Malignant hyperthermia is a rare, life-threatening, autosomal-dominant, pharmacogenetic, anesthetic-related disorder that
occurs in susceptible patients following the administration of a triggering agent, such as inhaled halogenated volatile anesthetics
or depolarizing neuromuscular blocking agent. Once triggered, a rapidly progressive hypermetabolic reaction involving sustained
muscle contraction occurs with catastrophic consequences. Recent advances in our understanding of malignant hyperthermia have
decreased the fatality rate from >70% to <5% per episode.
Malignant hyperthermia can occur at any time following administration of a triggering agent. Many triggers of malignant hyperthermia
are used during the routine administration of general anesthesia. Pharmacologically, malignant hyperthermia triggers include
the halogenated volatile anesthetics including halothane, isoflurane, desflurane, sevoflurane, and enflurane and the depolarizing
neuromuscular blocking agent, succinylcholine.
The reported incidence of malignant hyperthermia episodes ranges from 1 in 5000 anesthetics to 1 in 50,000 to 150,000 anesthetics.
Malignant hyperthermia occurs more commonly in children and young adults, in men more frequently than women, and in all ethnicities
in equal proportion. Additionally, many cases of malignant hyperthermia may go undetected because many susceptible patients
are never anesthetized, have short durations of exposure, or have mild, uncomplicated presentations that are never diagnosed.
Given the rarity and lethality of malignant hyperthermia, all health care providers in the perioperative setting should be
able to identify and institute timely life-saving therapy for this disorder. Collaboration between all members of the perioperative
team is imperative in the successful treatment of malignant hyperthermia. This article provides a basic overview of this rare,
life-threatening disorder and discusses the pharmacologic agents involved in its treatment.
Malignant hyperthermia has been linked to mutations within the calcium channel receptor, known as the ryanodine receptor (RYR1),
within the sarcoplasmic reticulum.
To date, more than 40 different point mutations in the gene encoding RYR1 have been discovered.
These mutations are translated into a dysfunctional receptor with resultant uncontrolled release of calcium from the sarcoplasmic
reticulum that leads to a prolonged and sustained muscle fiber contraction.
The sustained muscle contraction produces a rapid depletion of adenosine triphosphate (ATP) with a concomitant increase in
glucose metabolism, oxygen consumption, and heat production. Acidosis, hyperthermia, and ATP depletion lead to the destruction
of the sarcolemma, cell death, and release of intracellular materials.
This series of events leads to a hypermetabolic crisis, including electrolyte imbalances, cardiac arrhythmias, hyperthermia,
acidosis, disseminated intravascular co-agulopathy, and death.
The gold standard test for identifying susceptibility to malignant hyperthermia is the skeletal muscle contracture test.
This test, which uses a small piece of live muscle from biopsy, assesses the muscular contractility in response to halothane
and caffeine exposure.
The strength of contractility is a function of free calcium in the myoplasm. Exposure to halothane and caffeine increases
the skeletal muscle contractility in patients who are susceptible to malignant hyperthermia.
The sensitivity of this test for predicting the development of malignant hyperthermia is approximately 97% and the specificity,
This test is costly, is only performed in a limited number of specialized testing centers, and because it requires fresh
muscle specimen, patients must travel to one of these specialized centers.
Genetic testing for the mutations that result in malignant hyperthermia is also available with advantages over the muscle
contracture test that include reduced invasiveness and lower cost. The disadvantage of genetic testing is a substantially
lower sensitivity with only a 30% detection rate for patients at risk for malignant hyperthermia.
Malignant hyperthermia symptoms can occur within a few minutes to a few hours of initial exposure to a triggering agent (Table
Early clinical signs of malignant hyperthermia include a steadily rising heart rate and end-tidal carbon dioxide (ETCO
2) concentration. Although frequently also cited as an initial sign of malignant hyperthermia, masseter muscle spasm may be
seen following succinylcholine administration in patients who do and do not develop malignant hyperthermia.
