Malignant hyperthermia
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Malignant hyperthermia (MH or MHS for "malignant hyperthermia syndrome") is a life-threatening condition resulting from a genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs that occurs during or after anaesthesia. It is related to, but distinct from, the neuroleptic malignant syndrome.
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Signs, symptoms and diagnosis
The phenomenon presents with muscular rigidity, followed by a hypermetabolic state showing increased oxygen consumption, increased carbon dioxide production, and increased temperature (hyperthermia), proceeding to rhabdomyolysis with rapid rising of blood levels of myoglobin, creatine kinase (CK/CPK) and potassium.
Halothane, a rarely used volatile anaesthetic, has been linked to a large proportion of cases, however, all volatile anesthetics are potential triggers of malignant hyperthermia. MH does not occur with every exposure to triggering agents, and susceptible patients may undergo multiple uneventful episodes of anesthesia before developing an episode of MH. The symptoms usually develop within one hour after anesthesia.
Diagnosis
The diagnosis of MH is by muscle biopsy done at an approved center under local anesthesia. The fresh biopsy is bathed in a solution containing caffeine and halothane (the "caffeine-halothane contracture test", CHCT) and observed for contraction; under good conditions, the sensitivity is 97% and the specificity 78% (Allen et al 1998). Negative biopsies are not definitive, so any patient who is suspected to have MH by history is generally treated with non-triggering anesthetics even if the biopsy was negative. Some researchers advocate the use of the "calcium-induced calcium release" test in addition to the CHCT to make the test more specific.
Pathophysiology
Disease mechanism
Malignant hyperthermia is caused in a large proportion (al least 50%) of cases by a mutation the ryanodine receptor on sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium (Gillard et al 1991). In normal muscle, the receptor releases small amounts of calcium when triggered, which is then reabsorbed into the SR for the next cycle of contraction. In MH, the receptor does not close properly after having opened in response to a stimulus. The result is excessive release of calcium, which is reabsorbed into the SR in a futile cycle; this process consumes large amounts of ATP (adenosine triphosphate), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including potassium, myoglobin, creatine and creatine kinase.
Animal model
Research into malignant hyperthermia was limited until the discovery of "porcine stress syndrome" in pigs, a condition in which stressed pigs develop "pale, soft, exudative" flesh (a manifestation of the effects of malignant hyperthermia) rendering their meat unmarketable at slaughter. This "awake triggering" was not observed in humans, and initially cast doubts on the value of the animal model, but subsequently susceptible humans were discovered to "awake trigger" (develop malignant hyperthermia) in stressful situations. This supported the use of the pig model for research. Pig farmers use halothane cones in swine yards to expose piglets to halothane. Those that die were MH-susceptible, thus saving the farmer the expense of raising a pig whose meat he would not be able to market.
Gillard et al discovered the causative mutation in humans only after similar mutations had first been described in pigs.
Genetics
About 30 mutations in the ryanodine receptor have been described, which are transmitted in an autosomal dominant fashion. The gene is located on the long arm of the nineteenth chromosome (19q13.1). Various other genes have been implicated, but the majority of cases is associated with ryanodine receptor mutations.
Epidemiology
The incidence has been reported to be between 1:4,500 to 1:60,000 procedures involving general anaesthesia. This disorder occurs worldwide and affects all racial groups. Most cases however occur in children and young adults, which might be related to the fact that many older people will have already had surgeries and thus would know about and be able to avoid this condition.
Treatment
Dantrolene is a muscle relaxant that works directly on the ryanodine receptor to prevent the release of calcium. Pretreatment with dantrolene has been advocated in the past to prevent MH, but this is probably unreliable, and the long half-life of the drug may leave patients weak for extended periods. The only sure way to prevent MH is avoid the use of triggering agents in patients known or suspected of being suseptable to MH.
After the widespread introduction of treatment with dantrolene the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%.
The substance azumolene, chemically related to dantrolene, is under investigation for use in MH.
History
The syndrome was first recognised in one affected family by Denborough et al in 1962.
References
- Allen GC, Larach MG, Kunselman AR. The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry. Anesthesiology 1998;88:579-88. PMID 9523799.
- Denborough MA, Forster JF, Lovell RR, Maplestone PA, Villiers JD. Anaesthetic deaths in a family. Br J Anaesth 1962;34:395-6. PMID 13885389.
- Gillard EF, Otsu K, Fujii J, Khanna VK, de Leon S, Derdemezi J, Britt BA, Duff CL, Worton RG, MacLennan DH. A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics 1991;11:751-5. PMID 1774074.