Using DNA Techniques for Detecting Susceptibility of Malignant Hyperthermia

Abstract

Malignant Hyperthermia (MH) is a pharmacogenetic clinical syndrome that in its classic form is one of the most devastating anesthesia related complications. It occurs during anesthesia with a volatile halogenated alkane such as halothane and/or the administration of the depolarizing muscle relaxant succinylcholine. MH is truly an example of the interaction of genes and the environment. At the physiological and biochemical level, MH predisposes susceptible individuals to an acute increase in cytosolic Ca2+ during general anesthesia with volatile anesthetics or depolarizing muscle relaxants. In addition, several studies suggest that MH susceptibility is commonly associated with increased resting cytosolic Ca2+. Mutations have been identified in MH-susceptible (MHS) individuals in two key proteins of EC coupling, the Ca2+ release channel of the SR, ryanodine receptor type 1 (RyR1) and the α1 subunit of the dihydropyridine receptor causing dysregulation of EC coupling. This dysfunctional Ca2+ release causes increase in the intracellular myoplasmic calcium which leads to increase in the activity of pumps and exchangers trying to correct the increase in sarcoplasmic Ca2+ increases the need for ATP. All of these events leads to muscle contracture especially of the masseter, with generalized rigidity, and heat production. Hypermetabolism associated to the sarcoplasmic calcium elevation causing tachycardia which may be observed as an early sign along with the masseter rigid contraction. This hypercatabolic state leads to ATP depletion, high oxygen consumption and carbon dioxide production resulting in hypoxemia and hypercapnia. The current treatment of choice is the intravenous administration of dantrolene, the only known antidote. Dantrolene is a muscle relaxant that appears to work directly on the ryanodine receptor to prevent the release of calcium. After the widespread introduction of treatment with dantrolene, the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 5%. Dantrolene should be given as 2.5 mg/kg rapidly through large-bore IV, if possible. This may be repeated as frequently as needed until the patient responds with a decrease in ETCO2, decreased muscle rigidity, and/or lowered heart rate. Large doses (>10mg/kg) may be required for patients with persistent contractures or rigidity. Discontinuation of triggering agents is a must, and supportive