key: cord-345040-cuau2dcy authors: Alom, Samiha; Haiduc, Ana Alina; Melamed, Naomi; Axiaq, Ariana; Harky, Amer title: Use of ECMO in COVID-19 patients: Does the evidence suffice? date: 2020-07-30 journal: J Cardiothorac Vasc Anesth DOI: 10.1053/j.jvca.2020.07.070 sha: doc_id: 345040 cord_uid: cuau2dcy nan Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gathered worldwide attention for its potentially fatal course and complex clinical manifestations. This novel virus primarily affects the cardiorespiratory system, which can lead to acute respiratory distress syndrome (ARDS) and shock [1] . Whilst severe and critically ill patients account for 15-26% of patients, there are currently no targeted COVID-19 therapeutics [2] . At present, the mainstay of management is supportive care, with focus on delivering oxygen early in the disease course [3] . In March 2020, the World Health Organisation (WHO) released interim guidelines that advocate the use of extracorporeal membrane oxygenation (ECMO) to support the cardiorespiratory system in patients who fail maximal conventional therapies with ARDS [4] . In this letter, we have performed a systematic review of literature to summarize the evidence behind using ECMO in COVID-19 patients. We have performed a comprehensive electronic literature search following 'Preferred Reporting Items for Systematic Reviews and Metaanalysis' (PRISMA) guidelines and using key words 'COVID-19' 'SARS-CoV2' 'Coronavirus' 'ECMO' 'Extracorporeal membrane oxygenation' 'VA-ECMO' 'VV-ECMO' 'Outcomes' 'Respiratory support' 'circulatory support' either as MeSH terms or in the combined key-word formats. Our results showed a total of 102 articles that were retrieved from the database search and through snowballing. Following exclusion of duplicates and screening, a total of 25 articles were selected for inclusion in this systematic review ( Figure 1 ). The characteristics of these studies are summarised in table 1. Upon combining the data from all the studies, overall there were 3428 patients diagnosed with COVID-19, 612 patients diagnosed with ARDS and 479 placed on ECMO, with VV-ECMO being the most commonly utilised type. ECMO was often adopted as salvage therapy for patients commonly experiencing COVID-19-induced ARDS and/or other COVID-19 complications [5] [6] [7] [8] . The overall mortality rate following the collation of the data from the 25 articles selected in this review was 19.83%. This value can, however, only be used as an estimate since some articles did not report mortality outcomes for their patients put on ECMO, making the mortality rate subject to increase. Despite this, this figure shows promise that ECMO is not detrimental for critically ill patients with COVID-19. A small number of studies presented high rates of mortality for patients with COVID-19. Three studies in this review reported 100% mortality for patients with ARDS put on ECMO, while Yang et al reported a similarly high mortality rate of 83.33% (15 deaths in total) [9] [10] [11] [12] . In addition, Guan et al reported that all 5 patients that were put on ECMO experienced the composite primary endpoint that consisted of admission to the ICU, use of mechanical ventilation or death [13] . Other studies reporting poor outcomes for ECMO include Zeng et al [16] . Whilst 3 patients did recover following ECMO, 4 patients (2 of which were comatose) remained on ECMO and 5 patients died. Despite this however, the study attributed half the deaths to septic shock and multiple organ failure which required VA-ECMO support. While we are not sure whether the patients in question experienced multiple organ failure whilst on ECMO, if this was the case it would provide an explanation for the negative outcome due to the absolute contraindication between ECMO and multiple organ failure (as depicted in ELSO guidelines) [14] . Li et al depicted rather ambivalent results, reporting a 50% mortality rate [15] . However, upon closer look at the demographic data, 3 out of the 4 deaths occurred in patients with comorbidities over the age of 75. Similarly, Marullo et al did not indicate any strong conclusions for the use of ECMO, whereby the difference between the number of patients weaned off ECMO (60) and the number of deaths following ECMO (57) was marginal [16] . However, like Li et al, the study highlighted the increased risk of patients over 60 who possessed comorbidities, characteristics that were consistent with the mortality that was reported in the study. Loforte et al also reported that 3 out of 4 patients were weaned off ECMO, and while a 75% weaning rate appears successful, one of the three weaned patients eventually died after VV-ECMO removal [17] . The final patient died due to severe gastrointestinal bleeding while on ECMO, highlighting the potentially fatal complications associated with ECMO (with bleeding being the most frequent) [18] . Thus, with 2 patients out of the four eventually expiring, this study also provides no conclusive indication of the effectiveness of ECMO for COVID- Whilst these studies have reported either negative or equivocal results, several considerations should be noted. Firstly, many of these articles consist of a small sample and thus no reliable conclusions can be made. Secondly, some of the articles did not provide information with regards to the patient's disease severity at the time of ECMO initiation, so we cannot know if ECMO was perhaps administered too late to have a significant effect in a severely deteriorating patient. Many of the case reports/series included in this review reported positive outcomes, and