Table 1: Clinical Presentation of Malignant Hyperthermia
Caffeine-halothane contracture testing of patients who developed these spasms found that only 28% to 50% of these patients
were susceptible to malignant hyperthermia. Muscle rigidity is also prevalent in patients with malignant hyperthermia, especially
in the jaw, chest, and extremities and is frequently refractory to neuromuscular blocking agents. As the crisis progresses,
late clinical signs such as cyanosis, cardiac arrhythmias, mixed respiratory and metabolic acidosis, and various electrolyte
imbalances may arise.
Of note, rhabdomyolysis is another frequent feature of the disorder related to the destruction of skeletal muscle tissue.
As a result, patients commonly develop myoglobinemia, myoglobinuria, hyperkalemia, hyperphosphatemia, and hypocalcemia. Acute
renal failure requiring renal replacement therapy may occur due to myoglobin precipitation in the renal tubules and close
observation and laboratory monitoring of urine for myoglobin should be instituted.
Although the initial descriptions of this syndrome are centered on the development of severe, rapidly developing hyperthermia,
it is known that its occurrence is often late in the development of malignant hyperthermia. When it occurs, the temperature
may rise as quickly as 1°C every 5 minutes.
Patients may progress to severe acidosis, shock, and ventricular fibrillation in as quickly as 20 minutes from the onset of
hyperthermia. Oxygen stores are more rapidly depleted when the patient is hyperthermic with an increase in consumption to
at least 2 to 3 times normal. Mixed venous oxygenation also decreases indicating increased oxygen extraction by the skeletal
muscles. Disseminated intra-vascular coagulation is also associated with the elevated core body temperature. Patients may
present with one or any combination of the above mentioned clinical signs that may evolve into sudden, unexplained cardiac
Several disorders have a similar clinical presentation to malignant hyperthermia. Neuroleptic malignant syndrome is characterized
by muscle rigidity, hyperthermia, hyperkalemia, acidosis, autonomic instability, and altered mental status most often occurring
after the use of neuroleptic agents such as haloperidol, but it has also been implicated with the use of non-neuroleptic agents.
Other disorders that resemble malignant hyperthermia include thyroid storm, pheochromocytoma, heat stroke, and cocaine/ecstasy
Treatment of malignant hyperthermia requires the rapid identification of symptoms, discontinuation of the triggering agent,
institution of dantrolene therapy, and control of associated symptoms. After the triggering agent has been discontinued, if
the surgical procedure must continue, a non-triggering anesthetic technique should be implemented. This may involve the use
of opioids, sedatives, and non-depolarizing neuromuscular blockers as needed (Table
Table 2: Safe Agents for Susceptible Malignant Hyperthermia Patients
Dantrolene therapy, a skeletal muscle relaxant that inhibits the excitation-contraction coupling in skeletal muscle without
affecting neuromuscular transmission or the electrical properties of the muscle, should also be initiated as rapidly as possible
to prevent the development of the rapidly deteriorating clinical course described above.
Dantrolene preparation should begin as soon as possible as it entails a time-consuming reconstitution process and requires
several people for its rapid preparation. The powdered drug dissolves slowly and requires 60 mL of sterile water for injection
added to each 20-mg vial. After reconstitution, dantrolene 2.5 mg/kg/dose should be administered rapidly through a large-bore
IV, if possible.
Doses may be repeated every 5 minutes as needed for regulation of signs and symptoms. The typically described upper limit
of dosing is 10 mg/kg cumulative dose; however, more may be used if clinically indicated.
After the acute crisis has been controlled, dantrolene 1 mg/kg every 4 to 6 hours or alternatively 0.25 mg/kg/hr continuous
infusion for 24 hours is recommended.
Following reconstitution, dantrolene is stable at room temperature for 6 hours when protected from light.
Adverse effects associated with dantrolene include loss of grip strength, muscle weakness, drowsiness, dizziness, and injection
site reactions, including pain, erythema, and swelling. Extravasation of dantrolene has been associated with tissue necrosis.
