Postanaesthetic shivering

Address for correspondence: Maria Bermudez Lopez, MD, PhDUniversity Hospital of Lucus AugustiClinic of AnaesthesiaDepartment of Anaesthesiology,Int Care Medicine and Pain MedicineStreet Doctor Ulises Romero no 1,Lugo, SpainE-mail: majobl79@gmail.com

Romanian Journal of Anaesthesia and Intensive Care 2018 Vol 25 No 1, 73-81

REVIEW ARTICLE

Postanaesthetic shivering – from pathophysiology topreventionMaria Bermudez Lopez

Department of Anaesthesiology, Intensive Care Medicine and Pain Medicine, Clinic of Anaesthesia, University Hospital of Lucus Augusti,Lugo, Spain

AbstractPostoperative shivering is a common complication of anaesthesia. Shivering is believed to increase

oxygen consumption, increase the risk of hypoxemia, induce lactic acidosis, and catecholamine release.Therefore, it might increase the postoperative complications especially in high-risk patients. Moreover,shivering is one of the leading causes of discomfort for postsurgical patients.

Shivering is usually triggered by hypothermia. However, it occurs even in normothermic patients duringthe perioperative period. The aetiology of shivering has been understood insufficiently. Another potentialmechanism is pain and acute opioid withdrawal (especially with the use of short-acting narcotics). Besidesthat shivering is poorly understood, the gold standard for the treatment and prevention has not been definedyet. Perioperative hypothermia prevention is the first method to avoid shivering. Many therapeutic strategiesfor treating shivering exist and most are empiric. Unfortunately, the overall quality of the antishiveringguidelines is low. Two main strategies are available: pharmacological and non-pharmacological antishiveringmethods. The combination of forced-air warming devices and intravenous meperidine is the most validatedmethod. We also analysed different medications but final conclusion about the optimal antishivering medicationis difficult to be drawn due to the lack of high-quality evidence.

Nevertheless, control of PS is possible and clinically effective with simple pharmacological interventionscombined with non pharmacological methods.

However, to be consistent with the most up-to-date, evidence-based practice, future antishiveringtreatment protocols should optimize methodological rigor and transparency.

Keywords: postoperative shivering, postanaesthetic complications, hypothermia

Received: 10 March 2018 / Accepted: 30 March 2018 Rom J Anaesth Intensive Care 2018; 25: 73-81

IntroductionPostoperative shivering is a frequent complication

of anaesthesia; it has been reported to range from 20to 70% in general anaesthesia [1]. Shivering is believedto increase oxygen consumption and increase the riskof hypoxemia; it might also increase postoperative com-plications. Shivering is usually triggered by hypother-mia. However, it occurs even in normothermic patients

DOI: http://dx.doi.org/10.21454/rjaic.7518.251.xum

during the perioperative period. The aetiology of shi-vering is not understood sufficiently [2]. In addition tothe fact that shivering is poorly understood, the goldstandard for the treatment and prevention has not beendefined yet. Because of its importance as a postope-rative complication and the lack of evidence aboutaetiology and treatment, this narrative review of thepublished literature on this topic is necessary. Shivering,a syndrome involving involuntary oscillatory contrac-tions of skeletal muscles, is a common and challengingside effect of anaesthesia and targeted temperaturemodulation [3]. Shivering is a physiologic response tocold exposure and the body’s next step in heat preser-vation after peripheral vasoconstriction [4]. Postope-rative shivering (PS) is an involuntary, oscillatorymuscular activity during early recovery after anaes-thesia. Shivering is defined as the fasciculation of theface, jaw, or head or muscle hyperactivity lasting longer

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than 15 seconds [5]. This phenomenon is a commonoccurrence observed in the postanaesthesia care unit.Previous studies have reported an incidence of 5% to65% after general anaesthesia and 30% to 33% afterepidural procedures [6]. The overall shivering incidencein a recent meta-analysis was 34% [4].

