Perioperative Shivering

Received from the Department of Anesthesia and Intensive Care, OLV Hospital, Aalst, Belgium; and the Outcomes Research™ Institute and Department of Anesthesiology, University of Louisville, Louisville, Kentucky.IN homeothermic species, a thermoregulatory system coordinates defenses against cold and heat to maintain internal body temperature within a narrow range, thus optimizing normal physiologic and metabolic function. The combination of anesthetic-induced thermoregulatory impairment and exposure to a cool environment makes most unwarmed surgical patients hypothermic. 1–7Although shivering is but one consequence of perioperative hypothermia, and rarely the most serious, it occurs frequently (i.e. , 40–60% after volatile anesthetics), 8,9and it remains poorly understood. While cold-induced thermoregulatory shivering remains an obvious etiology, the phenomenon has also been attributed to numerous other causes.Our first goal is to review the organization of the thermoregulatory system, and particularly the physiology of postanesthetic shivering. We then discuss the pharmacology of thermoregulation and review the putative mechanisms and sites of action of various antishivering drugs.Historically, the lateral spinothalamic tract was considered the sole thermoafferent pathway, projecting to the hypothalamic thermoregulatory centers. 10However, evidence suggests that the majority of these ascending pathways terminate in the reticular formation 11,12and that thermosensitive neurons exist at several regions outside the preoptic-anterior hypothalamus, including the ventromedial hypothalamus, 13the midbrain, 14–17the medulla oblongata, 18,19and the spinal cord. 20,21Multiple inputs from various thermosensitive sites are integrated at numerous levels within the spinal cord and brain to provide a coordinated pattern of defense responses. 22,23The temperature-regulating system of mammals is often divided into three components: thermosensors and afferent neural pathways, integration of thermal inputs, and effector pathways for autonomic and behavioral regulation. The major afferent thermoregulatory structures and the efferent shivering pathway are depicted in figure 1.The thermosensitivity of the spinal cord and its thermoregulatory significance is beyond doubt 24–29and has been reviewed comprehensively. 20Its ability to sense and modulate thermal signals was pivotal for development of the currently accepted multiple-input, multilevel concept of thermoregulation. 22In fact, all thermoregulatory effector mechanisms are modulated by spinal cord temperature. In intact 30and chronically spinalized 31dogs and rabbits, 32selective cooling of the spinal cord induces cold tremor. In humans, shivering is rare and of low intensity below the level of injury in patients with spinal cord transection. 33Thermosensitive sites that are not associated with defined anatomic structures appear to be dispersed in the lower brain stem. 34Experiments in rats suggest that heat gain responses are powerfully regulated by a tonic inhibitory mechanism located in the midbrain and upper pons. 35In the reticular formation ‡of the rat, two anatomically separate groups of neurons are involved in thermal responsiveness and control of thermoregulatory muscle tone and shivering. 14A comparative study in vertebrates also concluded that peripheral thermal input to the hypothalamic areas is via the polysynaptic nonspecific reticular areas in the brainstem. 12The nucleus raphe magnus in the medulla contains a relatively high percentage of serotonergic thermoresponsive neurons, with a preponderance of warm responsive neurons. 18The locus subcoeruleus is a circumscribed area in the pons ventromedially to the locus coeruleus, 36which contains the largest cluster of noradrenergic neurons in the brain. 37The nucleus raphe magnus and the subcoeruleus area appear to be important relay stations in the transmission of thermal information from skin to hypothalamus. 36,38These areas seem to be responsible for the modulation rather than the generation of thermal afferent information. 39–41Most investigators accept that the preoptic region of the anterior hypothalamus is the dominant autonomic thermoregulatory controller in mammals. However, preoptic-anterior hypothalamus neurons also respond to nonthermal information, e.g. , reproductive hormones, 42plasma osmolality, 43–45glucose concentration, 43,46blood pressure, 47noxious stimuli, 48carbon dioxide, 49and emotional stimuli. 50Much of the excitatory input to warm-sensitive neurons in the preoptic-anterior hypothalamus comes from the hippocampus, 51which links the limbic system (emotion, memory, and behavior) to thermoregulatory responses.In addition, the level of activity in preoptic neurons is modulated by arousal state 52and suprachiasmatic nucleus activity, 53which may explain why changes in body temperature are associated with sleep and circadian rhythms. Thus, warm-sensitive neurons in the preoptic-anterior hypothalamus not only sense core temperature but also compare local information with thermal and nonthermal synaptic afferents arriving over ascending pathways. These interactions are inevitable because the thermoregulatory system has few specific effector organs and must be understood as a part of the adaptive responses of the organism as a whole. 