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Temperature Management in Acute

Neurologic Disorders
Yekaterina K. Axelrod, MD
Michael N. Diringer, MD
Department of Neurology, Washington University School of Medicine,
660 South Euclid Avenue, Campus Box 8111, St. Louis, MO 63110-1093, USA
Neurology/Neurosurgery Intensive Care Unit, BarnesJewish Hospital,
St. Louis, MO 63110-1093, USA
Section of Neurologic Intensive Care, Washington University School of Medicine,
660 South Euclid Avenue, St. Louis, MO 63110-1093, USA
Department of Neurological Surgery, Washington University School of Medicine,
660 South Euclid Avenue, St. Louis, MO 63110-1093, USA
Department of Anesthesiology, Washington University School of Medicine,
660 South Euclid Avenue, St. Louis, MO 63110-1093, USA
Body temperature is tightly controlled in humans at approximately 37

the optimal temperature for function of many organs. This temperature is
mediated in the hypothalamus, which regulates the balance between the
production and conservation of heat and heat loss. The main source of
heat in the body is the thermal energy produced in active visceral organs
and tissues by metabolic processes, also known as obligatory thermogenesis.
Additional heat generation, referred to as facultative thermogenesis, is
accomplished through voluntary muscular and behavioral activity or invol-
untarily by the autonomic nervous and endocrine systems. Heat also may be
gained passively by conduction and convection from the environment, when
ambient temperature exceeds body temperature, and by radiation from solar
or other sources.
Heat can dissipate by four means. During rest, radiation accounts for
about 60% of heat loss, evaporation for 20%, and convection combined
with conduction for another 20%. Conversely, during exercise, evaporation
This article originally appeared in Critical Care Clinics, volume 22, issue 4.
* Corresponding author. Department of Neurology, Washington University School of
Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO 63110-1093, USA.
E-mail address: (M.N. Diringer).
0733-8619/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
Neurol Clin 26 (2008) 585603
becomes the dominant mechanism, accounting for 80% of heat loss,
whereas 15% of heat is lost by convection/conduction, and only 5% is
lost by radiation [1]. Temperature, humidity, and velocity of surrounding
air can alter these proportions making heat exchange more or less eective.
Several physiologic mechanisms are involved in temperature homeostasis,
all of which are coordinated through the hypothalamus. The thermosensi-
tive neurons located in the hypothalamus, skin, and spinal cord constantly
monitor body temperature [2]. Cold and warm sensitive neurons of the hy-
pothalamus mediate thermoregulatory responses. Cooling of the preoptic/
anterior hypothalamus (POAH) promotes heat production through shiver-
ing, an increase in the metabolic rate, and, to a lesser degree in adults,
sympathetically mediated nonshivering thermogenesis generated by mito-
chondrial uncoupling proteins in the brown fat [3]. Internal heat is preserved
by vasoconstriction of the cutaneous circulation leading to relative surface
cooling, which initiates behavior aimed at warming (increased food and
warm beverage intake, seeking environment with higher temperatures, add-
ing layers of insulation). Piloerection is a minor mechanism of heat preser-
vation in humans. With warming of the POAH, heat loss is promoted by
cutaneous vasodilation and diaphoresis, an increase in the respiratory rate
to enhance heat loss, inhibition of uncoupling proteins in the brown fat,
and behavioral modulations intended to lose heat.
Core temperature typically exhibits diurnal rhythmicity with a nadir of
about 37.2

C in the morning and a peak of approximately 37.7

C in the af-
ternoon [4]. These circadian variations are controlled by the suprachiasmatic
nucleus [5]. In addition, the hypothalamic set-point is sensitive to numerous
hormones, including sex steroids, catecholamines, and thyroid hormones.
Brain temperature and body temperature
Human brain is metabolically more active than other organs. The brain
accounts for 2% to 3% of the total body weight, whereas it consumes 20%
of the oxygen and 25% of the glucose used by the organism at rest. As
a result of its high metabolic rate, brain generates a considerable amount
of heat. Heat dissipation is limited by a thick layer of insulation provided
by the skull, highly vascular scalp, and hair. Brain temperature under nor-
mal circumstances depends on three main factors: (1) rate of local heat
production (ie, cerebral metabolic activity), (2) cerebral blood ow (also
correlates with underlying neuronal activity), and (3) temperature of the per-
fusing blood [6].
The dierence between brain and body core temperatures is debated.
Several studies in normal humans and in patients with traumatic brain
injury (TBI) found that brain temperatures ranged from 0.3

