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Coronavirus disease 2019 (COVID-19) is a complex respiratory syndrome that occurs secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Up to 15–30 percent of COVID-19 patients develop severe illness including acute respiratory distress syndrome (ARDS) and require intensive care1–4. Although the benefit of extracorporeal life support (ECLS) was initially unclear in COVID-19-related ARDS patients, further study and revised guidelines by the Extracorporeal Life Support Organization (ELSO) working group have supported this therapy, contingent on sufficient hospital resources5,6.
ECLS has been associated with an increased risk of bleeding and thrombotic complications7. COVID-19 contributes additional risk of thrombotic events8. A recent study of neurologic complications in COVID-19 patients supported with ECLS also revealed a higher incidence of strokes in this cohort9. COVID-19 patients are at further increased risk of pneumothoraces requiring chest tube insertion10. Recent studies have reported survival in COVID-19-related ARDS patients supported with ECLS close to 50%, with worse clinical outcomes in later waves11–14. A meta-analysis assessing mortality in COVID-19 reported age, body mass index (BMI), and duration of extracorporeal membrane oxygenation (ECMO) support as significant predictors15.
Limited data exist to compare adverse events and clinical outcomes between COVID-19-related ARDS patients and non-COVID-19-related ARDS patients supported with ECLS. Considering differences in pathophysiology and clinical management between these two groups of patients, we conducted an observational propensity-score matched study with a historical cohort to better understand the relative rates of complications.
Patients and Methods Data CollectionThis study protocol was deemed eligible for expedited review by the Institutional Review Board at Columbia University Irving Medical Center (AAAT0563). All patients with positive nasal polymerase chain reaction (PCR) for SARS-CoV-2 infection with ARDS cannulated to veno-venous (V-V) or veno-arteriovenous (V-AV) ECLS at our urban high-volume referral center from March 1st, 2020, through June 1st, 2021, were included in the COVID group. A retrospective chart review was performed on all patients with ARDS from infectious and/or inflammatory etiology who were supported with ECLS from January 1st, 2012, to January 1st, 2020 (Control group). Patients bridged to transplant or those with other etiologies of respiratory failure were excluded. Criteria for ECLS cannulation were patients with respiratory failure meeting ELSO indications5 despite being maximized on additional medical therapies including prone positioning, neuromuscular blocking agents (NMBAs), and pulmonary vasodilators16. Hospital resource availability was also considered during COVID-19 surges. All historical controls and nearly all COVID-19 patients were cared for in the same intensive care unit with expertise in ECLS management.
ECLS Cannulation TechniqueWe use the Cardiohelp HLS Set Advanced 7.0 ECLS system (Maquet, Getinge, USA) for adult respiratory failure patients. Percutaneous cannulation with the Seldinger technique is used for the great majority of patients receiving V-V ECLS or V-AV ECLS. We preferentially use two-site cannulation (femoral–jugular or femoro–femoral), and cannulate the femoral artery, as clinically indicated, for V-AV. We use 23Fr–29Fr multiperforated cannulas for drainage (Next Gen, Medtronic, MN, USA or Maquet, Getinge, USA), and 18Fr–22Fr EOPA cannulas for reinfusion (Medtronic). We typically place the largest size cannulas but adapt to the patient’s anticipated ECLS blood flow rate needs based on body surface area (BSA) and anticipated cardiac output. Unless contraindicated, 5000 IU of heparin is given after the vessels are dilated and allowed to circulate for 3 minutes before cannulation. Cannulas are backbled after placement and then typically flushed with saline to further prevent clotting before circuit initiation. During the pandemic, we elected to use larger bore drainage cannulae to obtain higher flows in the COVID group. Despite this, no difference in cannulation site bleeding was observed.
Clinical OutcomesData abstracted included age, sex, comorbidities, BMI, acute physiology and chronic health evaluation (APACHE) II score, relevant clinical history, pre- and post-cannulation arterial blood gases, mechanical ventilator settings, ECLS procedural equipment, clinical laboratory values, and clinical course. The primary outcome was major bleeding and stroke complications. Secondary outcomes were mortality and pre-cannulation characteristics. A major bleeding complication was classified as a binary variable and defined as: 1) requiring surgical intervention and/or 2) according to the International Society on Thrombosis and Hemostasis (ISTH)17 criteria: acute decline (<1 hour of hemoglobin of >1.24 mmol/L or the need for >2 units packed red blood cell [PRBC] transfusion). The decision to insert a chest tube for clinically significant pneumothorax or pleural effusion, based on chest radiographs and/or computed tomography (CT) scans, was at the discretion of the thoracic surgeon on call. Acute kidney injury (AKI) and indications for continuous V-V hemodialysis for acute renal failure in critically ill patients practice guidelines are described elsewhere18,19.
