Download - Fever During Anesthesia

2Fever during anaesthesia

Chiharu Negishi*

Assistant Professor

Department of Anaesthesia, Tokyo Womens Medical University, 8-1 Kawada-cho, Shinjuku-ku,

Tokyo 162-8666, Japan

Rainer LenhardtAssistant Director, Assistant Professor

Outcomes Researche Institute, Department of Anesthesiology, University of Louisville, 501 East Broadway,

Suite 210, Louisville, KY 40202, USA

Fever occurs when pyrogenic stimulation activates thermal control centres. Fever is commonduring the perioperative period, but rare during anaesthesia. Although only a limited number ofstudies are available to explain how anaesthesia affects fever, general anaesthesia seems to inhibitfever by decreasing the thermoregulatory-response thresholds to cold. Opioids also inhibit fever;however, the effect is slightly less than that of general anaesthesia. In contrast, epiduralanaesthesia does not affect fever. This suggests that hyperthermia, which is often associated withepidural infusions during labour or in the post-operative period, may be a true fever caused byinflammatory activation. Accordingly, this fever might be diminished in patients who receiveopioids for pain treatment. Post-operative fever is a normal thermoregulatory response usually ofnon-infectious aetiology. Fever may be important in the host defence mechanisms and should notbe routinely treated lest the associated risks exceed the benefits.

Key words: fever; anaesthesia; volatile anaesthetics; intravenous anaesthetics; opioids; epiduralanalgesia; temperature; thermoregulation; thermoregulatory threshold; inflammation; cytokines;pyrogen; antipyretic; treatment of fever.

FEVER

Normal thermoregulatory control and fever

Thermoregulatory responses can be characterized by thresholds, which are defined asthe core temperatures (at a designated skin temperature) that trigger physiologicaldefences against excessive heat or cold. The difference between the sweating andvasoconstriction thresholds defines the inter-threshold range; temperatures within thisrange do not trigger thermoregulatory defences.1 The inter-threshold range, which is

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* Corresponding author. Tel.: 81-3-5269-7336; Fax: 81-3-5269-7336.E-mail address: [email protected] (C. Negishi).

normally only a few tenths of a degree centigrade2, is sometimes approximated as asingle target core temperature (setpoint).

Fever is a regulated increase in body temperature. It develops when pyrogenicstimulation activates hypothalamic thermoregulatory control centres. During fever, thesetpoint increases and there is a synchronous elevation in the cold-response and warm-response thresholds, i.e. heat loss and heat production are regulated to a highertemperature. The precision of thermoregulatory control remains normal, and the inter-threshold range is similar to that of normothermic individuals.2,3 (Figure 1).

Passive hyperthermia is also an increase in body temperature but a distinct entity inwhich the thermoregulatory setpoint is normal. Passive hyperthermia is a conditionthat develops when heat production by the body exceeds heat loss.

During general anaesthesia, most patients become hypothermic.1 However,hyperthermia occurs at relatively high incidence during anaesthesia in paediatricpatients, in patients with brain stroke or injury or acute peritonitis, or in patientsundergoing otolaryngeal surgery. It is not always easy to distinguish fever from passivehyperthermia during general anaesthesia. However, fever is likely to be accompanied byvasoconstriction and shivering at emergence of anaesthesia or in the post-anaesthesiacare unit.

Role of fever

For millennia, fever has been considered a protective response to combatinfection4,5, and it has provided a useful warning to clinicians. Recently, it hasbeen increasingly realized that fever is one part of a complex host defence responseto infection or non-infectious diseases.6 The benefit of the increase in body

Normalthermoregulation

Sweating

Vasoconstriction

shivering

Fever

37C

Figure 1. Thermoregulatory change during fever. The precision of thermoregulatory control remains normalduring fever, but is centred around an elevated temperature. This synchronous elevation in the cold and warmthreshold range can be considered a setpoint increase. The inter-threshold range is the difference betweenthe warm- and the cold-response threshold. The inter-threshold range during fever is kept in a narrow rangeas during normal thermoregulation.

