European journal of drug metabolism and pharmacokinetics · 2026
Kinetics of Sevoflurane Vaporized Directly in Extracorporeal Membrane Oxygenators-Ex Vivo Findings and Pharmacokinetic/Pharmacodynamic Simulations.
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Morales Castro Diana, Alm Mark, Carini Federico Carlos, Fischer Courtney, Roman-Sarita Georgiana, Dresser Linda, Granton John, Chen Eric, Shekar Kiran, Fan Eddy
Аннотация
BACKGROUND: Although sedation is commonly used in patients undergoing venovenous extracorporeal membrane oxygenation (V-V ECMO), the use of volatile anesthetics is less frequent, and there is limited data on the pharmacokinetics/pharmacodynamics (PK/PD) of these sedatives (e.g., sevoflurane) directly vaporized into ECMO circuits. We aimed to develop a kinetic model for sevoflurane vaporized in ex vivo ECMO oxygenators to inform the design of a pilot clinical trial to evaluate the safety, feasibility, and in vivo PK/PD model of such a strategy in patients supported with V-V ECMO.
METHODS: We conducted ex vivo trials using three ECMO circuits primed with Ringer's lactate, and the ECMO pump speed set to achieve a fluid flow rate of 5 L/min. Sevoflurane was vaporized at concentrations of 1-8% with sweep gas flow (SGF) rates of 1-10 L/min. We analyzed sevoflurane concentrations in the ECMO circuit using headspace gas chromatography-mass spectrometry and monitored environmental sevoflurane concentrations for safety. We used sequential PK/PD modeling to simulate clinical conditions, targeting sedation levels defined by processed electroencephalography (Patient State Index [PSI] 40-60), using pharmacodynamic parameters derived from non-ECMO populations.
RESULTS: Sevoflurane effectively crossed polymethyl pentene (PMP) membranes, rapidly reaching maximum concentrations (Cmax) to values consistent with clinical targets for deep sedation (i.e., PSI < 60). Clearance increased significantly with higher SGF (p < 0.001), while both the volume of distribution and clearance increased with vaporized concentrations (p < 0.001). Environmental levels of sevoflurane (< 0.019 ppm/h) remained below safety thresholds (< 2 ppm/h).
CONCLUSIONS: Our ex vivo findings demonstrate the feasibility of using sevoflurane vaporized directly into ECMO circuits as a sedative strategy. These results provide a robust foundation for translating this delivery strategy into a pilot clinical trial aimed at optimizing ECMO sedation with inhaled sevoflurane in patients with severe ARDS.
METHODS: We conducted ex vivo trials using three ECMO circuits primed with Ringer's lactate, and the ECMO pump speed set to achieve a fluid flow rate of 5 L/min. Sevoflurane was vaporized at concentrations of 1-8% with sweep gas flow (SGF) rates of 1-10 L/min. We analyzed sevoflurane concentrations in the ECMO circuit using headspace gas chromatography-mass spectrometry and monitored environmental sevoflurane concentrations for safety. We used sequential PK/PD modeling to simulate clinical conditions, targeting sedation levels defined by processed electroencephalography (Patient State Index [PSI] 40-60), using pharmacodynamic parameters derived from non-ECMO populations.
RESULTS: Sevoflurane effectively crossed polymethyl pentene (PMP) membranes, rapidly reaching maximum concentrations (Cmax) to values consistent with clinical targets for deep sedation (i.e., PSI < 60). Clearance increased significantly with higher SGF (p < 0.001), while both the volume of distribution and clearance increased with vaporized concentrations (p < 0.001). Environmental levels of sevoflurane (< 0.019 ppm/h) remained below safety thresholds (< 2 ppm/h).
CONCLUSIONS: Our ex vivo findings demonstrate the feasibility of using sevoflurane vaporized directly into ECMO circuits as a sedative strategy. These results provide a robust foundation for translating this delivery strategy into a pilot clinical trial aimed at optimizing ECMO sedation with inhaled sevoflurane in patients with severe ARDS.