Propensity ScorePropensity score matching was used to estimate the average marginal effect of COVID-19 in patients supported with ECLS support accounting for patient (1) age, (2) BMI, (3) APACHE II score on admission, and (4) duration of ECLS support as covariates. Three propensity score matching models were evaluated and the nearest neighbor with 1:1 matching without replacement, calipers set to 0.1 yielded the best balance (see Figure 1, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A877). This model uses regressions to estimate how likely a patient with defined characteristics is to be categorized in the treatment group of interest, in this case, COVID-19. Total dataset before matching included 43 COVID and 95 Control cases; of which 18 COVID cases were unmatched and subsequently removed from the analysis. After matching, the covariate balance was assessed and all standardized mean differences (SMD) for the covariates were below 0.1, except APACHE II score (SMD = 0.152) suggesting an adequate balance.
Statistical AnalysisContinuous data were tested for normal distribution by the Kolmogorov-Smirnov test and are presented as mean/standard deviation (SD) or median/interquartile range (IQR). Groups were compared with Student’s t-tests or Mann-Whitney-U tests. Categorical variables are represented as counts/percentages and groups compared by χ2 tests of independence or Fischer’s exact tests. Statistical significance was established at P less than.05. All statistical analyses were performed with R v. 4.1.2 (Vienna, Austria) through R Studio v. 1.4.1106 (Boston, MA) and propensity score matching using the MatchIt package20.
ResultsA total of 56 patients were included in the analysis with 28 matched patients per group. Overall, the median age was 40 (IQR: 34, 50.25) years old, BMI 31.59 (IQR: 25.85, 36.27) kg/m2, APACHE II score 25.00 (IQR: 21.75, 32.25), and duration of ECLS support 22.57 (SD = 16.29) days with adequate covariate balance and no significant differences between groups (Figure 1, see Table 1, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A877). The two most common etiologies of ARDS for the Control group were bacterial pneumonia (n = 12, 42.9%) and influenza (n = 9, 32.1%); Table 2, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A877 shows ARDS etiology and salvage therapies in both groups.
Figure 1.: A: Love plot showing unadjusted and adjusted propensity score analysis using nearest neighbor methodology with standardized mean differences of covariates. B: Variance ratios.
DemographicsDemographics and comorbidities are presented in Table 1. There were no significant differences in comorbidities between COVID and Control groups. While 30.4% patients had no past medical history, the most frequent comorbidities were hypertension (n = 16, 28.6%), diabetes mellitus (n = 15, 26.8%), and asthma (n = 13, 23.2%).
Table 1. - Patient Demographics Overall N = 56 Control N = 28 COVID-19 N = 28 p Sex – Male (%) 35 (62.5) 17 (60.7) 18 (64.3) 1 Age (median [IQR]) 40.00APACHE, Acute Physiology and Chronic Health Evaluation; IQR, interquartile range.
Patients were intubated on median hospital day 2 in both groups, as shown in Table 2. ECLS was initiated later in the COVID group (hospital day 7.5 vs. 2, p = 0.001) and usually with larger drainage cannulae (25 vs. 23 French, p < 0.001). Precannulation ventilator settings and precannulation arterial blood gas values are shown in Table S3, Supplemental Digital Content 1, https://links.lww.com/ASAIO/A877 and were similar between both groups, except for partial pressure of arterial oxygen (PaO2) which was higher in the COVID group (67.5 vs. 56.5 mm Hg, p = 0.007).
Table 2. - Extracorporeal Life Support Hospital Course Overall N = 56 Control N = 28 COVID-19 N = 28 p ECLS procedure and course Duration of ECLS, in days (median [IQR]) 16.50ECLS, extracorporeal life support; ETT, endotracheal tube; Fr, French; IQR, interquartile range.
The most frequently observed complications were AKI (n = 47, 83.9%) and acute renal failure receiving renal replacement therapy (RRT) (n = 33, 58.9%); these data are presented in Table 3. Major bleeding complications were significantly different between COVID and Control groups (18 vs. 9, n = 0.031). Increased nasopharyngeal, oropharyngeal and neck bleeding in the COVID group accounted for some of this difference (10 vs. 1, p = 0.005). Notably, strokes occurred twice as often in the COVID group (6 vs. 3, p = 0.469). Further, when compared to the Control group, more patients in the COVID group required a chest tube for pneumothorax or pleural effusion (13 vs. 8, p = 0.296).
Complication (%) Overall N = 56 Control N = 28 COVID-19 N = 28 p Major bleeding complication* 27 (48.2) 9 (32.1) 18 (64.3) 0.031 Hemorrhagic shock 12 (21.4) 6 (21.4) 6 (21.4) 1 Naso/oropharyngeal/neck 11 (19.6) 1 (3.6) 10 (35.7) 0.005 Thoracic 16 (28.6) 9 (32.1) 7 (25.0) 0.768 Gastrointestinal/abdominal 5 (8.9) 2 (7.1) 3 (10.7) 1 Peripheral 9 (16.1) 4 (14.3) 5 (17.9) 1 Stroke 9 (16.1) 3 (10.7) 6 (21.4) 0.469 Ischemic 4 (7.1) 0 (0.0) 4 (14.3) 0.111 Hemorrhagic 5 (8.9) 3 (10.7) 2 (7.1) 1 Limb ischemia 12 (21.4) 5 (17.9) 7 (25.0) 0.746 Chest tube 21 (37.5) 8 (28.6) 13 (46.4) 0.269 Acute kidney injury 47 (83.9) 24 (85.7) 23 (82.1) 1 Acute renal failure requiring RRT 33 (58.9) 19 (67.9) 14 (50.0) 0.277 Cardiac arrest 18 (32.1) 8 (28.6) 10 (35.7) 0.775*Major Bleeding Complication: Requiring intervention and/or >2u PRBC transfusion.
