key: cord-0923587-v8y92o6c
authors: Zayat, Rashad; Kalverkamp, Sebastian; Grottke, Oliver; Durak, Koray; Dreher, Michael; Autschbach, Rüdiger; Marx, Gernot; Marx, Nikolaus; Spillner, Jan; Kersten, Alex
title: Role of Extracorporeal Membrane Oxygenation in Critically Ill COVID‐19 Patients and Predictors of Mortality
date: 2020-11-24
journal: Artif Organs
DOI: 10.1111/aor.13873
sha: 60231320cd4cc7596071dc65f85e8b39adb9b256
doc_id: 923587
cord_uid: v8y92o6c

BACKGROUND: The role of extracorporeal membrane oxygenation (ECMO) in the management of critically ill COVID‐19 patients remains unclear. Our study aims to analyze the outcomes and risk factors from patients treated with ECMO. METHODS AND RESULTS: This retrospective, single‐center study includes 17 COVID‐19 patients treated with ECMO. Univariate and multivariate parametric survival regression identified predictors of survival. Nine patients (53%) were successfully weaned from ECMO and discharged. The incidence of in‐hospital mortality was 47%. In a univariate analysis, only four out of 83 pre‐ECMO variables were significantly different; IL‐6, PCT, and NT‐proBNP were significantly higher in non‐survivors than in survivors. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score was significantly higher in survivors. After a multivariate parametric survival regression, IL‐6, NT‐proBNP and RESP scores remained significant independent predictors, with hazard ratios (HR) of 1.069 [95%‐CI: 0.986‐1.160], p= 0.016 1.001 [95%‐CI: 1.000‐1.001], p=0.012; and 0.843 [95%‐CI: 0.564‐1.260], p=0.040, respectively. A prediction model comprising IL‐6, NT‐proBNP, and RESP score showed an area under the curve (AUC) of 0.87, with a sensitivity of 87.5% and 77.8% specificity compared to an AUC of 0.79 for the RESP score alone. CONCLUSION: The present study suggests that ECMO is a potentially lifesaving treatment for selected critically ill COVID‐19 patients. Considering IL‐6 and NT‐per‐BNP, in addition to the RESP score, may enhance outcome predictions.

our patient data management systems (Philips IntelliSpace Critical Care and Anesthesia and Siemens Medico). Complications occurring post-ECMO implantation, including multi-organ failure and hemocompatibility-related adverse events (HRAE), including bleeding and thromboembolic events, were recorded and analyzed.

Critically ill COVID-19 patients, who presented with commonly accepted ECMO indications as suggested by the Extracorporeal Life Support Organization (ELSO) [16] , in whom all other treatments options have been exhausted: lung protective invasive mechanical ventilation (MV); prone positioning; neuro-muscular blockade; and inhaled nitric oxide (iNO) rescue therapy, were considered for ECMO treatment.

Our center's standard operating procedure includes an evaluation by the ECMO-team consisting of intensivist physicians, cardiothoracic surgeons, and pneumologists during daily ICU rounds.

The ECMO-team made the decision on the initiation of ECMO support after bedside assessment of the patient.

Our standard approach for the treatment of isolated respiratory failure is VV ECMO utilization.

Percutaneous cannulation, using the Seldinger technique [17] , was our technique of choice for VV ECMO. Depending on the desired flow rate, and whenever possible, bi-caval single-site cannulation, using a dual-lumen cannula (27 to 31 Fr), was preferentially performed over two-site cannulation (femoral-jugular or femoral-femoral) with 19 to 25 Fr cannula. The decision whether single site double-lumen cannulation or two sites cannulation to be performed depends on many factors. Briefly, in general, when a patient with high BSA (2.2-2.5 m 2 ), a 25 Fr venous cannula as a drainage cannula is necessary, and for venous-return, a 17-19 Fr cannula will be appropriate to achieve enough flow with adequate carbon dioxide clearance and oxygenation. In our experience, the double-lumen cannula 27-31 Fr will not provide enough flow and adequate gas exchange in such settings. The double-lumen cannula's insertion and positioning are more complex and require more experience and the ability to perform precise transesophageal echocardiography guidance. Therefore, in emergent cases or when performing cannulation in an external hospital, the two sites' cannulation (femoral-jugular) is more accessible, safer, and faster. Another factor in choosing the cannulae was the cannula's availability during the COVID-19 pandemic.

