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.

越来越多的人认识到需要优化儿童的镇静策略， 呼吸衰竭患者需气管插管和机械通气。父R 01“镇静 儿科急性呼吸衰竭患者的管理”解决了这一需求，目的是 研究护士实施的目标导向舒适算法对机械持续时间的影响 通风.正如拨款提案中所描述的那样，该算法的实施将影响许多 影响机械通气持续时间的因素，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，在每个组（干预，对照）和 在整个队列中，将观察机械通气持续时间的变化。虽然这 变异性可能与给药的药物总剂量、估计实际药物剂量的能力 暴露（药代动力学）可更好地了解反应的变异性 （药效学）。此外，在相似的药物暴露下反应的变化可能是由于 药物遗传学驱动的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暴露和反应将受到非遗传性（例如器官） 功能障碍、疾病程度、年龄、体重）和遗传性（例如药物代谢中的多态性 系统或药物受体）因子。我们的长期研究目标是 通过优化呼吸衰竭治疗方案，改善需要机械通气的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）确定遗传和非遗传因素， 这是儿童对吗啡和咪达唑仑的药物依赖反应的变异性的基础， 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，可预测 麻醉/镇静剂量范围要求，提供充分治疗，同时最大限度地减少呼吸机天数 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性化治疗， 在最大限度地减少通气时间的同时优化镇静的目标。