Original Investigation 

Caring for the Critically Ill Patient

Isoflurane-Based Inhaled Sedation in Mechanically Ventilated Adults With Acute Hypoxemic Respiratory Failure: The SAVE-ICU Randomized Clinical Trial

Angela Jerath, Marat Slessarev, Claudio Martin, et al

JAMA Published Online: October 14, 2026

doi: 10.1001/jama.2026.18471

Key Points

Question  Among mechanically ventilated adult patients with acute hypoxemic respiratory failure, does an inhaled sedation strategy using isoflurane with intravenous adjuncts as clinically needed reduce hospital mortality compared with usual intravenous sedation strategy?

Findings  In this pragmatic, open-label, randomized clinical trial of 780 patients, there was no difference in hospital mortality risk between patients receiving inhaled sedation and those receiving intravenous sedation (42.5% vs 43.8%). Ventilator- and intensive care unit–free days were similar between groups, as were measures of quality of life and disability scores.

Meaning  Among mechanically ventilated patients with acute hypoxemic respiratory failure, an inhaled sedation strategy with predominantly isoflurane did not reduce hospital mortality compared with usual intravenous sedation.

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