Trial reportCritical care medicine2013
Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury.
Trial report in Critical care medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
22 citing papers in PubMed, 2 syntheses or guidelines pooled it, 57 citations in OpenAlex.
- Hypothermia for traumatic brain injury.The Cochrane database of systematic reviews · 2017Pooled it
- Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.Circulation · 2015Guideline
- Advances and Challenges in Traumatic Brain Injury from a Forensic Perspective.Current neuropharmacology · 2025Review
- Pharmacotherapy variability and precision medicine in neurocritical care.Frontiers in neurology · 2025Review
- Treating Seizures and Improving Newborn Outcomes for Infants with Hypoxic-Ischemic Encephalopathy.Clinics in perinatology · 2024Review
- The influence of temperature on the metabolic activity of CYP2C9, CYP2C19, and CYP3A4 genetic variantsXenobiotica; the fate of foreign compounds in biological systems · 2023Article
- Traumatic Brain Injury: A Forensic Approach: A Literature Review.Current neuropharmacology · 2020Review
- Evaluation of Two Fosphenytoin Loading Dose Regimens and Monitoring in Infants and Neonates Less Than Six Months of Age.The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG · 2020Article
- Phenytoin-induced hypothermia.BMJ case reports · 2019Article
- Therapeutic Hypothermia and Targeted Temperature Management With or Without the "Cold Stress" Response.Therapeutic hypothermia and temperature management · 2017Article
- ABCB1 genotype is associated with fentanyl requirements in critically ill children.Pediatric research · 2017Article
- A "Metamorphosis" in Our Approach to Treatment Is Not Likely to Result From a Meta-Analysis of the Use of Therapeutic Hypothermia in Severe Traumatic Brain Injury.Critical care medicine · 2017Article
- Variability of Post-Cardiac Arrest Care Practices Among Cardiac Arrest Centers: United States and South Korean Dual Network Survey of Emergency Physician Research Principal Investigators.Therapeutic hypothermia and temperature management · 2017Article
- Effect of Hypothermia and Targeted Temperature Management on Drug Disposition and Response Following Cardiac Arrest: A Comprehensive Review of Preclinical and Clinical Investigations.Therapeutic hypothermia and temperature management · 2016Review
- Review
- Combination Therapies for Traumatic Brain Injury: Retrospective Considerations.Journal of neurotrauma · 2016Article
- Effect of administration of neuromuscular blocking agents in children with severe traumatic brain injury on acute complication rates and outcomes: a secondary analysis from a randomized, controlled trial of therapeutic hypothermia.Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies · 2015Article
- Vancomycin pharmacokinetic parameters in patients with acute brain injury undergoing controlled normothermia, therapeutic hypothermia, or pentobarbital infusion.Neurocritical care · 2015Article
- Pediatric head injury: a pain for the emergency physician?Clinical and experimental emergency medicine · 2015Review
- Therapeutic Hypothermia in Children and Adults with Severe Traumatic Brain Injury.Therapeutic hypothermia and temperature management · 2014Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
objectivePreclinical 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.
designPharmacokinetic analysis of subjects participating in a multicenter randomized phase III study of therapeutic hypothermia for severe traumatic brain injury.
settingICU at the Children's Hospital of Pittsburgh. PATIENTS: Nineteen children with severe traumatic brain injury.
interventionsNone. MEASUREMENTS AND MAIN
resultsA 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.
conclusionsTherapeutic 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.
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