Download MH-associated diseases: who really needs a non

Seminars in Anesthesia, Perioperative Medicine and Pain (2007) 26, 113-119
MH-associated diseases: who really needs a
non-triggering technique?
Ronald S. Litman, DO, FAAP
From the Department of Anesthesiology and Critical Care, The Children’s Hospital of Philadelphia, Philadelphia,
Pennsylvania.
KEYWORDS:
Hyperthermia;
Rhabdomyolysis;
Ryanodine;
Anesthetic
complications;
Central core
myopathy;
Dystrophinopathy
Malignant hyperthermia (MH) is a pharmacogenetic clinical syndrome that occurs in patients with
preexisting abnormal skeletal muscle. It manifests clinically as a hypermetabolic crisis when a
MH-susceptible individual is exposed to an inhalational anesthetic or a depolarizing muscle relaxant
(ie, succinylcholine).
© 2007 Elsevier Inc. All rights reserved.
History and incidence
In 1962, Denborough and colleagues described a young man
who, while waiting for surgery for his fractured leg, described
10 of his relatives that died without explanation during or
following general anesthesia.1 Despite his anesthesiologist’s
use of a new anesthetic called halothane, the man developed
severe hyperthermia, tachycardia, and tachypnea, and remarkably, survived the event using aggressive cooling. Upon subsequent investigation of the patient’s family, Denborough
noted an autosomal dominant pattern of the anesthetic-related
illness, and concluded that the susceptibility to this disorder
was inherited. Once published, this report stimulated the publication of additional cases of anesthetic-induced hypermetabolism, many of which were accompanied by muscle rigidity,
rhabdomyolysis, hyperkalemia, renal failure, disseminated intravascular coagulation (DIC), and death. Over subsequent
years, the syndrome became known as malignant hyperthermia
(MH), because of its often fatal nature and association with
Address reprint requests and correspondence: Ronald S. Litman, Department of Anesthesiology and Critical Care, The Children’s Hospital of
Philadelphia, 34th Street and Civic Center Blvd., Philadelphia, PA 19104.
E-mail: [email protected].
0277-0326/$ -see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1053/j.sane.2007.06.007
uncontrolled high body temperature. Further investigation
showed a predisposition to MH when susceptible patients were
exposed to inhalational agents or succinylcholine (and frequently both). Eventually, dantrolene, a nonspecific muscle
relaxant that inhibits intracellular calcium accumulation, was
shown to be an effective antidote and decreased MH-related
mortality from 40% to less than 5%.
The incidence of MH susceptibility has been reported to
be as low as 1 in 250,0002 and as high as 1 in 200,3
depending on the geographical region studied. The true
prevalence is unknown because of unrecognized or aborted
reactions and the variable penetrance of the inherited trait.
Furthermore, many MH-susceptible patients may never be
exposed to anesthetic triggering agents. Almost all MHsusceptible patients are phenotypically normal and will only
manifest the clinical characteristics of MH when exposed to
anesthetic triggering agents.
Clinical features
The first signs of an acute MH episode are manifestations of
systemic, uncontrolled hypermetabolism during general an-
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Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 26, No 3, September 2007
esthesia with a triggering agent. Presenting signs may include tachycardia, hypertension, muscle rigidity, and hypercarbia, the last of which reflects an increase in the
production of CO2. The most common initial sign of acute
MH is an unexplained rise in end-tidal carbon dioxide that
does not readily decrease with increases in minute ventilation. The clinical presentation is not uniform and the time of
onset is variable between patients. The presence of masseter
muscle spasm following administration of succinylcholine
may herald the onset of MH in some patients. Cardiac
dysrhythmias, including ventricular tachycardia or fibrillation, may indicate an undiagnosed underlying hyperkalemia
as a result of fulminant muscle damage. Localized or generalized muscle rigidity, despite the presence of neuromuscular blockade, indicates a state of unabated muscular contracture, and is strongly indicative of MH when other signs
are present.
In cases of known MH, there is wide variability in the
interval between exposure to the triggering agent and development of symptoms. The time between onset of initial
signs and development of fulminant MH is also variable and
unpredictable.
Hyperthermia is a late sign of MH and may not be
present at the time of the diagnosis. Hyperthermia is likely
caused by continuous muscle contractures that generate
more heat than the body can dissipate to the environment.
Body temperature can increase at a rate of 1° to 2°C every
5 minutes. Severe hyperthermia (core temperature greater
than 44°C) may occur, and can lead to a marked increase in
oxygen consumption, CO2 production, widespread vital organ dysfunction, and disseminated intravascular coagulation (DIC). Prior to the development of hyperthermia, the
CO2 absorbent in the anesthesia machine often becomes
warm to the touch as a result of the exothermic reaction with
the patient’s exhaled CO2.
