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8
Exertional Heat Illness, Exertional
Rhabdomyolysis, and Malignant Hyperthermia:
Is There a Link?
Sheila Muldoon,
1,2
Patricia Deuster,
3
Maria Voelkel,
1
John Capacchione,
1
and Rolf Bunger
4
1
Department of Anesthesiology,
2
Malignant Hyperthermia Biopsy Center,
3
Department of Military and
Emergency Medicine, and
4
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.
INTRODUCTION
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?
THE CLINICAL ENTITIES
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’’
74
CHEST CONDITIONS
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
(E-mail: smuldoon@usuhs.mil).
1537-890X/0702/74Y80
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.
8
episodes exceeds 70%, but with modern intraoperative
monitoring (specifically end-expired CO
2
) 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
anesthesia.
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).
THE QUESTIONS
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.
8
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
31
P-nuclear
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
31
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
a
/Rhabdomyolysis and MH
Author Reason for Workup Total Patients Total MHS
b
Patients Total MHN
c
Patients Patients With RyR1 Mutation
Hackl et al. (18) EHI 5 3 2 N/A
d
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
a
EHI: Exertional Heat Illness, including exertional heat stroke.
b
MHS: MH susceptible. This group includes MH equivocal diagnoses by IVCT.
c
MHN: MH negative by IVCT.
d
N/A: Genetic screen was not performed on these cases.
e
Has studied more than 250 cases.
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8
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
j1
.He
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.
8
ATP-dependent pumps and the Na
+
/Ca
2+
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%
V
˙O
2max
) may have been insufficient to induce symptoms
(32). Indeed, one study did show that MHS individuals who
were exercised at 120% V
˙O
2max
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
2+
]
i
) 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
2+
]
I,
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
2+
]
i
. 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
31
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 www.acsm-csmr.org
Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
8
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.
CONCLUSION
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 www.mhaus.org, and clinical guidelines for EHI
(army personnel) are available at http://chppmwww.apgea.
army.mil/documents/tbmeds/tbmet507.pdf. Recommenda-
tions for management of ER are currently being developed
but were not available at completion of this manuscript.
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