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Effects of Hypothermia on Pharmacokinetics and Pharmacodynamics

A Systematic Review of Preclinical and Clinical Studies

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Abstract

Examples of clinical applications of therapeutic hypothermia in modern clinical medicine include traumatic cardiac arrest, ischaemic stroke and, more recently, acute perinatal asphyxia in neonates. The exact mechanism of (neuro)protection by hypothermia is unknown. Since most enzymatic processes exhibit temperature dependency, it can be expected that therapeutic hypothermia may cause alterations in both pharmacokinetic and pharmacodynamic parameters, which could result in an increased risk of drug toxicity or therapy failure. Generalizable knowledge about the effect of therapeutic hypothermia on pharmacokinetics and pharmacodynamics could lead to more appropriate dosing and thereby prediction of clinical effects. This article reviews the evidence on the influence of therapeutic hypothermia on individual pharmacokinetic and pharmacodynamic parameters. A literature search was conducted within the PubMed, Embase and Cochrane databases from January 1965 to September 2008, comparing pharmacokinetic and/or pharmacodynamic parameters in hypothermia and normothermia regarding preclinical (animal) and clinical (human) studies. During hypothermia, pharmacokinetic parameters alter, resulting in drug and metabolite accumulation in the plasma for the majority of drugs. Impaired clearance is the most striking effect. Based on impaired clearance, dosages should be decreased considerably, especially for drugs with a low therapeutic index. Hypothetically, high-clearance compounds are affected more than low-clearance compounds because of the additional effect of impaired hepatic blood flow. The volume of distribution also changes, which may lead to therapy failure when it increases and could lead to toxicity when it decreases. The pH-partitioning hypothesis could contribute to the changes in the volumes of distribution for weak bases and acids, depending on their acid dissociation constants and acid-base status. Pharmacodynamic parameters may also alter, depending on the hypothermic regimen, drug target location, pharmacological mechanism and metabolic pathway of inactivation. The pharmacological response changes when target sensitivity alters. Rewarming patients to normothermia can also result in toxicity or therapy failure. The integrated effect of hypothermia on pharmacokinetic and pharmacodynamic properties of individual drugs is unclear. Therefore, therapeutic drug monitoring is currently considered essential for drugs with a low therapeutic index, drugs with active metabolites, high-clearance compounds and drugs that are inactivated by enzymes at the site of effect. Because most of the studies (74%) included in this review contain preclinical data, clinical pharmacokinetic/pharmacodynamic studies are essential for the development of substantiated dose regimens to avoid toxicity and therapy failure in patients treated with hypothermia.

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No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, Division of Laboratory Medicine & Pharmacy, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands

    Marcel P. H. van den Broek PharmD, Antoine C. G. Egberts & Carin M. A. Rademaker

  2. Department of Neonatology, Wilhelmina Children’s Hospital, Utrecht, the Netherlands

    Floris Groenendaal

  3. Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands

    Antoine C. G. Egberts

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  1. Marcel P. H. van den Broek PharmD
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van den Broek, M.P.H., Groenendaal, F., Egberts, A.C.G. et al. Effects of Hypothermia on Pharmacokinetics and Pharmacodynamics. Clin Pharmacokinet 49, 277–294 (2010). https://doi.org/10.2165/11319360-000000000-00000

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