Malignant Hyperthermia

Malignant hyperthermia (MH) is a life-threatening clinical syndrome of hypermetabolism involving the skeletal muscle. It is triggered in susceptible individuals primarily by the volatile inhalational anesthetic agents and the muscle relaxant succinylcholine, though other drugs have also been implicated as potential triggers. ^[1] MH is not an allergy but an inherited disorder that is found both in humans and in swine.

In persons susceptible to MH, the ryanodine receptor in skeletal muscle is abnormal, ^[2] and this abnormality interferes with regulation of calcium in the muscle. An abnormal ryanodine receptor that controls calcium release causes a buildup of calcium in skeletal muscle, resulting in a massive metabolic reaction.

This hypermetabolism causes increased carbon dioxide production, metabolic and respiratory acidosis, accelerated oxygen consumption, heat production, activation of the sympathetic nervous system, hyperkalemia, disseminated intravascular coagulation (DIC), and multiple organ dysfunction and failure. Early clinical signs of MH include an increase in end-tidal carbon dioxide (even with increasing minute ventilation), tachycardia, muscle rigidity, tachypnea, and hyperkalemia. Later signs include fever, myoglobinuria, and multiple organ failure.

Anesthetics are inconsistent in triggering MH. A susceptible individual may undergo anesthesia with MH-triggering agents on multiple occasions without incident but may still react to such agents on a subsequent occasion. A history of uneventful anesthesia with MH-triggering agents does not rule out susceptibility to MH. In fact, there are reports of MH episodes occurring even with the use of supposedly safe agents.

More than 30 mutations account for human MH. ^[3] Genetic testing is available to establish a diagnosis, but the caffeine halothane contracture test (CHCT) remains the criterion standard. Dantrolene, the antidote, decreases the loss of calcium from the sarcoplasmic reticulum in the skeletal muscle and restores normal metabolism. ^{[4, 5]} Early detection and treatment improve the outcome.

MH is a subclinical myopathy that allows large quantities of calcium to be released from the sarcoplasmic reticulum (SR) of skeletal muscle and cause a hypermetabolic state after exposure to triggering agents. Altered calcium channel gating kinetics in the SR is the underlying cause. The sustained elevation of calcium allows excessive stimulation of aerobic and anaerobic glycolytic metabolism, which accounts for respiratory and metabolic acidosis, rigidity, altered cell permeability, and hyperkalemia.

Arterial carbon dioxide tension (PaCO₂) may exceed 100 mm Hg, and pH may drop below 7. The earliest sign is increased end-tidal carbon dioxide. A threefold increase in oxygen consumption and a 15- to 20-fold increase in blood lactate can be seen. Tachycardia, dysrhythmias, and a sympathetic catecholamine surge occur. The hypermetabolism evokes a massive exothermic response, leading to extreme temperature elevation. Rhabdomyolysis leads to increased levels of potassium, myoglobin, and creatine kinase, as well as edema formation.

The elevated myoglobin may damage the kidneys. Without adequate treatment, the process may progress to multiple organ failure and death. Dantrolene inhibits the release of calcium from the SR and reverses the process. Calcium-channel blockers are associated with hyperkalemia if used in conjunction with dantrolene and are not recommended.

The large ischemic demands imposed by the hypermetabolic state prevailing during acute MH can severely impair myocardial function. The extreme temperature elevation, hyperkalemia, acidosis, and cerebral edema can affect the central nervous system (CNS), causing coma, areflexia, and dilated pupils. Activation of the sympathetic nervous system occurs early.

DIC can occur as a consequence of the release of tissue thromboplastin. Pulmonary changes are secondary to systemic effects. Eventually, metabolic exhaustion ensues, leading to increased cellular permeability, whole-body edema, compartment syndrome in the extremities, cerebral edema, and death.

MH is inherited as an autosomal dominant trait with reduced penetrance. It is associated with mutations in two genes: RYR1, which encodes the skeletal muscle isoform of the calcium-release channel of the sarcoplasmic reticulum (ryanodine receptor type 1 [RYR-1]), ^[6] and CACNA1S, which encodes the alpha subunit of the L-type calcium channel isoform of the sarcolemma (dihydropyridine receptor). An aberrant termination of RYR-1 activity is found in MH-susceptible persons.

RYR1 is located on chromosome 19. Mutations in this gene occur in at least 50% of persons with MH and all families of central core disease. More than 30 mutations and one deletion are associated with a positive CHCT, a clinical MH episode, or both. CHCT is the criterion standard for establishing the diagnosis of MH.

Muscle biopsy for MH is done at five sites in North America; the patient must travel to the testing center to have the biopsy performed. Genetic DNA testing can be done with a blood sample sent to one of the four testing sites.

The reported frequency of MH in the United States ranges from 1 in 10,000 patients receiving anesthetics to 1 in 50,000; the reported frequency in children is higher. The true incidence of MH has not been established with precision, because of a lack of universal reporting in the United States. In addition, many MH-susceptible persons have not been exposed to the triggering agents. The annual number of suspected MH cases per year in the United States is around 700.

Larach et al reported that in 291 MH episodes recorded in the North American Malignant Hyperthermia Registry database between 1987 and 2006, there were eight cardiac arrests and four deaths, and the median age of patients experiencing cardiac arrest or death was 20 years. ^[7]

If an MH reaction is treated early in the process, complete recovery can be expected. Multiple organ failure and death can occur, however, and one or two deaths are reported to the MH hotline each year. Before the approval of dantrolene by the US Food and Drug Administration (FDA) in the late 1970s for use in the treatment of MH, the mortality of an acute MH reaction was greater than 70%. Currently, the mortality of acute MH is less than 5%.

In 1981, family members of patients who had died of MH founded the Malignant Hyperthermia Association of the United States (MHAUS) to provide information to the lay public and health care workers about MH and to support research and education. In 1982, MHAUS started an around-the-clock hotline to answer questions about MH and to give guidance concerning treatment of acute cases. A North American registry keeps reports of acute MH cases for research purposes. All hotline reports are reviewed.

The telephone number for the MHAUS hotline is (800) MH-HYPER or (800) 644-9737. The MHAUS Web site at www.mhaus.org can be used for information and protocols.