2

Fever during anaesthesia

Chiharu Negishi
*
Assistant Professor
Department of Anaesthesia, Tokyo Womens Medical University, 8-1 Kawada-cho, Shinjuku-ku,
Tokyo 162-8666, Japan
Rainer Lenhardt
Assistant 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 common
during the perioperative period, but rare during anaesthesia. Although only a limited number of
studies are available to explain how anaesthesia affects fever, general anaesthesia seems to inhibit
fever 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, epidural
anaesthesia does not affect fever. This suggests that hyperthermia, which is often associated with
epidural infusions during labour or in the post-operative period, may be a true fever caused by
inammatory activation. Accordingly, this fever might be diminished in patients who receive
opioids for pain treatment. Post-operative fever is a normal thermoregulatory response usually of
non-infectious aetiology. Fever may be important in the host defence mechanisms and should not
be routinely treated lest the associated risks exceed the benets.
Key words: fever; anaesthesia; volatile anaesthetics; intravenous anaesthetics; opioids; epidural
analgesia; temperature; thermoregulation; thermoregulatory threshold; inammation; cytokines;
pyrogen; antipyretic; treatment of fever.
FEVER
Normal thermoregulatory control and fever
Thermoregulatory responses can be characterized by thresholds, which are dened as
the core temperatures (at a designated skin temperature) that trigger physiological
defences against excessive heat or cold. The difference between the sweating and
vasoconstriction thresholds denes the inter-threshold range; temperatures within this
range do not trigger thermoregulatory defences.
1
The inter-threshold range, which is
1521-6896/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
Best Practice & Research Clinical Anaesthesiology
Vol. 17, No. 4, pp. 499517, 2003
doi:10.1016/S1521-6896(03)00068-5, www.elsevier.com/locate/jnlabr/ybean
*
Corresponding author. Tel.: 81-3-5269-7336; Fax: 81-3-5269-7336.
E-mail address: bxh07473@nifty.com (C. Negishi).
normally only a few tenths of a degree centigrade
2
, is sometimes approximated as a
single target core temperature (setpoint).
Fever is a regulated increase in body temperature. It develops when pyrogenic
stimulation activates hypothalamic thermoregulatory control centres. During fever, the
setpoint 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 higher
temperature. 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 in
which the thermoregulatory setpoint is normal. Passive hyperthermia is a condition
that 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 paediatric
patients, in patients with brain stroke or injury or acute peritonitis, or in patients
undergoing otolaryngeal surgery. It is not always easy to distinguish fever from passive
hyperthermia during general anaesthesia. However, fever is likely to be accompanied by
vasoconstriction and shivering at emergence of anaesthesia or in the post-anaesthesia
care unit.
Role of fever
For millennia, fever has been considered a protective response to combat
infection
4,5
, and it has provided a useful warning to clinicians. Recently, it has
been increasingly realized that fever is one part of a complex host defence response
to infection or non-infectious diseases.
6
The benet of the increase in body
Normal
thermoregulation
Sweating
Vasoconstriction
shivering
Fever
37C
Figure 1. Thermoregulatory change during fever. The precision of thermoregulatory control remains normal
during fever, but is centred around an elevated temperature. This synchronous elevation in the cold and warm
threshold range can be considered a setpoint increase. The inter-threshold range is the difference between
the warm- and the cold-response threshold. The inter-threshold range during fever is kept in a narrow range
as during normal thermoregulation.
500 C. Negishi and R. Lenhardt
temperature on host defence is not entirely clear. Several animal studies have
examined the effect of temperature on the mortality rate during bacterial infection.
Kluger et al. demonstrated the effect of elevated body temperature on survival rate
of the desert iguana (Dipsosaurus dorsalis) infected with bacteria (Aeromonas
hydrophila).
7
They showed a clear correlation between the increase in body
temperature following bacterial infection and the host survival rate. In another study,
Vaughum et al
8
demonstrated the effect of fever on the survival rate of infected
rabbits. They showed that antipyretic use reduced body temperature and
signicantly decreased the host survival rate. Temperature modulation to the higher
setpoint during infection is also observed in sh, which suggests that fever is an
adaptive response in numerous species.
Although fever may be benecial for infected patients, the associated symptoms,
such as increasing cardiac output, oxygen consumption, and energy consumption, are
sometimes harmful. In such cases, antipyretic use needs to be considered, especially for
the 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 roles
in the control of body temperature. The major endogenous pyrogens include
interleukin-1, interleukin-6, tumour necrosis factor (TNF-alpha), and interferon-
alpha.
1114
The other factors, including macrophage inammatory protein, also
contribute.
15
The entire molecular aspect of how these endogenous cytokines send
signals to the brain to induce prostaglandin (PG) E
2
, the nal mediator of fever, is
not completely known. However, in addition to this humoral mechanism, vagal
afferent signals seem to be another important pathway for induction of fever.
1618
Once fever is induced, the core target temperature is set at a higher
temperature. That is, all thermoregulatory response thresholds (core temperatures
triggering responses) occur at higher temperatures. As a result, cold-defences such
as vasoconstriction and shivering are strongly augmented in the early stage
of fever.
19
During fever, the inter-threshold range is kept in the narrow range
as in the normal condition.
3
The maximal temperature usually does not exceed
42 8C.
Fever is just one part of an acute response to inammation and, like other parts of
the response, it is mediated by the immune, endocrine and neuronal systems. During
the course of fever, various mediators are released that modulate it. The entire
mechanism of inammation is complex, and these mediators usually up-regulate and
down-regulate each other (Figure 2). For example, endogenous pyrogens, which are
pro-inammatory cytokines, activate the release of endogenous antipyretics or
cryogens that act to reduce fever. Interleukin-10, glucocorticoids, vasopressin, alpha-
melanocyte-stimulating hormone (alpha-MSH), nitric oxide, and TNF-alpha in certain
situations, all appear to be endogenous antipyretics.
2023
They may be acting to prevent
body temperature from rising to dangerous levels, to decrease the setpoint after some
period of fever, or both.
Adding to these endogenous mediators, many drugs administered during the
perioperative period possess potentially immunomodulator effects. Antipyretics and
steroids decrease fever by modifying the neuronal and adrenal axis. Sedatives and
opioids seem to reduce fever by both central and peripheral mechanisms. In
addition, 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 been
done in the past, further investigations will be needed to understand the entire
inammatory response and the immunomodulator effect of drugs during the
perioperative period.
FEVER
vasoconstriction
shivering
heat production
setpoint elevation
sensory
afferent nerve
vagal
afferent
nerve
PGE
2
AVP
alpha-MSH
CNS
endogenous pyrogens
IL-6 IL-1 TNF-alpha
antipyretics
IL-10
TNF-alpha*
Figure 2. Generation of fever. Exogenous pyrogens (LPS, endotoxin, etc.) and other pyrogenic stimulations
induce 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 E
2
(PGE
2
) in the central nervous system.
PGE
2
alters the ring rate of thermosensitive neurons in the anterior hypothalamus (setpoint elevation). The
vagal afferent nerve and also the cutaneous sensory nerve seem to transport signals to induce fever. Especially
in the later stage of fever, antipyrogens and other factors, including AVP and alpha-MSH, are involved in
attenuating fever. CNS central nervous system, PGE
2
prostaglandin E
2
; 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 inhibitory
responses.
p
TNF-alpha acts as an inhibitor of fever under certain circumstances.
502 C. Negishi and R. Lenhardt
FEVER DURING ANAESTHESIA
Thermoregulatory control during anaesthesia
Most perioperative temperature changes result from alterations in thermoregulatory
control. The effects of anaesthesia and sedatives on thermoregulatory responses are
well established. Volatile anaesthetics, propofol, opioids and sedatives all slightly
increase the sweating threshold while markedly decreasing the vasoconstriction and
shivering thresholds.
2429
As a result, the sweating-to-vasoconstriction inter-threshold
range, which is usually only a few tenths of a degree centigrade (8C), increases to a 2
4 8C range, depending on the drug and dose.
1
Volatile anaesthesia and fever
Fever is relatively rare during general anaesthesiaespecially considering how often
pyrogenic aetiologies are likely to be present during the perioperative period. This
suggests that general anaesthesia per se attenuates fever by the lowering of
thermoregulatory thresholds of cold defences.
The effect of desurane anaesthesia on fever has been evaluated using a human
fever model in which fever was induced by intravenous administration of IL-2 to
male volunteers.
30
Desurane anaesthesia produced a dose-dependent inhibition of
IL-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 general
anaesthesia.
The mechanisms by which anaesthesia inhibits manifestation of fever are not
completely understood. However, one possible mechanism is a central action of
volatile anaesthetics.
24
The other possibility is a peripherally mediated inhibition via
reduced release of pyrogenic cytokines.
31
To clarify the thermoregulatory effects of
desurane anaesthesia on fever, the thermoregulatory thresholds for sweating and
vasoconstriction were determined with 0.6 MAC desurane anaesthesia with fever
Practice points
fever is a regulated elevation of body temperature, whereas passive
hyperthermia is the condition in which heat generated by the body exceeds
its heat loss
fever is one part of the inammatory response and may be benecial for host
defence mechanisms
fever is induced by endogenous pyrogens and probably by vagal signals; it is
mediated 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 of
the role of fever, the mechanism of fever as one part of acute inammatory
response, and the effects of perioperatively used drugs on fever
Fever during anaesthesia 503
induced by IL-2.
3
The combination of IL-2 administration and desurane anaesthesia
increased the sweating threshold and reduced the vasoconstriction threshold
compared to IL-2 alone. Consequently, the inter-threshold range increased;
however, the range was signicantly less than during desurane anaesthesia
alone. This reason is unclear, but one possibility is that fever-induced activation of
the sympathetic nervous system compensates for a fraction of the anaesthetic-
induced thermoregulatory impairment
32
(Figure 4).
To evaluate the peripherally mediated inhibition by anaesthesia, plasma cytokine
levels during desurane anaesthesia combined with fever were measured in the same
study.
3
Desurane did not affect the plasma concentration of the circulating cytokines
induced by IL-2 administration (IL-1ra, IL-6, IL-8, IL-10, TNF-alpha). Thus, it appears
that desurane decreases the thermoregulatory thresholds of cold defences via a
central action.
Although a central inhibitory mechanism appears to play an important role in
anaesthesia-mediated suppression of fever, there is also evidence that anaesthetics
are immunosuppressive as well. Recently, in vivo and in vitro studies demonstrated
that both volatile and intravenous anaesthetics and opioids suppress cytokine
production and activity.
3338
Roytblat et al demonstrated that, before cardiac
pulmonary bypass, ketamine (0.25 mg/kg) reduces serum interleukin-6 (IL-6)
concentration during and post surgery.
39
In addition, alfentanil and propofol
Elapsed Time (h)
C
o
r
e