Pathophysiology aspectsThe fundamental tremor frequency on the electro-

myogram in humans is typically near 200 Hz. This basalfrequency is modulated by a slow, 4-8 cycles/ min,waxing-and-waning pattern [7, 8]. In 1972 Soliman etal. found two different patterns of shivering: a tonicpattern similar to normal shivering, and a phasic wavepattern similar to a pathologic clone. In 1991, Sessleret al. published that both patterns (tonic and clonic)were thermoregulatory in volunteers [8, 9]. The tonicpattern showed a constant sinusoide form of normalshivering and it seems to be a thermoregulatory answerto the intraoperative hypothermia. By contrast, theclonic pattern is not a normal component of thermo-regulatory shivering and it seems to be specific ofrecovery from volatile anaesthesia. This pattern ofshivering might come from the lost of inhibitionproduced by general anaesthesia in the control of spinalreflexes.

Shivering is elicited when the preoptic region of thehypothalamus is cooled. Efferent signals mediatingshivering descend in the medial forebrain bundle. Spinalalpha motor neurons and their axons are the finalcommon path for both coordinated movement andshivering [10]. A typical cold tremor has a specificrhythm in the form of grouped discharges in theelectromyography. During continued cold stimulationof the skin or the spinal cord, motor neurons are re-cruited in a sequence of increasing size, starting withthe small gamma motor neurons that are followed bythe small tonic alpha motor neurons, and finally, thelarger phasic alpha motor neurons [11, 12].

In other studies with surgical patients, not volunteers,research demonstrated a different incidence of nonthermoregulatory shivering in normothermic postope-rative patients [13]. A tonic stiffening pattern of mus-cular activity was observed as a non-temperature-dependent effect of isoflurane anaesthesia. Anotherobserved pattern was a spontaneous electromyogra-phic clonus that required both hypothermia and residualisoflurane end-tidal concentrations between 0.4 and0.2% [8].

Mathew et al. describe the following shivering scorewhich assesses the severity of shivering. 0: no shiver-ing; 1: mild fasciculations of face and neck and electro-cardiography (ECG) disturbances in the absence ofvoluntary activity of the arms; 2: visible tremor in the

muscle group; 3: gross muscular activity involving theentire body [14].

AetiologyThe combination of anaesthetic-induced thermore-

gulatory impairment and exposure to a cool envi-ronment makes most unwarmed surgical patientshypothermic. Shivering is usually triggered by hypo-thermia. However, it occurs even in normothermicpatients during the perioperative period. The aetiologyof shivering has not been understood sufficiently [1].While cold induced thermoregulatory shivering remainsan obvious aetiology, the phenomenon has also beenattributed to numerous other causes: pain, disinhibitedspine reflexes, decreased sympathetic activity,respiratory alcalosis. The conventional explanation forpostanaesthetic tremor is that anaesthetic inducedthermoregulatory inhibition abruptly dissipates, thusincreasing the shivering threshold towards normal.Discrepancy between the persistent low body tempera-ture and the now, near-normal threshold activatessimple thermoregulatory shivering. Difficulties with thisproposed explanation include the observations thattremor frequently is not observed in markedly hypo-thermic patients and that tremor occurs commonly innormothermic patients [15].

Perioperative hypothermia is defined as a core tem-perature, 33°C to 35°C, while the shivering thresholdin nonanaesthetized patients is 35.5°C. Anaestheticagents increase the heat response thresholds and de-crease the cold response thresholds so that the normalinterthreshold range (hypothalamic set point) isincreased [16]. However, the study of Sessler et al.[8] suggested that special factors related to surgery,stress or pain, might contribute to the genesis of post-operative tremor because they failed to identify anyshivering-like activity in normothermic volunteers. Painmight facilitate shivering in both postoperative patientsand in women having spontaneous term labor. Themechanism of thermoregulation is tightly linked to otherhomeostatic systems, including the control of pain. Painand temperature signals are transmitted along similarfibber systems that synapse in dorsal horn regions.Rostral ventromedial medulla regulates analgesia tonoxious stimuli and has a thermoregulatory responseto peripheral warming and cooling. One of the importantfunctions of the rostral ventromedial medulla is tomodulate the amount of pain and temperature inputascending from the spinal cord by gating the trans-mission of neuronal signals at the level of the dorsalhorns [17]. In general, instead of the commonly heldview of a single thermoregulatory integrator (i.e., thepreoptic area of the hypothalamus) with multiple inputsand outputs, modern concepts include integrators for

