Opioids and Analgesics
Opioids commonly are used for shivering control during therapeutic hypothermia, with meperidine the most well-described agent for this indication. Compared to other opioids, such as morphine, fentanyl and alfentanil, meperidine appears to be a more effective antishivering agent.11,12 Its superiority is suggested partly due to activity at ê-receptors rather than μ-receptors. Additionally, meperidine also may affect NMDA (N-methyl-D-aspartate) receptors, á-receptors, and neurotransmitters including 5-HT (5-hydroxytryptamine) and norepinephrine.13,14 Wrench et al reported a dose effect associated with meperidine for postanesthetic shivering control, where the minimum effective dose was 25 mg.15 Some studies have suggested the need for higher doses of meperidine to lower the shivering threshold to 33.5ºC effectively.11 Meperidine also was shown to have a synergistic effect with skin surface warming in reducing this threshold in healthy volunteers.16 Despite a lack of placebo-controlled randomized studies, meperidine has shown to be effective in shivering control in other comparative trials involving active medications such as buspirone, dexmedetomidine and ondansetron.17-21 The concern with the routine use of meperidine is the toxicity, which may cause central nervous system excitation, among other conditions.

Other pure μ-opioid receptor agonists (e.g., morphine, alfentanil, fentanyl) also have been evaluated, primarily in postanesthetic shivering studies.12,17, 22-24 Results have been mixed on their efficacy for shivering control.12 Overall, higher doses of morphine (loading dose 1 to 4 mg/kg, followed by 0.2 to 0.5 mg/kg/hr), alfentanil (250 μg) and fentanyl (1.7 μg/kg) were necessary for effective shivering control, with lower doses proving to be ineffective. Fentanyl weakly binds to the ê-receptor and may require higher concentrations to achieve this effect.12 As with propofol, an increase in the plasma concentrations was reported with morphine, fentanyl and alfentanil due to a decrease in elimination.25-28 These findings suggest therapeutic hypothermia may result in toxicities if not monitored closely. More pharmacokinetic studies are needed to evaluate the effect of hypothermia on drugs commonly used in the critical care unit.

α-Agonists
Thermoregulation through α-receptors is mediated mainly through centrally distributed á2-receptors. Clonidine is the most widely studied α-agonist for shivering control. Prophylactic use of clonidine (75 μg intravenous) lowered the threshold of vasoconstriction in healthy volunteers.29 Additionally, a linear relationship between increased clonidine dose (3-9 μg/kg) and greater shivering thresholds was reported.30 In a randomized trial, following a single dose of clonidine (0.15 mg intravenous), all 20 patients stopped shivering; 16 responded within five minutes.31 Comparatively, after receiving one dose of meperidine (25 mg intravenous), 18 of 20 patients stopped shivering, and the remaining two patients responded after the second dose. The average onset of action for meperidine and clonidine was 2.7 and 3.1 minutes, respectively. From these data, clonidine appears to be as effective as meperidine for postanesthetic shivering, but the ability of clonidine to cause bradycardia must be monitored, especially since hypothermia induces bradycardia as well. Dexmedetomidine is a newer α-agonist with an affinity to á2- receptors eight times stronger than clonidine. Dexmedetomidine successfully reduced the shivering threshold and vasoconstriction threshold in healthy volunteers.32 In elective surgery patients, dexmedetomidine (1 μg/kg) given at the time of wound closure significantly reduced postanesthesia shivering (compared to patients who received saline [15% vs. 55%, respectively]) and was comparable to meperidine 0.5 mg/kg (10%).18 Additionally, dexmedetomidine (target plasma concentration 0.4 ng/mL), when given in combination with meperidine (target plasma concentration 0.3 μg/mL), appears to offer additive effects in reducing the shivering threshold in healthy volunteers.19 Compared to the control group (no treatment), dexmedetomidine and meperidine significantly lowered the shivering threshold by 0.7ºC and 1.2ºC, respectively. Meperidine plus dexmedetomidine, however, reduced the shivering threshold by 2ºC. This agent deserves further study for its utility in the clinical setting of moderate hypothermia.

