History

In 1960, Denborough and Lovell reported the first case of anesthesia-induced hypermetabolism in a patient with a familial history of multiple anesthetic deaths during ether administration. The patient survived a halothane-induced malignant hyperthermia (MH) episode. In 1969, Kalow and Britt described a metabolic error of skeletal muscle metabolism in patients who had recovered from MH episodes. This finding formed the scientific basis for modern diagnostic contracture testing. In 1975, Harrison reported the efficacy of dantrolene in treating porcine MH, a treatment that, used in humans, has lowered the mortality rate associated with this rare problem from as high as 80% to below 10%.

Incidence and mortality

The incidence of MH reportedly ranges from 1:4500 to 1:60,000 general anesthetics (geographic variation is related to the gene prevalence). Approximately 50% of MH-susceptible (MHS) individuals have had a previous triggering anesthetic without developing MH symptoms. MH is rare in infants, and the incidence decreases after age 50 years, with the highest prevalence of clinical symptoms in males. The reasons for these variations are not understood.

MH has been clearly associated with central core and multi-minicore disease. MH-like symptoms have been associated with other neuromuscular disorders, such as Duchenne muscular dystrophy, although morbidity and mortality are likely to be related to rhabdomyolysis after receiving succinylcholine rather than true MH. The use of nontriggering anesthesia is recommended for these patients. Association with other conditions such as myotonia, sudden infant death syndrome, neuroleptic malignant syndrome, and exercise-induced death in adults is controversial.

Genetics

MH has an autosomal dominant pattern of inheritance, with clinical heterogeneity and variable expression. A single-gene mutation responsible for MH has been identified in a swine model of MH (ryanodine receptor). The ryanodine receptor is a protein that comprises the calcium-release channel in the skeletal muscle sarcoplasmic reticulum, a site shown to be defective in MHS swine.

Unfortunately, human MH is far more complicated genetically. The ryanodine gene (RYR1) (MHS1 locus) encodes the type 1 ryanodine receptor. Mutations in this gene can be identified in 70% to 80% of MHS individuals or people with central core disease. More than 90 mutations have been identified, with more than half of the mutations having been identified in only one family or a few families. The other known MH gene is the CACMA1S (MHS5 locus), which encodes the subunit of the dihydropyridine receptor L-type calcium channel. The two identified mutations in this gene account for only about 1% of all MHS. Three additional loci have been mapped (MHS2, MHS4, and MHS6), but the genes have not been identified. The rate of spontaneous mutation is unknown but is probably less than 10% of all cases of MH.

Appropriate patient selection for genetic testing is very important. In a patient with a positive caffeine-halothane muscle biopsy or very strong family history of unequivocal MH, complete sequence analysis of RYR1 coding results in a 70% to 80% rate of detection. In the case of a multigenerational family (two or more) with unequivocal MH in at least 10 members, linkage analysis for all MHS loci can be performed, and new sites can be detected. However, screening of a single individual with a new diagnosis of clinical MH against the common RYR1 sites will be positive in only 20% to 30% of cases. Thus, a single preoperative genetic screening test in humans is unlikely to be available in the near future.

Clinical presentation

The onset of clinical signs can be acute and fulminant or delayed. MH can occur at any time during the anesthetic administration and has been reported to occur as late as 24 h postoperatively.

Trismus (masseter muscle spasm) following inhalation induction and administration of succinylcholine is associated with an approximately 50% incidence of MH diagnosed by contracture testing. Trismus, rarely seen now due to the avoidance of succinylcholine in children undergoing anesthesia, is often not associated with signs of a fulminant MH episode; however, patients must be closely observed for evidence of hypermetabolism as well as rhabdomyolysis. The presence of whole-body rigidity or signs of hypermetabolism following trismus increases the risk of MH susceptibility as a cause, as does a peak creatine phosphokinase level exceeding 25,000 IU/L postoperatively.

Clinical signs and symptoms reflect a state of highly increased metabolism. The onset of hyperthermia is often delayed (Table 245-1). The earliest signs of MH include increased end-tidal CO₂ levels, tachycardia, and tachypnea (in an unparalyzed patient). The results of laboratory tests can be used to support a diagnosis of MH (Table 245-2).

