Herein, we report the descriptive data collected from seven ECMO centers in Wuhan during the COVID-19 pandemic, which accounted for almost all of the ECMO cases in Wuhan. To the best of our knowledge, this is the largest cohort of ECMO-treated patients that has been reported since the COVID-19 outbreak. Altogether, 94 patients received ECMO treatment. Among them, 27 patients were successfully weaned from ECMO, 15 were fully recovered and discharged from the hospital, 8 remained in hospital, and 65 died. The crude in-hospital mortality rate of patients who received ECMO therapy in Wuhan during the COVID-19 pandemic was 73.9%. This rate is in contrast to a previous that reported a mortality rate of 32% during the H1N1 pandemic in 2009  and another study that reported a mortality rate of 65% during the Middle East respiratory syndrome pandemic in 2012 . The relatively high mortality rate in this study might be attributable to the following factors. 1) Expert ECMO centers and experienced ECMO specialists were lacking during the COVID-19 outbreak, especially during the early phases when medical systems were overwhelmed. From January 24 to March 8, multiple medical teams and additional ECMO resources were dispatched from all over the nation to Wuhan to combat COVID-19. On February 2, a stringent quarantine policy was implemented, resulting in a decreasing trend in the daily numbers of confirmed cases thereafter . At that time, the shortages of medical resources began to be alleviated, especially in the ICUs. However, ECMO as a salvage therapy might not have been effective in critically ill patients for whom timely treatment had been delayed, leading to substantial irreversible hypoxemic injuries to various organs. 2) Knowledge regarding the etiology, progression dynamics, and effective therapies was scarce during the early phases of the COVID-19 outbreak. Deaths related to this limited experience were reflected by an ECMO-related mortality rate that approached 92% in January 2020. 3) Expertise in ECMO varied among hospitals, which led to significant 3- to 4-fold differences in successful weaning between hospitals (data not shown). Hence, centralized management of multidisciplinary care at high-volume ECMO therapy centers would be ideal. During the later phases of the COVID-19 pandemic in Wuhan, ECMO patients were transferred between hospitals, leading to improvements in survival.
Our study revealed that a pre-ECMO PaCO2 > 60 mmHg was an independent risk factor for a failure to wean from ECMO. This result was consistent with previous studies in which hypercapnia was identified as a marker of poor prognosis related to ECMO therapy [9, 10]. Moreover, the pre-ECMO PaCO2 was included in the Respiratory ECMO Survival Prediction-Score model used to predict the outcome of ECMO therapy . As the COVID-19-induced ARDS progresses, disrupted vasoregulation and massive alveolar microthrombi increase the alveolar dead space and cause a high ventilation–perfusion ratio . Additionally, sputum arising from proteinaceous and fibrinous exudates, pulmonary hemorrhage, cell debris, and nosocomial infection all contribute to airway obstruction and lobular consolidation . Therefore, hypercapnia is an indicator of progression from type 1 to type 2 respiratory failure and a potential signal of ventilation disorders and disease severity. These phenomena suggest that the reversibility of a COVID-19 patients with severe hypercapnia should be evaluated cautiously before ECMO implementation. In contrast, the implementation of ECMO at an early stage before hypercapnia may lead to a better prognosis.
Zhang et al. reported that a D-dimer concentration 4 × ULN was the cutoff value for predicting the in-hospital death of a COVID-19 patient . Our results showed that this D-dimer cutoff was independently correlated with decreased odds of weaning from ECMO, consistent with recent findings suggesting that an elevated D-dimer level predicts a poor outcome in COVID-19 patients [14–16]. Moreover, Tang et al. demonstrated a correlation of prophylactic heparin use with reduced mortality in patients with D-dimer levels exceeding 3.0 mg/L . D-dimer is a rational marker for disease severity and prognosis because i) an elevated D-dimer level is caused mainly by inflammation associated with COVID-19 and subsequent coagulation activity , and ii) massive microvascular thrombosis formation in the alveolar capillaries secondary to vasculitis can trigger ARDS during COVID-19 [13, 14].
We and other researchers consistently noted that lymphopenia was an indicator of disease severity and a substantial predictor of an unfavorable outcome of COVID-19 [15, 17]. Although the underlying mechanisms remain to be elucidated, the main reason likely involves the ability of COVID-19 to induce the exhaustion of lymphocytes, particularly T lymphocytes . As lymphocyte repletion is pivotal in the recovery from COVID-19, ECMO-induced lymphopenia and impaired immunity should be carefully evaluated during treatment .
Supportive care remains the mainstay of COVID-19 treatment in the absence of proven effective drugs. Most patients on ECMO also received prolonged IMV support, which requires meticulous airway management. In these patients, tracheotomy would reduce the need for sedation, enable oral intake, facilitate the efficient suction of secretions, allow for early rehabilitation, and facilitate weaning from IMV. We demonstrated that patients who received a tracheotomy had independently increased odds of ECMO weaning, even in the presence of greatly delayed therapy (median duration: 25 days post-intubation). Prolonged intubation and associated sedation would inevitably render the patient vulnerable to ventilator-associated pneumonia, which would further exacerbate the disease. The observed high mortality rate in the present study may be partially ascribed to the delay in tracheotomy. This delay may be attributable to i) concerns about tracheotomy-provoked aerosol-mediated transmission due to a lack of knowledge about the transmission dynamics of SARS-CoV-2 during the early phases of the pandemic and ii) concerns about uncontrollable bleeding due to heparization. In fact, tracheotomy might be considered before ECMO initiation. Otherwise, the anticoagulation intensity should be reduced, and deep anesthesia would be required at the time of tracheotomy during an ECMO run .
Our propensity score-matched analysis revealed that critically ill COVID-19 patients who received ECMO had a better survival outcome than those who received only IMV. Here, ECMO was frequently used as a last resort when IMV therapy failed to provide oxygenation support, and not as a prophylactic therapy. Our finding was consistent with those of the CESAR study  and an analysis of the application of ECMO for H1N1-related ARDS . IMV strategies such as a higher PEEP, lung recruitment maneuvers, and a prone position might help during the early phase of refractory hypoxemia. However, most patients with COVID-19-related ARDS require a high driving pressure to maintain satisfactory oxygenation and overcome a low lung compliance, which increases the risk of ventilator-induced lung injury. Although ECMO is expertise- and cost-intensive and carries a higher likelihood of complications, this option provides a full support for oxygenation and CO2 removal, enables a “lung rest” ventilatory strategy, and provides time for virus clearance and lung recovery.
Our study has some limitations. First, the retrospective and uncontrolled nature increases the risk of bias in the study. Patients from seven hospitals were enrolled, and each patient was treated at the discretion of the treating hospital or even the attending physicians, without a consensus or a standard clinical pathway. Second, the respirator parameters (e.g., plateau pressures, tidal volumes, or PEEPs) were not routinely recorded. This limitation prohibited us from evaluating the role of IMV in the outcome of ECMO use. Third, although we included nearly all ECMO patients in Wuhan, the sample size remained relatively small. Therefore, the strength of our findings might be limited.