Neurobehavioral Disorders after Appendectomy in Childhood

摘要 对儿童时期接受手术和麻醉后的神经毒性的担忧已经持续了近几年 20年来，部分原因是没有确凿的证据证明它的存在，也没有足够的证据 证明事实并非如此的证据。评估神经行为结果的大规模观察性研究 在暴露于麻醉和手术后，产生了不同的结果，但没有一个表现出来 可操作的、没有混淆的证据表明风险增加。这项提案旨在更好地定义 麻醉和手术暴露与随后的神经行为障碍之间的关联(定义 行为障碍、情绪障碍和焦虑症)通过对现有的 有可能克服以前研究的局限性的医疗补助数据。这项研究使用了一种新的 检验问题的方法：(1)使用反映随机接触的自然实验 手术(在控制了年龄、性别和种族后近乎随机的阑尾切除事件)与 与生活方式或疾病相关的治疗本身可能与长期神经行为有关 结果，以及(2)通过使用多变量匹配技术来解释潜在的可观察性 在队列中的基线差异，我们有能力比较大约68,000名暴露的队列 儿科阑尾切除术患者34,000名配对对照，两者可观察到的密切平衡 以及潜在的不可察觉的风险因素。这使我们能够更好地研究是否存在长期的联系 全身麻醉下手术暴露与随后的不良神经行为结果之间的关系 孩子们。最后，(3)我们还将检查68,000名急性疾病患者的医疗控制组 如胃肠炎、蜂窝织炎和社区获得性肺炎，以检查神经行为障碍 在不接受手术或麻醉的这一组中是升高的。这项研究将检查ADHD的结果， 行为障碍、焦虑、抑郁和双相情感障碍，进行一项多变量匹配队列研究 比较医疗补助计划中暴露和未暴露儿童的研究结果的风险。我们 假设接受阑尾切除术的患者将增加这些研究结果的风险 与对照组相比。我们将确定所有3至15岁接受过阑尾切除术的患者，以及 将每个患者与5名相同年龄的对照组进行匹配，省略任何暴露于 在初步分析中或有复杂慢性证据的神经行为障碍的基线病史 并在阑尾切除治疗组和接受阑尾切除术的儿童之间进行第二次1：1匹配 因急症入院。这项研究的结果将推广到阑尾切除术以外的领域。 正是因为阑尾炎是随机发生的(在年龄、性别和种族匹配后)，应该有助于 告知护理者与全身麻醉和手术相关的潜在神经行为风险。

ABSTRACT Concern about neurotoxicity following exposure to surgery and anesthesia in childhood has persisted for nearly two decades, in part because there is no conclusive evidence to prove that it exists, nor is there adequate evidence to prove that it does not. Large-scale observational studies evaluating neurobehavioral outcomes after exposures to anesthesia and surgery have generated variable results, but none have demonstrated actionable, un-confounded evidence suggesting increased risk. This proposal seeks to better define the association between exposure to anesthesia and surgery and subsequent neurobehavioral disorders (defined as behavioral disruptive disorders, mood disorders, and anxiety disorders) through a new analysis of existing Medicaid data that has the potential to overcome limitations of previous studies. This study uses a new approach for examining the question by: (1) using a natural experiment that reflects a stochastic exposure to surgery (the near random event of appendectomy after controlling for age, sex and race) that is not associated with lifestyle or disease-related treatments that may themselves be associated with long-term neurobehavioral outcomes, and (2) through the use of multivariate matching techniques to account for potential observable baseline differences in cohorts, we have the ability to compare an exposed cohort of approximately 68,000 pediatric appendectomy patients with 340,000 matched controls that are closely balanced for both observable and potentially unobservable risk factors. This enables us to better study if there is a long-term association between operative exposure with general anesthesia and subsequent adverse neurobehavioral outcomes in children. Finally, (3) we will also examine a 68,000-patient medical control group with acute medical conditions such as gastroenteritis, cellulitis and, community-acquired pneumonia to examine if neurobehavioral disorders are elevated in this group not exposed to surgery or anesthesia. The study will examine outcomes of ADHD, conduct disorders, anxiety, depression and bipolar disorder, to conduct a multivariate matched cohort study to compare the hazard of study outcomes between exposed and unexposed children in Medicaid. We hypothesize that patients with appendectomy will have an elevated hazard of these study outcomes as compared to controls. We will identify all patients who underwent appendectomy from ages 3 to 15 years, and match each patient to 5 controls who were the same age, omitting any exposed or control patient with a baseline history of neurobehavioral disorders in the primary analysis or with evidence of complex chronic disease, and perform a second 1:1 match between the appendectomy treated group and children who were admitted for acute medical conditions. The results of this study will be generalizable beyond appendectomy precisely because appendicitis occurs randomly (after matching on age, sex, and race) and should aid in informing caregivers about potential neurobehavioral risks associated with general anesthesia and surgery.