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Abstract and Figures

Heat stroke is a life-threatening condition clinically diagnosed as a severe elevation in body temperature with central nervous system dysfunction that often includes combativeness, delirium, seizures, and coma. Classic heat stroke primarily occurs in immunocompromised individuals during annual heat waves. Exertional heat stroke is observed in young fit individuals performing strenuous physical activity in hot or temperature environments. Long-term consequences of heat stroke are thought to be due to a systemic inflammatory response syndrome. This article provides a comprehensive review of recent advances in the identification of risk factors that predispose to heat stroke, the role of endotoxin and cytokines in mediation of multi-organ damage, the incidence of hypothermia and fever during heat stroke recovery, clinical biomarkers of organ damage severity, and protective cooling strategies. Risk factors include environmental factors, medications, drug use, compromised health status, and genetic conditions. The role of endotoxin and cytokines is discussed in the framework of research conducted over 30 years ago that requires reassessment to more clearly identify the role of these factors in the systemic inflammatory response syndrome. We challenge the notion that hypothalamic damage is responsible for thermoregulatory disturbances during heat stroke recovery and highlight recent advances in our understanding of the regulated nature of these responses. The need for more sensitive clinical biomarkers of organ damage is examined. Conventional and emerging cooling methods are discussed with reference to protection against peripheral organ damage and selective brain cooling. © 2015 American Physiological Society. Compr Physiol 5: 611-647, 2015.
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Review Article
Medical Progress
1978
·
N Engl J Med, Vol. 346, No. 25
·
June 20, 2002
·
www.nejm.org
The New England Journal of Medicine
H
EAT
S
TROKE
A
BDERREZAK
B
OUCHAMA
, M.D.,
AND
J
AMES
P. K
NOCHEL
, M.D.
From the Medical and Surgical Intensive Care Unit and Comparative
Medicine Department, King Faisal Specialist Hospital and Research Cen-
ter, Riyadh, Saudi Arabia (A.B.); and the Department of Internal Medicine,
Presbyterian Hospital of Dallas, Dallas (J.P.K.). Address reprint requests to
Dr. Knochel at the Department of Internal Medicine, Presbyterian Hospital
of Dallas, 8198 Walnut Hill Ln., Dallas, TX 75231, or at jamesknochel@
texashealth.org.
EAT stroke is a life-threatening illness charac-
terized by an elevated core body temperature
that rises above 40°C and central nervous
system dysfunction that results in delirium, convul-
sions, or coma.
1
Despite adequate lowering of the body
temperature and aggressive treatment, heat stroke is
often fatal, and those who do survive may sustain per-
manent neurologic damage.
1,2
Data from the Centers
for Disease Control and Prevention show that from
1979 to 1997, 7000 deaths in the United States were
attributable to excessive heat.
3
The incidence of such
deaths may increase with global warming and the pre-
dicted worldwide increase in the frequency and inten-
sity of heat waves.
4-8
Research performed during the past decade has
shown that heat stroke results from thermoregulatory
failure coupled with an exaggerated acute-phase re-
sponse and possibly with altered expression of heat-
shock proteins.
9-23
The ensuing multiorgan injury re-
sults from a complex interplay among the cytotoxic
effect of the heat and the inflammatory and coagula-
tion responses of the host.
9-21
In this article, we sum-
marize the pathogenesis of heat stroke as it is currently
understood and explore the potential therapeutic and
preventive strategies. Key terms used in this discussion
are defined in Table 1.
DEFINITION AND INCIDENCE
Heat stroke is defined clinically as a core body tem-
perature that rises above 40°C and that is accompa-
nied by hot, dry skin and central nervous system ab-
normalities such as delirium, convulsions, or coma.
Heat stroke results from exposure to a high environ-
mental temperature (in which case it is called classic,
H
or nonexertional, heat stroke) or from strenuous ex-
ercise (in which case it is called exertional heat stroke).
1
On the basis of our understanding of the pathophys-
iology of heat stroke, we propose an alternative def-
inition of this condition: it is a form of hyperthermia
associated with a systemic inflammatory response lead-
ing to a syndrome of multiorgan dysfunction in which
encephalopathy predominates.
Data on the incidence of heat stroke are imprecise
because this illness is underdiagnosed and because the
definition of heat-related death varies.
25,26
In an ep-
idemiologic study during heat waves in urban areas
in the United States, the incidence of heat stroke varied
from 17.6 to 26.5 cases per 100,000 population.
26
Most people affected by classic heat stroke are very
young or elderly, poor, and socially isolated and do not
have access to air conditioning.
25,27
In Saudi Arabia,
the incidence varies seasonally, from 22 to 250 cases
per 100,000 population.
28
The crude mortality rate
T
ABLE
1.
G
LOSSARY
OF
T
ERMS
.
