Volatile Anesthetic Pharmacokinetics During Extracorporeal Membrane Oxygenation

Official title

Volatile Anesthetic Pharmacokinetics During Extracorporeal Membrane

Overview

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.

Interventions

• Other Sevoflurane vaporized in ECMO machines
  Sevoflurane will be directly vaporized into the ECMO machine through the sweep gas.

Primary outcome measures

• Sevoflurane plasma concentrations [Time frame: 7 days]

Secondary outcome measures (4)

• Percentage of sevoflurane in ECMO exhausted gas [Time frame: 7 days]
• Respiratory dynamics and respiratory effort [Time frame: 7 days]
• Plasma levels of ventilator-induced lung injury biomarkers [Time frame: 7 days]
• Required doses of sedative adjuvants [Time frame: 7 days]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• McMullan V, Alston RP, Tyrrell J. Volatile anaesthesia during cardiopulmonary bypass. Perfusion. 2015 Jan;30(1):6-16. doi: 10.1177/0267659114531314. Epub 2014 Apr 14. PMID 24732827
• LaGrew JE, Olsen KR, Frantz A. Volatile anaesthetic for treatment of respiratory failure from status asthmaticus requiring extracorporeal membrane oxygenation. BMJ Case Rep. 2020 Jan 15;13(1):e231507. doi: 10.1136/bcr-2019-231507. PMID 31948977
• Fan E, Gattinoni L, Combes A, Schmidt M, Peek G, Brodie D, Muller T, Morelli A, Ranieri VM, Pesenti A, Brochard L, Hodgson C, Van Kiersbilck C, Roch A, Quintel M, Papazian L. Venovenous extracorporeal membrane oxygenation for acute respiratory failure : A clinical review from an international group of experts. Intensive Care Med. 2016 May;42(5):712-724. doi: 10.1007/s00134-016-4314-7. Epub 2016 Ma PMID 27007108
• Cheng V, Abdul-Aziz MH, Roberts JA, Shekar K. Overcoming barriers to optimal drug dosing during ECMO in critically ill adult patients. Expert Opin Drug Metab Toxicol. 2019 Feb;15(2):103-112. doi: 10.1080/17425255.2019.1563596. Epub 2019 Jan 3. PMID 30582435
• Shekar K, Roberts JA, Mcdonald CI, Fisquet S, Barnett AG, Mullany DV, Ghassabian S, Wallis SC, Fung YL, Smith MT, Fraser JF. Sequestration of drugs in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. Crit Care. 2012 Oct 15;16(5):R194. doi: 10.1186/cc11679. PMID 23068416
• Shekar K, Roberts JA, Mullany DV, Corley A, Fisquet S, Bull TN, Barnett AG, Fraser JF. Increased sedation requirements in patients receiving extracorporeal membrane oxygenation for respiratory and cardiorespiratory failure. Anaesth Intensive Care. 2012 Jul;40(4):648-55. doi: 10.1177/0310057X1204000411. PMID 22813493
• Bellgardt M, Ozcelik D, Breuer-Kaiser AFC, Steinfort C, Breuer TGK, Weber TP, Herzog-Niescery J. Extracorporeal membrane oxygenation and inhaled sedation in coronavirus disease 2019-related acute respiratory distress syndrome. World J Crit Care Med. 2021 Nov 9;10(6):323-333. doi: 10.5492/wjccm.v10.i6.323. eCollection 2021 Nov 9. PMID 34888158
• Rand A, Zahn PK, Schildhauer TA, Waydhas C, Hamsen U. Inhalative sedation with small tidal volumes under venovenous ECMO. J Artif Organs. 2018 Jun;21(2):201-205. doi: 10.1007/s10047-018-1030-9. Epub 2018 Mar 5. PMID 29508167

Identifiers

NCT: NCT05680545 · 22-6007 · 2022-2746

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