Malignant Hyperthermia

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Malignant hyperthermia is a rare but potentially life-threatening genetically-inherited condition in which severe autonomic instability is induced by exposure to various anesthetics. The most common offending agents are halothane (and any other halogenated anesthetic compound) and succinylcholine, and usually the manifestations of fever, hypertension, tachycardia, muscle rigidity, and hypercapnia occur within an hour of anesthetic exposure. Its relevance to nephrologists is that (a) rhabdomyolysis-induced renal failure may result as a consequence, and (b) the pathophysiology is mediated by the electrolyte calcium.
In most cases, malignant hyperthermia is inherited in an autosomal dominant fashion due to mutations in the ryanodine receptor. This is a calcium channel found within the sarcoplasmic reticulum of of muscle cells which, when activated, leads to enhanced intracellular calcium release into the cytoplasm. The end result of all the reported mutations in the ryanodine receptor is to lower the activation threshold and increase the deactivation threshold of the channel–thereby leading to unregulated intracellular calcium release. The process of recompartmentalizing the excess intracellular Ca is a process which is highly ATP-dependent, and the depletion of ATP from myocytes leads to muscle cell damage, leaking myoglobin (as well as K, PO4, and CK) into the circulation.
The condition is diagnosed on clinical grounds, but screening may be warranted in an individual who will require general anesthesia who has an affected family member. Screening can take the form of either sequencing the full ryanodine receptor gene, or by performing something called the “caffeine-halothane contracture test”, in which a muscle biopsy is taken and then bathed in solutions of caffeine or halothane, and observing the muscle contraction response.
Treatment of malignant hyperthermia, aside from supportive care, requires the use of dantrolene–a muscle relaxant which inhibits the ryanodine receptor and prevents the increase in intracellular calcium. The introduction of dantrolene has dramatically reduced the mortality of malignant hyperthermia from over 80% in the 1960s to less than 10%.

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