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Neurologic Disorders
Yekaterina K. Axelrod, MD
a,b,c
,
Michael N. Diringer, MD
a,b,c,d,e,
*
a
Department of Neurology, Washington University School of Medicine,
660 South Euclid Avenue, Campus Box 8111, St. Louis, MO 63110-1093, USA
b
Neurology/Neurosurgery Intensive Care Unit, BarnesJewish Hospital,
St. Louis, MO 63110-1093, USA
c
Section of Neurologic Intensive Care, Washington University School of Medicine,
660 South Euclid Avenue, St. Louis, MO 63110-1093, USA
d
Department of Neurological Surgery, Washington University School of Medicine,
660 South Euclid Avenue, St. Louis, MO 63110-1093, USA
e
Department of Anesthesiology, Washington University School of Medicine,
660 South Euclid Avenue, St. Louis, MO 63110-1093, USA
Thermoregulation
Body temperature is tightly controlled in humans at approximately 37
C,
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: diringerm@neuro.wustl.edu (M.N. Diringer).
0733-8619/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ncl.2008.02.005 neurologic.theclinics.com
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 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
586 AXELROD & DIRINGER
[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,
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
2
(PGE
2
) is synthesized in the
hypothalamus, stimulating temperature elevation [15].
Blatteis and colleagues [16] summarized an alternative concept of fever
origin, in which PGE
2
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
587 TEMPERATURE MANAGEMENT IN ACUTE NEUROLOGIC DISORDERS
PGE
2
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
2
-
independent immediate elevation in temperature and enhances local PGE
2
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
2
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
2
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
588 AXELROD & DIRINGER
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 or 1.2
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
C to 33
C for 48 hours
mainly with intravascular catheters followed by a slow rewarming phase
591 TEMPERATURE MANAGEMENT IN ACUTE NEUROLOGIC DISORDERS
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 to 31
C to 39.0
C)
and acetaminophen with cooling blanket group (from 39.1
C to 38.6
C).
The mean body temperature in the acetaminophen-only group increased
from 39.2
C to 39.4
C.
External cooling by using water-cooled blankets, rotary fans, and spong-
ing the body surface with water also are of limited ecacy. Sponging has
593 TEMPERATURE MANAGEMENT IN ACUTE NEUROLOGIC DISORDERS
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) 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.
595 TEMPERATURE MANAGEMENT IN ACUTE NEUROLOGIC DISORDERS
Summary
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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