C
ONDITION
D
EFINITION
Heat wave Three or more consecutive days during which
the air temperature is >32.2°C
Heat stress Perceived discomfort and physiological strain
associated with exposure to a hot environ-
ment, especially during physical work
Heat stroke Severe illness characterized by a core temper-
ature >40°C and central nervous system
abnormalities such as delirium, convulsions,
or coma resulting from exposure to environ-
mental heat (classic heat stroke) or strenuous
physical exercise (exertional heat stroke)
Heat exhaustion Mild-to-moderate illness due to water or salt
depletion that results from exposure to high
environmental heat or strenuous physical
exercise; signs and symptoms include intense
thirst, weakness, discomfort, anxiety, dizzi-
ness, fainting, and headache; core temper-
ature may be normal, below normal, or
slightly elevated (>37°C but <40°C)
Hyperthermia A rise in body temperature above the hypotha-
lamic set point when heat-dissipating mech-
anisms are impaired (by drugs or disease) or
overwhelmed by external (environmental
or induced) or internal (metabolic) heat
Multiorgan-dysfunction
syndrome
Continuum of changes that occur in more than
one organ system after an insult such as trau-
ma, sepsis, or heat stroke
24
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·
June 20, 2002
·
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·
1979
associated with heat stroke in Saudi Arabia is estimat-
ed at 50 percent.
28
The incidence of heat exhaustion in Saudi Arabia,
in contrast, ranges from 450 to more than 1800 cases
per 100,000 population. Why a mild illness develops
in response to heat (as in heat exhaustion) in some
people, whereas in others the condition progresses to
heat stroke, is unknown. Genetic factors may deter-
mine the susceptibility to heat stroke; candidate sus-
ceptibility genes include those that encode cytokines,
coagulation proteins, and heat-shock proteins involved
in the adaptation to heat stress.
13-23
PATHOGENESIS
To understand the pathogenesis of heat stroke, the
systemic and cellular responses to heat stress must be
appreciated. These responses include thermoregula-
tion (with acclimatization), an acute-phase response,
and a response that involves the production of heat-
shock proteins.
Thermoregulation
Body heat is gained from the environment and is
produced by metabolism. This overall heat load must
be dissipated to maintain a body temperature of 37°C,
a process called thermoregulation.
1
A rise in the tem-
perature of the blood by less than 1°C activates pe-
ripheral and hypothalamic heat receptors that signal
the hypothalamic thermoregulatory center,
29
and the
efferent response from this center increases the deliv-
ery of heated blood to the surface of the body. Active
sympathetic cutaneous vasodilation then increases
blood flow in the skin by up to 8 liters per minute.
30
An increase in the blood temperature also initiates
thermal sweating.
31,32
If the air surrounding the sur-
face of the body is not saturated with water, sweat
will vaporize and cool the body surface. The evapo-
ration of 1.7 ml of sweat will consume 1 kcal of heat
energy.
32
At maximal efficiency in a dry environment,
sweating can dissipate about 600 kcal per hour.
31-33
The thermal gradient established by the evaporation
of sweat is critical for the transfer of heat from the
body to the environment. An elevated blood temper-
ature also causes tachycardia, increases cardiac output,
and increases minute ventilation.
1,30-33
As blood is
shunted from the central circulation to the muscles
and skin to facilitate heat dissipation, visceral perfu-
sion is reduced, particularly in the intestines and kid-
neys.
30
Losses of salt and water by sweating, which
may amount to 2 liters or more per hour, must be
balanced by generous salt supplementation to facili-
tate thermoregulation.
33,34
Dehydration and salt de-
pletion impair thermoregulation.
34
Acclimatization
Successive increments in the level of work per-
formed in a hot environment result in adaptations that
eventually allow a person to work safely at levels of
heat that were previously intolerable or life-threaten-
ing.
1
The process of acclimatization to heat takes sev-
eral weeks and involves enhancement of cardiovascular
performance, activation of the renin–angiotensin–
aldosterone axis, salt conservation by the sweat glands
and kidneys, an increase in the capacity to secrete
sweat, expansion of plasma volume, an increase in the
glomerular filtration rate, and an increase in the abil-
ity to resist exertional rhabdomyolysis.
35
Acute-Phase Response
The acute-phase response to heat stress is a coordi-
nated reaction that involves endothelial cells, leuko-
cytes, and epithelial cells and that protects against tis-
sue injury and promotes repair.
36
Interleukin-1 was the
first known mediator of the systemic inflammation in-
duced by strenuous exercise.
37
A variety of cytokines
are now known to be produced in response to endog-
enous or environmental heat (Table 2).
22,38-43,46-51
Cy-
tokines mediate fever, leukocytosis, increased synthesis
of acute-phase proteins, muscle catabolism, stimulation
of the hypothalamic–pituitary–adrenal axis, and ac-
tivation of leukocytes and endothelial cells.
22,51-53
The
interleukin-6 produced during heat stress modulates
local and systemic acute inflammatory responses by
controlling the levels of inflammatory cytokines
22,51,54
;
interleukin-6 also stimulates hepatic production of an-
tiinflammatory acute-phase proteins, which inhibit the
production of reactive oxygen species and the release
of proteolytic enzymes from activated leukocytes.
36,51,54
Other acute-phase proteins stimulate endothelial-cell
adhesion, proliferation, and angiogenesis, thus con-
tributing to repair and healing.
