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Is There a Link between Malignant Hyperthermia and Exertional Heat Illness?

  • North American MH Registry of MHAUS


Exertional heat illness (EHI) and malignant hyperthermia (MH) are two potentially lethal conditions. It has been suggested that a subset of MH susceptible persons may be predisposed to EHI. We examine the current understanding of these disorders and explore evidence of a relationship. Screening for the muscle type I ryanodine receptor gene should help clarify the relationship between MH and EHI.
Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
Exertional Heat Illness, Exertional
Rhabdomyolysis, and Malignant Hyperthermia:
Is There a Link?
Sheila Muldoon,
Patricia Deuster,
Maria Voelkel,
John Capacchione,
and Rolf Bunger
Department of Anesthesiology,
Malignant Hyperthermia Biopsy Center,
Department of Military and
Emergency Medicine, and
Department of Anatomy, Physiology and Genetics, Uniformed Services University
of the Health Sciences, Bethesda, MD
MULDOON, S., P. DEUSTER, M. VOELKEL, J. CAPACCHIONE, and R. BUNGER. Exertional heat illness, exertional
rhabdomyolysis, and malignant hyperthermia: Is there a link? Curr. Sports Med. Rep. Vol. 7, No. 2, pp. 74Y80, 2008. This short
review discusses possible links between exertional heat illness (EHI), malignant hyperthermia (MH), and exertional rhabdomyolysis (ER).
Evidence on clinical, genetic, and functional aspects, though limited, is compared through individual case reports and a small number of
clinical studies. Typically, MH occurs during anesthesia and surgery, EHI during strenuous exercise in hot and humid environments, and
ER unrelated to heat and humidity after strenuous exercise. Genetic analysis of the RYR1 gene has identified various mutations,
especially in MH, but also in some cases of EHI and in number of ER cases as well. Pathophysiologically, loss of intracellular calcium
control appears to be a common feature. Recommendations for treatment and recovery include cooling and administration of
dantrolene for MH, cooling and aggressive fluid administration for EHI, and physical rest and aggressive intravenous fluid
administration for ER.
Previously, malignant hyperthermia (MH), exertional
heat illness (EHI), and exertional rhabdomyolysis (ER)
have been considered related syndromes. However, the
current literature regarding this relationship is not exten-
sive. Hopkins stated in a recent article, ‘‘there is a link
between MH and exertional heat illness,’’ but the nature of
this link and the relationship between these events was not
enumerated (1). To provide a comprehensive discussion,
this review will include publications over a broad period of
time to address several questions: 1) Can EHI and ER be
pathophysiologically (i.e., mechanistically) linked to MH?
Conversely, can MH be mechanistically linked to EHI and
ER? 2) What are the appropriate functional and genetic
tests to differentiate between MH, EHI, and ER? And 3)
When should individuals who suffer from MH, EHI, or ER
resume strenuous physical activity?
Malignant Hyperthermia
MH is an uncommon, autosomal, dominantly inherited
disorder of calcium handling in skeletal muscle, mainly
caused by mutations in the gene coding for the type one
ryanodine receptor (RyR1). RyR1 functions as a calcium ion
channel in the sarcoplasmic reticulum (SR) membrane
regulating the release of calcium from the SR. Until
challenged by ‘‘triggering’’ inhalational anesthetics and/or
succinylcholine, patients with MH, many of whom are
physically fit, are asymptomatic. Triggering anesthetics can
cause a life-threatening, fulminant episode of MH. Such
episodes are characterized by hypermetabolism with variable
signs and symptoms including tachycardia, hypercarbia,
metabolic acidosis, generalized or localized muscle rigidity,
rhabdomyolysis, hyperthermia, and if untreated, death.
Dantrolene, a compound that blocks release of calcium from
the SR via the RyR1, can provide effective treatment of such
episodes. Without treatment, mortality from ‘‘fulminant’’
Address for correspondence: Sheila Muldoon, M.D., Department of Anesthesiology,
Director of Malignant Hyperthermia Biopsy Center, Uniformed Services University
of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814
Current Sports Medicine Reports
Copyright *2008 by the American College of Sports Medicine
Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
episodes exceeds 70%, but with modern intraoperative
monitoring (specifically end-expired CO
) and the admin-
istration of dantrolene, the death rate has decreased to less
than 7%.
The diagnosis of MH is typically based upon a personal or
family history of a clinical MH episode during anesthesia, or
upon a positive response to the caffeine halothane contrac-
ture test (CHCT), an in-vitro muscle bioassay. In North
America, this test is used to diagnose patients as MH-
susceptible (MHS) or MH-normal (MHN) (2). Muscle
fibers from MHS individuals are markedly more sensitive
to RyR1 agonists including 4-chloro-m-cresol and ryanodine
than MHN or normal muscle fibers. The CHCT has a very
high sensitivity (97%) with a somewhat reduced specificity
(78%) (2). The CHCT is invasive, expensive, and, because
of the potentially life-threatening danger of a false-negative
diagnosis, is designed to err on the side of a false-positive
diagnosis. Additionally, the CHCT must be performed upon
freshly excised muscle strips at one of the few MH
diagnostic centers in the U.S.; patients therefore may have
to travel to have the test performed. In Europe, a similar
test, the in vitro contracture test (IVCT), is in use. The
IVCT has three diagnostic categories: MHS, MHN, and
MH equivocal (MHE). MHE indicates that the IVCT is
positive to either caffeine or halothane, but not to both (3).
To date, no better tests have been developed, but research
into genetic testing is ongoing.
The incidence of MH during general anesthesia is
estimated at 1 in 4,200 (suspicion of MH) to 1 in 250,000
(fulminant MH) (4). Males are more frequently affected
than females, and a muscular build appears to be a
predictive risk factor. Published case reports have linked
prior intraoperative MH events with later events without
Exertional Heat Illness
EHI is a disorder of excessive heat production, coupled
with insufficient heat dissipation. Although serious heat
illness events have been associated with adverse health
conditions, medications, and environmental factors, many
persons with EHI are normal and healthy before their EHI
episodes. In some cases, EHI can progress to exertional heat
stroke (EHS).
The accepted diagnostic criteria for EHS include central
nervous system (CNS) abnormalities coupled with extreme
hyperthermia (i.e., a core body temperature higher than
40Y40.6-C or 104Y105-F). Neurological impairment may
first appear as inappropriate behavior, impaired judgment,
delirium, coma, or seizures (5). EHS can cause critical injury
to all organ systems in the body, including thermoreg-
ulatory, renal, cardiovascular, musculoskeletal, and hepatic.
Data on the incidence of EHS in the general population
is imprecise, but at least 994 hospitalizations for heat stroke
were reported by the U.S. Army based upon medical records
between 1980 and 2002 (6). A total of 37 deaths were
reported for this group, and associated conditions noted in
the medical records for the fatal cases included prior
respiratory infections, influenza, and streptococcal pneumo-
nia. Females are affected more often than males and
Caucasians more frequently than African American and
Hispanic individuals. Heat exhaustion is a milder form of
EHI, with no serious CNS signs. Exertional rhabdomyolysis
(ER), described later in this article, is a frequent complica-
tion of EHI, particularly in victims of heat stroke. EHI
occurs commonly in the summer or when unacclimated
people physically overexert themselves.
The key elements for treating acute EHI are rapid cooling
of core body temperature (to below 39-C or 102.2-F) and
aggressive hydration to restore intravascular volume, correct
electrolyte imbalances, and maintain urine output. Dantro-
lene has been used successfully to treat EHS in cases where
there is a history of MH, but its use in other cases of EHS is
not recommended.
Exertional Rhabdomyolysis
ER is a syndrome of diverse etiology characterized by
destruction of the skeletal muscle cell membrane resulting
in massive release of intracellular creatine kinase (CK),
potassium (K
), myoglobin, and other intracellular constit-
uents. ER can occur in response to strenuous physical
activity, particularly exercise eccentric in nature, when
mechanical or metabolic stress damages muscle fibers. This
muscle damage can occur in the absence of high environ-
mental temperatures. ER also is seen as a consequence of
exertional heat exposure, coexisting with sickle cell trait or
use of dietary supplements (7,8).
Although the diagnostic criteria for ER are somewhat
controversial, clinical practice guidelines recognize a serum
CK level Q5 times normal and a urine analysis positive for
myoglobinuria as diagnostic. CK levels may peak between 12
and 96 hours after the end of exercise and then decline prog-
ressively. Musculoskeletal pain typically occurs 24Y48 h after
extreme or non-familiar exercise: cola-colored urine is the
primary sign reported by persons experiencing acute ER (7).
Although the true incidence of ER is unknown, 43.3% of
students in a Taiwan high school were identified as having
ER following an endurance test (9). In the United States,
most reported ER cases concern military recruits (2%Y40%)
within the first 6 d of basic training. Low levels of physical
fitness and early introduction of repetitive exercises increase
risk of ER. Long distance runners, weight lifters, and, less
commonly, football players, are all at risk for ER (7).
The primary treatment goal is to preserve renal function
by early fluid replacement in an attempt to prevent acute
renal failure. Monitoring fluid intake, serum electrolytes,
and acid base status is necessary to prevent serious
complication and expedite recovery. Most cases are self-
modulating with no evidence of long-term renal or muscle
injury. Individuals who present with recurrent generalized
abnormal clinical findings or acute renal failure may have
an underlying metabolic myopathy (7).
Can MH, EHI, and ER be Mechanistically Linked?
What is the link between EHI/EHS and MH?
The link between EHI/EHS and MH has been the subject
of debate in the literature for decades and has been reviewed
Volume 7 Number 2 March/April 2008 Exertional Heat Illness, Exertional Rhabdomyolysis, and Malignant Hyperthermia 75
Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
numerous times (10Y14). Several similarities between EHI
and MH have been noted: excessive heat production that
exceeds dissipation capability and rhabdomyolysis. Both
syndromes can occur in otherwise healthy individuals over a
wide range of ages. Some persons who present with signs
and symptoms of EHI have later been shown to be MHS.
Much of our knowledge regarding a link between EHI and
MH is derived from case reports. In particular, a number of
athletes and soldiers collapsing from EHI have subsequently
tested positive with either IVCT or CHCT, which renders a
diagnosis of MHS (Table) (15Y17). The case reports by
Hackl et al. are fairly typical (18). He performed the IVCT
on five patients who developed fever and severe myolysis
during exercise. MHS was confirmed in three, whereas a
negative IVCT ruled out MHS in the other two. In a recent
case report, a 16-yr-old muscular athlete with hyperthermia,
altered mental status, and respiratory distress during football
practice is described. Multi-system organ failure ensued,
which he survived, and MH was suspected because of a
history of ER prior to his heat stroke. However, the CHCT
was negative, which eliminated the diagnosis of MHS (19).
One large study has investigated in-vitro muscle contrac-
ture responses and metabolic energetic changes in survivors of
EHS. Since 1988, 250 EHS survivors have been examined in
Marseille, France, using the IVCT combined with
magnetic resonance (NMR). Subtle but distinct NMR
differences were found in MHS patients compared to EHS
survivors when tested with mild exercise (20). In the most
recent study, 26 EHS subjects had an abnormal IVCT and
abnormal muscle energetics as measured by
P-NMR (21).
Italian investigators described 45 patients with EHS who
underwent IVCT at least three months after their EHS.
Nineteen of the 45 patients were diagnosed as MHS by the
IVCT, and eight of 19 were classified as MHE; clinically, these
patients would be treated as MHS. Histopathological studies
revealed various muscle abnormalities including rhabdomy-
olysis, mitochondrial myopathy, denervation type II atrophy,
AMPD deficiency, and other non-specific findings as well as
normal features. No compelling relationship between the
IVCT and cellular morphology (histopathological findings)
were noted. Persons with central core disease were found
only in the MHS group (22). In each of these studies, this
issue of whether there was an underlying MHS in the EHS
cases could be clarified by full molecular screening of the
RYR1 gene or a standardized exercise intolerance panel, but
these analyses have not been performed.
Another example where genetic analysis of parents and
patients may have helped to clarify whether there is an
underlying MHS in an EHS case is provided by Hopkins et al.
(23). This investigator reports on two soldiers who collapsed
with EHS and subsequently underwent the IVCT. Muscle
from both patients was found to be MHE (abnormal
responses to halothane, normal responses to caffeine).
Muscle from the father of one patient also showed an
abnormal response to halothane, and the muscle from the
father of the second patient responded abnormally strong to
ryanodine, the most specific RyR1 agonist available.
Hopkins interpreted these results to indicate that the
soldiers had an underlying inherited abnormality of skeletal
muscle similar to, but not identical to, that of MHS (23).
What is the nature of the link between MH and EHS?
An important question is whether persons with docu-
mented MH episodes are more susceptible to EHI. Again,
sporadic case reports provide only anecdotal evidence
suggesting that individuals genetically susceptible to MH
may, as a class, be at increased risk for EHS or ER. One
well-known case reported by Tobin et al. was a child who
had an unequivocal MH episode during anesthesia and later
died of EHS (24). Post-mortem DNA analysis identified an
RYR1 gene mutation (R163C), which is considered causa-
tive for MH; the father shared the same RYR1 mutation.
TABLE. Literature case reports reporting links between EHI
/Rhabdomyolysis and MH
Author Reason for Workup Total Patients Total MHS
Patients Total MHN
Patients Patients With RyR1 Mutation
Hackl et al. (18) EHI 5 3 2 N/A
Hopkins et al. (23) EHI 2 2 0 N/A
Ogletree et al. (15) EHI 1 1 0 N/A
Figarella-Branger et al. (22) EHI 45 19 26 N/A
Hunter et al. (16) EHI 1 1 0 N/A
Kochling et al. (17) EHI 1 1 0 N/A
Bendahan et al. (21) EHI 26 (250) 26 (80) 0 N/A
Fink et al. (19) EHI 1 0 1 N/A
Wappler et al. (28) Rhabdomyolysis 12 10 2 3
Davis et al. (30) Rhabdomyolysis 3 3 0 3
Loke et al. (29) Rhabdomyolysis 1 1 0 1
EHI: Exertional Heat Illness, including exertional heat stroke.
MHS: MH susceptible. This group includes MH equivocal diagnoses by IVCT.
MHN: MH negative by IVCT.
N/A: Genetic screen was not performed on these cases.
Has studied more than 250 cases.
76 Current Sports Medicine Reports
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Another unpublished case also illustrates a likely genetic
link between MHS and EHI. Following a clinical MH episode
during anesthesia, a young man was found to beMHS (positive
CHCT); 5 yr after his first MH episode, he developed two
episodes of EHI under conditions of high environmental heat
and humidity, one of which was categorized as EHS. There-
after he developed two more episodes of ER, this time without
hyperthermia, in a moderate climate. Clinically, one inci-
dence was a mild episode, but the other was severe with
maximum CK of 160,000 IU, coupled with abnormal liver
function tests and increased serum creatinine values. His
father was also found CHCT-positive, pointing to a related
familial trait. Unfortunately, no genetic analyses have been
performed to identify an RYR1 mutation.
A third report by Ryan et al. described a 23-yr-old male
police recruit whose family had a positive history of MHS
(25). The recruit was in excellent physical condition but
developed rigidity and cardiac arrest during moderate exercise
on a day that was cool and dry (13-Cor54-F and 54%
humidity). Following a brief warm-up period of calisthenics
and stretching, he began a 3-mile run at 8.5 minImile
was initially among the leaders, with his pace well below
usual, but surprisingly he dropped out near the end and was
noted to be stumbling and disoriented. He was placed in a
cool area and hosed down with water, but became ashen,
tachypnic with an irregular heartbeat, and stopped breathing.
Cardiopulmonary arrest occurred and he was transferred to
the local hospital, but resuscitation was unsuccessful. His
temperature 2 hr post-mortem was markedly elevated (41-C
or 106-F), and the potassium level in his vitreous humour was
also elevated. His family has a history of MHS: his brother
had a positive CHCT, and his nephew had a clinical MH
episode. Because MH is inherited in an autosomal dominant
fashion, this young man had a 50% chance of being MHS as
the first-degree relative of an MHS individual. It is thus
conceivable that the familial trait of MH increased the risk
for EHI in this police recruit. However, in the absence of an
RYR1 mutation considered to be causative for MH, there is
no definitive proof that this EHI-like case was actually an
‘‘awake’’ MH episode.
In each of these cases, the positive history of MH supports
that a personal or family history of MH should be regarded
as a risk factor for EHI. Finally, it should be noted that the
individuals in all of these cases were in a competitive
environment, which suggests a psychological component, as
well as physical stress (10).
What is the link between ER and MH?
Unlike EHI/EHS, ER occurs in both cool and warm
environments. However, similar to MH, ER also is a
hypermetabolic state wherein the skeletal cell membrane
is severely compromised and serum CK values are markedly
increased. As previously mentioned, small studies and case
reports are how connections have been developed. In
particular, Poels et al. performed IVCT on six patients with
non-anesthetic-induced rhabdomyolysis, two of whom had
ER (26). Five of the six were IVCT-positive, which suggests
that the association between MH and unexplained non-
anesthetic induced rhabdomyolysis is ‘‘not exceptionally rare.’’
In an earlier case report, Poels et al. pointed out that
dantrolene, the key antidote in an MH episode, was effective
in a patient with ER (27). Although genetic analysis of the
RYR1 was not available at that time, more recent inves-
tigations of 12 persons with ER, of whom 10 were diagnosed
as MHS and one as MHE by IVCT, identified three variants
(R163C, G341R, and G2434R) in the RYR1 gene of three
unrelated patients (28). This analysis of limited sections of
the RYR1 gene suggests a possible link between ER and a
mutated RYR1 gene, as with MH.
This interpretation is also consistent with a recent report
describing a young boy who experienced episodes of
generalized body rigidity with dyspnea and painful calf
spasms. It was noted that ‘‘Up to 100 of these episodes were
reported by the patient to have occurred over a 3-yr period,
and though not associated with any anesthetic but were
apparently associated with hot weather and emotional
stress.’’ Resting CK levels were normal, but a CHCT at 18
yr of age was positive; histopathology confirmed normal
skeletal muscle, as is typical for MHS cases. After sequenc-
ing the entire RYR1 gene, a previously reported variant,
R2336H, in exon 43 was identified; this variant has been
associated with both anesthetic and non-anesthetic episodes
of MH (29). In a separate study, two ER cases revealed a
common R401C mutation (30).
Taken together, these few cases suggest that one
mechanism of non-anesthetic-induced ER could be certain
RYR1 mutations that are also associated with MH.
What Tests Can Differentiate Between MH, EHI,
and ER?
Biochemical, genetic, and functional bioassay tests for
determining susceptibility to EHI and ER and for differ-
entiating between MH, EHI, and ER are not currently
available, but they are needed. One non-differentiating test
used for these three clinical events is serum CK concen-
tration. Unexplained, persistently elevated serum CK, a
non-specific finding in the absence of neuromuscular
disease, should serve to alert anesthesiologists and sports
medicine physicians to a greater than normal risk of MH,
EHI, and ER (31).
The CHCT and IVCT were primarily developed to
diagnose MHS, but they also have been used to probe for a
relationship between these three clinical entities. However,
these tests cannot provide a reliable differential diagnosis. In
fact, they may have added to the conundrum as described
previously in this article. The observation that many persons
with EHI and ER are positive to either the CHCT or IVCT
has raised the basic mechanistic question whether EHI or ER
are simply modified clinical expressions of MH, or con-
versely, whether MH is a special case of the much more
frequent EHI or ER. The CHCT and IVCT test for
maintenance of cellular calcium homeostasis, i.e., the basic
pathophysiology of MH, which comprises a defect in the
RyR1. Disturbances in calcium homeostasis lead to intra-
cellular calcium overload, which in turn can lead to
cytoskeletal and muscle membrane digestion followed by
the release of intracellular constituents (e.g., myoglobin,
potassium, CK, and lactate dehydrogenase) into the blood,
which is common in the evolution of MH, EHI, and ER.
The link between cellular calcium handling mediated by
Volume 7 Number 2 March/April 2008 Exertional Heat Illness, Exertional Rhabdomyolysis, and Malignant Hyperthermia 77
Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
ATP-dependent pumps and the Na
exchanger is
shown schematically in the Figure. Such mechanistic
approaches should form the basis of all biochemical, genetic,
and functional tests to determine and differentiate MH,
EHI, and ER.
Other biochemical tests commonly used for MH and
other myopathies, but non-differentiating between MH,
EHI, and ER, reveal altered enzyme activities in, for exam-
ple, myoadenylate deaminase/AMPD deficiency, carnitine
palmitolytransferase/CPTII, and glycogen phosphorylase/
McArdle`s disease. In terms of genetics, common mutations
in the genes associated with these and related enzymes also
should be considered. In addition to these and the known
RYR1 mutations, variants in other genes may determine
susceptibility to MH, EHS, and ER. In this regard, candidate
genes currently considered include the dihydropyridine
receptor (DHPR), a gene that encodes proteins for a
voltage-dependent L-type calcium channel found in the
transverse tubule of muscles, mitochondrial genes that
determine the functionality of proteins for the respiratory
chain and hence energy metabolism and oxidative phos-
phorylation of ADP to ATP including associated translocases
on the inner mitochondrial membrane, genes that encode
for cytokines, coagulation proteins, and heat shock proteins
may also be contributors to the incidence and expression of
MH, EHI, and ER. These genes are areas of fertile research
but not available as clinical tests.
Functional testing may be one of the best approaches in
terms of differentiating between MH, EHI, and ER. One
possibility is the response to exercise testing under various
but highly controlled environmental conditions. Under ther-
moneutral conditions, at least four controlled exercise studies
have found no differences in the thermoregulatory, hormonal,
and metabolic responses to exercise in MHS as compared with
control subjects. However, the MHS participants may not
have included individuals with previous exercise- or heat-
related symptoms, and the level of exertion (40%Y80%
) may have been insufficient to induce symptoms
(32). Indeed, one study did show that MHS individuals who
were exercised at 120% V
exhibited delayed recovery
in muscle energy metabolism. It is interesting to note that
heat tolerance testing has been shown to discriminate
between heat tolerant and intolerant soldiers, and such
testing is used in Israel to determine whether EHI victims
can be retained in or need to be discharged from the military
(33). In addition, Heled et al. are developing a step-up test to
Figure. Simplified diagram of skeletal muscle subcellular organization pertinent to intracellular calcium homeostasis and the RyR1-DHPR receptors.
Extracellular fluid and SR lumen have high millimolar calcium concentrations. Intracellular sarcoplasmic free calcium concentrations ([Ca
) is in the
upper nanomolar to low micromolar range. Maintenance of such large calcium gradients requires chemical adenosine triphosphate (ATP) energy, much
like the actomoysin-ATPase-driven contraction. Muscle relaxation, too, requires ATP-dependent calcium reuptake into the SR (SR calcium pump) and/or
calcium extrusion into the extracellular space (sarcolemmal calcium pump). In a fulminant MH episode, loss of cellular calcium control is mainly caused by
dysfunction of the RyR1 (probably mainly failure to close the RyR1 calcium channel), and this can be fatal, if the resulting SR calcium leak cannot be
stopped. In the case of EHI, the physical overexertion per se of the contractile elements can lead to massive ATP use and hence likely to cellular
deenergization, which, if sufficiently severe, will lead to energetic failure of the calcium pumps, accumulation of [Ca
and lack of muscle relaxation
(contracture). In the case of ER, if there is a defect or leak in the sarcolemma, extracellular Na
and calcium ions will diffuse into the sarcoplasm, resulting
in accumulation of [Ca
. Intracellular calcium overload may also stimulate calcium-sensitive proteases (caspases), liposomal enzymes, and nuclear
DNAses, potentially resulting in autolytic destruction of the sarcolemma. Muscle ischemia/anoxia is probably not typical of EHI or ER but is a likely
complication of MH contracture. Bendahan et al. have provided
P-NMR evidence consistent with cellular deenergization and acidification playing a key
role in the pathogenesis of EHI and MH. (Reprinted from Vander, A., J. Sherman, and D. Luciano. Human Physiology. In: The Mechanisms of Body
Function, 8th ed. 2001, p. 128. Copyright *2001 The McGraw-Hill Companies. Used with permission.)
78 Current Sports Medicine Reports
Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
determine whether abnormal increases in post-exercise
serum CK levels can be used to predict susceptibility to ER
(34). It is hoped that evaluation of exercise (in)tolerance
under selective conditions where heat and humidity can be
controlled will differentiate between MH, EHI, and ER, but
this has not been done to date.
When Should Individuals with MH, EHI, or ER
Resume Strenuous Physical Activity?
Recovery from MH
Complete recovery from the sequelae of a fulminant MH
episode includes normalization of serum electrolytes, CK,
creatinine, and liver function tests. Patients who have
recovered from MH events frequently complain of fatigue,
muscle cramps, and heat intolerance for 3Y6 months after an
acute event. In our experience, most of the patients recover
with time. However, we recommend a period of 6Y12
months before resumption of a moderately strenuous
exercise program. Serial monitoring of CK and urinalysis
for myoglobinuria on a monthly basis is recommended.
Elevated CK or myoglobinuria after exercise are suggestive
of inadequate muscle recovery or ongoing muscle damage.
Resumption of strenuous exercise is probably contingent
upon age, severity of episode, fitness level before the
episode, the specific type of exercise, and the presence of
specific RYR1 mutations, as some mutations may be more
pathogenic than others. Because of the linkages between
EHI, ER, and MH, we recommend genetic and functional
exercise testing as part of a complete and thorough work-up
before a decision to return to normal exercise is made.
Recovery from EHI
Recovery from EHI is typically determined by normal-
ization of serum electrolytes, CK, creatinine, liver function
tests, and normal mental status (35). When EHI victims meet
these conditions, they can resume light to moderate exercise
for 15 minutes daily. Maximal efforts, such as competitive
running, and competitive sports, such as football, should not
be permitted until recovery is complete. Football uniforms,
in particular, contribute significantly to the heat load. If the
victim does not exhibit heat intolerance after 3 months post-
EHI episode, recommendations can be modified to an
unrestricted exercise/workload, but maximal exertion, par-
ticularly during significant heat load conditions, should be
avoided. If no further heat intolerance is manifest during
exercise in high environmental temperatures, the patient
may resume normal activities. Heat tolerance testing where
exercise is performed in a controlled environmental chamber
would be very useful in these cases.
Recovery from ER
As with EHI, normalization of serum electrolytes, CK,
creatinine, and liver function tests should be achieved
before resumption of exercise (36). Time to recovery will
vary depending upon the factors that precipitated ER and
risk stratification. Risk stratification is based upon several
factors. High-risk individuals are categorized as those who
demonstrate delayed recovery, persistently elevated CK,
acute renal failure complication, personal or family history
of similar symptoms, MH, or sickle cell trait, personal
history of severe muscle pain with activity or heat injury,
complications of drug or supplement use, or CK greater than
100,000 U/L. Low-risk individuals are categorized as those
who do not demonstrate any of the high-risk conditions but
do demonstrate rapid clinical and CK recovery with exercise
restriction, high level of physical fitness with a history of
intense training, no personal or family history of rhabdo-
myolysis, exercise-induced severe muscle pain, muscle
cramps, or heat injury, or involvement of diagnosed viral
or infectious disease (6).
Low-risk persons should have restrictedor limited aerobic or
anaerobic exercise for at least 72 h post-ER and be encouraged
to drink fluids. If CK returns to within normal limits by that
time, light outdoor exercise can resume, but no strenuous
physical activities. Physical activities should be self-paced for
at least 1 wk. and if at the end of 1 wk CK is normal, regular
outdoor duty and physical training can be resumed.
In contrast, high-risk persons should be referred to
neurology or sports medicine physicians. Their evaluation
will determine return to activity recommendations and future
testing, which could include a muscle biopsy for standard
histopathological panels, exercise intolerance panels, electro-
myographic testing, genetic screens for AMPD, CPTII,
McArdle`s, and RYR1, or a CHCT. Functional exercise
testing, such as a step test, may be useful for correlating serum
changes in CK levels and physical performance under stan-
dardized laboratory conditions.
It is important to remember that all of this information
and the appropriate clinical guidelines are based upon ex-
pert consensus and not direct evidence. No evidence exists
to support the clinical guidelines. Only future research will
be able to determine whether published clinical practice
guidelines for the prevention and acute management of
MH, EHI, and ER are justified. Guidelines for MH can be
found at, and clinical guidelines for EHI
(army personnel) are available at http://chppmwww.apgea. Recommenda-
tions for management of ER are currently being developed
but were not available at completion of this manuscript.
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Volume 7 Number 2 March/April 2008 Exertional Heat Illness, Exertional Rhabdomyolysis, and Malignant Hyperthermia 79
Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
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80 Current Sports Medicine Reports
... Exertional heat stroke (EHS) and MH can occur in young, otherwise healthy individuals and both are associated with a high metabolic (ATP) demand, accelerated oxidative, chemical and mechanical stress of skeletal muscles and presumably uncontrolled increases in intracellular Ca 2+ [13,[15][16][17]. Although controversial [18], it has been suggested that EHS may be a consequence of Ca 2+ dysregulation in the skeletal muscle that mimics that observed with MH [17,19]. ...
... Exertional heat stroke (EHS) and MH can occur in young, otherwise healthy individuals and both are associated with a high metabolic (ATP) demand, accelerated oxidative, chemical and mechanical stress of skeletal muscles and presumably uncontrolled increases in intracellular Ca 2+ [13,[15][16][17]. Although controversial [18], it has been suggested that EHS may be a consequence of Ca 2+ dysregulation in the skeletal muscle that mimics that observed with MH [17,19]. As such, Ca 2+ dysregulation, which is an underlying feature of MH, is frequently listed as a coexisting feature in both conditions. ...
... Because MH culminates in EHS-like symptoms due to the excessive metabolic heat generated during the sustained skeletal muscle contractions (Fig. 1), it is no surprise that these two conditions share similar clinical symptoms [15,17,19]. Nonetheless, EHS is a consequence of combined environmental and metabolic heat generation from only a few, albeit large, active skeletal muscle groups that are directly involved in the physical activity [18,28]. ...
Full-text available
Exertional heat stroke (EHS) and malignant hyperthermia (MH) are life-threatening conditions, triggered by different environmental stimuli that share several clinical symptoms and pathophysiological features. EHS manifests during physical activity normally, but not always, in hot and humid environments. MH manifests during exposure to haloalkane anesthetics or succinylcholine, which leads to a rapid, unregulated release of calcium (Ca2+) within the skeletal muscles inducing a positive-feedback loop within the excitation–contraction coupling mechanism that culminates in heat stroke-like symptoms, if not rapidly recognized and treated. Rare cases of awake MH, independent of anesthesia exposure, occur during exercise and heat stress. It has been suggested that EHS and MH are mediated by similar mechanisms, including mutations in Ca2+ regulatory channels within the skeletal muscle. Rapid cooling, which is the most effective treatment for EHS, is ineffective as an MH treatment; rather, a ryanodine receptor antagonist drug, dantrolene sodium (DS), is administered to the victim to prevent further muscle contractions and hyperthermia. Whether DS can be an effective treatment for EHS victims remains uncertain. In the last decade, multiple reports have suggested a number of mechanistic links between EHS and MH. Here, we discuss aspects related to the pathophysiology, incidence, diagnosis and treatment. Furthermore, we present evidence regarding potential overlapping mechanisms between EHS and MH and explore current knowledge to establish what is supported by evidence or a lack thereof (i.e. conjecture).
... If this is correct, then there must be a primary or secondary abnormality in the muscles that causes them to continue producing heat after exercise even though they are not producing external work. The evidence is that some humans are susceptible to this abnormal response which can be genetically determined and may be induced by agents, such as drug use or fasting, for example 6,76 . ...
... Rather, we should perhaps look for the obscure explanations for most cases of heatstroke. These would include skeletal muscle metabolic abnormalities and other unusual environmental influences 6,76 . If skeletal muscle abnormalities are present, the drug dantrolene may be effective, because it acts to reduce calcium release from the ryanodine receptor of the sarcoplasmic reticulum, a possible site of some of the skeletal muscle abnormalities associated with malignant hyperpyrexia and probably exertional heatstroke 6,76 . ...
... These would include skeletal muscle metabolic abnormalities and other unusual environmental influences 6,76 . If skeletal muscle abnormalities are present, the drug dantrolene may be effective, because it acts to reduce calcium release from the ryanodine receptor of the sarcoplasmic reticulum, a possible site of some of the skeletal muscle abnormalities associated with malignant hyperpyrexia and probably exertional heatstroke 6,76 . ...
A remarkable feature of the human species is our great capacity to lose heat and to regulate our body temperatures when exposed to heat. The Heinrich (Hunting) hypothesis theorises that this capacity evolved in early hominids and provided an extraordinary evolutionary advantage since it allowed our human ancestors to chase nutritionally-dense but non-sweating mammals like large antelope, to their (lesser) limits of thermoregulatory failure. In this fatigued state, the exhausted animals were more easily killed. It is further hypothesised that it was the consumption of the high protein/fat diet made possible by the capture of such animals that fuelled the development of the higher brain centres on which superior human intelligence depends. But the key physiological point is that during the hunt, early hominids had no access to fluid, the carrying of which would have hindered their ability to run. Thus for their evolutionary progress to have occurred, humans had to evolve a sweating mechanism to prevent overheating during exercise, as well as the capacity to continue exercising in the heat even though they were becoming increasingly dehydrated as the duration of the hunt increased and the environmental conditions likely became more severe. Until 1969 the advice given to endurance athletes mirrored this understanding of our evolutionary biology. Thus human athletes were advised not to drink during exercise. But the development of the world's first "sports drink" in Florida in the 1960s led gradually, but perhaps inevitably, to the promotion of a novel dogma that humans need to drink "as much as tolerable" during exercise if they are to avoid heatstroke and to optimise their performances. In this article this and three other dogmas that have evolved simultaneously over the past 35 years are analysed. These are: (i) that dehydration is the most important determinant of the body temperature during exercise; (ii) that athletes collapse after exercise because of a circulatory collapse caused by dehydration and hyperthermia; and (iii) that heatstroke always occurs in otherwise normal, healthy athletes who simply exercise too hard for too long in exceptionally hot conditions. Rather, it is argued in this paper that (i) all the published evidence supports the belief that health and performance during exercise are optimised by drinking according to the dictates of thirst ("ad libitum"); (ii) the brain sets both the work rate and the rectal temperature during exercise specifically to insure that heatstroke will almost never occur in otherwise healthy humans. As a result, the rectal temperature is determined principally by the exercising work rate; (iii) that post-exercise collapse in athletes who remain conscious is due to a low peripheral vascular resistance to which dehydration makes essentially no contribution; and (iv) that heatstroke is more likely due to an exaggerated and explosive thermogenesis that develops in genetically-predisposed individuals on exposure to exercise and other triggering environmental factors. It is also suggested that the skeletal muscles are the site of this florid thermogenesis and that the leakage of toxic proteins into the circulation from damaged muscles, and not the hyperthermia, is the more likely cause of the multiple organ failure that typifies fatal heatstroke.
... This link was substantiated by the description of EHS in patients with familial or personal histories of MH [9,10]. MH susceptibility has been viewed as a risk factor for EHS, and some authors have suggested that EHS subjects should be investigated by MH susceptibility screening [11][12][13]. A decade ago, Muldoon et al. suggested that individuals who collapse from exertional heat illness should be screened for MH. ...
... A decade ago, Muldoon et al. suggested that individuals who collapse from exertional heat illness should be screened for MH. This raises two important questions: are individuals who have suffered from MH at risk for EHS, and are EHS subjects at risk for MH [12]? ...
Full-text available
Objective: The identification of a predisposition toward malignant hyperthermia (MH) as a risk factor for exertional heat stroke (EHS) remains a matter of debate. Such a predisposition indicates a causal role for MH susceptibility (MHS) after EHS in certain national recommendations and has led to the use of an in vitro contracture test (IVCT) to identify the MHS trait in selected or unselected EHS patients. The aim of this study was to determine whether the MHS trait is associated with EHS. Methods: EHS subjects in the French Armed Forces were routinely examined for MHS after experiencing an EHS episode. This retrospective study compared the features of IVCT-diagnosed MHS (iMHS) EHS subjects with those of MH-normal EHS patients and MH patients during the 2004-2010 period. MHS status was assessed using the European protocol. Results: During the study period, 466 subjects (median age 25 years; 31 women) underwent MHS status investigation following an EHS episode. None of the subjects reported previous MH events. An IVCT was performed in 454 cases and was diagnostic of MHS in 45.6% of the study population, of MH susceptibility to halothane in 18.5%, of MH susceptibility to caffeine in 9.9%, and of MH susceptibility to halothane and caffeine in 17.2%. There were no differences in the clinical features, biological features or outcomes of iMHS EHS subjects compared with those of MH-normal or caffeine or halothane MHS subjects without known prior EHS episode. The recurrence rate was 12.7% and was not associated with MH status or any clinical or biological features. iMHS EHS patients exhibited a significantly less informative IVCT response than MH patients. Conclusions: The unexpected high prevalence of the MHS trait after EHS suggested a latent disturbance of calcium homeostasis that accounted for the positive IVCT results. This study did not determine whether EHS patients have an increased risk of MH, and it could not determine whether MH susceptibility is a risk factor for EHS.
... Malignant hyperthermia shares similarities with EHS. In the past decade, reports have highlighted similarities between EHS and malignant hyperthermia (MH; see Ref. 54), which is a reaction triggered by a haloalkane class of anesthetic drugs that includes halothane, enflurane, isoflurane, sevoflurane, and desflurane. People with the genetic predisposition to MH have a mutation in the ryanodine 1 receptor (RyR1), located in the sarcoplasmic reticulum of skeletal muscles, and develop sustained skeletal muscle contractions in a positive feedback loop. ...
Full-text available
During the past several decades, the incidence of exertional heat stroke (EHS) has increased dramatically. Despite an improved understanding of this syndrome, numerous controversies still exist within the scientific and health professions regarding diagnosis, pathophysiology, risk factors, treatment and return to physical activity. This review examines the following eight controversies: 1) reliance on core temperature for diagnosing and assessing severity of EHS; 2) hypothalamic damage induces heat stroke and this mediates "thermoregulatory failure" during the immediate recovery period; 3) EHS is a predictable condition primarily due to overwhelming heat stress; 4) heat-induced endotoxemia mediates systemic inflammatory response syndrome in all EHS cases; 5) non-steroidal anti-inflammatory drugs for EHS prevention; 6) EHS shares similar mechanisms with malignant hyperthermia; 7) cooling to a specific body core temperature during treatment for EHS; and 8) return to physical activity based on physiological responses to a single exercise heat tolerance test. In this review, we present and discuss the origins and the evidence for each controversy and propose next steps to resolve the misconception.
... [1][2][3] Although some MHsusceptible (MHS) individuals are asymptomatic in a nonclinical environment, others report a history of muscle pain, heat intolerance, and an overreaction to stress. [4][5][6][7] Early research in MH focused on the sympathetic nervous system as a potential trigger of the syndrome, identifying increased baseline levels of adenylyl cyclase and cyclic adenosine monophosphate (cAMP) in MHS subjects. 8,9 In the late 1970s, researchers noted that MHS swine had higher baseline catecholamine levels than did controls and that administration of phentolamine (α-adrenergic blocker), performance of an adrenalectomy, or the use of a continuous lidocaine epidural successfully mitigated the rise of catecholamine levels and prevented some fatal responses to anesthetics. ...
Full-text available
Malignant hyperthermia (MH) crises may induce morbidity or death in MH-susceptible (MHS) individuals. The only sensitive method of determining susceptibility is the caffeine-halothane contracture test, requiring muscle biopsy. Early research on MH demonstrated an abnormal response to catecholamines in MHS individuals. The purpose of this study was to determine whether MHS B lymphocytes would demonstrate an increased sensitivity to norepinephrine as indicated by an adrenergic augmentation of intracellular calcium ion (Ca²⁺) accumulation, to possibly develop a less invasive laboratory assay for determining MH susceptibility. The fluorescent Ca²⁺ indicator dye fura-2 acetoxymethyl was used to identify Ca²⁺ flux within Epstein-Barr virus- immortalized MH-negative (MHN) and MHS B cells exposed to the RyR1 agonist 4-chloro-m-cresol (4-CmC) before and after administration of 1 μM of norepinephrine. In the presence of 4-CmC and norepinephrine, the area under the curve dose responses were significantly elevated in MHS B cells compared with MHN B cells (F[1,10] = 27.37; P < .01). Epstein-Barr virus-immortalized B cells from MHS humans displayed an increased sensitivity to norepinephrine compared with those from MHN individuals. These data suggest that an abnormal response to exogenous norepinephrine could potentially be used to develop a diagnostic laboratory assay to determine MH susceptibility.
... Compte tenu de la parenté clinique entre HMA et CCE et de l'existence d'un modèle porcin de l'HMA, certains auteurs ont suggéré la recherche d'une HMA chez les patients ayant présenté un CCE (37). La première série mondiale, issue de la cohorte des CCE militaires français, avait montré une prévalence de 20 % du e. sagui trait HMS, bien plus importante que celle retrouvée en population générale, estimée à 1,48 % chez des patients asymptomatiques ou entre 1 000 à 1/3 000 en population générale en France (38)(39)(40)(41). ...
Full-text available
Exertional heat stroke (EHS) is a life threatening disease with fatal outcome without appropriate treatment. The onset of EHS is a conjunction of environmental and individual factors. Among these factors, motivation and some body core temperature kinetics during strenuous exercise, could constitute novel approaches. Treatment of EHS is no longer an issue: immersion in iced water is the standard strategy and should be implemented within 30 minutes to reduce temperature to a threshold ranging between 38.6°C and 38.8°C. The French Health Forces Southern Platform routinely investigate EHS among the military population. Le coup de chaleur d’exercice est une pathologie grave, pouvant être mortelle sans traitement. Sa survenue est la conjonction de plusieurs facteurs, liés à l’individu et l’environnement, dont l’accumulation déclenche un coup de chaleur d’exercice. Parmi ces facteurs, la motivation et certains profils d’ascension thermique à l’effort pourraient constituer de nouvelles pistes. Le traitement est assez standardisé, consistant en l’immersion dans l’eau glacée ou à défaut la plus froide possible, dans un délai de moins de 30 minutes de façon à faire baisser la température corporelle jusqu’à un seuil compris entre 38,6 °C à 38,8 °C. L’exploration du coup de chaleur d’exercice dans le Service de santé des armées français est toujours réalisée au sein des hôpitaux militaires de la plateforme sud.
... Malignant hyperthermia (MH) is an inherited, pharmacogenetic disorder of the skeletal muscle, characterized by dangerous hypermetabolic state after anesthesia with succinylcholine and/or volatile halogenated anesthetic agents. MH may also be triggered in susceptible individuals by severe exercise in hot conditions, infections, neuroleptic drugs and overheating in infants [1][2][3][4] . ...
Thermoregulation includes many physiological, molecular/cellular, and genetic mechanisms that are highlighted in Chap. 2. Molecular and cellular mechanisms of thermal tolerance (on a whole-body level) and relationships to EHS (exertional heat stroke) susceptibility include pathways associated with immune, endocrine, antioxidant, metabolic, skeletal muscle, and nervous system function. Research clearly implicates pathophysiology arising from LPS (lipopolysaccharide)-induced TLR4 (toll-like receptor 4) activation and subsequent endotoxemia/sepsis-induced inflammation and tissue damage. However, the role is not clearly defined because many have not considered the vast complexity in LPS and TLR-associated positive feedback to inflammation. We present aspects of immune function that complicate the relationship between endotoxemia and EHS pathophysiology that should be studied in future research and make it difficult to associate immune-related genotypes with EHS risk. Additionally, we present molecular targets of pharmacological treatments and individual genotypes associated with susceptibility to heat stress and MH (malignant hyperthermia) to depict novel molecular mechanisms likely associated with pathophysiology and EHS susceptibility.
Heat stroke is the most severe manifestation of heat illness. Classic heat stroke (CHS) is defined as central nervous system (CNS) dysfunction and severe hyperthermia as a consequence of heat exposure at rest and affects mostly vulnerable populations (i.e., elderly during heat waves and/or children left in vehicles). Exertional heat stroke (EHS) shares a similar definition as CHS, except it is triggered in young, otherwise healthy individuals during physical exertion in a hot or temperate environment. CHS and EHS have long been a topic of interest in physiology and have been extensively studied; yet, there are many misconceptions regarding the impact of heat on organ systems as well as the etiology that predisposes certain individuals to collapse. This chapter discusses five misconceptions that have skewed our understanding of heat stroke pathophysiology, mainly due to misinterpretation of data, conjecture that has become dogma as well as limitations in the approaches to study the condition.
Full-text available
Six subjects susceptible to malignant hyperthermia (MHS) and seven control subjects exercised for 4 min at 120% of their calculated maximal oxygen uptake on a bicycle ergometer. Mean (SEM) muscle pH, measured with a needle-tipped electrode in the vastus lateralis muscle, decreased from a resting value of 7.16 (0.04) to 6.78 (0.04) after exercise in the control group, and from 7.15 (0.05) to 6.56 (0.05) in the MHS group (P < 0.01 compared with control group). A further decrease in muscle pH to 6.68 (0.06) by 5 min after exercise occurred in the control group, followed by incomplete recovery to 7.06 (0.04) 30 min after exercise. In the MHS group, however, muscle pH decreased to 6.45 (0.05) 5 min after exercise before recovering slowly to only 6.64 (0.07) after 30 min (P < 0.01 compared with control group). There was no difference in muscle temperature, venous pH or venous lactate concentrations between the two groups. The results show that there is abnormal recovery of muscle pH after short-duration, high-intensity exercise in MHS subjects.
In brief: Malignant hyperthermia is a rare muscle disorder that may be fatal. Susceptible individuals are unusually sensitive to anesthetics that allow rapid accumulation of calcium into the cells. High calcium levels lead to a hypermetabolic state, causing heat production and breakdown of the muscle cells. A case history is presented of a college football player who suffered a near heat stroke. Subsequent investigation showed that the player had malignant hyperthermia. Several authors have suggested a similarity between malignant hyperthermia and heat stroke—possibly they are the same disease with different triggering mechanisms.
To the Editor: Malignant hyperthermia (MH) is an autosomal dominant condition in which certain anesthetics trigger calcium dysregulation in skeletal muscle, resulting in a catastrophic, life-threatening hypermetabolic syndrome.1 More than 50% of families with MH have mutations in the gene encoding the ryanodine receptor (RYR1).2 In a porcine model of MH, nonanesthetic, stress-induced deaths have been reported in pigs homozygous for the Arg614Cys mutation in the RYR1 gene,3 but this phenomenon has not been reported in humans with MH mutations. To our knowledge, we report the first case of nonanesthetic, stress-induced hyperpyrexic death in an individual with a history of MH.
Metabolic anomalies are known in skeletal muscles of patients with malignant hyperthermia (MH). The authors used 31-phosphorus (31P) magnetic resonance spectroscopy (MRS) to compare metabolic changes of the finger flexor muscles recorded throughout two rest-exercise-recovery protocols (each including aerobic or ischemic exercise) in 26 healthy persons and in 13 MH-susceptible (MHS) persons who were unequivocally diagnosed by in vitro halothane-caffeine contracture tests on muscle biopsies. No abnormality was observed at rest and during recovery periods. A larger phosphocreatine decrease associated with an early drop of pH was noted during the first minute of both exercise periods for MHS patients compared with controls. The early pH decrease indicated a disorder affecting glycolytic activation, probably reflecting defects of Ca2+ cycling, and provided a sensitivity of 77% for MHS diagnosis. A diagnostic strategy based on the retrospective analysis of 19 selected MR parameters was developed. An MRS score, corresponding to the number of abnormal values among the 19 parameters, was calculated and provided sensitivity and specificity rates of 100%; that is, no false-positive or false-negative results were found. A prospective analysis of 10 new participants further confirmed these findings. These results (1) further confirm that MH is associated with the preexistence of latent muscular disorders; (2) enhance the potential diagnostic capacity of MRS, although it should be tested prospectively on a larger group of participants; and (3) allows the characterization of several abnormal metabolic profiles, in persons with MHS, reflecting the recently described polymorphism of MH.
Rhabdomyolysis, a syndrome of skeletal muscle breakdown with leakage of muscle contents, is frequently accompanied by myoglobinuria, and if sufficiently severe, acute renal failure with potentially life-threatening metabolic derangements may ensue. A diverse spectrum of inherited and acquired disorders affecting muscle membranes, membrane ion channels, and muscle energy supply causes rhabdomyolysis. Common final pathophysiological mechanisms among these causes of rhabdomyolysis include an uncontrolled rise in free intracellular calcium and activation of calcium-dependent proteases, which lead to destruction of myofibrils and lysosomal digestion of muscle fiber contents. Recent advances in molecular genetics and muscle enzyme histochemistry may enable a specific metabolic diagnosis in many patients with idiopathic recurrent rhabdomyolysis. © 2002 Wiley Periodicals, Inc. Muscle Nerve 25: 000–000, 2002
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests in response to anesthetic triggering agents. Central core disease (CCD) is a myopathy closely associated with MH. Both MH and CCD are primarily disorders of calcium regulation in skeletal muscle. The ryanodine receptor (RYR1) gene encodes the key channel which mediates calcium release in skeletal muscle during excitation–contraction coupling, and mutations in this gene are considered to account for susceptibility to MH (MHS) in more than 50% of cases and in the majority of CCD cases. To date, 22 missense mutations in the 15,117 bp coding region of the RYR1 cDNA have been found to segregate with the MHS trait, while a much smaller number of these mutations is associated with CCD. The majority of RYR1 mutations appear to be clustered in the N-terminal amino acid residues 35-614 (MH/CCD region 1) and the centrally located residues 2163-2458 (MH/CCD region 2). The only mutation identified outside of these regions to date is a single mutation associated with a severe form of CCD in the highly conserved C-terminus of the gene. All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein, with the exception of the mutation in the C-terminus, which resides in the lumenal/transmembrane region. Functional analysis shows that MHS and CCD mutations produce RYR1 abnormalities that alter the channel kinetics for calcium inactivation and make the channel hyper- and hyposensitive to activating and inactivating ligands, respectively. The likely deciding factors in determining whether a particular RYR1 mutation results in MHS alone or MHS and CCD are: sensitivity of the RYR1 mutant proteins to agonists; the level of abnormal channel-gating caused by the mutation; the consequential decrease in the size of the releasable calcium store and increase in resting concentration of calcium; and the level of compensation achieved by the muscle with respect to maintaining calcium homeostasis. From a diagnostic point of view, the ultimate goal of development of a simple non-invasive test for routine diagnosis of MHS remains elusive. Attainment of this goal will require further detailed molecular genetic investigations aimed at solving heterogeneity and discordance issues in MHS; new initiatives aimed at identifying modulating factors that influence the penetrance of clinical MH in MHS individuals; and detailed studies aimed at describing the full epidemiological picture of in vitro responses of muscle to agents used in diagnosis of MH susceptibility. Hum Mutat 15:410–417, 2000. © 2000 Wiley-Liss, Inc.
Malignant hyperthermia may be a human stress syndrome, of which heat stroke is one manifestation. Two men in military service who had episodes of exertional heat stroke, and their immediate family members, were tested for susceptibility to malignant hyperthermia by in-vitro contracture tests on skeletal muscle samples. Muscle from both patients had a normal response to caffeine but an abnormal response to halothane. Muscle from the father of one patient had an abnormal response to halothane, and that from the father of the second patient had an abnormal response to ryanodine. The results indicate that clinical heat stroke may be associated with an underlying inherited abnormality of skeletal muscle that is similar, but not identical, to that of malignant hyperthermia.
A few cases of non-anaesthetic-induced rhabdomyolysis in humans, predisposed to malignant hyperthermia (MH), have been described in literature. We studied a group of 6 consecutive patients with unexplained and recurrent attacks of rhabdomyolysis with the test used to determine susceptibility to MH, the in vitro contraction test (IVCT). The results of the IVCT showed 5 of these 6 patients to be MH susceptible. In cultured muscle cells from one of these patients a disturbed calcium homeostasis could be demonstrated. The relation between MH and recurrent rhabdomyolysis is discussed.
Muscle biopsy and in vitro contracture tests for diagnosis of susceptibility to malignant hyperthermia (MH) were performed in two patients who had developed fever and severe myolysis during exercise. MH susceptibility was confirmed in one patient but in the other, exercise-induced heat stroke proved to be the correct diagnosis. Clinical presentation and epidemiology of exercise-induced MH and its relation to the heat stroke syndrome are discussed.