Scand J Med Sci Sports 2011: 21: 742–748
doi: 10.1111/j.1600-0838.2011.01333.x
Review
The pathopysiology of heat stroke: an integrative view of the final
common pathway
Y. Epstein1, W. O. Roberts2
1
Sheba Medical Center, Heller Institute of Medical Research, Tel Hashomer and the Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel, 2Department of Family Medicine and Community Health, University of Minnesota, Minneapolis,
Minnesota, USA
Corresponding author: Y. Epstein, Sheba Medical Center, Heller Institute of Medical Research, Tel Hashomer and the Sackler
Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel. Tel: 1972 3 530 3564, Fax: 1972 3 737 7002, E-mail:
hlrinst@post.tau.ac.il
Accepted for publication 15 April 2011
Heat stroke is defined as a condition in which body
temperature is elevated to such a level that it becomes a
noxious agent causing body tissue dysfunction and damage
with a characteristic multi-organ clinical and pathological
syndrome. Marked hyperthermia, usually above 40.5 1C
and associated encephalopathy, occurs after thermoregula-
tion is subordinated to circulatory and metabolic demands
and to the associated systemic inflammatory reaction.
Exertional heat stroke is a function of both intrinsic and
Heat stroke is a potentially fatal disorder caused by
elevated core temperatures from either internal me-
tabolic heat produced by activity or external envir-
onmental heat added to the body that cannot be
removed to maintain a normal core temperature.
Body temperature and risk for exertional heat stroke
are modulated by both intrinsic and extrinsic factors.
Intrinsic modulators like genetics, fitness, acclimati-
zation, illness, medications, and sleep quality can
alter individual risk and outcomes, while extrinsic
modulators like exercise intensity and duration,
clothing and equipment, high ambient temperature,
high relative humidity, and solar radiation can affect
the group risk and outcomes. The rising core tem-
perature seen in heat stroke sets off a cascade of
physiologic responses to preserve temperature home-
ostasis and, at some critical tissue temperature,
pathophysiologic responses that result in tissue and
organ failure. Activity modifications, either intrinsic
intentional or subconscious brain-related reduction
in work intensity or extrinsic administrative changes
in group activity, combined with early recognition
and treatment of heat stroke can reduce both mor-
bidity and mortality in this syndrome that mostly
affects young athletes and soldiers in active pursuits
(exertional heat stroke) or the elderly, the very
742
& 2011 John Wiley & Sons A/S
extrinsic modulators. Intrinsic modulators like genetics,
fitness, acclimatization, illness, medications, and sleep qual-
ity can alter individual risk and outcomes, while extrinsic
modulators like exercise intensity and duration, clothing
and equipment, ambient temperature, relative humidity, and
solar radiation can affect the group risk and outcomes. This
review integrates the current theoretical and accepted
knowledge of physiological alterations into one model that
depicts a common pathway from heat stress to heat stroke.
young, and others without adequate resources or
means to escape the heat (classical heat stroke)
(Knochel & Goodman, 1997; Epstein et al., 2004).
The former is a sporadic event related more to
physical activity than to climatic conditions,
although often heat stress is a contributing factor
(Shibolet et al., 1976; Epstein et al., 1999), while the
latter is characteristic of heat waves and often
appears as an epidemic in an affected region (Bou-
chama et al., 2007; Robine et al., 2008). Recognizing
and interrupting the pathophysiologic processes
early in the uncompensable phase limits the potential
for adverse outcomes.
A requisite for intact homeostasis is regulating
body core temperature. At rest and in comfortable
environmental conditions, 37 1C is considered a
‘‘normal’’ core body temperature, but under exer-
cise-heat stress ‘‘normal’’ body temperature will be
higher (Werner, 1993). Body temperature is regulated
centrally (Boulant, 1996). In short, the preoptic
anterior hypothalamic neurons sense hypothalamic
temperature and also receive afferent inputs from
thermoreceptors in the skin and spinal cord. These
neurons, therefore, are capable of integrating central
and peripheral thermal information, and this inte-
gration allows the selection of thermoregulatory
 The pathophysiology of heat stroke
responses that are appropriate for the internal and and 2009. Classical heat stroke, which characterizes
external conditions (Boulant, 1974, 1996). From a the elderly, is very common during heat waves; for
thermodynamic perspective body temperature is example, it was reported that during the heat wave in
maintained by thermoregulatory mechanisms that Europe in 2003 tens of thousands people died from
adequately balance heat loss with heat gain. Heat is heat-related injuries (Robine et al., 2008). This re-
generated within the body by metabolic processes view will summarize the accepted and theoretical
and is absorbed from the environment when ambient pathophysiological alterations that form a common
temperature is higher than skin temperature. Heat is pathway from compensable and uncompensable heat
dissipated from the body as sensible loss (conduc- stress to heat stroke and its associated morbidity and
tion, convection, and radiation) and insensible loss mortality.
