Isoflurane-Based Inhaled Sedation in Mechanically Ventilated Adults With Acute Hypoxemic Respiratory Failure

Importance: Rigorous evidence for inhaled sedation using isoflurane in mechanically ventilated patients with acute hypoxemic respiratory failure (AHRF) is limited. Objective: To evaluate whether an inhaled sedation strategy lowers hospital mortality compared with usual care intravenous sedation strategy in mechanically ventilated adults with AHRF. Design, Setting, and Participants: Pragmatic, effectiveness, open-label, superiority, randomized clinical trial in 14 intensive care units (ICUs) in Canada. Adults (≥18 years) receiving sedation for less than 72 hours and receiving mechanical ventilation for AHRF from non-COVID respiratory failure (ratio of partial pressure of arterial oxygen [Pao2] to fraction of inspired oxygen [Fio2] <300 mm Hg) or COVID-19 were enrolled between September 2020 and March 2025 with follow-up through June 2025. Intervention: Patients were randomized to an inhaled sedation strategy using isoflurane with intravenous adjuncts as clinically needed or to a usual intravenous sedation care strategy. Sedatives were titrated to achieve the desired target sedation score guided by clinical teams and continued until extubation or death. Main Outcomes and Measures: Primary outcome was all-cause hospital mortality. Secondary outcomes included ICU- and ventilator-free days at day 30; hospital-free days at day 60; use of refractory hypoxemia adjunctive therapies; delirium- and coma-free days at day 14; and quality-of-life and disability scores at 3 months. Results: Of 786 patients randomized, 780 were included in the primary analysis (mean age, 61.1 years; 34.0% female; 73.7% non-COVID AHRF, mean Pao2:Fio2 ratio, 152.6 mm Hg); 385 in the inhaled sedation and 395 in the intravenous sedation groups. In the inhaled sedation group, 49.9% to 55.4% of patients received concomitant intravenous sedation on any day during the first 14 days after randomization. At hospital discharge, 161 of 379 patients (42.5%) in the inhaled sedation group had died, compared with 171 of 390 patients (43.8%) in the intravenous sedation group (risk ratio, 0.98 [95% CI, 0.84 to 1.14]; P = .85). There was no effect modification in prespecified subgroup analyses for age, sex, and COVID-19 status. ICU-, ventilator-, and hospital-free days were similar between groups. The inhaled sedation group received more adjunctive therapies for hypoxemia (239 [63.9%] vs 214 [55.0%]; between-group difference, 8.89% [95% CI, 1.95% to 15.83%]) and had fewer delirium- and coma-free days (between-group difference, -0.95 [95% CI, -1.69 to -0.22]). There was no difference in quality-of-life and disability scores between groups. Conclusions and Relevance: In mechanically ventilated adults with AHRF, an inhaled sedation strategy using isoflurane with intravenous adjuncts as clinically needed did not reduce hospital mortality compared with an intravenous sedation strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT04415060.

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Journal
JAMA
Published
2026-10-14
DOI
https://doi.org/10.1001/jama.2026.18471
Primary Topic
Respiratory Support and Mechanisms
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article
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article

Isoflurane-Based Inhaled Sedation in Mechanically Ventilated Adults With Acute Hypoxemic Respiratory Failure

Roupen Hatzakorzian, Ahmed F. Hegazy, Martin Girard, Dominique Bérard et al.
JAMA
Respiratory Support and Mechanisms
article

Isoflurane-Based Inhaled Sedation in Mechanically Ventilated Adults With Acute Hypoxemic Respiratory Failure

Roupen Hatzakorzian, Ahmed F. Hegazy, Martin Girard, Dominique Bérard, Michaël Chassé, Jason Shahin, Françis Bernard, Lorenzo Del Sorbo, John Basmaji, Rebecca Porteous, Tina Yan, Pierre-Alexis Lépine, François Martin Carrier, Geneviève Parent-Racine, Maxime Tissot-Therrien, Kosar Ali Khwaja, Étienne J. Couture, Emad Al Azazi, Vimoshana Vijayakumar, Mehvash Qureshi, Marat Slessarev, François Lamontagne, Ewan C. Goligher, Angela Jerath, Frédérick D’Aragon, Anushka Jayasekara, Eileen Campbell, Tracey Bentall, Lilia Kaustov, Jessica Haines, Sherissa Microys, Dave Gleeton, Denise Morris, Mathieu Simon, Irene Watpool, Karim Serri, Michael J. Jacka, Brian H. Cuthbertson, Hilary Meggison, Elizabeth Wilcox, Tina Romagnuolo, Lazar Milovanovic, Janek Manoj Senaratne, Sabrina Araujo de França, Martin Albert, David Neilipovitz, Ian M. Randall, Ruxandra L Pinto, Damon C. Scales, Beth Linseman, Tim Winterburn, Stephanie Dunster, Cassiopée Paradis-Gagnon, Georgiana Roman-Sarita, Maria Kobylecky, Sylvie Bourbonnais, Peter Goldberg, Mélissa Gagnon-Hamelin, Hesham Abdelhady, Jonathan Hooper, Virginie Williams, Jeanine P. Wiener-Kronish, Michelle Stephens, Julie Nardi, Briar Coman, Bourke Tillman, Andréa Gagnon-Hamelin, Martin Chapman, Irina Zaborovskaya, Francesca Lamothe, Niall Ferguson, Andreanne Cote, Zhongcong Xie, Philip Graham, Phil Lau, Audrey Lachapelle, Brenda Lécuyer, Maude St-Pierre, Jeremy Richard Grushka, SAVE-ICU Investigators and the Canadian Critical Care Trials Group, David Williamson, Buffy Keay, Paula Sharman, Bernadette Fernando, Michelle Alexander, Brenda Morgan, Lynne Kelly, Larissa Johnson, Joanne Martin, Han-Ting Wang, Claudio Martin, Michael Long, Jennifer Hamilton, Iman Hussain, Vito Nobile Fidanza, Courtney Hooper, Tammi Breymann, Amanda Rampersaud, Eily Shaw, Yiorgos Alexandros Cavayas
article en