5-HT modulators
The thermoregulatory effect of 5-HT is poorly understood since both hypo- and hyperthermia have been reported. Nevertheless, medications affecting 5-HT have been investigated for their role in reducing shivering during hypothermic therapy. At a 60-mg dose, buspirone – a 5-HT1a partial agonist – reduced the shivering threshold by 0.7ºC.21 Additionally, a 30-mg dose combined with low-dose meperidine produced a similar reduction in shivering threshold compared to a large dose of meperidine alone (2.3ºC).21

Also, in the combination group, patients experienced less respiratory depression and sedation than the large-dose meperidine group. These data suggest that buspirone may improve safety when given concurrently with meperidine. Tramadol exerts its analgesic effect through inhibition of norepinephrine and 5-HT reuptake, so it has been studied for postoperative shivering. Studies suggested that tramadol decreased both vasoconstriction and shivering threshold,33 and was comparable to meperidine for postanesthetic shivering control at the 0.5 mg/kg dose.34 In a randomized trial, a higher dose of tramadol (1 mg/kg intravenously) was more effective in shivering control compared to 0.5 mg/kg meperidine.35

Significantly fewer patients experienced shivering at 10 minutes following injection of tramadol. Ondansetron is a 5-HT3 antagonist used for nausea and vomiting. When it was given prophylactically at a dose of 8 mg, 15% of patients experienced postoperative shivering compared to 57% in the saline control group.36 Ondansetron also was compared to meperidine in patients with spinal anesthesia.20 The incidence of shivering was similar in the ondansetron- and meperidine-treated groups (8%) and was significantly lower than in the placebo group (36%). Since ondansetron has no hemodynamic or respiratory effects, more clinical trials are warranted to investigate its antishivering effect for induced hypothermia.

Cholinomimetics
The neurotransmitter acetylcholine has been studied for its thermoregulatory effect. In the early 1970s and 1980s, both hypothermic and hyperthermic effects of acetylcholine were reported in various animal studies.37-40 Scientists believed that the difference in the thermoeffect of acetylcholine likely was due to the activation of different parts of the hypothalamus and different animals.

While the exact mechanism of acetylcholine and thermoregulation has not been delineated, Baird et al demonstrated that direct injection of acetylcholine resulted in decreased shivering through vasodilation in animals.41 Physostigmine, a cholinesterase inhibitor, was studied for postoperative shivering control in humans42; in a comparative trial, Horn et al found that it significantly reduced shivering compared to placebo, and was comparable  to meperidine and clonidine.42 More nausea and vomiting were reported in the physostigmine group, but no significant reduction in heart rate was observed. Considering the limited amount of evidence and the potential side effects, such as seizure and respiratory depression, it is difficult to justify its routine role in the management of therapeutic hypothermia-induced shivering.

NMDA Antagonists
Magnesium sulfate has been investigated as an adjunctive therapy to meperidine-based regimens for shivering control. The proposed mechanism of action in magnesium is its antagonistic action on NMDA receptors. Although the exact mechanism is unknown, inhibition of NMDA receptors is associated with reduced release of norepinephrine and 5-HT, which has a thermoregulatory effect. Magnesium sulfate is an attractive choice for shivering control because hypomagnesemia commonly is observed during induced hypothermia. Additionally, magnesium sulfate has been investigated for its neuroprotective property, which may provide additive benefit in patients with brain injury.43-46 In a study of healthy volunteers, magnesium infusion reduced the shivering threshold by 0.3ºC and led to a significant increase in serum magnesium; however, this reduction was not clinically significant in counteracting the shivering effect of therapeutic hypothermia.47 In another study, magnesium infusion (4 to 6 g intravenous bolus followed by 1-3 g/hr until rewarming) shortened the time to achieve target temperature and improved patient comfort when added to a meperidine-based regimen (50-100 mg).48 Magnesium has also been shown to prevent postoperative shivering.49

Ketamine also has NMDA receptor antagonist properties. Lowdose ketamine (0.5 mg/kg) appeared to be effective in the prevention of shivering following general or regional anesthesia compared to placebo50,51; however, its role in induced hypothermia has not been examined, and caution should be exercised due to its psychomimetic effects such as hallucinations and delirium. In patients with brain injury, ketamine also causes an increase in intracranial pressure and so should be monitored closely.

Miscellaneous Agents
Other medications of interest include neuromuscular blocking agents (NMBA), dantrolene, methylphenidate and doxapram. These agents control the muscular symptoms of shivering, but their use normally is reserved as a last therapeutic option. Hypothermia decreases the clearance of many NMBAs. Studies showed a significant increase in the duration of action of vecuronium, rocuronium and pancuronium, which may result in prolonged paralysis.2, 52-54 Most data concerning other agents, including dantrolene, methylphenidate and doxapram, were generated during the perioperative setting. Due the side effects associated with these medications, their use for therapeutic hypothermia is limited.

