Pathophysiology of acute malignant hyperthermia

Exposure of an individual who has a genetic susceptibility (ryanodine receptor [RYR1] or dihydropyridine receptor [DHP] mutation) to an anesthetic triggering agent (ie, volatile inhalational anesthetic agent, succinylcholine, or both) may result in malignant hyperthermia. This reaction is caused by an altered calcium balance between the lumen of the sarcoplasmic reticulum (SR) and the sarcoplasm. Normally, muscle cell depolarization is sensed by the DHP receptor, which is thought to signal RYR1 opening by a direct physical connection. In malignant hyperthermia, accumulation of abnormally high levels of calcium in the sarcoplasm causes uncontrolled anaerobic and aerobic metabolism and sustained muscle cell contraction. This results in the clinical manifestations of respiratory acidosis, metabolic acidosis, muscle rigidity, and hyperthermia. If the process continues unabated, adenosine triphosphate (ATP) depletion eventually causes widespread muscle fiber hypoxia (cell death, rhabdomyolysis), which manifests clinically as hyperkalemia and myoglobinuria and an increase in creatine kinase. Dantrolene sodium binds to RYR1, causing it to favor the closed state, thereby reversing the uninhibited flow of calcium into the sarcoplasm.