Abstract

Importance: Rigorous evidence for inhaled sedation using isoflurane in mechanically ventilated patients with acute hypoxemic respiratory failure (AHRF) is limited. Objective: To evaluate whether an inhaled sedation strategy lowers hospital mortality compared with usual care intravenous sedation strategy in mechanically ventilated adults with AHRF. Design, Setting, and Participants: Pragmatic, effectiveness, open-label, superiority, randomized clinical trial in 14 intensive care units (ICUs) in Canada. Adults (≥18 years) receiving sedation for less than 72 hours and receiving mechanical ventilation for AHRF from non-COVID respiratory failure (ratio of partial pressure of arterial oxygen [Pao2] to fraction of inspired oxygen [Fio2] <300 mm Hg) or COVID-19 were enrolled between September 2020 and March 2025 with follow-up through June 2025. Intervention: Patients were randomized to an inhaled sedation strategy using isoflurane with intravenous adjuncts as clinically needed or to a usual intravenous sedation care strategy. Sedatives were titrated to achieve the desired target sedation score guided by clinical teams and continued until extubation or death. Main Outcomes and Measures: Primary outcome was all-cause hospital mortality. Secondary outcomes included ICU- and ventilator-free days at day 30; hospital-free days at day 60; use of refractory hypoxemia adjunctive therapies; delirium- and coma-free days at day 14; and quality-of-life and disability scores at 3 months. Results: Of 786 patients randomized, 780 were included in the primary analysis (mean age, 61.1 years; 34.0% female; 73.7% non-COVID AHRF, mean Pao2:Fio2 ratio, 152.6 mm Hg); 385 in the inhaled sedation and 395 in the intravenous sedation groups. In the inhaled sedation group, 49.9% to 55.4% of patients received concomitant intravenous sedation on any day during the first 14 days after randomization. At hospital discharge, 161 of 379 patients (42.5%) in the inhaled sedation group had died, compared with 171 of 390 patients (43.8%) in the intravenous sedation group (risk ratio, 0.98 [95% CI, 0.84 to 1.14]; P = .85). There was no effect modification in prespecified subgroup analyses for age, sex, and COVID-19 status. ICU-, ventilator-, and hospital-free days were similar between groups. The inhaled sedation group received more adjunctive therapies for hypoxemia (239 [63.9%] vs 214 [55.0%]; between-group difference, 8.89% [95% CI, 1.95% to 15.83%]) and had fewer delirium- and coma-free days (between-group difference, -0.95 [95% CI, -1.69 to -0.22]). There was no difference in quality-of-life and disability scores between groups. Conclusions and Relevance: In mechanically ventilated adults with AHRF, an inhaled sedation strategy using isoflurane with intravenous adjuncts as clinically needed did not reduce hospital mortality compared with an intravenous sedation strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT04415060.

JAMA
Western University (CA), Sunnybrook Health Science Centre (CA), University Health Network (CA), Université de Sherbrooke (CA), Harvard University (US), Outcomes Research Consortium (US), University of Toronto (CA), Toronto Western Hospital (CA), Alberta Hospital Edmonton (CA), Grey Nuns Community Hospital (CA), Ottawa Hospital (CA), McGill University Health Centre (CA), University of Alberta Hospital (CA), Massachusetts General Hospital (US), Institut universitaire de cardiologie et de pneumologie de Québec (CA), Hôpital du Sacré-Cœur de Montréal (CA), Centre Hospitalier de l’Université de Montréal (CA), The University of Texas Health Science Center (US), Sunnybrook Research Institute, London Health Sciences Centre Research Institute (CA)
Good health and well-being
Openalex Percentile: Top 13%
Respiratory Support and Mechanisms
DOISourceOpenAlex
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