Abstract
Background
Optimal anticoagulation strategies for COVID-19 patients with the acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) remain uncertain. A higher incidence of intracerebral hemorrhage (ICH) during VV ECMO support compared to non-COVID-19 viral ARDS patients has been reported, with increased bleeding rates in COVID-19 attributed to both intensified anticoagulation and a disease-specific endotheliopathy. We hypothesized that lower intensity of anticoagulation during VV ECMO would be associated with a lower risk of ICH. In a retrospective, multicenter study from three academic tertiary intensive care units, we included patients with confirmed COVID-19 ARDS requiring VV ECMO support from March 2020 to January 2022. Patients were grouped by anticoagulation exposure into higher intensity, targeting anti-factor Xa activity (anti-Xa) of 0.3–0.4 U/mL, versus lower intensity, targeting anti-Xa 0.15–0.3 U/mL, cohorts. Mean daily doses of unfractionated heparin (UFH) per kg bodyweight and effectively measured daily anti-factor Xa activities were compared between the groups over the first 7 days on ECMO support. The primary outcome was the rate of ICH during VV ECMO support.
Results
141 critically ill COVID-19 patients were included in the study. Patients with lower anticoagulation targets had consistently lower anti-Xa activity values over the first 7 ECMO days (p < 0.001). ICH incidence was lower in patients in the lower anti-Xa group: 4 (8%) vs 32 (34%) events. Accounting for death as a competing event, the adjusted subhazard ratio for the occurrence of ICH was 0.295 (97.5% CI 0.1–0.9, p = 0.044) for the lower anti-Xa compared to the higher anti-Xa group. 90-day ICU survival was higher in patients in the lower anti-Xa group, and ICH was the strongest risk factor associated with mortality (odds ratio [OR] 6.8 [CI 2.1–22.1], p = 0.001).
Conclusions
For COVID-19 patients on VV ECMO support anticoagulated with heparin, a lower anticoagulation target was associated with a significant reduction in ICH incidence and increased survival.
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Background
Despite an impressive gain of knowledge throughout the COVID-19 pandemic, the management of COVID-19 patients with acute respiratory distress syndrome (ARDS) remains challenging [1]. For these patients, venovenous extracorporeal membrane oxygenation (VV ECMO) can be a potential life-saving intervention facilitating lung protective ventilation [2, 3]. However, the use of ECMO is associated with serious complications such as an increased bleeding risk and hemotrauma [4]. In addition, patients with critical COVID-19 exhibit unique abnormalities in coagulation which can increase the risk of both bleeding and thrombotic events [31].
Aside from anticoagulation targets, management strategies of critically ill COVID-19 patients have been adapted during the course of the pandemic. In order to counteract profound inflammation, dexamethasone and tocilizumab have been increasingly used, with varying effects on patient outcomes [32,33,34]. From a pathophysiological viewpoint, it would be plausible that attenuated inflammation could decrease the risk of ICH, independent of anti-Xa levels. Indeed, we found decreased CRP and ferritin levels in the lower anti-Xa group, probably reflecting a more frequent use of anti-inflammatory drugs later in the pandemic. Interleukin 6 (IL-6) levels were slightly higher in the low anti-Xa group, in line with observations that IL-6 serum levels even can increase after administration of tocilizumab [35]. Taking dexamethasone and tocilizumab use into account in our analysis, the occurrence of ICH was still the main risk factor for mortality, whereas use of dexamethasone and tocilizumab was not associated with better patient survival. However, these results should be interpreted with caution, as we cannot rule out residual confounders affecting treatment decisions and inflammation. Of note, ECMO runtime was slightly longer and organ support tended to decrease in the low anti-Xa group, both probably affecting ICH risk. Thus, further large-scale studies specifically including patients requiring ECMO support should clarify effects of different anticoagulation strategies and the use of anti-inflammatory medication on global patient outcomes such as ICU length of stay, the need for mechanical ventilation, long-term neurologic sequelae of patients affected by bleeding, and mortality [31].
Our study has to account for limitations. We had a relatively small population of COVID-19 patients of VV ECMO, but overall mortality was similar to previous VV ECMO studies [10, 12, 36] and the consistency of the results across multiple centers adds generalizability to our findings. The retrospective nature of this study prevented us from inferring causality, and we cannot exclude the possibility of unmeasured confounders. Furthermore, our study did not analyze different viral mutants nor did it account for specific ICU patient management strategies such as ventilation, proning or sedation strategies. These all might have contributed to the lower observed overall mortality in the low anti-Xa cohort. The lower anti-Xa target was deployed later in the COVID-19 pandemic in response to the higher rates of ICH observed in earlier phases of the pandemic. Eligibility criteria for VV ECMO and practices for ICU and ventilator management during VV ECMO support evolved to some degree at the participating centers over the course of the pandemic, potentially contributing to higher survival rates in the lower anti-Xa group.
Conclusions
A less intense anticoagulation target (anti-Xa activity 0.15–0.3 U/mL) was associated with a decreased incidence of ICH and lower mortality in COVID-19 patients on VV ECMO support. Our results highlight the need for prospective studies to evaluate anticoagulation regimens in ARDS patients on ECMO support.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- anti-Xa:
-
Anti-factor Xa activity
- ARDS:
-
Acute respiratory distress syndrome
- CCT:
-
Cranial computed tomography
- ELSO:
-
Extracorporeal Life Support Organization
- ICH:
-
Intracerebral hemorrhage
- ICU:
-
Intensive care unit
- IL-6:
-
Interleukin 6
- RT-PCR:
-
Real-time reverse transcriptase-polymerase chain reaction
- SOFA score:
-
Sequential Organ Failure Assessment score
- UFH:
-
Unfractionated heparin
- VV ECMO:
-
Venovenous extracorporeal membrane oxygenation
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DAH, DF, LCW, EWG, SS, SD, BS and CB designed the study protocol. DAH, DF, LCW, EBK, AP, EWG and SS collected the data. PDWG and BS did the formal statistical analysis. All authors discussed and interpreted the findings. DAH wrote the initial draft of the manuscript. All authors read and approved the final manuscript.
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The study was performed and data were acquired with approval of all responsible local ethics committees (Kantonale Ethikkommission Zürich, BASEC 2021-00825; Ethikkommission University Hospital Bonn number 196/21; BIDMC Committee on Clinical Investigation under IRB protocol 2017P000310) and shared through an executed Data Use Agreement.
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Supplementary Information
Additional file 1: Table S1.
Linear mixed effect model for the prediction of the anti-Xa activity.
Additional file 2: Table S2.
Competing risk regression model for intracranial hemorrhage treating death without intracranial hemorrhage as a competing event and study site as a frailty term.
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Hofmaenner, D.A., Furfaro, D., Wild, L.C. et al. Reduced anticoagulation strategy is associated with a lower incidence of intracerebral hemorrhage in COVID-19 patients on extracorporeal membrane oxygenation. ICMx 11, 38 (2023). https://doi.org/10.1186/s40635-023-00525-3
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DOI: https://doi.org/10.1186/s40635-023-00525-3