(evaporation of sweat) (Gonzalez, 1988). Teleologi-
cally, work intensity will always be maintained at a
level that will ensure that the rate of metabolic heat Thermoregulation (the compensatory phase)
production will not be a limiting factor and that the
Body heat is produced by cell metabolism and can
activity is completed with a safe core body tempera-
also be gained from the environment. The accumu-
ture; metabolic heat production and heat loss even-
lated heat load must be dissipated at the same rate as
tually reach a steady state. In other words, the
it is produced or gained to maintain body tempera-
physiological strain that results from heat stress is a
ture within the accepted or safe physiological range.
function of the ability to maintain body core tem-
An increase in core body temperature activates
perature at a compensable level. However, this is not
peripheral and hypothalamic heat receptors, which
always the case; strenuous exercise in hot humid
in turn, activate an increase in cardiac output,
conditions is an example of increased heat produc-
vasodilate skin blood vessels, and stimulate sweat
tion combined with impaired heat dissipation. If
gland secretion (Wenger et al., 1976; Roberts et al.,
either the normal thermoregulatory mechanisms are
1977; Rowell, 1983).
overwhelmed or the predisposing factors affecting
Adjustments in cardiovascular activity are critical
normal heat dissipation or abnormal heat production
to body temperature regulation as the cardiovascular
cause the body core temperature to rise to uncom-
system transfers heat from the core and working
pensable levels, the extensive multiorgan collapse
muscles to the body surface. Adequate skin blood
that constitutes the syndrome of heat stroke will
flow is imperative for this heat transfer to occur and
ensue.
is achieved by increasing and/or by redistributing
Heat stroke is the most serious of the syndromes
cardiac output to ensure blood flow for heat transfer
associated with excess body heat. Bouchama and
at the skin surface. Active sympathetic mediated
Knochel (2002) have recently defined heat stroke
cutaneous vasodilatation concomitant with splanch-
as, ‘‘a form of hyperthermia associated with a sys-
nic vasoconstriction can increase the cardiac output
temic inflammatory response leading to a syndrome
to 20–25 L/min resulting in an increase in skin blood
of multiorgan dysfunction in which encephalopathy
flow to 8 L/min (Rowell, 1983; Johnson & Proppe,
predominates.’’ Marked hyperthermia – usually
1996; Charkoudian, 2003). The shunting of blood
above 40.5 1C, occurs after thermoregulation is sub-
from the central circulation to the skin reduces
ordinated to circulatory collapse, to increased cellu-
visceral perfusion, particularly in the intestine and
lar metabolic demands, and to the systemic
the kidney (Rowell, 1983; Nadel et al., 1979). When
inflammatory response syndrome (Bouchama &
body temperature cannot be regulated by sensible
Knochel, 2002; Leon & Helwig, 2010). The severity
heat loss, sweating is initiated. Thermal sweating
of the illness depends on the critical thermal max-
closely parallels the increase in body temperature
imum, a term that attempts to quantify the level and
(Snellen, 1966; Stolwijk et al., 1967; Saltin et al.,
duration of elevated cell temperature that will initiate
1970; Nadel et al., 1971), and maximum sweat rates
tissue injury (Shapiro et al., 1973; Bynum et al.,
are reached when core temperature has risen to
1978).
 39 1C (Ladell, 1957; Wyndham et al., 1965).
In daily routines, people tend to overlook heat
Side by side with the physiological effector me-
safety rules. Heat injuries and heat stroke events are
chanisms, a cascade of intracellular reactions that
not as rare as believed. According to the US Armed
promote both cell protection and cell repair – the
Forces Health Surveillance Center (2010), during
acute-phase response – is initiated.
2009, 2361 cases of EHI were reported among active
duty military recruits; 323 were EHS. The crude
incidence rate for EHI, excluding EHS, was 1.41 in Acute-phase response
2009, with a rate of 4.32 among those 20 years and
younger. The overall rate of EHS ranged between The acute-phase response is a coordinated reaction
0.22 and 0.27 per 1000 person-years between 2005 involving endothelial cells, leukocytes, and epithelial

743
Epstein & Roberts
cells that protect against tissue injury and promote
cell repair (Baumann & Gauldie, 1994; Gabay &
Kushner, 1999). Following heat stress, cellular pro-
tection during the acute phase response is mediated
by initiating the production of stress proteins – the
heat shock proteins (HSPs) (Lin, 1999; Leon, 2007;
Sonna et al., 2007). HSPs are a family of molecular
chaperones that regulate the tissue reaction from
potentially cell lethal stresses like heat, ischemia,
hypoxia, endotoxin, physical activity, oxidative
stress, nitrosative stress, and others. HSPs exert their
protective effect through several lines of cellular
activity: (a) by preventing the disaggregation of
denatured proteins and assisting the refolding of
denatured proteins into their native configuration;
(b) by attenuating the loss of epithelial barrier
integrity and preventing endotoxin leakage across
the intestine wall; (c) by attenuating arterial hypo-
tension to reduce cerebral ischemia and neural da-
mage; and (d) by interfering with oxidative stress and
blocking the apoptotic cell-signaling pathways (Yang
& Lin, 1999; Lin & Chang, 2004; Yan et al., 2006).
