Effects of hypothermia on drug disposition, metabolism, and response: A focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system
Top Cited Papers
- 1 September 2007
- journal article
- review article
- Published by Ovid Technologies (Wolters Kluwer Health) in Critical Care Medicine
- Vol. 35 (9), 2196-2204
- https://doi.org/10.1097/01.ccm.0000281517.97507.6e
Abstract
Therapeutic hypothermia has been shown to decrease neurologic damage in patients experiencing out-of-hospital cardiac arrest. In addition to being treated with hypothermia, critically ill patients are treated with an extensive pharmacotherapeutic regimen. The effects of hypothermia on drug disposition increase the probability for unanticipated toxicity, which could limit its putative benefit. This review examines the effects of therapeutic hypothermia on the disposition, metabolism, and response of drugs commonly used in the intensive care unit, with a focus on the cytochrome P450 enzyme system. A MEDLINE/PubMed search from 1965 to June 2006 was conducted using the search terms hypothermia, drug metabolism, P450, critical care, cardiac arrest, traumatic brain injury, and pharmacokinetics. Twenty-one studies were included in this review. The effects of therapeutic hypothermia on drug disposition include both the effects during cooling and the effects after rewarming on drug metabolism and response. The studies cited in this review demonstrate that the addition of mild to moderate hypothermia decreases the systemic clearance of cytochrome P450 metabolized drugs between ∼7% and 22% per degree Celsius below 37°C during cooling. The addition of hypothermia decreases the potency and efficacy of certain drugs. This review provides evidence that the therapeutic index of drugs is narrowed during hypothermia. The magnitude of these alterations indicates that intensivists must be aware of these alterations in order to maximize the therapeutic efficacy of this modality. In addition to increased clinical attention, future research efforts are essential to delineate precise dosing guidelines and mechanisms of the effect of hypothermia on drug disposition and response.Keywords
This publication has 52 references indexed in Scilit:
- Moderate hypothermia in neonatal encephalopathy: Efficacy outcomesPediatric Neurology, 2005
- Therapeutic hypothermia after cardiac arrest.: An advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on ResuscitationResuscitation, 2003
- New Research in the Field of Stroke: Therapeutic Hypothermia after Cardiac ArrestStroke, 2003
- Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac ArrestThe New England Journal of Medicine, 2002
- Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced HypothermiaThe New England Journal of Medicine, 2002
- A Phase II Study of Moderate Hypothermia in Severe Brain InjuryJournal of Neurotrauma, 1993
- Cardiovascular Responses to Clamping of the Aorta during Epidural and General AnesthesiaAnesthesia & Analgesia, 1979
- Hepatic clearance of drugs. III. Additional experimental evidence supporting the “wellstirred” model, using metabolite (MEGX) generated from lidocaine under varying hepatic blood flow rates and linear conditions in the perfused rat liverin situ preparationJournal of Pharmacokinetics and Biopharmaceutics, 1977
- Hepatic clearance of drugs. II. Experimental evidence for acceptance of the “well-stirred” model over the “parallel tube” model using lidocaine in the perfused rat liverin situ preparationJournal of Pharmacokinetics and Biopharmaceutics, 1977
- Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearanceJournal of Pharmacokinetics and Biopharmaceutics, 1977