36
The increased expres-
sion of the gene encoding interleukin-6 in human
muscle cells, but not in blood monocytes, during the
acute-phase response to exercise suggests that the on-
set of inflammation is local.
22,41,42
The systemic pro-
gression of the inflammatory response is secondary
and involves other cells, such as monocytes.
41
A sim-
ilar sequence of events has been shown to occur in
sepsis.
55
Heat-Shock Response
Nearly all cells respond to sudden heating by pro-
ducing heat-shock proteins or stress proteins.
56,57
Ex-
pression of heat-shock proteins is controlled primarily
at the level of gene transcription. During heat stress,
one or more heat-shock transcription factors bind to
the heat-shock element, resulting in an increased rate
of transcription of heat-shock proteins.
56,57
Increased
levels of heat-shock proteins in a cell induce a tran-
sient state of tolerance to a second, otherwise lethal,
stage of heat stress, allowing the cell to survive.
23,56,57
Blocking the synthesis of heat-shock proteins either
at the gene-transcription level or by specific antibodies
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·
N Engl J Med, Vol. 346, No. 25
·
June 20, 2002
·
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The New England Journal of Medicine
renders the cells extremely sensitive to a minor de-
gree of heat stress.
16,58
In vivo, cellular tolerance pro-
tects laboratory animals against hyperthermia, arterial
hypotension, and cerebral ischemia.
15,16
The protec-
tion conferred against heat-stroke injury correlates
with the level of heat-shock protein 72, which accu-
mulates in the brain after the priming heat-shock treat-
ment.
15,16
The mechanism by which heat-shock pro-
teins protect cells may relate to their function as
molecular chaperones that bind to partially folded or
misfolded proteins, thus preventing their irreversible
denaturation.
56
Another possible mechanism involves
heat-shock proteins that act as central regulators of
the baroreceptor-reflex response during severe heat
stress, abating hypotension and bradycardia and con-
ferring cardiovascular protection.
16
Progression from Heat Stress to Heat Stroke
Thermoregulatory failure, exaggeration of the acute-
phase response, and alteration in the expression of
heat-shock proteins may contribute to the progression
from heat stress to heat stroke.
Thermoregulatory Failure
The normal cardiovascular adaptation to severe heat
stress is an increase in cardiac output by up to 20 liters
*Data are from studies in human subjects. NA denotes data not available.
†Whole-body hyperthermia may be induced in cancer therapy.
T
ABLE
2.
E
FFECT
OF
H
EAT
S
TRESS
AND
H
EAT
S
TROKE
ON
C
IRCULATING
C
YTOKINES
,
C
YTOKINE
R
ECEPTORS
, G
ROWTH
F
ACTORS
,
AND
C
HEMOKINES
.*
C
YTOKINE
OR
F
ACTOR
H
EAT
S
TRESS
H
EAT
S
TROKE
R
EFERENCE
EXERCISE
-
INDUCED
ENVIRON
-
MENTAL
THERA
-
PEUTIC
CLASSIC EXERTIONAL
Tumor necrosis
factor
a
Increased or
unchanged
Unchanged Increased or
unchanged
Increased or
unchanged
Increased Bouchama et al.,
11
Espersen et al.,
38
Robins et al.,
39
Camus et al.,
40
Ostrowski et al.,
41
Moldoveanu
et al.,
42
Suzuki et al.,
43
Chang
44
Interleukin-1
b
Increased or
unchanged
NA Increased Increased or
unchanged
Increased Cannon and Kluger,
37
Robins et al.,
39
Ostrowski et al.,
41
Moldoveanu
et al.,
42
Chang,
44
Bouchama et al.
45
Interleukin-2 Decreased or
unchanged
NA Unchanged NA NA Espersen et al.,
38
Robins et al.
39
Interleukin-6 Increased Increased Increased Increased Increased Robins et al.,
39
Moldoveanu et al.,
42
Suzuki et al.,
43
Chang,
44
Bouchama
et al.,
45
Hammami et al.
46
Interleukin-8 Increased NA Increased NA NA Pedersen and Hoffman-Goetz,
22
Robins et al.,
39
Suzuki et al.
43
Interleukin-10 Increased Increased Increased Increased NA Pedersen and Hoffman-Goetz,
22
Robins et al.,
39
Suzuki et al.,
43
Bouchama et al.
47
Interleukin-12 Increased or
unchanged
NA Unchanged NA NA Pedersen and Hoffman-Goetz,
22
Robins et al.,
39
Suzuki et al.,
43
Akimoto et al.
48
Interleukin-1–receptor
antagonist
Increased NA NA NA NA Pedersen and Hoffman-Goetz,
22
Ostrowski et al.,
41
Suzuki et al.
43
Soluble interleukin-2
receptor
Increased NA NA Increased NA Pedersen and Hoffman-Goetz,
22
Suzuki et al.,
43
Hammami et al.
46
Soluble interleukin-6
receptor
NA Increased NA Decreased NA Hammami et al.
