Volatile Anesthetic Pharmacokinetics During Extracorporeal Membrane Oxygenation

Respiratory Failure Clinical Trial

— Vol-ECMO  

Official title:

Volatile Anesthetic Pharmacokinetics During Extracorporeal Membrane

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05680545
• Other study ID #: 22-6007
• Secondary ID: 2022-2746
• Status: Not yet recruiting
• Phase: N/A
• Start date: July 1, 2024
• Est. completion date: June 30, 2025

Study information

• Verified date: November 2023
• Source: University Health Network, Toronto
• Contact: Diana Morales Castro, MD
• Phone: +1 416 340-3131
• Email: diana.moralescastro[@]uhn.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 10
• Est. completion date: June 30, 2025
• Est. primary completion date: December 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Respiratory Failure
• Respiratory Insufficiency

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University Health Network, Toronto	The Physicians' Services Incorporated Foundation

References & Publications (9)

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. — View Citation

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. — View Citation

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 Mar 23. — View Citation

Ferrando C, Aguilar G, Piqueras L, Soro M, Moreno J, Belda FJ. Sevoflurane, but not propofol, reduces the lung inflammatory response and improves oxygenation in an acute respiratory distress syndrome model: a randomised laboratory study. Eur J Anaesthesiol. 2013 Aug;30(8):455-63. doi: 10.1097/EJA.0b013e32835f0aa5. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: J Artif Organs. 2018 Apr 5;: — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sevoflurane plasma concentrations	Plasma concentrations of sevoflurane will be measured with gas chromatography and mass spectrometry	7 days
Secondary	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
Secondary	Respiratory dynamics and respiratory effort	Driving pressure, occlusion pressure, and P0.1 pressures will be measured with the patients mechanical ventilator daily	7 days
Secondary	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
Secondary	Required doses of sedative adjuvants	The doses of other sedatives and analgesics, including opioids, antipsychotics, benzodiazepines, ketamine and propofol will be recorded	7 days