Optimizing Sedative Dose in Preterm Infants Undergoing Treatment for Respiratory Distress Syndrome

The intubation-surfactant-extubation (INSURE) procedure is used worldwide to treat preterm newborn infants suffering from respiratory distress syndrome, which is caused by an insufficient amount of the chemical surfactant in the lungs. With INSURE, the infant is intubated, surfactant is administered via the tube to the trachea, and at completion the infant is extubated. This improves the infant’s ability to breathe and thus decreases the risk of long-term neurological or motor disabilities. To perform the intubation safely, the newborn infant first must be sedated. Despite extensive experience with INSURE, there is no consensus on what sedative dose is best. This article describes a Bayesian sequentially adaptive design for a multi-institution clinical trial to optimize the sedative dose given to preterm infants undergoing the INSURE procedure. The design is based on three clinical outcomes, two efficacy and one adverse, using elicited numerical utilities of the eight possible elementary outcomes. A flexible Bayesian parametric trivariate dose-outcome model is assumed, with the prior derived from elicited mean outcome probabilities. Doses are chosen adaptively for successive cohorts of infants using posterior mean utilities, subject to safety and efficacy constraints. A computer simulation study of the design is presented. Supplementary materials for this article are available online.

气管插管-肺表面活性物质给药-拔管（intubation-surfactant-extubation，INSURE）流程目前在全球范围内被用于治疗因肺部化学表面活性物质缺乏引发呼吸窘迫综合征的早产新生儿。采用该流程时，需先对新生儿实施气管插管，通过插管将表面活性物质注入其气管，操作完成后拔除插管。该流程可改善新生儿的呼吸功能，进而降低其远期神经或运动功能障碍的发生风险。为安全开展气管插管操作，需预先对新生儿给予镇静处理。尽管INSURE流程已积累了大量临床应用经验，但目前学界尚未就最佳镇静剂量达成共识。本文针对一项多中心临床试验设计了贝叶斯序贯自适应方案，旨在优化接受INSURE流程的早产新生儿的镇静给药剂量。该设计基于三项临床结局指标（两项疗效指标与一项不良事件指标），并结合8种潜在基础结局的征询赋值数值效用值进行构建。研究采用灵活的贝叶斯参数化三变量剂量-结局模型，其先验分布由征询得到的平均结局概率推导而来。后续入组的新生儿队列将基于后验平均效用值自适应选择给药剂量，且需严格遵循安全性与有效性约束条件。本文还针对该设计方案开展了计算机模拟研究。本文补充材料可在线获取。