KIDS KETAMINE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项合作研究的长期目标有两个：1)使儿童的紧急程序镇静安全、有效，并在心理上无损伤；2)开发预防精神分裂症的药理策略。氯胺酮是FDA批准的麻醉剂，正成为儿童紧急镇静的首选镇静剂/止痛剂，因为与其他现有药物相比，它能引起深度镇静，并最大限度地减少呼吸抑制。然而，紧急反应是氯胺酮的一种重要不良反应，其特征是认知功能的一过性改变、分离和轻微的精神分裂症样症状。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地诱导的。NMDA受体功能低下可以抑制大脑关键区域的兴奋性(胆碱能/谷氨酸)投射，这被认为是解释精神分裂症的关键特征。几种阻止兴奋性递质过度释放的治疗方法也被证明可以防止氯胺酮诱导的NMDA受体功能低下对人类的认知和行为影响。α-2肾上腺素能激动剂可以在突触前抑制乙酰胆碱的释放，可以预防健康成人中轻微的氯胺酮诱导的行为和认知症状。然而，这一预防策略尚未在儿童中进行评估。目前，儿童正在接受NMDA拮抗剂氯胺酮的临床指征治疗，这一年龄段是旨在预防精神分裂症的药物策略的重要目标。这项申请提出了一项双盲、安慰剂对照、随机试验，以测试FDA批准的α-2肾上腺素能激动剂右美托咪定在预防儿童氯胺酮引起的精神症状方面的安全性和有效性。计划中的初步分析将使用方差分析评估低氧血症预防治疗对临床和认知变量的影响。拟议的实验与未来对精神分裂症高危人群的预防试验有关，并与预防NMDA拮抗剂麻醉剂(氯胺酮、一氧化二氮)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).