Authors: Kim H et al.
Anesthesiology, November 25, 2025. DOI: 10.1097/ALN.0000000000005811
Summary
This pharmacokinetic study evaluated how extracorporeal membrane oxygenation (ECMO) flow rate affects the clearance and systemic exposure of midazolam in critically ill adults receiving venoarterial ECMO. Midazolam is widely used for sedation in ECMO patients, but ECMO circuits can sequester drug, alter distribution, and reduce metabolism, producing substantial variability. To improve understanding of these effects, the investigators developed a population pharmacokinetic model incorporating both parent-drug and metabolite kinetics.
Serial plasma samples from 19 adults during ECMO and 11 after ECMO were analyzed. A two-compartment model for midazolam and its active metabolite, 1-hydroxymidazolam, adequately described concentration-time data. ECMO flow rate emerged as a significant covariate: higher flow rates increased midazolam clearance, requiring higher infusion rates to achieve equivalent plasma concentrations. Simulations showed that at 5 L/min of ECMO flow, infusion rates needed to be approximately 1.6 times higher to achieve the same midazolam exposure as at 1 L/min.
ECMO flow rate also influenced sedative offset. As flow increased, the time for plasma midazolam levels to fall by 70% after stopping a 24-hour infusion decreased—from about 20 hours at 1 L/min to about 16 hours at 5 L/min. Thus, patients at lower ECMO flows may experience delayed awakening even with standard dosing. Exposure plateaued above ~3 L/min, likely reflecting severe illness and limited hepatic clearance reserve in high-flow patients.
Although sampling limitations and lack of paired sedation scores restricted full pharmacokinetic–pharmacodynamic modeling, the study provides an initial framework linking ECMO flow rate to midazolam disposition and recovery kinetics. Future work incorporating standardized sampling and sedation scoring may further optimize dose adjustments in ECMO-supported patients.
Key Points
• ECMO circuits significantly alter midazolam pharmacokinetics, affecting clearance and systemic exposure.
• Higher ECMO flow rates require higher midazolam infusion rates to maintain equal plasma concentrations.
• Sedative offset is delayed at lower ECMO flow rates, especially during ECMO weaning.
• Simulation results may guide clinicians in adjusting sedation based on ECMO flow changes.
• The model provides foundational insight but requires further study before informing precise dosing strategies.
Thank you for allowing us to use this article from Anesthesiology.