Researchers have found in a randomized trial (IsoCOMFORT) that inhaled isoflurane sedation was as effective as IV midazolam for children aged 3 to 17 years in the ICU on mechanical ventilation. Isoflurane also led to faster extubation and reduced opioid use. The study supports the ongoing shift away from midazolam and other benzodiazepines due to concerns about delirium, withdrawal, and neurological risks in pediatric patients. The study was published inThe Lancet: Respiratory Medicinejournal by Jordi M. and colleagues. The IsoCOMFORT trial was an assessor-masked, active-controlled, randomized, non-inferiority phase 3 study. Between January 2021 and January 2023, children aged 3–17 years who were critically ill and needed invasive mechanical ventilation for ≥12 hours were enrolled. The participants were assigned randomly in a 2:1 ratio to receive inhaled isoflurane or intravenous midazolam through an interactive web-based randomization system. Randomization was stratified on age, type of admission (planned or unplanned), and country, using size 3 and 6 permuted blocks. The main outcome measure was the proportion of time that the participants had an adequate sedation level, without the use of rescue sedatives, within a predetermined target range on the COMFORT Behaviour (COMFORT-B) scale. Sedation was monitored every two hours, and the endpoint was measured over a treatment period of up to 48±6 hours. Non-inferiority was established with a margin of –9.36 percentage points, and the result was evaluated in the full analysis set of individuals who had received at least 6 hours of therapy and had at least three valid COMFORT-B scores. Key Findings 96 children were randomized, 63 to the isoflurane group and 33 to the midazolam group. The full analysis set comprised 92 participants (mean age 7.7 years; 38% female, 62% male). For this population, the mean percentage of time spent in the target sedation range was: 68.94% (95% CI: 52.83–85.05) in the isoflurane group 62.37% (95% CI: 44.70–80.04) in the midazolam group The least-squares mean difference was 6.57 percentage points (95% CI: –8.99 to 22.13), establishing non-inferiority, since the lower bound was greater than the pre-specified margin of –9.36 percentage points. With respect to safety, 94 participants were administered at least one dose of study treatment. Serious adverse events occurred in 19 (31%) of 61 children in the isoflurane group and 8 (24%) of 33 in the midazolam group. Notably, none of the adverse events were found to be related to the study drug. A case of severe treatment-related hypotension in each group and three children in the isoflurane arm stopped treatment as a result of adverse events were encountered. There were no treatment-related deaths. The IsoCOMFORT trial found that inhaled isoflurane was as effective as intravenous midazolam for sustaining target levels of sedation in critically ill children on mechanical ventilation. With similar efficacy and a favorable safety profile, isoflurane is an attractive alternative sedative strategy in pediatric ICUs. The implications of this study may help extend sedation practices and individualize care for critically ill pediatric patients. Miatello, J., Palacios-Cuesta, A., Radell, P., Oberthuer, A., Playfor, S., Amores-Hernández, I., Barreault, S., Biedermann, R., Charlo Molina, M. T., Encarnación Martínez, J., Kuehne, B., Mencía, S., Méndez, M. D., Menzel, C., Morin, L., Oviedo, L., Piloquet, J.-E., Falkenhav, M., Sackey, P., … Ramnarayan, P. (2025). Inhaled isoflurane for sedation of mechanically ventilated children in intensive care (IsoCOMFORT): a multicentre, randomised, active-control, assessor-masked, non-inferiority phase 3 trial. The Lancet. Respiratory Medicine.https://doi.org/10.1016/s2213-2600(25)00203-6