Intracranial Hemorrhages on Extracorporeal Membrane Oxygenation: Differences Between COVID-19 and Other Viral Acute Respiratory Distress Syndrome

Benjamin Seeliger, Michael Doebler, Daniel Andrea Hofmaenner, Pedro D Wendel-Garcia, Reto A Schuepbach, Julius J Schmidt, Tobias Welte, Marius M Hoeper, Hans-Jörg Gillmann, Christian Kuehn, Stefan Felix Ehrentraut, Jens-Christian Schewe, Christian Putensen, Klaus Stahl, Christian Bode, Sascha David, Benjamin Seeliger, Michael Doebler, Daniel Andrea Hofmaenner, Pedro D Wendel-Garcia, Reto A Schuepbach, Julius J Schmidt, Tobias Welte, Marius M Hoeper, Hans-Jörg Gillmann, Christian Kuehn, Stefan Felix Ehrentraut, Jens-Christian Schewe, Christian Putensen, Klaus Stahl, Christian Bode, Sascha David

Abstract

Objectives: Extracorporeal membrane oxygenation (ECMO) is a potentially lifesaving procedure in acute respiratory distress syndrome (ARDS) due to COVID-19. Previous studies have shown a high prevalence of clinically silent cerebral microbleeds in patients with COVID-19. Based on this fact, together with the hemotrauma and the requirement of therapeutic anticoagulation on ECMO support, we hypothesized an increased risk of intracranial hemorrhages (ICHs). We analyzed ICH occurrence rate, circumstances and clinical outcome in patients that received ECMO support due to COVID-19-induced ARDS in comparison to viral non-COVID-19-induced ARDS intracerebral hemorrhage.

Design: Multicenter, retrospective analysis between January 2010 and May 2021.

Setting: Three tertiary care ECMO centers in Germany and Switzerland.

Patients: Two-hundred ten ARDS patients on ECMO support (COVID-19, n = 142 vs viral non-COVID, n = 68).

Interventions: None.

Measurements and main results: Evaluation of ICH occurrence rate, parameters of coagulation and anticoagulation strategies, inflammation, and ICU survival. COVID-19 and non-COVID-19 ARDS patients showed comparable disease severity regarding Sequential Organ Failure Assessment score, while the oxygenation index before ECMO cannulation was higher in the COVID group (82 vs 65 mm Hg). Overall, ICH of any severity occurred in 29 of 142 COVID-19 patients (20%) versus four of 68 patients in the control ECMO group (6%). Fifteen of those 29 ICH events in the COVID-19 group were classified as major (52%) including nine fatal cases (9/29, 31%). In the control group, there was only one major ICH event (1/4, 25%). The adjusted subhazard ratio for the occurrence of an ICH in the COVID-19 group was 5.82 (97.5% CI, 1.9-17.8; p = 0.002). The overall ICU mortality in the presence of ICH of any severity was 88%.

Conclusions: This retrospective multicenter analysis showed a six-fold increased adjusted risk for ICH and a 3.5-fold increased incidence of ICH in COVID-19 patients on ECMO. Prospective studies are needed to confirm this observation and to determine whether the bleeding risk can be reduced by adjusting anticoagulation strategies.

Trial registration: ClinicalTrials.gov NCT04853953.

Conflict of interest statement

Dr. Seeliger is supported by Program of Hannover Medical School for Clinician Scientists (PRACTIS), funded by the Deutsche Forschungsgemeinschaft (DFG, ME 3696/3-1) and the German Center for Lung Research (DZL). Dr. David received funding from the German Centre for Lung Research. Dr. Hoeper received funding from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, and Pfizer. Dr. Putensen’s institution received funding from the DFG (PU 219/2-3); he received funding from Pluristem Ltd and Dräger Medical. Dr. Bode is supported by the DFG (BO 3640/2-1) and the Federal Ministry of Education and Research (01KI20343). Dr. David’s institution received funding from the German Research Foundation (DA1209/4-3), DFG, DZL, Cytobsorbents, Octapharma, and Terumo; he received funding from Terumo, Octapharma, and Cytosorbents. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Figures

Figure 1.
Figure 1.
Primary endpoint of intracranial hemorrhage (ICH) in COVID-19 and other viral acute respiratory distress syndromes. Cumulative incidence function for ICH and death from other causes (competing event) in venovenous extracorporeal membrane oxygenation patients with COVID-19 versus controls (CTRL) (A). Cumulative incidence of ICH and death as multistate comparison is shown in (B) demonstrating increased incidence of ICH in COVID-19 patients. Multivariable competing risk regression model using study site as a random-effect term with subhazard ratios (SHRs) and 97.5% CIs (C). BMI = body mass index, IQR = interquartile range, SOFA = Sequential Organ Failure Assessment, UFH = unfractionated heparin.
Figure 2.
Figure 2.
Impact of intracranial hemorrhage (ICH) on mortality and anticoagulation regimens. Kaplan-Meier survival curve stratified by presence of intracranial hemorrhage ICH for the entire cohort (COVID-19 and controls) demonstrating ICH as a risk factor for mortality (A) and multivariable Cox regression model for 90-d ICU mortality using study site as a random-effect term (B). Comparison of mean unfractionated heparin (UFH) dose per kg bodyweight over the first 7 d of extracorporeal membrane oxygenation (ECMO) between COVID-19 and controls (C). Comparison of UFH dose per kg bodyweight over the first 7 d of ECMO stratified by anticoagulation strategy in the COVID-19 cohort (D). ACT = activated clotting time, aPTT = activated partial thromboplastin time, BMI = body mass index, HR = hazard ratio, IU = international units, SOFA = Sequential Organ Failure Assessment.

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