QJ /Vfec/1997; 90:13-18
Review
QJM
Malignant hyperthermia susceptibility: anaesthetic
implications and risk stratification
R. BEN ABRAHAM, A. CAHANA, R.M. KRIVOSIC-HORBER1 and A. PEREL
From the Department of Anesthesiology, Sheba Medical Center, Sackler School of Medicine,
Tel-Aviv University, Israel, and ^ Department d 'Anesthesie Reanimation Chirurgicale I, Hospital
B, Centre Hospitalier Regional Universitaire, 59037 Lille Cedex, France
Received 71 June 7996 and in revised form 22 September 7996
Summary
anaesthesia machine should be carefully washed to
remove traces of halogenated agents, and the use
of fresh disposable anaesthetic circuits is recommended. Early diagnosis of the syndrome by alert,
informed anaesthesiologists, and the immediate
administration of dantrolene and other supportive
measures, has reduced mortality. Patients with MH
susceptibility should be instructed to alert the anaesthesiologist about their condition whenever anaesthesia is needed. Although people diagnosed with
MH susceptibility should not change their lifestyle
in general, military service is limited.
Introduction
Malignant hyperthermia susceptibility (MHS) manifests when a susceptible individual is given general
anaesthesia using triggering agents, such as any of
the potent volatile anaesthetics, and a depolarizing
muscle relaxant (succinylcholine). Malignant hyperthermia (MH) is a syndrome of intense and abrupt
striated muscle hypermetabolic reaction, resulting in
hyperthermia and rhabdomyolysis. The clinical picture is often dramatic, with intense tachycardia,
overproduction of CO 2 , muscular rigidity, respiratory
and metabolic acidosis, hyperkalaemia and terminal
haemodynamic collapse. The pathophysiology of the
MH reaction involves inherited oversensitivity to
triggering agents which, when used on MHS patients,
can cause rapid accumulation of calcium in striated
muscle myoplasm, resulting in muscle contracture
followed by rhabdomyolysis and an intense heatproducing reaction.
Due to its abrupt onset and violent character, an
MH reaction is a medical emergency requiring
immediate action from the anaesthesiologist. The
main treatment is a drug called dantrolene, which is
a non-specific muscle relaxant. It probably acts by
blocking the release of calcium from the sarcoplasmic reticulum of skeletal muscle cells.1 Before
dantrolene was used in the treatment of an MH
reaction, mortality was well above 50%. 2 Improved
awareness and understanding of the MH syndrome,
better pre-anaesthetic identification of MHS patients,
together with much better intra- and post-operative
Address correspondence to Dr A. Cahana, Department of Anesthesiology, Sheba Medical Center, Sackler School of
Medicine, Tel-Aviv University, Israeli Center for MH Research and Treatment, Tel-Hashomer, Israel 52621
© Oxford University Press 1997
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Malignant hyperthermia (MH) is a rare autosomal
dominant trait that predisposes individuals to great
danger when exposed to certain anaesthetic triggering agents, such as potent volatile anaesthetics
and succinylcholine. Sudden hypermetabolic reaction occurs in skeletal muscle, leading to hyperthermia and massive rhabdomyolysis. Precautions
must be taken before the anaesthesia of M H susceptible patients. No triggering agents should be
administered, central body temperature and ETCO2
should be carefully monitored, and dantrolene
must be immediately available. In addition, the
14
R. Ben Abraham et al.
Anaesthesia for MHS patients
An individual with known or suspected MHS should
not be denied general anaesthesia on this basis
alone. Elective surgery should however be done only
in hospitals equipped with the knowledge and expert-
ise needed to treat an MH reaction.16 Although it
has been recommended in the past that out-patient
surgery should be avoided in these patients,17 it is
now clear that out-patient surgery can be performed
safely in MHS patients, provided that careful postoperative monitoring is continued for at least 4 h. In
addition to routine pre-operative evaluation, baseline
ECG and CPK levels are desired.
Preparation in the operating room (OR)
The OR must be free of anaesthetic vapours, and
the anaesthesia machine should not be contaminated
with volatile anaesthetics. Since keeping a dedicated
anaesthesia machine reserved for MHS patients only
is expensive, a protocol was suggested for preparing
the anaesthesia machine in case of an MH episode.18
This can be done by removing vapourizers, flushing
the machine with oxygen at a rate of 10 1/min for
5 min, replacing the fresh gas outlet hose and using
a new disposable circuit. Reservoir bags, ventilator
bellows and soda lime should also be changed, since
all volatile anaesthetics, and especially halothane,
have a high solubility in rubber, and by removing
parts of the circle system a more rapid washout can
be accomplished. 19 Systems incorporating a nonrebreathing valve and a Bain system are not recommended for use in these cases, unless very high flow
of O 2 can be provided. 20
Dantrolene therapy
First discovered by Harrison to be of value in the
therapy of MH crises in pigs,25 dantrolene was later
confirmed as of value in a number of human MH
episodes,26 and became the drug of choice in the
prevention and treatment of acute MH crises.
