Humidity impacts volatile anesthetic and heat responses of malignant hyperthermia susceptible mice

Malignant Hyperthermia (MH) is characterized by life-threatening whole-body hyperthermic reactions triggered by volatile anesthetics in susceptible individuals. MH susceptibility (MHS) and exertional heat stroke (EHS) are linked to mutations in the type I ryanodine receptor (RYR1). However, the discordance between the estimated prevalence of RYR1 MHS mutations in the general population (1:625-1,075) and the occurrence of MH episodes during anesthesia (1:100,000) suggests additional factors beyond genetics.

Using an established MHS mouse model (Y524S or YS mice), 10-12-week-old WT and YS mice were exercised on a treadmill (20° incline, 15 m/min, 60 min) and/or exposed to heat (15 min at 37℃) or 2% isoflurane either in a low or high humid environment. A second cohort of 10-12-week-old WT and YS mice were exposed to 2% isoflurane under a low or high humid environment. Vehicle or dantrolene (4 mg/kg) was administered during isoflurane exposure once the rectal temperature reached 39℃. Rectal temperature was continuously monitored under all conditions. In addition, historical humidity and temperature data were collected from dates on which MHS individuals either experienced or did not experience a defined MH episode.

In young, but not older, YS male mice, survival rates significantly decreased during heat challenge (HR Dry/Humid = 0.1621, P = 0.018) and isoflurane exposure in a humid environment (HR Dry/Humid = 0.2273, P = 0.035). Dantrolene improved survival (HR DMSO/Dantrolene ranging from 4.959 to 8.667 in all conditions) and slowed the rate of core temperature increase in young YS mice regardless of humidity. Humidity was similarly associated with increased MH occurrence (AUC = 0.8104, P = 0.0026) in male MHS patients.

Absolute humidity was associated with worsened outcomes during heat and isoflurane exposure in male MHS mice and an increase in MH occurrence in male MHS patients. These results support maintaining humidity levels within operating suites at lower levels of current guidelines, especially where dantrolene is not available.