while these studies cannot provide us with robust evidence to make overarching conclusions, they can help us identify patient characteristics that are ideal for ECMO. Six case reports and two case series reported positive endpoints (weaned off ECMO/discharged from hospital) for patients on ECMO [19] [20] [21] [22] [23] [24] [25] [26] [27] . The literature posited that early timing of ECMO support may have resulted in successful outcomes. Zhan et al and Taniguchi et al indicated that early ECMO provision could have enabled the recovery of their patients, whereby their organ oxygen supply was protected and lung injury resulting from mechanical damage (ventilators) was avoided [26, 27] . Firstenberg et al, also highlighted that the most critical aspect to starting therapy is the timing between reaching the threshold for indication and the decision to begin therapy, whereby their judicious decision to initiate ECMO resulted in the patient's discharge [21] . Additionally, Taniguchi et al highlighted how the use of ECMO to stabilise oxygenation and rest the lungs can also have a role in improving outcomes [26] . Recognition and treatment of the cause of deteriorating oxygenation is imperative. In the context of this case, the patient may have experienced worsening oxygenation due to aggravation of ARDS by COVID-19 pneumonia. Whereby inflammatory results were stronger than pulmonary congestion, ECMO was initiated to aid the patient's recovery [28] [29] [30] . The main contraindications for the use of ECMO are summarized in table 2 according to ELSOM guidelines. Upon comparing our results to wider literature, we found that they have similarly endorsed the use of VV-ECMO. According to a systematic review and meta-analysis which included the CESAR [31] and EOLIA [32] trials amongst others, the use of VV-ECMO in acute severe respiratory failure was associated with a 60-day reduced mortality (RR 0.73, 95% CI 0.58-0.92) when compared with conventional mechanical ventilation [33] . Although the CESAR study has been largely opposed by many clinicians, yet the EOLIA study showed no significant difference in overall mortality. Additionally, ELSO also reported a 40% expected survival to discharge on VA [34] compared to 58% on VV [35] , however this has not been compared to conventional care so the survival advantage of VV is unknown [36, 37] . The use of VV-ECMO in COVID-19 ARDS is supported by multiple guidelines [4, 14, 38, 39] . VV-ECMO provides respiratory support and is most commonly used in severe respiratory failure. As SARS-COV-2 pneumonia is characterised in most cases by acute respiratory failure with some progressing to ARDS, VV-ECMO has been increasingly used. In contrast, VA-ECMO provides both respiratory and haemodynamic support and is used in cases of cardiogenic shock as a result of cardiac injury, myocarditis, acute myocardial infarction or decompensated cardiac failure. As COVID-19 is associated with high incidence (22%) of cardiovascular complications, in particular myocarditis, heart failure and a prothrombotic state, VA-ECMO could have an important role in these patients [40] . Drawing from data published so far, we propose the following algorithm outlined in Figure 2 . Patients presumed suitable for ECMO should be identified early, to minimise the risk of complications associated with prolonged ventilator use. In addition, we suggest that if the decision to use ECMO is endorsed, referral to tertiary centres with established expertise and standardized ECMO protocols should ideally be done. Additionally, since the combination of systemic inflammatory response and the need for anticoagulation in ECMO can lead to an imbalance in the pro and anticoagulant pathways and increase the risk of both thrombotic and haemorrhagic complications, care should be taken to ensure a balanced coagulation profile during ECMO [41] . In addition to existing guidelines, several prediction tool scores including the PRESERVE ( (AUC 0.75 (95% CI 0.57 to 0.92, P = 0.01) and RESP scores (AUC 0.81 (95% CI 0.67 to 0.95, P = 0.035) have been developed to aid decision making regarding the use of VV-ECMO based on best predicted outcomes [42] . The survival after veno-arterial-ECMO (SAVE) score can be used to identify patients that would benefit more from VA-ECMO and balance use with availability of resources [43] . However, whilst these tools have been shown to be a good predictor of survival of patients with ARDS placed on VV-ECMO, they do not account for the unique pathophysiology involving the cytokine storm encountered in COVID-19 patients. To conclude, there is currently not enough evidence to support ECMO utilisation in COVID- 19 , we recommend that ECMO should be used with caution and should comply with current guidelines. Ongoing research should help in understanding this pattern and the benefit of ECMO in COVID-19 patients on Intensive care unit. A risk-benefit analysis should be undertaken for patients, and all decisions should be made on a case-by-case basis. Due to the paucity of data in this area, particularly for use of VA-ECMO, no reliable overarching conclusions can be made on ECMO utilisation for COVID-19. However, this perhaps be explained by the fact that ARDS (for which VV-ECMO is used) is far more prevalent among COVID-19 patients compared to those with shock (where VA-ECMO is used). Secondly, since several studies did not report patient outcomes, we have gaps in our data as we cannot make any assumptions on whether ECMO has a positive or negative effect on the patients. The lack of data on outcomes also prevented us from performing a