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.
Similar content being viewed by others
References
Varon J, Acosta P. Therapeutic hypothermia: past, present, and future. Chest 2008; 133(5): 1267–74
Seder DB, Jarrah S. Therapeutic hypothermia for cardiac arrest: a practical approach. Curr Neurol Neurosci Rep 2008; 8(6): 508–17
Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008; 55(3): 363–89
Nathan HJ, Parlea L, Dupuis JY, et al. Safety of deliberate intraoperative and postoperative hypothermia for patients undergoing coronary artery surgery: a randomized trial. J Thorac Cardiovasc Surg 2004; 127(5): 1270–5
Shiozaki T, Sugimoto H, Taneda M, et al. Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. J Neurosurg 1993; 79(3): 363–8
van Bel F, Groenendaal F. Long-term pharmacologic neuroprotection after birth asphyxia: where do we stand?. Neonatology 2008; 94(3): 203–10
Edwards AD, Yue X, Squier MV, et al. Specific inhibition of apoptosis after cerebral hypoxia-ischaemia by moderate post-insult hypothermia. Biochem Biophys Res Commun 1995; 217(3): 1193–9
Gonzalez FF, Ferriero DM. Therapeutics for neonatal brain injury. Pharmacol Ther 2008; 120(1): 43–53
Groenendaal F, van Bel F. Neuroprotection after perinatal asphyxia: recent advances and future perspectives. In: Mishra OP, editor. Mechanisms of hypoxic brain injury in the newborn and potential strategies for neuroprotection. Trivandrum: Transworld Research Network, 2007: 77–97
Zhu C, Wang X, Xu F, et al. The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia. Cell Death Differ 2005; 12(2): 162–76
Azzopardi D, Brocklehurst P, Edwards D, et al. The TOBY study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr 2008; 8: 17
Globus MY, Alonso O, Dietrich WD, et al. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem 1995; 65(4): 1704–11
Roka A, Melinda KT, Vasarhelyi B, et al. Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy. Pediatrics 2008; 121(4): e844–9
Subramanian S, Agarwal R, Deorari AK, et al. Acute renal failure in neonates. Indian J Pediatr 2008; 75(4): 385–91
Tarcan A, Tiker F, Guvenir H, et al. Hepatic involvement in perinatal asphyxia. J Matern Fetal Neonatal Med 2007; 20(5): 407–10
Bartelink IH, Rademaker CM, Schobben AF, et al. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet 2006; 45(11): 1077–97
Gupta BD, Sharma P, Bagla J, et al. Renal failure in asphyxiated neonates. Indian Pediatr 2005; 42(9): 928–34
Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol 2005; 32(1): 18–24
Nouri S, Mahdhaoui N, Beizig S, et al. Acute renal failure in full term neonates with perinatal asphyxia: prospective study of 87 cases. Arch Pediatr 2008; 15(3): 229–35
Karlsson M, Satas S, Stone J, et al. Liver enzymes cannot be used to predict liver damage after global hypoxia-ischemia in a neonatal pig model. Neonatology 2009; 96(4): 211–8
Stavchansky S, Tung IL. Effect of hypothermia on the intestinal absorption of uracil and L-dopa in the rat. J Pharm Sci 1987; 76(9): 688–91
Shepherd AMM, Emslie-Smith D, Stevenson IH. Antipyrine elimination in patients with hypothermia. Br J Clin Pharmacol 1976; 3(5): 958–9P
Stavchansky S, Tung IL. Effects of hypothermia on drug absorption. Pharm Res 1987; 4(3): 248–50
Filippi L, la Marca G, Fiorini P, et al. Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy. Epilepsia 2009; 50(11): 2355–61
Koren G, Barker C, Bohn D, et al. Influence of hypothermia on the pharmacokinetics of gentamicin and theophylline in piglets. Crit Care Med 1985; 13(10): 844–7
Miller RD, Agoston S, van der Pol F, et al. Hypothermia and the pharmacokinetics and pharmacodynamics of pancuronium in the cat. J Pharmacol Exp Ther 1978; 207(2): 532–8
