Anesthesiology 2009; 111:102–9 Copyright © 2009, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Nefopam and Alfentanil Additively Reduce the Shivering Threshold in Humans whereas Nefopam and Clonidine Do Not Pascal Alfonsi, M.D.,* Andrea Passard, M.D.,* Vale´ rie Gaude–Joindreau, R.N.,† Bruno Guignard, M.D.,* Daniel I. Sessler, M.D.,‡ Marcel Chauvin, M.D.§ Background: Induction of therapeutic hypothermia is often stroke severity, infarct size, and mortality,5 and admis- complicated by shivering. Nefopam reduces the shivering sion hypothermia is an independent predictor of good threshold with minimal side effects. Consequently, nefopam is short-term outcome.6 Hypothermia also reduces intracra- an attractive component for induction of therapeutic hypother- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/1/102/248687/0000542-200907000-00022.pdf by guest on 24 September 2021 mia. However, nefopam alone is insufficient; it will thus need to nial pressure, and might improve recovery from cata- be combined with another drug. Clonidine and alfentanil each strophic strokes resulting from middle cerebral artery reduce the shivering threshold. This study, therefore, tested the occlusion.7 And finally, magnetic resonance imaging ex- hypothesis that nefopam, combined either with clonidine or amination suggests a trend for decreased infarct growth alfentanil, synergistically reduces the shivering threshold. 8 Methods: For each combination, ten volunteers were studied in patients treated with moderate hypothermia. on 4 days. Combination 1: (1) control (no drug); (2) nefopam However, thermoregulatory defenses are usually well (100 ng/ml); (3) clonidine (2.5 ␮g/kg); and (4) nefopam plus maintained, even in stroke victims.9 Consequently, it is clonidine (100 ng/ml and 2.5 ␮g/kg, respectively). Combination difficult to induce hypothermia in these patients. Fur- 2: (1) control (no drug); (2) nefopam (100 ng/ml); (3) alfentanil thermore, shivering induces thermal discomfort,10 along (150 ng/ml); and (4) nefopam plus alfentanil (100 ng/ml and 11 150 ng/ml, respectively). Lactated Ringer’s solution (approxi- with sympathetic nervous system activation and con- 12 mately 4°C) was infused to decrease core temperature. Mean sequent tachycardia and hypertension. Routine clinical skin temperature was maintained at 31°C. The core temperature use of therapeutic hypothermia thus depends on the that increased oxygen consumption to more than 25% of base- development of drugs that inhibit cold defenses. Many line identified the shivering threshold. such drugs are already known, but they are all anesthet- Results: With nefopam and clonidine, the shivering thresh- 13,14 15,16 olds were significantly lower than on the control day. The ics or sedatives, and most produce substantial shivering threshold decreased significantly less than would be respiratory toxicity in therapeutic doses. Most stroke patients are not mechanically ventilated or ؍ expected on the basis of the individual effects of each drug (P 0.034). In contrast, the interaction between nefopam and alfen- even maintained in critical care units. Any generally useful tanil on shivering was additive, meaning that the combination reduced the shivering threshold as much as would be expected drug or drug combination will thus have to produce min- by the individual effect of each drug. imal respiratory depression. Combinations of various drugs Conclusions: Nefopam and alfentanil additively reduce the have previously been tested in an effort to achieve thermal shivering threshold, but nefopam and clonidine do not. tolerance without major adverse effects.17,18 When meper- idine and dexmedetomidine are combined, for example, NUMEROUS animal data suggest that mild hypothermia they additively reduce shivering threshold.17 The combina- 1,2 is protective against cerebral ischemia, especially stroke. tion of buspirone and meperidine is even more promising Mild hypothermia improves neurologic outcomes in sur- because it produces a synergistic reduction in shiver- 3,4 vivors of out-of-hospital cardiac arrest. In acute stroke ing.17,18 Meperidine, though, causes both sedation and re- patients, body temperature is associated with initial spiratory depression. Furthermore, its metabolite—normep- eridine—promotes seizures. The search continues for a This article is accompanied by an Editorial View. Talke P: It’s drug or drug combination that defeats shivering without ᭜ hot to be cool. ANESTHESIOLOGY 2009; 111:10–1. excessive sedation, respiratory depression, or hemody- namic instability. Nefopam is a centrally acting analgesic19,20 that is struc- * Attending Anesthesiologist, § Professor and Chair, † Research Nurse, De- turally related to orphenadrine and