54Classic neuronal models of the hypothalamus functionally separate the integrative and effector neurons controlling thermoregulatory responses. 55However, electrophysiologic studies suggest that some anterior hypothalamic neurons act as sensors as well as integrators 56and suggest a link between neuronal firing rate and the range of thermosensitivity. 57The model of Boulant 57identifies different groups of warm-sensitive neurons, distinguished by their spontaneous firing rates. Varying combinations of afferent inputs trigger different groups of warm-sensitive neurons, and effector mechanisms are therefore activated in an orderly fashion (fig. 2).All neuronal models of temperature regulation use the concept of the common central command: multiple inputs are integrated into a common efferent signal to the effector systems. 58In both animals 59and humans, 60effector mechanisms are called on in an orderly fashion, ensuring optimal regulation at minimum cost. The principal defenses against hypothermia in humans include skin vasomotor activity, nonshivering thermogenesis, shivering, and sweating.Heat loss is normally regulated without the major responses of sweating or shivering because cutaneous vasodilation and vasoconstriction usually suffice. 56,61Thermoregulatory vasoconstriction 62decreases cutaneous heat loss 63,64and constrains metabolic heat to the core thermal compartment. 65,66This usually prevents body temperature from decreasing the required additional 1°C required to activate intraoperative shivering. 67–70Normal thermoregulatory shivering is thus a last-resort defense that is activated only when behavioral compensations and maximal arteriovenous shunt vasoconstriction are insufficient to maintain core temperature.Nonshivering thermogenesis is the result of cellular metabolic processes that do not produce mechanical work. Thermoregulatory nonshivering thermogenesis has been demonstrated in the human neonate 71and in rodents, but its existence in adult humans is uncertain, 72as it is not observed in anesthetized adults 73or infants. 74Shivering is an involuntary, oscillatory muscular activity that augments metabolic heat production. Vigorous shivering increases metabolic heat production up to 600% above basal level. 75However, a doubling of metabolic heat production is all that can be sustained over long periods. 76The fundamental tremor frequency on the electromyogram in humans is typically near 200 Hz. This basal frequency is modulated by a slow, 4–8 cycles/min, waxing-and-waning pattern (fig. 3). 77,78Shivering is elicited when the preoptic region of the hypothalamus is cooled. 79Efferent signals mediating shivering descend in the medial forebrain bundle. 80Classically, a central descending shivering pathway was thought to arise from the posterior hypothalamus. 81–85Although the preoptic-anterior hypothalamus is thought to suppress shivering by inhibition of the posterior hypothalamus, 86experimental evidence is lacking. Thermally induced changes in neuronal activity in the mesencephalic reticular formation 87and the dorsolateral pontine and medullary reticular formation 14exert descending influences on the spinal cord that increase muscle tone. 14It remains to be determined whether the reticulospinal neurons receive synaptic input directly from the preoptic-anterior hypothalamus or from the posterior hypothalamus.Spinal α motor neurons and their axons are the final common path for both coordinated movement and shivering. 88A typical cold tremor has a specific rhythm in the form of grouped discharges in the electromyography. 89–91One hypothesis suggests that excitability of motor neurons is inversely proportional to cell size. 92,93During continued cold stimulation of the skin or the spinal cord, motor neurons are recruited in sequence of increasing size, starting with the small γ motor neurons that are followed by the small tonic α motor neurons, and finally, the larger phasic α motor neurons. 92,94,95The larger α motor neurons are more likely to manifest synchronized discharges than smaller ones. 96Synchronization of motor neurons during shivering may be mediated by recurrent inhibition through Renshaw cells, a group of inhibitory interneurons identified in the cat. 97,98Reflex activation of α motor neurons via the γ muscle spindle loop (instability of the stretch reflex feedback system), is another potential but controversial mechanism that could determine the rhythm and frequency of α motor neurons discharges. 99–101Patients report that shivering is remarkably uncomfortable, and some even find the accompanying cold sensation worse than surgical pain. Moreover, shivering per se may aggravate postoperative pain simply by stretching surgical incisions. Shivering also occasionally impedes monitoring techniques, 102,103increases intraocular 104and intracranial 105pressures, and is especially disturbing to mothers during labor and delivery. 106Shivering can double or even triple oxygen consumption and carbon dioxide production, although the increases are typically much smaller. 