Hypothermia's Impact on Pharmacology (HIP)

• Physiologic manifestations of cardiac arrest and Multiple Organ Dysfunction Syndrome (MODS) in relation to morphine and midazolam [ Time Frame: 2.5 years ] [ Designated as safety issue: No ]
  The objective of this aim is to identify the physiologic manifestations of cardiac arrest and MODS that underlie the variability in morphine and midazolam pharmacokinetics.
  
  

• Impact of genetic factors [ Time Frame: 2.5 years ] [ Designated as safety issue: No ]
  The objective of this aim is to estimate the impact of genetic factors that underlie the variability in morphine and midazolam pharmacokinetics, specifically in the setting of pediatric cardiac arrest. In this aim we will investigate the effect of genotype on pharmacokinetic parameters for morphine and midazolam.
  
  

• Manifestations of hypothermia [ Time Frame: 2.5 years ] [ Designated as safety issue: No ]
  The objective of this aim is to identify the manifestations of hypothermia that underlie the variability in morphine and midazolam pharmacokinetics in children after cardiac arrest. In this aim we will investigate the effect of body temperature on PK parameters for morphine and midazolam.
  
  

Background:

Therapeutic hypothermia is used in the pediatric intensive care unit, and is being studied in the setting of pediatric cardiac arrest. Following cardiac arrest, multiple organ dysfunction syndrome, 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 trial, "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. 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.

Objectives:

The objectives of this ancillary study, Hypothermia's Impact on Pharmacology, are:

1. To identify the physiologic manifestations of cardiac arrest and MODS that underlie the variability in morphine and midazolam pharmacokinetics;
2. To estimate the impact of genetic factors on the variability in morphine and midazolam pharmacokinetics, specifically in the setting of pediatric cardiac arrest and
3. To estimate the impact of hypothermia on the variability in morphine and midazolam pharmacokinetics in children after 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.

Study Design:

Prospective pharmacokinetic study