Hypothermia's Impact on Pharmacology

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. 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 study, Hypothermia's Impact on Pharmacology 2, are

1. To estimate the impact of hypothermia on the variability in morphine and midazolam
pharmacokinetics in children after cardiac arrest and

2. To estimate the impact of genetic factors on the variability in morphine and midazolam
pharmacokinetics, specifically in the setting of hypothermia.

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

Inclusion Criteria:

- Be greater than or equal to three (3) kg

- Receiving or have received morphine and/or midazolam as part of clinical care

- Receiving hypothermia after any cardiac arrest

- Provide Informed Consent

Exclusion Criteria:

- Receiving renal replacement therapy [example Continuous Veno-Venous Hemofiltration
(CVVH), Continuous Veno-Venous Hemodialysis (CVVHD), and Continuous Veno-Venous
Hemodiafiltration (CVVHDF)]

- Receiving plasmapheresis