107,108These large increases in metabolic requirement might predispose to difficulties patients with existing intrapulmonary shunts, fixed cardiac output, or limited respiratory reserve. However, shivering is rare in elderly patients 109–111because age per se impairs normal thermoregulatory control. 112–117Because shivering intensity is markedly reduced in elderly and frail patients, it is unlikely that shivering itself provokes serious adverse outcomes in these patients.Likewise, shivering is rarely associated with clinically important hypoxemia because hypoxia itself inhibits this response. 118,119Morbid cardiac outcomes associated with mild perioperative hypothermia appear to be mediated by a mechanism more subtle than shivering— perhaps the associated marked increase in plasma catecholamine concentrations. 120Shivering is common in hypothermic patients recovering from general anesthesia. 121–123The conventional explanation for postanesthetic tremor is that anesthetic-induced thermoregulatory inhibition abruptly dissipates, thus increasing the shivering threshold toward normal. Discrepancy between the persistent low body temperature and the now, near-normal, threshold activates simple thermoregulatory shivering. Difficulties with this proposed explanation include the observations that tremor frequently is not observed in markedly hypothermic patients 122and that tremor occurs commonly in normothermic patients. 124However, a subsequent study 78suggested that special factors related to surgery (such as stress or pain) might contribute to the genesis of postoperative tremor because it failed to identify any shivering-like activity in normothermic volunteers. Pain might facilitate shivering-like tremor in both postoperative patients 125and in women having spontaneous term labor. 126Any increase in the thermoregulatory set-point (fever) may be associated with normal thermoregulatory shivering in normothermic or even hyperthermic patients. 124,127Surgical stress may increase the thermoregulatory set-point in the postoperative period: even in the absence of clinically evident signs of infection, 25% of postoperative patients reach core temperatures of 38°C, and 50% of them reach 38.4°C. 128Of course, there are many other reasons surgical patients might develop a fever, including infection, atelectasis, and release of pyrogenic substances by injured tissues.Three patterns of muscular activity were observed in hypothermic volunteers during emergence from isoflurane anesthesia. 78The first was a tonic stiffening and appeared to be largely a direct, non–temperature-dependent effect of isoflurane anesthesia. Near 0.3% end-tidal isoflurane concentration, a second pattern was overt: synchronous, tonic waxing and waning. This was by far the most common pattern and resembled that produced by cold-induced shivering in unanesthetized volunteers, or “true” thermoregulatory shivering. 77The third observed pattern was a spontaneous electromyographic clonus that required both hypothermia and residual isoflurane end-tidal concentrations between 0.4 and 0.2% (fig. 4). During epidural anesthesia, synchronous waxing-and-waning patterns were present; however, no abnormal (i.e. , clonic) electromyogram patterns were detected. 129Despite alternative etiologies in some patients, normal thermoregulatory shivering in response to core and skin hypothermia remains by far the most common cause of postoperative shivering. The remainder of this review therefore focuses on normal thermoregulatory shivering.Although it is not possible to focus a thermal stimulus to a single cell, there are thermosensitive units in the hypothalamus that might be considered thermoresponsive. 130These units may be activated by direct thermal stimulation or by other interconnected interneurons responding to thermal stimulation of the skin or distant areas in the central nervous system. Thermoresponsiveness of these units is not constant but varies significantly over time 52,131and depends on the state of vigilance 52,132and cortical activity. 133–135Recent work demonstrated the potential for arousal state to combine with thermal influences to create the appearance that cells are thermosensitive or thermoresponsive when, in fact, they may not be responding directly to temperature. Thus, when electroencephalographic state changes are taken into account, all changes in firing rate of preoptic-anterior hypothalamic cells that appeared to be responsive to changes in skin temperature are associated with electroencephalographic state changes. 136Single-unit responses in the rostral ventromedial medulla, which consists of the nucleus raphe magnus and adjacent brain stem regions, are not specific for temperature manipulations but reflect changes in electroencephalogram–electromyogram activity, which in turn is determined by a variety of factors, including thermal and noxious stimuli. 