meta-analysis as the effect size could not be calculated. Therefore, the overall mortality rate that we reported (which included studies without reported outcomes) may be subject to change. Thirdly, as the characteristics of patients included in the studies were not always mentioned, we cannot make any assumptions on how ECMO reduces mortality in particular groups of people. Since demographic factors and presence of comorbidities have great influence over COVID-19 prognosis, these variables should be taken into consideration as potential determinants of patients' outcomes, alongside with initiation of ECMO as a treatment. While ECMO is usually provided alongside with a primary treatment, many of the patients received numerous alternative therapies on top of that. Therefore, it is unclear to what extent ECMO utilisation contributed to treating and healing the patient. Fourthly, there is inconsistency amongst papers regarding the threshold used for deciding the use of ECMO. For example, some patients may have received ECMO at later and more critical stages which would have had increased baseline risk of mortality. In addition, institutions with low numbers of ECMO machines may have prioritised critical patients, as they are in more need of salvage therapy which could have also reflected in the reported mortality rates (selection bias). Additionally, use of different guidelines, if guidelines were used at all, may have also contributed to different outcomes in patients. Therefore, although we have provided an overall mortality rate after collation of all the data, the rate estimate does not account for treatment variations (time of ECMO initiation and technique). PaO2:FiO2 = ratio of partial pressure of oxygen in arterial blood to the fractional concentration of oxygen in inspired air. PaCO2 = partial pressure of carbon dioxide in arterial blood. EMCO = extracorporeal membrane oxygenation. PEEP = positive end-expiratory pressure. *L-phenotype has been associated with preserved lung compliance and shown to have favourable outcomes with ECMO [29] . Adapted from the Extracorporeal Life Support Organisation (ELSO) [14] . [17] . A Review of Coronavirus Disease-2019 (COVID-19) Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Evaluation and Treatment Coronavirus (COVID-19), in StatPearls Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance SARS-CoV-2 in Spanish Intensive Care Units: Early experience with 15-day survival in Vitoria Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Comparison of Hospitalized Patients with ARDS Caused by COVID-19 and H1N1 Characteristics, treatment, outcomes and cause of death of invasively ventilated patients with COVID-19 ARDS in Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical Characteristics of Coronavirus Disease 2019 in China Extracorporeal Life Support Organization COVID-19 Interim Guidelines Extracorporeal Membrane Oxygenation for Coronavirus Disease Extracorporeal membrane oxygenation for critically ill patients with coronavirus-associated disease 2019: an updated perspective of the European experience Veno-venous Extracorporeal Membrane Oxygenation support in COVID-19 respiratory distress syndrome Predictive factors of bleeding events in adults undergoing extracorporeal membrane oxygenation. Ann Intensive Care Calculated decisions: COVID-19 calculators during extreme resource-limited situations First successful treatment of COVID-19 induced refractory cardiogenic plus vasoplegic shock by combination of pVAD and ECMO -a case report Successful COVID-19 rescue therapy by extracorporeal membrane oxygenation (ECMO) for respiratory failure: a case report COVID-19 Respiratory Failure: Targeting Inflammation on VV-ECMO Support A sporadic COVID-19 pneumonia treated with extracorporeal membrane oxygenation in Tokyo, Japan: A case report Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma Veno-venous extracorporeal membrane oxygenation for severe pneumonia: COVID-19 case in Japan Successful treatment of COVID-19 using extracorporeal membrane oxygenation, a case report The role of extracorporeal life support for patients with COVID-19: Preliminary results from a statewide experience Nationwide system to centralize decisions around extracorporeal membranous oxygenation use for severe COVID-19 pneumonia in Japan Extracorporeal Membrane Oxygenation in the Treatment of Severe Pulmonary and Cardiac Compromise in COVID-19: Experience with 32 patients Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis Extracorporeal Life Support Organization (ELSO): Guidelines for Adult Cardiac Failure Extracorporeal Life Support Organization (ELSO): Guidelines for Adult Respiratory Failure Complications of Extracorporeal Membrane Oxygenation for Treatment of Cardiogenic Shock and Cardiac Arrest: A Meta-Analysis of 1,866 Adult Patients Cannulation techniques for extracorporeal life support Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19) COVID-19: Interim Guidance on Management Pending Empirical Evidence. From an American Thoracic Society-led International Task Force Cardiovascular Collapse in COVID-19 Infection: The Role of Veno-Arterial Extracorporeal Membrane Oxygenation (VA-ECMO) COVID-19 and ECMO: the interplay between coagulation and inflammation-a narrative review External validation of scores proposed for estimation of survival probability of patients with severe adult respiratory distress syndrome undergoing extracorporeal membrane oxygenation therapy: a retrospective study Predicting survival after ECMO for refractory cardiogenic shock: the survival after veno-arterial-ECMO (SAVE)-score