key: cord-0892553-slpbckoe
authors: Tisminetzky, Manuel; Ferreyro, Bruno L.; Fan, Eddy
title: Extracorporeal Membrane Oxygenation in COVID-19
date: 2022-01-10
journal: Crit Care Clin
DOI: 10.1016/j.ccc.2022.01.004
sha: ff3a6211e52a1bef3e4b568f73f0550e85ee5c49
doc_id: 892553
cord_uid: slpbckoe

Extracorporeal membrane oxygenation (ECMO) is an intervention for severe acute respiratory distress syndrome (ARDS). Despite COVID-19 related ARDS might have some distinct features, its overall clinical presentation resembles ARDS from other etiologies. Thus, similar evidence-based practices for its management should be applied. These include lung-protective ventilation, prone positioning, and adjuvant strategies such as ECMO, when appropriate. Current evidence suggests that ECMO in COVID-19 related ARDS has similar efficacy and safety profile as for non-COVID-19 ARDS. The high number of severe COVID-19 cases and demand for therapies such as ECMO poses a unique opportunity to increase our understanding on how to optimize this intervention.

At the end of 2019 an outbreak of pneumonia due to a novel severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) was discovered in the city of Wuhan, China. 1 While the majority of cases of COVID-19 present with mild symptoms including fever, cough, and myalgia, a substantial number of patients develop acute hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS). 2, 3 Resembling other etiologies of ARDS, the treatment for severe presentations of COVID-19 frequently involves invasive mechanical ventilation and, in most severe cases, extracorporeal membrane oxygenation (ECMO). 4 Extracorporeal membrane oxygenation constitutes a costly and resource intense treatment for severe ARDS. 5 In the context of the COVID-19 pandemic and with an increasing number of patients requiring admission to an intensive care unit (ICU) worldwide, the appropriateness of use of treatments such as ECMO has been focus of some discussions. 6 The objective of this review is to describe the role of venovenous (VV) ECMO in patients with COVID-19 related ARDS.

2. ECMO for ARDS: rationale and history J o u r n a l P r e -p r o o f Acute respiratory distress syndrome is associated with high morbidity and mortality due to direct or indirect lung injury leading to multiorgan dysfunction. 7, 8 Mechanical ventilation remains the cornerstone of support for this syndrome, with the main goal to unload the respiratory muscles, providing adequate gas exchange while the lungs recover from the original insult. 9 While mechanical ventilation is a life-saving intervention, it can also lead to ventilator-induced lung injury (VILI) through different mechanisms. 10 The fundamental principle of lung-protective ventilation is to allow for adequate gas exchange while preventing VILI. 11, 12 In the most severe cases, lungprotective ventilation alone may be insufficient to achieve such goals and adjuvant strategies are needed. In this setting, ECMO can provide gas exchange bypassing the lungs allowing for a reduction in the intensity of mechanical ventilation. 13 The most frequent configuration used in this context (VV-ECMO) consists of a drainage cannula that withdraws deoxygenated blood from a central vein (e.g., femoral vein), a mechanical pump coupled with an oxygenator and a return cannula that restores oxygenated blood to the circulation through another central vein (e.g., internal jugular vein). 13 ECMO is not a novel technology and its successful application in a setting of acute respiratory failure was first described in the early 1970s. However, its utilization remained restricted to neonatal and pediatric patients for decades. 14, 15 Following technological advances, a new window of opportunity for ECMO in adults with acute respiratory failure opened during the Influenza A (H1N1) pandemic in 2009. During this time, ECMO was used in adults with severe ARDS as a salvage therapy. 16 Despite increasing enthusiasm and use, it remained unclear whether it was associated with a survival benefit. 17 J o u r n a l P r e -p r o o f Also in 2009, the Conventional ventilatory support vs. extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR) trial compared the efficacy, safety, and cost-effectiveness of standard of care in mechanical ventilation to VV-ECMO. 18 There was a significant increase in survival without disability in the group randomized to referral for ECMO consideration.

Importantly, only 70% of the conventional treatment group received lung protective ventilation in this pragmatic trial. Furthermore, only 76% of the patients allocated to the ECMO group actually received ECMO. The main conclusion of this trial was that referring patients to a centre of excellence capable of providing ECMO improved outcome, but it could not prove that ECMO by itself was responsible for this. 19 To help address this gap, the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial randomized patients with severe ARDS to receive treatment with VV-ECMO or conventional mechanical ventilation. The trial was stopped early for futility, with 60-day mortality of 35% in the ECMO group and 46% in the control group. 20 Although this result was not statistically significant, most secondary outcomes. In addition, a post hoc Bayesian analysis concluded that the posterior probability of a mortality benefit with ECMO was high even when using a strongly skeptical prior distribution. 21 Finally, the benefit of VV-ECMO on mortality in patients with severe ARDS is supported by individual patient data, study level, and network meta-analyses. 12, [22] [23] [24] 3. COVID-19 related ARDS: Is it really different?

