Inhaled vs. intravenous sedation in moderate-to-severe acute respiratory distress syndrome: a meta-analysis of randomized controlled trials

Acute respiratory distress syndrome (ARDS) is associated with substantial morbidity and mortality, and sedation is crucial to facilitate mechanical ventilation. The role of inhaled volatile sedation in moderate-to-severe ARDS remains unclear, particularly across COVID-19 and non-COVID-19 ARDS populations. We aimed to evaluate the effects of inhaled sedation on all-cause mortality and secondary clinical, physiological, and inflammatory outcomes, with predefined subgroup analyses by COVID-19 status. We performed a systematic review and meta-analysis of randomized controlled trials comparing inhaled agents (sevoflurane/isoflurane) to intravenous sedation in adults. PubMed, Embase, and Cochrane CENTRAL were searched through January 2026. RoB-2 and GRADE approaches were used. Risk ratios (RRs), hazard ratios (HRs), and mean differences (MDs) with 95% CIs were pooled using random-effects models, with prespecified subgroup analyses and leave-one-out sensitivity analyses. Five RCTs (896 patients; 50.7% COVID-19) were included. Inhaled sedation did not affect 28–30-day mortality (RR 1.10; 95% CI 0.93, 1.30). Time-to-event analysis suggested a higher mortality hazard with inhaled sedation (HR 1.27; 95% CI 1.03, 1.57; I²=0%), strongly influenced by the largest trial, with reduced precision and loss of statistical significance after leave-one-out exclusion. Trial sequential analysis indicated insufficient evidence to confirm or exclude an important mortality effect. Subgroup analysis suggested higher hazard of mortality among non-COVID-19 patients (HR 1.71; 95% CI 1.23, 2.38). Inhaled sedation was associated with fewer ventilator-free days (MD − 2.28; p = 0.008) and increased airway resistance (MD 4.75 cmH₂O/L/s; p = 0.02), whereas PaO₂/FiO₂ and rescue therapies showed no differences. Norepinephrine doses were higher with inhaled sedation. Inhaled sedation was not associated with improvements in patient-centered outcomes in moderate-to-severe ARDS. The time-to-event mortality signal should be interpreted cautiously because the pooled estimate was strongly influenced by the largest trial. Current evidence remains insufficient to establish a clinically important mortality effect. Further adequately powered randomized trials are needed.