References

1.  Bernard SA, Buist M. Induced hypothermia in critical care medicine: a review. Crit Care Med. 2003;31(7):2041.

2.  Aziz L, et al. Effect of hypothermia on the in vitro potencies of neuromuscular blocking agents and on their antagonism by neostigmine. Br J Anaesth.1994;73(5):662.

3.  Ralley FE, et al. The effects of shivering on oxygen consumption and carbon dioxide production in patients rewarming from hypothermic cardiopulmonary bypass. Can J Anaesth. 1988;35(4):332.

4.  Ohlson KB, et al. Thermogenesis inhibition in brown adipocytes is a specific property of volatile anesthetics. Anesthesiology. 2003;98(2):437.

5.  Xiong J, Kurz A, Sessler DI, et al. Isoflurane produces marked and nonlinear decreases in the vasoconstriction and shivering thresholds. Anesthesiology.1996;85(2):240.

6.  Matsukawa T, et al. Propofol linearly reduces the vasoconstriction and shivering thresholds. Anesthesiology. 1995;82(5):1169.

7.  Cheong KF, Chen FG, Yau GH. Postanaesthetic shivering--a comparison of thiopentone and propofol. Ann Acad Med Singapore. 1998;27(5):729.

8.  Cheong KF, Low TC. Propofol and postanaesthetic shivering. Anaesthesia. 1995;50(6):550.

9.  Singh P, et al. A comparison of thiopentone and propofol with respect to the incidence of postoperative shivering. Anaesthesia. 1994;49(11):996.

10.  Leslie K, et al. Mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium. Anesth Analg. 1995;80(5):1007.

11.  Kurz A, et al. Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold. Anesthesiology. 1997;86(5):1046.

12.  Wrench IJ, et al. Comparison between alfentanil, pethidine and placebo in the treatment of post-anaesthetic shivering. Br J Anaesth. 1997;79(4):541.

13.  De Witte J, Sessler DI. Perioperative shivering: physiology and pharmacology. Anesthesiology. 2002;96(2):467-84.

14.  Mahmood MA, Zweifler RM. Progress in shivering control. J Neurol Sci. 2007;261(1-2):47.

15.  Wrench IJ, et al. The minimum effective doses of pethidine and doxapram in the treatment of post-anaesthetic shivering. Anaesthesia. 1997;52(1):32.

16.  Kimberger O, Ali SZ, Markstaller M, et al. Meperidine and skin surface warming additively reduce the shivering threshold: a volunteer study. Crit Care. 2007;11(1):R29.

17.  Alfonsi P, et al. The effects of pethidine, fentanyl and lignocaine on postanaesthetic shivering. Anaesthesia. 1995;50(3):214.

18.  Bicer C, et al. Dexmedetomidine and meperidine prevent postanaesthetic shivering. Eur J Anaesthesiol. 2006;23(2):149.

19.  Doufas AG, et al. Dexmedetomidine and meperidine additively reduce the shivering threshold in humans. Stroke. 2003;34(5):1218.

20.  Kelsaka E, Baris S, Karakaya D, Sarihasan B. Comparison of ondansetron and meperidine for prevention of shivering in patients undergoing spinal anesthesia. Reg Anesth Pain Med. 2006;31(1):40.

21.  Mokhtarani M, et al. Buspirone and meperidine synergistically reduce the shivering threshold. Anesth Analg. 2001;93(5):1233-9.

22.  Lyons B, et al. The treatment of postanaesthetic shivering: a double blind comparison between alfentanil and pethidine. Acta Anaesthesiol Scand. 1995;39(7):979.

23.  Pauca AL, et al. Effect of pethidine, fentanyl and morphine on post-operative shivering in man. Acta Anaesthesiol Scand. 1984;28(2):138.

24.  Rodriguez JL, et al. Morphine and postoperative rewarming in critically ill patients. Circulation. 1983;68(6):1238.

25.  Arpino PA, Greer DM. Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest. Pharmacotherapy. 2008;28(1):102.

26.  Petros A, Dunne N, Mehta R, et al. The pharmacokinetics of alfentanil after normothermic and hypothermic cardiopulmonary bypass. Anesth Analg. 1995;81(3):458.

27.  Statler KD, et al. Moderate hypothermia may be detrimental after traumatic brain injury in fentanyl-anesthetized rats. Crit Care Med. 2003;31(4):1134.

28.  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.

