Inhaled Isoflurane vs IV Sedation: No Mortality Benefit in Hypoxemic Respiratory Failure

In mechanically ventilated adults with acute hypoxemic respiratory failure (AHRF), an inhaled sedation strategy using isoflurane, with intravenous adjuncts as clinically needed, did not reduce hospital mortality compared with usual intravenous sedation. The results come from the SAVE-ICU randomized clinical trial, published online in JAMA.

The investigators noted that rigorous evidence for isoflurane-based inhaled sedation in this population is limited. The pragmatic, open-label, superiority trial ran in 14 intensive care units (ICUs) in Canada between September 2020 and March 2025. It enrolled adults receiving mechanical ventilation for non-COVID AHRF or COVID-19. The Canadian Institute for Health Research, the Government of Ontario, and other Canadian funders supported the trial.

Of 786 randomized patients, 780 were included in the primary analysis (mean age, 61.1 years; 34.0% female). Hospital mortality was 42.5% in the inhaled sedation group and 43.8% in the intravenous sedation group (risk ratio, 0.98; 95% CI, 0.84-1.14; P =0.85). ICU-, ventilator-, and hospital-free days were similar. In the inhaled sedation group, 49.9% to 55.4% of patients also received intravenous sedation on any given day during the first 14 days.

The inhaled sedation group received more adjunctive therapies for hypoxemia (63.9% vs 55.0%) and had fewer delirium- and coma-free days (between-group difference, −0.95; 95% CI, −1.69 to −0.22). Quality-of-life and disability scores did not differ. All 5 serious adverse events occurred in the isoflurane group. The investigators said it is unclear whether these were related to isoflurane or to patient- and disease-related factors.

The authors noted two practical constraints. Inhaled sedation requires specialized equipment, which made blinding clinical teams impossible, and proficiency with the delivery system likely varied across centers. In addition, intravenous sedatives were permitted and commonly used alongside isoflurane, so the findings cannot separate the effect of isoflurane from that of the overall sedation strategy.

Source: Jerath A, Slessarev M, Martin C, et al. Isoflurane-based inhaled sedation in mechanically ventilated adults with acute hypoxemic respiratory failure: the SAVE-ICU randomized clinical trial. JAMA. Published online October 14, 2026. doi:10.1001/jama.2026.18471