C to 2

C higher
than core temperatures [710]. One study monitored cerebral and rectal tem-
peratures in 61 patients admitted to a neurologic ICU with TBI, subarach-
noid hemorrhage (SAH), or stroke with low Glasgow Coma Scale scores
[11]. There was a trend toward higher temperatures in the brain; however,
statistical signicance was not reached. Another study did not nd the brain
temperatures to be higher in a series of 20 adults with severe TBI [12]. Mon-
itoring techniques, timing of measurements, and heterogeneity of the popu-
lations may explain the variable results found in these studies.
Hyperthermia and fever
Whenever heat production exceeds dissipation, the accumulation of heat
causes body temperature to increase. There is no standard numeric deni-
tion of what constitutes abnormally elevated temperature; the choice is usu-
ally arbitrary (generally considered O37.538

C). Hyperthermia may be

classied as controlled (secondary to a change in hypothalamic set-point),
or uncontrolled.
In uncontrolled hyperthermia, thermoregulatory heat loss mechanisms
usually are fully employed, but are unable to lower temperature to the nor-
mal physiologic thermal set-point. Examples include vigorous physical exer-
cise or exertion, dehydration, immersion in hot uids, or heatstroke. Severe
cases of uncontrolled hyperthermia with temperatures greater than 41

also called extreme pyrexia, may be seen with hypothalamic lesions (strokes
and tumors), with endocrine disturbances (thyroid storm or pheochromocy-
toma crisis), with malignant hyperthermia of anesthesia, with neuroleptic
malignant syndrome, or in association with several drugs of abuse [13].
Fever, or controlled hyperthermia, represents an upward shift of the
hypothalamic set-point and is associated with an increase in core tempera-
ture to an optimal level for host defense. It is an ancient adaptive mecha-
nism, usually associated with infections and intended to improve host
survival. Temperature almost never increases beyond 42