The positioning of the cannulae was performed under transesophageal echocardiographic control. The anticoagulation management for VV ECMO is to achieve and maintain a targeted activated partial thromboplastin time (aPTT) of 40-50 sec. (1 to 1.5 times above the normal range [20-35 sec.] ), using unfractionated heparin. During our study period, an increased risk of thromboembolic events in critically ill COVID-19 patients was reported. Therefore, by 01/04, we Accepted Article altered anticoagulation in ECMO patients to aPTT of 50-60 seconds or an activated clotting time (ACT) of 170-180 seconds. As recommended by ELSO [18] , careful examinations of the whole ECMO circuit, using a flashlight, were performed twice per day to detect white platelet/fibrin thrombi and clots, usually identified as dark non-moving areas on the surfaces. Pre and post membrane pressures are continuously monitored. Clotting in the oxygenator is represented by increasing membrane lung pressure gradient [18] Laboratory analysis Detailed laboratory analyses were performed daily and included complete blood count electrolytes; measures of hemostasis; hemolysis markers; biochemical tests of cardiac, renal, and liver function; NT-pro-brain natriuretic peptide (NT-proBNP); interleukin 6 (IL-6); procalcitonin (PCT); plasma C-reactive protein (CRP); fibrinogen; and D-dimers. Blood gas analyses were performed in intervals of 1-2 h.

Throat-swabs, tracheal secretions, or bronchoscopic alveolar lavage were obtained for SARS-CoV-2 testing from each patient immediately at admission. COVID-19 infection was confirmed by real-time reverse-transcription-polymerase-chain-reaction (RT-PCR) assays.

Categorical variables are presented as absolute numbers and percentages. Continuous variables were tested for normal distribution with the Kolmogorov-Smirnov test and presented as the median and interquartile range (IQR) for non-normally distributed variables and mean ± standard deviation (SD) for normally distributed data. Comparison between survivors and non-survivors was accomplished through univariate analyses using a Mann-Whitney U-test or T-test, where appropriate. Categorical variables were analyzed using Fisher's exact test. To identify predictors of in-hospital mortality and calculate the hazard ratio (HR) with a 95%-confidence interval (95%-CI), a multivariate parametric survival regression analysis was performed. The entry criteria for the multivariate analysis was a p-value < 0.05 in the univariate analysis. We examined the receiver-operator characteristic (ROC) curve and area under the curve (AUC) from each independent predictor, and all predictors combined, as a prediction model. Kaplan-Meier survival curves were generated, and the log-rank test was used for a linear trend. All statistical

This article is protected by copyright. All rights reserved comparisons were two-sided. P-values < 0.05 were considered significant. Parametric survival regression and ROC curves analyses were performed with STATA (Release 16, StataCorp, College Station, TX). All other analyses were performed using R (Version 3.6, Vienna, Austria) and the Jamovi project (Version 1.2, https://www.jamovi.org).

During the study period, 17 COVID-19 patients were treated with ECMO. Table 1 One patient had a history of cardiac surgery; one patient had coronary artery disease, with a history of myocardial infarction and percutaneous coronary intervention; four patients (24%) were active smokers; five patients (29%) had pneumonia in their medical history; and one patient had a history of lung surgery, due to adenocarcinoma; one patient was on immunosuppressive medication because of kidney transplantation. All patients had a PaO2/FiO2 ratio < 100 before ECMO initiation (range 53-75). The median duration of MV before ECMO was three days (3, 15) .

Eight patients (47%) had iNO before ECMO support.

Three patients (18%) received antiviral medication, all 17 patients required antibiotics for bacterial superinfection, and all patients had prone position treatment and initial neuromuscular blockade.

In the last blood gas analysis prior to ECMO, the median pO 2 was 77 mmHg (67, 93) and the median pCO 2 was 66 mmHg (47, 77). Prior to ECMO implantation, the mean leukocyte number was 14 ± 6.9 /nL, median IL-6 level was 255 pg/nL (112, 404), median PCT was 5.1 µg/L (0.56, 6.9), median C-reactive protein was 186 ng/mL (120, 280), NT-proBNP was 1765 pg/mL (605, 4122) and creatine kinase-MB was 21 U/L (18, 27) . Further details are presented in Table 1 .

Details of all ICU scores just before ECMO initiation and on the last day of ECMO support are presented in Table 2 . Glasgow coma score (GCS) at hospital admission was 13.8±0.8. Prior to ECMO initiation, mean scores were as follows: Sequential organ failure assessment score (SOFA) 11.9 ± 9.4 9; Richmond Agitation Sedation Scale (RASS) -2.9 ± 5.1; Simplified Acute Physiology Score II (SAPS II) 46.1 ± 11.8; Respiratory Extracorporeal Membrane Oxygenation

This article is protected by copyright. All rights reserved Survival Prediction (RESP) score -1.0 ± 2.7; predicted survival probability ranged from 15% to 75%.

