Risk-Stratifying Patients at an Increased Risk of Malignant Hyperthermia: Improving Safety by Expanding Beyond Classic Tenets

Abstract

Malignant hyperthermia (MH) is classically described as an autosomal dominant myopathy involving type 1 ryanodine receptor (RYR1), which predisposes affected individuals to potentially life-threatening sequela when exposed to volatile anesthetics or depolarizing skeletal muscle relaxants, such as succinylcholine. In cases where malignant hyperthermia or anesthetic induced rhabdomyolysis (AIR) is triggered, significant morbidity and often mortality can result. In an ambulatory anesthetic setting, family history of malignant hyperthermia and history of anesthetic-related events is typically utilized to screen out susceptible individuals. Furthermore, in cases where suspicion of increased risk for MH susceptibility is present, volatile agents and depolarizing muscle relaxants are avoided, per recommendations of Malignant Hyperthermia Association of US. However, MH phenotype has been found to be inherited with incomplete penetrance and variable expression. Investigations into the molecular genetics of MH have revealed over 400 different variants in the RYR1 gene, with fewer than 40 variants that have been functionally characterized. Exome studies have suggested that the incidence of RYR1 variants in general population is as high as 1 in 2000-3000 persons. These data suggest that potential for triggering malignant hyperthermia is much greater than previously estimated, even if a fulminant reaction is not encountered. Estimates based on genomic analysis call for increased index of suspicion in patient selection for ambulatory anesthesia, compelling for improved risk stratification, as well as improved level of preparedness to treat malignant hyperthermia. This is especially pertinent for providers that administer anesthesia to pediatric populations, as pediatric patients have been documented to exhibit MH/AIR response in the absence of volatile anesthetic exposure.