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

越来越多的人认识到有必要优化儿童的镇静策略 使用气管插管和机械通气的呼吸衰竭患者。家长R01《镇静》 《儿科急性呼吸衰竭患者的管理》满足了这一需求，目的是 护士实施目标导向舒适度算法对机械治疗持续时间影响的研究 通风。正如拨款提案中所描绘的那样，该算法的实施将对许多 影响机械通气持续时间的因素，如苏醒程度、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，在每个组内(干预、对照)和 在整个队列中，将观察到机械通风持续时间的变化。虽然这件事 可变性可能与所用药物的总剂量、估计实际药物的能力有关 暴露(药代动力学)可能有助于更好地了解反应的可变性 (药效学)。此外，在类似的药物暴露下，反应的差异可能会导致 药物遗传学导致受体水平上药物作用的差异。因此，我们的假设是 咪达唑仑和吗啡药物的暴露和反应都会受到非遗传性(如器官)的影响 功能障碍、疾病程度、年龄、体重)和可遗传性(例如药物代谢的多态 系统或药物受体)可以定量定义的因素。我们的长期研究目标是 通过优化呼吸机辅助治疗改善呼吸衰竭患儿的预后 在他们的护理中使用的镇静策略。此辅助R01应用程序的目标是 是实现这一长期目标的下一步，是1)确定可遗传和不可遗传的因素 儿童对吗啡和咪达唑仑的药物暴露反应的变异性 在重症监护环境中进行气管插管和机械通气；2)开发和验证 群体药代动力学(PK)-药效学(PD)模型预测 麻醉/镇静剂量范围要求，提供适当治疗，但最大限度地减少呼吸机天数 适用于在重症监护环境中进行气管插管和机械通气的儿童。这 模型最终可用于需要机械通气的儿童的个体化治疗 优化镇静的同时最大限度地减少呼吸机持续时间的目标。

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.