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

• 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
• 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

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：安全有效的疼痛缓解是儿童未满足的关键医疗需求。在美国，~6 每年有100万儿童接受痛苦的手术。阿片类药物是首选的镇痛剂，以减少手术 痛苦由于阿片类药物的治疗指数较窄，儿童间的反应差异很大， 30%接受手术的儿童遭受严重的不良反应。几起死亡和缺氧brian 呼吸抑制（RD）造成的损伤归因于儿童使用阿片类药物。儿童 阻塞性睡眠呼吸暂停（OSA）患者对阿片类药物诱导的RD更敏感，且发生率增加。 目前的试错式阿片类药物剂量仅基于体重，损害了安全性并增加了经济效益。 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的儿童间变异性缺乏了解， 药效学也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（CNS）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作用。QP是一种实时、非侵入性的数字化， 以及瞳孔大小和对光反应的客观测量。几个与RD相关的遗传标记 孩子们已经被确认了。这项创新的研究独特地使用了已知的遗传风险因素， 新的生物标志物QP可更好地预测儿童术后RD。长期目标是个性化疼痛 为每个儿童提供正确剂量的正确镇痛剂，提高安全性和有效性， 降低围手术期护理的成本。总体目标是积极主动地确定儿童的个人 使用QP（一种临床适应性强的新型非侵入性工具）在床边评估阿片类药物诱导RD的风险。这 关键的新知识将积极主动地识别有RD风险的儿童并改善结果。鼓励 初步数据支持使用QP作为儿童RD的预测因子。核心假设是， 术中QP，在术中吗啡推注剂量之前和之后，预测术后吗啡- 诱导的RD（主要安全性结局），比相应的血液吗啡浓度更好地预测RD， 并改善了基于遗传学的儿童RD预测。具体目标是：1）确定瞳孔效应 术中吗啡可预测术后RD，2）确定术中QP措施是否 是比血吗啡浓度更好的术后RD的预测因子;如果OSA儿童有 与没有OSA的儿童相比，对阿片类药物的药效学敏感性更高，以及3）改善 通过整合QP措施和已知的术后RD遗传风险因素，进行临床RD。最终，关键 这项研究中新的QP和基于遗传学的预测知识将积极识别有风险的儿童， 术后RD，并指导以正确剂量个性化使用正确的镇痛药，以最大限度地提高手术效果 减轻疼痛，同时最大限度地减少数百万接受手术的儿童可预防的严重不良反应。