Clinical observations by Wang et al. (2001) re-
vealed that serum HSP70 levels were elevated in
healthy volunteers whose body core temperature
was 39 1C or above. This, according to other inves-
tigators, demonstrates the induced transient state of
heat stress tolerance that allows cell survival in this
relatively hostile environment (Moseley, 1997; Polla
et al., 1998; Horowitz, 2007). Others have shown that
heat acclimation is characterized by higher basal
levels of HSP70 with an extended half life, which
was hypothesized to be part of the biochemical
protective change associated with heat acclimation
(Maloyan et al., 1999; Yamada et al., 2007). Wang et
al. (2001) also noted a decrease in HSP70 levels in
many heat stroke patients; a response that was more
pronounced in severe heat stroke. In parallel, circu-
lating antibodies to HSP70 have been found in many
of the patients with serious heat stroke (Wang et al.,
2001; Wu et al., 2001) and injection of anti-HSP70
antibodies into the hypothalamus enhanced the onset
of heat stroke (Li et al., 2001), leading these research-
ers to conclude that the increased levels of HSP70
correlate with a better outcome for heat stroke
patients. Conversely, higher levels of HSP70 anti-
body might contribute to the lower levels of HSP70,
which in turn can accelerate the development of heat
stroke.
Thermoregulatory failure (the uncompensable phase)
The pathophysiology leading to heat stroke and its
progression to a multiorgan dysfunction syndrome is
a complex interplay of the acute physiological altera-
tions associated with hyperthermia (e.g. circulatory
744
failure, hypoxia, and increased cellular metabolic
demands), the direct cell suppression and cytotoxi-
city of heat, the systemic inflammatory response, and
failure of the coagulation system (Horowitz & Hales,
1998; Epstein, 2000; Hall et al., 2001; Bouchama &
Knochel, 2002; Horowitz, 2007; Leon & Helwig,
2010).
Heat stress elicits sweating and associated fluid
losses. Sweat-related fluid losses, which can easily be
41–2 L/h, will result in hypohydration, if not re-
plenished by adequate fluid intake during activity,
reducing effective blood volume and cardiac output.
Body fluid is also transferred from the intravascular
space to the interstitial fluid space during heat stress
(Senay, 1986). This reduction in total blood volume
together with the increase in peripheral cutaneous
blood flow volume further reduces central venous
pressure (Hales, 1987). Although dehydration is not
a direct cause of heat stroke, when present, it may
attenuate heat transfer and heighten the cardiovas-
cular collapse. Sawka et al. (1984) show in their
literature summary that hypohydration results in
increased core body temperature and heart rate at
rest and during exercise, and that above a certain
threshold ( 5% reduction in body weight) sweat
rates are reduced. Although it is rare clinically to see
exertional heat stroke victims cease sweating (Shibo-
let et al., 1967), it is a more common finding in
classical heat stroke (Knochel & Goodman, 1997).
Classic heat stroke cases become more dehydrated
because of behavioral and physiological impair-
ments; they suffer from underlying illnesses and using
drugs that might impair thermoregulation (Hart et
al., 1982; Bouchama et al., 2007).
When heat stress transitions beyond the ‘‘compen-
sable phase,’’ the central venous pressure decreases
significantly and the ability to transfer heat to the
body surface is decreased, resulting in further eleva-
tion of core temperature. This heat-induced circula-
tory failure promotes the accumulation of body heat
and accelerates both the thermoregulatory failure
and the progression to heat stroke (Senay, 1986;
Hales, 1987). It has been suggested that thermoregu-
lation is intact and body temperature can be regu-
lated, as long as skin blood flow is o30% of total
cardiac output (Y. Shapiro, personal communica-
tion). Once this threshold is crossed, the drop in
central venous pressure is accentuated and resulting
cardiac decompensation reduces effective heat trans-
fer to the skin.
