IATROGENIC OPIOID DEPENDENCE IN CRITICALLY ILL CHILDREN

描述：(申请人摘要) 儿科重症监护病房中的危重儿童经常需要 长期镇静和止痛。芬太尼起效快，时间短 作用持续时间和稳定的血流动力学特征。因此，它是最多的 用于儿科持续镇静和镇痛的理想阿片类药物 重症监护室。然而，持续使用芬太尼通常 导致耐受性的快速发展，逐渐的剂量增加，以及 最终导致医源性阿片类药物依赖。芬太尼停用于 这些儿童会引发急性戒断综合症，这可能 影响对孩子的照顾。目前，人们对此还不完全了解。 哪些患者有阿片依赖和戒断的风险，也没有 有一种经过验证的方法可以客观地评估 戒烟。尽管医源性阿片类药物戒断的最佳治疗方法 危重儿童尚未确诊综合征，口服美沙酮 经常被用来促进芬太尼的停用，同时防止迹象 以及戒断症状。然而，目前还没有关于 美沙酮在该患者群体中的最佳剂量或药代动力学。 这项提议旨在产生关于医源性的广泛方面的数据 芬太尼依赖，包括诊断和评估其严重程度， 其发生的危险因素测定及药代动力学研究 芬太尼和美沙酮对危重儿童的影响。的具体目标 这些研究是：1)验证临床评分工具，供 床边护士客观评估医源性芬太尼的严重程度 禁欲综合症。此计分工具可用于确定何时 芬太尼停药治疗是必要的；2)对芬太尼进行量化 通过测量芬太尼在人体内的累积面积进行暴露 药物浓度-时间曲线；3)评价各系统之间的关系 芬太尼暴露与医源性阿片类药物戒断综合征的风险；以及 4)确定美沙酮的药代动力学和生物利用度 用于治疗这些危重儿童的芬太尼停药。这些 数据将显著增强我们对阿片类药物戒断的理解 增加我们对芬太尼和美沙酮的认识 药代动力学，这两个因素都是安全使用这些药物的关键 从特工到孩子。

DESCRIPTION: (Applicant's Abstract) Critically ill children in the pediatric intensive care unit often require long-term sedation and analgesia. Fentanyl has a rapid onset, short duration of action, and stable hemodynamic profile. Thus, it is the most desirable opioid for continuous analgesia and sedation in the pediatric intensive care unit. However, continuous administration of fentanyl often leads to rapid development of tolerance, progressive dose escalations, and ultimately iatrogenic opioid dependence. Discontinuation of fentanyl in these children will precipitate acute abstinence syndrome which may compromise the care of the child. Currently, it is not fully understood which patients are at risk for opioid dependence and withdrawal, nor is there a validated method of objectively assessing the severity of withdrawal. Although the optimal treatment of iatrogenic opioid abstinence syndrome has not been established in critically ill children, oral methadone is often used to facilitate fentanyl discontinuation while preventing signs and symptoms of withdrawal. However, no data are available regarding the optimal dose or pharmacokinetics of methadone in this patient population. This proposal aims to generate data on wide ranging aspects of iatrogenic fentanyl dependence, including diagnosis and evaluation of its severity, determination of risk factors for its development, and the pharmacokinetics of fentanyl and methadone in critically ill children. The specific aims of these studies are: 1) to validate a clinical scoring tool to be used by the bedside nurse to objectively measure the severity of iatrogenic fentanyl abstinence syndrome. This scoring tool may be used to determine when treatment of fentanyl withdrawal is necessary; 2) to quantitate fentanyl exposure by measuring fentanyl's cumulative area under the concentration-time curve; 3) to evaluate the relationship between systemic fentanyl exposure and the risk of iatrogenic opioid abstinence syndrome; and 4) to define the pharmacokinetics and bioavailability of methadone which is used to treat fentanyl withdrawal in these critically ill children. These data will significantly augment our understanding of opioid withdrawal in critically ill children and increase our knowledge of fentanyl and methadone pharmacokinetics, both of which are critical in safely administering these agents to children.