T
e
m
p

(

C
)
0.6 MAC
1.0 MAC
34
35
36
37
38
39
0 8 10
0.0 MAC
Anesthesia
2 4 6
IL-2
IL-2
Figure 3. Fever during anaesthesia. Change in core temperature after administration of 50 000 IU/kg of
interleukin-2 (IL-2) followed by a second dose of 100 000 IU/kg 2 hours later. The rst dose of IL2 dened
elapsed time zero; anaesthesia was started after 3 elapsed hours and continued for 5 hours. Data are
presented as means ^ SDs. Core temperatures during 0.6 MAC and 1.0 MAC desurane differed signicantly
from the control day between 3.5 and 7.5 elapsed hours; temperatures during 1.0 MAC differed signicantly
from 0.6 MAC from 5.5 to 8.5 elapsed hours. Reproduced from Negishi C et al (1998, Anesthesiology 88:
11621169) with permission.
504 C. Negishi and R. Lenhardt
anaesthesia diminishes release of IL-6 during abdominal surgery compared with
isourane anaesthesia.
40
Plasma concentrations of IL-6 are associated with fever.
41,42
These ndings 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 thermoregulatory
control
2429
; they slightly increase the sweating threshold and markedly decrease the
vasoconstriction 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, the
most likely prediction is that the two effects occur simultaneously; that is, the
combination of general anaesthesia and fever simply produces an expanded inter-
threshold range around the elevated setpoint. Then, the decrease in thermoregulatory
thresholds of cold defences will diminish fever in the cold environment of around 22 8C,
36
38
40
Control Fever&
Anesth
Fever Anesth
T
h
r
e
s
h
o
l
d