C, however, which
may be explained partly by the limitations in ring rates of the thermosen-
sitive neurons [14].
Two mechanisms have been proposed to explain the genesis of fever. In
brief, according to the conventional concept, host leukocytes and macro-
phages produce pyrogenic cytokines when exposed to a range of foreign
products, such as whole microorganisms, various toxins, proteins, lipopoly-
saccharides, and peptidoglycans. Other substances, including complement,
antigen-antibody complexes, and lymphocyte-derived molecules, known as
endogenous pyrogens, also are capable of stimulating cytokine release. In
response to circulating cytokines (interleukin-1, interleukin-6, tumor necro-
sis factor-a, and interferons), prostaglandin E
) is synthesized in the
hypothalamus, stimulating temperature elevation [15].
Blatteis and colleagues [16] summarized an alternative concept of fever
origin, in which PGE
is synthesized rapidly in the cyclooxygenase pathway
from arachidonic acid [17] by the Kuper cells of the liver. These cells are
activated by the complement cascade component 5a that is released in
response to invading pathogen, independent of the cytokines. Next, either
is transported to the hypothalamus via the bloodstream, or the vagal
and noradrenergic pathways convey its pyrogenic signals to the POAH.
Norepinephrine seems to play an important role in this process. In animal
models, norepinephrine microinjected into the POAH causes PGE
independent immediate elevation in temperature and enhances local PGE
synthesis, producing a relatively delayed febrile response [18,19]. According
to this alternative theory, the slower pyrogenic cytokine mechanism of fever
contributes to the later temperature increase and fever maintenance [16].
In the hypothalamus, PGE
seems to decrease the ring rate of the neu-
rons resulting in an upward shift of the thermal set-point [20,21]. The organ-
ism responds by engaging heat conservation and production mechanisms to
increase body temperature to the new set-point and maintain elevated
temperature. When PGE
is cleared, the temperature set-point returns to
baseline [21], and heat loss mechanisms are initiated.
Pyrogens are counterbalanced by so-called cryogens, a group of mole-
cules limiting the magnitude of fever to levels that are not detrimental to
the body. These endogenous antipyretics include interleukin-4, interleukin-
10, arginine vasopressin, glucocorticoids, a-melanocyte-stimulating hor-
mone, and others [22]. Tumor necrosis factor-a, perhaps the main cytokine
moderator of fever, may act as a cryogen or as a pyrogen depending on the
conditions [23].
Fever in critically ill patients
Hyperthermia is common in various critical illnesses and conditions. The
most frequent temperature elevation seen in surgical ICUs is a short self-
limiting postoperative fever reecting an inammatory response to surgery.
Other, more serious causes of pyrexia in the ICU include infections, alcohol
and drug withdrawals, central nervous system insults, venous thromboem-
bolism, myocardial infarction, ileus, gastrointestinal hemorrhage, acute
pancreatitis, acalculous cholecystitis, adrenal insuciency, and hyperthy-
roidism. Numerous medications used in the ICU may be pyrogenic, includ-
ing antibiotics, anticonvulsants, agents with anticholinergic properties, and
sympathomimetics [24]. Febrile episodes can be seen with transfusions of
blood products. Many molecules produced in the body during critical illness
are able to stimulate pyrogenesis, including activated complement, antigen-
antibody complexes, inammatory bile acids, certain lymphocyte products,
urate crystals, and others [25].
Fever in acute neurologic disorders
Fever also is common in critically ill patients with acute neurologic or
neurosurgical disorders. In a retrospective review, pyrexia was reported in
47% of patients admitted to a neurologic ICU. Each additional day in the
ICU increased the risk of fever by 32%. Of all patients who remained in
the neurologic ICU for 2 weeks, 93% developed fever [26]. In a series of
4295 patients, elevated temperatures were associated with increased ICU
and hospital length of stay, higher mortality, and worse outcome after con-
trolling for complications, diagnoses, severity of illness, and age [27].
Acute neurologic insults associated with fever include TBI, SAH, ische-
mic stroke, intracerebral hemorrhage (ICH), and seizures [2629]. Temper-
ature elevations beyond 38

C have been described in more than two thirds

of patients with SAH or TBI [28]. In patients with ischemic stroke, fever
was detected in more than 60% of patients during the rst 72 hours [30].
In one study, 91% of the patients with ICH developed temperatures greater
than 37.5

C at least once during the rst 72 hours of hospitalization [31].

Approximately one third of patients with pontine hemorrhage developed
extreme pyrexia early after onset [32]. Overall in a neurologic ICU popula-
tion, febrile episodes are attributed to infection in only half of patients
The precise mechanism of noninfectious fever or central fever in acute
disorders of the central nervous system is not well understood. The neuro-
inammatory cascade initiated by numerous primary brain insults, such
as hypoxia; ischemia; reperfusion; or the presence of blood products in
the brain parenchyma, subarachnoid space, or ventricles, results in the
synthesis of PGE
and resetting of the hypothalamic thermostat to a higher
temperature [31,34,35]. Direct mechanical damage or compression of the
POAH and disruption of the inhibitory pathways from the midbrain also
could play a role in the pathogenesis of fever [3639].
Fever and neuronal injury
Experimental data indicate that hyperthermia has a detrimental eect on
the brain. In animal models of focal and global cerebral ischemia, elevated
brain temperature worsens outcome [3942]. A temperature increase of only