Succinylcholine and all inhalation anesthetic agents are triggers for MH, with the newer short-acting inhalation agents being less likely to trigger MH, as compared with halothane and other longer-acting agents. Potassium is unlikely to cause MH; however, the administration of potassium has been reported to have caused retriggering in a patient treated for MH. Safe anesthetic agents include nitrous oxide, etomidate, ketamine, propofol, all opioids, all local anesthetics, all barbiturates, and all nondepolarizing neuromuscular blocking agents. Drugs used for reversal of neuromuscular blockade are also safe.

Mechanism

Exposure to triggering anesthetic agents causes decreased control of intracellular calcium, resulting in release of free unbound ionized Ca²⁺ from storage sites. The calcium pumps attempt to restore homeostasis, which results in adenosine triphosphate (ATP) utilization, increased aerobic and anaerobic metabolism, and a runaway metabolic state. Rigidity occurs when unbound myofibrillar Ca²⁺ approaches the contractile threshold.

Treatment of malignant hyperthermia crisis

The treatment of MH begins with immediate discontinuation of triggering agents and hyperventilation of the patient with 100% O₂. Dantrolene (2 mg/kg) should be intravenously administered early and rapidly when MH is suspected; the dose should be repeated every 5 min to effect or to a maximum of 10 mg/kg (this limit may be exceeded if necessary). After the initial signs of MH have been successfully treated, dantrolene should continue to be intravenously administered at a rate of 1 mg/kg every 6 h for 24 to 48 h to prevent recrudescence of symptoms. Calcium channel blockers should not be concomitantly administered with dantrolene because myocardial depression has been demonstrated with this combination in swine. Treatment efficacy is monitored with arterial blood gases, serum creatine phosphokinase concentrations, and vital signs. Dantrolene has unpleasant side effects (nausea, malaise, muscle weakness) but is generally well tolerated and has minimal toxicity in intravenously administered doses for the treatment of MH.

Symptomatic treatment includes, as appropriate, cooling (taking care to avoid hypothermia); the use of antiarrhythmic agents, diuretics such as mannitol and furosemide (although these drugs are rarely needed because of the mannitol in dantrolene), and sodium bicarbonate; and the management of hyperkalemia with insulin and glucose.

Anesthesia for patients with malignant hyperthermia susceptibility

Pretreatment with dantrolene is not recommended who have MHS. Nontriggering anesthetic agents should be used, and the anesthesia machine should be prepared by removing vaporizers (if possible), replacing hoses, and flushing the system with high-flow air or O₂ (10 L/min). The Malignant Hyperthermia Association of the United States (MHAUS) recommends that older anesthesia machines be flushed for a minimum of 20 min and no longer recommends that the soda lime canister be changed. For some newer anesthesia machines (e.g., Dräger Fabius), MHAUS recommends flushing for a minimum of 60 min. This time can be decreased if the integrated breathing system and diaphragm are replaced with autoclaved components. Because of the large number of newer anesthesia delivery systems on the market, MHAUS recommends following the manufacturer’s guidelines to determine the appropriate washout procedure.

Monitoring should include all standard monitors with an emphasis on monitoring end-tidal CO₂, O₂ saturation by pulse oximetry, and core temperature (skin monitors may not reflect core changes). Arterial and central venous pressures should be monitored only if indicated by the surgical procedure or the patient’s medical condition.

Evaluation of the patient with malignant hyperthermia susceptibility

Patients are referred for evaluation of MH susceptibility for a number of reasons (Box 245-1). A serum creatine phosphokinase level is often obtained in patients who are thought to be MHS. This value is elevated in approximately 70% of affected individuals; therefore, the results may be inconclusive.

The muscle biopsy contracture test is the only reliable diagnostic test for MH. Muscle is tested with caffeine and halothane alone, or in combination, and contracture responses are measured. This test has been standardized in European and North American laboratories. Genetic testing is helpful in an unequivocal case of clinical MH, in biopsy-proven cases, and in families in which a genetic mutation has been identified.

Source for further assistance

MHAUS is a lay organization with a medical MH expert advisory group that provides support for patients and anesthesia providers. It publishes books, pamphlets, and a quarterly newsletter at nominal costs; sponsors a website (mhaus.org); and manages a 24-h hotline (1-800-MHHYPER) to provide assistance to anesthesia providers managing MHS patients or treating patients with acute MH episodes.