Inhaled isoflurane for sedation of mechanically ventilated children in intensive care (IsoCOMFORT): a multicentre, randomised, active-control, assessor-masked, non-inferiority phase 3 trial.

Summary

In this multicentre, assessor-masked non-inferiority RCT in ventilated children, inhaled isoflurane achieved a non-inferior proportion of time within target sedation (COMFORT-B) compared with intravenous midazolam. Serious adverse events were similar across groups and not attributed to study drugs, with no treatment-related deaths.

Key Findings

• Non-inferiority met: least-squares mean difference in target COMFORT-B time 6.57 percentage points (95% CI -8.99 to 22.13) favoring isoflurane within the non-inferiority margin.
• Target sedation time: 68.94% (isoflurane) vs 62.37% (midazolam).
• Serious adverse events occurred in 31% (isoflurane) vs 24% (midazolam), none judged related; one severe hypotension per group; no treatment-related deaths.

Clinical Implications

Isoflurane can be considered as an alternative to midazolam for maintaining target sedation in ventilated children, enabling centers with vaporizer capability to adopt inhaled sedation without compromising efficacy or safety.

Limitations

• Sedation period limited to up to 48±6 hours; long-term outcomes were not assessed.
• Sample size modest (n=96), with 2:1 randomization leading to smaller control group.

Future Directions

Evaluate longer sedation courses, compare with other IV sedatives (e.g., propofol, dexmedetomidine), and assess outcomes including ventilation duration, delirium, and neurodevelopment.