137Similar results (no thermoresponses observed within a given electroencephalographic state) were obtained for single-unit activity in the subcoeruleus area. 138Several classes of substances, including biogenic monoamines, cholinomimetics, cations, endogenous peptides, and possibly N -methyl-d-aspartate (NMDA) receptor antagonists, appear to modulate central thermoregulatory control mechanisms. In this section, we discuss these chemically induced changes in thermosensitivity and modulation of thermosensitivity by drugs used to control postanesthetic shivering. The predominant site of action of the discussed drugs is in most, if not all, instances difficult to establish.Potent antishivering properties have been attributed to numerous drugs. 105,139–154The normal functions of these drugs are diverse. Not discussed further in this review is the use of neuromuscular blocking agents to suppress shivering in hypothermic patients who are mechanically ventilated. 155,156The Monoamine Theory of thermoregulation was born with Feldberg and Myers’ suggestion in 1963 that the balance of norepinephrine and serotonin (5 hydroxytryptamine 5-HT) in the preoptic-anterior hypothalamus controls the body temperature set-point. 157Initially, specific thermoregulatory responses were demonstrated in the cat by direct intracerebroventricular injection of adrenergic and serotonergic neurotransmitters. The monoamines seemed to have opposite effects: 5-HT caused shivering and vasoconstriction and a concomitant increase in core temperature, whereas norepinephrine and epinephrine lowered the normal resting temperature of the cat and attenuated the 5-HT-induced hyperthermia. 158In similar experiments, other species reacted in the opposite way, i.e. , norepinephrine increased and 5-HT decreased body temperature. These interspecies differences have been reviewed in detail by other investigators. 159–161Contradictory results were reported for monoamines in a given species as well, and were attributed to differences in dosage, 162microinjection technique, 163ambient temperature, 164,165and other factors. 166Neurotransmitters modulate the synaptic input on temperature-sensitive neurons and may have profound effects on their firing rates and range of thermosensitivity. The way thermal signals from cold and warm sensors are integrated in the hypothalamus led to speculation that the set-point of the thermoregulatory system could be easily manipulated if the few specific inputs consisted of certain transmitters. 167This turned out to be a considerable oversimplification because thermoregulatory thresholds are determined by multiple modulatory thermal and nonthermal inputs (that are not all monoaminergic) and take place at all levels of hierarchy in the thermoregulatory system. Nevertheless, the balance between the modulatory 5-HT and norepinephrine inputs may be responsible for short- and long-term thermoregulatory adaptive modifications of the shivering threshold. 39,55,168Norepinephrine microdialyzed into the preoptic area of conscious guinea pigs reduces core temperature, a reduction that is abolished by coadministration of the α2-adrenoceptor antagonists yohimbine and rauwolscine. 169The α2-adrenoceptor agonist clonidine evokes dose-dependent reductions in core temperature, whereas α1-, β1-, and β2-adrenoceptor agonists and antagonists do not induce significant changes in core temperature. Elevation of the ambient temperature to 40°C induces a selective increase in the release of norepinephrine perfusates collected with a push-pull cannula from the rostral hypothalamus of the cat, 170whereas decreasing the ambient temperature to 2°C markedly reduces the norepinephrine release from the preoptic-anterior hypothalamic area of the rat. 1715-Hydroxytryptamine may influence both heat production and heat loss pathways. Apart from interspecies differences, 5-HT elicits divergent thermoregulatory responses at different thermosensitive sites within the hypothalamus. Injection of 5-HT into the preoptic area of cats evokes hypothermia accompanied by vasodilation. 172When 5-HT is injected into the rostral hypothalamus of cats, hyperthermia associated with shivering is evoked. 172In rat midbrain slice preparations, the majority of warm-sensitive units and all cold-sensitive units are inhibited by 5-HT. 173In contrast, 5-HT activates the majority of temperature-sensitive units in the medulla oblongata of the rat. 173Opposite modulatory inputs from noradrenergic and serotonergic neurons in the lower brain stem modify the composite skin temperature signal integrated at the level of the hypothalamus, thereby shifting the thresholds and slopes for thermoregulatory responses. 168In different physiologic situations, e.g. , during cold adaptation or during fever, the interthreshold range (temperatures between the sweating and shivering thresholds) widens or narrows. In cold-adapted guinea pigs, for example, serotonergic input dominates and produces a wide interthreshold zone with an average body temperature of 38°C (compared with 39°C when the norepinephrine input dominates). 174Similarly, the interthreshold zone nearly doubles in cold-adapted humans, mainly because the shivering threshold is reduced by approximately 1°C to 35.4°C. 175Despite multiple confounding factors, there is increasing evidence for the involvement of monoaminergic brain systems in adaptive changes in thermoregulation (fig. 5). 