During hyperthermia, blood shifts preferentially
from the mesenteric circulation to the working mus-
cles and the skin, leading to ischemia and hyperper-
meability of the gut (Rowell, 1983; Shapiro et al.,
1986; Moseley et al., 1994; Pals et al., 1997; Hall
et al., 2001). Splanchnic vasoconstriction and the
secondary diminished splanchnic blood flow result in

increased anaerobic metabolism, impaired lactic acid
turnover in the liver, and increased systemic acidosis.
The damage to cell membranes and intracellular
bridges allows endotoxin to leak into the vascular
space producing an endotoxin-mediated shock syn-
drome with hypotension, tachycardia, and inade-
quate organ perfusion (Bouchama & Knochel,
2002; Lambert, 2004). Heat stress that leads to
increased cellular metabolic demands combined
with reduced splanchnic blood flow results in intest-
inal and hepatocellular hypoxia, which generates
highly reactive oxygen and nitrogen species (Hall et
al., 2001; Yang & Lin, 2002; Lambert, 2004; Chang
et al., 2007) accelerating mucosal injury associated
with decreased blood flow (Siejo & Wielock, 1985;
Hubbard, 1990). The insult to the integrity of the
intestinal wall reduces its permeability barrier, en-
abling a massive leak of endotoxins into the circula-
tion (Lambert, 2004; Leon, 2007). Under normal
circumstances, endotoxins that leak from the intes-
tine wall into the circulation are rapidly detoxified
and inactivated in the liver (Treon et al., 1992).
However, under severe heat stress, the reduction in
hepatic portal vein blood flow combined with ther-
mally altered hepatocyte function severely reduces
the capacity to detoxify the subsequent surge of
endotoxins (Gathiram et al., 1988).
The resulting endotoxemia induces an increased
production and release of inflammatory cytokines.
This, in turn, provokes endothelial-cell activation
and the release of endothelial vasoactive factors,
such as nitric oxide and endothelins. Both pyrogenic
cytokines and endothelium-derived factors coupled
with intracellular ion imbalance create a vicious cycle
that is characterized in heat stroke by very high body
temperature and circulatory collapse (Horowitz &
Hales, 1998; Blatteis, 2000; Bouchama & Knochel,
2002). The increase in the levels of inflammatory
cytokines is associated with high intracranial pres-
sure, decreased cerebral blood flow, and severe
neuronal injury (Bouchama & Knochel, 2002; Yan
et al., 2006). In addition, heat stress induces cerebral
ischemia and blood-brain-barrier disruption that
result in extravasations of substances into the brain
extracellular compartment causing vasogenic edema
and cell injury; the release of endogenous pyrogens
also hampers the thermoregulatory center functions
(Sharma & Dey, 1986; Wijsman & Shivers, 1993;
Chan, 2001).
Concomitant deterioration of total cellular energy
induces a metabolic cascade that leads to irreversible
cell damage (Siejo & Wielock, 1985; Hubbard et al.,
1987). These findings lead to the hypothesis that
cellular energy depletion contributes to the patho-
physiology of heat stroke (Hubbard et al., 1987;
Hubbard, 1990). According to this model, lactic
acidosis that results from increased energy require-
The pathophysiology of heat stroke
ments stimulates the ATP-dependent Na1–K1
pump. The pump activity produces more heat and
in combination with depressed mitochondrial re-
spiratory function reduces cellular energy levels.
ATP depletion and, consequently, failure of the
ion-transport systems also lead to intracellular
Ca11 accumulation, which, along with the accumu-
lation of lactic acid, forms a vicious cycle that
ultimately results in cell hypoxia and necrosis (Hub-
bard, 1990; Gaffin & Hubbard, 2001; Yan et al.,
2006).
The flux of potassium ions across the cell mem-
branes is mediated by various temperature-depen-
dent mechanisms and during hyperthermia there is a
net loss of intracellular K1 and a corresponding rise
in extracellular and intravascular plasma K1 (Gaffin,
1999). Severe hyperthermia also causes a net rise in
intracellular Ca11 through activation of various
transport systems (Gaffin, 1999; Koratich & Gaffin,
1999). Some of the intracellular ionic changes related
to hyperthermia are mediated by inhibition of the
Na1–H1 exchange mechanism, changes in mem-
brane conductance for ions, along with the activation
of the Na1–K1 ATPase-dependent pump (Gaffin &
Hubbard, 2001).
Pathophysiology of heat stroke: the integrative model
The mediation of metabolic changes and tissue
damage that lead to heat stroke is not fully under-
stood. It probably results from a complex interplay
among the acute physiological alterations asso-
ciated with hyperthermia (e.g., circulatory failure,
hypoxia, and increased cellular metabolic demand),
the direct cell function suppression and cytotoxicity
of heat, and the combined inflammatory and coa-
gulation defect responses. Based on the cumulative
existing knowledge and theories, the current hy-
pothesis is that heat stress driven beyond the ‘‘com-
pensable phase’’ significantly decreases central
venous pressure, which, in response to markedly
decreased circulatory transport capacity, signifi-
cantly elevates core temperature. The circulatory
failure that accompanies thermoregulatory failure is
aggravated by endotoxemia. The latter stimulates
increased production of inflammatory cytokines
that in turn induce hypotension, circulatory col-
lapse, and increased body core temperature. The
combined effects of circulatory failure leading to a
multiorgan failure and CNS dysfunction is typical
of heat stroke (Fig. 1).
