Clinical trial NCT05680545: Volatile Anesthetic Pharmacokinetics During Extracorporeal Membrane Oxygenation
Official title: Volatile Anesthetic Pharmacokinetics During Extracorporeal Membrane
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Respiratory Failure
Keywords: Extracorporeal membrane oxygenation
Volatile anesthetics
Sedation
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: The Physicians' Services Incorporated Foundation
First posted: 2023-01-11
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective, single-center, open-label, pharmacokinetic study
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Sevoflurane plasma concentrations
timeFrame: 7 days
Secondary outcomes:
measure: Percentage of sevoflurane in ECMO exhausted gas
timeFrame: 7 days
measure: Respiratory dynamics and respiratory effort
timeFrame: 7 days
measure: Plasma levels of ventilator-induced lung injury biomarkers
timeFrame: 7 days
measure: Required doses of sedative adjuvants
timeFrame: 7 days
Other outcomes:
Locations:
Study officials:
affiliation: University Health Network, Toronto
name: Diana Morales Castro, MD
role: PRINCIPAL_INVESTIGATOR
References:
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