C or 1.2

C results in a greater zone of injury and permanent neuronal loss

after an ischemic insult [43].
Exacerbation of brain injury may be mediated by numerous mechanisms
during hyperthermia. Higher brain temperature accelerates excitotoxic neu-
rotransmitter release from the ischemic or injured brain. The brains of
febrile animals exhibit higher levels of excitotoxic substances compared
with brains of animals without fever [44]. Cortical oxygen free radical pro-
duction after a global ischemic insult is markedly inuenced by the brain
temperature [45]. Additionally, the extent of blood-brain barrier disruption
during ischemia is remarkably sensitive to brain temperature. The extrava-
sation of protein tracers across the barrier is markedly enhanced by intrai-
schemic fever [46]. Outcome may be aected when the temperature
alterations occur during or after the insult. Even small fever reductions
occurring after the insult are associated with improved outcomes in terms of
postinsult neurologic function and histopathologic ndings [47,48].
Benets of lowering brain temperature
Hypothermia seems to be neuroprotective in animal models working
through several dierent mechanisms. It reduces the release of excitotoxic
neurotransmitters [49,50], diminishes the oxidative stress [51], preserves
the integrity of the blood-brain barrier with suppression of cerebral edema
[52], decreases postischemic inammation [5355], normalizes acid-base
status in the brain [56,57], and helps restore protein synthesis [58]. Hypo-
thermia also decreases cerebral metabolism with reduced consumption of
oxygen and glucose [59]. Although production of adenosine triphosphate
is reduced by hypothermia, the rate of adenosine triphosphate consumption
is decreased to a greater degree than production, resulting in an overall
improvement of the energy balance [60].
In rodent models of cerebral ischemia, hypothermia led to a signicant
increase in the number of surviving neurons [40,6163]. More relevant to
the clinical situation, hypothermia induced after cerebral ischemia also im-
proved neuron survival [64,65] and reduced the volume of the infarcted area
[66]. When initiated 2 hours after reperfusion, hypothermia led to a 50%
preservation of hippocampal neurons, whereas when delayed by 24 hours,
it was not eective [67]. Studies suggest that prolonged hypothermia for
24 hours is needed for sustained neuroprotection after 2 months [64]. Func-
tionally, postischemic hypothermia improves water maze performance [68]
and diminishes neurologic decits [64,69].
Fever and neuronal injury in patients
With numerous studies indicating that fever is an independent predictor
of poor outcome in patients with various acute disorders of the central ner-
vous system [7074], fever management has become a common practice in
neurologic/neurosurgical ICUs. According to American Heart Association
guidelines for the management of patients with acute ischemic stroke and
spontaneous ICH, body temperature should be maintained at a normal level
[75,76]. Fever management also is recommended by the American Associa-
tion of Neurological Surgeons as a means of preventing secondary injury in
patients with head trauma [77]. Although hypothermia decreases intracra-
nial pressure (ICP) [7880], there is no strong evidence to date that fever
reduction improves clinical outcome in this population.
In a selected group of cardiac arrest patients, induction and mainte-
nance of hypothermia of 33

C for 24 hours signicantly improved neuro-

logic and overall outcome [81,82]. A meta-analysis of the data from the
hypothermia trials established that for one additional neurologically intact
survivor, only seven patients needed to be treated [83]. The American
Heart Association and the Advanced Life Support Task Force of the In-
ternational Liaison Committee on Resuscitation recommend hypothermia
for patients who have had cardiac arrest [84].
Ischemic stroke
Hyperthermia is common in patients with ischemic stroke. In one pro-
spective study, 43% of patients developed fever (O38.3

C) during the rst

week of hospitalization. Patients with high fever were far more likely to
die within the rst 10 days after insult than patients with lower temperature
[70]. An increase in temperature of 0.5

C has been associated with signi-

cantly worse outcomes in stroke patients [85]. Elevated body temperature
is associated with clinical deterioration, larger infarct size, and increased
cerebrospinal uid levels of glutamate and glycine [86].
Mild spontaneous hypothermia may be associated with more favorable
outcome after ischemic stroke. A 1

C decrease in body temperature after

acute ischemic stroke nearly doubled the odds of a good outcome, indepen-
dent of other factors [87]. In a retrospective study of 390 patients, the pa-
tients who were hypothermic on admission (within 6 hours of onset) had
lower mortality and improved function in a dose-dependent manner [88].
The rst report of therapeutic hypothermiainthe ischemic stroke population
was published in 1998 [89]. Patients with severe ischemic stroke in the middle
cerebral arteryterritorywere treatedwithmoderate hypothermia(33

C) bysur-
face cooling. Forty-four percent of patients died as a result of rebound cerebral
edema andherniationduring rewarming. Alater case series bythe same authors
reported on 50 patients with large middle cerebral artery strokes and edema
who were cooled to 33