If the hypermetabolism continues unabated, it leads to
cellular hypoxia, which is manifested by progressive and
worsening metabolic acidosis. If untreated, continued myocyte death and rhabdomyolysis result in life-threatening
hyperkalemia, myoglobinuria, renal failure, and DIC.
Once recognized, treatment of MH includes immediate
discontinuation of the anesthetic triggering agent and administration of dantrolene sodium. Supportive measures are
instituted to reverse the associated hyperthermia, acidosis,
and hyperkalemia, and to prevent myoglobinuria-induced
renal failure.
Pathophysiology of MH
Malignant hyperthermia susceptibility (MHS) is conferred
by inheritance of a mutation of a calcium-regulating structure in the muscle cell, most commonly the ryanodine receptor (RYR1), which resides on the sarcoplasmic reticulum
and is responsible for regulating calcium entry into the
myocyte.4 A mutation in the gene for RYR1, which is
located on chromosome 19, causes production of an abnormal ryanodine receptor (mutations of other calcium-regulating structures have also been identified). When a MHS
patient is exposed to an anesthetic triggering agent, the
abnormal ryanodine receptor may remain open for an abnormally long duration, thus allowing too much calcium to
be released into the myocyte.5,6 The accelerated hypermetabolism, which is characteristic of an acute MH episode, is
caused by the overwhelming accumulation of calcium in the
muscle cell, thus activating the contractile machinery until
the cell uses up ATP, and releases creatine kinase (CK) and
potassium into the circulation.
Diagnosing MH susceptibility
The most widely used and most sensitive method for determining whether an individual is susceptible to MH is the
caffeine– halothane contracture test (CHCT).7 The sensitivity of the CHCT is at least 97%, but in North America, the
specificity is lower— up to 22% of patients may have a
false-positive test.8
Patients with a positive or equivocal CHCT can now
undergo molecular genetic analysis to identify a causative
mutation. Family members of a proband with an identified
MH-causative mutation may also be offered genetic testing
without having to undergo a CHCT.9 Genetic analysis is
fairly straightforward, as a DNA sample can be obtained
from buccal cells, white blood cells, muscle cells, or other
tissue. Molecular genetic testing uses a panel of mutations
that includes the most common RYR1 mutations and detects
mutations in approximately 25% to 30% of susceptible
individuals.10
Relationship between MH and known disease
entities
Determining the causation or association of MHS with a
particular disease entity is extremely difficult. In considering the chain of credible evidence for determination of
causation/association, prospective randomized controlled
trials and cohort studies are not feasible, which leaves only
case control studies, and case reports and case series. Furthermore, close examination of these published reports reveals a number of problems inherent in the fact that no real
gold standard of MHS diagnosis exists (the CHCT has a
false-positive rate up to 22%), and definitive diagnosis of
specific syndromes is also often in doubt. Most recently,
genetic linkage and pedigree analysis studies have furthered
the definitive diagnosis of various syndromes and their link
to MHS. I will review these diseases as well as the evidence
for MHS associated with a number of other diseases.
I think of three types of categories when considering a
disease’s link to MHS: 1) those that are definitely linked to
MHS by either genetic linkage or overwhelming clinical
Litman
MH-Associated Diseases
115
evidence [central core disease (CCD), multiminicore myopathy, and the King-Denborough syndrome/phenotype];
2) those that probably do not predispose to MHS but patients who receive triggering agents may manifest signs and
symptoms similar to MH (eg, dystrophinopathies, channelopathies, heat/exercise-induced rhabdomyolysis); and
3) those diseases that have been purported to be linked to
MHS, but the evidence of this linkage is weak or nonexistent [eg, Noonan’s syndrome, arthrogryposis, osteogenesis
imperfecta, mitochondrial myopathies, neuroleptic malignant syndrome (NMS)].
most common type is characterized by limb weakness, scoliosis, and respiratory impairment during early childhood. A
second type also includes extraocular muscle impairment. A
third type shows prominent proximal lower extremity weakness without the respiratory involvement, and the last type
is associated with arthrogryposis.