500 C. Negishi and R. Lenhardt

temperature on host defence is not entirely clear. Several animal studies haveexamined the effect of temperature on the mortality rate during bacterial infection.Kluger et al. demonstrated the effect of elevated body temperature on survival rateof the desert iguana (Dipsosaurus dorsalis) infected with bacteria (Aeromonashydrophila).7 They showed a clear correlation between the increase in bodytemperature following bacterial infection and the host survival rate. In another study,Vaughum et al8 demonstrated the effect of fever on the survival rate of infectedrabbits. They showed that antipyretic use reduced body temperature andsignificantly decreased the host survival rate. Temperature modulation to the highersetpoint during infection is also observed in fish, which suggests that fever is anadaptive response in numerous species.

Although fever may be beneficial for infected patients, the associated symptoms,such as increasing cardiac output, oxygen consumption, and energy consumption, aresometimes harmful. In such cases, antipyretic use needs to be considered, especially forthe elderly or patients with poor cardiac or pulmonary function.

Process of fever

Normally, thermoregulatory control is principally neuronally mediated.9,10 However,during fever, humoral mediators such as endogenous pyrogens play important rolesin the control of body temperature. The major endogenous pyrogens includeinterleukin-1, interleukin-6, tumour necrosis factor (TNF-alpha), and interferon-alpha.1114 The other factors, including macrophage inflammatory protein, alsocontribute.15 The entire molecular aspect of how these endogenous cytokines sendsignals to the brain to induce prostaglandin (PG) E2, the final mediator of fever, isnot completely known. However, in addition to this humoral mechanism, vagalafferent signals seem to be another important pathway for induction of fever.1618

Once fever is induced, the core target temperature is set at a highertemperature. That is, all thermoregulatory response thresholds (core temperaturestriggering responses) occur at higher temperatures. As a result, cold-defences suchas vasoconstriction and shivering are strongly augmented in the early stageof fever.19 During fever, the inter-threshold range is kept in the narrow rangeas in the normal condition.3 The maximal temperature usually does not exceed42 8C.

Fever is just one part of an acute response to inflammation and, like other parts ofthe response, it is mediated by the immune, endocrine and neuronal systems. Duringthe course of fever, various mediators are released that modulate it. The entiremechanism of inflammation is complex, and these mediators usually up-regulate anddown-regulate each other (Figure 2). For example, endogenous pyrogens, which arepro-inflammatory cytokines, activate the release of endogenous antipyretics orcryogens that act to reduce fever. Interleukin-10, glucocorticoids, vasopressin, alpha-melanocyte-stimulating hormone (alpha-MSH), nitric oxide, and TNF-alpha in certainsituations, all appear to be endogenous antipyretics.2023 They may be acting to preventbody temperature from rising to dangerous levels, to decrease the setpoint after someperiod of fever, or both.

Adding to these endogenous mediators, many drugs administered during theperioperative period possess potentially immunomodulator effects. Antipyretics andsteroids decrease fever by modifying the neuronal and adrenal axis. Sedatives andopioids seem to reduce fever by both central and peripheral mechanisms. Inaddition, surgical procedures and pre-operative examinations activate the immune

Fever during anaesthesia 501

system to some degree. Even though numerous clinical and basic studies have beendone in the past, further investigations will be needed to understand the entireinflammatory response and the immunomodulator effect of drugs during theperioperative period.

FEVER

vasoconstrictionshiveringheat production

setpoint elevation

sensoryafferent nerve

vagalafferentnerve

PGE2AVP

alpha-MSH

CNS

endogenous pyrogens

IL-6 IL-1TNF-alpha

antipyretics

IL-10TNF-alpha*

Figure 2. Generation of fever. Exogenous pyrogens (LPS, endotoxin, etc.) and other pyrogenic stimulationsinduce pyrogenic cytokines (IL-1, TNF-alpha, IL-6). Circulating IL-6, which is induced by both IL-1 and TNF-alpha, is considered to be the key cytokine for inducing prostaglandin E2 (PGE2) in the central nervous system.PGE2 alters the firing rate of thermosensitive neurons in the anterior hypothalamus (setpoint elevation). Thevagal afferent nerve and also the cutaneous sensory nerve seem to transport signals to induce fever. Especiallyin the later stage of fever, antipyrogens and other factors, including AVP and alpha-MSH, are involved inattenuating fever. CNS central nervous system, PGE2 prostaglandin E2; AVP arginine vasopressin;alpha-MSH melanocyte stimulating hormone; IL-1 interleukin-1; IL-6 interleukin-6; TNF-alpha tumour necrosis factor-a. Solid arrows indicate stimulus responses, and broken arrows indicate inhibitoryresponses. pTNF-alpha acts as an inhibitor of fever under certain circumstances.