RRT, renal replacement therapy.
In this propensity score analysis comparing clinical complications between COVID-19-related ARDS with non-COVID-19-related ARDS patients supported with ECLS, there was an increased incidence of major bleeding complications in COVID-19 patients. We integrated propensity analysis scores as a statistical approach in an attempt to reduce selection bias and known confounding in this observational study. Although a higher incidence of strokes and more chest tubes were observed in the COVID group and, these findings did not reach statistical significance. Despite the increased risk of adverse events in this matched cohort, inpatient survival to discharge (n = 14, 50% vs. n = 17, 60.7%) was not statistically different although numerically higher in the Control group.
Bleeding and Thromboembolic ComplicationsIn COVID-19, derangements in the coagulation cascade leading to increased thromboembolic events and bleeding complications have been reported7,8,21–23. Indeed, our study’s results are similar to Autschbach et al.24 and Helms et al.8 who reported increased incidence of thromboembolic events and pulmonary artery embolism in COVID-19-related ARDS patients as compared with non-COVID-19-related ARDS patients (42% vs. 12%, p = 0.031 and 11.7% vs. 2.1%, p = 0.008). Increased risk of bleeding and intracerebral hemorrhage have also been suggested in COVID-19 patients supported with ECLS9,25,26. Rates of major bleeding comparing COVID-19-related ARDS to non-COVID-19-related ARDS were relatively high in both groups, but not statistically different (42% vs. 62%)24. While seemingly paradoxical, thrombotic and hemorrhagic complications could both be related to COVID-19-mediated inflammatory endothelial damage, the latter being further triggered by therapeutic anticoagulation22,25.
Considering evolving evidence surrounding thromboembolic complications, our center increased our goal-activated partial thromboplastin (aPTT) time from 40–60 to 60–80 seconds in COVID-19 patients supported with ECLS. Indeed, we cannot exclude that the increased incidence of bleeding may be associated with a higher level of therapeutic anticoagulation, while reducing risk of thrombotic complications. Future study with attention to hemostasis parameters and platelet activity during ECLS may yield insights into improving outcomes in critically ill COVID-19-related ARDS patients.
In our study, COVID-19 patients were twice as likely to have a stroke when compared to the Control group. This clinically meaningful finding did not reach statistical significance but is consistent with larger studies on neurologic outcomes in COVID-19 patients supported with ECLS9.
Survival to DischargeDespite the purported success of using ECLS in ARDS patients during the influenza A(H1N1) pandemic early reports cautioned against its use in COVID-19 patients28. Large multicenter cohort studies later suggested that mortality in COVID-19 patients supported with ECLS appeared to be similar to patients with non-COVID-19-related ARDS11,12. Mortality in our COVID group was 50%, which is consistent with these larger studies13.
Survival to discharge in our Control group (60.7%) is consistent with other reported in other studies (60–70%) investigating ECLS in patients with ARDS over the last 10 years29–31. Duration of ECLS as a covariate in the propensity score analysis may have introduced a selection bias in the historical cohort skewing toward relatively sicker patients. Given that the median duration of ECLS was considerably shorter in the non-COVID-19 patients, matching based on the duration of ECLS ends up selecting for the long duration non-COVID-19 patients to compare with the average duration seen in the COVID-19 patients creates a bias toward similar mortality rates. These differences in severity may not be fully accounted for in the APACHE II score alone.
Study LimitationsAlthough our propensity score matched model was adequately balanced, our single-center study was limited by a small sample size of 56 total patients. Including more patients from the available pool would have been preferable, but likely at the expense of model performance. Although we accounted for covariates of interest, namely (1) age, (2) BMI, (3) duration of ECLS run, and (4) APACHE II score, we could not account for other measured or unmeasured risk factors in our model.
Duration of ECLS as a covariate in the propensity score analysis may have introduced a selection bias in the historical cohort skewing toward relatively sicker patients. Inflammatory/infectious-related ARDS encompasses a heterogenous mix of pathophysiology that may not be fully accounted for in the APACHE II score alone. Given the resource-intensive nature of ECLS, the selection of COVID patients for ECLS during peak surges was highly variable32–36. Our mortality data should be interpreted with caution given the possible selection bias generated by the propensity score analysis. Lastly, our cohort dates to January 2012 and we acknowledge that there have been changes in the provision of intensive care, ECLS, and technology that create inherent differences between the cohorts.
ConclusionsWhen compared to the Control group, ECLS in the propensity-matched COVID group was associated with more major bleeding complications, strokes, and chest tube placements. The use of ECLS in patients with COVID-19-related ARDS appears to be associated with an increased risk of complications.
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