49
Soluble tumor necrosis
factor receptors
(p55 and p75)
Increased Increased or
unchanged
Increased Increased NA Pedersen and Hoffman-Goetz,
22
Hammami et al.
49
Interferon-g Increased or
unchanged
NA Unchanged Increased NA Pedersen and Hoffman-Goetz,
22
Robins et al.,
39
Suzuki et al.,
43
Bouchama et al.
45
Interferon-a Increased or
unchanged
NA Unchanged NA NA Suzuki et al.,
43
Viti et al.
50
Granulocyte colony-
stimulating factor
Increased NA Increased NA NA Pedersen and Hoffman-Goetz,
22
Robins et al.,
39
Suzuki et al.
43
Macrophage-inhibitor
proteins
Increased NA Unchanged NA NA Pedersen and Hoffman-Goetz,
22
Robins et al.
39
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per minute and a shift of heated blood from the core
circulation to the peripheral circulation.
30
An inability
to increase cardiac output because of salt and water
depletion, cardiovascular disease, or a medication that
interferes with cardiac function can impair heat tol-
erance and result in increased susceptibility to heat
stroke.
1
Exaggeration of the Acute-Phase Response
It is possible that the gastrointestinal tract fuels the
inflammatory response.
12,40,59-63
During strenuous ex-
ercise or hyperthermia, blood shifts from the mesen-
teric circulation to the working muscles and the skin,
leading to ischemia of the gut and intestinal hyper-
permeability.
12,30,59-63
There is abundant evidence of
hyperpermeability during heat stress in animal mod-
els but much less evidence of this phenomenon in
humans.
9,10,12,59-63
In rats, heat stress leads to increased
metabolic demand and reduced splanchnic blood flow,
which in turn induce intestinal and hepatocellular
hypoxia; the hypoxia results in the generation of high-
ly reactive oxygen and nitrogen species that acceler-
ate mucosal injury.
12,59
Intestinal mucosal permeability to iodine-125–
labeled endotoxin increases in heat-stressed rats that
have a core temperature of 45°C.
60
In heat-stressed
primates, endotoxin from the gut enters the circulation
at a core temperature of 40°C, and its concentration
increases as the core temperature rises.
9,10
Endotox-
emia may then cause hemodynamic instability and
death. Administration of antiendotoxin antibodies be-
fore heat stress occurs attenuates hemodynamic insta-
bility and improves outcome, suggesting that endotox-
in is involved in the progression from heat stress to
heat stroke.
10
In humans, high concentrations of en-
dotoxin, inflammatory cytokines, and acute-phase pro-
teins are found in the blood after strenuous exer-
cise.
22,40,61,62
Increased intestinal permeability occurs
in athletes exercising at 80 percent or more of max-
imal oxygen consumption.
61
In summary, in the model of heat stroke based on
experiments in animals and observations in humans
(Fig. 1), local and systemic insults associated with heat
stress, such as splanchnic hypoperfusion, alter the im-
munologic and barrier functions of the intestines.
12,59-63
This alteration allows leakage of endotoxins, increased
production of inflammatory cytokines that induce
endothelial-cell activation, and release of endothelial
vasoactive factors such as nitric oxide and endothe-
lins.
9,10,12,63,64
Both pyrogenic cytokines and endothe-
lium-derived factors can interfere with normal ther-
moregulation by raising the set point at which
sweating is activated and by altering vascular tone,
particularly in the splanchnic circulation, thereby
precipitating hypotension, hyperthermia, and heat
stroke.
9,10,12,63
Alteration of Heat-Shock Response
Increased levels of heat-shock proteins protect cells
from damage by heat, ischemia, hypoxia, endotoxin,
and inflammatory cytokines.
23,56,57
In persons who are
subjected to heat stress, examination of muscle tissue,
blood monocytes, and serum reveals that such a heat-
shock response occurs in vivo.
17,65-67
Attenuation of the
heat-shock response during heat stroke suggests that
this adaptative response is protective.
17,23
Conditions
associated with a low level of expression of heat-
shock proteins — for instance, aging, lack of acclima-
tization to heat, and certain genetic polymorphisms
— may favor the progression from heat stress to heat
stroke.
17,23,68
PATHOPHYSIOLOGY
Heat stroke and its progression to multiorgan-dys-
function syndrome are due to a complex interplay
among the acute physiological alterations associated
with hyperthermia (e.g., circulatory failure, hypoxia,
and increased metabolic demand), the direct cytotox-
icity of heat, and the inflammatory and coagulation
responses of the host.
11-15,18-21,44,45,69-72
This constella-
tion of events leads to alterations in blood flow in the
microcirculation and results in injury to the vascular
endothelium and tissues (Fig. 2).
18,19,73-76
Heat
Studies in cell lines and animal models suggest that
heat directly induces tissue injury.
69,70
The severity of
the injury depends on the critical thermal maximum,
a term that attempts to quantify the level and dura-
tion of heating that will initiate tissue injury.
69-71
A
critical thermal maximum beyond which near-lethal
or lethal injury occurs has been determined in various
mammalian species.
