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

描述(申请人提供)：每年有大量儿童接受全身麻醉手术。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(如异氟醚、咪达唑仑、一氧化二氮)可增强未成熟脑组织中神经细胞的死亡，在一些研究中，剂量低于达到手术麻醉平面所需的剂量。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。这项申请寻求资助美国参与一项国际、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。总共有220名接受腹股沟疝修补术的婴儿将在27个月的时间里在美国的9个地点进行登记。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。因为在我们的试验阶段总共有24名患者入选，所以在这个项目期间还将有另外196名患者入选。另外440名婴儿将在澳大利亚和英国的地点注册，总注册人数为660人。非美国网站的资金已经获得。基本假设是，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相同的。主要终点将是贝利婴幼儿发展量表第三版(BSID-III)的认知得分。次要终点包括BSID-III的语言和运动综合得分，麦克阿瑟-贝茨交流发展问卷的得分，以及神经学状况。第二个假设是，两组患者在术后12小时内的呼吸暂停发生率相同。多元线性或Logistic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平均数差异的双侧95%可信区间在-5和+5分以内，则接受2岁认知得分等同的基本假设。鉴于全身麻醉在婴儿手术中的广泛使用，这一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有神经毒性，考虑到此类药物在婴儿外科手术中的使用频率，公共卫生影响将是巨大的。如果全身麻醉和区域麻醉的神经发育结果相同，这将支持目前使用的全身麻醉药的安全性。

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.