(

C
)
Figure 4. Thermoregulation during fever and anaesthesia. The inter-threshold ranges (as dened by the
difference between the sweating and vasoconstriction thresholds) were comparable on the control and
the fever alone day: 0.5 ^ 0.5 versus 0.4 ^ 0.4 8C. In contrast, anaesthesia (Anesth) signicantly increased the
inter-threshold range to 1.9 ^ 0.6 8C. When desurane and IL2 were combined, the inter-threshold range
was 1.2 ^ 0.6 8C, which was signicantly greater than during fever alonebut also signicantly less than
during anesthesia alone. Reproduced from Lehhardt R et al (1999, Anesthesiology 90: 15871595) with
permission.
Fever during anaesthesia 505
which is a typical temperature in operating rooms. However, the specic effect of each
intravenous anaesthetic remains to be determined.
OPIOIDS AND FEVER
Opioids are common anaesthetic adjuvants and remain the dominant treatment for
post-operative surgical pain. It is well established that opioid administration increases
warm-response thresholds and decreases cold-response thresholds, thus signicantly
increasing the inter-threshold range.
26,27
This pattern of inhibition is similar to that
produced by general anaesthesia
24,25
, although the magnitude is somewhat less.
Opioids also suppress fever in a dose-dependent fashion. Fentanyl and alfentanil, both
m-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, signicantly reduced febrile response to
IL-2 administration. Alfentanil also signicantly reduced IL-2-induced fever; the reduction
was comparable at high and low plasma concentrations (100 and 200 ng/ml). This may
suggest that even low doses of alfentanil inhibit fever. Physicians thus need to be aware of
opioid use in intensive care units or during the post-operative period because opioids can
attenuate fever, which is an important symptom of infection.
The effects of fentanyl and alfentanil on plasma concentrations of cytokines were also
measured in the same studies.
43,44
Neither fentanyl nor alfentanil infusion shows
signicant effects on the plasma concentrations of cytokines induced by IL-2
administration (IL-6, TL-8, IL-10 and TNF-alpha). The interaction between opioids
and immune responses has, however, been widely reported. Opioids, even at clinical
doses, are immunosuppressive.
45
Beilin et al reported that even a small dose of fentanyl
suppressed natural killer cell cytotoxicity, and with a large dose the effect was long
lasting.
46
They suggest that large-dose fentanyl be used with caution, especially in
cancer patients. The mechanism of the immunomodulator effect of opioids appears to
be both centrally and peripherally mediated.
4749
However, the clinical relevance of
Practice points
volatile anaesthesia suppresses fever in dose-dependent manner. The inhibitory
mechanism appears to be mainly a central action, which decreases cold
response thresholds; however, its peripheral effects on endogenous pyrogens
may affect fever in some parts
considering that most anaesthetics and sedatives have similar thermoregulatory
effects at a normal setpoint, intravenous anaesthesia might suppress fever as
well 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 on
fever
506 C. Negishi and R. Lenhardt
the immunomodulator effect of opioids, including its dose, tolerance, and acute and
chronic administration, remains controversial.
NEURAXIAL ANAESTHESIA AND FEVER
Thermal perturbation of neuraxial anaesthesia
During surgery, hypothermia associated with neuraxial anaesthesia is commonly
observed, although it is not as widely recognized as hypothermia during general
anaesthesia.
50,51
As with general anaesthesia, re-distribution is a major cause of core
hypothermia during epidural and spinal analgesia. At the typical operation room
temperature, core temperature decreases 0.8 ^ 0.3 8C in the rst hour of epidural or
spinal anaesthesia and re-distribution contributes 89% of this initial decrease.
52
This
decrease in core temperature is about half as much as occurs during general
anaesthesia, and the rate is determined by the inequality between heat loss and heat
production as well as block level.
Neuraxial anaesthesia also inhibits thermal control of the body by a central
mechanism but to a lesser degree than general anaesthesia.
5254
However, with
neuraxial anaesthesia peripheral nerve block is a more important cause of hypothermia.
Sufcient core hypothermia will trigger vasoconstriction and shivering even during
neuraxial anaesthesia, but only in the unblocked areas. Vasoconstriction and shivering in
this limited area are usually insufcient to prevent further hypothermia. This inability of
thermoregulatory defences during neuraxial analgesia sometimes induces serious
hypothermia, especially during major operations requiring a high block level.
Epidural analgesia and fever
In spite of the thermal perturbations of neuraxial anaesthesia, epidural analgesia is
frequently associated with hyperthermia, especially during labour and the post-
operative period. Several studies demonstrate that average temperature is higher in
patients given epidural analgesia for labour or post-operative pain treatment.
55,56
The
clinical importance of this paradoxical hyperthermia associated with epidural
anaesthesia 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 require
more attention to be paid to opioid use during post-operative periods or in the
ICU, because fever is an important symptom of infection
Research agenda
further evaluation of peripheral and central action of opioids on inammatory
response can help elucidate the thermoregulatory effects of opioids on fever
Fever during anaesthesia 507
It is unclear whether this core temperature elevation is true fever or passive
hyperthermia. Epidural analgesia per se is unlikely to induce immunoactivation or
fever.
58,59
During epidural analgesia the sweating threshold slightly increases.
Epidural anaesthesia also reduces sweating in the blocked area. Thus, epidural
analgesia can induce passive hyperthermia if metabolic expenditure increases and
heat production exceeds heat loss. Therefore, epidural analgesia itself is assumed
to cause hyperthermia associated with epidural analgesia, especially during
labour.
6063
However, the same theory does not explain hyperthermia associated
with epidural analgesia during the post-operative period. These patients have
normal metabolic rates, and a hospital environment is not warm enough to induce
passive hyperthermia. Patients who are not given epidural analgesia during labour
or post-operative period usually receive opioids instead. Opioids such as fentanyl
and alfentanil reduce the febrile response.
43,44
For example, 0.2% ropivacaine
epidural analgesia (with and without fentanyl) does not affect fever, whereas
intravenous fentanyl infusion attenuated it (Figure 5).
44
Such results lead to an
alternative potential aetiology: hyperthermia observed in patients given epidural
analgesia during labour or the post-operative period results from pyrogen-induced
fever. Thus, fever is observed in patients given epidural analgesia, but not in the
patients given opioids, because opioids are antipyretics.
Fever can occur by both infectious and non-infectious aetiologies. Hyperthermia
associated with epidural analgesia is often observed in the patients without infection.
63
Supporting this hypothesis, the maternal serum IL-6 concentration increases during
36
37
38
39
C
o
r
e

