Impact of extracorporeal membrane oxygenation on drug pharmacokinetics
Year: 2025
Type: dissertation
Study design: Observational Study
Abstract: Extracorporeal membrane oxygenation (ECMO) is a temporary life-support therapy for severe acute cardiac and/or respiratory failure. Over the past 15 years, its use has expanded, driven by technical advancements that have improved safety, ease of use, and efficacy. Drug dosing in critically ill patients presents a major challenge, as critical illness induces profound pathophysiological changes that significantly alter pharmacokinetics (PK). ECMO may further affect PK through mechanisms such as drug sequestration, as well as drug dilution due to circuit-related volume expansion, potentially leading to suboptimal drug exposure and unfavourable clinical outcomes. Except for selected antibiotics, PK data in ECMO patients remain scarce, and no robust dosing guidelines exist. This PhD thesis aimed to enhance our understanding of ECMO’s impact on drug PK. First, we conducted a review of ex vivo drug sequestration studies, developing a meta-regression model to better characterise factors influencing drug sequestration. We also conducted a prospective bicentric observational PK study of levosimendan and propofol, two lipophilic drugs likely to be sequestered in ECMO circuits. Using population PK modelling and existing literature, we sought to determine whether drug PK differed between patients with and without ECMO. Our review confirmed that lipophilicity is a major predictor of drug sequestration and provided the first quantitative evidence that drug ionisation also plays a role. In our propofol PK clinical study, 40 adults, 20 with and 20 without ECMO, contributed 300 plasma samples. Propofol PK was comparable between ECMO and non-ECMO patients, suggesting that standard dosing guidelines are applicable to patients on ECMO. In our levosimendan PK clinical study, 15 adults and 6 children on ECMO contributed 155 plasma samples. The PK of levosimendan appeared unaffected in adults when compared to non critically ill patients. However, in children, ECMO significantly altered levosimendan PK, with an increase of both clearance and volume of distribution. Model-based simulations demonstrated that these changes resulted in plasma concentrations approximately half those observed in adults when the same weight-adjusted dose was administered. Moreover, children exhibited impaired levosimendan metabolism, probably mainly due to an immature microbiome and enzymatic activity, resulting in markedly reduced exposure to its long-acting active metabolite OR-1896. This is expected to blunt the sustained haemodynamic effects mediated by OR-1896, which are anticipated to persist for at least one week following the completion of a levosimendan infusion. Our findings pave the way for optimised levosimendan dosing in this vulnerable population. In conclusion, ECMO had no major impact on the PK of levosimendan and propofol in adults but profoundly affected levosimendan PK in children.
Source: IRIS
Author: Bertin, Stéphane
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7133078030