Neurodevelopment of Children Exposed to Anesthesia: A Population-Based Assessment

描述（由申请人提供）：在美国，每年有超过一百万的幼儿接触用于诱导和维持全身麻醉的药物。越来越多的证据表明，动物发育中的大脑暴露于酒精、麻醉剂和镇静药物中，可能会导致神经退行性变化，对学习和行为产生不利影响。这些变化与啮齿动物和非人类灵长类动物的长期行为变化有关。这些观察结果的临床意义是一个激烈争论和关注的话题，因为很少有关于麻醉暴露如何影响神经发育的人类研究。现有的研究表明，在年轻时接触多种麻醉剂，而不是单一麻醉剂，与学习障碍的频率增加有关，但所有现有的人类研究都有明显的局限性。这项研究的长期目标是提高用于幼儿全身麻醉的药物的安全性。本应用程序的总体目标是确定儿童麻醉暴露是否与神经发育异常有关。其核心假设是，儿童在幼年时接触多种麻醉剂会损害其日后在神经发育表现的详细测试中的表现。为了实现这一目标，本提案的具体目的是确定三岁前暴露于麻醉是否与儿童神经发育异常有关。利用独特的基于人口的资源，罗切斯特流行病学项目，将确定1994年至2007年间出生在明尼苏达州奥姆斯特德县且目前仍居住在该地区的一组儿童。在这个队列中，3岁前暴露于麻醉的儿童与未暴露于麻醉的儿童的倾向相匹配。受试者（麻醉和未麻醉的受试者）将在智力、记忆功能、执行功能、运动完整性、语言和言语发展以及学术成就等领域进行详细的神经心理学测试，以检验多次（而非单一）麻醉暴露与这些领域的表现受损有关的假设。儿童还将收到来自国家毒理学研究中心的操作性测试电池。这将允许将儿童的结果与已发表的关于麻醉暴露如何影响婴儿恒河猴的研究进行比较。测试将在7-11岁和15-19岁（在不同的儿童组中）进行，以探索任何观察到的效果的持久性。这项研究的预期成果将是麻醉剂引起的人类神经毒性的第一个详细表型（如果确实发现了神经毒性的证据）。在美国，每年有超过100万3岁以下的儿童接受麻醉，因此这一发现的潜在影响不能被夸大。这种表型将有助于解释临床前数据，潜在地设计策略以减轻麻醉引起的损伤，并帮助患者和临床医生做出明智的决定。

DESCRIPTION (provided by applicant): Over one million young children are exposed to drugs used to induce and maintain general anesthesia each year in the United States. Mounting evidence shows that exposure of the developing brains of animals to alcohol, anesthetic and sedative medications may cause neurodegenerative changes with adverse effects on learning and behavior. These changes are associated with long-term changes in behavior, both in rodents and in non-human primates. The clinical significance of these observations is a topic of intense debate and concern, as there are very few human studies of how anesthetic exposure may affect neurodevelopment. Existing studies show that exposure to multiple, but not single, anesthetics at a young age is associated with an increased frequency of learning disabilities, but there are significant limitations of all existing human studies. The long term goal of this researc is to improve the safety of drugs that produce general anesthesia in young children. The overall objective of this application is to determine whether exposure of children to anesthesia is associated with neurodevelopmental abnormalities. The central hypothesis is that exposure to multiple anesthetics at a young age will impair later performance of children on detailed tests of neurodevelopmental performance. To achieve the objective, the Specific Aim of this proposal is to determine if exposure to anesthesia prior to age three is associated with neurodevelopmental abnormalities in children. Using a unique population-based resource, the Rochester Epidemiology Project, a cohort of children born in Olmsted County, MN between 1994 and 2007 and still currently resident in the area will be identified. From this cohort children exposed to anesthesia prior to age 3 will be propensity matched to children not exposed to anesthesia. Subjects (those exposed to anesthesia and those not exposed) will undergo detailed neuropsychological testing in the domains of intellectual ability, memory function, executive function, motor integrity, language and speech development, and academic achievement to test the hypothesis that multiple, but not single, exposures to anesthesia are associated with impaired performance in these domains. Children will also receive the Operant Test Battery from the National Toxicological Research Center. This will allow for comparison of results in children with published studies of how anesthetic exposure affects infant rhesus monkeys. Testing will be performed at ages 7-11 and 15-19 (in separate groups of children) to explore the persistence of any observed effects. The expected product of this research will be the first detailed phenotype of anesthetic- induced neurotoxicity in humans (if indeed evidence of neurotoxicity is found). More than one million children under the age of 3 years undergo anesthesia annually in the US so that the potential impact of this finding cannot be overstated. This phenotype would assist in interpreting the pre-clinical data, potentially devising strategies to mitigate anesthesia-induced injury, and assist patients and clinicians in making informed decisions.