Details of ECMO settings and clinical progression, during and after ECMO, are shown in Table 3 .

Sixteen (94%) patients had VV ECMO, and one patient received VA ECMO. Nine patients (53%) had one-site cannulation, with a dual-lumen cannula in the right internal jugular vein (IJV). Seven patients (41%) received two-site cannulations in the internal femoral artery and IJV. One patient had two-site cannulations using the femoral artery and vein. One patient, who initially received VV ECMO with two site cannulations, suffered myocardial infarction during ECMO-support, decompensated, and developed cardiogenic shock with predominant severe right heart failure and required a switch to VA ECMO using femoral-artery and vein cannulation. Nine patients (53%) were assessed, cannulated, and retrieved by our mobile ECMO-team from a peripheral hospital. The mean ECMO flow was 4.5 ± 1 L/min. Hemoperfusion for cytokine adsorption using the CytoSorb® (Cytosorbents, New Jersey, USA) or HA-380 cartridges (Jafron Biomedical, Zhuhai City, China) was applied to eight patients (47%).

Median ECMO support lasted 16 (11, 21) days. On average, each ECMO circuit required one exchange of the oxygenators. We had 20 exchanges in 17 ECMO circuits. In three patients with prolonged ECMO-support, replacement of the oxygenator was required twice. As of June 1, 2020, nine patients (53%) have been weaned successfully from ECMO and discharged, and eight patients (47%) died while on ECMO support. Septic shock with vasoplegia and multi-organ failure was the leading cause of death (88%). Seven patients (41%) developed right heart failure while on ECMO-support, and eight patients (47%) received iNO during ECMO. The median duration of iNO treatment was two days (0, 4). One patient suffered a myocardial infarction while on VV ECMO support. The supplementary Table S1 demonstrates a comparison between double-lumen and two sites cannulation. There were no significant differences between the two different cannulation approaches in blood flow, survival, ICU stays, or adverse events incidence.

Details about HRAE are presented in Table 4 . The incidence of ischemic stroke was 12%, and hemorrhagic stroke was 29%. Five patients had a pulmonary embolism (29%). The incidence of peripheral thromboembolic events was 29%. Eight patients (47%) had airway bleeding requiring transfusion of packed red blood cells (PRBCs). The median length of ICU stay was 24 days (14, 54) days, and the total length of hospital stay was 24 days (17, 55). p=0.045. IL-6 and PCT were also significantly higher in non-survivors: 112 pg/mL (80, 287) vs. 422 pg/mL (267, 1120), p=0.013, and 6.7 ng/mL (5.5, 9.1) vs. 1.1 ng/mL (0.5, 2.7), p=0.026, respectively. All other characteristics and laboratory data, prior to ECMO support, did not differ by survival status (Table 1) .

Of the ICU scores, the RESP score was significantly higher in survivors; 0.2 ± 2.0 vs. -2.6 ± 2.8, p=0.046. All other scores did not differ significantly between the two groups ( Table 2) . Pre-ECMO SOFA scores did not differ between survivors and non-survivors (Table 2 ). However, within each group, the SOFA score increased during ECMO support. It was significantly higher at last before ECMO-cessation within each group compared to pre-ECMO SOFA score (survivors: 9.8±2.23 vs.

13.0±2.1, p= 0.007) and (non-survivors: 12.5±7.9 vs. 16.9±8.8, p=0.004).

Three non-surviving patients (38%) and two surviving patients (22%) had a history of pneumonia (NS, p>0.05). The cannulation site and ECMO configuration did not differ between survivors and non-survivors (Table 3) . Median ECMO support time for non-survivors was 14.5 days (9.5, 22), and the maximum duration was 61 days. The median survival time for the whole cohort was 62 days (Figure 1 ). For the survivors' group, the median ECMO support time was 16 days (11, 19) , and the maximum duration was 27 days. 

Supplementary Table S2 shows the time course of laboratory parameters comparing eight patients treated with ECMO plus cytokine adsorber and nine patients who received ECMO without cytokine adsorber. Only CRP levels decreased significantly in the hemoperfusion group, starting at day three of ECMO support. They remained markedly lower for seven days (Figure Accepted Article S1). IL-6 and PCT did not differ between the groups ( Figure S1 ). Three patients (37%) in the ECMO + hemoperfusion group and five patients (55.5%) in the ECMO only group did not survive to hospital discharge (NS log-rank test, p>0.05) ( Figure S1 ).

