Neurobehavioral Disorders after Appendectomy in Childhood

摘要 对儿童期手术和麻醉后神经毒性的担忧持续了近20年。 二十年，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它的存在。 有证据证明它不是。评估神经行为结局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，但没有一个人证明 可操作的、无混淆的证据表明风险增加。这项建议旨在更好地界定 暴露于麻醉和手术与随后的神经行为障碍之间的关联（定义 作为行为破坏性障碍，情绪障碍和焦虑症），通过对现有的 医疗补助数据有可能克服以前研究的局限性。这项研究使用了一种新的 研究问题的方法：（1）使用自然实验，反映随机暴露于 手术（在控制年龄、性别和种族后，阑尾切除术几乎是随机事件）， 与生活方式或疾病相关的治疗，可能本身与长期的神经行为 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结果。 队列中的基线差异，我们能够比较约68，000个暴露队列 儿科阑尾切除术患者与340，000名匹配的对照组， 和潜在的不可观察的风险因素。这使我们能够更好地研究，如果有一个长期的关联 全身麻醉手术暴露与随后的不良神经行为结果之间的关系 孩子最后，（3）我们还将检查68，000名患有急性医疗状况的患者的医疗对照组 如肠胃炎、蜂窝织炎和社区获得性肺炎，以检查是否有神经行为障碍 在未接受手术或麻醉的人群中升高。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，进行多变量配对队列研究， 比较医疗补助中暴露和未暴露儿童之间研究结果的危险。我们 假设阑尾切除术患者的这些研究结果风险升高， 与对照相比。我们将确定所有3至15岁接受阑尾切除术的患者， 将每名患者与5名年龄相同的对照组进行匹配，忽略任何暴露或对照组患者， 主要分析中有神经行为障碍基线史或有复杂慢性 疾病，并进行第二次1：1的比赛之间的阑尾切除术治疗组和儿童谁是 因急性疾病入院这项研究的结果将普遍超越阑尾切除术 正是因为阑尾炎的发生是随机的（在年龄、性别和种族匹配之后）， 告知护理人员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.