Ham J, Miller RD, Benet LZ, et al. Pharmacokinetics and pharmacodynamics of d-tubocurarine during hypothermia in the cat. Anesthesiology 1978; 49(5): 324–9
Bansinath M, Turndorf H, Puig MM. Influence of hypo and hyperthermia on disposition of morphine. J Clin Pharmacol 1988; 28(9): 860–4
Tortorici MA, Kochanek PM, Bies RR, et al. Therapeutic hypothermia-induced pharmacokinetic alterations on CYP2E1 chlorzoxazone-mediated metabolism in a cardiac arrest rat model. Crit Care Med 2006; 34(3): 785–91
Schaible DH, Cupit GC, Swedlow DB, et al. High-dose pentobarbital pharmacokinetics in hypothermic brain-injured children. J Pediatr 1982; 100(4): 655–60
Iida Y, Nishi S, Asada A. Effect of mild therapeutic hypothermia on phenytoin pharmacokinetics. Ther Drug Monit 2001; 23(3): 192–7
Heier T, Clough D, Wright PM, et al. The influence of mild hypothermia on the pharmacokinetics and time course of action of neostigmine in anesthetized volunteers. Anesthesiology 2002; 97(1): 90–5
Fukuoka N, Aibiki M, Tsukamoto T, et al. Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia. Resuscitation 2004; 60(2): 225–30
Kadar D, Tang BK, Conn AW. The fate of phenobarbitone in children in hypothermia and at normal body temperature. Can Anaesth Soc J 1982; 29(1): 16–23
Leslie K, Bjorksten AR, Ugoni A, et al. Mild core hypothermia and anesthetic requirement for loss of responsiveness during propofol anesthesia for craniotomy. Anesth Analg 2002; 94(5): 1298–303
Delin NA, Kjartansson KB, Pollock L, et al. Redistribution of regional blood flow in hypothermia. J Thorac Cardiovasc Surg 1965; 49: 511–6
Lazenby WD, Ko W, Zelano JA, et al. Effects of temperature and flow rate on regional blood flow and metabolism during cardiopulmonary bypass. Ann Thorac Surg 1992; 53(6): 957–64
Kondratiev TV, Myhre ES, Simonsen O, et al. Cardiovascular effects of epinephrine during rewarming from hypothermia in an intact animal model. J Appl Physiol 2006; 100(2): 457–64
Chen RY, Chien S. Plasma volume, red cell volume, and thoracic duct lymph flow in hypothermia. Am J Physiol 1977; 233(5): H605–12
Chen RY, Chien S. Hemodynamic functions and blood viscosity in surface hypothermia. Am J Physiol 1978; 235(2): H136–43
D’Amato HE, Hegnauer AH. Blood volume in the hypothermic dog. Am J Physiol 1953; 173(1): 100–2
Lofstrom B. Changes in blood volume in induced hypothermia. Acta Anaesthesiol Scand 1957; 1(1–2): 1–13
Wong KC. Physiology and pharmacology of hypothermia. West J Med 1983; 138(2): 227–32
Groenendaal F, De Vooght KMK, van Bel F. Blood gas values during hypothermia in asphyxiated term neonates. Pediatrics 2009; 123: 170–2
Strichartz GR, Sanchez V, Arthur GR, et al. Fundamental properties of local anesthetics: II. Measured octanol: buffer partition coefficients and pKa values of clinically used drugs. Anesth Analg 1990; 71(2): 158–70
Lönnqvist PA, Herngren L. Plasma protein binding of lidocaine during hypothermic conditions. Perfusion 1993; 8: 221–4
Kalser SC, Kelvington EJ, Randolph MM. Drug metabolism in hypothermia: uptake, metabolism and excretion of S35-sulfanilamide by the isolated, perfused rat liver. J Pharmacol Exp Ther 1968; 159(2): 389–98
Perlovich GL, Volkova TV, Bauer-Brandl A. Thermodynamic study of sublimation, solubility, solvation, and distribution processes of atenolol and pindolol. Mol Pharm 2007; 4(6): 929–35
Kato Y, Hirate J, Sakaguchi K, et al. Enhancement of phenytoin binding to tissues in rats by heat treatment. J Pharm Pharmacol 1989; 41(2): 125–6
McAllister Jr RG, Tan TG. Effect of hypothermia on drug metabolism: in vitro studies with propranolol and verapamil. Pharmacology 1980; 20(2): 95–100