Heat stroke: a multiorgan failure
The described vicious cycle that leads to the circu-
latory collapse and to severe hyperthermia underlies
745
Epstein & Roberts
Fig. 1. The sequence of events that lead to heat stroke
transitions through the compensable to the uncompensable
phase. Exercise and/or environmental heat stress initiate a
thermoregulatory response, ‘‘the compensable phase’’
(above the horizontal dashed red line) with increased cardiac
output (CO) and redistribution of blood flow (BF). When
the individual heat stress threshold is surpassed, central
venous pressure (CVP) begins to decrease significantly and
core temperature (Tc) begins to elevate rapidly. This ther-
moregulatory failure is aggravated by circulatory failure,
endotoxemia, and intracellular ion imbalance (energy deple-
tion). Renal dysfunction/failure, liver dysfunction/failure,
and coagulopathy develop secondary to the combined high
body temperature and circulatory collapse (the linkage to
heat stroke is depicted by the dotted line). The multiorgan
failure is ultimately life threatening, especially when disse-
minated intravascular coagulation ensues.
the clinical picture of heatstroke. Two findings –
hyperthermia and central nervous system dysfunc-
tion – must be present for a diagnosis of heat stroke
(Shibolet et al., 1976; Shapiro & Seidman, 1990;
Bouchama & Knochel, 2002). The core temperature
may range from 40 1C to 47 1C (Bouchama &
Knochel, 2002) and brain dysfunction or encepha-
lopathy is usually severe, but may be subtle (Gath-
iram et al., 1988; Blatteis, 2000; Bouchama &
Knochel, 2002). The most serious complications of
heat stroke are those falling within the category of
critical organ dysfunction and include severe ence-
phalopathy, rhabdomyolysis, acute renal failure,
acute respiratory distress syndrome, myocardial
injury, hepatocellular injury, intestinal ischemia,
pancreatic injury, and hemorrhagic complications,
especially disseminated intravascular coagulation
(Shibolet et al., 1967; Shibolet et al., 1976; Shapiro
& Seidman, 1990). While extreme hyperthermia is
the trigger for the vicious cycle leading to heat
stroke, it is noteworthy that the fatal outcome of
the syndrome is due to multiorgan failure (Fig. 1).
The term heat stroke is misleading in view of the
global, not focal, nature of the encephalopathy
and the concomitant multisystem pathophysiology
746
involved in the syndrome. While a term such as
heat-induced encephalopathy may more accurately
depict the brain changes, it does not address the
other affected organ systems.
Influencing heat stroke outcomes
The key to successful resuscitation of heat stroke
victims is early recognition and rapid cooling. The
earlier intervention in the pathophysiologic cascade
from compensable to uncompensable heat tolerance
occurs, the less likely there will be an adverse out-
come. Field recognition requires a keen awareness
of the prodromal symptoms and signs of early heat
intolerance and a rectal temperature measurement
to estimate the core temperature (Shapiro & Seid-
man, 1990). Once hyperthermia is documented,
rapid cooling by any method available reduces
morbidity and can be lifesaving (Hadad et al.,
2004). Cold water immersion is the method of
choice, but rapidly rotating ice water-soaked towels,
cool water immersion, or continuously spraying
with cold water can be nearly as effective (Hadad
et al., 2004; Casa et al., 2007). The goal is to remove
as much excess body heat as rapidly as possible to
interrupt the ‘‘uncompensable cascade’’ and to pre-
serve cell function and organ integrity. Using rapid
cooling treatment methods in the field has lead to
excellent outcomes for heat stroke recognized on
site. With rapid cooling, organ function that was
directly suppressed by overheated cells (brain, heart,
and kidney) clinically returns to normal if organ
perfusion is maintained and cell death is minimized
(Roberts, 2006). Limiting activity in very hot con-
ditions will reduce the incidence of heat stroke, but
exertional heat stroke has been documented even in
low risk conditions (Epstein et al., 1999; Roberts,
2006). Thus, early recognition and intervention to
disrupt the downhill cascade into heat stroke are
lifesaving.
