Impact of Hypothermia on Midazolam and Morphine Pharmacokinetics

描述(由申请人提供)：治疗性低温在儿科重症监护病房中的应用越来越频繁，目前正在研究儿科心脏骤停的情况。心脏骤停后，多器官功能障碍综合征(MODS)，尤其是肝肾功能不全是常见的，并影响药物的代谢和排泄。此外，关于体温过低对儿童的 代谢药物。在设置低温时，可能需要调整剂量，以避免药物剂量不足和过量。镇静剂和鸦片类药物的不当剂量和药物积累可能会加剧现有的神经、循环和呼吸衰竭。对体内实际药物和代谢物浓度的测量(药代动力学)提供了有关儿童如何代谢药物的信息。此外，给不同儿童给予相同剂量的药物后，这些浓度的差异可能是药物代谢系统(药物遗传学)遗传驱动的差异造成的。最后，这些基因差异对体温过低的反应可能不同。家长R01“儿童心脏骤停后的治疗性低温”，比较了治疗性常温与低温改善神经系统存活率的疗效，为研究器官衰竭、药物遗传学和低温对新陈代谢、清除和药物处置的影响提供了一个独特的机会。因此，我们的主要假设是，即使考虑了器官功能障碍和遗传差异的潜在混杂可量化因素，吗啡和咪达唑仑的处置也会受到温度管理的影响。此辅助R01应用程序的目标是：1)确定心脏骤停后器官功能障碍对吗啡和咪达唑仑药代动力学的影响；2)确定低温对吗啡和咪达唑仑药代动力学的影响；3)确定药物代谢系统的基因多态性对心脏骤停儿童低温反应的影响。将利用复杂的建模和模拟技术来研究与危重疾病、药物处置、药物遗传学和温度调节相关的高度动态的生理学变化。使用这种方法创建的模型将被实施，以优化这些危重儿童的预期治疗。 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和体温调节，特别是低温对心脏骤停后儿童体内吗啡和咪达唑仑的药代动力学的影响。还将检查其他变量，如疾病程度、年龄、体重和器官功能障碍。这项拟议的工作将促进对低温和药物遗传学之间复杂相互作用的理解，以及它们对危重儿童药物代谢和整体处置的影响。

DESCRIPTION (provided by applicant): Therapeutic hypothermia is being used more frequently in the pediatric intensive care unit, and is being studied in the setting of pediatric cardiac arrest. Following cardiac arrest, multiple organ dysfunction syndrome (MODS), especially renal and hepatic dysfunction, is common and affects the metabolism and excretion of drugs. In addition, very little is known about the impact of hypothermia on a child's ability to metabolize medications. Dose adjustments may be required in the setting of hypothermia to avoid under-dosing and over- dosing of medications. Improper dosing and drug accumulation of sedatives and opiates can worsen existing neurologic, circulatory and respiratory failure. The measurement of the actual drug and metabolite concentrations in the body (pharmacokinetics) provides information on how a child metabolizes medications. In addition, variability in these concentrations after the administration of equal doses to different children may result from genetically driven differences in drug metabolizing systems (pharmacogenetics). Finally, these genetic differences may respond differently to hypothermia. The parent R01, "Therapeutic Hypothermia After Pediatric Cardiac Arrest", comparing the efficacy of therapeutic normothermia vs. hypothermia to improve neurologic survival provides a unique opportunity to study the impact of organ failure, pharmacogenetics and hypothermia on metabolism, clearance and drug disposition. Thus, our overarching hypothesis is that morphine and midazolam disposition will be affected by temperature management even when accounting for potentially confounding quantifiable factors of organ dysfunction and genetic differences. The objectives of this ancillary R01 application, Hypothermia's Impact on Pharmacology (HIP) are to 1) determine the impact of organ dysfunction following cardiac arrest on the pharmacokinetics of morphine and midazolam, 2) identify the impact of hypothermia on the pharmacokinetics of morphine and midazolam and 3) identify the influence of polymorphisms on drug metabolizing systems on the response to hypothermia in children who have experienced cardiac arrest. Sophisticated modeling and simulation techniques will be utilized to examine the highly dynamic changes in physiology associated with critical illness, drug disposition, pharmacogenetics and temperature modulation. The models created using this approach will be implemented to optimize the prospective treatment of these critically ill children. PUBLIC HEALTH RELEVANCE: This project will use sophisticated modeling and simulation techniques to evaluate the impact of genetics and temperature modulation, specifically hypothermia, on the pharmacokinetics of morphine and midazolam in children after cardiac arrest. Additional variables such as degree of illness, age, weight and organ dysfunction on will be examined. This proposed work will advance the understanding of the complex interaction between hypothermia and pharmacogenetics, and their impact on drug metabolism and overall disposition in critically ill children.