Like CCD, MMD is caused by a mutation of the RYR1
gene, and thus, has overlap with mutations responsible for
MHS. Its association with MHS is less than that seen with
CCD, but many families have been identified with both, and
therefore, patients should be considered MHS until proven
otherwise with a negative CHCT.19
Diseases clearly linked with MHS
King–Denborough syndrome/phenotype
Central core disease (CCD)
The King–Denborough syndrome, or phenotype, is a
rare, recessively inherited disorder associated with a consistent set of physical findings that may include short stature, pectus excavatum or carinatum, undescended testicles,
subclinical or apparent myopathy (the majority of patients
will demonstrate baseline elevated CK levels), ptosis and/or
strabismus, and spine abnormalities such as scoliosis. It is
often confused with Noonan syndrome, which is similar, but
usually has a cardiac component and lacks the myopathic
features. A common or consistent genotype has not been
identified for King–Denborough patients, but we know that
they possess a propensity toward MHS, borne out in both
clinical episodes and CHCT analysis.20,21
CCD is a congenital myopathy associated with mutations
on the ryanodine gene (RYR1) on chromosome 19, the same
gene that harbors many MH-causative mutations.11 In certain geographical areas of Europe, the prevalence in children is between 3.5 and 5/100,000.12 The North American
prevalence is unknown. It appears to be inherited in an
autosomal dominant manner.
The clinical characteristics of CCD vary between affected individuals, and often consist of motor delay during
infancy or early childhood, with a predominance of lower
extremity proximal weakness. Secondary musculoskeletal
abnormalities may include congenital hip dislocation, foot
deformities, scoliosis, and joint contractures. Children with
CCD may require general anesthesia for surgical procedures
such as gastrostomy tube insertion, muscle biopsy, and
correction of orthopedic problems.13
Since the clinical features are variable, the diagnosis of
CCD is confirmed by the histologic findings of central cores
(ie, absence of visible cellular material) within the muscle
cells. In most patients, the disease is not debilitating or
progressive with age.
It has long been known that many families with CCD
also prove to be MHS. This can be explained by the close
genetic association (mutations on the same gene that may
often overlap),14,15 positive MH contracture testing of patients with confirmed CCD, and clinical episodes of anesthesia-associated MH in patients with the disease.16,17 There
exist some families with CCD that are not MHS; however,
in the interest of patient safety relating to administration of
general anesthesia, patients with CCD should be treated as
if they are also MHS, even without supporting MHS testing.
Multiminicore disease
Multiminicore disease (MMD) is a congenital myopathy
inherited in an autosomal recessive fashion. Histologically,
the affected muscle tissue demonstrates cores, but unlike
CCD, they do not run the entire length of the fiber.18
Clinically, four subtypes have been identified. The classic,
Diseases with an anesthesia-induced MH-like
syndrome
There are many diseases in which triggering agents have
caused similar signs and symptoms to MH but the definitive
link to MHS is absent. Examples include, but are not limited
to, the muscular dystrophies, McArdle’s disease, myoadenylate deaminase deficiency, CPT-2 deficiency, the channelopathies, heat stroke, and exercise-induced rhabdomyolysis.
Muscular dystrophies
The muscular dystrophies encompass a wide variety of
myopathic diseases. The most common are Duchenne’s
muscular dystrophy (DMD) and Becker’s muscular dystrophy (BMD), both of which have been reported to be associated with MH-like symptoms when affected patients received triggering agents.
DMD is an X-linked recessive disease that usually presents in early childhood as weakness and motor delay.
Additional clinical manifestations include pseudohypertrophy of the calves and markedly elevated baseline creatine
kinase (CK). Progressive and severe muscle atrophy and
weakness cause loss of the ability to ambulate. DMD patients ultimately succumb in early adulthood secondary to a
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Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 26, No 3, September 2007
progressive cardiomyopathy and ventilatory pump insufficiency. DMD is caused by a mutation on the X-chromosome
that prevents formation of dystrophin, a muscle-stabilizing
protein.22
Despite several case reports of children with DMD that
seemingly develop MH,23 no definitive genetic link between
DMD and malignant hyperthermia has been found, and
many patients with DMD have been exposed to general
anesthetic agents without incident. Existing case reports of
anesthetic-related complications in DMD patients represent
inhalational anesthetic-induced rhabdomyolysis,24-29 succinylcholine-induced hyperkalemia,30-32 or a coincidental inheritance of both mutations. Additional confusion results
from the fact that rhabdomyolysis resulting from exposure
to inhalational anesthetics may also be associated with hypermetabolism, a hallmark of MH.33 Furthermore, muscle
contracture tests from patients with muscular dystrophies
may prove falsely positive.32
Although many patients with DMD have successfully
received inhalational anesthetics without a problem, and
DMD does not appear to be linked to MHS, the most
prudent and safest recommendation is to avoid their use in
children known to be affected with DMD and in boys with
a history suspicious for progressive motor delay during
early childhood because of the possibility of precipitating
rhabdomyolysis.34 There will always be uncommon situations where the benefit-to-risk ratio of using inhalational
anesthetics in such patients will be sufficiently high, such as
the difficult airway, or impossible intravenous access. In
these situations, anesthesiologists should decide, on a caseby-case basis, whether the use of inhalational agents for a
short period of time is warranted.