Dantrolene is a diphenylhydantoin analogue which
is poorly soluble in water. Although the mechanism
of action is still unclear, dantrolene appears to inhibit
release of calcium from the sarcoplasmic reticulum
to the myoplasm.25
Dantrolene is manufactured in a lyophilized formulation which also contains mannitol and sodium
hydroxide. Each vial contains 20 mg dantrolene, 3 g
mannitol and enough sodium hydroxide to raise the
pH to 9.5. The lyophilized contents of each vial
must be reconstituted with 60 ml sterile water. In an
acute MH episode, a supply of at least 36 vials of
dantrolene should be available for immediate use,
which corresponds to a maximal dosage of 10 mg/kg
in a 70 kg adult.21'22 Dantrolene should be administered repeatedly in 2-3 mg/kg doses every 5-10 min,
until symptoms are controlled.
The issue of dantrolene prophylaxis in MHS
patients is unresolved and is still under current
investigation.2'23'24 In view of the very low incidence
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monitoring and early use of dantrolene, has decreased
mortality from acute fulminant MH episodes to
10%. 3 ' 4
The incidence of MH reaction during anaesthesia
is estimated at from 1/15 000 in children, to 1/50 000
in adults.5 The acute MH syndrome is more prevalent
in young individuals, with more than 50% of cases
occurring before the age of 15.6 The MHS patient is
normally in apparent good health, but suffers from
subclinical myopathy which can be dramatically
exposed when triggering agents are used during
anaesthesia.
The mode of inheritance of MHS is autosomal
dominant with reduced penetrance and variable
expressivity, although sporadic cases and recessive
autosomal hereditary patterns have occasionally been
seen.8 In recent years, a mutation in chromosome
19q13.1, linked to a mutation in the ryanodine
receptor gene, was discovered to be linked to MHS. 9
Nevertheless, the exact nature of the molecular
defect is still unknown. The population at risk for
developing MH during anaesthesia is: (i) survivors of
an MH reaction, or patients with a positive caffeine
halothane contracture test (CHCT); (ii) first-degree
relatives of such patients or members of known
MHS families with neuromuscular disorders, with
increased levels of creatine kinase (CPK) in serum;10
(iii) patients who suffer from Duchenne muscular
dystrophy, King-Denborough syndrome or Central
Core Myopathy, 10 this last being almost certainly
related to MH; 1 1 (iv) patients who have exhibited
masseter muscle spasm during anaesthesia with halothane and succinylcholine; 12 (v) patients with a
history of Neuroleptic Malignant Syndrome or heat
stroke, although the association with MHS may
appear coincidental. 10 ' 14 ' 15
The in vitro caffeine halothane contracture test
has been widely used to diagnose MH susceptibility.7
This test reveals abnormally high sensitivity of muscle
from affected individuals to the contracture effect of
halothane and caffeine. The test is not completely
accurate and high specificity is often sacrificed to
achieve high sensitivity.66 DNA-based diagnostic
tests are currently available for those MH susceptible
families (15%) in which a mutation in the RYR1
gene has been discovered.67 These diagnostic tests
are however invasive and require freshly biopsied
muscle, and therefore are done only in special
centres dedicated to MH diagnosis.
Malignant hyperthermia
(0-0.62%) of MH reaction 26 ' 27 in MHS patients who
receive a trigger-free anaesthetic for minor elective
surgery, the common practice is not to use dantrolene
pre-operatively on a routine basis.27'28 This eliminates
the muscle weakness and nausea frequently associated with dantrolene treatment.29 Similarly, even in
patients with one of the myopathies, dantrolene
prophylaxis is not recommended because of its
tendency to cause post-operative weakness and
respiratory complications. 30 ' 31
Dantrolene prophylaxis is also avoided in obstetric
patients since it can cause uterine atony leading to
excessive blood loss.32 It also crosses the placenta,
causing neonatal weakness. If elective caesarean
section is planned for MHS patients, regional anaesthesia is preferred, and if emergency caesarean
section is carried out, than a rapid sequence induction using safe agents with a high dose of nondepolarizing muscle relaxants for relaxation is recommended.22
Supportive treatment
Premedication
The MHS patient should be the first on the OR
program in order to minimize stress and anxiety, and
to reduce exposure time to vapors of volatile anaesthetics.22 Pre-operative sedation with barbiturates,
benzodiazepines and opiates to reduce anxiety is an
important part of the anaesthetic management.
Phenothiazines should be avoided because of the
possible association between MH and the neuroleptic
malignant syndrome (NMS).14 The use of atropine is
not recommended because it can enhance sympathomimetic activity which can induce a hypermetabolic
reaction.22 In addition there are reports of increased
rigidity and mortality when MH reactions occur in
the presence of atropine.33 Parasympatholytic drugs
like atropine and glycopyrrolate, however, have been
used safely in MHS patients,34 especially in children
where administration of atropine offers certain
advantages, such as prevention of bradycardia during
induction. Some authors recommend that an i.v.
infusion should be started several hours before opera-
tion, to minimize the emotional stress associated
with vein puncture. Expanding blood volume before
induction of anaesthesia is also advisable to prevent
hypotension, since the use of vasopressor agents is
contraindicated in these cases.33
Induction and maintenance of anaesthesia
Anaesthesia for MHS patients should be as stressfree as possible. Careful monitoring of central temperature (rectal or oesophageal) and ETCO2 is mandatory. Elevation of ETCO2 is an early sign of a possible
impending reaction.35'36 Whenever suitable, local or
regional anaesthesia is advisable because these techniques are reported to be safer.37 All volatile anaesthetics, including the newer agents such as desflurane
and sevoflurane, must be avoided. 38 The use of
depolarizing relaxants is also absolutely forbidden.
