A multicenter clinical trial found that inhaled isoflurane was as effective as intravenous midazolam in maintaining sedation among critically ill children on mechanical ventilation, with additional benefits in reducing opioid use and shortening time to extubation.
The phase 3 trial enrolled 92 children aged 3 to 17 years who were admitted to 19 pediatric intensive care units in Spain, France, Germany, and the United Kingdom. These children required sedation for mechanical ventilation lasting at least 12 hours. Participants were randomly assigned in a 2:1 ratio to receive either inhaled isoflurane (n=59) or intravenous midazolam (n=33). Sedation depth was guided by the COMFORT Behaviour scale, with assessments every 2 hours.
The primary outcome was the percentage of time patients remained within their prescribed sedation range without the use of rescue sedation. The least-squares mean time in target range was 68.94% (95% confidence interval [CI], 52.83–85.05) for isoflurane and 62.37% (44.70–80.04) for midazolam. The between-group difference was 6.57 percentage points (95% CI, –8.99 to 22.13), meeting the predefined margin for non-inferiority.
“Among critically ill children, the effectiveness of sedation with inhaled isoflurane was non-inferior to that of intravenous midazolam, offering an alternative medication in children receiving mechanical ventilation,” said Jordi Miatello of AP-HP Paris Saclay University, Bicêtre Hospital, France, and colleagues.
Opioid use during the treatment period was significantly lower in the isoflurane group. The least-squares mean dose of opioids, expressed in intravenous fentanyl equivalents, was 2.1 µg/kg per hour (95% CI, 1.3–2.9) for isoflurane and 4.6 µg/kg per hour (95% CI, 3.5–5.6) for midazolam (p=0.0004).
Among children who were extubated after sedative discontinuation, the median time to extubation was shorter in the isoflurane group—0.75 hours (interquartile range [IQR], 0.25–1.50) versus 1.09 hours (IQR, 0.49–5.50) for midazolam (p=0.011).
Adverse events were common in both groups but were generally mild or moderate. In the isoflurane group, 51 of 61 patients (84%) reported at least one adverse event, compared with 21 of 33 (64%) in the midazolam group. Serious adverse events occurred in 19 patients (31%) receiving isoflurane and 8 (24%) receiving midazolam; none were attributed to the study treatments.
Three patients in the isoflurane group discontinued treatment due to adverse events: one with hyperthermia, one with hypotension, and one with increased intracranial pressure. No patients in the midazolam group discontinued treatment for this reason. One patient in the isoflurane group and two in the midazolam group died during follow-up; all deaths were unrelated to the study drugs.
The need for rescue sedation was reported in 23 of 59 patients (39%) in the isoflurane group and 17 of 33 (52%) in the midazolam group (p=0.24).
These findings support inhaled isoflurane as a viable alternative to midazolam for sedating children undergoing mechanical ventilation.
Full disclosures can be found in the published study.
Source: The Lancet Respiratory Medicine