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Background <p>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.</p> Methods <p>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&#xa0;L/min. Sevoflurane was vaporized at concentrations of 1–8% with sweep gas flow (SGF) rates of 1–10&#xa0;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.</p> Results <p>Sevoflurane effectively crossed polymethyl pentene (PMP) membranes, rapidly reaching maximum concentrations (<i>C</i><sub>max</sub>) to values consistent with clinical targets for deep sedation (i.e., PSI&#xa0;&lt;&#xa0;60). Clearance increased significantly with higher SGF (<i>p</i>&#xa0;&lt;&#xa0;0.001), while both the volume of distribution and clearance increased with vaporized concentrations (<i>p</i>&#xa0;&lt;&#xa0;0.001). Environmental levels of sevoflurane (&lt;&#xa0;0.019&#xa0;ppm/h) remained below safety thresholds (&lt;&#xa0;2&#xa0;ppm/h).</p> Conclusions <p>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.</p>

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Kinetics of Sevoflurane Vaporized Directly in Extracorporeal Membrane Oxygenators—Ex Vivo Findings and Pharmacokinetic/Pharmacodynamic Simulations

  • 期刊论文

  • 发表日期：

    2026年5月7日

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  • Diana Morales Castro,
  • Mark Alm,
  • Federico Carlos Carini,
  • Courtney Fischer,
  • Georgiana Roman-Sarita,
  • Linda Dresser,
  • John Granton,
  • Eric Chen,
  • Kiran Shekar,
  • Eddy Fan

摘要

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.