POST ANAESTHESIA SHIVERING (PAS): A REVIEW

Transcription

1 88 Indian J. Anaesth. 2003; 47 (2) : INDIAN JOURNAL OF ANAESTHESIA, APRIL REVIEW ARTICLE SUMMARY POST ANAESTHESIA SHIVERING (PAS): A REVIEW Dr. Pradip K. Bhattacharya 1 Dr. Lata Bhattacharya 2 Dr. Rajnish K. Jain 3 Dr. Ramesh C. Agarwal 4 Post Anaesthesia Shivering (PAS) occurs in 40% of patients recovering from general anaesthesia and most of the times is preceded by central hypothermia and peripheral vasoconstriction indicating that it almost is always thermoregulatory mechanism, which even today is ill understood. Some shivering may not be thermoregulatory, thus making the management of PAS complex. The physiology of PAS, organisation of the thermoregulatory mechanism, various measures for prevention and the methods both pharmacological and non pharmacological, of effective managements are reviewed in this article. Introduction In homeothermic species, a thermoregulatory system coordinates defenses against environmental temperature to maintain internal body temperature within a narrow range, thus optimizing normal body function. The combination of anaesthetic induced thermoregulatory impairment and exposure to a cool environment makes most unwarmed surgical patients hypothermic, as Pickering wrote in 1956: The most effective system for cooling a man is to subject him to anaesthesia. Santorio discovered the clinical value of temperature in 1646 but it took two centuries more, before body temperature was recognized by Wunderlich as a key parameter. In anaesthesia its importance was not understood till mid of 1960 s when first case of malignant hyperthermia was observed. Unfortunately, except in some isolated cases temperature monitoring has not yet become a standard practice, nor is the measures instituted to lessen changes in core temperature during the perioperative period. Inadvertent hypothermia is associated with numerous adverse outcomes in the postoperative period. Shivering is an important complication of hypothermia, it is a complicated response of the body that includes at least three different patterns of muscular activity 1 It occurs frequently i.e. 40 to 60 % after volatile anaesthetic, but still it remains poorly understood. Obvious etiology although is said to be cold induced, but some shivering 1. MD., Assistant Prof., Anaesthesia, BMHRC, Bhopal 2. MD., Reader, Anaesthesia, JLN Cancer Hospital, Bhopal 3. MD., Associate Prof. Anaesthesia, BMHRC, Bhopal 4. DA., MD., Professor, Anaesthesia, BMHRC, Bhopal Correspond to : Dr. Rajnish K. Jain Associate Prof. Anaesthesiology & Critical Care, Bhopal Memorial Hospital & Research Centre, Bhopal Tele-Fax: rajnishkjain@hotmail.com like tremors are not thermoregulatory. 2,3 Despite the availability of various drugs and technologies to prevent hypothermia it continues to remain an ongoing problem in the perioperative period. First of all our goal will be to review the organization of the thermoregulatory system, and particularly the physiology of postanaesthetic shivering, followed by discussion considering consequences, preventive and curative measures. Thermoregulation The processing of thermoregulatory response has three components: Afferent thermal sensing, Central regulation and Efferent responses. Together they work to maintain normal core body temperature (Fig-1). Afferent thermal sensing Signals from cold receptors travel along a delta fibres and Signals from warmth receptors are conveyed by C fibres. Thermal inputs get integrated at the level of spinal cord, its ability to sense and modulate thermal signals was pivotal for development of currently accepted multiple multilevel concept of thermoregulation. 4 In fact all thermoregulatory effector mechanisms are modulated by spinal cord, eventually it arrives at the hypothalamus, the primary thermoregulatory control center in mammals.