71
Observations in selected groups,
including marathon runners, normal volunteers, and
patients with cancer who are treated with whole-body
hyperthermia, suggest that the critical thermal max-
imum in humans is a body temperature of 41.6°C to
42°C for 45 minutes to 8 hours.
71
At extreme tem-
peratures (49°C to 50°C), all cellular structures are
destroyed and cellular necrosis occurs in less than five
minutes.
69
At lower temperatures, cell death is largely
due to apoptosis.
70
Although the pathways of heat-
induced apoptosis have not been identified, the in-
duction of heat-shock proteins is protective.
57
Cytokines
The plasma levels of inflammatory cytokines (tumor
necrosis factor a [TNF-a], interleukin-1b, and inter-
feron-g) and antiinflammatory cytokines (interleukin-
6, soluble TNF receptors p55 and p75, and interleu-
kin-10) are elevated in persons with heat stroke; cool-
ing of the body to a normal temperature does not re-
sult in the suppression of these factors.
11,44,45,47,49
The
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The New England Journal of Medicine
Figure 1. The Sequence of Events in the Progression of Heat Stress to Heat Stroke.
Heat stress induces thermoregulatory, acute-phase, and heat-shock responses. Thermoregulatory failure, exaggeration
of the acute-phase response, and alteration in the expression of heat-shock proteins, individually or collectively, may
contribute to the development of heat stroke. Active cutaneous vasodilatation and splanchnic vasoconstriction permit
the shift of heated blood from the central organs to the periphery, from which heat is then dissipated to the environ-
ment. This change may also lead to splanchnic hypoperfusion and ischemia, resulting in increased production of reac-
tive oxygen and nitrogen species, which may in turn induce intestinal mucosal injury and hyperpermeability. Endotox-
ins may then leak into the circulation and enhance the acute-phase response, leading to increased production of
pyrogenic cytokines and nitric oxide. Both cytokines and nitric oxide can interfere with thermoregulation and precipitate
hyperthermia, hypotension, and heat stroke. The solid arrows indicate pathways for which there is clinical or experi-
mental evidence, and the broken arrows indicate putative pathways.
Exercise or
heat exposure
Heat stress
Thermoregulatory
response
Acute-phase
response
Exaggerated
acute-phase
response
Altered
heat-shock
response
Heat-shock
response
Splanchnic
vasoconstriction
Cutaneous
vasodilatation
Production of
reactive oxygen
and nitrogen species
Increased intestinal
permeability
Endotoxemia
Release of
nitric oxide
Thermoregulatory
failure, circulatory
shock, and
heat stroke
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N Engl J Med, Vol. 346, No. 25 · June 20, 2002 · www.nejm.org · 1983
Figure 2. Possible Pathophysiological Mechanisms of Heat Stroke.
Hyperthermia due to passive heat exposure or to exercise may facilitate the leakage of endotoxin from the intestine to the systemic
circulation as well as the movement of interleukin-1 or interleukin-6 proteins from the muscles to the systemic circulation. The result
is excessive activation of leukocytes and endothelial cells, manifested by the release of proinflammatory and antiinflammatory cy-
tokines (e.g., tumor necrosis factor a [TNF-a], interleukin-1, interleukin-6, and interleukin-10), up-regulation of cell-surface adhesion
molecules, and shedding of soluble cell-surface adhesion molecules (e.g., E-selectin, L-selectin, and intercellular adhesion molecule
1 [ICAM-1]) as well as activation of coagulation (with decreased levels of proteins C and S and antithrombin III) and inhibition of
fibrinolysis. The inflammatory and coagulation responses to heat stroke, together with direct cytotoxic effects of heat, result in in-
jury to the vascular endothelium and microthrombosis. The solid arrows indicate pathways for which there is clinical or experimen-
tal evidence, and the broken arrows indicate putative pathways.
Increase in TNF-a,
interleukin-1,
interleukin-6,
interleukin-10
Decrease in
protein C,
protein S,
antithrombin III
Interleukin-1,
interleukin-6
Endotoxin
Tissue factor
Thrombin
Monocyte
Inhibition of
fibrinolysis
Clot
Monocyte
Neutrophil
ICAM-1
Increase in
thrombomodulin
L-selectin
b
2
integrin
Increase in
E-selectin
Increase in
von Willebrand
factor antigen
Fibrin monomers
Intestine
Muscle
Inflammatory Response
to Heat Stroke
Coagulation Response
to Heat Stroke
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The New England Journal of Medicine
levels of interleukin-6 and TNF receptors correlate
with severity of heat stroke.
45,49
An imbalance between inflammatory and antiin-
flammatory cytokines may result in either inflamma-
tion-associated injury or refractory immunosup-
pression. Although dynamic studies of the cytokine
response in patients with heat stroke have not yet
been performed, both of these mechanisms may be
important. In patients with heat stroke, the incidence
of infection is high.
2
Studies in rats and rabbits have
shown that heat stroke induces systemic and local
(central nervous system) production of TNF-a and
interleukin-1.
