorrhage During Venovenous Extracorporeal Membrane Oxygenation for COVID-19.
      • Zahid M.J.
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      • Galvez-Jimenez N.
      • Martinez N.
      Hemorrhagic stroke in setting of severe COVID-19 infection requiring Extracorporeal Membrane Oxygenation (ECMO).
      • Heman-Ackah S.M.
      • Su Y.S.
      • Spadola M.
      • et al.
      Neurologically Devastating Intraparenchymal Hemorrhage in COVID-19 Patients on Extracorporeal Membrane Oxygenation: A Case Series.
      – have been reported as occurring more frequently in patients with COVID-19 supported with ECMO than in non-COVID ECMO cases, but, when normalized to ECMO run duration, such complication rates appear similar to historical data.
      • Barbaro R.P.
      • MacLaren G.
      • Boonstra P.S.
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry.
      In the setting of observational data, the similar normalized rates must be interpreted with caution. Multiple centers have adjusted their anticoagulation thresholds, but there are insufficient data to support anticoagulation strategies and monitoring other than usual practices.

      McMichael ABV, Ryerson LM, Ratano D, Fan E, Faraoni D, Annich GM. 2021 ELSO Adult and Pediatric Anticoagulation Guidelines. Asaio j. 2022;68(3):303-310.

      Additionally, there is no evidence to suggest different blood transfusion thresholds for patients with COVID-19 during ECMO support.
      • Ramanathan K.
      • MacLaren G.
      • Combes A.
      • Brodie D.
      • Shekar K.
      Blood transfusion strategies and ECMO during the COVID-19 pandemic - Authors' reply.

      ECMO as a Bridge to Lung Transplantation

      COVID-19-related ARDS has often demonstrated a more prolonged recovery process than what is typically seen for ARDS of other etiologies, and the duration of ECMO support for patients with severe disease has increased as the pandemic has evolved.
      • Barbaro R.P.
      • MacLaren G.
      • Boonstra P.S.
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry.
      Lung transplantation may be considered in select patients who have persistent severe respiratory failure – assuming otherwise appropriate candidacy with preserved extra-pulmonary organ function – and may be particularly relevant for those who are unable to wean from ECMO, with initial reports demonstrating post-transplant outcomes comparable to those with non-COVID end-stage lung disease.
      • Bharat A.
      • Machuca T.N.
      • Querrey M.
      • et al.
      Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries.
      ,
      • Roach A.
      • Chikwe J.
      • Catarino P.
      • et al.
      Lung Transplantation for Covid-19-Related Respiratory Failure in the United States.
      However, determination of the potential for recovery of native lung function and optimal timing of transplantation remain areas of uncertainty that warrant further investigation.
      • Bermudez C.A.
      • Crespo M.M.
      The Case for Prolonged ECMO for COVID-19 ARDS as a Bridge to Recovery or Lung Transplantation.
      ,
      • Cypel M.
      • Keshavjee S.
      When to consider lung transplantation for COVID-19.

