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

通过瞳孔测量法预测阿片类药物引起的儿童呼吸抑制

基本信息

批准号：
9754219
负责人：
Senthilkumar Sadhasivam
金额：
$ 23.63万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754219
关键词：
ABCB1 gene Absence of pain sensation Adult Adverse effects Analgesics Biological Biological Markers Blood Bolus Infusion Brain Brain Stem Cessation of life Child Childhood Clinical Clinical Research Data Development Dose Drug Kinetics Economic Burden Genes Genetic Genetic Markers Genetic Models Genetic Polymorphism Genotype Goals Incidence Individual Injury Intravenous Knowledge Length of Stay Life Light Measures Medical Metabolism Morphine Neuraxis Obstructive Sleep Apnea Operative Surgical Procedures Opioid Outcome POU2F1 gene Pain Pain management Pathway interactions Patient Self-Report Pediatric Surgical Procedures Perioperative Perioperative Care Pharmacodynamics Pharmacology Postoperative Nausea and Vomiting Postoperative Pain Postoperative Period Public Health Pupil Race Reaction Research Risk Risk Factors Safety Sedation procedure Serious Adverse Event Site Sleep Apnea Syndromes Surrogate Markers Therapeutic Index Time Tonsillectomy Variant Ventilatory Depression Weight Work adverse outcome base care costs combinatorial cost depressive symptoms digital genetic risk factor genetic variant high risk improved improved outcome innovation insight multidisciplinary novel novel marker opioid use pain relief pharmacokinetics and pharmacodynamics point of care predictive marker predictive tools prospective respiratory response sex surgical pain tool

项目摘要

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.

项目摘要：安全有效的缓解疼痛是儿童未满足的关键医疗需求。在美国，〜6 百万儿童每年接受疼痛手术。阿片类药物是减少手术的首选镇痛药疼痛。因为阿片类药物具有狭窄的治疗指数和反应的巨大儿童间差异，所以 30％的接受手术的儿童患有严重的不良反应。几次死亡和缺氧的Brian 呼吸抑郁症（RD）受伤已归因于儿童的阿片类药物使用。有孩子阻塞性睡眠呼吸暂停（OSA）对阿片类药物引起的RD的发生率更高，并且增加了。目前的试用阿片类药物剂量仅基于体重，损害了安全性并增加了经济未经治疗的疼痛和严重不良事件的负担。这个主要的公共卫生问题是可以预防的。目前，对阿片类药代动力学和儿童间变异性缺乏了解还有几乎完全缺乏可靠的，实时的床头工具来评估阿片类药物的中枢神经系统（CNS）作用。定量的互化学测定法（QP）是一种安全，有效的工具评估阿片类药物在儿童中的脑干功能和镇痛作用。 QP是一个实时的，无创的数字，和客观测量学生的大小和对光的反应。与RD相关的几个遗传标记儿童已经被确定。这项创新研究独特地使用已知的遗传危险因素和新颖的生物标志物QP可以更好地预测儿童术后RD。长期目标是个性化痛苦为每个孩子提供正确剂量的正确剂量的管理，提高安全性和效率降低定期护理的成本。总体目标是主动确定儿童的个人使用QP（一种临床适应性，新颖和非侵入性工具）在床边诱发阿片类药物引起的RD的风险。这关键的新知识将主动确定有RD风险并改善结果的儿童。鼓励初步数据支持使用QP作为儿童RD的预测因子。中心假设是术中QP术中和之后术中吗啡剂量之前和之后，术后吗啡 - 诱导的RD（主要安全结果），比相应的血液浓度更好地预测RD，并改善儿童基于遗传学的RD预测。具体目的是1）确定的瞳孔影响术中的术中吗啡，可预测术后RD，2）确定术中QP测量是否是否是术后RD的预测指标，而不是血液吗啡浓度。如果有OSA的孩子有与没有OSA的儿童相比，对阿片类药物的药效学敏感性更高，3）提高预测临床RD通过整合QP测量和术后RD的已知遗传风险因素。最终，批评来自这项研究的新的QP和基于遗传学的预测知识将主动确定有风险的儿童术后RD，并在正确剂量下指导右止痛药的个性化使用以最大程度地进行手术缓解疼痛的同时，在数百万接受手术的儿童中最大程度地减少了可预防的严重不良影响。