13,72
The increase in the levels of these
inflammatory cytokines is associated with high intra-
cranial pressure, decreased cerebral blood flow, and
severe neuronal injury. Interleukin-1–receptor antag-
onists or corticosteroids given to animals before heat
stroke attenuate neurologic injury, prevent arterial
hypotension, and improve survival.
13,14
Although such
studies support the possibility that cytokines have a
pathogenic role, studies of neutralizing antibodies or
genetically modified mice are needed to determine
both the pattern and the role of these factors in heat
stroke.
Coagulation Disorders and Endothelial-Cell Injury
Endothelial-cell injury and diffuse microvascular
thrombosis are prominent features of heat stroke.
Therefore, disseminated intravascular coagulation and
alterations in the vascular endothelium may be impor-
tant pathologic mechanisms in heat stroke.
18-21,73-76
Studies involving the use of molecular markers of
coagulation and fibrinolysis have delineated the early
steps of coagulation abnormalities.
20,21
The onset of
heat stroke coincides with the activation of coagula-
tion, as assessed by the appearance of thrombin–anti-
thrombin III complexes and soluble fibrin monomers
and below-normal levels of protein C, protein S, and
antithrombin III. Fibrinolysis is also highly activated,
as shown by increased levels of plasmin–a
2
-antiplas-
min complexes and
D-dimers and decreased levels of
plasminogen. Normalization of the core temperature
inhibits fibrinolysis but not the activation of coagu-
lation, which continues; this pattern resembles that
seen in sepsis.
20
The endothelium controls vascular tone and per-
meability, regulates leukocyte movement, and main-
tains a balance between procoagulant and anticoag-
ulant substances. Hyperthermia in vitro promotes a
prothrombotic state, enhances vascular permeability,
and increases the cell-surface expression of adhesion
molecules and the shedding of their soluble form.
77,78
Circulating levels of von Willebrand factor antigen,
thrombomodulin, endothelin, metabolites of nitric
oxide, soluble E-selectin, and intercellular adhesion
molecule 1 are elevated in patients with heat
stroke.
18,19,53,64,79
Modulation of the expression of b
2
-
integrins, characterized by up-regulation of CD11b
and down-regulation of CD11a on the surface of cir-
culating lymphocytes, has been reported in patients
with heat stroke, suggesting that there is an active
endothelial cell–leukocyte interaction in vivo.
53
CLINICAL AND METABOLIC
MANIFESTATIONS
Two findings — hyperthermia and central nervous
system dysfunction — must be present for a diagno-
sis of heat stroke (Table 3).
1,86
The core temperature
may range from 40°C to 47°C.
1
Brain dysfunction
is usually severe but may be subtle, manifesting only
as inappropriate behavior or impaired judgment; more
often, however, patients have delirium or frank co-
ma.
1,86
Seizures may occur, especially during cooling.
1
All patients have tachycardia and hyperventilation. In
either classic or exertional heat stroke, the arterial car-
bon dioxide tension is often less than 20 mm Hg.
1
Twenty-five percent of patients have hypotension.
86
Patients with nonexertional heat stroke usually have
respiratory alkalosis.
1
In contrast, those with exertional
heat stroke nearly always have both respiratory alka-
losis and lactic acidosis.
1
Hypophosphatemia and hy-
pokalemia are common at the time of admission.
Hypoglycemia is rare. Hypercalcemia and hyperpro-
teinemia, reflecting hemoconcentration, may also
occur. In patients with exertional heat stroke, rhabdo-
myolysis, hyperphosphatemia, hypocalcemia, and hy-
perkalemia may be important events after complete
cooling.
The most serious complications of heat stroke are
those falling within the category of multiorgan-dys-
function syndrome. They include encephalopathy,
rhabdomyolysis, acute renal failure, acute respiratory
distress syndrome, myocardial injury, hepatocellular
injury, intestinal ischemia or infarction, pancreatic in-
jury, and hemorrhagic complications, especially dis-
seminated intravascular coagulation, with pronounced
thrombocytopenia.
1,21
TREATMENT
Immediate cooling and support of organ-system
function are the two main therapeutic objectives in
patients with heat stroke (Table 3).
1,2,80-87
Cooling
Effective heat dissipation depends on the rapid
transfer of heat from the core to the skin and from
the skin to the external environment.
80-82
In persons
with hyperthermia, transfer of heat from the core to
the skin is facilitated by active cutaneous vasodilata-
tion.
30,81,82
Therapeutic cooling techniques are there-
fore aimed at accelerating the transfer of heat from
the skin to the environment without compromising
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the flow of blood to the skin.
80-85
This is accomplished
by increasing the temperature gradient between the
skin and the environment (for cooling by conduction)
or by increasing the gradient of water-vapor pressure
between the skin and the environment (for cooling
by evaporation), as well as by increasing the velocity
of air adjacent to the skin (for cooling by convection).
In practice, cold water or ice is applied to the skin,
which is also fanned (Table 4). Most such methods
lower the skin temperature to below 30°C, trigger-
ing cutaneous vasoconstriction and shivering. To over-
come this response, the patient may be vigorously
massaged, sprayed with tepid water (40°C), or exposed
to hot moving air (45°C), either at the same time as
cooling methods are applied or in an alternating fash-
ion.