FEVER DURING ANAESTHESIA

Thermoregulatory control during anaesthesia

Most perioperative temperature changes result from alterations in thermoregulatorycontrol. The effects of anaesthesia and sedatives on thermoregulatory responses arewell established. Volatile anaesthetics, propofol, opioids and sedatives all slightlyincrease the sweating threshold while markedly decreasing the vasoconstriction andshivering thresholds.2429 As a result, the sweating-to-vasoconstriction inter-thresholdrange, which is usually only a few tenths of a degree centigrade (8C), increases to a 24 8C range, depending on the drug and dose.1

Volatile anaesthesia and fever

Fever is relatively rare during general anaesthesiaespecially considering how oftenpyrogenic aetiologies are likely to be present during the perioperative period. Thissuggests that general anaesthesia per se attenuates fever by the lowering ofthermoregulatory thresholds of cold defences.

The effect of desflurane anaesthesia on fever has been evaluated using a humanfever model in which fever was induced by intravenous administration of IL-2 tomale volunteers.30 Desflurane anaesthesia produced a dose-dependent inhibition ofIL-2-induced fever, with 1.0 MAC essentially obliterating the temperature increase(Figure 3). The results of this study may explain why fever is rare during generalanaesthesia.

The mechanisms by which anaesthesia inhibits manifestation of fever are notcompletely understood. However, one possible mechanism is a central action ofvolatile anaesthetics.24 The other possibility is a peripherally mediated inhibition viareduced release of pyrogenic cytokines.31 To clarify the thermoregulatory effects ofdesflurane anaesthesia on fever, the thermoregulatory thresholds for sweating andvasoconstriction were determined with 0.6 MAC desflurane anaesthesia with fever

Practice points

fever is a regulated elevation of body temperature, whereas passivehyperthermia is the condition in which heat generated by the body exceedsits heat loss

fever is one part of the inflammatory response and may be beneficial for hostdefence mechanisms

fever is induced by endogenous pyrogens and probably by vagal signals; it ismediated by neuronal and hormonal mediators

during the perioperative period, external factors, such as anaesthesia,sedatives, surgical procedures and perioperative examinations, modulate fever

Research agenda

the use of new and more precise technologies will further our understanding ofthe role of fever, the mechanism of fever as one part of acute inflammatoryresponse, and the effects of perioperatively used drugs on fever


induced by IL-2.3 The combination of IL-2 administration and desflurane anaesthesiaincreased the sweating threshold and reduced the vasoconstriction thresholdcompared to IL-2 alone. Consequently, the inter-threshold range increased;however, the range was significantly less than during desflurane anaesthesiaalone. This reason is unclear, but one possibility is that fever-induced activation ofthe sympathetic nervous system compensates for a fraction of the anaesthetic-induced thermoregulatory impairment32 (Figure 4).

To evaluate the peripherally mediated inhibition by anaesthesia, plasma cytokinelevels during desflurane anaesthesia combined with fever were measured in the samestudy.3 Desflurane did not affect the plasma concentration of the circulating cytokinesinduced by IL-2 administration (IL-1ra, IL-6, IL-8, IL-10, TNF-alpha). Thus, it appearsthat desflurane decreases the thermoregulatory thresholds of cold defences via acentral action.