Cfor 48 to 72 hours [90]. Bradycardia, thrombocytope-

nia, and pneumonia were the most commonly seen complications. Despite
a 30% incidence of herniation during rewarming, the outcome with hypother-
mia was reported to be better than in historical controls. The same group later
reported that with controlled rewarming, ICP control was improved [91].
More recently, intravascular devices have been used to cool stroke
patients rapidly. Six patients with severe acute ischemic stroke had hypo-
thermia induced and maintained by circulating temperature-adjusted saline
in a closed-loop system of a central catheter in the inferior vena cava [92].
Temperature was reduced by 1.4

C per hour, and a target temperature of


C to 33

C was reached in approximately 2 to 4 hours. No outcome

data were available in this safety and feasibility study. Another small
(n 40) pilot multicenter trial of mild hypothermia was conducted in
patients with acute ischemic stroke evaluating the feasibility of endovascular
cooling; no dierence in clinical outcome was shown [93].
A more recently conducted small study compared decompressive hemi-
craniectomy with a combination of mild hypothermia with hemicraniectomy
[94]. After hemicraniectomy, patients were cooled to 35

C for 48 hours
mainly with intravascular catheters followed by a slow rewarming phase
of 1

C per 24 hours. A trend toward better outcome was shown in the com-
bined treatment group.
Traumatic brain injury
There was a burst of interest in the 1940s and early 1950s in the use of
hypothermia to treat patients with severe head injury [95]. No further devel-
opments occurred until 40 years later, however, when several small single-
center trials of therapeutic hypothermia for treatment of TBI suggested
some benet [9698]. In a retrospective review of 1069 patients with severe
TBI, mild-to-moderate hypothermia to 32

C to 33

C led to a 22% relative

reduction in the risk of poor outcome [99]. In a large prospective random-
ized multicenter trial of 392 patients with severe TBI, however, hypothermia
failed to show benet [78]. Surface cooling was used to maintain a tempera-
ture of 33

C for 48 hours, but had no impact on mortality or functional

outcome. Some concern has been expressed regarding intercenter variability
in the treatment protocols and delay in application of hypothermia. The
mandatory rewarming at 48 hours independent of ICP has been cited as
a possible contributor to the lack of benet. Subgroup analysis showed a bet-
ter outcome in the patients who were hypothermic at presentation [100].
Numerous other studies using a variety of end points and subgroups sug-
gested some benet [79,101], yet a more recent meta-analysis did not show
any overall benet of induced hypothermia [102].
Aneurysmal subarachnoid hemorrhage
Fever is common in aneurysmal SAH [26,29,102] and, after controlling
for hemorrhage severity or presence of infection, is independently associated
with vasospasm and poor outcome [73,103]. Studies of therapeutic hypo-
thermia in small groups of patients with poor grade SAH and refractory
vasospasm showed promising results [104106]. In hypothermic SAH
patients, the degree of oxygen metabolic rate reduction was greater than
cerebral blood ow reduction representing a state of luxury perfusion
[107]. This state should allow the brain to tolerate lower cerebral blood
ow without energy failure.
Hypothermia has been suggested as a neuroprotective mechanism during
intracranial aneurysm surgery, to mitigate the eects of temporary vessel
occlusion. Initial small trials showed encouraging results [108,109]. A large
prospective multicenter trial of intraoperative hypothermia in patients with
good grade SAH found no benet, however [110].
Intracerebral hemorrhage
The duration of fever within the rst 72 hours after ICH is associated
with poor outcome; it also may contribute independently to the clinical
outcome [31]. Elevated temperature was an independent predictor for early
neurologic deterioration in patients with ICH [111]. No trials of applied
therapeutic hypothermia have been performed yet.
Status epilepticus
In a small case series of patients with refractory status epilepticus, hypo-
thermia of 30

