Malignant hyperthermia

Published on 07/02/2015 by admin

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Last modified 07/02/2015

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Malignant hyperthermia

Denise J. Wedel, MD

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).

Table 245-1

Clinical Signs of Malignant Hyperthermia

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