Although a central inhibitory mechanism appears to play an important role inanaesthesia-mediated suppression of fever, there is also evidence that anaestheticsare immunosuppressive as well. Recently, in vivo and in vitro studies demonstratedthat both volatile and intravenous anaesthetics and opioids suppress cytokineproduction and activity.3338 Roytblat et al demonstrated that, before cardiacpulmonary bypass, ketamine (0.25 mg/kg) reduces serum interleukin-6 (IL-6)concentration during and post surgery.39 In addition, alfentanil and propofol

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Figure 3. Fever during anaesthesia. Change in core temperature after administration of 50 000 IU/kg ofinterleukin-2 (IL-2) followed by a second dose of 100 000 IU/kg 2 hours later. The first dose of IL2 definedelapsed time zero; anaesthesia was started after 3 elapsed hours and continued for 5 hours. Data arepresented as means ^ SDs. Core temperatures during 0.6 MAC and 1.0 MAC desflurane differed significantlyfrom the control day between 3.5 and 7.5 elapsed hours; temperatures during 1.0 MAC differed significantlyfrom 0.6 MAC from 5.5 to 8.5 elapsed hours. Reproduced from Negishi C et al (1998, Anesthesiology 88:11621169) with permission.


anaesthesia diminishes release of IL-6 during abdominal surgery compared withisoflurane anaesthesia.40 Plasma concentrations of IL-6 are associated with fever.41,42

These findings suggest that general anaesthesia, especially intravenous anaesthetics,also modulates fever by a peripheral mechanism, at least in part.

Intravenous anaesthetics and sedatives

The effects of intravenous anaesthetics on fever have not been formally reported.However, most anaesthetics and sedatives have similar effects on thermoregulatorycontrol2429; they slightly increase the sweating threshold and markedly decrease thevasoconstriction and shivering thresholds, and thus increase the inter-threshold range.1

On the other hand, fever is a regulated increase in the thermoregulatory thresholds,but does not decrease the precision of thermoregulatory control. Taken together, themost likely prediction is that the two effects occur simultaneously; that is, thecombination of general anaesthesia and fever simply produces an expanded inter-threshold range around the elevated setpoint. Then, the decrease in thermoregulatorythresholds of cold defences will diminish fever in the cold environment of around 22 8C,

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Fever Anesth

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Figure 4. Thermoregulation during fever and anaesthesia. The inter-threshold ranges (as defined by thedifference between the sweating and vasoconstriction thresholds) were comparable on the control andthe fever alone day: 0.5 ^ 0.5 versus 0.4 ^ 0.4 8C. In contrast, anaesthesia (Anesth) significantly increased theinter-threshold range to 1.9 ^ 0.6 8C. When desflurane and IL2 were combined, the inter-threshold rangewas 1.2 ^ 0.6 8C, which was significantly greater than during fever alonebut also significantly less thanduring anesthesia alone. Reproduced from Lehhardt R et al (1999, Anesthesiology 90: 15871595) withpermission.


which is a typical temperature in operating rooms. However, the specific effect of eachintravenous anaesthetic remains to be determined.

OPIOIDS AND FEVER

Opioids are common anaesthetic adjuvants and remain the dominant treatment forpost-operative surgical pain. It is well established that opioid administration increaseswarm-response thresholds and decreases cold-response thresholds, thus significantlyincreasing the inter-threshold range.26,27 This pattern of inhibition is similar to thatproduced by general anaesthesia24,25, although the magnitude is somewhat less.

Opioids also suppress fever in a dose-dependent fashion. Fentanyl and alfentanil, bothm-receptor agonists with a rapid onset, were evaluated for their effect on fever.43,44

Fentanyl, at a plasma concentration of 2.5 ng/ml, significantly reduced febrile response toIL-2 administration. Alfentanil also significantly reduced IL-2-induced fever; the reductionwas comparable at high and low plasma concentrations (100 and 200 ng/ml). This maysuggest that even low doses of alfentanil inhibit fever. Physicians thus need to be aware ofopioid use in intensive care units or during the post-operative period because opioids canattenuate fever, which is an important symptom of infection.