A less severe (yet debilitating) related disease is the
Becker-type muscular dystrophy. Similar features to DMD
include calf pseudohypertrophy, cardiomyopathy, and elevated serum levels of CPK. However, the onset of weakness
in Becker-type dystrophy is later in life than with DMD, and
death often occurs at a later age than with DMD. The
anesthetic considerations are identical to those for DMD.
Succinylcholine-induced hyperkalemia has been reported in
a BMD patient.35
Although the dystrophinopathies are not formally associated with MHS, affected patients demonstrate similar
signs and symptoms when exposed to triggering agents.
Therefore, triggering agents should be avoided in such patients. Furthermore, many pediatric anesthesiologists believe that children with motor delay in the first decade of life
should be considered susceptible to these complications and
should not receive inhalational anesthetic agents or succinylcholine.
Clinical features include muscle cramping, exercise intolerance, and rhabdomyolysis. There is one report of a MHS
patient with McArdle’s36 and numerous reports of patients with McArdle’s that developed perioperative complications including rhabdomyolysis.37,38 Thus, patients
with McArdle’s should probably not receive triggering
agents.
Myoadenylate deaminase deficiency
Myoadenylate deaminase (MAD) is a muscle-specific
enzyme involved in the energy metabolism of skeletal muscle. Patients with an inherited deficiency demonstrate exercise intolerance characterized by muscles cramps, elevated
CK levels (baseline and increased after exercise), and rhabdomyolysis on occasion. One patient with both MAD and an
underlying mitochondrial myopathy was positive for MHS
by contracture testing.39 However, there is no additional
evidence of its predisposition toward MHS, and thus, patients with MAD deficiency should not be considered MHS;
however, it may be prudent to avoid triggering agents in
these patients.
Carnitine palmitoyl transferase type 2 (CPT2)
deficiency
CPT2 deficiency is a type of fatty acid oxidation disorder
in which there is abnormal breakdown of fats for energy.
It affects both sexes and is inherited in an autosomal recessive manner. Clinical features include muscle weakness or
cramps and exercise intolerance associated with rhabdomyolysis. There are a number of reports of patients with CPT2
deficiency who developed perioperative rhabdomyolysis but
no definitive link to MHS.40,41 Because of these case reports, CPT2 deficiency should probably be considered in a
similar category as the above entities, and thus, triggering
agents should be avoided.
Heat- and exercise-induced rhabdomyolysis
There have been reports of the association between MHS
and rhabdomyolysis or death from heat stroke42 and strenuous exercise.43,44 It has been postulated that MHS patients,
by virtue of their underlying muscle abnormality, are predisposed to these complications under stressful conditions,
such as extreme heat or exercise. Therefore, patients with a
history (or immediate family history) of heat or exerciseinduced rhabdomyolysis should probably not receive triggering agents.
McArdle’s disease
McArdle’s disease (also known as Glycogen Storage
Disease Type V) is a relatively uncommon syndrome
caused by the absence of muscle phosphorylase, and thus,
the inability of muscle to break down glycogen into lactate.
Diseases linked to MHS without evidence
A number of disease entities have been reported to be linked
with MHS. However, in each disease, evidence of MHS or
patient harm in association with administration of triggering
Litman
MH-Associated Diseases
agents is lacking when the case is examined critically.
Diseases in this category include Noonan’s syndrome, arthrogryposis, osteogenesis imperfecta, the mitochondrial
myopathies, and neuroleptic malignant syndrome (NMS).
Noonan’s syndrome
Noonan’s syndrome is an inherited constellation of
anomalies in males that consists of short stature, webbed
neck, low set ears, congenital heart disease, pectus excavatum, and varying degrees of developmental delay or mental
retardation. It has been loosely associated with MHS; however, there are no convincing case reports or proof of association by contracture testing or genetic mutation analysis.
Because of the similarity of features, Noonan’s syndrome
has been confused with King–Denborough syndrome,
which may explain reports of the association of Noonan’s
with MHS. Thus, children with Noonan’s syndrome are not
considered to be MHS.