Finally, the suggested paradigm highlights several
still unresolved questions regarding the pathophy-
siology as well as the clinical and supportive manage-
ment of heatstroke. For example, is there a genetic
factor involved in EHS in light of the fact that it is a
sporadic event, which in general is related to a state
of ‘‘heat intolerance?’’ Using rapid cooling will
effectively reduce body temperature; however, what
supportive treatment should be employed, beyond
symptomatic treatment, to enhance recovery? And,
to assess pre- and post-exposure risks: is there a
biomarker that can reflect an individual’s level of
tolerance to heat?
Key words: hyperthermia, heat stress, heat strain, heat
intolerance.

References
Armed Forces Health Surveillance
Center. Update: heat injuries, active
component, US Armed Forces, 2009.
Silver Springs, MD; MSMR, 2010.
Baumann H, Gauldie J. Acute phase
response. Immunol Today 1994: 15:
74–80.
Blatteis CM. The afferent signalling of
fever. J Physiol 2000: 526: 470.
Bouchama A, Dehbi B, Mohamed G,
Matthies F, Shoukri M, Menne B.
Prognostic factors in heat waves-
related deaths. Arch Intern Med 2007:
167: 2170–2176.
Bouchama A, Knochel JM. Heat stroke.
N Engl J Med 2002: 346: 1978–1988.
Boulant JA. The effect of firing rate on
preoptic neuronal thermosensitivity. J
Physiol 1974: 240: 661–669.
Boulant JA. Hypothalamic neurons
regulating body temperature. In:
Fregly MJ, Blatteis CM, eds.
Handbook of physiology;, Vol 1. New
York, NY: Oxford University Press,
1996: 105–126.
Bynum GD, Pandolf KB, Schuette WH,
Goldman RF, Lees DE, Whang-Peng
J, Atkinson ER, Bull JM. Induced
hyperthermia in sedated humans and
the concept of critical thermal
maximum. Am J Physiol 1978: 235:
R228–R236.
Casa DJ, McDermott BP, Lee EC,
Yeargin SW, Armstrong LE, Maresh
CM. Cold water immersion: the gold
standard for exertional heatstroke
treatment. Sport Sci Rev 2007: 35: 141–
149.
Chan PH. Reactive oxygen radicals in
signaling and damage in the ischemic
brain. J Cereb Blood Flow Metab 2001:
21: 2–14.
Chang C-K, Chang C-P, Liu S-Y, Lin M-
T. Oxidative stress and ischemic
injuries in heat stroke. Prog Brain Res
2007: 162: 525–546.
Charkoudian N. Skin blood flow in adults
human thermoregulation: how it
works, when it does not, and why.
Mayo Clin Proc 2003: 78: 603–612.
Epstein Y. Heat stroke: lessons we tend to
forget. Am J Med Sports 2000: 2: 143–
152.
Epstein Y, Hadad E, Shapiro Y.
Pathological factors underlying
hyperthermia. J Therm Biol 2004: 29:
487–494.
Epstein Y, Moran D, Shapiro Y, Sohar E,
Shemer J. Exertional heat stroke – a
case series. Med Sci Sports Exerc 1999:
31: 224–228.
Gabay C, Kushner I. Acute-phase
proteins and other systemic responses
to inflammation. N Engl J Med 1999:
340: 448–454 [Erratum, N Engl J Med
1999: 340: 1376].
The pathophysiology of heat stroke
Gaffin SL. Simplified calcium transport
and storage pathways. J Therm Biol
1999: 24: 251–264.
Gaffin SL, Hubbard RW.
Pathophysiology of heatstroke. In:
Pandolf KB, Burr RE, eds. Textbook
of military medicine: medical aspects of
harsh environments, Vol I. Bethesda,
MD: US Department of the Army,
office of the Surgeon General, 2001:
161–209.
Gathiram P, Wells MT, Brock-Utne JG,
Gaffin SL. Portal and systemic arterial
plasma lipopolysaccharide
concentrations in heat stressed
primates. Circ Shock 1988: 25:
223–230.
Gonzalez RR. Biophysics of heat transfer
and clothing considerations. In:
Pandolf KB, Sawka MN, Gonzalez
RR, eds. Human performance
physiology and environmental
medicine at terrestrial extremes.
Carmel, IN: Cooper Publishing Group,
1988: 45–96.
Hadad E, Rav-Acha M, Heled Y, Epstein
Y, Moran DS. Heat stroke: a review of
cooling methods. Sports Med 2004: 34:
501–511.
Hales JRS. Proposed mechanisms
underlying heat stroke. In: Hales JRS,
Richards DAB, eds. Heat stress:
physical exertion and environment.
Amsterdam, the Netherlands:
Elsevier Science Publishers BV, 1987:
85–102.
Hall DM, Buettner GR, Oberley LW, Xu
L, Matthes RD, Gisolfi CV.
