M. Raguindin et al.: J Extra Corpor Technol 2026, 58, 57--64 63
COVID-19 subgroup analysis
The differences in baseline characteristics between groups, including VV ECMO, pre-ECMO therapeutic anticoagulation, respiratory illness, and renal failure, are likely due to the COVID-19 population in the post-group. Hypercoagulability has been well documented in COVID-19 patients. It has been proposed that the inflammatory response from cytokine release interferes with endothelial function and activates the coagulation cascade [ 12, 14 ]. This could help explain why 20 % of patients in the post-group were receiving anticoagulation prior to ECMO for VTE. COVID-19 patients in our study required a wider range of bivalirudin doses, had a higher percentage of aPTTs out of range, and took longer to reach therapeutic aPTTs. All patients in the COVID-19 group had renal failure, but they required similar bivalirudin doses to those without renal failure. Since the starting doses in our protocol are lower for renal impairment, it took longer to become therapeutic due to the need for multiple dose adjustments in the COVID-19 group. Prevalence of renal failure requiring renal replacement therapy has been reported in patients with COVID-19, with proposed mechanisms including cytokine release leading to inflammation and thrombotic microangiopathy [ 14 ]. In our patients, CRRT was typically started for renal failure and not volume management or cytokine release alone. Given the unique pathophysiology of COVID-19 and bivalirudin renal dose findings not in line with the rest of the cohort without COVID-19, no changes were made to our institutional protocol.
Although the range of therapeutic doses is not well documented in the literature, the reported average doses of 0.18 and 0.2 mg / kg / h fall within the range of our study [ 11, 12 ]. Interestingly, the percentage of aPTTs out of range does not necessarily correlate with other published retrospective findings of bivalirudin use in COVID-19 patients on ECMO. One study found that the percentage of aPTTs at goal was maintained more consistently in patients with COVID-19 versus non- COVID-19. However, only 11 % of their COVID-19 patients required renal replacement therapy after ECMO initiation compared to 26 % non-COVID-19 patients, both rates which are much lower than in our current study [ 11 ]. Bissell and colleagues reported a median time to therapeutic range of 20 h, in line with the findings of this study, despite only 55 % of their patients being on CRRT compared to 100 % of patients in our study [ 12 ]. However, these two studies included 42 and 33 COVID-19 patients, respectively, compared to the sample size of nine patients at our institution, and only utilized a single aPTT goal range of 60--80 s [ 11, 12 ].
Limitations
This study has limitations. It was retrospective in nature, thereby relying on accurate documentation in the electronic medical record. Previously collected data was used for the pre-group, and no data was recollected. Some endpoints were defined in a non-standard way to allow direct comparison between the post-group and the previously collected data in the pre-group, while other endpoints were not previously collected in the pre-group to allow for comparison in the postgroup. This study did not seek to evaluate the effectiveness of nomogram dose adjustments for achieving therapeutic aPTTs, and thus, not all aspects of the protocol could be assessed for appropriateness. There was a small sample size in both groups, especially when evaluating the COVID-19 subgroup, and findings for that population should only be considered hypothesis-generating. The primary outcome was also not able to be evaluated for all patients in an already small group. The time to first circuit thrombosis was not collected, which may have allowed us to draw more definitive conclusions on pre-ECMO systemic anticoagulation.
Conclusion
In conclusion, the results of this study suggest that adopting a standardized pharmacist-directed protocol for bivalirudin in ECMO rapidly achieves therapeutic anticoagulation levels. Furthermore, the recommended bivalirudin starting doses in our current institutional protocol are appropriate. Based on the data in the post-group, our institution’ s current DTI protocol monitoring was changed to once daily aPTTs after achieving two consecutive therapeutic aPTTs. Given the current published evidence, further studies evaluating bivalirudin dosing strategies and appropriate aPTT goals in both patients with and without COVID-19 are needed to better evaluate efficacy and safety outcomes and to further elucidate dosing considerations.
Funding The authors received no funding to conduct this research.
Conflicts of interest The authors declare no conflict of interest.
Data availability statement
The research data associated with this article are included in the article.
Author contribution statement
Miranda Raguindin, Casey Bardsley, Hasan Kazmi, and Ashley Milkovits designed the study. Miranda Raguindin performed the research and analyzed the data. Hasan Kazmi and Ashley Milkovits provided assistance in data analysis. Miranda Raguindin wrote the original manuscript draft, and all authors contributed to the final version.
Ethics approval
The study was undertaken as a Health Care Delivery Improvement Project, and as such was not reviewed as Human Subjects Research by the Institutional Review Board. References
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