      Surge Capacity and ECMO

      Crisis Standards of Care

      During the pandemic, surges in case volume often led to the implementation of contingency or crisis standards of care, requiring triage of critical care resources, including intensive care unit beds, medical supplies and staffing. At the same time, there was an increased demand for ECMO – a highly resource-intensive intervention with potential for prolonged use of critical care services
      • Combes A.
      • Brodie D.
      • Bartlett R.
      • et al.
      Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients.
      – due to the high incidence of severe, refractory ARDS among patients with COVID-19. Many institutions, in an effort to provide medical care to the greatest number of patients, became more stringent with patient selection for ECMO – or abandoned the use of ECMO altogether.
      • Supady A.
      • Badulak J.
      • Evans L.
      • Curtis J.R.
      • Brodie D.
      Should we ration extracorporeal membrane oxygenation during the COVID-19 pandemic?.
      • Supady A.
      • Brodie D.
      • Curtis J.R.
      Ten things to consider when implementing rationing guidelines during a pandemic.
      • Supady A.
      • Curtis J.R.
      • Abrams D.
      • et al.
      Allocating scarce intensive care resources during the COVID-19 pandemic: practical challenges to theoretical frameworks.
      • Abrams D.
      • Lorusso R.
      • Vincent J.L.
      • Brodie D.
      ECMO during the COVID-19 pandemic: when is it unjustified?.
      For those centers that continued to perform ECMO despite resource constraints, non-traditional staffing models were helpful in maintaining operations.
      • Agerstrand C.
      • Dubois R.
      • Takeda K.
      • et al.
      Extracorporeal Membrane Oxygenation for Coronavirus Disease 2019: Crisis Standards of Care.
      In settings of reduced ECMO capacity, it may be necessary to apply more stringent exclusion criteria based on patient characteristics associated with increased mortality and longer ECMO run duration (Figure 3).
      • Badulak J.
      • Antonini M.V.
      • Stead C.M.
      • et al.
      Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization.
      Pre-designed triage systems may be useful in standardizing which patients should receive ECMO at varying levels of capacity, and may also help achieve equitable access to ECMO by establishing allocation policies that avoid discrimination based on age, race, ethnicity, disability or socioeconomic status.
      • Supady A.
      • Curtis J.R.
      • Abrams D.
      • et al.
      Allocating scarce intensive care resources during the COVID-19 pandemic: practical challenges to theoretical frameworks.
      Figure thumbnail gr3
      Figure 3Patient selection and contingency flowsheet for ECMO during a pandemic Contraindications algorithm for V-A and V-V ECMO use (COVID-19 and non-COVID-19) during a pandemic based on system capacity. The impact of duration on high-flow nasal cannula and/or noninvasive mechanical ventilation in addition to invasive mechanical ventilation is unknown. COVID-19, coronavirus disease 2019; CPR, cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; PaCO2, partial pressure of carbon dioxide in arterial blood; PaO2:FiO2, ratio of partial pressure of oxygen in arterial blood to the fractional concentration of oxygen in inspired air; PEEP, positive end-expiratory pressure; V-A, venoarterial; V-V, venovenous.From Badulak J, Antonini MV, Stead CM, et al. Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization. ASAIO J. 2021;67(5):485-495.

      Regional and National Coordination

      Over the course of the pandemic, the coordination of ECMO programs at regional and national levels was leveraged to more effectively standardize ECMO candidacy and allocate resources. In Paris, a regional network coordinated care of 17 hospitals to pool resources, systematize ECMO candidacy evaluations, and expanded mobile ECMO capacity in an effort to improve resource utilization, streamline workflow for clinicians, optimize management of patients prior to ECMO initiation, and facilitate data collection.
      • Lebreton G.
      • Schmidt M.
      • Ponnaiah M.
      • et al.
      Extracorporeal membrane oxygenation network organisation and clinical outcomes during the COVID-19 pandemic in Greater Paris, France: a multicentre cohort study.
      ,
      • Levy D.
      • Lebreton G.
      • Pineton de Chambrun M.
      • et al.
      Outcomes of Patients Denied Extracorporeal Membrane Oxygenation during the COVID-19 Pandemic in Greater Paris, France.
      Chile used a National Advisory Commission to help coordinate ECMO referrals, provide consistent patient selection, optimize capacity, and distribute educational materials.
      • Diaz R.A.
      • Graf J.
      • Zambrano J.M.
      • et al.
      Extracorporeal Membrane Oxygenation for COVID-19-associated Severe Acute Respiratory Distress Syndrome in Chile: A Nationwide Incidence and Cohort Study.
      The United Kingdom modified a preexisting national system to balance ECMO cases among centers in order to help manage capacity.
      • Camporota L.
      • Meadows C.
      • Ledot S.
      • et al.
      Consensus on the referral and admission of patients with severe respiratory failure to the NHS ECMO service.
      The creation or utilization of existing regional or national ECMO networks has been encouraged by the Extracorporeal Life Support Organization (ELSO), which has an “ECMO Availability Map” to help guide such coordination efforts.
      • Badulak J.
      • Antonini M.V.
      • Stead C.M.
      • et al.
      Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization.
      ,

      Extracorporeal Life Support Organization (ELSO). Membership > ECMO Availability Map. Available at: https://www.elso.org/Membership/ECMOAvailabilityMap.aspx. Accessed April 1, 2022.

