Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury.
Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury.
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DOI：
10.1097/ccm.0b013e318292316c
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发表时间：
2013-10
影响因子：
8.8
通讯作者：
Pediatric TBI Consortium: Hypothermia Investigators
中科院分区：
文献类型：
--
作者：
Empey PE;Velez de Mendizabal N;Bell MJ;Bies RR;Anderson KB;Kochanek PM;Adelson PD;Poloyac SM;Pediatric TBI Consortium: Hypothermia Investigators
Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurological 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 CYP2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of the study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe TBI. Pharmacokinetic analysis of subjects participating in a multicenter randomized Phase III study of therapeutic hypothermia for severe TBI. Intensive care unit at the Children’s Hospital of Pittsburgh Nineteen children with severe TBI. None A total of 121 total and 114 free phenytoin levels were evaluated retrospectively in 10 hypothermia- and 9 normothermia-treated children who were randomized to 48h 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 post-treatment periods(8 days). A trend towards 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 to 2.53 mg/h) 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. Therapeutic hypothermia significantly reduces phenytoin elimination in children with severe TBI 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.