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each thermoregulatory response. Furthermore, theseintegrators are distributed among numerous levelswithin the nervous system, with each being facilitatedor inhibited by levels above and below. Therefore,shivering can be divided into two types [18]. The mostcommon type is thermoregulatory shivering, whichcorrelates with cutaneous vasoconstriction in responseto hypothermia [13]. In contrast, approximately 15%of shivering responses is from non-thermoregulatoryshivering, which is associated with cutaneous vaso-dilation and possibly with pain [19].

More recent studies have also reported an increasedincidence of PS after remifentanil administration [20].Remifentanil was associated with an increased inci-dence of postoperative shivering compared with alfen-tanil or fentanyl, but no significant difference was seenwhen compared with sufentanil [2]. In this case themechanisms underlying are considered to include acuteopioid tolerance of short-acting narcotics, which isclosely related to the activation of the N-methyl-D-aspartate (NMDA) receptor. Nakasuji et al. comparedtwo doses of remifentanil and concluded that remifen-tanil-induced PS is not a phenomenon of intraoperativehypothermia. The higher incidence of PS with higherdoses of remifentanil probably reflects acute opioidtolerance and stimulation of N-methyl-D-aspartatereceptors, similar to hyperalgesia [21]. The authordeveloped three mechanisms that may account for PSafter remifentanil administration.

First, remifentanil is eliminated faster than otheropioids. Opioids inhibit thermoregulatory responses;thus shivering does not occur during surgery becausethe threshold of shivering decreases below bodytemperature [22]. The threshold might return to normalimmediately after discontinuance of remifentanil dueto the drug’s kinetics. When the threshold increasesfaster than the increase in body temperature during reco-very from general anaesthesia, shivering is triggered.

The second mechanism is related to pain; in fact,remifentanil at high doses induced PS more frequentlythan at low doses. This result is in accordance withhyperalgesia caused by high doses of remifentanil inprevious studies. In consequence, patients who are ad-ministered high doses of remifentanil are sensitive toshivering after sudden discontinuation [21]. Anothermechanism is that shivering is a sign of opioid with-drawal caused by acute tolerance. Short-acting opioidslike remifentanil could cause opioid tolerance andhyperalgesia, especially when higher doses are admi-nistered continuously. The NMDA receptors arethought to play a major role in the development of acuteopioid tolerance because remifentanil-induced hyper-algesia can be prevented by low doses of ketamine, atypical NMDA antagonist. It was speculated thatremifentanil stimulates the NMDA receptors and

glycine as an additive in the remifentail dose coulddirectly stimulate NMDA receptors and prophylacticketamine was reported to be effective to prevent PS[23]. In addition, magnesium is a non-competitiveNMDA receptor antagonist and intraoperative infusionof magnesium sulphate reduced PS [24]. Regardingshivering post neuroaxial anaesthesia the mechanismmight be different. Both neuraxial (epidural and spinalanaesthesia) and general anaesthesia are associatedwith a significant incidence of shivering, and theincidence is 40%-60% in regional anaesthetic patientsand up to 60% in general anaesthetic ones [25].Shivering differs from general anaesthesia to neuraxialanaesthesia. General anaesthesia could impair thecentral thermoregulation, but spinal anaesthesia affectscentral and peripheral thermoregulation, by enlargingthe interthreshold range via raising the sweatingthreshold and decreasing the vasoconstriction andshivering thresholds. The core temperature decreasewill be in a plateau after 3-4 h in general anaesthesiabut in the neuraxial anaesthesia there is no plateau,because in neuroaxial anaesthesia the vasoconstrictionwill not be evoked when the core temperature triggersthe reset vasoconstriction threshold, in contrast withgeneral anaesthesia. Thus, more heat will be lost, andmore incidences will occur in neuraxial anaesthesia.For instance, the primary mechanism of perioperativehypothermia during caesarean delivery under spinalanaesthesia is because of redistribution of the intravas-cular volume from the core to peripheral compartmentbelow the level of sympathectomy, predisposing thebody to radiant heat loss [26]. Beside this, spinalanaesthesia itself slightly decreases the threshold-fortriggering vasoconstriction and shivering above thelevel of the block. In addition, Doufas and colleaguesreported slight decreases in thresholds during epiduralanaesthesia based on an apparent increase in lowerbody skin temperature [27].