McAllister Jr RG, Tan TG, Todd EP. Effect of hypothermia on the metabolism of propranolol, quinidine, and verapamil [abstract]. Clin Pharmacol Ther 1978; 23(1): 121
Fritz HG, Holzmayr M, Walter B, et al. The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs. Anesth Analg 2005; 100(4): 996–1002
Kalser SC, Kelvington EJ, Kunig R, et al. Drug metabolism in hypothermia: uptake, metabolism and excretion of C14-procaine by the isolated, perfused rat liver. J Pharmacol Exp Ther 1968; 164(2): 396–404
Kalser SC, Kelvington EJ, Randolph MM, et al. Drug metabolism in hypothermia: I. Biliary excretion of C 14-atropine metabolites in the intact and nephrectomized rat. J Pharmacol Exp Ther 1965; 147: 252–9
Kalser SC, Kelvington EJ, Randolph MM, et al. Drug metabolism in hypothermia: II. C 14-atropine uptake, metabolism and excretion by the isolated, perfused rat liver. J Pharmacol Exp Ther 1965; 147: 260–9
Mortensen B, Dale O. Effects of hypothermia on the elimination of ethanol, diazepam and oxazepam in rat liver slice incubations. Acta Anaesthesiol Scand 1995; 39(2): 199–204
Daemen MJ, Thijssen HH, Vervoort-Peters HT, et al. The effect of pento-barbitone anaesthesia and hypothermia on the hepatic clearance of in-docyanine green and S(−)-acenocoumarol in the rat. J Pharm Pharmacol 1986; 38(2): 122–5
Nishida K, Okazaki M, Sakamoto R, et al. Change in pharmacokinetics of model compounds with different elimination processes in rats during hypothermia. Biol Pharm Bull 2007; 30(9): 1763–7
Beaufort TM, Proost JH, Maring J, et al. Effect of hypothermia on the hepatic uptake and biliary excretion of vecuronium in the isolated perfused rat liver. Anesthesiology 2001; 94(2): 270–9
Lundgren-Eriksson L, Carlsson A, Eksborg S, et al. Pharmacokinetics of doxorubicin and epirubicin in mice during chlorpromazine-induced hypothermia. Cancer Chemother Pharmacol 1997; 40(5): 419–24
Satas S, Hoem NO, Melby K, et al. Influence of mild hypothermia after hypoxia-ischemia on the pharmacokinetics of gentamicin in newborn pigs. Biol Neonate 2000; 77(1): 50–7
Leslie K, Sessler DI, Bjorksten AR, et al. Mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium. Anesth Analg 1995; 80(5): 1007–14
Caldwell JE, Heier T, Wright PM, et al. Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium. Anesthesiology 2000; 92(1): 84–93
Kalser SC, Kelly MP, Forbes EB, et al. Drug metabolism in hypothermia: uptake, metabolism and biliary excretion of pentobarbital-2-C 14 by the isolated, perfused rat liver in hypothermia and euthermia. J Pharmacol Exp Ther 1969; 170(1): 145–52
Greven J. The effect of hypothermia on the diuretic action of furosemide in anesthetized rats. Naunyn Schmiedebergs Arch Pharmacol 1973; 280(1): 71–8
Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med 2007; 35(9): 2196–204
Taniguchi H, Pyerin W. Phospholipid bilayer membranes play decisive roles in the cytochrome P-450-dependent monooxygenase system. J Cancer Res Clin Oncol 1988; 114(4): 335–40
Soons PA, De Boer A, Cohen AF, et al. Assessment of hepatic blood flow in healthy subjects by continuous infusion of indocyanine green. Br J Clin Pharmacol 1991; 32(6): 697–704
Withey WR, Chapman BJ, Munday KA. Cause of the reduction in renal blood flow in the hypothermic (27 degrees C) dog. Resuscitation 1974; 3(4): 265–71
Withey WR, Chapman BJ, Munday KA. Distribution of blood flow in the hypothermic (27 degrees C) dog kidney. Clin Sci Mol Med Suppl 1976; 51(6): 583–8
Munday KA, Noble AR. Renin secretion in the hypothermic dog. J Physiol 1970; 206(2): 38–9P
Liu X, Borooah M, Stone S, et al. Serum gentamicin concentrations in en-cephalopathic infants are not affected by therapeutic hypothermia. Pediatrics 2009; 124(1): 310–5
Meijer DK. Current concepts on hepatic transport of drugs. J Hepatol 1987; 4(2): 259–68