80-83
There have been no controlled studies com-
paring the effects of these various cooling techniques
on cooling times and outcome in patients with heat
stroke.
No pharmacologic agents that accelerate cooling
are helpful in the treatment of heat stroke. Although
the use of dantrolene sodium has been considered, this
agent was found ineffective in a double-blind, random-
ized study.
86
The role of antipyretic agents in heat
stroke has not been evaluated, despite findings that
pyrogenic cytokines are implicated in heat stress.
Recovery of central nervous system function during
cooling is a favorable prognostic sign and should be
expected in the majority of patients who receive
prompt and aggressive treatment. Residual brain dam-
age occurs in about 20 percent of the patients and is
associated with high mortality.
1,2
*Data are from Knochel and Reed,
1
Graham et al.,
80
Wyndham et al.,
81
Weiner and Khogali,
82
Al-Aska et al.,
83
White et al.,
84,85
and Bouchama et al.
86
†Heat stroke should be suspected in any patient with changes in mental status during heat stress, even if his or her core temperature is <40°C.
‡There is no evidence that one cooling technique is superior to another. Noninvasive techniques that are easy to apply, well tolerated, and not likely to
cause cutaneous vasoconstriction are preferred.
§There is no evidence to support a specific temperature end point at which cooling should be halted. However, a rectal temperature of 39.4°C has been
used in large series and has proved to be safe.
86
¶Hypotension usually responds to volume expansion and cooling. Vasodilatory shock and primary myocardial dysfunction may underlie sustained hypo-
tension that is refractory to volume expansion. Therapy should be individualized and guided by the patient’s clinical response.
TABLE 3. MANAGEMENT OF HEAT STROKE.*
CONDITION INTERVENTION GOAL
Out of hospital
Heat stress (due to heat wave, summer
heat, or strenuous exercise), with
changes in mental status (anxiety,
delirium, seizures, or coma)
Measure the patient’s core temperature (with a rectal probe)
If the core temperature is >40°C, move the patient to a cool-
er place, remove his or her clothing, and initiate external
cooling‡: cold packs on the neck, axillae, and groin; con-
tinuous fanning (or opening of the ambulance windows);
and spraying of the skin with water at 25°C to 30°C
Diagnose heat stroke†
Lower the core temperature to <39.4°C, pro-
mote cooling by conduction, and promote
cooling by evaporation
Position an unconscious patient on his or her side and clear
the airway
Minimize the risk of aspiration
Administer oxygen at 4 liters/min Increase arterial oxygen saturation to >90%
Give isotonic crystalloid (normal saline) Provide volume expansion
Rapidly transfer the patient to an emergency department
In hospital
Cooling period Confirm diagnosis with thermometer calibrated to measure
high temperatures (40°C to 47°C)
Hyperthermia Monitor the rectal and skin temperatures; continue cooling Keep rectal temperature <39.4°C§ and skin
temperature 30°C–33°C
Seizures Give benzodiazepines Control seizures
Respiratory failure Consider elective intubation (for impaired gag and cough re-
flexes or deterioration of respiratory function)
Protect airway and augment oxygenation (arte-
rial oxygen saturation >90%)
Hypotension¶ Administer fluids for volume expansion, consider vasopres-
sors, and consider monitoring central venous pressure
Increase mean arterial pressure to >60 mm Hg
and restore organ perfusion and tissue oxy-
genation
Rhabdomyolysis Expand volume with normal saline and administer intrave-
nous furosemide, mannitol, and sodium bicarbonate
Prevent myoglobin-induced renal injury: pro-
mote renal blood flow, diuresis, and alkaliza-
tion of urine
Monitor serum potassium and calcium levels and treat hyper-
kalemia
Prevent life-threatening cardiac arrhythmia
After cooling Supportive therapy Recovery of organ function
Multiorgan dysfunction
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1986 · N Engl J Med, Vol. 346, No. 25 · June 20, 2002 · www.nejm.org
The New England Journal of Medicine
Prevention
Heat stroke is a preventable illness, and thorough
knowledge of the disorder can help to reduce mor-
tality and morbidity.
1,3
Although classic heat stroke
is predominant in very young or elderly persons and in
those who have no access to air conditioning,
1-3,25-27
it
is also relatively common among persons with chron-
ic mental disorders or cardiopulmonary disease and
those receiving medications that interfere with salt and
water balance, such as diuretics, anticholinergic agents,
and tranquilizers that impair sweating.
1-3,25-27
Exertion-
al heat stroke may be seen in manual laborers, military
personnel, football players, long-distance runners, and
those who ingest an overdose of cocaine or amphet-
amines.
1
To prevent both types of heat stroke, people
can acclimatize themselves to heat, schedule outdoor
activities during cooler times of the day, reduce their
level of physical activity, drink additional water, con-
sume salty foods, and increase the amount of time they
spend in air-conditioned environments.