The effects of fentanyl and alfentanil on plasma concentrations of cytokines were alsomeasured in the same studies.43,44 Neither fentanyl nor alfentanil infusion showssignificant effects on the plasma concentrations of cytokines induced by IL-2administration (IL-6, TL-8, IL-10 and TNF-alpha). The interaction between opioidsand immune responses has, however, been widely reported. Opioids, even at clinicaldoses, are immunosuppressive.45 Beilin et al reported that even a small dose of fentanylsuppressed natural killer cell cytotoxicity, and with a large dose the effect was longlasting.46 They suggest that large-dose fentanyl be used with caution, especially incancer patients. The mechanism of the immunomodulator effect of opioids appears tobe both centrally and peripherally mediated.4749 However, the clinical relevance of

Practice points

volatile anaesthesia suppresses fever in dose-dependent manner. The inhibitorymechanism appears to be mainly a central action, which decreases coldresponse thresholds; however, its peripheral effects on endogenous pyrogensmay affect fever in some parts

considering that most anaesthetics and sedatives have similar thermoregulatoryeffects at a normal setpoint, intravenous anaesthesia might suppress fever aswell as volatile anaesthesia

Research agenda

the effect of intravenous anaesthesia on fever needs to be evaluated anaesthetic effects on endogenous pyrogens and antipyretics should be

assessed to help determine the thermoregulatory effects of anaesthetics onfever


the immunomodulator effect of opioids, including its dose, tolerance, and acute andchronic administration, remains controversial.

NEURAXIAL ANAESTHESIA AND FEVER

Thermal perturbation of neuraxial anaesthesia

During surgery, hypothermia associated with neuraxial anaesthesia is commonlyobserved, although it is not as widely recognized as hypothermia during generalanaesthesia.50,51 As with general anaesthesia, re-distribution is a major cause of corehypothermia during epidural and spinal analgesia. At the typical operation roomtemperature, core temperature decreases 0.8 ^ 0.3 8C in the first hour of epidural orspinal anaesthesia and re-distribution contributes 89% of this initial decrease.52 Thisdecrease in core temperature is about half as much as occurs during generalanaesthesia, and the rate is determined by the inequality between heat loss and heatproduction as well as block level.

Neuraxial anaesthesia also inhibits thermal control of the body by a centralmechanism but to a lesser degree than general anaesthesia.5254 However, withneuraxial anaesthesia peripheral nerve block is a more important cause of hypothermia.Sufficient core hypothermia will trigger vasoconstriction and shivering even duringneuraxial anaesthesia, but only in the unblocked areas. Vasoconstriction and shivering inthis limited area are usually insufficient to prevent further hypothermia. This inability ofthermoregulatory defences during neuraxial analgesia sometimes induces serioushypothermia, especially during major operations requiring a high block level.

Epidural analgesia and fever

In spite of the thermal perturbations of neuraxial anaesthesia, epidural analgesia isfrequently associated with hyperthermia, especially during labour and the post-operative period. Several studies demonstrate that average temperature is higher inpatients given epidural analgesia for labour or post-operative pain treatment.55,56 Theclinical importance of this paradoxical hyperthermia associated with epiduralanaesthesia is that hyperthermia often prompts clinical interventions such as work-ups for infection and newborn sepsis.57

Practice points

systemic administration of opioids seems to inhibit fever. This may requiremore attention to be paid to opioid use during post-operative periods or in theICU, because fever is an important symptom of infection

Research agenda

further evaluation of peripheral and central action of opioids on inflammatoryresponse can help elucidate the thermoregulatory effects of opioids on fever


It is unclear whether this core temperature elevation is true fever or passivehyperthermia. Epidural analgesia per se is unlikely to induce immunoactivation orfever.58,59 During epidural analgesia the sweating threshold slightly increases.Epidural anaesthesia also reduces sweating in the blocked area. Thus, epiduralanalgesia can induce passive hyperthermia if metabolic expenditure increases andheat production exceeds heat loss. Therefore, epidural analgesia itself is assumedto cause hyperthermia associated with epidural analgesia, especially duringlabour.6063 However, the same theory does not explain hyperthermia associatedwith epidural analgesia during the post-operative period. These patients havenormal metabolic rates, and a hospital environment is not warm enough to inducepassive hyperthermia. Patients who are not given epidural analgesia during labouror post-operative period usually receive opioids instead. Opioids such as fentanyland alfentanil reduce the febrile response.43,44 For example, 0.2% ropivacaineepidural analgesia (with and without fentanyl) does not affect fever, whereasintravenous fentanyl infusion attenuated it (Figure 5).44 Such results lead to analternative potential aetiology: hyperthermia observed in patients given epiduralanalgesia during labour or the post-operative period results from pyrogen-inducedfever. Thus, fever is observed in patients given epidural analgesia, but not in thepatients given opioids, because opioids are antipyretics.