29.  Delaunay L, et al. Clonidine comparably decreases the thermoregulatory thresholds for vasoconstriction and shivering in humans. Anesthesiology. 1993;79(3):470.

30.  Nicolaou G, et al. Clonidine decreases vasoconstriction and shivering thresholds, without affecting the sweating threshold. Can J Anaesth. 1997;44(6):636.

31.  Schwarzkopf KR, et al. A comparison between meperidine, clonidine and urapidil in the treatment of postanesthetic shivering. Anaesth Intensive Care. 2001;92(1):257.

32.  Talke P, et al. Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. Anesthesiology. 1997;87(4):835.

33.  De Witte JL, et al. Tramadol reduces the sweating, vasoconstriction, and shivering thresholds. Anaesth Intensive Care. 1998;87(1):173.

34.  Tsai YC, Chu KS. A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients. Anaesth Intensive Care. 2001;93(5):1288.

35.  Bhatnagar S, et al. Tramadol for postoperative shivering: a double-blind comparison with pethidine. Anaesth Intensive Care. 2001;29(2):149.

36.  Powell RM, Buggy DJ. Ondansetron given before induction of anesthesia reduces shivering after general anesthesia. Anesth Analg. 2000;90(6):1423.

37.  Avery DD. Intrahypothalamic adrenergic and cholinergic injection effects on temperature and ingestive behavior in the rat. Neuropharmacology. 1971;10(6):753.

38.  Beckman AL, Carlisle HJ. Effect of intrahypothalamic infusion of acetylcholine on behavioural and physiological thermoregulation in the rat. Nature. 1969;221(5180):561.

39.  Crawshaw LI. Effect of intracranial acetylcholine injection on thermoregulatory responses in the rat. J Comp Physiol Psychol. 1973;83(1):32.

40.  Myers RD, Yaksh TL. Control of body temperature in the unanaesthetized monkey by cholinergic and aminergic systems in the hypothalamus. J Physiol. 1969;202(2):483.

41.  Baird JA, et al. Thermoregulatory responses to the injection of monoamines, acetylcholine and prostaglandins into a lateral cerebral ventricle of the echidna. J Physiol. 1974;236(3):539.

42.  Horn EP, et al. Physostigmine prevents postanesthetic shivering as does meperidine or clonidine. Anesthesiology. 1998;88(1):108.

43.  Aslanyan S,et al. Magnesium for treatment of acute lacunar stroke syndromes: further analysis of the IMAGES trial. Stroke. 2007;38(4):1269.

44.  Boet R, et al. Intravenous magnesium sulfate to improve outcome after aneurysmal subarachnoid hemorrhage: interim report from a pilot study. Acta neurochir. 2005;95:263.

45.  Chan MT, et al. Magnesium sulfate for brain protection during temporary cerebral artery occlusion. Acta Neurochir. 2005;95:107.

46.  Schmid-Elsaesser R, et al. Intravenous magnesium versus nimodipine in the treatment of patients with aneurysmal subarachnoid hemorrhage: a randomized study. Neurosurgery. 2006;58(6):1054.

47.  Wadhwa A, Sengupta P, Durrani J, et al. Magnesium sulphate only slightly reduces the shivering threshold in humans. Br J Anaesth. 2005;94(6):756.

48.  Zweifler RM, et al. Magnesium sulfate increases the rate of hypothermia via surface cooling and improves comfort. Stroke. 2004;35(10):2331.

49.  Kizilirmak S, et al. Magnesium sulfate stops postanesthetic shivering. Ann N Y Acad of Sci. 1997;813:799.

50.  Dal D, et al. Efficacy of prophylactic ketamine in preventing postoperative shivering. Br J  Anaesth. 2005;95(2):189.

51.  Sagir O, et al. Control of shivering during regional anaesthesia: prophylactic ketamine and granisetron. Acta anaesthesiol Scand. 2007;51(1):44.

52.  Beaufort AM, et al. The influence of hypothermia (surface cooling) on the time-course of action and on the pharmacokinetics of rocuronium in humans. Eur J Anaesthesiol. 1995;11:95.

53.  Caldwell JE, et al. Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium. Anesthesiology 2000;92(1):84-93.

54.  Thomas R, et al. Prospective randomised double-blind comparative study of rocuronium and pancuronium in adult patients scheduled for elective 'fast-track' cardiac surgery involving hypothermic cardiopulmonary bypass. Anaesthesia. 2003;58(3):265.

Disclosures