T
e
m
p

(

C
)
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 temperatures
after administration of 50 IU/g of interleukin-2 followed by a second dose of 100 IU/g 2 hours later. The rst
dose of IL2 dened elapsed time zero. Data are presented as means ^ SDs. Error bars for the epidural days
are omitted for clarity, but were similar to those shown for control and intravenous fentanyl. Reproduced
from Ref. 43:1Negishi C et al (2001, Anesthesiology 98: 218222) with permission.
508 C. Negishi and R. Lenhardt
labour are not always associated with intra-amniotic inammation, and IL-6
concentrations are strongly associated with intrapartum fever.
64
It is also well known
that inammatory cytokines are increased during the post-operative period.
41
PARALYSIS AND FEVER
Once fever occurs, the vasoconstriction, shivering and sweating thresholds increase
synchronously. Especially at the start of fever, vasoconstriction and shivering play the
important role of increasing body temperature. During anaesthesia, however, muscle
relaxants are often administered for intubation or paralysis during surgical procedures.
Paralysis, of course, prevents shivering and the associated increase in metabolic heat
production, leaving the development of fever entirely dependent on thermoregulatory
vasoconstriction. The alteration of vasomotor tone by general anaesthesia is one of the
primary factors that inuences intraoperative core temperature.
6567
However, it
seems to be effective enough to increase core temperature during fever combined with
general anaesthesia and paralysis. For example, under complete paralysis, which
obliterates muscle activity and prevents increasing metabolic rate, thermoregulatory
vasoconstriction was nonetheless able to maintain fever during 0.6 MAC isourane
anaesthesia.
68
Paralysis can reduce the magnitude of fever, but clinically its effect seems
to be less important than anaesthetic-induced inhibition of fever.
POST-OPERATIVE FEVER
The inammatory response can be induced by infectious or non-infectious
aetiologies such as body injury, surgical procedure, malignant tumour, brain stroke
etc. Fever is associated with the inammatory 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 of
epidural 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-induced
inhibition of fever
Fever during anaesthesia 509
during the post-operative period.
41,6972
Post-operative fevers seem to be induced
mainly by the inammatory reaction activated by surgery, but psychological stress
also can induce fever.
73
The anaesthetic technique used during surgery appears to
have little effect on post-operative fever
41
, 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, but
the reported numbers vary with type and duration of surgery, patient age, pre-
existing inammation and surgical site.
41,6972
It seems principally to be determined
by the severity of surgical invasion, as well as the existence of post-operative
infection.
Clinically, fever is considered the earliest and most easily detected sign of
infection in surgical patients. For this reason, it is important to measure core body
temperature in the early post-operative period. Post-operative changes in core
temperature and plasma concentrations of IL-6 in the rst 24 hours have been
evaluated in the patient undergoing elective abdominal, non-cardiac thoracic or
major abdominal surgeries.
41
One fourth of the patients had a maximum urinary
bladder temperature greater than 38.5 8C. The increase in core temperature was
associated with shivering and vasoconstriction until the core temperature reached
its 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 in
core temperature and plasma IL-6 concentration. Only one patient of the febrile
patients had an infection. This study suggests that fever during the post-operative
period is common and that it may be a normal inammatory response induced by
surgical stress, not by infection. Plasma IL-6 concentration seems to be a good
predictor 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 to
determine the source or to exclude a serious infection. It is well known that
work-ups for infections add extra medical costs.
69,74,75
Because it is known that
most febrile patients are bacteriologically negative
41,6971,76
routine evaluation of
post-operative fever may not always be needed. Instead, clinicians should consider
how common fever is in post-operative patients and restrict fever work-ups to
high-risk patients and patients in whom there are other indications of infection.
Factors such as c-reactive protein (CRP) elevation, white blood cell count, and
other 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 normal
inammatory response induced by surgical stress, not by infection
physicians should restrict fever work-ups to high-risk patients and patients
with other indications of infection
plasma IL-6 concentration seems to be a good predictor of post-operative fever
and acts as a pyrogen in post-surgical patients
510 C. Negishi and R. Lenhardt
TREATMENT OF FEVER
Infection, trauma, injury and surgical stimulation all induce the inammatory response,
which includes fever. Fever is the most common probleminhospitalized patients. Although
scientic knowledge about the inammatory response is increasing, it remains
controversial whether fever is benecial or harmful to the host defence.
4,5
However,
there are many animal experiments
7,8
and clinical observations
77,78
suggesting that
3.0
2.5
2.0
1.5
1.0
38.0
37.5
37.0
36.5
35.0
V
a
s
o
c
o
n
s
t
r
i
c
t
i
o
n
G
r
a
d
i
e
n
t
#