PS has been anecdotally observed to be frequentand severe in cannabis smokers following generalanaesthesia. It has been suggested that cannabis hasanalgesic effects mediated via CB1 receptors in syner-gy with opioid and noradrenergic receptors (alpha-2effects). Moreover, there is a suggestion that pain andtemperature signals are transmitted along similar fibbersystems in the dorsal horn of the spinal cord. Cannabishas been shown to interfere with both thermogenicand nonthermogenic mechanisms of PS [16].

Clinical impactDespite the important function of shivering elevating

the body’s core temperature, it can be associated withimportant adverse effects to both healthy individualsand hospitalized patients, such as those recovering from

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anaesthesia [4]. Patients report that shivering is remar-kably uncomfortable, and some even find the accom-panying cold sensation worse than surgical pain. Inaddition, shivering might stretch surgical incisions and,as a consequence, it may intensify post surgical pain[5]. Besides the obvious discomfort in the recoveryperiod, PS increases oxygen consumption, induce lacticacidosis, carbon dioxide production, and catecholaminerelease, resulting in increased cardiac output, heart rate,and arterial pressure. Shivering also occasionally im-pedes monitoring techniques, increases intraocular andintracranial pressures, and is especially disturbing tomothers during labor and delivery [28]. Vigorousshivering increases metabolic heat production up to600% above basal level. Besides this, PS is believedto increase oxygen consumption by 300% to 400%and increase the risk of hypoxemia [29]. It can lead tocritical ischemia in the postoperative period [2, 15].

Shivering may also be associated with increasedadrenergic and sympathetic hyperactivity and subse-quent organ dysfunction such as myocardial ischemia.In addition, shivering may cause patient discomfort andincrease the likelihood of postoperative complicationssuch as infection, pain, and bleeding [3, 8]. Shiveringmay be associated with delayed wound healing andincreased hospital stay. These increases in metabolicrequirement also might predispose to difficulties patientswith existing intrapulmonary shunts, fixed cardiacoutput, or limited respiratory reserve. However, owingto age impairing of normal thermoregulatory control,shivering is rare in elderly patients [30]. Becauseshivering intensity is reduced in elderly and frail patients,it is unlikely that shivering itself provokes seriousadverse outcomes in these patients [15]. Hence, PSshould be avoided in patients with diminished cardiopul-monary reserve.

Regarding gender, women showed a higher inci-dence of shivering than men [31]. Consequently,suppressing shivering in hospitalized patients is a logicaland important step in increasing comfort and reducingshivering-related complications [4].

TreatmentPS is a very common complication of surgery owing

to postoperative pain and postanaesthesia hypothermiaand is distressing for both patients and clinicians.Hence, effective treatment of PS has become im-perative with increasing awareness of the significantbenefits of maintaining euthermia intra and after anaes-thesia [4]. Many therapeutic strategies for treating shi-vering exist and most are empiric. Unfortunately, theoverall quality of the antishivering guidelines is low.While published analyses have established the efficacyof individual pharmacological and physical treatment

options, few studies of combination antishivering the-rapy exist [3].

In addition, shivering is encountered in diversesettings and with different durations and intensities.Shivering in the postanaesthetic care area can berather brief and justify a different algorithm than thatused in the intensive care unit to treat prolongedshivering in intubated patients with intracranial hyper-tension or after cardiac arrest [3]. In our review wefocus in postoperative shivering. The American Societyof Anesthesiologists (ASA) guideline recommendingforced-air warming devices and meperidine receivedthe highest validation [3]. Consequently, we have twomain strategies: pharmacological and non-pharmacological antishivering methods.