Arthrogryposis
Arthrogryposis is a condition of congenital joint contractures that occurs in a variety of different inherited neurogenic or myogenic syndromes.45 Affected patients have
demonstrated hyperthermia and hypermetabolic responses
to general anesthesia, but MH has not been observed with
any certainty.46,47 Therefore, these patients should not be
considered to be MHS.
Osteogenesis imperfecta
MH has been reported in children with osteogenesis
imperfecta (OI); however, the diagnoses have not been
confirmed by contracture testing or genetic mutation analysis.48,49 The clinical diagnosis is further complicated by
reports of such children developing non-MH-associated hyperthermia50 and metabolic acidosis.51 Until there are more
convincing reports or genetic evidence confirming the link
between OI and MH, these children should not be considered to be MHS, but should be observed for development of
hyperthermia in the perioperative period.
Mitochondrial myopathies
The mitochondrial myopathies are a group of genetic
diseases whose origin is a defect in mitochondrial function,
causing interference with normal adenosine triphosphate
(ATP) production. Although mitochondrial defects can affect almost every organ system, those organs with high
metabolic rates—such as the heart, brain, and skeletal muscle—are particularly vulnerable. ATP depletion results in
accumulation of lactate, a byproduct of anaerobic metabolism. Clinical manifestations include abnormalities of the
heart (eg, cardiomyopathy, conduction defects), skeletal
muscle (eg, atrophy, weakness), and central nervous system
117
(eg, seizures, encephalopathy, peripheral neuropathies, ophthalmologic manifestations), among many others. Examples
of mitochondrial diseases include chronic progressive external ophthalmoplegia, Kearns–Sayre syndrome, Leigh’s
disease, Leber’s hereditary optic neuropathy (LHON), mitochondrial myopathy, and myoclonic epilepsy with lactic
acidosis and stroke-like episodes (MELAS syndrome).
There is no definitive genetic link between mitochondrial
disease and MH susceptibility. In the presence of muscle
atrophy, elective use of succinylcholine is contraindicated,
as it may cause life-threatening hyperkalemia. Inhalational
agents have been used safely in patients with mitochondrial
diseases.
Neuroleptic malignant syndrome (NMS)
NMS, which may occur when an individual is exposed to
an antipsychotic medication, shares many similarities with
MH, including the clinical presentation and treatment (ie,
dantrolene).52,53 However, no known genetic or causal association exists between MH susceptibility and NMS.
Evaluation of the hypotonic infant
An almost daily dilemma for pediatric anesthesiologists is
the hypotonic infant without a definitive diagnosis who
presents for a diagnostic muscle biopsy. How does one pick
out the infants with the diseases for which administration of
inhalational agents is contraindicated? Unfortunately, there
is no certain method; however, the approach is relatively
straightforward. Diseases that warrant administration of a
non-triggering technique include the congenital myopathies
central core disease (CCD) and multiminicore disease
(MMD), both of which are considered to be lower motor
neuron diseases. Yet, in infancy, it is nearly impossible to
differentiate these two entities with the myriad other congenital myopathies or congenital dystrophies. In infancy,
the most common cause of hypotonia of unknown etiology
is likely to be central in origin (ie, upper motor neuron
lesion). These can be differentiated from the lower motor
neuron diseases by their presence of normal or hyperactive
reflexes. Furthermore, infants with central disease often
have a depressed level of consciousness, whereas infants
with a peripheral myopathy are usually alert and cognitively
normal for age. Additional evidence against a diagnosis of
CCD or MMD include laboratory evidence characteristic of
metabolic diseases (eg, hyperammonemia, lactic acidosis,
etc.). However, increased creatine kinase, although diagnostically nonspecific, is associated with diseases that confer
MH susceptibility or anesthetic-induced rhabdomyolysis.54
Conclusions
Susceptibility of MH has been reported to occur in a wide
variety of patients with different diseases. Those with dis-
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Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 26, No 3, September 2007
eases of the muscle warrant close attention, with contracture
testing and genetic mutational analysis to determine the true
association with MHS. There are only three entities with a
convincing link with MHS: central core disease, multiminicore disease, and King-Denborough syndrome. Other muscles diseases, such as the dystrophinopathies, McArdle’s disease, myoadenylate deaminase deficiency, carnitine palmitoyl
transferase type 2 (CPT2) deficiency, and heat- or exerciseinduced rhabdomyolysis, have all been associated with signs
and symptoms similar to acute MH, and therefore, patients
with these entities should probably avoid triggering agents.
Other patients with diseases purported to be linked with
MH, but for which there is no convincing proof, such as
Noonan’s syndrome, osteogenesis imperfecta, arthrogryposis, mitochondrial myopathies, and NMS, may continue to
safely receive triggering agents when indicated.
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