2 BHATTACHARYA P., BHATTACHARYA L., JAIN R., AGARWAL R. : POST ANAESTHESIA SHIVERING 89 Two anatomically separate groups of neurons are involved in thermal responsiveness and control the thermoregulatory muscle tone and shivering in the reticular formation of rat. 5 A comparative study in vertebrates also concludes that peripheral thermal input to the hypothalamic areas is via the polysynaptic nonspecific reticular areas in the brain stem. The nucleus raphe magnus and the subcoeruleus area of the brainstem are important relay stations in the transmission of thermal information from skin to hypothalamus. Central regulation Preoptic region of the anterior hypothalamus is the dominant autonomic thermoregulatory controller in mammals. Much of the excitatory input to warm sensitive neurons comes from hippocampus, which links the limbic system (emotion, memory, and behavior) to thermoregulatory responses. Warm sensitive neurons in the preoptic anterior hypothalamus along with sensing of core temperature also compare local information with thermal and nonthermal synaptic afferents arriving from ascending pathways. Electrophysiological studies suggest that some anterior hypothalamic neurons act as Sensors as well as integrators. These interactions are inevitable because the thermoregulatory system has few specific effector organs, and must be understood as a part of adaptive response of the organism as a whole 6 (Fig.2 and 3). Efferent responses Multiple inputs are integrated into a common efferent signal to the effector systems. In both animals and humans, 7 effector mechanisms are called upon in an orderly fashion, ensuring optimal regulation. The principle defense against hypothermia in humans includes skin vasomotor activity, nonshivering thermogenesis, shivering and sweating. Heat loss is normally regulated by cutaneous vasodilatation or vasoconstriction, sweating and shivering are major response of the body to heat regulation. 7 Thermoregulatory shivering is thus a last resort defense that is activated only when behavioral compensations and maximal arterio-venous shunt vasoconstriction are insufficient to maintain core temperature. Nonshivering thermogenesis is the result of cellular metabolic process that does not produce mechanical work; it has been demonstrated in human neonate 8 and in rodents. Shivering It is an involuntary, oscillatory muscular activity that augments metabolic heat production upto 600% above basal level. 9 Shivering is elicited when the preoptic region of the hypothalamus is cooled. Efferent shivering pathway arises and descends from the posterior hypothalamus. Increase in muscle tone during shivering is due to temperature-induced changes in neuronal activity in mesencephalic reticular formation and dorsolateral pontine and medullary reticular formation. 5 Synchronization of motor neurons during shivering may be mediated by recurrent inhibition through renshaw cells, a group of inhibitory interneurons identified in cats. 10 Heat balance and shivering The processes that lead to core hypothermia in regional and general anaesthesia are similar. 11 As in general anaesthesia, the initial hypothermia in regional anaesthesia results from redistribution of body heat from the core to the periphery. 12 Patients given spinal or epidural anaesthetics cannot reestablish core temperature equilibrium, because peripheral vasoconstriction remains impaired. Shivering in these patients produces relatively little amount of heat, because it is restricted to the small muscle mass cephalad to the block. Shivering occurs in approximately 40% of unwarmed patients who are recovering from general anaesthesia and in about 50% of patients with a core temperature of 35.5 degree centigrade and in 90% of patients with a core temperature of 34.5 degree centigrade.

3 90 INDIAN JOURNAL OF ANAESTHESIA, APRIL 2003 It is associated with substantial adrenergic activation 13 and discomfort. 14 Some patients find accompanying cold sensation worse than surgical pain. Consequences of shivering Shivering can double or even triple oxygen consumption and carbon dioxide production. Prospective randomized data suggest that high risk patients assigned to only 1.3 degree Celsius core hypothermia were three times more likely to experience adverse myocardial outcomes. 15 Marked increase in plasma catecholamine level is perhaps associated with high-risk cardiac complications. 13 Shivering increases intraocular 16 and intracranial 17 pressures. It is especially disturbing to mothers during labour and delivery. Since shivering intensity is markedly reduced in elderly and frail patients, it is unlikely that shivering itself provokes serious adverse outcomes in these patients. Similarly shivering is rarely associated with clinically important hypoxemia, because hypoxemia itself inhibits this response. 