diphenhydramine.19 partment of Anesthesia, Hoˆpital Ambroise Pare´, Boulogne France; ‡ Professor and Chair, Department of Outcomes Research, The Cleveland Clinic, Cleveland, Nefopam reduces the shivering threshold without having Ohio. any discernable effect on the vasoconstriction or sweating Received from the Department of Anesthesiology, Hoˆpital A-Pare´, Boulogne thresholds.21 In vitro and in vivo studies indicate that France, and Department of Outcomes Research, The Cleveland Clinic, Cleveland, Ohio. Submitted for publication October 17, 2008. Accepted for publication nefopam’s properties are mediated by inhibition of cate- April 6, 2009. Supported by Medical Research Association (REDAR, Boulogne, cholamine reuptake.22 Nefopam also directly interacts with France), Laboratoires Biocodex (Compie`gne, France). The sponsor was not ␣ 22 involved in subject recruitment, data acquisition, or analysis of results. None of 2-adrenoceptors. And finally, nefopam is a noncompet- 23 the investigators has a personal financial interest in this research. itive N-Methyl-D-Aspartate receptor antagonist. Each of Address correspondence to Dr. Alfonsi: Department of Anesthesiology, Hoˆpi- these receptors also mediates thermoregulatory respon- tal Ambroise Pare´, 9 Avenue Charles de Gaulle, Boulogne-Billancourt, 92100, 24 France. [email protected], www.or.org. Information on purchas- ses. Nefopam does not have sedative and hemodynamic ing reprints may be found at www.anesthesiology.org or on the masthead page effects as do ␣ agonists, nor does it cause respiratory at the beginning of this issue. ANESTHESIOLOGY’s articles are made freely accessible 2 25 to all readers, for personal use only, 6 months from the cover date of the issue. depression as do opioids. Anesthesiology, V 111, No 1, Jul 2009 102 NEFOPAM, ALFENTANIL, AND CLONIDINE ON SHIVERING 103 Consequently, nefopam is an attractive component of The study was conducted in a single-blind fashion. The a pharmacologic strategy for induction of therapeutic volunteers were studied on four or six randomly-as- hypothermia. The difficulty is that nefopam alone is signed days, each separated by at least 48 h: (1) control, insufficiently potent because even fairly high doses do no drug; (2) nefopam at a target plasma concentration of not lower the shivering threshold (triggering core temper- 0.1 ␮g/ml (Nefopam); (3) clonidine 2.5 ␮g/kg IV ature) to target core temperatures (usually 33 to 34°C) (Clonidine); (4) clonidine 2.5 ␮g/kg IV and nefopam at a needed for therapeutic hypothermia. From previous data, a target plasma concentration of 0.1 ␮g/ml combination blood concentration of 200 ng · mlϪ1 of nefopam would be (Combi 1); (5) alfentanil at a target plasma concentration necessary to achieve the target temperature in almost all of 0.15 ␮g/ml (Alfentanil); (6) nefopam and alfentanil the patients. That corresponds to the administration of 80 combination at target concentrations of 0.1 ␮g/ml and ␮ to 90 mg of nefopam in adults — a dose that is almost four 0.15 g/ml, respectively (Combi 2). Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/1/102/248687/0000542-200907000-00022.pdf by guest on 24 September 2021 times the usual 20 mg given for postoperative analgesia. An 18-cm-long 4.5-French catheter (Vygon, Ecouen, Even though these doses have been previously adminis- France) was introduced through an antecubital vein. tered without deleterious consequences,26 and even This catheter was used for cold-fluid infusion and blood though they are far from toxic,27–29 they probably are not sampling. A venous catheter was inserted into the other appropriate for routine use. To facilitate induction of ther- arm for drug administration. Throughout the study pe- apeutic hypothermia, nefopam will thus have to be com- riod, mean skin temperature was maintained at 30°C by bined with another drug. adjusting the ambient temperature. Among the drugs known to lower the shivering thresh- Thermal manipulation began 30 min after the study drugs old, most act via catecholaminergic pathways, opiate were started. Lactated Ringer’s solution cooled to 4°C was receptors, or both. Drugs from these therapeutic classes infused at rates sufficient to decrease tympanic membrane are thus obvious candidates for combination with nefo- temperature 1 to 2°C/h. Fluid was given until the shivering ␣ pam. Clonidine is an 2 agonist, and alfentanil is a pure threshold was identified or a total of 70 ml/kg was given. A ␮ agonist. Both lower the shivering threshold.15,30 Be- pediatric forced-air cover connected to a warmer (Warm- fore introducing a new combination into clinical prac- touch, Mallinckrodt, Inc., St. Louis, MO) was rolled up tice, it is thus of considerable interest to consider the around