      The purported effectiveness of these examples also provides a rationale for establishing new networks where none currently exist. However, the ability to coordinate ECMO across a region will depend, in large part, on the established healthcare systems in that area.

      Development of New ECMO Centers

      Initial guidance early in the pandemic recommended against development of new ECMO centers,
      • Shekar K.
      • Badulak J.
      • Peek G.
      • et al.
      Extracorporeal Life Support Organization Coronavirus Disease 2019 Interim Guidelines: A Consensus Document from an International Group of Interdisciplinary Extracorporeal Membrane Oxygenation Providers.
      ,
      • Bartlett R.H.
      • Ogino M.T.
      • Brodie D.
      • et al.
      Initial ELSO Guidance Document: ECMO for COVID-19 Patients with Severe Cardiopulmonary Failure.
      given the concerns over the implementation of a resource-heavy intervention in inexperienced centers that may be dealing with simultaneous surge capacity issues. Retrospective data from new ECMO centers developed in the Middle East and India – under the guidance of established centers – did report acceptable survival in these new programs overall compared to established ECMO centers (55% vs. 45%, OR 1.65; 95% CI 0.75-3.67), although, as the authors note, patient selection likely differed between the centers with selection bias favoring the new centers. In light of this relative success, and recognizing the potential need for ECMO in regions that otherwise would not have access to ECMO, ELSO has updated its guidance to recommend that establishment of new ECMO centers may be considered in select cases where regional resources exist to support these programs, there is sufficiently high demand, and there is close collaboration with experienced centers to optimize outcomes.
      • Badulak J.
      • Antonini M.V.
      • Stead C.M.
      • et al.
      Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization.

      Evaluating Effectiveness of ECMO in an Ongoing Pandemic

      Surveillance and Study Design Approaches

      Early data during a pandemic of a novel disease must be interpreted with caution given the potential for misleading data due to study designs and population characteristics. Determining the effectiveness of ECMO during an evolving pandemic requires ongoing surveillance as well as design and implementation of studies that have the ability to assess both short- and longer-term outcomes, and especially patient-centered outcomes.
      • MacLaren G.
      • Fisher D.
      • Brodie D.
      Treating the Most Critically Ill Patients With COVID-19: The Evolving Role of Extracorporeal Membrane Oxygenation.
      National and international registries are useful in centralizing data and may serve as platforms for analysis and dissemination of information.

      Extracorporeal Life Support Organization (ELSO). Resources > Guidelines. Available at: https://www.elso.org/Resources/Guidelines.aspx. Accessed April 1, 2022.

      As the course of a pandemic takes shape and data begins to accumulate, especially results from clinical trials, the community must learn to pivot toward practices that are more evidence-based.
      While traditional RCTs are considered the “gold standard” for providing credible, unbiased evidence for the efficacy of an intervention, they can be difficult to organize and perform in real-time during a rapidly evolving pandemic, especially with a resource-intensive therapy such as ECMO, substantial limitations in staffing and funding to conduct such trials, and a perceived lack of clinical equipoise for randomization. A number of different study designs have been employed during the COVID-19 pandemic in an effort to approximate an RCT using observational data (Table 2), including: emulation trials,
      • Shaefi S.
      • Brenner S.K.
      • Gupta S.
      • et al.
      Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19.
      ,
      • Urner M.
      • Barnett A.G.
      • Bassi G.L.
      • et al.
      Venovenous extracorporeal membrane oxygenation in patients with acute covid-19 associated respiratory failure: comparative effectiveness study.
      registry randomized controlled trials, and matched-pair analyses.
      • Whebell S.
      • Zhang J.
      • Lewis R.
      • et al.
      Survival benefit of extracorporeal membrane oxygenation in severe COVID-19: a multi-centre-matched cohort study.
      Adaptive platform trials and weighted lottery systems can also provide a more rapid assessment of ECMO efficacy, the latter of which can provide potentially large sample sizes and a more equitable approach to resource allocation.
      • White D.B.
      • Angus D.C.
      A Proposed Lottery System to Allocate Scarce COVID-19 Medications: Promoting Fairness and Generating Knowledge.
      Given that temporal changes during the pandemic – including emergence of viral variants and evolution of management strategies – are likely to impact ECMO efficacy and effectiveness, more adaptive and flexible study designs are likely to have the greatest success in providing high-quality evidence in a timely fashion.
      • Granholm A.
      • Alhazzani W.
      • Derde L.P.G.
      • et al.
      Randomised clinical trials in critical care: past, present and future.
      Table 2Study Designs in a Pandemic, Pros and Cons
      Study designProsCons
      Randomized Controlled Trial (RCT)•Gold standard design