Mechanisms of circulatory and
intestinal barrier dysfunction during
whole body hyperthermia. Am J
Physiol 2001: 280: H509–H521.
Hart GR, Anderson RJ, Crumpler CP,
Shulkin A, Reed G, Knochel JP.
Epidemic classical heat stroke:
clinical characteristics and course
of 28 patients. Medicine 1982: 61:
189–197.
Horowitz M. Heat acclimation and cross
tolerance against novel stressors:
genomic- physiological linkage. Prog
Brain Res 2007: 162: 373–392.
Horowitz M, Hales JRC.
Pathophysiology of hyperthermia. In:
Blatteis CM, ed. Physiology and
pathophysiology of temperature
regulation. Singapore, Singapore:
World Scientific Publishing Co, 1998:
229–245.
Hubbard RW. Heatstroke
pathophysiology: the energy depletion
model. Med Sci Sports Exerc 1990: 22:
19–28.
Hubbard RW, Mathew CB, Durkot MJ,
Francesconi RP. Novel approaches to
the pathophysiology of heat stroke: the
energy depletion model. Ann Emerg
Med 1987: 16: 1066–1075.
Johnson JM, Proppe DW.
Cardiovascular adjustments to heat
stress. In: Fregly MJ, Blatteis CM, eds.
Handbook of physiology;, Vol 1. New
York, NY: Oxford University Press,
1996: 215–243.
Knochel JP, Goodman EL. Heat stroke
and other forms of hyperthermia. In:
Mackowiak PA, ed. Fever: basic
mechanisms and management.
Philadelphia, PA: Lippincott-Raven
Pub., 1997: 437–457.
Koratich M, Gaffin SL. Mechanisms of
calcium transport in human endothelial
cells subjected to hyperthermia.
J Therm Biol 1999: 24: 245–249.
Ladell WSS. Disorders due to heat.
Trans R Soc Trop Med Hyg 1957: 51:
189–207.
Lambert GP. Role of gastrointestinal
permeability in exertional heatstroke.
Exerc Sport Sci Rev 2004: 32: 185–190.
Leon LR. Heat stroke and cytokines.
Prog Brain Res 2007: 162: 481–524.
Leon LR, Helwig BG. Heat stroke:
role of the systemic inflammatory
response. J Appl Physiol 2010: 109:
1980–1988.
Li P-L, Chao Y-M, Chan SHH, Chan
JYH. Potentiation of baroreceptor
reflex response by heat shock protein
70 in nucleus tractus solitarii confers
cardiovascular protection during
heatstroke. Circulation 2001: 103:
2114–2119.
Lin MT. Pathogenesis of an experimental
heatstroke model. Clin Exp Parmacol
Physiol 1999: 26: 826–827.
Lin M-T, Chang C-P. The
neuropharmacological basis of heat
intolerance and its treatment. J
Thermal Biol 2004: 29: 463–469.
Maloyan A, Palmon A, Horowitz M.
Heat acclimation increases the basal
HSP72 level and and alters its
production dynamics during heat
stress. Am J Physiol 1999: 276: R1506–
R1515.
Moseley PL. Heat shock proteins and
heat adaptation of the whole organism.
J Appl Physiol 1997: 83: 1413–1417.
Moseley PL, Gapen C, Wallen ES, Walter
ME, Peterson MW. Thermal stress
induces epithelial permeability. Am J
Physiol 1994: 36: C425–C434.
Nadel ER, Cafarelli E, Roberts MF,
Wenger CB. Circulatory regulation
during exercise in different ambient
temperatures. J Appl Physiol 1979: 46:
430–437.
Nadel ER, Mitchell JW, Saltin B,
Stolwijk JAJ. Peripheral modifications
to the central drive for sweating. J Appl
Physiol 1971: 31: 828–833.
747
Epstein & Roberts
Pals KL, Chang RT, Ryan AJ, Gisolfi
CV. Effect of running intensity on
intestinal permeability. J Appl Physiol
1997: 82: 571–576.
Polla BS, Bachelet M, Elia G, Santoro
MG. Stress proteins in inflam-
mation. Ann N Y Acad Sci 1998: 851:
75–85.
Roberts MF, Wenger CB, Stolwijk JAJ,
Nadel ER. Skin blood flow and
sweating changes following exercise
training and heat acclimation. J Appl
Physiol 1977: 43: 133–137.
Roberts WO. Exertional heat stroke
during a cool weather marathon: a case
study. Med Sci Sports Exerc 2006: 38:
1197–1202.
Robine JM, Cheung SL, Le Roy S, Van
Oyen H, Griffiths C, Michel JP,
Hermann FR. Death toll exceeded
70,000 in Europe during the summer of
2003. C R Biol 2008: 331: 171–178.
Rowell LB. Cardiovascular aspects of
human thermoregulation. Circ Res
1983: 52: 367–379.
