The GAS trial: neurocognitive outcomes 5 years after infant anesthesia

 描述(申请人提供)：每年数以百万计的婴幼儿接受全身麻醉手术。这种暴露是否会增加儿童的神经发育风险，目前还没有确定。在动物模型中的研究提供了令人信服的证据，表明常用的药物(如七氟醚、异氟醚、异丙酚、咪达唑仑、一氧化二氮)可促进未成熟脑细胞的死亡，在一些研究中，剂量低于达到手术麻醉平面所需的剂量。一些儿童的回溯性队列研究表明，早期接触全身麻醉，即使是一次短暂的接触，也与后来的学习困难有关。然而，这些数据的临床意义是有争议的，因为没有一项研究使用随机试验的黄金标准设计来评估儿童在婴儿期接触麻醉剂后的神经发育，因此限制了可以得出的因果关系的推断。这项申请寻求为美国网站提供资金，以完成GAS研究，这是一项正在进行的国际、前瞻性、多地点、随机、对照、等效性试验，比较接受全身或区域清醒麻醉后儿童的神经发育。共有149名婴儿接受了腹股沟疝修补术，这是一种常见的手术，可以使用任何一种麻醉形式进行，在美国的10个地点进行了登记。另有573名婴儿在澳大利亚/新西兰、英国、加拿大、意大利和荷兰的地点登记，总登记人数为722人。注册工作已于2013年1月完成。基本假设是，接受全身麻醉或区域清醒麻醉的儿童在5岁时的神经发育结果是相同的。主要终点是韦克斯勒学前班和小学智商量表上的全量智商。次级终点包括评估特定领域的测试分数，包括注意力/执行功能、言语/语言技能、记忆和学习、社会知觉、视觉运动整合、感觉运动技能、学业成就、行为和适应技能。如果调整后的治疗组平均数差异的双侧95%可信区间在-5和+5分以内，则5岁时全量智商等同的基本假设将被接受。鉴于全身麻醉在婴儿手术中的广泛使用，研究结果将对公众健康产生重大影响，要么支持全身麻醉的安全性，要么表明需要在这一患者群体中考虑替代镇静策略。

 DESCRIPTION (provided by applicant): Each year millions of infants and toddlers undergo surgery that involves exposure to general anesthesia. Whether such exposure increases a child's neurodevelopmental risk has never been established. Studies in animal models provide compelling evidence that commonly used agents (e.g., sevoflurane, isoflurane, propofol, midazolam, nitrous oxide) enhance neuronal cell death in the immature brain, in some studies at doses lower than those required to achieve a surgical plane of anesthesia. Some retrospective cohort studies in children have shown that early exposure to general anesthesia, even a single short exposure, is associated with later learning difficulties. The clinical implications of these data are controversial, however, because none of the studies used the gold standard design of a randomized trial to evaluate neurodevelopment in children after exposure to anesthetic agents in infancy, thus limiting the inferences that can be drawn about causality. This application seeks funding for USA sites to complete the GAS study, an ongoing international, prospective, multi-site, randomized, controlled, equivalence trial comparing children's neurodevelopment following receipt of general or regional awake anesthesia. A total of 149 infants who underwent inguinal herniorrhaphy, a common surgery that can be performed using either form of anesthesia, were enrolled at 10 sites in the USA. An additional 573 infants were enrolled at sites in Australia/New Zealand, the United Kingdom, Canada, Italy and the Netherlands, for a total enrollment of 722. Enrollment was completed in January 2013. The primary hypothesis is that neurodevelopmental outcomes at 5 years of age are equivalent in children who received general anesthesia or regional awake anesthesia. The primary endpoint is the Full Scale IQ on the Wechsler Preschool and Primary Scale of Intelligence. Secondary endpoints include test scores that assess specific domains, including attention/executive function, verbal/language skills, memory and learning, social perception, visuomotor integration, sensorimotor skills, academic achievement, behavior, and adaptive skills. The primary hypothesis of equivalence in Full Scale IQ at 5-years of age will be accepted if the 2-sided 95% confidence interval of the adjusted treatment group difference in means lies within -5 and +5 points. In light of the widespread use of general anesthesia in infant surgery, the results will have substantial public health implications, either supporting the safety of general anesthesia or indicating the need to consider alternative sedation strategies in this patient population.