Non-triggering anaesthetics
All authors agree that barbiturates are non-triggering
agents and suggest that they might even play a role
in protection and inhibition of MH crises in humans,
as it was shown in pigs.3 Similarly, benzodiazepines
are also considered safe agents to be used in the
anaesthesia of MHS patients.3 Etomidate was shown
experimentally not to cause MH syndrome in susceptible pigs but compared to thiopental it has less
protective effect.40
Several studies suggest that propofol is safe for
MHS patients: it did not cause an MH episode in
MHS pigs,41'42 and has been given many times to
MHS patients without any reported side-effects.43
Furthermore, there are many reports on the use of
propofol in patients with myopathies which may be
related to MH, without untoward effects.44 Because
of the rapid recovery time, propofol seems an ideal
choice for short procedures in MHS patients under
general anaesthesia.
Ketamine use in MHS patients remains controversial. Most experts do not recommend its use because
of its sympathomimetic effects. On the other
hand, all opiates are considered safe non-triggering
agents.46 It has been reported that diagnostic muscle
biopsies are taken in England and North America
under general anaesthesia using fentanyl without any
adverse reactions.16 This was further reported for
alfentanyl 47 and for sufentanil.48
Nitrous oxide (NO2) is considered a safe agent in
MHS patients although one report mentioned the
possibly of a slight triggering effect.49 However, it
has been used many times in MHS patient without
any problems.50
Although one report suggests that d-tubocurarine
and gallamine may be unsafe in MHS patients,51
authors agree about the safety of other non-
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A set of drugs for the acute treatment of MH crises
must be kept at the OR. These should include
procainamide, sodium bicarbonate, furosemide,
mannitol, regular insulin, 50% glucose and propranolol. Full equipment for resuscitation, insertion of
arterial and central lines, bladder catheterization and
a cooling machine with blankets should be prepared,
as well as an ample supply of tubes, syringes and
means of taking multiple arterial and venous blood
samples. It is recommended that cool saline solution
and ice are to hand.
15
16
R. Ben Abraham et al.
Emergence and extubation
Emergence and extubation should be smooth and
stress-free as possible in MHS patients undergoing
surgery. If residual neuromuscular block persists, or
if dantrolene in doses higher than 3.5 mg/kg was
given, it is recommended to continue with mechanical ventilation until full spontaneous recovery
occurs.22 Episodes of hypoxia or hypercarbia should
be avoided, as they can trigger an MH reaction. MH
reactions have been reported to occur in the postoperative period, even if non-triggering anaesthesia
was used.56 Therefore, continued supervision in the
recovery room for at least 4 h, including monitoring
of heart rate and temperature is recommended.57
MH consultation and risk stratification
The MH reaction is fortunately rare. However, in
recent years awareness of this syndrome has greatly
increased, and an increased number of CHCT
resulted in more patients diagnosed as MHS. Since
primary prevention is an important issue in MH, it
should be explained to the patient that administration
of general anaesthesia to MHS subjects is safe,
providing that no triggering agents are used, routine
monitoring including temperature is performed, and
dantrolene is available in case of an MH episode.
The meaning of autosomal dominant transmission
of MH should be clarified to the patient, and the
anaesthesiologist should encourage patients and their
families to refer to special diagnostic centres. It
should also be explained that MHS does not carry
increased risk for heart disease, sudden infant death
syndrome (SIDS) or stress reaction after sport activity.
Sport is safe provided heat stroke is prevented.64
Certain professions, such as those involving exposure
to halogenated hydrocarbons and organ solvents,
and constant strenuous physical activities should be
avoided. 65 In view of this, military authorities are
reluctant to enlist MHS individuals, especially in
field positions, although it seems reasonable to allow
limited-activity military service.
Anaesthesiologists are advised to adopt a strict
monitoring regime including temperature and ETCO2/
since with adequate monitoring an MH reaction can
be detected long before serious complications have
occurred. In cases of suspected MH reaction, serum
potassium, CPK and myoglobin levels should be
documented. The patient should then be referred to
an appropriate consultation after a full explanation
about the MH episode from the anaesthesiologist in
charge. Patients found to be positive to MH should
be provided with a bracelet noting: 'malignant hyperthermia, no potent inhalation anaesthetics or succinylcholine', and should be instructed that whenever
anaesthesia is needed, the anaesthesiologist must be
notified of their special sensitivity. Cognizance and
a high index of suspicion among anaesthesiologists
remain the cornerstones of MH management.
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