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Extracorporeal Membrane Oxygenation in COVID-19

Extracorporeal membrane oxygenation (ECMO) is an intervention for severe acute respiratory distress syndrome (ARDS). Although COVID-19-related ARDS has 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 the understanding on how to optimize this intervention.

ECMO constitutes a costly and resource-intense treatment of 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 such treatments as ECMO has been the focus of some discussions. 6 This review describes the role of venovenous (VV) ECMO in patients with COVID-19-related ARDS.

EXTRACORPOREAL MEMBRANE OXYGENATION FOR ACUTE RESPIRATORY DISTRESS SYNDROME: RATIONALE AND HISTORY
ARDS is associated with high morbidity and mortality caused by 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 Although mechanical ventilation is a life-saving intervention, it can also lead to ventilator-induced lung injury through different mechanisms. 10 The fundamental principle of lung-protective ventilation is to allow for adequate gas exchange while preventing ventilator-induced lung injury. 11,12 In the most severe cases, lung-protective 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 (eg, femoral vein), a mechanical pump coupled with an oxygenator, and a return cannula that restores oxygenated blood to the circulation through another central vein (eg, 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 use 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 Also in 2009, the Conventional Ventilatory Support Versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial compared the efficacy, safety, and cost-effectiveness of standard of care in mechanical ventilation with 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 center 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 60day mortality of 35% in the ECMO group and 46% in the control group. 20 Although this difference was not statistically significant, a number of secondary outcomes and a post-hoc analyses favoured ECMO. 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] COVID-19-RELATED ACUTE RESPIRATORY DISTRESS SYNDROME: IS IT REALLY DIFFERENT?
The definition of ARDS encompasses clinical and radiologic criteria along with the presence of typical risk factors for direct or indirect lung injury. 25,26 Clinical and biologic heterogeneity within ARDS is therefore implied and has been topic of extensive research. [27][28][29][30] Since the beginning of the pandemic, the overwhelming number of patients with COVID-19 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-19related ARDS as a distinct entity was challenged.
Indeed, the current body of clinical, physiologic, and pathologic data seems to support the notion that this disease, although 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 Venovenous Extracorporeal Membrane Oxygenation in COVID-19-Related Acute Respiratory Distress Syndrome: Old and New Challenges 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 to the attention of clinicians and the public at the same time, leading to a detailed description of patients' 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 toward this intervention. 42,43 Extracorporeal Membrane Oxygenation in COVID-19-Related Acute Respiratory Distress Syndrome: Clinical Outcomes 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 with 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 Lippi 6 described that among 17 patients that required ECMO early in the pandemic mortality was 94%. However, mortality in the non-ECMO group was also considerably high, the sample was rather small, and data regarding baseline characteristics were missing. Huang and colleagues 46 found similar results and suggested using ECMO only for younger patients without preexisting diseases, but these data were also derived from a small case series. Thus, these Extracorporeal Membrane Oxygenation in COVID-19 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 because of COVID-19 ARDS showed that 60-day mortality was significantly lower (35%) than the previous reports. 47 Schmidt and colleagues 39 reported a retrospective cohort of 83 patients placed on ECMO for COVID-19 ARDS comparing their results with those of the EOLIA trial. Despite having a greater severity of hypoxemia in their cohort, these patients had a similar 90-day mortality. 39 Based in part on these results, the Extracorporeal Life Support Organization advocated for the use of ECMO in specialized centers only. 48,49 A retrospective cohort study that included 319 patients on ECMO from 24 ICUs in Spain and Portugal reported similar results (mortality 35%). 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. 40,50 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 patients without COVID-19. 18,22,23 Although encouraging, none of these studies had a comparative non-ECMO control group. Therefore, Shaefi and colleagues 51 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. Patients with severe hypoxia who received ECMO had a lower mortality compared with those who did not (35% vs 47%), similar estimates as observed in the EOLIA trial. 20 Despite known limitations, well-conducted observational research has an important role in understanding the efficacy of this intervention, given the lack of feasibility for another randomized trial.

Extracorporeal Membrane Oxygenation in COVID-19: Patient Selection
Patient selection for VV-ECMO in patients with COVID-19 should follow the same guiding principles as for ARDS from other causes (Fig. 1). 52 Before initiation of ECMO is considered, referring centers should ensure conventional management has been optimized, including lung-protective ventilation, adequate level of positive end-expiratory pressure, prone positioning, and consideration of deep sedation/ neuromuscular paralysis. If all these strategies fail or when lung-protective ventilation cannot be achieved (ie, a need for injurious ventilation), ECMO should be considered in  the absence of factors associated with poor benefit, such as advanced age, comorbidities, multiorgan dysfunction, and prolonged duration of invasive mechanical ventilation. 52,53 Although patient selection focuses on time from initiation of invasive ventilation to ECMO cannulation, increasing awareness of time on noninvasive respiratory support (eg, high-flow oxygen, noninvasive ventilation) before intubation is being raised as a potential predictor of outcome and a key parameter for adequate patient selection. 37

