Mild Hypothermia Alters Propofol Pharmacokinetics and Increases the Duration of Action of Atracurium Kate Leslie, MB, BS, FANZCA*, Daniel I. Sessler, MD*, Andrew R. Bjorksten, PhDt, and Azita Moayeri, BA* *Thermoregulation Research Laboratory, Department of Anesthesia,University of California, San Francisco,California; and tDepartment of Anaesthesia, Royal Melbourne Hospital, Parkville, Victoria, Australia Mild intraoperative hypothermia is common. We there- fore studied the effects of mild hypothermia on propo- fol pharmacokinetics, hepatic blood flow, and atra- curium duration of action in healthy volunteers. Six young volunteers were studied on two randomly as- signeddays, at either 34°Cor 37°C. Anesthesia was in- duced with thiopental, 3 mg/kg, and maintained with 70%N,O and 0.6%isoflurane. Core hypothermia was induced by conductive and convective cooling. On the other study day, normothermia was maintained by a Bair Hugger@(Augustine Medical, Inc., Eden Prairie, MN) forced-air warmer. Propofol, 1 mg/kg lean body mass (LBM), then was given, followed by a 4-h infusion at 5 mg * kg-’ *h-i. After 2 h, atracurium 0.5 mg/kg was administered as an intravenous bolus. Indocya- nine green was administered for estimation of he- patic blood flow. Arterial blood was assayed for propofol and indocyanine green concentration. Phar- macokinetic analysis was performed using NON- MEM. Resultsare reported asmeans? SEM. Propofol blood concentrations averaged -28% more at 34°C than at 37°C (P < 0.05). Hepatic blood flow decreased 23% +- 11% in normothermic volunteers during the propofol infusion, and 33% t 11% in hypothermic volunteers (P = not significant). A three-compart- ment mamillary model fitted the data best. Inclusion of hepatic blood flow change from the prepropofol baselineasa covariate for total body clearance signif- icantly improved the fit. The intercompartmental clearanceswere decreasedin the presenceof hypo- thermia. Core hypothermia prolonged the time to re- covery of the first twitch in the train-of-four to 10%of its control value (Tl = 10%)after atracurium admin- istration by -60% (P < 0.05),from 44 + 4 min to 68 ? 7 min. In contrast, Tl = 25%-75% remained un- changed. We conclude that 3°C of core hypothermia increased propofol blood concentrations and pro- longed atracurium duration of action. Hepatic blood flow was decreasedduring propofol administration, and this change was a significant predictor of propo- fol clearance,indicating that the effect of propofol on hepatic blood flow impairs the clearanceof propofol itself. (Anesth Analg 1995;80:1007-14) A lthough mild intraoperative hypothermia is common (l), the effects of mild hypothermia on anesthetic drug pharmacology are not well known. The volatile anesthetics are well defined, their potency increasing linearly as temperature decreases (=5%/“C) (2). Few studies have investigated the ef- fects of mild hypothermia on intravenous drugs (3-6), and the pharmacokinetics of propofol during mild This study was supported by National Institutes of Health Grants GM39723 and GM49670, Augustine Medical, Inc., and Wellcome Australia Ltd. Presented in part at the Annual Meeting of the American Society of Anesthesiologists, Washington, DC, October 9-12, 1993. Accepted for publication December 22, 1994. Address correspondence to Daniel I. Sessler, MD, Thermoregula- tion Research Laboratory, University of California, San Francisco, CA 94143-0648. hypothermia remain unknown. In normothermic pa- tients, propofol is rapidly and extensively redistrib- uted, and has high clearance (7-9). Presumably, like other drugs with high extraction, propofol clearance is dependent on hepatic blood flow. If hypothermia sig- nificantly decreases hepatic blood flow (10) or alters volumes of distribution or clearance of propofol as it does with other drugs (3-6), higher propofol blood concentrations should result. Mild hypothermia prolongs the duration of action of the muscle relaxants d-tubocurarine (-32°C) (11) and vecuronium (34.5”C) (12). Atracurium has not been studied during mild hypothermia, even though its unique metabolism (13) may mean that it is differ- ently affected by hypothermia than either d-tubocura- rine or vecuronium. We therefore studied the effects of mild hypothermia on atracurium duration of action, and on propofol pharmacokinetics and hepatic blood flow, in healthy volunteers. 01995 by the International Anesthesia Research Society 0003-2999/95/$5.00 Anesth Analg 1995;80:1007-14 1007