The GAS trial: neurocognitive outcomes 5 years after infant anesthesia

 描述（由申请人提供）：每年有数百万婴儿和幼儿接受涉及全身麻醉的手术。这种暴露是否会增加儿童的神经发育风险从未得到证实。动物模型的研究提供了令人信服的证据，表明常用的药物（例如，七氟烷、异氟烷、丙泊酚、咪达唑仑、一氧化二氮）在一些研究中以低于实现手术麻醉平面所需的剂量增强未成熟脑中的神经元细胞死亡。一些儿童回顾性队列研究表明，早期暴露于全身麻醉，即使是一次短暂的暴露，也与以后的学习困难有关。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金标准设计来评估婴儿期暴露于麻醉剂后儿童的神经发育，从而限制了可以得出的因果关系的推论。本申请旨在为美国研究中心提供资金，以完成GAS研究，这是一项正在进行的国际、前瞻性、多中心、随机、对照、等效性试验，旨在比较接受全身或局部清醒麻醉后儿童的神经发育。在美国的10个研究中心，共招募了149名接受腹股沟疝修补术的婴儿，腹股沟疝修补术是一种常见的手术，可以使用任何一种麻醉形式进行。另外573名婴儿在澳大利亚/新西兰、英国、加拿大、意大利和荷兰的研究中心入组，总入组人数为722名。入组于2013年1月完成。主要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等同的。主要终点是韦氏学龄前和小学智力量表的全量表智商。次要终点包括评估特定领域的测试分数，包括注意力/执行功能、口头/语言技能、记忆和学习、社会感知、视觉整合、感觉运动技能、学业成绩、行为和适应技能。如果校正后的治疗组平均值差异的双侧95%置信区间在-5和+5分范围内，则可接受5岁时全量表IQ等效的主要假设。鉴于全身麻醉在婴儿手术中的广泛使用，该结果将具有重大的公共卫生意义，无论是支持全身麻醉的安全性，还是表明需要考虑在该患者人群中采用替代镇静策略。

 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.