Advances in malignant hyperthermia: pathophysiology, diagnosis and management

Abstract

Malignant hyperthermia (MH) is a rare genetic disorder triggered by volatile anaesthestics and depolarizing muscle relaxants like sevoflurane, desflurane, and succinylcholine. It is mainly associated with pathogenic variants in the RYR1 and CACNA1S genes that disrupt calcium regulation in skeletal muscles, causing uncontrolled calcium release from the sarcoplasmic reticulum and a hypermetabolic crisis with rhabdomyolysis, muscle rigidity, hypercapnia, hyperthermia, and multiorgan failure. Since its first clinical description in the 1960s, clinical signs such as tachycardia, rising end-tidal CO₂ (ETCO₂), and sudden hyperthermia remain essential for detection. Diagnosis relies on invasive muscle contracture tests like the Caffeine-Halothane contracture test (CHCT) and in vitro contracture test (IVCT). Next-generation sequencing (NGS) identifies mutations in RYR1, CACNA1S, and related excitation–contraction coupling genes. Despite incomplete genotype-phenotype correlations, mechanisms including oxidative stress and sodium-calcium channel dysregulation improve understanding of MH susceptibility. Management requires immediate cessation of triggering agents, intravenous dantrolene, and supportive care including cooling, correction of acidosis, electrolyte control, and monitoring of cardiac and renal complications. Patients should be monitored for recurrence within 24 hours and receive genetic counselling, medical alert identification, and family screening due to autosomal dominant inheritance. Emerging research explores CRISPR/Cas9 correction of RYR1 mutations, antisense oligonucleotide therapy to suppress mutant transcripts, and antioxidants N-acetylcysteine and Trolox to reduce reactive oxygen species-mediated muscle injury; animal studies show improved calcium regulation but human trials are needed. Preventive measures include temperature and ETCO₂ monitoring, regional anaesthesia in obstetrics, and total intravenous anaesthesia, when necessary, supported by collaboration among anaesthesiologists, geneticists, intensivists, and surgeons.