Fever can occur by both infectious and non-infectious aetiologies. Hyperthermiaassociated with epidural analgesia is often observed in the patients without infection.63

Supporting this hypothesis, the maternal serum IL-6 concentration increases during

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0 1 2 3 4 5 6 7 8 9

Elapsed Time (h)

IL-2 IL-2

Control Epidural Ropivacaine Epidural Ropivacaine & Fentanyl Intravenous Fentanyl

Figure 5. Fever during epidural anaesthesia and intravenous administration of fentanyl. Core temperaturesafter administration of 50 IU/g of interleukin-2 followed by a second dose of 100 IU/g 2 hours later. The firstdose of IL2 defined elapsed time zero. Data are presented as means ^ SDs. Error bars for the epidural daysare omitted for clarity, but were similar to those shown for control and intravenous fentanyl. Reproducedfrom Ref. 43:1Negishi C et al (2001, Anesthesiology 98: 218222) with permission.


labour are not always associated with intra-amniotic inflammation, and IL-6concentrations are strongly associated with intrapartum fever.64 It is also well knownthat inflammatory cytokines are increased during the post-operative period.41

PARALYSIS AND FEVER

Once fever occurs, the vasoconstriction, shivering and sweating thresholds increasesynchronously. Especially at the start of fever, vasoconstriction and shivering play theimportant role of increasing body temperature. During anaesthesia, however, musclerelaxants are often administered for intubation or paralysis during surgical procedures.

Paralysis, of course, prevents shivering and the associated increase in metabolic heatproduction, leaving the development of fever entirely dependent on thermoregulatoryvasoconstriction. The alteration of vasomotor tone by general anaesthesia is one of theprimary factors that influences intraoperative core temperature.6567 However, itseems to be effective enough to increase core temperature during fever combined withgeneral anaesthesia and paralysis. For example, under complete paralysis, whichobliterates muscle activity and prevents increasing metabolic rate, thermoregulatoryvasoconstriction was nonetheless able to maintain fever during 0.6 MAC isofluraneanaesthesia.68 Paralysis can reduce the magnitude of fever, but clinically its effect seemsto be less important than anaesthetic-induced inhibition of fever.

POST-OPERATIVE FEVER

The inflammatory response can be induced by infectious or non-infectiousaetiologies such as body injury, surgical procedure, malignant tumour, brain strokeetc. Fever is associated with the inflammatory responses and is usually observed

Practice points

epidural analgesia does not suppress fever it remains controversial whether epidural analgesia per se causes hyperthermia

during labour or post-operative period

Research agenda

a prospective and randomized clinical trial is needed to evaluate the aetiology ofepidural fever during labour

Practice point

paralysis slightly reduces the magnitude of fever by preventing shivering,although its effect seems to be less important than anaesthetic-inducedinhibition of fever


during the post-operative period.41,69 72 Post-operative fevers seem to be inducedmainly by the inflammatory reaction activated by surgery, but psychological stressalso can induce fever.73 The anaesthetic technique used during surgery appears tohave little effect on post-operative fever41, but many drugs used in the post-operative periodsuch as opioids, sedatives and NSAIDspossess immunomodu-lator effects and, therefore, may modulate post-operative fever.

The incidence of fever during the post-operative period seems high, butthe reported numbers vary with type and duration of surgery, patient age, pre-existing inflammation and surgical site.41,6972 It seems principally to be determinedby the severity of surgical invasion, as well as the existence of post-operativeinfection.

Clinically, fever is considered the earliest and most easily detected sign ofinfection in surgical patients. For this reason, it is important to measure core bodytemperature in the early post-operative period. Post-operative changes in coretemperature and plasma concentrations of IL-6 in the first 24 hours have beenevaluated in the patient undergoing elective abdominal, non-cardiac thoracic ormajor abdominal surgeries.41 One fourth of the patients had a maximum urinarybladder temperature greater than 38.5 8C. The increase in core temperature wasassociated with shivering and vasoconstriction until the core temperature reachedits peak, suggesting that this increase in core temperature was true fever.Leukocyte counts did not relate to the increase in core temperature; however,there was a positive relationship between the post-operative increase incore temperature and plasma IL-6 concentration. Only one patient of the febrilepatients had an infection. This study suggests that fever during the post-operativeperiod is common and that it may be a normal inflammatory response induced bysurgical stress, not by infection. Plasma IL-6 concentration seems to be a goodpredictor of post-operative fever and acts as a pyrogen in post-surgical patients(Figure 6).

