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

药理学对呼吸衰竭患者通气持续时间的影响

• 批准号: 8266354
• 负责人: Athena F. Zuppa
• 金额: $ 40.98万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266354
• 关键词: Acute respiratory failure; Address; Affect; Age; Algorithms; Applications Grants; Benzodiazepines; Binding; Blood specimen; CYP3A4 gene; Caring; Catechols; Child; Childhood; Clinical; Data; Dose; Drug Exposure; Drug Kinetics; Drug Receptors; Drug effect disorder; Environmental air flow; Enzymes; Failure; Functional disorder; Gender; Genetic Polymorphism; Genetic Variation; Glucuronosyltransferase; Goals; Grant; Hepatic; Intensive Care; Intervention; Intubation; Kidney; Knowledge; Mechanical ventilation; Midazolam; Modeling; Morbidity - disease rate; Morphine; Narcotics; Nurses; Opiates; Opioid Receptor; Organ; Organ Weight; Other Genetics; Outcome; P-Glycoprotein; Parents; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacology; Population; Race; Research; Respiratory Failure; Risk; Sampling; Sedation procedure; System; Target Populations; Techniques; Titrations; Transferase; Uridine Diphosphate; Variant; Ventilator; Ventilatory Depression; Weight; Work; base; cohort; cost effective; design; experience; group intervention; improved; information gathering; models and simulation; mortality; patient safety; pharmacodynamic model; pharmacokinetic model; predictive modeling; receptor; response; sedative

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.

人们越来越认识到需要优化的儿童镇静策略 气管插管并机械通风的呼吸衰竭。父母R01“镇静 小儿急性呼吸衰竭患者的管理“解决这一需求的目的 研究由护士实施目标指导的舒适算法对机械持续时间的影响 通风。正如赠款提案中所述，该算法的实施将影响许多 影响机械通气持续时间的因素，例如觉醒水平，强制性滴定 以及总剂量的鸦片和苯二氮卓类药物。但是，在每个组中（干预，控制）和 在整个队列中，将观察到机械通气持续时间的变化。虽然这个 可变性可能与施用药物的总剂量相关，该药物的能力估算实际药物的能力 暴露（药代动力学）可能可以更好地了解响应中的可变性 （药效学）。此外，在类似药物暴露时的反应变化可能是由 药物遗传学在受体水平上的药物作用差异。因此，我们的假设是 咪达唑仑和吗啡药物的暴露和反应将受到非可遗物的影响（例如器官 功能障碍，疾病程度，年龄，体重）和可遗传（例如药物代谢的多态性 系统或药物受体）可以定义的因素。我们的长期研究目标是 改善呼吸衰竭儿童的结果，需要通过优化机械通气 在他们护理中使用的镇静策略。此辅助R01应用程序的目标，该应用程序 是朝着这个长期目标迈出的下一步，是1）确定可遗传和非可遗物的因素 基于对吗啡和咪达唑仑的药物暴露响应的变异性的基础 气管插管并在重症监护环境中进行机械通风，2）开发和验证 人群药代动力学（PK） - 症状动力学（PD）模型，可预测 麻醉/镇静剂量范围需求，可提供适当的治疗，但最大程度地减少呼吸机天数 对于在重症监护环境中进行气管插管和机械通风的儿童。这 模型最终可用于在需要机械通气的儿童中个性化治疗 优化镇静的目标，同时最大程度地减少通风持续时间。