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

Key numbers

• 34.0% female
• 73.7% non-COVID AHRF
• 49.9% to 55.4% of patients

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.

Angela Jerath, Marat Slessarev, Claudio Martin, Frédérick D'Aragon, François Martin Carrier, Janek Senaratne, Hilary Meggison, Jonathan Hooper, Yiorgos Alexandros Cavayas, Ewan C Goligher, Etienne J Couture, Ian M Randall, Roupen Hatzakorzian, Michael Jacka, Jeanine Wiener-Kronish, Zhongcong Xie, Ruxandra Pinto, Iman Hussain, Brian H Cuthbertson, SAVE-ICU Investigators and the Canadian Critical Care Trials Group

Leverage2 / 5

Reusable within one subfield (a technique, dataset, or protocol a few groups will adopt).

10% of this desk’s rubric

Magnitude3 / 5

Large gain: roughly 2x, or a clear new state of the art on a hard, unsaturated problem.

20% of this desk’s rubric

Evidence4 / 5

Strong: large scale, preregistered, independently replicated, or a well-powered randomized trial.

32% of this desk’s rubric

Novelty3 / 5

A genuinely new approach to an open problem.

8% of this desk’s rubric

Trajectory2 / 5

Some room to improve with obvious engineering.

5% of this desk’s rubric

Stakes3 / 5

Meaningful benefit to many people within a few years.

25% of this desk’s rubric

• Citations0 (reference 20, via openalex, Oct 20, 2026, 06:17 UTC)

• Reviewed by heuristic-v7 on Oct 20, 2026, 06:17 UTC. Paper type: clinical.
• Categories: Journal Article
• BRIEF, No.7 in the Medicine edition of October 20, 2026.