Effects of general vs. regional anesthesia on infant neurodevelopment and apnea

描述（由申请人提供）：每年有大量儿童接受全身麻醉的手术。这种暴露是否会增加儿童的神经发育风险尚未确定。动物模型研究提供了令人信服的证据，表明常用药物（如异氟醚、咪达唑仑、氧化亚氮）在一些研究中，其剂量低于外科麻醉所需的剂量，可增强未成熟大脑中的神经元细胞死亡。然而，这些数据的临床意义是有争议的，因为没有前瞻性研究评估儿童在婴儿期接触麻醉剂后的神经发育。本申请为美国参与一项国际、前瞻性、多地点、随机、对照、等效试验，比较接受全麻或局部清醒麻醉后儿童神经发育情况。共有220名接受腹股沟疝修补术的婴儿，这是一种可以使用任何麻醉形式进行的常见手术，将在美国的9个地点进行为期27个月的登记。由于在我们的试点阶段共招募了24名患者，因此在该项目期间还将招募196名患者。另外440名婴儿将在澳大利亚和英国的站点注册，总注册人数为660人。非美国站点的资金已经获得。主要假设是2岁时接受全麻或区域清醒麻醉的儿童的神经发育结果是相同的。主要终点将是Bayley婴幼儿发育量表第三版（BSID-III）的认知评分。次要终点包括BSID-III的语言和运动综合得分，麦克阿瑟-贝茨交际发展量表得分和神经系统状态。第二个假设是，在手术后的前12小时内，两组的呼吸暂停率是相同的。多元线性或逻辑回归分析，调整潜在的混杂因素，将用于估计治疗组的差异。如果调整后的治疗组均数差异的双侧95%置信区间在-5和+5分以内，则接受2岁认知评分相等的主要假设。鉴于在婴儿手术中广泛使用全身麻醉，该结果可能具有重大的公共卫生影响。

DESCRIPTION (provided by applicant): Each year large numbers of children undergo surgery involving 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., isoflurane, 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. The clinical implications of these data are controversial, however, because no prospective study has evaluated neurodevelopment in children after exposure to anesthetic agents in infancy. This application seeks funding for U.S. participation in an international, prospective, multi-site, randomized, controlled, equivalence trial comparing children's neurodevelopment following receipt of general or regional awake anesthesia. A total of 220 infants who undergo inguinal herniorrhaphy, a common surgery that can be performed using either form of anesthesia, will be enrolled at 9 sites in the USA over a 27-month period. Because a total of 24 patients have been enrolled during our pilot phase, an additional 196 patients will be enrolled during this project. An additional 440 infants will be enrolled at sites in Australia and the United Kingdom, for a total enrollment of 660. Funding has been obtained for the non-USA sites. The primary hypothesis is that neurodevelopmental outcomes at 2 years of age are equivalent in children who received general anesthesia or regional awake anesthesia. The primary endpoint will be the Cognitive score on the Bayley Scales of Infant and Toddler Development-3rd edition (BSID-III). Secondary endpoints include the Language and Motor Composite scores on the BSID-III, scores on the MacArthur-Bates Communicative Development Inventory, and neurologic status. The secondary hypothesis is that apnea rates in the first 12 post-operative hours are equivalent in the treatment groups. Multiple linear or logistic regression analysis, adjusting for potential confounders, will be used to estimate treatment group differences. The primary hypothesis of equivalence in Cognitive score at 2-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 are likely to have substantial public health implications. PUBLIC HEALTH RELEVANCE: If general anesthesia is neurotoxic to infants under conditions of clinical use, the public health implications would be substantial given the frequency with which such agents are used in infant surgery. If general and regional awake anesthesia result in neurodevelopmental outcomes that are equivalent, this would support the safety of general anesthetics as currently used.