55,161Dopamine injected into the hypothalamus of the unanesthetized monkey in the same range of doses as norepinephrine induced hypothermia, but to a lesser degree. 176In single-unit studies, the spontaneous firing rate of cold-sensitive neurons of the cat's hypothalamus decreased when was with increased the firing rate of many warm-sensitive neurons in hypothalamic a was increased in push-pull perfusates within the preoptic-anterior hypothalamic area of the cat. cold shivering thermogenesis is inhibited after intracerebroventricular injection of in the in the system may a in central thermoregulation. pathways also may be involved in central via both as demonstrated in behavioral is some evidence for pathways in the rostral hypothalamus involved in thermoregulation and integration with other monoaminergic thermoregulatory pathways, as reviewed with antishivering a of of and normal body temperature. an antishivering a similar mechanism of it inhibits the of 5-HT different of in significant in human volunteers, a high of only the antishivering effect of are thought to a in the of postoperative shivering by agonists neurons, by increasing through in neuronal is to the range of thermosensitivity. activation of into cells, of on the the cell and the firing rate of heat gain units in the posterior hypothalamus. also with postanesthetic however, the of is rather is an with high for both to other antagonists , via of a central α2-adrenoceptor mechanism in the lower brainstem. receptor antagonists, as are currently for a possible in the and of postanesthetic shivering. are no temperature-regulating mechanisms. effects of the level of the pons may explain their antishivering In the rat locus coeruleus, and its neuronal firing rate and neurons in a locus to be a that activates heat production in locus is also the noradrenergic nucleus involved in the descending system, its activity regulated by modulate responses mediated by in the locus humans, α2-adrenoceptor with yohimbine significantly the effects of and its significantly 5-HT and increase 5-HT in the raphe raphe nucleus is part of the raphe and is considered one of the most important in the modulation of pain in the central nervous system. nucleus raphe magnus is an antishivering that activates heat loss mechanisms and inhibits thermogenesis during cold is the major in the raphe but of the raphe cells that to the spinal cord are not is also a significant of norepinephrine in the nucleus raphe and approximately of nucleus raphe magnus cells inhibitory of the nucleus raphe magnus on shivering is caused by to hypothalamic units and by a second pathway descending from the nucleus raphe magnus to the spinal cord cells are inhibited activation of noradrenergic units in the subcoeruleus region units in an area between the anterior hypothalamus and the posterior hypothalamus, and in the posterior hypothalamus of the subcoeruleus region descend to the pons and medulla and to motor neurons and autonomic cell groups in the spinal cord. as descending inhibition transmission of pain to the of the spinal cord may cutaneous thermal this remains the descending 5-HT from the locus with motor neurons, via cord the of these in the modulation of shivering remains to be anatomic for the antishivering effect of agonists can be at three a small of clonidine reduces the spontaneous firing rate in the locus reduces firing of neurons in the raphe the action of agonists in the locus may also increase activation of in the spinal cord. agonists are to release to norepinephrine and is in high in the spinal cord is involved in and suppress responses of neurons to noxious stimulation in the spinal effects of these at the may modulate cutaneous thermal input additional to noxious and the hypothalamus contains a high of microdialyzed into the hypothalamus, for example, activates reduces metabolic heat production, and produces of the preoptic-anterior hypothalamic area with the selective α2-adrenoceptor agonist yohimbine inhibited the hypothermic response of single-unit studies of the preoptic-anterior hypothalamus in cats, many other species, effect of on thermosensitive neurons remains The or may be because both and induce shivering, and a hyperthermic when injected into the hypothalamus of a conscious drugs have been used to the physiologic of the central system in thermoregulation. However, a of and other the for example, intracerebroventricular of in the shivering and hypothermia, rats hyperthermic when is injected into the hypothalamus. rabbits, injection of shivering. is evidence in that activity in the hypothalamus heat gain during heat or cold of for example, is markedly increased by at the sites within the preoptic-anterior hypothalamic area by peripheral but by at the same sites by peripheral the posterior hypothalamus, cold stress doubles Injection of a large of a into the posterior hypothalamus hypothermia, however, because of a of the receptor system involved in heat production. the brain also may in with monoaminergic and systems. of the and into the mesencephalic nucleus raphe magnus caused significant which was by local with a