title: Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury.
abstract: 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.
  
  
  METHODS
  Pharmacokinetic analysis of subjects participating in a multicenter randomized phase III study of therapeutic hypothermia for severe traumatic brain injury.
  
  
  METHODS
  ICU at the Children's Hospital of Pittsburgh.
  
  
  METHODS
  Nineteen children with severe traumatic brain injury.
  
  
  METHODS
  None.
  
  
  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 (Vmax) 4.6-fold (11.6-2.53 mg/hr) and reduced the overall Vmax 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.
authors.affiliation: 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.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Empey
authors.forename: Nieves
authors.initials: N
authors.lastname: Velez de Mendizabal
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bell
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.forename: Kacey B
authors.initials: KB
authors.lastname: Anderson
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: P David
authors.initials: PD
authors.lastname: Adelson
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D001930:Brain Injuries / Q000378:metabolism* / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007036:Hypothermia, Induced / Q000009:adverse effects / Q000379:methods*; D015278:Intensive Care Units, Pediatric; D008297:Male; D010414:Pennsylvania; D010672:Phenytoin / Q000097:blood / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D015599:Trauma Severity Indices
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin
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