18 Tremor patterns Three patterns of muscular activity were observed in hypothermic volunteers during emergence from isoflurane anaesthesia. 1 The first was a tonic stiffening and appeared to be largely a direct non-temperature dependant effect of isoflurane anaesthesia. A second pattern was overt synchronous tonic waxing and waning at near 0.3% end tidal isoflurane concentration. This was the commonest pattern and resembled that produced by cold induced shivering true thermoregulatory shivering. 19 The third pattern was spontaneous electromyographic clonus that required both hypothermia and residual isoflurane end tidal concentration between 0.4 and 0.2%. During epidural anaesthesia, synchronous waxing and waning patterns were present, however no abnormal EMG patterns were detected. 20 Dissipation of anaesthetic induced thermoregulatory inhibition, with the increase in shivering threshold towards normal is the conventional explanation for the post anaesthetic tremor. Tremor frequency is not observed in markedly hypothermic patients, it occurs commonly in normothermic patients. 2 Contradictory to this, one study 1 suggested that special factors related to surgery such as stress or pain might contribute to the genesis of postoperative tremor, since it failed to identify any shivering- like activity in normothermic volunteers. Pain might facilitate shivering like tremor in both postoperative patients 7 and in women having spontaneous term labour. 3 25% of postoperative patients reach a core temperature of 38 0 C and 50% of them reach C 7 and this eventually leads to an increase in thermoregulatory set point, which may be associated with normal thermoregulatory shivering. Normal thermoregulatory shivering remains by far the most common cause of postoperative shivering. Temperature monitoring Temperature monitoring must be accurate and consistant. Research indicates that during the perioperative period when core temperature rapidly changes, the relationship between the temperatures measured at various body sites may differ considerably. 21 Core temperature is measured in the pulmonary artery, distal esophagus, nasopharynx and tympanic membrane. 22 A recent survey found that infrared tympanic monitoring to be the preferred route of temperature measurement pre and post operatively. Research has indicated that the accuracy of temperature reading is dependent on the operator, patient anatomy, and the instrument. 23 Prevention of post anaesthesia shivering If we restrict ourselves to combat shivering solely with pharmaceuticals, than heat recovery will be still slower and the patient will be deprived of an important defense mechanism against reduction of core temperature, shivering therefore should first of all be prevented, thereby offsetting hypothermia. If it does occur, it should be treated, mainly by warming the patient and than administering medication to inhibit it. The benefits of cutaneous warming in the postoperative patients have been controversial, with some studies identifying benefits 24 and others failing to confirm faster rewarming. 25 Two factors contribute to rapid intraoperative transfer of heat from peripheral tissues to the core, the first is vasodilatation induced by central inhibition of thermoregulatory control 26,27 the second is that general anaesthesia itself induces peripherally mediated vasodilatation, which facilitates intracompartmental heat transfer. Taken together, these studies suggest that intraoperative cutaneous warming is faster than comparable postoperative warming. It seems clear that patients should be warmed during surgery rather than allowed to cool and then rescued postoperatively for prevention of post anaesthesia shivering. Cutaneous heat loss can be decreased by covering the skin (e.g. with surgical drapes, blankets or plastic bags). A single layer of an insulator reduces the heat loss by approximately 30%; unfortunately adding additional layers does not proportionately increase the benefit. 28 In most cases some form of active warming is required to prevent hypothermia. Forced air warming is generally the