Non-pharmacological therapyNumerous antishivering medications have been

reviewed. However, the adverse effects of medicationslimit their utility in many clinical settings. Pharmacothe-rapy can interfere with clinical impact in recovery afteranaesthesia, hinder neurologic examinations, and mighthave an effect on the hemodynamic and neurologicstate. Therefore, non-pharmacologic antishiveringmethods are commonly used instead of medications.

These methods work by preserving or restoring thebody temperature above the shivering threshold or bymasking the central shivering reflex via warmed skinsensory input [18]. Active cutaneous warming (electricheating, water-circulating garments, forced-air, radiantheating) is effective in the shivering management inthe perioperative and induced hypothermia settings.In contrast, evidence suggests that passive cutaneouswarming (cotton blanket, elastic bandage) and bodycore warming (heated fluid, heated air) are of limitedbenefit at best [18]. Park B et al. found that activecutaneous warming was associated with the highestprevalence of positive outcomes in the clinical settingsof undergoing surgery or induced hypothermia [18].There is agreement between these results and thecurrent American Society of Anesthesiologists TaskForce on Postanesthetic Care guidelines, which re-commend forced-air warming, a common method ofactive cutaneous warming, to reduce shivering in theperioperative setting [32]. The mechanism of activecutaneous warming by increasing body heat content,limiting heat redistribution from the core to peripheryand decreasing radiant heat loss leads to effectivecontrol of thermoregulatory shivering. In addition,surface warming interferes with peripheral input fromcutaneous thermoreceptors, which is responsible forapproximately 20% of the shivering response. Raisingthe theatre temperature could prevent shivering but itis insufficient as well.

Different studies performed in caesarean deliveryhave utilized upper body forced-air warming preope-

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ratively with efficacy. This suggests that the patientneeds to be warmed before sympathetic-mediatedvasodilation and core-periphery redistribution [33, 34].

However, in other studies applying forced-airwarming at the lower extremities, below the level ofsympathetic inhibition, the efficacy was lower [26].Nevertheless, the best area of application (upper orlower) is still undetermined.

The combined application of warmed i.v. fluids andforced-air warming has the potential to minimize coretemperature loss. Forced-air warming warms thepatient from outside in, whereas the warmed i.v. fluidmay prevent a decrease in body temperature in thesetting of redistribution hypothermia [26]. However,heated fluids limit convective heat loss only when largequantities are infused [8], which may explain the limitedeffectiveness of this method. In contrast, number ofstudies have found that warmed i.v. fluid as a singlemodality is effective in minimizing perioperative hypo-thermia [35, 36].

Airway heating with warmed and humidified air canraise nasopharyngeal, oesophageal, and core tempera-tures by reducing heat loss from respiratory evapo-ration of dry gases [37]. However, only 10% of heatloss occurs by evaporation, therefore warmed air haslittle effect on shivering. Despite the fact that there isno clear consensus regarding the best strategy for itsprophylactic and treatment, it has been reported thatPS could be prevented by warming the skin-surfaceand warming the administered fluid [25]. The optimaltiming and duration of an intervention may be an impor-tant factor to maximize the efficacy of nonpharmaco-logical methods. Future studies should address theoptimal timing and duration of application and the extentto which antishivering medications may have additiveor synergistic effects [18].

Pharmacological therapyMany drugs have been shown to be effective on

the prevention and treatment of PS, such as opioids,α2-agonists, anticholinergics, central nervous systemstimulants, corticosteroids. Owing to temperaturemodulation, it is tightly regulated by a complex andmultilevel control loop including the participation ofthermal receptors, spinal cord, brain stem, anteriorhypothalamus and cerebral cortex; the targetedantishivering therapy is complicated and has a widerange of medications.

