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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-B (F1))
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Pemberton, Victoria
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Children's Hospital of Philadelphia
United States
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Zane, Nicole R; Reedy, Michael D; Gastonguay, Marc R et al. (2017) A Population Pharmacokinetic Analysis to Study the Effect of Therapeutic Hypothermia on Vancomycin Disposition in Children Resuscitated From Cardiac Arrest. Pediatr Crit Care Med 18:e290-e297
Moorthy, Ganesh S; Jogiraju, Harini; Vedar, Christina et al. (2017) Development and validation of a sensitive assay for analysis of midazolam, free and conjugated 1-hydroxymidazolam and 4-hydroxymidazolam in pediatric plasma: Application to Pediatric Pharmacokinetic Study. J Chromatogr B Analyt Technol Biomed Life Sci 1067:1-9
Topjian, Alexis A; French, Benjamin; Sutton, Robert M et al. (2014) Early postresuscitation hypotension is associated with increased mortality following pediatric cardiac arrest. Crit Care Med 42:1518-23