4 BHATTACHARYA P., BHATTACHARYA L., JAIN R., AGARWAL R. : POST ANAESTHESIA SHIVERING 91 most effective available method, 29 but any method or combination of methods that maintain the core temperature above 36 0 C is adequate. Forced air warming or a combination of forced air warming along with fluid warming is required to maintain normal intraoperative and postoperative core temperatures. Pharmacotherapy Potent antishivering properties have been attributed to numerous drugs. 7,18,30 These drugs are substances of several classes including biogenic monoamines, cholinomimetics, cations, endogenous peptides and possibly N-methyl-D- aspartate (NMDA) receptor antagonists. All these appear to modulate central thermoregulatory control mechanisms. The normal functions of these drugs are diverse and the predominant site of action of most of these drugs is difficult to establish. 5 HT caused shivering and vasoconstriction and a concomitant rise in core temperature while, nor epinephrine and epinephrine lowered the normal resting temperature in cat and attenuated the 5 HT induced hyperthermia. 31 The balance between the modulatory 5 HT and nor epinephrine inputs may be responsible for short and long term thermoregulatory adaptive modifications of the shivering threshold. 32 Dopamine has also been found to induce hypothermia to a lesser extent in unanaesthetised monkey when injected into hypothalamus. 33 Nefopam an analgesic with powerful antishivering properties 18 is a potent inhibitor of synaptosomal uptake of 5 HT, nor epinephrine and dopamine. Tramadol is an antishivering drug 7 with a similar mechanism of action, it inhibits reuptake of 5 HT, norepinephrine and dopamine and, facilitates 5 HT release. 34 Cerebral a 2 - adrenoceptors are also thought to play a role in the attenuation of postoperative shivering by tramadol. 35 Acetylcholine and nicotine apparently induce vasoconstriction, shivering, and a hyperthermic reaction when injected into the hypothalamus of a conscious monkey, 34 in rabbits, intravenous injection of nicotine stops shivering. 36 Release of acetylcholine is markedly increased by 88% at the active acetylcholine releasing sites within the preoptic anterior hypothalamic area by peripheral cooling but suppressed by 80% at the same perfusion sites by peripheral warming. 37 Microinjection of the cholinoceptor agonists, carbachol and pilocarpine, into the mesencephalic nucleus raphe magnus caused significant hyperthermia which was blocked by local pretreatment with muscarinic receptor antagonist as well as a nicotinic receptor antagonist. 38 Physostigmine a nonselective centrally acting cholinesterase inhibitor is a potent antishivering drug. 7 In a prospective, randomized and double blind study, healthy adult patients who were premedicated with anticholinergic drug had a significant greater incidence of postoperative shivering than those in control group. 39 Activity of preoptic warm-sensitive neurons decreases and cold sensitive neurons increases with local application of thyrotropin releasing hormone thereby producing cold defense response and hyperthermia. 40 In contrast, activity of preoptic anterior warm sensitive neurons increases and cold sensitive neurons decreases with angiotensin II 41 and morphine 42 thereby producing hypothermia. Arginine vasopressin, adrenocorticotrophic hormone and melanocyte stimulating hormone are thought to act as endogenous antipyretics during fever. Pure m agonists including morphine, fentanyl and alfentanyl are better for treatment of postanaesthetic shivering. Alfentanyl is probably effective because increasing plasma concentrations linearly reduces the shivering threshold. 43 Epidurally administered sufentanyl in patient s produces a dose dependant decrease in shivering response and body temperature. 44 Epidural fentanyl also reduces the shivering threshold when added to lignocaine for epidural anaesthesia. 45 Meperidine decreases the shivering threshold almost twice as much as vasoconstriction threshold 46 and is not only an effective treatment for shivering, 47 but clearly more effective than equianalgesic concentrations of pure m receptor agonists. 48 The antishivering activity of meperidine may be partially mediated by k- opiod receptors. The positive ions calcium (Ca 2+ ) and sodium (Na + ) may play a functionally opposing role in mediation of body temperature. Excess of Ca 2+ into the posterior hypothalamus leads to a decrease in body temperature while excess of Na + ions increases body temperature. 49 Magnesium may be considered as physiologic calcium channel blocker. During cold exposure, magnesium concentration in plasma increases and in heat acclimatized volunteer s plasma magnesium decreases. 50 The possible physiological role in cold adaptation may thus explain the effectiveness of magnesium in decreasing the threshold of postanaesthetic shivering. Magnesium sulfate is a physiologically occurring competitive antagonist at NMDA-receptors and was found to stop post-anaesthetic shivering. 7 Ketamine, which is a competitive NMDA-receptor antagonist, also inhibits postanaesthetic shivering. It is likely that

