Volatile Anesthetic Pharmacokinetics During Extracorporeal Membrane Oxygenation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Volatile Anesthetic Pharmacokinetics During Extracorporeal Membrane

Conditions
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Respiratory Failure

Intervention / Treatment
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* Other: Sevoflurane vaporized in ECMO machines


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective, single-center, open-label, pharmacokinetic study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sevoflurane vaporized in ECMO machines<br>Patients' sedation will be managed with sevoflurane-based anesthesia directly vaporized into the ECMO machine. | Other: Sevoflurane vaporized in ECMO machines<br>* Sevoflurane will be directly vaporized into the ECMO machine through the sweep gas.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sevoflurane plasma concentrations | Plasma concentrations of sevoflurane will be measured with gas chromatography and mass spectrometry | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of sevoflurane in ECMO exhausted gas | The volume/volume percentage of sevoflurane will be measured with an infrared multi-gas analyzer sensor at the sweep gas outlet | 7 days | 
| Respiratory dynamics and respiratory effort | Driving pressure, occlusion pressure, and P0.1 pressures will be measured with the patients mechanical ventilator daily | 7 days | 
| Plasma levels of ventilator-induced lung injury biomarkers | As a surrogate for ventilator-induced lung injury, plasma levels of interleukins 6 and 8, and necrosis tumor factor will be measured daily | 7 days | 
| Required doses of sedative adjuvants | The doses of other sedatives and analgesics, including opioids, antipsychotics, benzodiazepines, ketamine and propofol will be recorded | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extracorporeal membrane oxygenation, Volatile anesthetics, Sedation