      •Minimizes bias and confounding

      •Best at determining efficacy
      •Time consuming and expensive making it difficult to perform in real time during a pandemic

      •Would need clinical equipoise
      Emulation of Target Trial or RCT•Can simulate RCT with preexisting observational data

      •Less time consuming and expensive

      •No ethical concerns
      •May still have residual bias and confounding
      Registry RCT•RCT that is less time consuming and expensive

      •No ethical concerns
      •Registries may lack necessary clinical information
      Matched-pair analyses•Allows for evaluation of treatment effect in an observational design•May still have residual bias and confounding
      Adaptive Platform Trial•Allows evaluation of multiple interventions which can be added or dropped during the study

      •Is useful when mechanism of disease is not well understood

      •Requires fewer patients
      •Requires multiple points of interim analysis

      Communication and collaboration

      Through the course of the pandemic, regional, national and international coordination has been crucial in knowledge sharing, research collaboration and development of guidelines. Remote learning and communication became a key component of health care provider education throughout the pandemic. Educational webinars and conferences by ELSO and other ECMO networks have been utilized to disseminate new data to both experienced and new ECMO centers and practitioners.
      • Badulak J.
      • Antonini M.V.
      • Stead C.M.
      • et al.
      Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization.

      Pediatric Access to ECMO During the Pandemic

      Children were generally less susceptible to severe illness associated with COVID-19 infection, though a new post-viral pathological process, Multisystem Inflammatory Syndrome in Children (MISC), was identified during the pandemic.
      • Lu X.
      • Zhang L.
      • Du H.
      • et al.
      SARS-CoV-2 Infection in Children.

      Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. 2020;383(4):334-346.

      • Feldstein L.R.
      • Tenforde M.W.
      • Friedman K.G.
      • et al.
      Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19.
      Access to ECMO for children with non-COVID-19 critical illness, congenital anomalies and emergent peri-operative indications, in addition to the infrequent pediatric patients who were critically ill with COVID-19, was preserved in many regions and recommended in guidelines.
      • Badulak J.
      • Antonini M.V.
      • Stead C.M.
      • et al.
      Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization.
      ,
      • Gerall C.
      • Cheung E.W.
      • Klein-Cloud R.
      • Kreines E.
      • Brewer M.
      • Middlesworth W.
      Allocation of resources and development of guidelines for extracorporeal membrane oxygenation (ECMO): Experience from a pediatric center in the epicenter of the COVID-19 pandemic.
      • DeFazio J.R.
      • Kahan A.
      • Fallon E.M.
      • et al.
      Development of pediatric surgical decision-making guidelines for COVID-19 in a New York City children's hospital.
      • Cho H.J.
      • Ogino M.T.
      • Jeong I.S.
      • et al.
      Pediatric intensive care preparedness and ECMO availability in children with COVID-19: An international survey.
      • Lemmon M.E.
      • Truog R.D.
      • Ubel P.A.
      Allocating Resources Across the Life Span During COVID-19-Integrating Neonates and Children Into Crisis Standards of Care Protocols.
      • Cleary A.
      • Chivers S.
      • Daubeney P.E.
      • Simpson J.M.
      Impact of COVID-19 on patients with congenital heart disease.
      In addition, many established pediatric ECMO centers expanded their admission criteria to facilitate the care of adult COVID patients who required ECMO and offload regional centers at capacity.
      • Gerall C.
      • Cheung E.W.
      • Klein-Cloud R.
      • Kreines E.
      • Brewer M.
      • Middlesworth W.
      Allocation of resources and development of guidelines for extracorporeal membrane oxygenation (ECMO): Experience from a pediatric center in the epicenter of the COVID-19 pandemic.
      ,
      • DeFazio J.R.
      • Kahan A.
      • Fallon E.M.
      • et al.
      Development of pediatric surgical decision-making guidelines for COVID-19 in a New York City children's hospital.
      ,
      • Yager P.H.
      • Whalen K.A.
      • Cummings B.M.
      Repurposing a Pediatric ICU for Adults.
      While there are many examples of successful shared resource allocation protocols, particular care was required to address the unique challenges of assessing mortality risk in the neonatal and pediatric populations. The COVID-19 pandemic highlighted that at times of critical care shortages, protocols which ensure equity across the life span should be employed.
      • Lemmon M.E.
      • Truog R.D.
      • Ubel P.A.
      Allocating Resources Across the Life Span During COVID-19-Integrating Neonates and Children Into Crisis Standards of Care Protocols.
      ,
      • Emanuel E.J.
      • Persad G.
      • Upshur R.
      • et al.
      Fair Allocation of Scarce Medical Resources in the Time of Covid-19.