(

C
)
C
o
r
e

T
e
m
p

(

C
)
Postop Time (hours)
Intraop
P
r
e
o
p
0 2 4 6 8 10 12 14 16 18
20
15
10
Shivering
Incidence
(%)
0
5
*
*
*
*
*
*
*
*
*
*
Figure 6. Postoperative fever. Core temperature, percentage of patients shivering and vasoconstriction
gradient 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 and
vasoconstriction, both of which diminish as core temperature reaches the new greater post-operative
setpoint. The increase in vasoconstriction gradient indicates increased vasomotor tone. #Forearm
minus ngertip 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, Fever
and Antipyresis; The Role of the Nervous System, pp. 112. Cambridge: Cambridge University Press,) with
permission.
Research agenda
the aetiology of post-operative fever and its role should be established to allow
efcient treatment of fever during the post-operative period
Fever during anaesthesia 511
antipyretic therapy potentially increases the duration and severity of certain infections.
Fever seems to be an adaptive response that evolved to aid the host defensive
inammatory response against pathogens. The elevated temperature enhances the activity
of immuneeffectorcells
79,80
, andinhibits bacterial growthof somepathogens.
81
This is why,
historically, malarial fever and hot bath has been used for treatment of bacterial infections.
Currently, most febrile patients are treated with antipyretic, mainly for patient
comfort. However, if fever renders host defences more active, it should not be treated
quickly. Furthermore, fever is considered an important marker for evaluating the
effectiveness of treatment. Whether fever is benecial or harmful depends on the actual
clinical circumstances, and antipyretic treatment should be evaluated on an individual
basis.
82
Letting fever take its natural course does not seem to be harmful for febrile
patients.
83
However, accompanying symptoms such as tachycardia, increased oxygen
consumption, and discomfort are maladaptive for some patients, and in these cases
antipyretic use ought to be considered. Specically, fever should be treated in patients
with cardiopulmonary dysfunction, acute brain stroke or injury, or in those whose
temperature exceeds 40 8C.
The primary treatments for fever are amelioration of the underlying cause and
administration of antipyretic medications. External active cooling including tepid sponge
baths for children is not recommended for non-sedated febrile patients
8486
although it
is effective for heat stroke patients with a normal thermoregulatory set point. Active
cooling does not reduce core temperature, but increases the metabolic rate, activates
the autonomic nervous system, and provokes thermal discomfort, because lowered
skin temperature activates thermoregulatory efforts to increase the body temperature
to the set point.
84
In contrast, cutaneous cooling reduces core temperature in critical
care patients who are sedated
87
or paralysed.
88
Fever occurs in almost half of the patients with acute brain stroke or injury.
89
The
mechanism of this hyperthermia remains unknown, but it is known that even mild brain
hyperthermia worsens the functional outcome by enhancing neurotransmitter release,
exaggerating oxygen radical production, extending blood-brain barrier breakdown, and
other mechanisms.
90
In contrast, mild hypothermia seems to have neuroprotective effects
on severe brain insults, and mild hypothermia (33 8C) signicantly improves neurological
outcomes.
91
Thus, it is recommended that fever be combated assiduously in patients with
acute brain stroke and injury to induce normothermia or mild hypothermia. Antipyretics
sometimes fail to decrease core temperature in these patients
92
; thus, external cooling
combined 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, is
diminished and mild hypothermia increases the risk of infection.
91
Practice points
fever may be benecial to host defence mechanism, and should not be treated
routinely
fever should be treated in patients with cardiopulmonary dysfunction, acute
brain stroke or injury, or in whom temperature exceeds 40 8C
active cooling is not effective to reduce core temperature if the febrile patient is
awake. It only increases the metabolic rate, activates the autonomic nervous
system, and provokes thermal discomfort
active cooling is effective for sedated and paralysed patients. It may be a useful
treatment of fever in patients with acute brain stroke or injury
512 C. Negishi and R. Lenhardt
SUMMARY
Fever occurs when pyrogenic stimulation activates hypothalamic control centres. It is
dened 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 acute
inammatory 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 to
be mainly a central action that decreases cold-response thresholds. However, other
inhibitory mechanisms, such as peripheral inhibition of endogenous pyrogens, may also
exist. Intravenous anaesthetics also have similar effects on thermoregulation. There-
fore, it may also suppress fever in a dose-dependent manner; however, a conrming
study has yet to be done. Paralysis slightly reduces the magnitude of fever by preventing
shivering, although its effect seems to be less important than anaesthetic-induced
inhibition of fever.
Unlike general anaesthesia, epidural analgesia does not seem to suppress fever. This
may explain why fever is frequently observed in patients given epidural analgesia during
labour or post-operatively.
Fever is associated with the inammatory responses and is commonly observed
post-operatively. It is usually caused by non-infectious aetiologies and most patients are