C to 31

C was combined with barbiturate coma, and success-

ful control of seizures was achieved [112]. There may be a potential role of
hypothermia in management of refractory seizures [113], and further studies
are warranted.
Treatment of fever
Standard fever management consists of antipyretic drug therapy and
external/physical cooling. Methods of physical cooling include external sur-
face cooling with water-lled or air-lled cooling blankets, ice packs, naso-
gastric or rectal lavage, and alcohol baths. A few novel methods of cooling
with intravascular devices and cooling helmets have been introduced more
Antipyretic pharmacologic agents, such as acetaminophen, acetylsalicylic
acid and other nonsteroidal anti-inammatory medications, and corticoste-
roids, seem to blunt the febrile response by inhibiting cyclooxygenase, the
substance catalyzing PGE
production in various tissues, including the
POAH [114]. Although antipyretic drugs have been used to reduce fever for
decades, they are not always ecacious, and use may be limited by side eects.
In a prospective trial, 75 patients with acute ischemic stroke (independent
of body temperature) were randomly assigned to 500 mg of acetaminophen
(low dose), 1000 mg of acetaminophen (high dose), or placebo, administered
six times a day for 5 days [115]. High-dose acetaminophen lowered body
temperature by 0.4

C compared with placebo at 24 hours, whereas low-

dose acetaminophen had no eect on body temperatures. After 5 days of
treatment, no dierences in temperature were found between the placebo
and either study group. A small pilot study found antipyretics and the cur-
rent methods of physical cooling to have limited ecacy in reducing fever
[116]. Fourteen febrile critically ill patients were treated with 650 mg of acet-
aminophen alone (n 5), acetaminophen with a cooling blanket (n 3), or
cooling blanket alone (n 6). Mean body temperature decreased minimally
after treatment in the physical coolingonly group (from 39.1

C to 39.0

and acetaminophen with cooling blanket group (from 39.1

C to 38.6

The mean body temperature in the acetaminophen-only group increased
from 39.2

C to 39.4

External cooling by using water-cooled blankets, rotary fans, and spong-
ing the body surface with water also are of limited ecacy. Sponging has
been shown to hasten temperature reduction, but is uncomfortable for
patients and challenging for nursing sta [117]. Surface cooling blankets
are poorly tolerated, do not work eciently, and can cause thermal injuries
to the skin. In addition, surface cooling methods in febrile patients frequently
elicit shivering, which increases the patients temperature, discomfort, and
metabolic demand [118]. As an alternative, air-cooled blankets were tested
in 220 neurologic critical care patients whose temperature reached or ex-
ceeded 38.3

C [119]. Patients were randomly assigned to receive either acet-

aminophen (650 mg every 4 hours; n 107) or acetaminophen with air
blanket therapy (n 113). Approximately one third of patients in both
groups remained febrile after treatment. Air blanket therapy tended to be
more successful (44% versus 36%; P value nonsignicant) in lowering
body temperature and showed a slight reduction in treatment failure (42%
versus 52%; P value nonsignicant) compared with acetaminophen alone.
Of the patients assigned to the air blanket group, however, 12% refused
the treatment or were unable to tolerate it compared with 2% of patients
in the acetaminophen group.
Numerous other, newer surface cooling devices have been evaluated
[120,121]. They use a variety of means to enhance contact between a cooling
surface, which is cooled by circulating water, and the skin. These methods
seem to be more eective in decreasing fever than traditional cooling blan-
kets. Temperature control (goal !37.2

C) was achieved in a fast and safe

manner, reducing fever burden by 75% in 23 critically ill neurologic patients
treated with a surface cooling system compared with conventional cooling
blankets [121]. Additionally, a trend toward lower Glasgow Coma Scale
score at the end of the cooling trial was noticed in the study group. A few
small preliminary studies directed toward regional brain cooling have
been conducted, in which cooling devices were applied to the head and
neck of patients with severe strokes and head injuries [122124]. This
approach may help eliminate certain adverse eects associated with global
hypothermia; however, larger studies in a broader patient population are
Intravascular cooling
There has been considerable interest more recently in alternative means
of controlling fever in patients with brain insults [93,125128]. Intravenous
infusion of refrigerated saline combined with a cooling blanket was evalu-
ated in a trial of hypothermia in 134 patients with postanoxic encephalop-
athy, TBI, and SAH. It was shown to reduce temperature rapidly with
minimal side eects [129]. The eectiveness of a catheter-based heat ex-
change system in treating fever was tested in a prospective randomized, non-
blinded trial comprising 296 patients with SAH, stroke, ICH, or head injury.
Conventional treatment of fever with antipyretics and cooling blankets was
compared with conventional treatment plus an intravascular cooling device
[127]. The catheter-based heat exchange system was signicantly more eec-
tive than conventional means in controlling fever with a 64% reduction in
fever burden. Neither infection rate nor risks associated with the catheter
were higher in the study population. Another intravascular cooling device
is being tested in a prospective, multicenter, National Institutes of
Healthfunded trial of hypothermia to 33