Steen H, Merema M, Meijer DK. A multispecific uptake system for taurocholate, cardiac glycosides and cationic drugs in the liver. Biochem Pharmacol 1992; 44(12): 2323–31
Tiribelli C, Lunazzi GC, Sottocasa GL. Biochemical and molecular aspects of the hepatic uptake of organic anions. Biochim Biophys Acta 1990; 1031(3): 261–75
Rademaker CMA, de Vries LS. Pharmacology review: lidocaine for neonatal seizure management. Neoreviews 2008; 9: e585–9
Horrow JC, Bartkowski RR. Pancuronium, unlike other nondepolarizing relaxants, retains potency at hypothermia. Anesthesiology 1983; 58(4): 357–61
Puig MM, Warner W, Tang CK, et al. Effects of temperature on the interaction of morphine with opioid receptors. Br J Anaesth 1987; 59: 1459–64
Riishede L, Nielsen-Kudsk F. Myocardial effects of adrenaline, isoprenaline and dobutamine at hypothermic conditions. Pharmacol Toxicol 1990; 66(5): 354–60
Heier T, Caldwell JE, Sessler DI, et al. Mild intraoperative hypothermia increases duration of action and spontaneous recovery of vecuronium blockade during nitrous oxide-isoflurane anesthesia in humans. Anesthesiology 1991; 74(5): 815–9
Swapna I, SathyaSaikumar KV, Murthy ChR, et al. Alterations in kinetic and thermotropic properties of cerebral membrane-bound acetylcholineesterase during thioacetamide-induced hepatic encephalopathy: correlation with membrane lipid changes. Brain Res 2007; 1153: 188–95
Broadley KJ, Duncan C. The contribution of metabolism to the hypothermia-induced supersensitivity of guinea-pig isolated atria; selective supersensitivity for beta-adrenoceptor agonists and their positive inotropic responses. Gen Pharmacol 1977; 8(5–6): 305–10
Simantov R, Snowman AM, Snyder SH. Temperature and ionic influences on opiate receptor binding. Mol Pharmacol 1976; 12(6): 977–86
Heier T, Caldwell JE, Sharma ML, et al. Mild intraoperative hypothermia does not change the pharmacodynamics (concentration-effect relationship) of vecuronium in humans. Anesth Analg 1994; 78(5): 973–7
Tortorici MA, Mu Y, Kochanek PM, et al. Moderate hypothermia prevents cardiac arrest-mediated suppression of drug metabolism and induction of interleukin-6 in rats. Crit Care Med 2009; 37(1): 263–9
Holley FO, Ponganis KV, Stanski DR. Effect of cardiopulmonary bypass on the pharmacokinetics of drugs. Clin Pharmacokinet 1982; 7(3): 234–51
Mand’ak J, Zivny P, Lonsky V, et al. Changes in metabolism and blood flow in peripheral tissue (skeletal muscle) during cardiac surgery with cardiopulmonary bypass: the biochemical microdialysis study. Perfusion 2004; 19(1): 53–63
Wissing H, Kuhn I, Rietbrock S, et al. Pharmacokinetics of inhaled anaesthetics in a clinical setting: comparison of desflurane, isoflurane and sevoflurane. Br J Anaesth 2000; 84(4): 443–9
Dale O, Brown Jr BR. Clinical pharmacokinetics of the inhalational anaesthetics. Clin Pharmacokinet 1987; 12(3): 145–67
Zhou JX, Liu J. The effect of temperature on solubility of volatile anesthetics in human tissues. Anesth Analg 2001; 93(1): 234–8
Mager DE, Woo S, Jusko WJ. Scaling pharmacodynamics from in vitro and preclinical animal studies to humans. Drug Metab Pharmacokinet 2009; 24(1): 16–24
Mahmood I. Interspecies scaling of renally secreted drugs. Life Sci 1998; 63(26): 2365–71
Gomase VS, Tagore S. Species scaling and extrapolation. Curr Drug Metab 2008; 9(3): 193–8
Goteti K, Brassil PJ, Good SS, et al. Estimation of human drug clearance using multiexponential techniques. J Clin Pharmacol 2008; 48(10): 1226–36
Sui X, Sun J, Wu X, et al. Predicting the volume of distribution of drugs in humans. Curr Drug Metab 2008; 9(6): 574–80
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.2165/11319360-000000000-00000