Saltin B, Gagge AP, Stolwijk JAJ. Body
temperature and sweating during
thermal transients caused by exercise. J
Appl Physiol 1970: 28: 318–327.
Sawka MN, Francesconi RP, Young AJ,
Pandolf KB. Influence of hydration
level and body fluids on exercise
performances in the heat. JAMA 1984:
252: 1165–1169.
Senay LC. Jr. An inquiry into the role of
cardiac filling pressure in
acclimatization to heat. Yale J Biol
Med 1986: 59: 247–256.
Shapiro Y, Alkan M, Epstein Y, Newman
F, Magazanik A. Increase in rat
intestinal permeability to endotoxin
during hyperthermia. Eur J Appl
Physiol 1986: 55: 410–412.
Shapiro Y, Rosenthal T, Sohar E.
Experimental heatstroke: a model in
dogs. Arch Intern Med 1973: 131:
688–692.
748
Shapiro Y, Seidman DS. Field and
clinical observations of exertional heat
stroke patients. Med Sci Sports Exerc
1990: 22: 6–14.
Sharma HS, Dey PK. Probable
involvement of 5-hydroxytryptamine in
increased permeability of blood-brain-
barrier under heat stress.
Neuropharmacology 1986: 25:
161–167.
Shibolet S, Coll R, Gilat T, Sohar E.
Heatstroke: its clinical picture and
mechanism in 36 cases. Q J Med 1967:
36: 525–548.
Shibolet S, Lancaster MC, Danon Y.
Heat stroke: a review. Aviat Space
Environ Med 1976: 47: 280–301.
Siejo BK, Wielock T. Cerebral
metabolism in ischemia: neurochemical
basis for therapy. Br J Anaesth 1985:
57: 47–62.
Snellen JW. Mean body temperature and
the control of thermal sweating. Acta
Physiol Pharmacol Med 1966: 19:
99–174.
Sonna LA, Sawka MN, Lilly CM.
Exertional heat illness and human gene
expression. Prog Brain Res 2007: 162:
321–346.
Stolwijk JAJ, Saltin B, Gagge AP.
Physiological factors associated with
sweating during exercise. J Aerospace
Med 1967: 39: 1101–1105.
Treon SP, Thomas P, Broitman SA.
Lipopolysaccharide (LPS) processing
by Kupffer cells releases a modified
LPS with increased hepatocyte
binding and decreased tumor
necrosis factor alpha stimulatory
capacity. Proc Soc Exp Biol Med 1992:
202: 153–158.
Wang Z-Z, Wang C-L, Wu T-C.
Autoantibody response to heat shock
protein 70 in patients with heatstroke.
Am J Med 2001: 111: 654–657.
Wenger CB, Roberts MF, Stolwijk JAJ,
Nadel ER. Nocturnal lowering of
thresholds for sweating and
vasodilatation. J Appl Physiol 1976: 41:
15–19.
Werner J. Temperature regulation during
exercise: an overwiew. In: Gisolfi CV,
Lamb DR, Nadel ER, eds. Perspective
in exercise science and sports medicine;
vol 6: exercise, heat, and
thermoregulation. Dubuque, IA:
Brown and Benchmark, 1993: 49–84.
Wijsman JA, Shivers RR. Heat stress
affects blood-brain-barrier
permeability to horseradish peroxidase
in mice. Acta Neuropathol 1993: 86:
49–54.
Wu T, Chen S, Xiao C, Xiao C, Wang C,
Pan Q, Wang Z, Xie M, Mao Z, Wu Y,
Tanguay RM. Presence of antibody
against the inducible Hsp71 in
patients with acute heat-induced
illness. Cell Stress Chaperon 2001: 6:
113–120.
Wyndham CH, Strydom NB, Morrison
JF, Williams CG, Bredell GA, Maritz
JS, Munro A. Criteria for physiological
limits for work in heat. J Appl Physiol.
1965: 20: 37–45.
Yamada PM, Amorim FT, Moseley P,
Robergs R, Schneider SM. Effect of
heat acclimation on heat shock
protein 72 and interleukin-10 in
humans. J Appl Physiol 2007: 103:
1196–1204.
Yan Y-E, Zhao Y-Q, Wang H, Fan M.
Pathophysiological factors underlying
heatstroke. Med Hypotheses 2006: 67:
609–617.
Yang CY, Lin MT. Oxidative stress in
rats with heatstroke induced
cerebral ischemia. Stroke 2002: 32:
232–239.
Yang Y-L, Lin M-T. Heat shock protein
expression protects against cerebral
ischemia and monamine overload in rat
heatstroke. Am J Physiol 1999: 276:
H1961–H1967.