1,3
Automobiles
should be locked, and children should never be left
unattended in an automobile during hot weather.
Despite accumulated knowledge and experience,
deaths during heat waves are still common
88-90
and have
been associated largely with social isolation in vulner-
able populations, lack of air conditioning, and increas-
es in heat during large gatherings for cultural or re-
ligious purposes.
25-28,88-90
A plan to improve weather
forecasting, alert those at risk, provide readily acces-
sible air-conditioned shelters, and reduce energy costs
during extreme weather so that air conditioning is af-
fordable may decrease morbidity and mortality during
heat waves.
88-90
In football players, modification of
practice schedules and avoidance of dehydration and
salt depletion have been found to be effective means
of preventing heat stroke.
91
Emerging Concepts
After the onset of heat stroke, normalizing the
body temperature may not prevent inflammation,
coagulation, and progression to multiorgan dysfunc-
tion.
2,11,18,20,45,49,53
For this reason, new approaches to
modulation of the inflammatory response are being
studied in animals. Immunomodulators such as in-
terleukin-1–receptor antagonists, antibodies to endo-
toxin, and corticosteroids improve survival in animals
but have not yet been studied in humans.
10,13,14
It is
uncertain whether anticytokine and anti-endotoxin
strategies will be more successful in heat stroke than
they have been in sepsis. New therapeutic interven-
tions aimed at limiting the activity of nuclear factor-
kB, a critical transcription factor in the regulation of
acute inflammation, may prove more successful: in a
model of inflammation-associated injury (mice with
sepsis), inhibition of nuclear factor-kB activity has
been found to improve survival, but it also appears
to promote apoptosis of hepatocytes.
92,93
Coagulation and fibrinolysis are frequently activated
during heat stroke and may lead to disseminated in-
travascular coagulation.
20,21
Replacement therapy with
recombinant activated protein C, which attenuates
both the coagulation and the inflammation, reduces
mortality in patients with severe sepsis and may be
useful in those with heat stroke as well.
20,94
Elucida-
tion of the molecular mechanisms that trigger the ac-
tivation of coagulation may lead to more specific ther-
apy, such as tissue-factor pathway inhibitors.
More important are potential therapeutic applica-
tions based on knowledge of the stress-response pro-
teins.
15,16
A logical goal for the next generation of
immunomodulators is selective pharmacologic induc-
tion of the expression of heat-shock proteins. Salicylate
and nonsteroidal antiinflammatory drugs activate heat-
shock transcription factors and induce the transcrip-
tion and translation of heat-shock proteins in mam-
malian cells.
57
This response enhances tolerance of heat
and cellular protection against heat stress. Although
excessive expression of the heat-shock proteins blocks
essential cellular processes, partial up-regulation of
these proteins may prove beneficial, particularly as a
preventive measure during a heat wave. Further stud-
ies are required to define the degree to which inflam-
matory and stress responses can be modulated in hu-
mans without interfering with essential immunologic
mechanisms.
*Because external cooling results in cutaneous vasoconstriction, vigo-
rous massaging of the skin is recommended.
81,82
†Internal cooling, which has been investigated in animals, is infrequently
used in humans.
84,85
Gastric or peritoneal lavage with ice water may cause
water intoxication.
‡The skin is covered with a fine gauze sheet that has been soaked in wa-
ter at 20°C while the patient is fanned. The fanning is reduced or stopped
if the skin temperature drops to <30°C.
83
§A body-cooling unit is a special bed that sprays atomized water at 15°C
and warm air at 45°C over the whole body surface to keep the temperature
of the wet skin between 32°C and 33°C.
82
TABLE 4. METHODS OF COOLING.
Techniques based on conductive cooling
External*
Cold-water immersion
Application of cold packs or ice slush over part of the body or the whole
body
Use of cooling blankets
Internal†
Iced gastric lavage
Iced peritoneal lavage
Techniques based on evaporative or convective cooling
Fanning the undressed patient at room temperature (20°C to 22°C)
Wetting of the body surface during continuous fanning‡
Use of a body-cooling unit§
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MEDICAL PROGRESS
N Engl J Med, Vol. 346, No. 25 · June 20, 2002 · www.nejm.org · 1987
CONCLUSIONS
The threat of heat stroke is increasing. Global warm-
ing is already causing heat waves in temperate cli-
mates.
4-8
The recognition that thermoregulatory fail-
ure and impaired regulation of inflammatory and
stress responses facilitate the progression from heat
stress to heat stroke and contribute to the severity of
tissue injury should make research in this direction
a priority. Greater knowledge of the cellular and mo-
lecular responses to heat stress will help point to novel
preventive measures and a new paradigm of immuno-
modulation. In this way, the multiorgan injury caused
by heat stroke might be minimized in many patients.
We are indebted to Yvonne Lock and Vickie Anderson for assist-
ance in the preparation of the manuscript.
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... Additionally, dizziness, red skin, and headache may occur. Classic heatstroke is characterized by a lack of perspiration, whereas exertional heatstroke is characterized by excessive sweating [17,20]. ...
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