Propofol and Fentanyl Pharmacokinetics and Pharmacodynamics in Extracorporeal Membrane Oxygenation

Rationale: 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 venovenous extracorporeal membrane oxygenation (V-V ECMO). Objective: Describe propofol and fentanyl PK/PD profiles in patients receiving V-V ECMO. Methods: Prospective, single-center, open-label PK/PD study at the Toronto General Hospital intensive care unit 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 (patient state index [PSI]) for sedation and expiratory occlusion pressure and airway occlusion pressure during the first 0.1 second for respiratory effort. Results: Eleven patients underwent 106 evaluations over a median follow-up of 146 (interquartile ranges, 116-146) hours. Patients' average age was 43 (standard deviation, 13) years, and 55% were female. Propofol and fentanyl PKs were best described by a two-compartment model. Propofol PSI PD were described using an effect compartment, with a coefficient of determination 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 oversedation (PSI <40) occurred in 74% of the observations. Female patients exhibited a higher sedative central volume of distribution and lower propofol clearance. Conclusions: 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.