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Therapeutic Hypothermia Decreases Phenytoin Elimination in Children with Traumatic Brain Injury*

Empey, Philip E. PharmD, PhD, BCPS1; Velez de Mendizabal, Nieves PhD2; Bell, Michael J. MD3,4; Bies, Robert R. PharmD, PhD2; Anderson, Kacey B. BS5; Kochanek, Patrick M. MD, MCCM3; Adelson, P. David MD6; Poloyac, Samuel M. PharmD, PhD, FCCM5

doi: 10.1097/CCM.0b013e318292316c
Pediatric Critical Care

Objective: Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurologic injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome P450 (CYP)-mediated drug metabolism, and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by cytochrome P450 2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of this study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe traumatic brain injury.

Design: Pharmacokinetic analysis of subjects participating in a multicenter randomized phase III study of therapeutic hypothermia for severe traumatic brain injury.

Setting: ICU at the Children’s Hospital of Pittsburgh.

Patients: Nineteen children with severe traumatic brain injury.

Interventions: None.

Measurements and Main Results: A sum of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia-treated and nine normothermia-treated children who were randomized to 48 hours of cooling to 32–33°C followed by slow rewarming or controlled normothermia. Drug dosing, body temperatures, and demographics were collected during cooling, rewarming, and posttreatment periods (8 d). A trend toward elevated free phenytoin levels in the hypothermia group (p = 0.051) to a median of 2.2 mg/L during rewarming was observed and was not explained by dosing differences. Nonlinear mixed-effects modeling incorporating both free and total levels demonstrated that therapeutic hypothermia specifically decreased the time-variant component of the maximum velocity of phenytoin metabolism (V max) 4.6-fold (11.6–2.53 mg/hr) and reduced the overall V max by ~ 50%. Simulations showed that the increased risk for drug toxicity extends many days beyond the end of the cooling period.

Conclusions: Therapeutic hypothermia significantly reduces phenytoin elimination in children with severe traumatic brain injury leading to increased drug levels for an extended period of time after cooling. Pharmacokinetic interactions between hypothermia and medications should be considered when caring for children receiving this therapy.

Supplemental Digital Content is available in the text.

1Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.

2Division of Clinical Pharmacology, School of Medicine and Indiana Clinical and Translational Sciences Institute, Indiana University, Indianapolis, IN.

3Department of Critical Care Medicine, School of Medicine, and the Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA.

4Department of Neurological Surgery, School of Medicine, and the Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA.

5Department of Pharmaceutical Sciences, Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.

6Division of Neurosurgery/Children's Neuroscience, Department of Child Health, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ.

* See also p. 2454.

Pediatric TBI Consortium Sites and Coinvestigators: USA—Carolinas Medical Center: W. Tsai, D. Bailey, D. Anderson; Children’s Hospital of Philadelphia: S. Friess, N. Thomas; Cincinnati Children’s Hospital: K. Bierbrauer, N. Walz; Cohen’s Children’s Hospital: S. Schneider, R. Pachilkis; Duke University: G. Grant, K. Gustafson; Penn State University: N. Thomas, C. F. Craig; Phoenix Children’s Hospital: S. Buttram, P. D. Adelson, M. Lavoie, J. Blackham; University of California, Davis: J. P. Muizelaar, M. Zwienenberg-Lee, S. Farias; University of Miami: J. Ragheb, B. Levin; University of Pittsburgh: M. Bell, S. Beers, S. Wisniewski; University of Texas, Southwestern – Children’s Hospital of Dallas: P. Okada, P. Stavinoha; University of Washington: R. Ellenbogen; Washington University: J. Pineda, D. White; New Zealand—Starship Children’s Hospital: J. Beca, K. Murrell; Australia—Princess Margaret Hospital: S. Erickson, C. Pestell.

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The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Dr. Empey received grant support from the National Institutes of Health (NIH). Dr. Bell received grant support from NIH. Dr. Bies has received grant support from Indiana CTSI through a gift of Eli Lilly and Company. He has received payment for lectures from NIGMS and has received travel reimbursements from Indiana CTSI, Uppsala University, and NIAID/NIDA. Dr. Poloyac received grant support from NIH and support for travel from the American College of Clinical Pharmacy. Dr. Kochanek received grant support from the Laerdal Foundation and National Institutes of Health and disclosed having United States provisional patents (Method of Inducing EPR Following Cardiopulmonary Arrest and Small Molecule Inhibitors of RNA Binding MOTIF (RBM) Proteins for the Treatment of Acute Cellular Injury) and a CMU Invention Disclosure (Validation of a Multiplex Biomarker Panel for Detection of Abusive Head Trauma in Well-Appearing Children Carnegie Mellon University, Center for Technology Transfer and Enterprise Creation). Dr. Adelson received grant support from NIH, Integra Life Sciences, and Codman and consulted for Tramatec.

Address requests for reprints to: Samuel M. Poloyac, PharmD, PhD, FCCM, 3501 Terrace Street, 807 Salk Hall, Pittsburgh, PA 15261. E-mail:

© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins