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 IsoCOMFORT trial aimed to compare the efficacy of inhaled sedation with isoflurane versus intravenous midazolam in the paediatric setting.

IsoCOMFORT试验旨在比较吸入异氟醚与静脉注射咪达唑仑在儿科环境中的镇静效果。

Methods

IsoCOMFORT was a randomised, active-control, assessor-masked, non-inferiority phase 3 trial conducted across 19 paediatric intensive care units in Spain, France, Germany, and the UK.

IsoCOMFORT 是一项在西班牙、法国、德国和英国的19个儿科重症监护病房进行的随机、活性对照、评估者盲法、非劣效性第3阶段试验。

Children aged 3-17 years who were critically ill and required invasive mechanical ventilation and sedation for an expected duration of at least 12 h were randomly assigned (2:1) via an interactive web-response system to inhaled sedation with isoflurane or to intravenous sedation with midazolam.

年龄在3-17岁之间，病情危重且需要侵入性机械通气和镇静治疗，预期持续时间至少为12小时的儿童，通过交互式网络响应系统随机分配（2:1），接受吸入性异氟醚镇静或静脉注射咪达唑仑镇静。

Randomisation was done in permuted blocks (sizes 3 and 6), stratified by age group, reason for intensive care unit admission (planned or unplanned mechanical ventilation), and country, with treatment allocation masked to outcome assessors.

随机分组采用置换分块法（分块大小为3和6），按年龄组、重症监护病房入院原因（计划性或非计划性机械通气）和国家进行分层，治疗分配对结果评估者设盲。

At baseline, a target range for sedation depth was prescribed based on the COMFORT Behaviour (COMFORT-B) scale, and sedation dosing was titrated to reach the target range.

基线时，根据COMFORT行为（COMFORT-B）量表规定了镇静深度的目标范围，并调整镇静剂量以达到目标范围。

Sedative treatment was planned for up to 48 h (±6 h).

计划对患者进行长达48小时（±6小时）的镇静治疗。

The primary endpoint was the percentage of time that an adequate sedation depth was maintained, in the absence of rescue sedation, within the individually prescribed target range, as monitored every 2 h for an expected minimum of 12 h (up to 48±6 h) with the COMFORT-B scale.

主要终点是维持在个体化目标范围内适当的镇静深度的时间百分比，无需额外镇静，在预期至少12小时内（最多48±6小时）每2小时使用COMFORT-B量表进行监测。

The primary endpoint was assessed for non-inferiority (margin -9·36 percentage points) in the full analysis set (all randomly assigned participants who received ≥6 h of the allocated study sedative and ≥3 masked COMFORT-B assessments), according to intention to treat.

主要终点是根据意向治疗原则，在全分析集（所有随机分配的参与者中，接受≥6小时指定研究镇静剂和≥3次蒙面COMFORT-B评估者）中评估非劣效性（界限为-9.36个百分点）

Safety was assessed in all participants who received study treatment.

所有接受研究治疗的参与者均进行了安全性评估。

The trial was registered with ClinicalTrials.gov, NCT04684238, and EudraCT, 2020-000578-31, and is completed.

该试验已在ClinicalTrials.gov注册，编号NCT04684238，在EudraCT注册，编号2020-000578-31，并已完成。

Results

Between Jan 14, 2021, and Jan 19, 2023, 96 children were randomly assigned: 63 to the isoflurane group and 33 to the midazolam group. 92 participants were included in the full analysis set (mean age 7·7 years [SD 4·1]; 35 [38%] female and 57 [62%] male).

从2021年1月14日至2023年1月19日，共有96名儿童被随机分配：63名进入异氟醚组，33名进入咪达唑仑组。共有92名参与者被纳入完整分析集（平均年龄7.7岁[标准差4.1]；35名[38%]女性和57名[62%]男性）。

The least-squares mean percentage of time in the COMFORT-B target range was 68·94% (95% CI 52·83-85·05) in the isoflurane group and 62·37% (44·70-80·04) in the midazolam group.

在COMFORT-B目标范围内的平均时间百分比，异氟醚组为68.94%（95%置信区间52.83-85.05），而咪达唑仑组为62.37%（95%置信区间44.70-80.04）。

The least-squares mean difference between treatments was 6·57 percentage points (95% CI -8·99 to 22·13), indicating non-inferiority, with the lower bound of the 95% CI exceeding the non-inferiority margin of -9·36 percentage points).

两组治疗的最小二乘平均差异为6.57个百分点（95%置信区间-8.99至22.13），表明非劣效性，95%置信区间的下限超过了-9.36个百分点的非劣效性边界。

In the safety set (n=94), serious adverse events occurred in 19 (31%) of 61 participants in the isoflurane group and eight (24%) of 33 participants in the midazolam group, none of which were considered related to study treatment.

在安全性分析集(n=94)中，61名接受异氟醚治疗的参与者中有19人(31%)和33名接受咪达唑仑治疗的参与者中有8人(24%)发生了严重不良事件，这些事件均被认为与研究治疗无关。

Treatment-related severe hypotension occurred in one participant per group, and three participants in the isoflurane group discontinued treatment due to adverse events.

每组各有1名参与者发生了与治疗相关的严重低血压，而异氟醚组有3名参与者因不良事件而停药。

No treatment-related deaths were reported.

未报告与治疗相关的死亡事件。

interpretation

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.

在重症儿童中，吸入异氟醚的镇静效果不劣于静脉注射的咪达唑仑，为接受机械通气的儿童提供了一种替代药物。

funding

Sedana Medical, Stockholm, Sweden.

Sedana Medical，瑞典斯德哥尔摩。