Malignant hypothermia is a potentially lethal, rare, pharmacogenetic skeletal muscle disorder characterized by a hypermetabolic reaction in response to all volatile anesthetics and depolarizing muscle relaxants. Patients display no signs or symptoms under normal conditions, although they may be associated with a subclinical myopathy. However, under the effect of an anesthetic, severe muscle contraction, and a rapid rise in body temperature, up to 40.5 degrees Celsius, is observed. Consumption of oxygen and production of carbon dioxide is increased, and so is the activity of the sympathetic nervous system. Other symptoms include, sore muscles, tachycardia, hypertension, cyanosis, metabolic acidosis, myogobinuria, and breakdown of muscle fiber (rhabdomyolysis). The latter symptom is especially dangerous, since the degraded muscle fibers tend to move into circulation, and block the structures of the kidney, causing kidney failure, evidenced by dark brown urine.
The patient's clinical signs under administration of anesthesia are enough to diagnose malignant hyperthermia. Additionally, the patient also shows elevated levels of creatinine phosphokinase, potassium, uric acid, and phosphate in the blood, and myoglobin in the urine. To test for susceptibility to MH, a Halothane caffeine test may be undertaken. This test can be especially useful for patients with a family history of MH or unexplained death during anesthesia, and are planning to undergo surgery themselves. The test involves placing a small muscle strip of the patient in a solution containing an anesthetic and monitoring for force of contraction. Moreover, genetic susceptibility tests that analyze the ryanodine receptor (RYR1) gene are also available for patients at risk. Once a susceptibility status is confirmed, the best strategy would be to avoid generalized anesthesia during surgery. In cases where hyperthermia has set in, antipyretic medications may be given to bring down the fever, in addition to medications to maintain kidney function.
World incidence data for malignant hypothermia are not available. However, a recent survey in Canada estimated that the disease occurs in 1 in every 14,000 live births.
MH has been shown to be transmitted in an autosomal dominant fashion. At least five different genetic loci have been implicated in the manifestation of this disease, of which the gene most commonly seen to be mutated, and the best characterized is the Ryanodine Receptor 1 gene (RYR1) on chromosome 19. The ryanodine receptor protein, seen on the sarcoplasmic reticulum (SR) of muscle cells, is responsible for enabling muscle contraction by releasing calcium from the SR. In MH, defects in the RYR1 gene diasble the closing mechanism of the receptor protein, leading to excessive release of calcium ions. Large amount of energy is wasted (and heat produced) in getting these calcium ions back into the SR. The muscle damage occurs principally due to the depletion in energy.