IsoCOMFORT: Inhaled Isoflurane for Sedation of Mechanically Ventilated Children 

• In ICU
• Tue, 22 Jul 2025

Current sedation for mechanically ventilated paediatric patients typically involves intravenous midazolam combined with opioids, and sometimes ketamine or α2-adrenergic agonists like clonidine or dexmedetomidine. Midazolam is the only drug officially approved for continuous sedation in this setting but is linked to prolonged wake-up times, withdrawal, delirium, and risks of accumulation in patients with kidney or liver issues. α2-adrenergic agonists are increasingly used off-label, though concerns exist about safety during prolonged sedation.

Inhaled sedation has long been standard for paediatric pre-operative care and has shown promise in small case series for critically ill children on ventilation, often as a rescue when intravenous sedation fails. These cases suggest inhaled agents like isoflurane or sevoflurane can reduce other sedative use, but controlled data are limited.

Sedation management remains challenging, with a systematic review showing that optimal sedation is achieved just over half the time, while oversedation and undersedation are common and clinically significant. To address this, the IsoCOMFORT trial evaluated inhaled isoflurane sedation via a specialised device compared to intravenous midazolam in critically ill ventilated children, aiming to improve sedation efficacy and safety.

The trial was a randomised, active-controlled, assessor-masked, non-inferiority phase 3 study conducted in 19 paediatric intensive care units across Spain, France, Germany, and the UK. It included critically ill children aged 3–17 years requiring invasive mechanical ventilation and sedation for at least 12 hours. Participants were randomly assigned in a 2:1 ratio to receive either inhaled isoflurane sedation or intravenous midazolam, with randomisation stratified by age, ICU admission reason, and country. Sedation depth was targeted using the COMFORT Behaviour (COMFORT-B) scale and titrated accordingly, with treatment planned for up to 48 hours. 

The primary endpoint was the percentage of time patients maintained adequate sedation within the prescribed target range without rescue sedation, assessed every 2 hours. Safety was evaluated in all treated participants. 

Between January 2021 and January 2023, 96 children were randomised—63 to isoflurane and 33 to midazolam, with 92 included in the full analysis (average age 7.7 years; 38% female). The mean percentage of time within the target sedation range (COMFORT-B) was 68.94% for isoflurane and 62.37% for midazolam. The difference of 6.57 percentage points demonstrated non-inferiority of isoflurane compared to midazolam. In the safety analysis (94 participants), serious adverse events occurred in 31% of the isoflurane group and 24% of the midazolam group, but none were linked to treatment. Severe hypotension related to treatment occurred in one patient per group, and three in the isoflurane group stopped treatment due to adverse events. No treatment-related deaths occurred.

The IsoCOMFORT trial demonstrated that inhaled isoflurane sedation is a safe and non-inferior alternative to intravenous midazolam for critically ill children aged 3–17 years requiring mechanical ventilation, with treatment up to 48 hours. Isoflurane showed clinical benefits including lower opioid and rescue sedative use, as well as shorter and more predictable extubation times, even in deeply sedated patients. 

Inhaled sedation with volatile anaesthetics like isoflurane has been established in adults and used sporadically in children, but IsoCOMFORT provides controlled evidence for its efficacy and safety as a first-line sedative in paediatric ICU. Adverse events with isoflurane were mostly mild and consistent with known effects of inhaled sedation; no treatment-related serious events or deaths occurred. Hypotension, a known reversible side effect, was the most notable.

Environmental concerns about inhaled anaesthetics’ greenhouse gas effects exist but can be mitigated by gas capture and recycling technologies; cost-effectiveness analyses suggest inhaled sedation may reduce healthcare costs. Overall, this trial and subsequent European Medicines Agency approval support inhaled isoflurane sedation via the Sedaconda ACD as a viable and effective sedation strategy in paediatric mechanical ventilation.

Source: The Lancet Respiratory Medicine

Image Credit: iStock 

References:

Miatello J, Palacios-Cuesta A, Radell P et al. (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.