bacteriologically negative. Thus, routine evaluation of post-operative fever may not
always be needed. Restricting fever work-ups to high-risk patients and patients with
other clinical signs of infection may be recommended.
Fever should not always be treated quickly because it is probably benecial to host
defence. However, antipyretic use should be considered when accompanying
symptoms, such as tachycardia or increased oxygen consumption, are harmful for
the patients. Cutaneous active cooling is not effective for reducing core
temperatureit increases the metabolic rate and thermal discomfort in the awake
febrile patient.
ACKNOWLEDGEMENTS
The authors thank Daniel I. Sessler MD. (Associate Dean, Weakley Distinguished
Research Chair, Director, Outcomes Researche Institute, University of Louisville) for
his support in performing the series of our fever studies and helpful comments on this
manuscript.
Research agenda
further research is warranted to better understand the fever mechanism
frequently observed in patients with brain stroke and injury
treatment strategy needs to be established for fever induced by acute stroke or
brain injury
Fever during anaesthesia 513
REFERENCES
* 1. Sessler DI. Perioperative hypothermia. New England Journal of Medicine 1997; 336: 17301737.
2. Lopez M, Sessler DI, Walter K et al. Rate and gender dependence of the sweating, vasoconstriction, and
shivering thresholds in humans. Anesthesiology 1994; 80: 780788.
* 3. Lenhardt R, Negishi C, Sessler DI et al. The effect of pyrogen administration on sweating and
vasoconstriction thresholds during desurane anesthesia. Anesthesiology 1999; 90: 15871595.
4. Kluger MJ, Kozak W, Conn CA et al. The adaptive value of fever. Infectious Disease Clinics of North America
1996; 10: 120.
5. Kluger MJ, Kozak W, Conn CA et al. Role of fever in disease. Annals of the New York Academy of Sciences
1998; 856: 224233.
* 6. Cooper KE. Fever Denition, Usefulness, Ubiquity. Fever and Antipyresis; The Role of the Nervous System. 112.
Cambridge: Cambridge University Press, 1995.
* 7. Kluger MJ, Ringler DH & Anver MR. Fever and survival. Science 1975; 188: 166168.
8. Vaughn LK, Veale WL & Cooper KE. Antipyresis: its effect on mortality rate of bacterially infected rabbits.
Brain Research Bulletin 1980; 5: 6973.
9. Kanosue K, Yanase-Fujiwara M & Hosono T. Hypothalamic network for thermoregulatory vasomotor
control. American Journal of Physiology 1994; 267: R283R288.
10. Kanosue K, Zhang Y-H, Yanase-Fujiwara M et al. Hypothalamic network for thermoregulatory shivering.
America Journal of Physiology 1994; 267: R275R282.
11. Dinarello CA, Bemheim HA, Duff GW et al. Mechanisms of fever induced by recombinant human
interferon. Journal of Clinical Investigation 1984; 74: 906913.
12. Dinarello CA, Cannon JG, Mier JWet al. Multiple biological activities of human recombinant interleukin 1.
Journal of Clinical Investigation 1986; 77: 17341739.
13. Dinarello CA, Cannon JG, Wolff SM et al. Tumor necrosis factor (cachectin) is an endogenous pyrogen
and induces production of interleukin 1. Journal of Experimental Medicine 1986; 163: 14331450.
14. Dinarello CA, Cannon JG, Mancilla J et al. Interleukin-6 as an endogenous pyrogen. Induction of
prostaglandin E2 in brain but not in peripheral blood mononuclear cells. Brain Research 1991; 562:
199206.
15. Davatelis G, Wolpe SD, Sherry B et al. Macrophage inammatory protein-1. A prostaglandin-independent
endogenous pyrogen. Science 1989; 243: 10661068.
16. Gaykema RPA, Dijkstra I & Tilders FJH. Subdiaphragmatic vagotomy suppresses endotoxin-induced
activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion. Endocrinology
1995; 136: 47174720.
17. Sehic E & Blatteis CM. Blockade of lipopolysaccharide-induced fever by subdiaphragmatic vagotomy in
guinea pigs. Brain Research 1996; 726: 160166.
18. Simons CT, Kulchitsky VA, Sugimoto N et al. Signaling the brain in systemic inammation: which vagal
branch is involved in fever genesis? American Journal of Physiology 1998; 275: R63R68.
19. Boulant JA. Thermoregulation. In Mackowiak PA (ed.) Fever: Basic Mechanisms and Management. pp 3558.
New York: Lippincott-Raven, 1997.
20. Lipton JM & Glyn JR. Central administration of peptides alters thermoregulation in the rabbit. Peptides
1980; 1: 1518.
21. Naylor AM, Ruwe WD & Veale WL. Antipyretic action of centrally administered arginine vasopressin but
not oxytocin in the cat. Brain Research 1986; 385: 156160.
22. Leon LR, Kozak W & Kluger MJ. Role of IL-10 in inammation. Studies using cytokine knockout mice.
Annals of the New York Academy of Sciences 1998; 856: 6975.
23. Leon LR, Kozak W, Rudolph K et al. An antipyretic role for interleukin-10 in LPS fever in mice. American
Journal of Physiology 1999; 276: R81R89.
24. Annadata RS, Sessler DI, Tayefeh F et al. Desurane slightly increases the sweating threshold, but
produces marked, non-linear decreases in the vasoconstriction and shivering thresholds. Anesthesiology
1995; 83: 12051211.
25. Matsukawa T, Kurz A, Sessler DI et al. Propofol linearly reduces the vasoconstriction and shivering
thresholds. Anesthesiology 1995; 82: 11691180.
26. Kurz A, Go JC, Sessler DI et al. Alfentanil slightly increases the sweating threshold and markedly reduces
the vasoconstriction and shivering thresholds. Anesthesiology 1995; 83: 293299.
27. Kurz A, Ikeda T, Sessler DI et al. Meperidine decreases the shivering threshold twice as much as the
vasoconstriction threshold. Anesthesiology 1997; 86: 10461054.
28. Talke P, Tayefeh F, Sessler DI et al. Dexmedetomidine does not alter the sweating threshold, but