5 92 INDIAN JOURNAL OF ANAESTHESIA, APRIL 2003 NMDA-receptor antagonist modulate thermoregulation at multiple levels, these areas are preoptic anterior hypothalamus and locus coerulus. The NMDA-receptors at dorsal horn of spinal cord modulate ascending nociceptive transmission. Methylphenidate is an analeptic agent that binds presynaptic sites on dopamine, nor epinephrine and 5-HT transport complexes, which in turn blocks reuptake of the respective neurotransmitters 7 and thus is effective for prevention and treatment of postanaesthetic shivering. Conclusion Since shivering is an accompanying part of general and regional anaesthesia and it leads to various consequences and discomfort to the patient, proper steps must be taken for its prevention and treatment. The most effective measures for prevention and treatment are forced air warming and fluid warming. The pharmacological agents for combating it are Nefopam, Tramadol, Physostigmine, Morphine, Fentanyl, and Pethidine etc. As the dictum says, prevention is better than cure, it holds true for shivering also and it should be practiced. The purpose of writing this article is to highlight the fact that there is still a lot to understand about the pathophysiology and management of post anaesthesia shivering, and thus more research is required in this subject. References 1. Sessler DI, Rubinstein EH, Moayeri A. Physiological responses to mild perianesthetic hypothermia in humans, Anesthesiology 1991; 75: Horn E-P, Sessler DI, Standl T, et al. Non-thermoregulatory shivering in patients recovering from isoflurane or desflurane anesthesia, Anesthesiology 1998; 89: Panzer O, Ghazanfari N, Sessler DI, et al. Shivering and shivering-like tremor during labour with and without epidural analgesia, Anesthesiology 1999; 90: Pehl U, Simon E, Schmid HA. Properties of spinal neuronal thermosensitivity in vivo and in vitro, Ann N Y Acad Sci 1997; 813: Asami T, Hori T, kiyohara T, Nakashima T. Convergence of thermal signals on the reticulospinal neurons in the midbrain, pons and medulla oblongata, Brain Res Bull 1988; 20: Hori T, Katafuchi T. Cell biology and the functions of thermosensitive neurons in the brain, Prog Brain Res 1998; 115: De Witte J, Sessler DI. Perioperative shivering: Pathophysiology and Pharmacology, Anesthesiology 2002; 96: Dawkins MJR, Scopes JW. Non-shivering thermogenesis and brown adipose tissue in the human new-born infant, Nature 1965; 206: Giesbrecht GG, Sessler DI, Mekjavic IB, Schroeder M, Bristow GW. Treatment of immersion hypothermia by direct body-tobody contact, J Appl Physiol 1994; 76: Lippold OCJ, Redfearn JWT, Vuco J. The influence of afferent and descending pathways on the rhythmical and arrhythmical components of muscular activity in man and the anaesthetized cat, J. Physiol 1959; 146: Bredahl C, Hindsholm KB, Frandsen PC. Changes in body heat during hip fracture surgery: a comparison of spinal analgesia and general anaesthesia, Acta Anaesthesiol Scand 1991; 35: Matsukawa T, Sessler DI, Christensen R, Ozaki M, Schroeder M. Heat flow and distribution during epidural anesthesia, Anesthesiology 1995; 83: Frank SM, Higgins MS, Breslow MJ, et al. The catecholamine, cortisol, and hemodynamic responses to mild perioperative hypothermia: a randomized clinical trial, Anesthesiology 1995; 82: Kurz A, Sessler DI, Narzt E, et al. Postoperative hemodynamic and thermoregulatory consequences of intraoperative core hypothermia, J Clin Anesth 1995; 7: Frank SM, Fleisher LA, Breslow MJ, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events: A randomized clinical trial. JAMA 1997; 277: Mahajan RP, Grover VK, Sharma SL, Singh H. Intraocular pressure changes during muscular hyperactivity after general anesthesia, Anesthesiology 1987; 66: Rosa G, Pinto G, Orsi P, et al. Control of post anaesthetic shivering with nefopam hydrochloride in mildly hypothermic patients after neurosurgery, Acta Anaesthesiol Scand 1995; 39: Iwashita H, Matsukawa T, Ozaki M, Seller DI, Imamura M, Kumazawa T. Hypoxemia decreases the shivering threshold in rabbits anesthetized with 0.2 MAC isoflurane, Anesth Analg 1998; 87: Israel DJ, Pozos RS. Synchronized slow-amplitude modulations in the electromyograms of shivering muscles, J Apl Physiol 1989; 66: Hynson JM, Sessler DI, Glosten B, McGuire J. Thermal balance and tremor patterns during epidural anesthesia, Anesthesiology 1991; 74: Krenzischek D, Frank S, Kelly S. Forced air warming vs. routine thermal care and core temperature measurement sites, J Post Anesth Nurs, 1995; 10: Sessler DI. Temperature monitoring. In: Miller R.D, editors. Anesthesia. Philadelphia: PA Lippincott, 1990: Weiss M, Sitzer V, Clarke M, et al. A comparison of temperature measurements using three ear thermometers, Appl Nurs Res, 1998; 11: Pathi V, Berg GA, Morrison j, Cramp G, McLaren D, Faichney A. The benefits of active rewarming after cardiac operations:

6 BHATTACHARYA P., BHATTACHARYA L., JAIN R., AGARWAL R. : POST ANAESTHESIA SHIVERING 93 A randomized prospective trial, J Thorac Cardiovasc Surg, 1996; 111: Moor AH, Pickett JA, Woolman PS, Bethune DW, Duthie DJR. Convective warming after hypothermic cardiopulmonary bypass, Br J Anaesth 1994; 73: Matsukawa T, Kurz A, Sessler DI, Bjorksten AR, Merrifield B, Cheng C. Propofol linearly reduces the vasoconstriction and shivering thresholds, Anesthesiology 1995; 82: Xiong J, Kurz A, Sessler DI, et al. Isoflurane produces marked and non-linear decreases in the vasoconstriction and shivering thresholds, Anesthesiology 1996; 85: Sessler DI, Schroeder M. Heat loss in humans covered with cotton hospital blankets, Anesth Analg 1993; 77: Kurz A, Kurz M, Poeschl G, Faryniak B, Redl G, Hackl W. Forced-air warming maintains intraoperative normothermia better than circulating-water mattresses. Anesth Analg 1993; 77: Powell RM, Buggy DJ. Ondansetron given before induction of anesthesia reduces shivering after general anesthesia, Anesth Analg 2000; 90: Feldberg W, Myers RD. Effects on temperature of amines injected into the cerebral ventricles. A new concept of temperature regulation, J Physiol 1964; 173: Zeisberger E, Roth J. Central regulation of adaptive responses to heat and cold. In: Fregly MJ, Blatteis CM, editors. Handbook of Physiology. New York: Oxford University Press, 1996: Myers RD, Yaksh TL. Control of body temperature in the unanesthetized monkey by cholinergic and aminergic systems in the hypothalamus. J Physiol 1969; 202: Driessen B, Reiman W. Interaction of the central analgesic tramadol, with the uptake and release of 5-hydroxyttryptamine in the rat brain in vitro, Br J Pharmacol 1992; 105: Krause T, Tonner PH, Scholz J, Schweers S, Schulte am Esch J. Interaction of tramadol with cerebral alpha2-adrenoceptors. Possible role in attenuation of postoperative shivering, Anesthesiology 1999; 91: A Mott JC. Effects of baroreceptor and chemoreceptor stimulation on shivering, J Physiol (London) 1963; 166: Myers RD, Waller MB. Differential release of acetylcholine from the hypothalamus and mesencephalon of the monkey during thermoregulation, J Physiol 1973; 230: Saxena AK, Tangri KK, Mishra N, Vrat S, Bhargava KP. Presence of cholinoceptors in mesencephalic raphe nuclei concerned in thermoregulation in rabbits, Clin Exp Pharmacol Physiol 1984; 11: Baxendale BR, Mahajan RP, Crossley AW. Anticholinergic premedication influences the incidence of postoperative shivering, Br J Anaesth 1994; 72: Hori T, Yamasaki M, Asami T, Koga H, Kivohara T. Responses of anterior hypothalamic-preoptic thermosensitive neurons to TRH and Cyclo (His-Pro), Neuropharmacology 1988; 27: Kiyohara T, Hori T, Shibata M, Nakashima T. Effects of angiotensin II on preoptic thermosensitive neurones in the rat. In: Hales JRS, editors. Thermal Physiology. New York: Raven Press, 1984; Baldino Jr F, Beckman AL, Adler MW. Actions of iontophoretically applied morphine on hypothalamic thermosensitive units, Brain Res 1980; 196: Lyons B, Carroll M, McDonald NJ. The treatment of postanaesthetic shivering: a double blind comparison between alfentanil and pethidine, Acta Anaesthesiol Scand 1995; 39: Sevarino FB, Johnson MD, Lema MJ, Datta S, Ostheimer GW, Naulty JS. The effect of epidural sufentanil on shivering and body temperature in the parturient, Anesth Analg 1989; 68: Wheelahan JM, Leslie K, Silbert BS. Epidural fentanyl reduces the shivering threshold during epidural lidocaine anesthesia, Anesth Analg 1998; 87: Kurz A, Ikeda T, Sessler DI, et al. Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold. Anesthesiology 1997; 86: Alfonsi P, Sessler DI, Du Manoir B, Levron J-C, le moing J- P, Chauvin M. The effects of meperidine and sufentanil on the shivering threshold in postoperative patients, Anesthesiology 1998; 89; Guffin A, Girard D, Kaplan JA. Shivering following cardiac surgery: hemodynamic changes and reversal, J Cardiothorac Vasc Anesth 1987; 1: Myers RD, Yaksh TL. Thermoregulation around a new set-point established in the monkey by altering the ratio of sodium to calcium ions within the hypothalamus, J Physiol 1971; 218: Stendig-Lindberg G, Moran D, Shapiro Y. How significant is magnesium in thermoregulation? J Basic Clin Physiol Pharmacol 1998; 9: