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Management of malignant hyperthermia: diagnosis

and treatment

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Therapeutics and Clinical Risk Management
14 May 2014
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Daniel Schneiderbanger Abstract: Malignant hyperthermia is a potentially lethal inherited disorder characterized by
Stephan Johannsen disturbance of calcium homeostasis in skeletal muscle. Volatile anesthetics and/or the depolar-
Norbert Roewer izing muscle relaxant succinylcholine may induce this hypermetabolic muscular syndrome due
Frank Schuster to uncontrolled sarcoplasmic calcium release via functionally altered calcium release receptors,
resulting in hypoxemia, hypercapnia, tachycardia, muscular rigidity, acidosis, hyperkalemia,
Department of Anaesthesia
and Critical Care, University of and hyperthermia in susceptible individuals. Since the clinical presentation of malignant hyper-
Wuerzburg, Wuerzburg, Germany thermia is highly variable, survival of affected patients depends largely on early recognition of
the symptoms characteristic of malignant hyperthermia, and immediate action on the part of the
attending anesthesiologist. Clinical symptoms of malignant hyperthermia, diagnostic criteria,
and current therapeutic guidelines, as well as adequate management of anesthesia in patients
susceptible to malignant hyperthermia, are discussed in this review.
Keywords: malignant hyperthermia, volatile anesthetics, succinylcholine, in vitro contracture
test, genetics

Introduction
Malignant hyperthermia (MH) is a rare, but life-threatening, autosomal-dominant
inherited disorder that may lead to metabolic crisis of skeletal muscle in susceptible
individuals following exposure to triggering agents, such as volatile anesthetics or
depolarizing muscle relaxants.1 Functionally altered calcium release channels cause
dysfunction of intracellular calcium homeostasis and uncontrolled calcium release
from the sarcoplasmic reticulum, which may lead rapidly to a fatal hypermetabolic
state known as MH crisis. Interestingly, in everyday life, most MH-susceptible (MHS)
individuals do not suffer from muscle symptoms. Nevertheless, MH is still a relevant
complication and every anesthesiologist must recognize the symptoms of an MH
episode and start appropriate treatment without delay.

History
From the beginning of the 20th century, there have been numerous case reports of
Correspondence: Frank Schuster anesthesia-associated deaths related to perioperative hyperthermia.2,3 However, it was
Department of Anesthesia not until 1960, when Denborough et al defined MH as an independent syndrome, that
and Critical Care, University of
Wuerzburg, Oberduerrbacher Strasse 6,
the link between deaths attributed to general anesthesia and a genetic predisposition was
D-97080 Wuerzburg, Germany postulated.4 In 1975, with the introduction of dantrolene as a specific ryanodine recep-
Tel +49 931 2013 0038
Fax +49 931 2013 0039
tor antagonist, a causative treatment became available5 and the mortality rate for acute
Email [email protected] MH crisis decreased from approximately 70%–80% to about 5%.6,7 Based on in vitro

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detection of halothane-induced and ­caffeine-induced contrac- ryanodine ­receptor ­subtype 1 (RYR1) at the sarcoplasmic
tures in skeletal muscle specimens from MHS individuals, reticulum, which responds by opening. RYR1, a large ion
the first diagnostic procedure was developed to distinguish channel, facilitates release of calcium from the sarcoplasmic
between MHS and MH-non-­susceptible (MHN) patients reticulum into the cytosol, leading to muscle contraction by
independently of a previous symptomatic MH event.8,9 initiating cross-linking of myofilaments. Active reuptake of
Following these observations, a standardized protocol for in calcium into the sarcoplasmic reticulum via an adenosine
vitro contracture testing was published by the European Malig- triphosphate-dependent calcium pump terminates the muscle
nant Hyperthermia Group in 1984, and a modified protocol was contraction.23
introduced by the North American Malignant Hyperthermia In an MH crisis, the triggering agent induces prolonged
Group 3 years later.10,11 After MH-associated mutations in opening of functionally altered ryanodine receptors, resulting
the ryanodine receptor gene were identified, guidelines for in uncontrolled release of calcium from the sarcoplasmic retic-
genetic testing allowing diagnosis of MH susceptibility in ulum and ongoing muscle activation presenting as rigidity.24–27
selected patients were published by the European Malignant Additionally, constant activation of aerobic and anaerobic
Hyperthermia Group in 2001 and are still under development metabolism results in increased oxygen consumption, leading
as more causative mutations become apparent.12 to hypoxia, progressive lactate acidosis, excessive production
of CO2, and increased body temperature (Figure 1).
Epidemiology Calcium reuptake into the sarcoplasmic reticulum and
MH occurs worldwide in all races.7 Children and young sustained muscle contraction consume large amounts of
adults are mostly affected, with a signif icant male adenosine triphosphate. Depletion of cellular adenosine
preponderance.7,13,14 According to a prevalence study in triphosphate stores leads to protracted muscular rigidity
New York State between 2001 and 2005, the estimated and finally to rhabdomyolysis, when breakdown of mem-
prevalence of MH was 2.5–4.5 times higher in males than brane integrity results in release of the contents of cells (eg,
in females.15 Since many MHS individuals experience no potassium, creatine phosphokinase, myoglobin) into the
symptoms in daily life, the true incidence of MH remains circulation.7,28
unknown. The predicted genetic prevalence is reported to be
one in 2,000, while the incidence of clinical MH episodes Genetics
varies regionally from one in 5,000 to one in 100,000.7,16,17 Three mammalian isoforms of the ryanodine receptor are
In contrast with fulminant episodes, abortive courses might known: RYR1, predominant in skeletal muscle; RYR2,
occur more frequently, but are difficult to diagnose due to primarily expressed in heart muscle; and RYR3, found
their mild symptoms.18 in the central nervous system and in skeletal and smooth
Recent developments in anesthesiology seem to have led muscle.29–31 From the early 1990s, mutations in the RYR1
to a decrease in the risk of severe MH crisis over the last few gene on chromosome 19q13.1 have been associated with a
years. Halothane, a potent MH-triggering agent, is no longer predisposition to MH.32 More than 300 RYR1 variants have
used in western countries.19 Compared with halothane, the been identified to date, but only 31 mutations have been
onset of MH is delayed with the volatile anesthetics cur- functionally tested in intracellular calcium-releasing stud-
rently in use,20,21 and is more likely to be abortive MH with ies and confirmed to be causative of MH according to the
attenuated symptoms. Further, the recommended indica- molecular genetics guidelines of the European Malignant
tions for succinylcholine, another possible triggering agent, Hyperthermia Group.33,34 Interestingly, a causative muta-
have been gradually restricted by international anesthesia tion in RYR1 was detected in only about 50%35 of MHS
societies.18,22 patients.36–38 The RYR1 gene is not solely responsible for
susceptibility to MH in all affected individuals. Another
Pathophysiology gene locus has been identified in MHS patients on chromo-
During excitation–contraction coupling, acetylcholine some 1q32, encoding the α1 subunit of the voltage-gated
evokes an action potential at the neuromuscular endplate. dihydropyridine receptor.39,40
This action potential is propagated to the transverse tubule,
causing displacement of the charge at the dihydropyridine Agents triggering MH
receptor. A conformational change at the voltage-gated It is well accepted that all volatile halogenated inhalational
dihydropyridine receptor is directly transmitted to the anesthetics (eg, halothane, enflurane, isoflurane, desflurane,

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Dovepress Management of malignant hyperthermia

Depolarization

Sarcolemma

Actin-myosin-
Transverse tubule

filaments
Sarcoplasmic
reticulum

Depolarization
DHP receptors
Activation
Ca2+
MH-TRIGGER

RYR1
Ca2+-ATPase

Ca2+

Sarcoplasmic
reticulum

sustained muscular activity

and muscle cell metabolism

enhanced oxygen consumption,

excessive CO2 and heat production

malignant hyperthermia crisis:

muscular rigidity rhabdomyolysis
hypercapnia hyperkalemia
hypoxemia hyperthermia
acidosis

Figure 1 Pathophysiologic changes during a malignant hyperthermia crisis.

Abbreviations: Ca2+, calcium; DHP receptor, dihydropyridine receptor; MH, malignant hyperthermia; RYR1, ryanodine receptor subtype 1.

sevoflurane) have the potential to induce an MH crisis in be in part a dose-dependent phenomenon, which is consistent
MHS individuals.41 Studies in MHS pigs and in vitro studies with the interindividual variability and graded incremental
indicate that nitrous oxide and the noble gas xenon do not contracture response of MHS muscle during the in vitro
trigger MH.42–45 Further, it is important to mention that expo- contracture test.20 The trigger potency of the depolarizing
sure to volatile anesthetics does not inevitably lead to MH. muscle relaxant succinylcholine has been unclear for a long
Several patients have reported a number of uneventful anes- time, although there is no doubt that this substance enhances
thesias before an MH episode occurred. Triggering MH might an MH reaction and decreases the likelihood of survival in

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Schneiderbanger et al Dovepress

patients who receive a combination of ­succinylcholine and Table 1 Clinical signs of malignant hyperthermia
a volatile anesthetic, compared with a volatile anesthetic Early Late
alone.6,20 However, two recent retrospective studies reported a Masseter spasm Hyperthermia
number of cases in which succinylcholine was the sole trigger Generalized muscular rigidity (50%–80%) Rhabdomyolysis
Tachycardia (.80%) Acute renal failure
of an MH event.18,46 Over the years, several drugs have been
Hypercapnia Cardiac arrhythmia
suspected to cause MH. However, in vitro and in vivo studies Hypoxia Hypotension
of serotonergic drugs, phosphodiesterase type III inhibitors, Combined metabolic-respiratory acidosis Circulatory failure
and ondansetron have not provided convincing evidence of
their propensity to act as MH triggers.20,47
Interestingly, there are some reports of fulminant MH-like Initial treatment
episodes occurring in the absence of anesthetic agents.48,49 MH The prognosis of an MH crisis depends on how soon MH is
episodes in the wake state have been described after excessive suspected and how rapidly appropriate treatment is initiated.
alcohol consumption,50 drug abuse,51 and extreme emotional Administration of trigger agents must be stopped immedi-
and physical stress.52 A noteworthy observation which was ately and anesthesia should be continued using intravenous
made, was that , many patients have tested MHS on in vitro con- opioids, sedatives, and, if necessary, nondepolarizing
tracture testing after an exercise-induced MH-like episode.53 muscle relaxants. The vaporizer used for administration of
volatile anesthesia should be removed from the anesthesia
Clinical presentation machine and the patient hyperventilated with 100% oxygen
Clinical symptoms of MH are highly variable, and range from at maximum fresh gas flow, increasing the minute volume by
abortive courses with mild or moderate symptoms to fulminant approximately 2–3-fold while aiming for an end tidal pCO2
MH crises with severe skeletal muscle hypermetabolism and within normal limits.
rhabdomyolysis. Excessive CO2 production presenting with Treatment includes immediate administration of dant-
an increase in end tidal CO2 concentration or hyperventilation rolene 2 mg/kg, which should be repeated every 5 minutes
while breathing spontaneously is a sensitive and specific early until the cardiac and respiratory systems are stabilized.
sign of imminent MH. An abrupt rise in end tidal CO2 may ­Dantrolene, a hydantoin derivative, acts as a specific ryano-
occur simultaneously with administration of succinylcholine.7,54 dine receptor antagonist and inhibits release of calcium from
Further early symptoms of an MH crisis may include tachy- the sarcoplasmic reticulum without improving its reuptake.
cardia, supraventricular or ventricular arrhythmia, and isolated Specific side effects are rare, but include prolonged breathing
masseter spasm or generalized muscular rigidity. 50–80% of problems, tissue necrosis after accidental extravasal injection,
patients develop arrythmia or muscular reactions.53 Nonspe- nausea, vomiting, headache, and dizziness.58
cific sinus tachycardia might be misinterpreted as inadequate One bottle for injection contains 20 mg of dantrolene that
anesthesia, which often delays the diagnosis of MH. Distinc- has to be dissolved in 60 mL aqua destillata. To administer
tive cyanosis indicating increased oxygen consumption may 2 mg/kg to an 80 kg patient, 160 mg of dantrolene (eight
occur later in the course of an MH episode. A rapid increase injection bottles) are necessary. A pharmacologic study
in temperature (to .38.8°C) is a relatively late sign. However, suggested estimating the dantrolene dose needed according
a rapid increase of .1°C in 15 minutes is diagnostically more to the amount needed to alleviate symptoms, eg, 5 mg/kg
relevant than the peak temperature.22,55 In some cases, there in 24 hours if 2.5–5 mg/kg was administered initially or
are no relevant changes in body temperature, particularly 10 mg/kg in 24 hours if 7.5–10 mg/kg was administered
if adequate treatment is started early.56,57 ­Arterial blood gas initially. If no improvement of symptoms is achieved after
analyses reveal a combination of respiratory and metabolic cumulative administration of 20 mg/kg, a diagnosis of MH
acidosis with negative base excess, lactemia, hypercapnia, and is doubtful and needs to be reconsidered (Table 2).57,59
hypoxemia. Fulminant MH crisis usually presents with paCO2
values .60 mmHg and a base excess of .8 mVal/L. As the Symptomatic treatment
MH episode progresses, rhabdomyolysis leads to hyperkalemia, Subsequent steps might be necessary to avoid further harm
increased creatine phosphokinase, and myoglobinemia, and to the patient, and volume resuscitation and administration
might result in acute renal failure. The end stage of a fulminant of vasopressors might be needed to stabilize ­hemodynamics.
MH crisis is characterized by multiorgan failure and circula- Repeated arterial blood gas analysis and monitoring of
tory collapse (Table 1).7 serum electrolyte, creatine phosphokinase, myoglobin, and

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Dovepress Management of malignant hyperthermia

Table 2 Possible differential diagnoses of acute malignant (“MHApp”) issued by the European Malignant Hyperthermia
hyperthermia crisis Group in cooperation with the North American Malignant
Differential diagnoses of malignant hyperthermia Hyperthermia Group can be consulted to support the initial
Inadequate depth of anesthesia
therapeutic management.1
Sepsis
Insufficient ventilation or spontaneous breathing
Malfunction of anesthesia machine Diagnosis of MH susceptibility
Anaphylactic reaction Diagnostic testing for MH susceptibility can be indicated
Pheochromocytoma
after an incident suspicious for MH in patients with nonspe-
Thyroid crisis
Neuromuscular disease cific myopathy or persistently elevated serum creatine kinase
CO2 increase due to laparoscopic procedure and in families with history of MH. For about 30 years, the
Drug intoxication in vitro contracture test using halothane and caffeine has
Serotonin syndrome
Malignant neuroleptic syndrome
been the gold standard for determining susceptibility to
MH independent of a clinical MH event. Following a surgi-
cal muscle biopsy, live muscle specimens are exposed to
lactate levels are important when determining the success defined concentrations of halothane or caffeine. If developing
of therapy. Administration of sodium bicarbonate or Tris contracture forces exceed given thresholds after exposure
buffer might be necessary to treat metabolic acidosis if pH to halothane and/or caffeine, the patient is diagnosed to be
is ,7.2. Forced diuresis using fluid and furosemide can help MHS. Absence of development of significant contracture
to prevent acute renal failure. Cardiac arrhythmias are often following exposure to these agents leads to a diagnosis of
reversible after administration of dantrolene. However, in MHN. There are two regional variations of this laboratory
some cases, administration of amiodarone or beta-blockers is test. The in vitro contracture test according to the European
indicated to treat persistent tachyarrhythmia. Administration Malignant Hyperthermia Group10 and the caffeine halothane
of calcium antagonists is contraindicated, because severe contracture test according to the North American Malignant
episodes of hyperkalemia have been reported in the context Hyperthermia Group11 differ slightly in the concentration
of dantrolene treatment. Hyperthermia should be treated by of substance applied to the tissue bath and in mode of
internal cooling with cold infusion fluids and external sur- application (incremental versus bolus). However, adequate
face cooling with ice packs placed in the axillae and groin sensitivity and specificity has been demonstrated for both
or specific cooling devices until body temperature reaches approaches.60,61 The previous existing intermediate diagno-
38.5°C.57 Surgery should be terminated as soon as possible sis of MH-equivocal that was given to patients in the event
and the patient should be transferred to an intensive care unit of a significant reaction either after halothane or caffeine
for further monitoring and treatment (Table 3). Telephone according to the European protocol has been abandoned in
hotlines specialized in MH counseling have been established the recent update of the European Malignant Hyperthermia
in a number of countries, and a smartphone application Group and replaced by the classification MHS in combination
with an “h” (MHSh) if contracture developed after halothane
Table 3 Immediate causative and symptomatic treatment of acute
only and a “c” (MHSc) if contracture occurred after caffeine
malignant hyperthermia crisis only. This measure led to further harmonization of the two
Causative treatment Symptomatic treatment
protocols.
Stop trigger agent, disconnect Inform surgeon, aim DNA analysis as an alternative to the invasive contrac-
vaporizer for termination of surgery ture test has been of increasing importance over the last
as soon as possible decade.12,62 Only a small blood sample is required to screen
Increase respiratory minute volume Stabilize hemodynamics
for an RYR1 mutation. Molecular genetic testing is often
2–4-fold with 100% oxygen and start antiarrhythmic therapy
at maximum fresh gas flow if appropriate used first line as a diagnostic tool, particularly in families
Administer dantrolene 2 mg/kg Apply internal and external with a known causative RYR1 mutation. At this time, a
initially cooling patient is diagnosed as MHS if one of the 31 known causative
Continue anesthesia Extend hemodynamic
with nontriggering drugs monitoring, insert arterial line
mutations is detected. However, the diagnostic classification
and central venous line if needed of many RYR1 mutations remains difficult, because their
Repeat dantrolene application until Treat metabolic acidosis, pathophysiologic impact with regard to initiating an MH
clinically stable (maximum 20 mg/kg) perform forced diuresis
reaction is not yet clear. Therefore, an in vitro contracture

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Schneiderbanger et al Dovepress

test is required to confirm or exclude MH susceptibility in machine for trigger-free anesthesia and for use in an acute
the event of an unclassified RYR1 mutation or if RYR1 MH crisis.69 Given that specific recommendations are lacking
mutation is absent. for many of the machines currently in use and that there is
A number of studies have focused on the development no clear-cut threshold for a residual concentration that is safe
of less invasive functional testing procedures for determin- in terms of not triggering an MH crisis, an option could be
ing predisposition to MH, eg, monitoring of intramuscular to provide a specific machine within the department that has
lactate levels by microdialysis after locally limited trigger never been contaminated with volatile agents.70
application in vivo63 or pharmacologic stimulation of B
lymphocytes in vitro, given that RYR1 is also expressed Conclusion
on human B lymphocytes.60 Although the results have been Because of the variable clinical presentation of MH, ranging
promising, none of these methods has progressed beyond the from abortive courses with only mild or moderate symptoms
experimental stage as yet. to fulminate MH crises, patient survival depends on early rec-
In summary, in vitro contracture testing and molecular ognition of symptoms of MH and prompt action on the part of
genetic testing are the two approved methods for diagnosing the attending anesthesiologist. In clinics that use known MH-
susceptibility to MH. Both procedures require specialized triggering agents for induction and maintenance of general anes-
testing centers and are not suitable for use as screening thesia, dantrolene must be available for immediate treatment
methods unless there is immediate suspicion of predisposi- and to reduce the risk of serious harm to the patient in the event
tion to MH. of an episode of MH. After a suspected MH event, the patient
should be referred to an MH center for further counseling.
Anesthesia in patients predisposed
to MH Disclosure
Providing safe anesthesia for MHS patients involves knowing The authors report no conflicts of interest in this work.
about previously diagnosed MH status or potential suscep-
tibility to MH. Although patients who have undergone an
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