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

描述（由申请人提供）： 对于气管插管和机械通气的呼吸衰竭患儿，人们越来越认识到需要优化镇静策略。父R 01“急性呼吸衰竭儿科患者的镇静管理”解决了这一需求，旨在研究护士实施的目标导向舒适算法对机械通气持续时间的影响。如资助提案中所述，该算法的实施将影响影响机械通气持续时间的许多因素，例如清醒水平、强制滴定以及阿片类药物和苯二氮卓类药物的总剂量。然而，在每组（干预组、对照组）内和整个队列中，将观察到机械通气持续时间的变化。尽管这种变异性可能与给药的药物总剂量相关，但估计实际药物暴露量（药代动力学）的能力可能有助于更好地理解反应（药效学）的变异性。此外，在相似的药物暴露的反应的变化可能会导致药物作用在受体水平的药物遗传学驱动的差异。因此，我们的假设是咪达唑仑和吗啡药物暴露和反应将受到可定量定义的非遗传性（例如器官功能障碍、疾病程度、年龄、体重）和遗传性（例如药物代谢系统或药物受体的多态性）因素的影响。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结局。该辅助R 01应用程序的目标是实现这一长期目标的下一步，是1）确定在重症监护环境中接受气管插管和机械通气的儿童中对吗啡和咪达唑仑的药物安全性反应变异性的遗传和非遗传因素，2）开发和验证群体药代动力学（PK）-药效学（PD）该模型可预测麻醉剂/镇静剂剂量范围要求，可为重症监护环境中气管插管和机械通气的儿童提供充分的治疗，同时最大限度地减少呼吸机天数。该模型最终可用于需要机械通气的儿童的个体化治疗，目的是优化镇静，同时最大限度地减少通气时间。 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）对因呼吸衰竭而机械通气并需要镇静的儿童中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，可用于需要机械通气的儿童的个性化治疗，其目标是优化镇静，同时最大限度地减少通气时间。

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.