Volatile Anesthetic Pharmacokinetics During Extracorporeal Membrane Oxygenation (Vol-ECMO)

The goal of this study is to design a pilot trial evaluating the safety, feasibility, pharmacokinetic modeling, and physiological effects of a volatile anesthetic, sevoflurane, directly administered in extracorporeal membrane oxygenation machines.

Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving therapy for catastrophic respiratory failure, including severe COVID-19. Optimal drug dosing in critically ill patients is challenging due to concomitant organ dysfunction, and with the addition of ECMO, the level of complexity significantly increases. ECMO PK interactions with intravenous (IV) sedatives are complex and therapeutic failures are often encountered, highlighting the need for alternative sedation strategies. To overcome these limitations, volatile anesthetics are a potential solution for sedation and analgesia. Nevertheless, their use has been limited during ECMO support due to the low respiratory volumes associated with the lung-protective strategies, and the concerns of bioavailability given the compromised native lung function. The overarching aim of this project is to evaluate a strategy to mitigate the influence of ECMO on sedatives pharmacokinetics, using volatile anesthetics directly vaporized into ECMO oxygenators. The study will consist of two phases: the ex-vivo trial an the in-vivo trial. For the ex-vivo trial, two ECMO circuits primed with Ringer's lactate will be used to design the dosing recommendations for the feasibility trial. Vaporized sevoflurane will be delivered directly into the membrane oxygenator with the ECMO gas and evacuated through the wall suction. Sevoflurane concentrations will be monitored with an infrared multi-gas analyzer sensor at the ECMO gas outlet. The test will be performed with different sweep flows and sevoflurane concentrations. Sevoflurane concentrations will be measured in the fluid to design a dosing model to conduct the in-vivo trial. The in-vivo trial will be a prospective, single-center, open-label, pilot feasibility/PK study of 10 patients receiving venovenous ECMO (VV ECMO) in the Medical-Surgical Intensive Care Unit (MSICU) at the Toronto General Hospital. Following informed consent, these patients will be enrolled and managed with sevoflurane-based anesthesia directly delivered into the ECMO machine. During their ECMO run, samples will be taken and sevoflurane concentrations analyzed with headspace gas chromatography and mass spectrometry. Sedation scales, surrogates of respiratory dynamics and effort, and biotrauma inflammatory cytokines levels will be obtained at the same time.

Patients' sedation will be managed with sevoflurane-based anesthesia directly vaporized into the ECMO machine.

The volume/volume percentage of sevoflurane will be measured with an infrared multi-gas analyzer sensor at the sweep gas outlet

Driving pressure, occlusion pressure, and P0.1 pressures will be measured with the patients mechanical ventilator daily

As a surrogate for ventilator-induced lung injury, plasma levels of interleukins 6 and 8, and necrosis tumor factor will be measured daily

The doses of other sedatives and analgesics, including opioids, antipsychotics, benzodiazepines, ketamine and propofol will be recorded

Inclusion Criteria: adult patients expected to be on VV ECMO support for a time frame of more than 24 hours and receiving a sevoflurane-based sedation protocol. Exclusion Criteria: lack of informed consent for participation pregnancy serum bilirubin > 150 μmol/L ongoing massive blood transfusion requirement (> 50% blood volume transfused in the previous 8 hours) therapeutic plasma exchange and/or renal replacement therapy in the preceding 24 hours expected death or withdrawal of life support in the next 48 hours.

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