KIDS KETAMINE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这项合作研究的长期目标有两个：1)使紧急程序性镇静安全、有效、对儿童无心理创伤；2)制定预防精神分裂症的药理学策略。氯胺酮，一种FDA批准的麻醉剂，正成为儿童紧急镇静的首选镇静/镇痛药，因为与其他可用药物相比，氯胺酮可产生深度镇静，且呼吸抑制最小。然而，紧急反应是氯胺酮的一个重要不良反应，其特征是认知功能的短暂改变、精神分离和轻度精神分裂症样症状。这些认知和行为效应是由氯胺酮和其他n -甲基-d -天冬氨酸（NMDA）谷氨酸受体拮抗剂剂量依赖性诱导的。NMDA受体功能低下可以解除对大脑关键区域兴奋性（胆碱能/谷氨酸能）投射的抑制，这被认为可以解释精神分裂症的关键特征。阻断过度兴奋性递质释放的几种治疗方法也被证明可以防止氯胺酮诱导的人类NMDA受体功能低下的认知和行为影响。α -2肾上腺素能激动剂可突触前抑制乙酰胆碱释放，可预防健康成人氯胺酮引起的轻度行为和认知症状。然而，这种预防策略尚未在儿童中进行评估。儿童目前接受NMDA拮抗剂氯胺酮的临床适应症治疗，这一年龄组是旨在预防精神分裂症的药理学策略的重要目标。本申请提出了一项双盲、安慰剂对照、随机试验，以测试右美托咪定的安全性和有效性，右美托咪定是一种FDA批准的α -2肾上腺素能激动剂，用于预防氯胺酮引起的儿童精神症状。计划的初步分析将使用方差分析评估假设的预防治疗对临床和认知变量的影响。拟议的实验与未来针对精神分裂症风险个体的预防试验有关，也与预防NMDA拮抗剂麻醉剂（氯胺酮、氧化亚氮）的不良反应有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-range objectives of this collaborative research are twofold: 1) to make emergency procedural sedation safe, effective, and psychologically atraumatic for children, and 2) to develop pharmacological strategies for preventing schizophrenia. Ketamine, an FDA approved anesthetic agent, is becoming the sedative/analgesic of choice for emergency sedation in children because it causes deep sedation with minimal respiratory depression in comparison to other available agents. However, emergence reactions are an important adverse effect of ketamine, characterized by transient changes in cognitive function, dissociation and mild schizophrenia-like symptoms. These cognitive and behavioral effects are dose-dependently induced by ketamine and other antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor. NMDA receptor hypofunction can disinhibit excitatory (cholinergic/glutamatergic) projections in key areas of the brain, and this has been proposed to explain key features of schizophrenia. Several treatments that block excessive excitatory transmitter release have also been shown to prevent cognitive and behavioral effects of ketamine-induced NMDA receptor hypofunction in humans. Alpha-2 adrenergic agonists, which can presynaptically inhibit acetylcholine release, can prevent mild ketamine-induced behavioral and cognitive symptoms in healthy human adults. However, this prevention strategy has not been evaluated in children. Children currently receive clinically-indicated treatment with the NMDA antagonist, ketamine, and this age group is an important target for pharmacological strategies aimed at the prevention of schizophrenia. This application proposes a double-blind, placebo-controlled, randomized trial to test the safety and effectiveness of dexmedetomidine, an FDA approved alpha-2 adrenergic agonist, in preventing ketamine-induced mental symptoms in children. Planned primary analyses will evaluate effects of the hyposthesized prevention treatment on clinical and cognitive variables using ANOVA. The proposed experiments are relevant to future prevention trials for individuals at risk for schizophrenia, and to preventing adverse effects of NMDA antagonist anesthetic agents (ketamine, nitrous oxide).