comparably and linearly reduces the vasoconstriction and shivering thresholds. Anesthesiology 1997; 87:
835841.
514 C. Negishi and R. Lenhardt
29. De Witte JL, Kim J-S, Sessler DI et al. Tramadol reduces the sweating, vasoconstriction, and shivering
thresholds in humans. Anesthesia and Analgesia 1998; 87: 173179.
* 30. Negishi C, Lenhardt R, Sessler DI et al. Desurane reduces the febccrile response to administration of
interleukin-2. Anesthesiology 1998; 88: 11621169.
31. Kotanidou A, Choi AM, Winchurch RA et al. Urethan anesthesia protects rats against lethal endotoxemia
and reduces TNF-alpha release. Journal of Applied Physiology 1996; 81: 23052311.
32. Sakata N, Morimoto A & Murakami N. Changes in plasma catecholamines during fever induced by
bacterial endotoxin and interleukin-1 beta. Japanese Journal of Physiology 1994; 44: 693703.
33. Galley HF, Dubbels AM & Webster NR. The effect of midazolam and propofol on interleukin-8 from
human polyphonuclear leukocytes. Anesthesia and Analgesia 1998; 86: 12891293.
34. Nader ND, Ignatowski TA, Kurek CJ et al. Clonidine suppresses plasma and cerebrospinal uid
concentrations of TNF-alpha during the perioperative period. Anesthesia and Analgesia 2001; 93:
363369.
35. Plachinta RV, Hayes JK, Cerilli LA et al. Isourane pretreatment inhibits lipopolysaccharide-induced
inammation in rats. Anesthesiology 2003; 98: 8995.
36. Loop T, Liu Z, Humar M et al. Thiopental inhibits the activation of nuclear factor kappaB. Anesthesiology
2002; 96: 12021213.
37. Giraud O, Molliex S, Rolland C et al. Halogenated anesthetics reduce interleukin-1beta-induced cytokine
secretion by rat alveolar type II cells in primary culture. Anesthesiology 2003; 98: 7481.
38. El Azab SR, Rosseel PM, De Lange JJ et al. Effect of VIMA with sevourane versus TIVA with propofol or
midazolam-sufentanil on the cytokine response during CABG surgery. European Journal of Anesthesiology
2002; 19: 276782.
39. Roytblat L, Talmor D, Rachinsky M et al. Ketamine attenuates the interleukin-6 response after
cardiopulmonary bypass. Anesthesia and Analgesia 1998; 87: 266271.
40. Crozier TA, Muller JE, Quittkat D et al. Effect of anesthesia on cytokine response to abdominal surgery.
British Journal of Anaesthesia 1994; 72: 280285.
* 41. Frank SM, Kluger MJ & Kunkel SL. Elevated thermostatic setpoint in postoperative patients. Anesthesiology
2000; 93: 14261431.
42. Miyawaki T, Maeda S, Koyama Y et al. Elevation of plasma interleukin-6 level is involved postoperative
fever following major oral and maxillofacial surgery. Oral Surgery, Oral Medicine, Oral Pathology, Oral
Radiology and Endodontics 1998; 85: 146152.
* 43. Negishi C, Lenhardt R, Ozaki K et al. Opioids inhibit febrile responses in humans, whereas epidural
analgesia does not: an explanation for hyperthermia during epidural analgesia. Anesthesiology 2001; 94:
218222.
* 44. Negishi C, Kim JS, Lenhardt R et al. Alfentanil reduces the febrile response to interleukin-2 in human.
Critical Care Medicine 2000; 3: 12951300.
45. Chao CC, Sharp BM, Pomeroy C et al. Lethality of morphine in mice infected with Toxoplasma Gondi.
Journal of Pharmacology and Experimental Therapeutics 1990; 242: 605609.
46. Beilin B, Shavit Y, Hart J et al. Effect of anesthesia based on large versus small doses of fentanyl on natural
killer cell cytotoxicity in the perioperative period. Anesthesia and Analgesia 1996; 82: 492497.
47. Carr DJ, Gerak LR & France CP. Naltrexone antagonizes the analgestic and immunosuppressive effects of
morphine in mice. Journal of Pharmacology and Experimental Therapeutics 1994; 269: 693698.
48. Fecho K, Maslonek KA, Dykstra LA et al. Assessment of the involvement of central nervous system and
peripheral opioid receptors in the immunomodulatory effects of acute morphine treatment in rat. Journal
of Pharmacology and Experimental Therapeutics 1996; 276: 626636.
49. Houghtling RA, Mellon RD, Tan RJ et al. Acute effects of morphine on blood lymphocyte proliferation and
plasma IL-6 level. Annals of the New York Academy of Sciences 2000; 917: 771777.
50. Frank SM, Beattie C, Christopherson R et al. Epidural versus general anesthesia, ambient operating room
temperature, and patient age as predictors of inadvertent hypothermia. Anesthesiology 1992; 77:
252257.
51. Jenkins J, Fox J & Sharwood-Smith G. Changes in body heat during transversical prostatectomy: a
comparison of general and epidural anesthesia. Anesthesia 1983; 38: 748753.
52. Matsukawa T, Sessler DI, Christensen R et al. Heat ow and distribution during epidural anesthesia.
Anesthesiology 1995; 83: 961967.
53. Emerick TH, Ozaki M, Sessler DI et al. Epidural anesthesia increases apparent leg temperature and
decreases the shivering threshold. Anesthesiology 1994; 81: 289298.
54. Kurz A, Sessler DI, Schroeder M et al. Thermoregulatory response threshold during spinal anesthesia.
Anesthesia and Analgesia 1993; 77: 721726.
55. Lieberman E & ODonoghue C. Unintended effects of epidural analgesia during labor: a systematic review.
American Journal of Obstetrics and Gynecology 2002; 186: S31S68.
Fever during anaesthesia 515
56. Bredtmann RD, Herden HN, Teichmann W et al. Epidural analgesia in colonic surgery. Results of a
randomized prospective study. British Journal of Surgery 1990; 77: 638642.
57. Lieberman E, Lang JM, Frigoletto F et al. Epidural analgesia, interpartum fever, and neonatal sepsis
evaluation. Pediatrics 1997; 99: 415419.
58. Fehder WP & Gennaro S. Immune alterations associated with epidural analgesia for labor and delivery.
American Journal of Maternal Child Nursing 1998; 23: 292299.