The fever in the post-operative period sometimes prompts diagnostic tests todetermine the source or to exclude a serious infection. It is well known thatwork-ups for infections add extra medical costs.69,74,75 Because it is known thatmost febrile patients are bacteriologically negative41,6971,76 routine evaluation ofpost-operative fever may not always be needed. Instead, clinicians should considerhow common fever is in post-operative patients and restrict fever work-ups tohigh-risk patients and patients in whom there are other indications of infection.Factors such as c-reactive protein (CRP) elevation, white blood cell count, andother clinical indicators should be increasingly used for the diagnosis of post-operative infection.

Practice points

fever during the post-operative period is common and may be a normalinflammatory response induced by surgical stress, not by infection

physicians should restrict fever work-ups to high-risk patients and patientswith other indications of infection

plasma IL-6 concentration seems to be a good predictor of post-operative feverand acts as a pyrogen in post-surgical patients


TREATMENT OF FEVER

Infection, trauma, injury and surgical stimulation all induce the inflammatory response,which includes fever. Fever is the most common problem in hospitalized patients. Althoughscientific knowledge about the inflammatory response is increasing, it remainscontroversial whether fever is beneficial or harmful to the host defence.4,5 However,there are many animal experiments7,8 and clinical observations77,78 suggesting that

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Figure 6. Postoperative fever. Core temperature, percentage of patients shivering and vasoconstrictiongradient in 271 patients during the pre-operative (Preop), intraoperative (Intraop), and post-operative(Postop) periods. The post-operative increase in core temperature is accompanied by shivering andvasoconstriction, both of which diminish as core temperature reaches the new greater post-operativesetpoint. The increase in vasoconstriction gradient indicates increased vasomotor tone. #Forearmminus fingertip skin-surface temperature gradient; *P , 0:05 versus intraoperative vasoconstriction gradient;P , 0:05 versus pre-operative core temperature. Reproduced from Ref. 6: Cooper K.E. (Ed.) (1995, Feverand Antipyresis; The Role of the Nervous System, pp. 112. Cambridge: Cambridge University Press,) withpermission.

Research agenda

the aetiology of post-operative fever and its role should be established to allowefficient treatment of fever during the post-operative period


antipyretic therapy potentially increases the duration and severity of certain infections.Fever seems to be an adaptive response that evolved to aid the host defensiveinflammatory response against pathogens. The elevated temperature enhances the activityof immuneeffectorcells79,80, and inhibits bacterial growthof somepathogens.81 This iswhy,historically, malarial fever and hot bath has been used for treatment of bacterial infections.

Currently, most febrile patients are treated with antipyretic, mainly for patientcomfort. However, if fever renders host defences more active, it should not be treatedquickly. Furthermore, fever is considered an important marker for evaluating theeffectiveness of treatment. Whether fever is beneficial or harmful depends on the actualclinical circumstances, and antipyretic treatment should be evaluated on an individualbasis.82 Letting fever take its natural course does not seem to be harmful for febrilepatients.83 However, accompanying symptoms such as tachycardia, increased oxygenconsumption, and discomfort are maladaptive for some patients, and in these casesantipyretic use ought to be considered. Specifically, fever should be treated in patientswith cardiopulmonary dysfunction, acute brain stroke or injury, or in those whosetemperature exceeds 40 8C.