THE COURSE OF EXTRACORPOREAL MEMBRANE OXYGENATION SUPPORT IN PATIENTS WITH COVID-19: PATIENT TRAJECTORIES
During the COVID-19 pandemic, many centers experienced increased demands for ECMO, even in those with previous long-standing experience. 39,40 This accentuated the multiple clinical trajectories that exist among these patients once they are initially placed on ECMO (Fig. 2). Certain patients exhibit lung recovery shortly after cannulation, and liberation from ECMO is quickly and successfully achieved. This group meets the foundational criteria and expectation when starting this treatment: ECMO as a bridge to recovery. At the other end of the spectrum, certain patients undergo prolonged treatment on ECMO without significant lung recovery, introducing unique clinical and ethical challenges. For these patients, ECMO can still be a bridge to recovery, but other trajectories are also possible, including discussions about lung transplantation candidacy or transitioning to palliative care. 54 Decision-making by patients and families/caregivers is influenced by the spectrum of clinical trajectories. Given the prolonged time that certain patients can be on ECMO (median time up to 30 days, see Table 1), this can also lead to important challenges for decision-making by policy makers, particularly during a pandemic where ICU beds and human resources are scarce. 42

THE COURSE OF EXTRACORPOREAL MEMBRANE OXYGENATION SUPPORT IN PATIENTS WITH COVID-19: COMPLICATIONS
During the course of ICU stay, patients on ECMO can suffer a range of complications, which can be life-threatening. These are categorized as the typical complications  observed because of prolonged critical illness, ECMO-specific complications, and those specific to COVID-19. 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 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, with frequent sources being oronasal, cannularelated, 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 of 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 Extracorporeal Life Support Organization report. 37,49 This could be explained by the lack of protocols to control relative changes in PaCO 2 early after cannulation, which was shown to be associated with an increased incidence of neurologic complications. 58 In face of these complications, recommendations for anticoagulation strategies and target were 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 because of 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 because ECMO cannulas could be perceived as persistent infectious sources. Because 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

NOVEL TECHNIQUES AND VARIATIONS IN PRACTICE
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 63 retrospectively collected data from 40 patients with COVID-19 ARDS supported on ECMO in two hospitals in Chicago. 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 because right ventricular dysfunction is a frequently reported cause of death in patients with COVID-19 ARDS. 64 The pandemic also raised awareness of the use of prone positioning, including increased use in nonintubated patients and during VV-ECMO. [65][66][67][68] In a report by Schmidt and colleagues, 39 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. Similar results were reported by Guervilly and colleagues, 69 suggesting prone positioning while on ECMO is associated with increased liberation from ECMO and survival. Finally, a recent study reported that the rate of complications was low (6%) and only 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 centers. 70 Titrating systemic anticoagulation to prevent clot formation while avoiding bleeding complications is one of the main challenges of ECMO management. Because of the scarce high-quality data, there is practice variation among centers particularly regarding the best method to monitor anticoagulation and the need for antithrombin supplementation. 71 Furthermore, an international survey from 50 different countries showed that up to 3% of the centers did not routinely prescribe anticoagulation for patients on VV ECMO. 72 To investigate the feasibility and safety of this approach, Kurihara and colleagues 73 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. Although done at a single center 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.

SUMMARY AND FUTURE DIRECTIONS
Despite early reports suggesting COVID-19-related ARDS should warrant distinct management, current evidence suggests that similar management principles to non-COVID-19 ARDS should be applied. These include lung-protective ventilation and the use of adjuvant treatments when appropriate. Data from large cohorts and observational studies emulating clinical trials suggest that the efficacy and outcomes of ECMO in the context of severe COVID-19 is similar to ARDS because of other risk factors. The spectrum of patients' trajectories range from short ECMO runs with full lung recovery to prolonged ECMO support with significant organ dysfunction. Typical complications, such as bleeding and thromboembolic events, are frequent in patients who receive treatment with ECMO, often presenting as life-threatening. Ongoing and future research will help understand whether alternative approaches for ECMO cannulation, prone positioning, and variations in anticoagulation practices can improve the safety and efficacy of this intervention. The ongoing pandemic poses a unique opportunity to improve the understanding of the strengths and limitations of this resource-intensive intervention. Finally, enhanced collaboration among centers locally, nationally, and internationally is key for rapidly generating an important body of clinical evidence.

CLINICS CARE POINTS
COVID-19-related ARDS resembles ARDS caused by other risk factors in its clinical presentation and outcomes.
Evidence-based principles of lung-protective ventilation and adjuvant therapies, such as ECMO, for the management of ARDS should be applied similarly for severe COVID-19.
Emerging evidence in the field currently suggests that the role of ECMO in the management of COVID-19-related ARDS is comparable with non-COVID-19 ARDS, and patient selection should follow similar principles.
Frequent complications of ECMO include acute kidney failure, major bleeding, thromboembolic events, and secondary infections.
The dramatically high number of patients requiring ECMO worldwide for COVID-19 ARDS poses an opportunity to study variations in practice, such as different cannulation techniques, prone positioning, and alternatives in the use of anticoagulation.