Highly effective antishivering medication classeswere centrally acting analgesics (tramadol), opioid re-ceptor agonists (meperidine, fentanyl), cholinesteraseinhibitors (physostigmine), and N-methyl-D-aspartatereceptor antagonists (ketamine, magnesium sulfate).Meanwhile, α2-central agonists (clonidine, dexmede-tomidina), and antiserotonergic (ondansetron) and anti-inflammatory drugs (dexamethasone) were relatively

less effective classes. This data support that medi-cations which interfere at different levels of thethermoregulatory loop have more efficacy (opioidagonist, NMDA antagonist) than those with only onefunction (α2-receptor agonist, antiserotonergic agents)or only at the peripheral level (nonsteroidal antiinflam-matory agents) [18].

Park et al. in a recent meta-analysis of all rando-mized, double-blinded, placebo controlled antishiveringmedications trials identified that clonidine, meperidine,tramadol, nefopam (a centrally acting nonopioid anal-gesic) and ketamine were the best performing pharma-cological agents [4].

However, few of them were recommended for theprevention of PS due to various side-effects. Forinstance, clonidine, a partial α2 adrenergic agonist, isrelated to bradycardia, hypotension and sedation.Ondansetron, a 5-TH3 receptor antagonist, is widelyused to prevent postoperative nausea and vomiting.Nevertheless, a systematic review of antishiveringmedication side effects is not possible as most studiesdoes not track side effects in a standardized way [4].

Opioid receptor agonistsMeperidine has a therapeutic effect on PS, and its

mechanism is likely to be associated with the activationof κ and μ-opioid receptor, acting principally on thecentral nervous system. Pethidine is the only opioidthat is an agonist at both the μ and κ receptors closelyrelated to the pathogenesis of shivering by reducingthe shivering threshold and triggering decreased coretemperature, which constitutes its anti-shivering effect.Meperidine is the most common intravenous drug usedfor treating and preventing shivering, as its equi-anal-gesic dose is much more efficient than other opioidssuch as fentanyl, alfentanil, sufentanil or morphine inpreventing shivering. Taking the adverse effects intoconsideration, accumulating studies show that mepe-ridine could increase the incidence of nausea andvomiting and induce respiratory depression [38].

In the systematic quality assessment of publishedantishivering protocols of Choi et al. a variety of indi-vidual and combination treatments were recommended,but skin warming and meperidine use were the mostcommonly cited strategies [3]. Regarding intrathecalvia low dose intrathecal meperidine as an adjuvant forspinal anaesthesia could effectively prevent shiveringand reduce need for rescue analgesics, yet still mightincrease the risk of nausea and vomiting [39]. Chianget al. studied the relationship between PS and freeflap failure owing to postoperative compromise, anddemonstrated that an optimal dose of meperidine couldprevent PS, which is shown to be associated with adecrease in the incidence of the early post-surgicalre-exploration rate of these free flaps related to circu-latory compromise [40].

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Tramadol is a synthetic opioid that acts at multiplesites. It is a weak μ-opioid receptor agonist and hasminimal activity at κ- or σ-receptors. It is also a partialinhibitor of norepinephrine and 5-hydroxytryptamine(5HT). Tramadol also reportedly inhibits the N-methyl-D-aspartic acid (NMDA) receptor at clinically relevantconcentrations. Different studies report its efficacy.Seifi et al. also reported that pethidine 0.5 mg/kg is aseffective as tramadol 1 mg/kg for PS during the first15 min after injection, while tramadol is associated withless side effects [41].

Heid et al. reported that the administration of 2 mg/kg tramadol reduced the incidence and extent of PSafter lumbar disc surgery under remifentanil isofluranegeneral anaesthesia [42]. Mohta et al. also reportedthat tramadol 2 mg/kg provided an effective combinationof anti-PS activity and analgesia without excessivesedation [43]. Nakagawa et al. showed that theadministration of tramadol (3 mg/kg) at induction ofanaesthesia significantly reduced the incidence of PSindependently of remifentanil concentration used intra-operatively [44]. Ketamine is a competitive antagonistat the NMDA receptor, suggesting that the anti-shivering effect of tramadol might be mediated by theNMDA receptor [44].