Eighty-one variables from Tables 1 and 2 were included in the univariate analysis; only four variables were independent factors with p<0.05. Pre-ECMO NT-proBNP levels were significantly higher in non-survivors: 4097 pg/mL (1765, 8065) vs. 706 (438, 1765) , p=0.043. Non-surviving patients also had significantly higher pre-ECMO IL-6 (p=0.013) and PCT values (p=0.026). The RESP score was significantly lower in non-survivors (p=0.046); the estimated survival from the RESP score was 29% ± 14% for non-survivors and 51% ± 12% for survivors. We entered RESP scores, NT-proBNP, IL-6, and PCT values into the multivariate parametric survival regression ( (Table 4 ). Using only the RESP score to predict mortality gave an AUC of 0.79 with 62.5% sensitivity and 100% specificity (Figure 3 ). We tested a prediction model for in-hospital mortality in COVID-19 patients treated with ECMO, with RESP scores and pre-ECMO IL-6 and NT-proBNP values. The model showed an AUC of 0.87 with 87.5% sensitivity and 77.8% specificity ( Figure 3 ). IL-6 alone had an AUC of 0.70 and, with a cut-off of 122 pg/mL, the sensitivity of 88.8% and specificity 50%. NT-proBNP had an AUC of 0.74, 88% sensitivity, and 55% specificity, with a 814 pg/mL cut-off.

ECMO support is recommended for critically ill COVID-19 patients who do not improve despite optimal ARDS standard therapies, including prone position, protective MV with high endexpiratory pressure, and low tidal volume [15, 16] . However, its exact role and benefits in COVID-19 patients remain uncertain.

In the present study, the outcomes and risk factor analyses of ECMO-support in 17 critically ill COVID-19 patients are reported. The key findings are summarized as follows. First, the rate of successful weaning from ECMO and survival to hospital discharge was 53%, demonstrating a reasonable outcome comparable to recently published data from the ELSO registry and the Paris-Sorbonne University Hospital Network [8, 19] .

This article is protected by copyright. All rights reserved Second, our analyses demonstrated that the RESP score is a reliable predictor of survival of COVID-19 patients treated with ECMO. Third, we identified high levels of IL-6 and NT-proBNP as independent predictors of in-hospital mortality. By adding IL-6 and NT-proBNP values to the RESP score, we demonstrated a superior prediction capability.

Patients who are successfully weaned from a prolonged ECMO-support and survive the severe COVID-19 diseases often require MV and have disability leading to a prolonged hospital stay and making the "awake ECMO" not the appropriate approach. Crotti et al. [20] clearly demonstrated that patients awaiting lung transplants and patients with COPD responded excellent to spontaneous breathing ECMO, while 50% of ARDS patients failed to tolerate "awake ECMO."

In this study, nine patients were discharged from the hospital after a prolonged weaning from MV and intensive physiotherapy treatment. Nevertheless, the majority were transferred to rehabilitation facilities (2 to 3 weeks) to continue recovery. These findings underline the need for future studies focusing on the long-term outcomes of these patients.

Another important finding in our study is the high rate of hemorrhagic stroke in COVID-19 patients treated with ECMO (29%) compared to the reported incidence of 1.8 -10.9% in non-COVID-19 ARDS patients [21, 22] . The high intracranial hemorrhage in COVID-19 has been reported in recently published studies [23, 24] . A possible explanation for the higher incidence of intracranial bleeding is the vasculopathy and anticoagulation disorder induced by COVID-19 [25] .

In this study, eight patients were discharged from the hospital after a prolonged weaning from MV and intensive physiotherapy treatment. Nevertheless, the majority were transferred to rehabilitation (2 to 3 weeks) to continue recovery.

The successful weaning rate from ECMO in our study is greater than previously reported rates [2, 12] . Jacobs et al. [12] reported on 32 COVID-19 patients from nine different hospitals; at the time of analysis, 17 patients (53%) were still alive on ECMO, and only five (15.6%) had been weaned from ECMO and MV [12] . Yang et al. [2] describe the clinical course of 52 critically ill COVID-19 patients from Wuhan, China, six required ECMO support, and mortality reached 83%.

Conversely, Marullo et al. [13] analyzed data from 333 COVID-19 patients using the ELSO registry and reported an overall mortality of only 17%. However, at the time of the analysis, the actual ECMO weaning rate was 18%, with the remaining patients still alive on ECMO support.

The patient selection might significantly contribute to the differences in these survival rates.

It is of utmost importance to identify risk factors and survival predictors to refine ECMO indications and offer it to COVID-19 patients most likely to benefit. Recent studies suggest that Accepted Article COVID-19 mortality is associated with virus-activated "cytokine storm syndrome" [26, 27] . The Cytokine storm describes a hyperactive immune response, defined by the release of interleukins, interferons, tumor necrosis factors, chemokines, and various mediators [27] . Previous clinical ARDS trials have confirmed that ARDS's hyper-inflammatory phenotype, characterized by increased pro-inflammatory cytokines, is associated with worse outcomes [28, 29] . The characteristics of this phenotype are most likely to correspond to those in cytokine storms.