The definition of ARDS encompasses clinical and radiological criteria along with the presence of typical risk factors for direct or indirect lung injury. 25, 26 Clinical and biological heterogeneity within ARDS is therefore implied and has been topic of extensive research. [27] [28] [29] [30] Since the beginning of the J o u r n a l P r e -p r o o f pandemic, the overwhelming number of COVID-19 patients admitted to ICUs around the globe allowed clinicians and researchers to appreciate this clinical heterogeneity and in consequence, treatment strategies based on different clinical features were suggested. 31 As more data emerged through the course of the pandemic, the characterization of COVID-19 related ARDS as a distinct entity was challenged.

Indeed, the current body of clinical, physiological, and pathological data seems to support the notion that this disease, while exhibiting some heterogeneity, has common features to ARDS secondary to other risk factors. [32] [33] [34] Accordingly, it is reasonable to apply the best evidence-based recommendations, particularly with respect to ventilatory strategies and adjutants to mechanical ventilation. 32,34

The role of VV-ECMO as a strategy for severe ARDS in the context of the COVID-19 pandemic exhibits old and new challenges. Given the increasing number of patients requiring ICU admission and ventilatory support, the role of ECMO was again brought into attention of clinicians and public at the same time, leading to a detailed description of patient's trajectories. [35] [36] [37] [38] [39] [40] [41] Furthermore, debate on whether ARDS secondary to COVID-19 is a different entity also led to questioning the role of VV-ECMO support in this context, and whether the existing evidence could be applied.

Finally, increasing concerns about ICU capacity and strain led to discussions about the appropriateness of ECMO as a highly technical intervention and to whether resources should be directed towards this intervention. 42, 43 J o u r n a l P r e -p r o o f

The literature surrounding the experience and outcomes of ECMO in patients with COVID-19 has transitioned from mainly anecdotical reports to large single and multicenter analyses (Table 1) . At the beginning of the pandemic, preliminary reports from China raised concerns highlighting increased mortality of COVID-19 related ARDS when compared to ARDS secondary to other risk factors. 6 The appropriateness of using a treatment that requires a highly specialized and technical team and a higher level of care at the bedside in the context of increased system strain was brought to the center of discussion. 6, 44, 45 In a pooled analysis, Henry and colleagues described that among 17 patients that required ECMO early in the pandemic mortality was as high as 94%. 6 However, mortality in the non-ECMO group was also considerably high, the sample was rather small and data regarding baseline characteristics was missing. Huang et al., found similar results and suggested using ECMO only for younger patients without pre-existing diseases, but this data was also derived from a very small case series. 46 Thus, these initial descriptions of ECMO for patients with severe COVID-19 were difficult to interpret and to translate into meaningful clinical recommendations.

In contrast, a prospective cohort study that included 17 patients on ECMO due to COVID-19 ARDS showed that 60-day mortality was significantly lower (35%) than the previous reports. 47 39 Based in part on these results, the Extracorporeal Life Support Organization (ELSO) advocated for the use of ECMO in specialized centres only. 48 49 J o u r n a l P r e -p r o o f A retrospective cohort study that included 319 patients on ECMO from 24 intensive care units in Spain and Portugal, reported similar results (mortality 35%). Interestingly, this study suggested a significant higher mortality during the second wave, which may be explained by patient-level (age, time on ventilator before cannulation) and center level characteristics. 50 40 Finally, a systematic review and meta-analysis of 1896 patients from 22 studies reported a pooled in-hospital mortality of 37%, similar to those from randomized trials and systematic reviews in non-COVID-19 patients. 18, 22, 23 Although encouraging, none of these studies had a comparative non-ECMO control group.

Therefore, Shaefi and colleagues emulated a target trial comparing mechanically ventilated patients with severe hypoxemia who received and those who did not receive ECMO within 7 days of ICU admission. 51 Severely hypoxemic patients who received ECMO had a lower mortality compared with those who did not (35% vs 47%), very similar estimates as observed in the EOLIA trial. 20 Acute renal failure with or without need for renal replacement therapy was consistently reported as one of the most frequent complications. 40, 50, 55 Whether this is solely related to the severity of COVID-19 infection or to ECMO support is unclear. Potential mechanisms by which ECMO can contribute to kidney failure include hemolysis, secondary infections, and major bleeding. 56 Major bleeding was frequently reported and often associated with worse outcome in patients with COVID-19 related ARDS supported with ECMO. 57 Interestingly, these complications are not usually associated with an identifiable coagulopathy and independent of heparin use. Clinically important bleeding in the largest cohorts was reported in 35% to 43% of the patients, being frequent sources oronasal, cannula related and hemothorax. 37, 39, 40, 47 In a French study, major bleeding requiring transfusions was significantly higher in patients that died but only 4% of the patients died from hemorrhagic shock. 40 A study conducted in Chile reported a surprisingly high rate of intracranial hemorrhage (13%), doubling what was published in the COVID-19 ELSO report. 37, 49 This could be explained by the lack of protocols to control relative changes in PaCO2 early after cannulation, which was shown to be associated with an increased incidence of neurological complications. 58 In face of these complications, recommendations for anticoagulation strategies and target were J o u r n a l P r e -p r o o f highly variable during the pandemic. 47, 59 Indeed, the optimal strategy for anticoagulation during ECMO remains one of the areas where further research is warranted.