Antiserotonergic agentsOpioid and non-opioid drugs are often used to treat

postoperative shivering, but they have potential sideeffects, including hypotension, hypertension, sedation,respiratory depression, nausea and vomiting. Morerecently, 5-HT3 receptor antagonists have emerged asmeans of preventing postoperative shivering. Accordingto meta-analysis by Zhoy C, 5-HT3 receptor anta-gonists appear to prevent postoperative shivering, witha broadly comparable efficacy to meperidine [45].

The preoptic area of the hypothalamus releases 5-HT3 to activate heat production pathways, and thusincrease body temperature. 5-HT3 antagonists mayprevent postoperative shivering by inhibiting reuptakeof 5-HT in the preoptic area.

5-HT3 antagonists effectively prevent postoperativeshivering after general anaesthesia and spinal anaes-thesia [45].

Ondansetron, a 5-HT3 (serotonin) antagonist, is ge-nerally used as an antiemetic but its efficiency andsafety in the prevention of PS remains controversial.Serotonin system plays an important role in thethermoregulation. The mechanisms of ondansetron onPS may be related to a central mechanism of the inhi-bition of 5-HT reuptake on the preoptic anterior hypo-thalamic region. Both 4 mg and 8 mg of ondansetronat the end of surgery could reduce the risk of PSsignificantly [46]. Ondansetron and meperidine havesimilar effects on the prevention of PS without signi-ficant association of ondansetron with bradycardia. In

contrast, ondansetron was significantly associated witha lower risk of hypotension. According to Li M et al.,meta-analysis treatment with ondansetron is safe, andmay reduce PS. This finding encourages the use ofondansetron to prevent PS [47].

Palonosetron is a new generation of a 5-HT3 anta-gonist which did not influence perioperative hypother-mia or PAS [48].

N-methyl-D-aspartate receptor antagonistKetamine is a noncompetitive NMDA receptor

antagonist and it has a central sympathomimetic effectby inhibition of postganglionic NE uptake. One of itseffects is to decrease core-to-peripheral heat distribu-tion.

Nakasuji et al. demonstrated that low-dose ketamineinfusion (blood concentration around 100 ng/mL) duringsurgery reduces the incidence of postoperativeshivering after remifentanil-based anaesthesia. Theyconcluded that the preventive effect of ketamine onthe development of remifentanil-induced shivering wasthrough a NMDA receptor antagonism during anaes-thesia. Nevertheless, the exact underlying mechanismfor this finding (residual sedative and analgesic effectsafter discontinuation or stimulation of the NMDAreceptors) remains to be determined. Nakasuji et al.consider the stimulation of the NMDA receptors isthe more likely underlying mechanism of remifentanil-induced PS rather than residual sedative and analgesiceffects [49].

Magnesium sulfate is a naturally occurring calciumantagonist and a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors. The drug notonly exerts a central effect but is also a mild musclerelaxant and thus may simultaneously reduce the gainof shivering (incremental shivering intensity withprogressing hypothermia) [24].

Intraoperative infusion of magnesium sulphatereduced PS. Magnesium is an effective treatment forpostoperative shivering. It reduces the shivering thre-shold by only a few tenths of a degree Celsius; however,many postoperative patients have core temperaturesonly slightly below the normal shivering threshold. Forthis reason, magnesium may be sufficient to attenuatepostoperative shivering [24].

Ryu et al. demonstrated that magnesium (bolus 50mg/kg i.v. and 15 mg/kg/h continuous infusion) duringa propofol-remifentanil-based total intravenousanaesthesia reduces postoperative shivering andPONV [50].

α2-receptor agonistAlpha2 adrenergic agonist receptors, which can lead

to reduced sympathetic activity and central regulationof vasoconstrictor tone, are a group of drugs that havebeen used to try to prevent postoperative shivering.According to the Cochrane review, there is evidence

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that clonidine and dexmedetomidine can reduce post-operative shivering, but patients given dexmedetomidinemay be more sedated. However, the quality of thisevidence is very low [51]. The doses, methods andtime of administration have a wide range of possibilities:orally or intravenous, intraoperatively or preoperatively.

The prophylactic administration of intravenousdexmedetomidine reduces the incidence of postanaes-thetic shivering in patients undergoing general anaes-thesia [52].