The mixed respiratory and metabolic acidosis should be treated with hyperventilation at 2 to 3 times the predicted minute
ventilation with 100% oxygen and intravenous administration of sodium bicarbonate. Hyperkalemia may precipitate cardiac arrhythmias
and therefore should be aggressively treated with insulin, dextrose, sodium bicarbonate, and calcium.
Initial management of cardiac arrhythmias includes treatment of the underlying acidosis and hyperkalemia. Cardiac arrhythmias
should not be treated with calcium channel antagonists (eg, verapamil, diltiazem) due to a severe drug interaction with dantrolene
resulting in hyperkalemia and cardiac arrest.
Persistent arrhythmias may necessitate the use of standard antiarrhythmic medications such as amiodarone and lidocaine.
Hyperthermia, a late clinical sign, should be treated with aggressive cooling measures. Core temperature must be monitored
using appropriate monitoring sites including the pulmonary artery, distal esophagus, nasopharynx, tympanic membrane, rectum,
bladder, or axilla. Cooling techniques include use of cold 0.9% sodium chloride intravenous fluids, lavage of the stomach,
bladder, rectal, or open cavity, and placement of ice packs on the neck, axilla, and groin. Cooling techniques should be suspended
when the core body temperature reaches 38°C.
Acute rhabdomyolysis should be treated with adequate hydration, urine alkalinization, and diuretics to maintain a urine output
of 2 mL/kg/hr.
Laboratory monitoring parameters include arterial and venous blood gases, electrolytes, coagulation parameters, myoglobinemia,
myoglobinuria, and creatine kinase. These should be performed immediately at the onset of the reaction and periodically thereafter.
The syndrome recurs in 25% of patients within 48 hours of a treated episode, necessitating the need for close intensive care
unit monitoring after the event.
A thorough preoperative assessment is essential to the prevention of malignant hyperthermia. Malignant hyperthermia has been
associated with many myopathies but the predisposition to malignant hyperthermia has only been established in 3 disorders.
They include Evans myopathy (named after the family in which malignant hyperthermia was first detected), central-core disease,
and King-Denborough syndrome.
Of note, susceptible patients who have undergone a previously uncomplicated general anesthetic with an inhaled volatile anesthetic
or succinylcholine may develop malignant hyperthermia during a subsequent anesthetic. Population studies have determined that
approximately 24% to 50% of patients with malignant hyperthermia had undergone a prior anesthetic procedure without incident.
The concentration of anesthetic, duration of exposure to triggering agents, and degree of malignant hyperthermia susceptibility
are thought to be significant factors in explaining this phenomenon.
If patients are known to be susceptible or if there is suspicionofsusceptibility,alternative anesthetic techniques including
spinal, epidural, regional, or local anesthesia should be used. If a susceptible patient must undergo general anesthesia,
the potent volatile anesthetics (halothane, isoflurane, desflurane, sevoflurane, enflurane) and succinylcholine must be avoided.
This is accomplished through the use of an anesthetic machine that has been thoroughly cleansed of volatile anesthetic residue
and an intravenous infusion of anesthetic, typically propofol. The use of dantrolene as prophylaxis prior to general anesthesia
in malignant hyperthermia susceptible patients is no longer a recommended practice.
Early recognition and prompt treatment of malignant hyperthermia have resulted in substantial reduction in morbidity and mortality.
A thorough preoperative assessment, knowledgeable health care professionals, and interdisciplinary collaboration can significantly
impact patient outcomes.
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Clinical Presentation of Malignant Hyperthermia
Early Signs and Symptoms
Late Signs and Symptoms
|| Mottled skin
| Masseter muscle spasms
| Generalized rigidity
||Disseminated intravascular coagulation
||Left ventricular failure
| Generalized erythematous flush
|| Pulmonary edema
|| Frothy sputum
Safe Agents for Susceptible Malignant Hyperthermia Patients
|Non-depolarizing neuromuscular blockers