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

描述（由申请人提供）：每年都有大量儿童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，异氟烷、咪达唑仑、一氧化二氮）在某些研究中以低于达到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。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婴儿期暴露于麻醉剂后儿童的神经发育。本申请旨在为美国参与一项国际性、前瞻性、多中心、随机、对照、等效性试验提供资金，该试验比较了接受全身或局部清醒麻醉后儿童的神经发育。在27个月的时间内，将在美国的9个研究中心共招募220名接受腹股沟疝修补术（一种可使用任一麻醉形式进行的常见手术）的婴儿。由于在我们的试验阶段共入组了24例患者，因此在本项目期间将再入组196例患者。另外440名婴儿将在澳大利亚和英国的研究中心入组，总入组人数为660人。已为非美国研究中心获得资金。主要假设是接受全身麻醉或区域清醒麻醉的儿童在2岁时的神经发育结果是等同的。主要终点将是贝利婴幼儿发育量表-第3版（BSID-III）的认知评分。次要终点包括BSID-III的语言和运动综合评分、MacArthur-Bates沟通发展量表评分和神经功能状态。次要假设是两个治疗组术后前12小时的呼吸暂停发生率相当。将使用多元线性或逻辑回归分析（调整潜在混杂因素）估计治疗组差异。如果校正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，则接受2岁时认知评分等效的主要假设。鉴于全身麻醉在婴儿手术中的广泛应用，该结果可能会对公共卫生产生重大影响。 公共卫生相关性：如果全身麻醉在临床使用条件下对婴儿具有神经毒性，鉴于此类药物在婴儿手术中使用的频率，公共卫生影响将是巨大的。如果全身麻醉和局部清醒麻醉导致的神经发育结局相同，则支持目前使用的全身麻醉剂的安全性。

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.