Bedside prediction of opioid-induced respiratory depression in children with pupillometry

项目概述：安全有效的止痛是儿童未得到满足的关键医疗需求。在美国，~6 每年有数百万儿童接受痛苦的手术。阿片类药物是减少外科手术的首选镇痛剂 疼痛。因为阿片类药物的治疗指数很窄，儿童之间的反应差异很大，超过 30%的接受手术的儿童遭受严重的不良反应。几例死亡和缺氧性布莱恩 呼吸抑制(RD)造成的伤害被归因于儿童使用阿片类药物。患有以下疾病的儿童 阻塞性睡眠呼吸暂停(OSA)对阿片类药物引起的RD更为敏感，发病率也更高。 目前仅以体重为基础的反复试验阿片类药物剂量，损害了安全性，增加了经济 未经治疗的疼痛和严重不良事件的负担。这一重大公共卫生问题是可以预防的。 目前，对阿片类药物药代动力学和儿童间变异性缺乏了解 药效学。而且几乎完全缺乏可靠的、实时的床边工具来评估 阿片类药物对中枢神经系统的影响。定量瞳孔测量(QP)是一种安全、有效的工具 评估儿童脑干功能和阿片类药物的镇痛效果。QP是一种实时、非侵入性的数字， 以及对瞳孔大小和对光的反应的客观测量。与糖尿病肾病相关的几个遗传标记 孩子们的身份已经确定。这项创新的研究独特地使用了已知的遗传风险因素和 新型生物标记物QP能更好地预测儿童术后RD。长期目标是将疼痛个人化 为每个儿童使用合适剂量的止痛药进行管理，提高安全性和有效性 降低围手术期护理成本。总体目标是积极主动地确定儿童个体 床边使用QP的阿片类药物引起RD的风险，QP是一种临床适用的、新颖的非侵入性工具。这 关键的新知识将主动识别有RD风险的儿童，并改善结果。鼓舞人心的是 初步数据支持将QP作为儿童RD的预测指标。中心假设是 术中静脉注射吗啡前后的QP预测术后吗啡- 诱导的RD(主要安全结果)，比相应的血液吗啡浓度更好地预测RD， 并改进了基于遗传学的儿童RD的预测。具体目标是：1)确定瞳孔效应 术中吗啡预测术后RD，2)确定术中QP措施 是术后RD的更好的预测指标，而不是血中吗啡浓度；如果OSA儿童有 与没有阻塞性睡眠呼吸暂停的儿童相比，阿片类药物的药效学敏感性更高，以及3)改善了对 结合QP措施和已知的术后RD遗传危险因素进行临床RD。归根结底，关键 来自这项研究的新的QP和基于遗传学的预测性知识将主动识别儿童患糖尿病的风险 术后RD，并指导个性化使用合适剂量的正确止痛药，以最大限度地提高手术效果 在减轻疼痛的同时，将数百万接受手术的儿童可预防的严重不良反应降至最低。

Project Summary: Safe and effective pain relief is an unmet critical medical need in children. In the U.S., ~6 million children undergo painful surgery each year. Opioids are the preferred analgesics to reduce surgical pain. Because opioids have narrow therapeutic indices and huge inter-child variations in responses, more than 30% of children undergoing surgery suffer from serious adverse effects. Several deaths and anoxic brian injuries from respiratory depression (RD) have been attributed to opioid use in children. Children with obstructive sleep apnea (OSA) are more sensitive to, and have an increased incidence of opioid-induced RD. Current trial-and-error opioid dosing, based solely on weight, compromises safety and increases the economic burden of untreated pain and serious adverse events. This major public health problem is preventable. Currently, there is a lack of understanding of inter-child variability in opioid pharmacokinetics and pharmacodynamics. There is also an almost complete lack of reliable, real-time, bedside tools to assess the central nervous system (CNS) effects of opioids. Quantitative Pupillometry (QP) is a safe, effective tool to assess brainstem function and analgesic effects of opioids in children. QP is a real-time, non-invasive digital, and objective measure of pupil size and reaction to light. Several genetic markers associated with RD in children have already been identified. This innovative study uniquely uses known genetic risk factors and the novel biomarker QP to better predict postoperative RD in children. The long-term goal is to personalize pain management with the right dose of the right analgesic for each child, improving safety and efficacy while reducing the cost of perioperative care. The overall objective is is to proactively determine children’s individual risk of opioid-induced RD at the bedside using QP, a clinically adaptable, novel and non-invasive tool. This critical new knowledge will proactively identify children at risk of RD and improve outcomes. Encouraging preliminary data are supportive of the use of QP as a predictor of RD in children. The central hypothesis is that intraoperative QP, before and after an intraoperative morphine bolus dose, predicts postoperative morphine- induced RD (primary safety outcome), better predicts RD than corresponding blood morphine concentration, and improves genetics-based prediction of RD in children. The specific aims are 1) Identify pupillary effects of intraoperative morphine that are predictive of postoperative RD, 2) Determine if intraoperative QP measures are better predictors of postoperative RD than blood morphine concentrations; and if children with OSA have higher pharmacodynamic sensitivity to opioids compared to children without OSA, and 3) Improve prediction of clinical RD by integrating QP measures and known genetic risk factors of postoperative RD. Ultimately, critical new QP and genetics-based predictive knowledge from this research will proactively identify children at risk for postoperative RD, and guide personalized use of the right analgesics at the right dose to maximize surgical pain relief while minimizing preventable serious adverse effects in millions of children undergoing surgery.