59. Kost-Byerly S, Tobin JR, Greenberg RS et al. Bacterial colonization and infection rate of continuous
epidural catheters in children. Anesthesia and Analgesia 1998; 86: 712716.
60. Frigoletto FD, Lieberman E, Lang JM et al. A clinical trial of active management of labor. New England
Journal of Medicine 1995; 333: 745750.
61. Philip J, Alexander JM, Sharma SK et al. Epidural analgesia during labor and maternal fever. Anesthesiology
1999; 90: 12711275.
62. Marx GF & Loew D. Tympanic temperature during labour and parturition. British Journal of Anaesthesia
1975; 47: 600602.
63. Gonen R, Korobochka R, Degani S et al. Association between epidural analgesia and intrapartum fever.
American Journal of Perinatology 2000; 17: 127130.
64. Smulian JC, Bhandari V, Vintzileos AM et al. Intrapartum fever at term: serum and histologic markers of
inammation. American Journal of Obstetrics and Gynecology 2003; 188: 269274.
65. Kurz A, Sessler DI, Christensen R et al. Heat balance and distribution during the core-temperature
plateau in anesthetized humans. Anesthesiology 1995; 83: 491499.
66. Matsukawa T, Sessler DI, Sessler AM et al. Heat ow and distribution during induction of general
anesthesia. Anesthesiology 1995; 82: 662673.
67. Plattner O, Ikeda T, Sessler DI et al. Postanesthetic vasoconstriction slows postanesthetic peripheral-to-
core transfer of cutaneous heat, thereby isolating the core thermal compartment. Anesthesia and Analgesia
1997; 85: 899906.
68. Lenhardt R, Negishi C, Sessler DI et al. Paralysis only slightly reduces the febrile response to interleukin-2
during isourane anesthesia. Anesthesiology 1998; 89: 648656.
69. Fleischlag J & Busuttil RW. The value of postoperative fever evaluation. Surgery 1983; 94: 358363.
70. Garibaldi RA, Brondine S, Mastumiya S et al. Evidence of the non-infectious etiology of early
postoperative fever. Infection Control 1985; 6: 273277.
71. Hobar PC, Masson JA, Herrera R et al. Fever after craniofacial surgery in the infant under 24 months of
age. Plastic and Reconstructive Surgery 1998; 102: 3236.
72. Thong WY, Strickler AG, Li S et al. Hyperthermia in the forty-eight hours after cardiopulmonary bypass.
Anesthesia and Analgesia 2002; 95: 14891495.
73. De Jongh RF, Visser KC, Booij LH et al. Interleukin-6 and perioperative thermoregulation and HPA-axis
activation. Cytokine 2003; 21: 248256.
74. Shulkin DJ, Kinosian B, Glick H et al. The economic impact of infections. An analysis of hospital costs and
charges in surgical patients with cancer. Archives of Surgery 1993; 128: 449452.
75. Theuer CP, Bongard FS & Klein SR. Are blood cultures effective in the evaluation of fever in perioperative
patients? American Journal of Surgery 1991; 162: 615618.
76. Ishikawa S, Ohtaki A, Takahashi T et al. Management of postoperative fever in cardiovascular surgery.
Journal of Cardiovascular Surgery (Torino) 1998; 39: 9597.
77. Bryant RE, Hood AF, Hood CE et al. Factors affecting mortality of gram-negative rod bacteria. Archives of
Internal Medicine 1971; 127: 120128.
78. Weinstein MR, Iannini PR, Stratton CWet al. Spontaneous bacterial peritonitis. A review of 28 cases with
emphasis on improved survival and factors inuencing prognosis. American Journal of Medicine 1978; 64:
592598.
79. Jampel HD, Duff GW, Gershon RK et al. Fever and immunoregulation. III. Hyperthermia augments the
primary in vitro humoral immune response. Journal of Experimental Medicine 1987; 157: 12291238.
80. Wang XY, Ostberg JR & Repasky EA. Effect of fever-like whole-body hyperthermia on lymphocyte spectrin
distribution, protein kinase C activity, and uropod formation. Journal of Immunology 1999; 162:
33783387.
81. Small PM, Tauber MG, Hackbarth CJ et al. Inuence of body temperature on bacterial growth rates in
experimental pneumococcal meningitis in rabbits. Infection and Immunity 1986; 52: 484487.
82. Marik PE. Fever in the ICU. Chest 2000; 117: 855869.
83. Gozzoli V, Schottker P, Suter P et al. It is worth treating fever in intensive care unit patients? Preliminary
results from a randomized trial of the effect of external cooling. Archives of Internal of Medicine 2001; 161:
121123.
* 84. Lenhardt R, Negishi C, Sessler DI et al. The effect of physical treatment of induced fever in human.
American Journal of Medicine 1999; 106: 550555.
516 C. Negishi and R. Lenhardt
85. Corrard F. Ways to reduce fever; are luke-warm water baths still indicated? Archives of Pediatrics 2002; 9:
311315.
86. Axelrod P. External cooling and the management of fever. Clinical Infectious Diseases 2000; 31(supplement
5): S224S229.
87. Poblete B, Romand JA, Pichard C et al. Metabolic effect of i.v. procetanol, metamizol or external cooling in
critically ill febrile sedated patients. British Journal of Anaesthesia 1997; 78: 123127.
88. Manthous CA, Hall JB, Olson D et al. Effect of cooling on oxygen consumption in febrile critically ill
patients. American Journal of Respiratory and Critical Care Medicine 1996; 151: 1014.
89. Kilpatrick MM, Lowry DW, Firlik AD et al. Hyperthermia in the neurosurgical intensive care unit.
Neurosurgery 2000; 47: 850855.
90. Myron DG & Busto R. Combating hyperthermia in acute stroke; a signicant clinical concern. Stroke 1998;
29: 529534.
91. Clifton GL, Allen S, Barrodale P et al. A phase II study of moderate hypothermia in severe brain injury.
Journal of Neurotrauma 1993; 10: 263271.
92. Dippel DWJ, van Breda EJ, van Gemert HMA et al. Effect of paracetamol (acetaminophen) on body
temperature in acute ischemic stroke; a double-blind, randomized phase II clinical trial. Stroke 2001; 32:
16071612.
Fever during anaesthesia 517