Impact of Pharmacology on Duration of Ventilation in Patients with Resp Failure

描述(由申请人提供)： 越来越多的人认识到需要优化呼吸衰竭患儿的镇静策略，这些患儿需要进行气管插管和机械通气。家长R01《儿科急性呼吸衰竭患者的镇静管理》解决了这一需求，目的是研究护士实施的目标导向舒适性算法对机械通气持续时间的影响。正如拨款建议中所描述的那样，该算法的实施将影响许多影响机械通风持续时间的因素，例如苏醒程度、强制滴定以及阿片剂和苯二氮卓类药物的总剂量。然而，在每组(干预、对照)内和整个队列中，将观察到机械通气持续时间的差异。虽然这种可变性可能与给药的总剂量相关，但估计实际药物暴露(药代动力学)的能力可能允许更好地理解反应的可变性(药效学)。此外，在类似的药物暴露下，反应的差异可能是由于药物遗传学导致受体水平上的药物作用的差异所致。因此，我们的假设是咪达唑仑和吗啡的药物暴露和反应将受到非遗传因素(如器官功能障碍、疾病程度、年龄、体重)和可遗传因素(如药物代谢系统或药物受体的多态性)的影响，这些因素可以定量定义。我们的长期研究目标是通过优化护理中使用的镇静策略来改善需要机械通气的呼吸衰竭儿童的预后。这一辅助R01应用程序是迈向这一长期目标的下一步，其目标是1)确定在重症监护环境中气管插管和机械呼吸的儿童中，药物暴露的可变性背后的可遗传和非遗传因素-对吗啡和咪达唑仑的反应，以及2)开发和验证可预测麻醉/镇静剂量范围要求的群体药代动力学(PK)-药效学(PD)模型，该模型可为重症监护环境中气管插管和机械通气的儿童提供适当的治疗并最大限度地减少呼吸机天数。这种模式最终可用于对需要机械通气的儿童进行个体化治疗，目的是优化镇静，同时最大限度地减少机械通气的持续时间。公共卫生相关性：该项目将使用复杂的建模和模拟技术来评估遗传学和其他变量(如疾病程度、年龄、体重和器官功能障碍)对因呼吸衰竭而使用机械通气并需要镇静的儿童吗啡和咪达唑仑的药代动力学和药效学的影响。这项拟议的工作将允许设计一种药理学模型，可用于对需要机械通风的儿童进行个体化治疗，目的是优化镇静，同时最大限度地减少呼吸机持续时间。

DESCRIPTION (provided by applicant): There has been increasing recognition of the need to optimize sedation strategies for children with respiratory failure who are tracheally intubated and mechanically ventilated. The parent R01 "Sedation Management in Pediatric Patients with Acute Respiratory Failure" addresses this need with the intent to study the impact of a Nurse-Implemented Goal-Directed Comfort Algorithm on the duration of mechanical ventilation. As delineated in the grant proposal, the implementation of this algorithm will impact many factors that influence duration of mechanical ventilation, such as level of awakeness, mandated titrations and total dose of opiates and benzodiazepines. However, within each group (intervention, control) and across the entire cohort, variation in the duration of mechanical ventilation will be observed. Although this variability may correlate with the total dose of drugs administered, the ability to estimate the actual drug exposure (pharmacokinetics) may allow for a better understanding of the variability in response (pharmacodynamics). Moreover, variation in response at similar drug exposures may result from pharmacogenetically driven differences in drug action at the receptor level. Thus our hypothesis is that midazolam and morphine drug exposure and response will be affected by both non-heritable (e.g. organ dysfunction, degree of illness, age, weight) and heritable (e.g. polymorphisms in drug metabolizing systems or drug receptors) factors that can be quantitatively defined. Our long-term research goal is to improve the outcome of children with respiratory failure requiring mechanical ventilation by optimizing the sedation strategies that are used in their care. The objectives of this ancillary R01 application, which is the next step toward this long-term goal, are to 1) identify heritable and non-heritable factors that underlie the variability in the drug exposure-response to morphine and midazolam in children who are tracheally intubated and mechanically ventilated in an intensive care setting and 2) develop and validate a population pharmacokinetic(PK)-pharmacodynamic(PD) model that is predictive for the narcotic/sedative dose range requirement that provides adequate treatment yet minimizes ventilator days for children who are tracheally intubated and mechanically ventilated in an intensive care setting. This model can be ultimately be used to individualize therapy in children requiring mechanical ventilation with the goal of optimizing sedation while minimizing the duration of ventilation. PUBLIC HEALTH RELEVANCE: This project will use sophisticated modeling and simulation techniques to evaluate the impact of genetics and other variables such as degree of illness, age, weight and organ dysfunction on the pharmacokinetics and pharmacodynamics of morphine and midazolam in children who are mechanically ventilated for respiratory failure, and require sedation. This proposed work will allow the design of a pharmacologic model that can be used to individualize therapy in children requiring mechanical ventilation with the goal of optimizing sedation while minimizing the duration of ventilation.