Propofol and Fentanyl Pharmacokinetics and Pharmacodynamics in Extracorporeal Membrane Oxygenation.

Abstract

Despite the potential risks associated with sedation, there is a paucity of pharmacokinetic/pharmacodynamic (PK/PD) data for propofol and fentanyl in patients supported with veno-venous extracorporeal membrane oxygenation (V-V ECMO). Describe propofol and fentanyl PK/PD profiles in V-V ECMO patients. Prospective, single-center, open-label PK/PD study at the Toronto General Hospital ICU between July 2022 and January 2023. Using high-performance liquid chromatography-tandem mass spectrometry, propofol and fentanyl total concentrations were measured during V-V ECMO. Sequential PK/PD modeling, using sex as a covariate, was conducted with processed electroencephalography (PSI) for sedation, and expiratory occlusion pressure (Pocc), and airway occlusion pressure during the first 0.1 seconds (P0.1) for respiratory effort. Eleven patients underwent 106 evaluations over a median (IQR) follow-up of 146 (116-146) hours. Patient's average (±SD) age was 43 (±13) years, and 55% were female. Propofol and fentanyl PK were best described by a two-compartment model. Propofol-PSI PD was described using an effect compartment, with a coefficient of determination (ρ2) of 0.78. There was a significant increase in propofol (p=0.01) and fentanyl (p=0.03) clearance within 10 minutes of ECMO initiation, plateauing after 8 hours of ECMO support. Despite this, patient over-sedation (PSI<40) occurred in 74% of the observations. Females exhibited higher sedative central volume of distribution and lower propofol clearance. ECMO initiation resulted in a time-limited increased sedative clearance. PSI accurately described sedative PD, but variable respiratory effort was observed irrespective of sedative plasma concentrations. Sex-based differences were found in sedative PK/PD parameters.