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

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.