Exercise-induced malignant hyperthermia

Exercise-induced malignant hyperthermia is an extremely rare pharmacogenetic-related condition in which vigorous physical exercise triggers a malignant hyperthermia-like crisis. Malignant hyperthermia (MH) is classically associated with exposure to volatile anesthetic agents or depolarizing muscle relaxants, but in this variant, strenuous exercise and/or heat exposure can provoke a similar hypermetabolic response in skeletal muscle. The condition primarily affects the musculoskeletal system, with uncontrolled skeletal muscle metabolism leading to rapidly rising body temperature (hyperthermia), severe muscle rigidity, rhabdomyolysis (breakdown of muscle tissue), metabolic acidosis, tachycardia, and potentially life-threatening hyperkalemia. If untreated, the crisis can progress to multi-organ failure, disseminated intravascular coagulation, and death. The underlying pathophysiology involves dysregulation of calcium release from the sarcoplasmic reticulum in skeletal muscle cells. In most cases, pathogenic variants in the RYR1 gene (encoding the ryanodine receptor type 1) are implicated, though variants in CACNA1S and other genes associated with malignant hyperthermia susceptibility may also be involved. The condition is inherited in an autosomal dominant pattern with variable penetrance, meaning that not all individuals carrying a pathogenic variant will experience a crisis, and triggers may vary among affected family members. Management of an acute episode centers on immediate cooling measures, intravenous dantrolene sodium (which inhibits calcium release from the sarcoplasmic reticulum), and aggressive supportive care including correction of metabolic acidosis and hyperkalemia. Preventive strategies include avoidance of extreme physical exertion, particularly in hot and humid environments, adequate hydration, and awareness of early warning signs such as unexplained muscle cramps, dark urine, or unusual fatigue during exercise. Genetic counseling is recommended for affected individuals and their families, and susceptibility testing (including the caffeine-halothane contracture test and/or genetic testing) should be offered to at-risk relatives. All individuals identified as susceptible should carry medical alert identification and inform healthcare providers of their condition prior to any surgical procedure requiring anesthesia.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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