C in awake ischemic stroke pa-

tients [130].
Adverse eects of lowering temperature
As mentioned previously, lowering core temperature engages the heat-
producing thermoregulatory mechanisms. If cutaneous vasoconstriction
fails to increase temperature, shivering is activated. It is a potent mechanism
of producing heatdthe metabolic rate is increased signicantly, yet no work
is performed by the muscles [131]. Under normal conditions, shivering
threshold is set at around 35.5

C [132]. In a febrile patient, when the hypo-

thalamic set-point is elevated, the thermoregulatory defenses are employed
at higher temperatures. Clinically, shivering is a major source of subjective
discomfort and metabolic stress with an increase in catecholamine release
and oxygen consumption [133]. Shivering also may increase ICP; it is impor-
tant to suppress shivering while reducing temperature in patients with acute
cerebral lesions. There are several ways of managing shivering, the most
eective being sedation and neuromuscular blockade, which implies me-
chanical ventilation [134,135]. Skin warming has been used with inconsistent
results [136138]. Meperidine alone or in combination with buspirone has
been used widely; however, the exact mechanism of shivering reduction is
unknown [139,140]. Temperature reduction with intravascular cooling
devices may be associated with less shivering [127].
Induction of profound therapeutic hypothermia (!32

C) may cause
a wide range of serious complications, the severity of which correlates with
the magnitude of cooling. Most common side eects are infections, especially
pneumonia [141]; arrhythmias, such as bradycardia; cardiac failure; hypoten-
sion; coagulopathy; thrombocytopenia; and electrolyte derangements
[78,142144]. Hypokalemia resulting from intracellular shift is seen during
hypothermia induction, whereas with rewarming, rebound hyperkalemia
may develop [145].
Lastly, reducing fever, especially in patients with infections, may not
always be benecial. Observational studies suggest that febrile patients
might be able to ght more eciently against infections [146148]. These
ndings encouraged a randomized trial evaluating the impact of aggressive
fever control using external and pharmacologic means of cooling in criti-
cally ill trauma patients [149]. A trend toward higher mortality rate was
noted in patients who received aggressive fever management, prompting
a premature termination of the study; however, TBI victims were excluded
from the study, making interpretation of the results dicult.
Considerable experimental data exist indicating a detrimental eect of
elevated temperature during and after acute brain insults. Numerous clinical
studies have found a consistent relationship between elevated temperature
and poor outcome. Similarly, reducing temperature below normal seems
to improve outcome in experimental models and in patients after cardiac
arrest. A causal relationship between fever and poor outcome in patients
with neurologic injury has not been established, however. No prospective
controlled trial has been performed to determine if control of fever improves
clinical outcome in nontraumatic neurologic ICU patients. In addition, two
large prospective human trials of induced hypothermia failed to show a ben-
et in severe TBI and in aneurysm surgery after SAH.
Decisions about clinical management must be made in the absence of de-
nitive trials. In such a situation, the decision as to whether to use a partic-
ular intervention must balance potential benet versus potential risk.
Current technology allows control of hyperthermia in a fairly safe, ecient,
and easy-to-use manner. With this minimal risk, it seems reasonable, in the
absence of infection, to treat fever aggressively early after acute central ner-
vous system insults. In infected patients, lowering temperature potentially
may compromise innate defense mechanisms, however, making aggressive
fever control a less preferable option.
Currently, outside the setting of cardiac arrest, there does not seem to be
compelling data to support the use of therapeutic hypothermia. The nega-
tive trials in TBI and SAH surgery should temper use in those settings.
Ongoing trials are expected to help determine if therapeutic hypothermia
has a role in the management of acute ischemic stroke.
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