Thromboembolic complications have also been described in these patients, including deep vein thrombosis, pulmonary embolism or circuit thrombosis. 60 Underlying mechanisms include endothelial dysfunction, platelet activation and disseminated intravascular coagulation. 61 This increased risk persists despite the use of different degrees of anticoagulation. 37, 40, 50 Infectious complications have been reported in up to 37% of patients receiving ECMO for COVID-19. 49 Ventilator-associated pneumonia was the most frequent source, followed by bloodstream infections, and Staphylococcus aureus the most commonly cultured organism. 49, 55 . Optimization of antimicrobial therapy in the context of extracorporeal life-support poses unique challenges due to the scarce literature describing pharmacokinetic and dosing requirements during ECMO. 62 In the occurrence of bloodstream infections, the optimal duration of therapy and the definition of adequate source control is complicated given ECMO cannulas could be perceived as persistent infectious sources. Since one of the main reported causes of death in this population is septic shock, identifying strategies to maximize source control and appropriate treatments of infections is paramount. 4 

The COVID-19 pandemic was also a unique opportunity to study novel approaches, adjuvant treatments and variations in practice. In this regard, alternative cannulation techniques, the use of prone positioning, and anticoagulation-free runs of ECMO require special attention.

Mustafa and colleagues retrospectively collected data from 40 patients with COVID-19 ARDS supported on ECMO in two hospitals in Chicago. 63 They used a single-access, dual stage right atrium-to-pulmonary-artery cannula, with drainage of blood from the right atrium lumen (decreasing right-sided preload), and oxygenated blood is returned into the pulmonary artery.

Their strategy included a focus on earlier discontinuation of mechanical ventilation and rehabilitation. By the time of the publication, all patients were successfully weaned off invasive mechanical ventilation, 80% had been decannulated, 73% had been discharged from hospital, and overall mortality was 15%. 63 These results may be associated with early mobilization, reduced need for sedation, and right ventricle support. The later might have been critical as right ventricular dysfunction is a frequently reported cause of death in patients with Covid-19 ARDS. 64 The pandemic also raised awareness of the utilization of prone positioning, including increased use in non-intubated patients and during VV-ECMO. [65] [66] [67] [68] In a report by Schmidt and colleagues, prone positioning was used in up to 81% of patients on VV ECMO and the authors suggested that this might have contributed to improve survival rates. 39 Similar results were reported by Guervilly and colleagues, suggesting prone positioning while on ECMO is associated with increased liberation from ECMO and survival. 69 Finally, a recent study reported that the rate of complications was low (6%) and only in 2% of proned patients needed to be supinated to resolve the complication. 70 Although this finding is reassuring, prone positioning during ECMO should be performed in experienced centres. 70 Titrating systemic anticoagulation to prevent clot formation while avoiding bleeding complications is one of the main challenges of ECMO management. Due to the scarce high-quality data, there is practice variation among centres particularly regarding the best method to monitor J o u r n a l P r e -p r o o f anticoagulation and the need for antithrombin supplementation. 71 Furthermore, an international survey from 50 different countries showed that up to 3% of the centres did not routinely prescribe anticoagulation for patients on VV ECMO. 72 In order to investigate the feasibility and safety of this approach, Kurihara and colleagues compared 38 patients that received systemic anticoagulation with 36 patients that received thromboprophylaxis. The group of patients who received systemic anticoagulation had higher rates of gastrointestinal bleeding, received more blood transfusions, and had higher rates of oxygenator dysfunction. 73 Although done at a single centre and with a small sample size, results were consistent with previous reports. 74 Given that hemorrhagic complications contribute to morbidity and mortality associated to ECMO, an anticoagulation-free approach is appealing, and could be an opportunity for future research. 

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FIGURE LEGENDS Figure 1. Patient selection criteria for VV-ECMO in patients with COVID-19 ARDS Abbreviations: PaO2/FiO2 ratio of arterial oxygen partial pressure to fractional inspired oxygen, PaCO2 Arterial partial pressure of Carbon dioxide, FiO2 Fraction of inspired oxygen, PEEP positive end-expiratory pressure, VT tidal volume

Patients on ECMO may present single or multiple organ failure which affects the duration of ECMO run and consequently clinical outcomes. The spectrum of clinical outcomes varies from complete lung recovery to death.J o u r n a l P r e -p r o o f We performed a search in PubMed for articles published in English language between December 2019 and September 2021, using combinations of the terms "COVID-19", "Extracorporeal membrane oxygenation" and "Acute respiratory distress syndrome". We determined relevance on the basis of content, focusing on studies including at least 15 participants. We also manually retrieved articles from references. Finally, we also searched for relevant reports at the ELSO registry website: www.elso.org.