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

描述（由申请人提供）：在美国，每年有超过一百万名幼儿暴露于用于诱导和维持全身麻醉的药物。越来越多的证据表明，将发育中的动物大脑暴露于酒精、麻醉剂和镇静剂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辩论和关注的话题，因为很少有关于麻醉剂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存在显着的局限性。这项研究的长期目标是提高幼儿全身麻醉药物的安全性。本申请的总体目标是确定儿童麻醉暴露是否与神经发育异常相关。中心假设是，在年轻时暴露于多种麻醉剂将损害儿童在详细的神经发育表现测试中的后期表现。为了实现这一目标，本提案的具体目标是确定3岁之前暴露于麻醉是否与儿童神经发育异常相关。使用一个独特的人口为基础的资源，罗切斯特流行病学项目，在奥姆斯特德县，明尼苏达州1994年和2007年之间出生，目前仍居住在该地区的儿童队列将被确定。在该队列中，3岁之前暴露于麻醉的儿童将与未暴露于麻醉的儿童进行倾向匹配。受试者（暴露于麻醉的受试者和未暴露的受试者）将在智力、记忆功能、执行功能、运动完整性、语言和言语发育以及学业成绩等领域接受详细的神经心理学测试，以检验多次（而非单次）暴露于麻醉与这些领域的表现受损相关的假设。儿童还将收到国家毒理学研究中心的操作测试电池。这将允许将儿童的结果与已发表的关于麻醉剂暴露如何影响恒河猴幼崽的研究进行比较。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影响的持续性。这项研究的预期成果将是麻醉剂诱导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100万名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，可能制定减轻麻醉诱导损伤的策略，并帮助患者和临床医生做出明智的决定。 公共卫生相关性：研究表明，婴儿动物暴露于全身麻醉会导致某些类型的神经细胞死亡，并可能与学习缺陷有关。目前尚不清楚这些研究是否与接受麻醉的儿童相关。该项目将确定在3岁之前暴露于麻醉是否与以后生活中的脑功能受损有关。出生并居住在特定地理区域的儿童将在7-11岁和15-19岁时接受功能测试，将暴露于麻醉的儿童与未暴露于麻醉的儿童进行比较。

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. PUBLIC HEALTH RELEVANCE: Studies suggest that exposure of infant animals to general anesthesia causes the death of some types of nerve cells and may be associated with learning deficits. It is not known if these studies are relevant to children undergoing anesthesia. This project will determine whether exposure to anesthesia prior to the age of 3 is associated with impaired brain function later in life. Children born and residing in a defined geographical area will be tested for their functioning at ages 7-11 and 15-19 years, comparing those children exposed to anesthesia to those not exposed to anesthesia.