The primary treatments for fever are amelioration of the underlying cause andadministration of antipyretic medications. External active cooling including tepid spongebaths for children is not recommended for non-sedated febrile patients8486 although itis effective for heat stroke patients with a normal thermoregulatory set point. Activecooling does not reduce core temperature, but increases the metabolic rate, activatesthe autonomic nervous system, and provokes thermal discomfort, because loweredskin temperature activates thermoregulatory efforts to increase the body temperatureto the set point.84 In contrast, cutaneous cooling reduces core temperature in criticalcare patients who are sedated87 or paralysed.88

Fever occurs in almost half of the patients with acute brain stroke or injury.89 Themechanism of this hyperthermia remains unknown, but it is known that even mild brainhyperthermia worsens the functional outcome by enhancing neurotransmitter release,exaggerating oxygen radical production, extending blood-brain barrier breakdown, andother mechanisms.90 In contrast, mild hypothermia seems to have neuroprotective effectson severe brain insults, and mild hypothermia (33 8C) significantly improves neurologicaloutcomes.91 Thus, it is recommended that fever be combated assiduously in patients withacute brain stroke and injury to induce normothermia or mild hypothermia. Antipyreticssometimes fail to decrease core temperature in these patients92; thus, external coolingcombined with sedation may be the most effective method. In each case, if fever is treated,particular attention for infection will be needed because fever, a sign of infection, isdiminished and mild hypothermia increases the risk of infection.91

Practice points

fever may be beneficial to host defence mechanism, and should not be treatedroutinely

fever should be treated in patients with cardiopulmonary dysfunction, acutebrain stroke or injury, or in whom temperature exceeds 40 8C

active cooling is not effective to reduce core temperature if the febrile patient isawake. It only increases the metabolic rate, activates the autonomic nervoussystem, and provokes thermal discomfort

active cooling is effective for sedated and paralysed patients. It may be a usefultreatment of fever in patients with acute brain stroke or injury


SUMMARY

Fever occurs when pyrogenic stimulation activates hypothalamic control centres. It isdefined as an increase in a setpoint and there is a synchronous elevation in the cold-response and warm-response thresholds. Fever is considered to be part of acuteinflammatory response; it is mediated by neuronal and hormonal factors.

During the perioperative period, fever is also modulated by exogenous factors.Volatile anaesthesia and opioids both inhibit fever. The inhibitory mechanism seems tobe mainly a central action that decreases cold-response thresholds. However, otherinhibitory mechanisms, such as peripheral inhibition of endogenous pyrogens, may alsoexist. Intravenous anaesthetics also have similar effects on thermoregulation. There-fore, it may also suppress fever in a dose-dependent manner; however, a confirmingstudy has yet to be done. Paralysis slightly reduces the magnitude of fever by preventingshivering, although its effect seems to be less important than anaesthetic-inducedinhibition of fever.

Unlike general anaesthesia, epidural analgesia does not seem to suppress fever. Thismay explain why fever is frequently observed in patients given epidural analgesia duringlabour or post-operatively.

Fever is associated with the inflammatory responses and is commonly observedpost-operatively. It is usually caused by non-infectious aetiologies and most patients arebacteriologically negative. Thus, routine evaluation of post-operative fever may notalways be needed. Restricting fever work-ups to high-risk patients and patients withother clinical signs of infection may be recommended.

Fever should not always be treated quickly because it is probably beneficial to hostdefence. However, antipyretic use should be considered when accompanyingsymptoms, such as tachycardia or increased oxygen consumption, are harmful forthe patients. Cutaneous active cooling is not effective for reducing coretemperatureit increases the metabolic rate and thermal discomfort in the awakefebrile patient.

ACKNOWLEDGEMENTS

The authors thank Daniel I. Sessler MD. (Associate Dean, Weakley DistinguishedResearch Chair, Director, Outcomes Researche Institute, University of Louisville) forhis support in performing the series of our fever studies and helpful comments on thismanuscript.

Research agenda

further research is warranted to better understand the fever mechanismfrequently observed in patients with brain stroke and injury

treatment strategy needs to be established for fever induced by acute stroke orbrain injury


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Fever during anaesthesiaFeverNormal thermoregulatory control and feverRole of feverProcess of fever

Fever during anaesthesiaThermoregulatory control during anaesthesiaVolatile anaesthesia and feverIntravenous anaesthetics and sedatives

Opioids and feverNeuraxial anaesthesia and feverThermal perturbation of neuraxial anaesthesiaEpidural analgesia and fever

Paralysis and feverPost-operative feverTreatment of feverSummaryAcknowledgementsReferences

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