Marullo et al. [13] speculated that the use of VA ECMO might offer better lung protection, as it can decrease IL-6 levels in the pulmonary circulatory system by bypassing the pulmonary circulation. Following recent studies [26, 30] , we found that higher levels of IL-6 before ECMO initiation increased mortality by 6%. Higher levels of IL-6 in ARDS patients have also been shown to increase the risk of mortality [31, 32] . However, the underlying mechanism, and the role of IL-6 in ARDS pathogenesis, has not yet been thoroughly investigated. During ECMO support, we did not detect a significant difference in IL-6 levels between survivors and non-survivors. One possible explanation for this is that both COVID-19 and ECMO support generate an extensive inflammatory response [33, 34] . Therefore, any significant difference between the groups in IL-6 levels before ECMO initiation vanished as soon as ECMO started. Risens et al. [33] also suggested IL-6 levels may predict the outcome of patients treated with ECMO. They analyzed 22 patients, including neonates and adults, and found that survivors had lower IL-6 levels than nonsurvivors [33] . With this in mind, we can speculate that another possible tool to eliminate the damaging effects of IL-6 and improve patients' outcomes might be the use of a cytokine adsorber while on ECMO support. Recent studies have suggested the use of hemoperfusion is beneficial in critically ill COVID-19 patients treated with ECMO and developed acute renal failure [35, 36] . In our study, we used hemoperfusion with cytokine adsorber in eight patients (47%). However, we did not detect any significant changes in IL-6 levels or outcomes when using the cytokine adsorber; only CRP levels decreased significantly in the hemoperfusion group.

Given the limited resources for ECMO therapy, a better understanding of contraindications to this treatment in severe COVID-19 patients is essential for patient selection. Marullo et al. and Gupta et al. [13, 37] found that patient age (>60 yrs.) was a major risk factor for COVID-19 patients treated with ECMO. In an analysis of >2000 COVID-19 patients, Gupta et al. [37] found that age (> 80 yrs.) and gender (male) are independent risk factors for mortality. However, in our analysis, we could not identify an effect of age or gender on survival. The median age in our study was 57 years (compared to 60.5 ± 14.5 yrs. in [37] ) and ranged from 39 to 73 yrs., with only five patients Accepted Article (29%) aged over 60 yrs. This might explain our findings' inconsistency and those from Marullo et al. and Gupta et al. [13, 37] .

Similar to other studies [12, 13] , we could not detect specific demographic or clinical variables to predict the outcome of COVID-19 patients treated with ECMO.

We found that the RESP score is reliable in predicting survival in COVID-19 patients treated with ECMO. This is in agreement with Yang et al. [38] , who have used the RESP score to help decisions on ECMO treatment for COVID-19 patients. They chose RESP's predicted survival of <40%, and age >65 yrs. as cut-offs to initiate ECMO support, giving excellent outcomes of 14% mortality rate, compared to reported mortality rates of 23% -61% [2, 14] .

Besides IL-6 and RESP scores, we also found a negative correlation between high levels of pre-ECMO's NT-proBNP and survival. Similar to our findings, recently published studies [2, 4, 39] have linked myocardial injury, as indicated by increased BNP, Troponin T, or CK-MB, with poor clinical outcomes.

We acknowledge important limitations to our study, namely the retrospective design and small sample size represent the major limitations. Second, our patients were treated in a high-volume tertiary academic hospital; this might limit our findings' generalizability. As a reason for our cohort's limited size, biases in patient selection and indication might have existed. Another limitation is the inability to estimate cut-off values for the variables included in the prediction model. One more important limitation is that we report only short-term outcomes from a small cohort. Thus, we cannot underline any definitive conclusions regarding patients' selection and predictors of survival. Given these limitations, validation of our findings in larger patient sample sizes and long-term follow up is required.

The present study suggests that ECMO is a valuable lifesaving treatment for selected critically ill COVID-19 patients. It may guide further investigations to optimize patient selection and identify predictors of in-hospital mortality.

Our study results suggest adding IL-6 and NT-proBNP to the RESP score for better prediction accuracy. Further knowledge and analysis are required to optimize patient selection criteria and improve outcomes of critically ill COVID-19 patients.

Tables. Table 1 . Demographics and clinical course before ECMO initiation. 

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This article is protected by copyright. All rights reserved 

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