Liu ZX et al. conclude in their meta-analysis thatdexmedetomidine shows superiority over placebo inthe prevention of postoperative shivering, but not overother anti-shivering agents. The beneficial effect canbe achieved through both intravenous and epiduralinjection [53]. Nevertheless, the time interval betweenthe last administration and the end of surgery shouldbe less than two hours, which is about the half-life ofdexmedetomidine. Regarding to the doses 1 mg/kgbolus is the most commonly used, 0.5 mg/kg i.v. mightbe sufficient for a preventive effect.

Dexmedetomidine suppresses the spontaneousfiring rate of neurons, decreases the central thermosen-sitivity, and finally reduces the vasoconstriction andshivering thresholds. Undesirable effects are sedation,bradycardia, hypotension and a dry mouth.

Nevertheless, due to its relatively high price andpotential side effects, the use of dexmedetomidine isnot recommended solely for the purpose of preventingpostoperative shivering [53].

Other drugsOther drugs aimed at the treatment and prophylactic

of PS have been found. Physostigmine inhibits PASthrough cholinergic system, but it can also cause nauseaand vomiting, increased heart rate and blood pressure.Doxapram, used as a stimulant in respiratory failure,had been proven to be effective on PS, but accompaniedwith a distinct side effect on hemodynamics. Hydro-cortisone (1-2 mgkg-1 i.v.) provides effective prophy-laxis against postoperative shivering in patientsundergoing day care knee arthroscopy under generalanaesthesia [54]. Nefopam, a centrally acting analgesicinhibiting synaptosomal reuptake of severalneurotransmitters: dopamine, NE and serotonin, is oneof the most studied effective antishivering drugs [4].

Prophylactic administration of parecoxib producesdual effects on antishivering and postoperative anal-gesia. This implies that cyclooxygenase 2-prostaglandinE2 pathways may be involved in the regulation of shi-vering [55].

Amino acid (AA) infusion is sometimes selected toavoid hypothermia during general anaesthesia. Aoki Yet al. showed that AA infusions administered in theperioperative period led to a small increase in the patientbody temperature, a decrease in the frequency of shi-

vering, a decrease in the time to extubation, and adecrease in the duration of hospitalization [56].

In summary, a final conclusion about the optimalantishivering medication is difficult to establish.Numerous studies have tested the efficacy of a largevariety of interventions that are thought to preventshivering in normothermic or hypothermic surgicalpatients. The relative efficacy of these interventions,however, remains unclear. Clonidine, meperidine,tramadol and ketamine are the most studied and areefficacious medications. Park SM et al. do notrecommend either the combination of medicationsgiven the paucity of available data (ketamine + mida-zolam or ketamine + naloxone). Beside this, there is awide heterogeneity regarding to doses, via and timingof administration [4].

The potential additive or synergistic effects ofpharmacotherapy and nonpharmacological methodswere studied by Kimberger et al., who found an additiveeffect between active cutaneous warming and i.v.meperidine [57]. It is, therefore, encouraging that somesimple and inexpensive interventions are effective inthe treatment of this adverse effect of anaesthesia andsurgery.

ConclusionPostanaesthetic shivering is a common complication

after anaesthesia which is remarkably uncomfortableto patients and it might lead to severe complicationsdue to the augmentation of oxygen consumption evoked.

Postoperative shivering can be either thermogenic(associated with hypothermia) or nonthermogenic(associated with pain modulation, surgical stress, etc.).

Effective prevention and treatment of shivering hasbecome an essential step in increasing postoperativecomfort and reducing shivering related complications.

Firstly, it is essential to keep the patient normo-thermic with non-pharmacological methods: warmingthe skin-surface and warming the administered fluid.Secondly, many drugs have been shown to be effectivein the prophylaxis of PS. Despite the lack of high-qualityevidence, control of PS is possible and clinicallyeffective with simple pharmacological interventionscombined with non-pharmacological methods.

However, to be consistent with the most up-to-date,evidence-based practice, future antishivering treatmentprotocols should optimize methodological rigor andtransparency.

Conflict of interestNothing to declare

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