      Health Care Providers and ECMO

      The COVID-19 pandemic has affected health care workers in a multitude of ways, notably through occupational stress and provider burnout.

      Myran DT, Cantor N, Rhodes E, et al. Physician Health Care Visits for Mental Health and Substance Use During the COVID-19 Pandemic in Ontario, Canada. JAMA Network Open. 2022;5(1):e2143160-e2143160.

      ,
      • Pfefferbaum B.
      • North C.S.
      Mental Health and the Covid-19 Pandemic.
      Surge situations and crisis standards of care have only amplified the pressure placed on health care providers through unfavorable changes in staffing models and increases in provider responsibilities, ethical dilemmas, and patient mortality, among others. Contingency and crisis standards for ECMO implementation during the COVID-19 pandemic have added to provider stress through a potentially heavy ethical burden of rationing care, potentially resulting in an inability, during surge conditions, to provide ECMO to those who meet standard criteria for initiation and would otherwise have received ECMO under less strained conditions. Prolonged ECMO run times and longer than usual time-to-recovery for these patients with ARDS
      • Barbaro R.P.
      • MacLaren G.
      • Boonstra P.S.
      • et al.
      Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry.
      can also contribute to healthcare provider burnout. Triage committees have been proposed to relieve bedside providers of these burdens by objectively and independently setting standards and developing guidelines for rationing decisions. However, operationalizing a triage committee amid a crisis is a complex and fraught undertaking that requires direct input from community leaders in order to address ethical and legal issues, along with the need for equity. The major function of an oversight committee under crisis conditions may simply be to offload the overburdened clinicians on the front lines.
      • Supady A.
      • Brodie D.
      • Curtis J.R.
      Ten things to consider when implementing rationing guidelines during a pandemic.

      Summary

      The COVID-19 pandemic has led to a marked increase in cases of ARDS globally, leading to a concomitant rise in demand for ECMO support. The utilization of ECMO during the pandemic has been complicated by numerous factors, including limited knowledge of ECMO-related outcomes, challenges in performing real-time, high-quality research in an ongoing evolving pandemic, difficulties in patient selection during episodic severe capacity restraints, the ethical dilemmas of rationing care, and excess strain not only on health care systems but on providers as well. As the pandemic eventually recedes and resources become more readily and consistently available to provide ECMO, both coordinated research and tailoring of guidelines will be necessary to understand the role of ECMO, provide the best care possible to patients with severe COVID-19-related ARDS, and to anticipate needs for future potential pandemics.
      Clinics Care Points
      • The COVID-19 pandemic has led to an increase in severe ARDS cases globally, increasing the demand for ECMO.
      • Outcomes of patients with COVID-19 managed with ECMO have evolved during the pandemic, with early data suggesting mortality rates similar to those with non-COVID-19 etiologies of ARDS, but later data suggesting increasing mortality and longer ECMO duration of support over time.
      • Eligibility criteria, cannulation and management strategies for patients with severe ARDS requiring ECMO thus far remain largely the same for patients with COVID-19.
      • Episodic surge capacity requirements have often led to crisis standards of care, which may include the rationing or tailoring of eligibility criteria of ECMO, particularly with respect to more stringent exclusion criteria.
      • Regional, national and international collaboration will continue to help inform ECMO providers, disseminate new information and aid in resource allocation.
      • Ongoing surveillance data and new research techniques will continue to inform the role of ECMO in the management of COVID-19-related ARDS.

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