Malignant hyperthermia and other myopathies

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What is malignant hyperthermia (MH) and its underlying defect?

Malignant hyperthermia is a disastrous and sudden syndrome evoked by the administration of triggering anesthetic agents, including volatile anesthetics and depolarizing neuromuscular blocking agents. Unfortunately, there is no distinct phenotype before exposure to the triggering agent. MH is a syndrome characterized by dysregulation of excitation-contraction coupling in skeletal muscle. Patients with MH have a persistent increase in the concentration of sarcoplasmic calcium, which increases the need for adenosine triphosphate (ATP), therefore producing heat with resultant hyperthermia. This is caused by abnormal function of the skeletal muscle ryanodine receptor RyR1 in MH susceptible (MHS) patients. The gene for this receptor is found on chromosome 19 in 50% to 80% of MHS patients.

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What is the inheritance pattern of MH and what are the triggering agents?

MH is thought to be inherited via an autosomal dominance pattern, although not strictly. Over 210 mutations in RyR1 exist in MHS patients, with an additional 4 mutations discovered in Cav1 (slow inactivating calcium channel) on the CACNL1A3 gene. The anesthesia drugs that trigger MH include volatile agents (ether, halothane, sevoflurane, isoflurane, desflurane) and depolarizing muscle relaxants (succinylcholine). Preadministration of sedatives, propofol, and nondepolarizing muscle relaxants may delay the onset of MH in MHS patients.

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Describe the cellular events, presentation, and metabolic abnormalities associated with MH

MH syndrome as the result of abnormal RyR1 receptor is characterized by a persistent increase in calcium within the sarcoplasmic reticulum. This increases the activity of pumps and exchangers to correct the increased sarcoplasmic calcium, thereby generating ATP. As a result, excessive heat production and increased oxygen consumption occur.

Presentation of MH is typically after normal induction of anesthesia, followed by onset of unexplained tachycardia, hypercarbia with adequate ventilation, hypoxia, a mixed metabolic and respiratory acidosis, and late increase in core body temperature over 38.8°C. Patients also develop muscle rigidity and rhabdomyolysis, hyperkalemia, and acute renal failure. In North America, any patient suspected of having an MH episode should be reported to Malignant Hyperthermia Association of the United States (MHAUS) via a hotline (800-644-9737) that is staffed 24 hours a day, 7 days a week. Outside of North America, MHAUS can be reached at 001-209-417-3722.

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How is MH treated?

• Call for assistance, as aggressive therapy requires more than one person.

• Turn off all triggering agents and hyperventilate the patient with 100% oxygen and flows greater than10 L/min.

• Switch to a nontriggering anesthetic, for example, propofol infusion.

• Notify the surgeon and operating room personnel of the situation and expedite conclusion of the procedure, even if it may require that surgery go unfinished.

• Administer dantrolene, 2.5 mg/kg; repeat every 5 minutes to a total dosage of 10 mg/kg, if needed. Dantrolene sodium inhibits calcium release via RyR1 antagonism, thereby reducing cellular hypermetabolism. Note that reconstitution of dantrolene is performed with sterile water.

• Monitor blood gases. Administer bicarbonate, 1 to 4 mEq/kg for a pH less than 7.1.

• Cool the patient using interventions, such as cold fluids and cooling blankets, but become less aggressive in reducing body temperature at about 38°C.

• Promote urine output (2 mL/kg/h), principally with aggressive fluid therapy. Note that mannitol and furosemide may also be required. Administration of bicarbonate will alkalinize the urine to protect the kidneys from myoglobinuria induced renal failure.

• Treat hyperkalemia with calcium chloride, bicarbonate, and insulin/glucose.

• Check for hypoglycemia and administer dextrose, particularly if insulin has been administered.

• Send coagulation studies (fibrinogen, prothrombin time, partial thromboplastin time, international normalized ratio) to monitor coagulation status.

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How does dantrolene work? How is it prepared?

Dantrolene impairs calcium-dependent muscle contraction. This rapidly halts the increased metabolism and secondarily results in a return to normal levels of catecholamines and potassium. The older preparation was prepared by mixing 20 mg of dantrolene containing 3 g of mannitol in 60 mL of sterile water. The newer formulation of dantrolene (Ryanodex) makes preparation much easier and only takes 20 seconds to reconstitute. It is supplied as 250 mg vials of dantrolene sodium with 125 mg mannitol in lyophilized powder form and is reconstituted with 5 mL sterile water.

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How is MH susceptibility assessed in an individual with a positive family history or prior suggestive event?

The diagnosis of MH is immensely difficult. There are clinical grading scales that have been developed to help determine how likely a suspected episode is a true MH episode. The gold standard for diagnosis is the caffeine-halothane contracture test (CHCT). The patient's muscle is biopsied and then exposed to incremental doses of halothane and caffeine. The muscle is then evaluated for degree of contracture. This test is offered at only five centers in the United States and two in Canada. It is 85% to 90% specific, and 99% to 100% sensitive.

Genetic testing for the abnormal RyR1 isoform is now available in the United States and other selected countries. The role for genetic testing is expanding. It is much cheaper than muscle biopsy/CHCT and can be performed on children who are considered too young to have CHCT (< 10 years of age or < 40 kg). Genetic testing is especially valuable in homogeneous populations in whom the genetic defect is prevalent. However, if genetic testing is negative in a susceptible individual, a CHCT must be performed. Limitations to genetic testing include low sensitivity, secondary to diverse mutations of genes.

Of note, exertional heat illnesses characterized by rhabdomyolysis may suggest that a patient is susceptible to MH.

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What are the indications for muscle biopsy and halothane-caffeine contracture testing?

• Definite indications: suspicious clinical history for MH, family history of MH, prior episode of masseter muscle rigidity (MMR).

• Possible indications: unexplained rhabdomyolysis during or after surgery, sudden perioperative cardiac arrest caused by hyperkalemia, mild to moderate MMR with evidence of rhabdomyolysis during surgery, exercise-induced hyperkalemia.

• Questionable indications: occurrence of neuroleptic malignant syndrome, sudden unexplained cardiac arrest during anesthesia or in the early postoperative period not associated with rhabdomyolysis.

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What is MMR, and what is its relation to MH?

MMR is defined as jaw muscle tightness and limb muscle flaccidity, following a dose of succinylcholine. There is a spectrum of masseter response, from a tight jaw to a rigid jaw to severe spasticity, or trismus, otherwise described as jaws of steel . Of concern, the mouth cannot be opened sufficiently to intubate in a patient with MMR. If jaws of steel are present, MH susceptibility is also likely to be present.

Note there is some controversy as to the management of patients experiencing MMR. Patients with masseter spasm should be closely monitored in the hospital for at least 24 hours. Creatine kinase (CK) levels should be checked every 6 hours. CK levels greater than 20,000 have a 95% predictive value that the patient is MH susceptible.

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