Evaluation of clinically relevant sevoflurane concentrations in the development of malignant hyperthermia in an Ryr1 mutant mouse model

Malignant hyperthermia (MH) is associated with mutations in the RYR1 gene; however, the effect of volatile anesthetic concentrations on the clinical symptoms of patients with MH is unknown. We investigated the effects of high concentrations of volatile anesthetics on MH development and progression. MH mouse models with R2509C mutation in Ryr1, all male, approximately 15 weeks old were administered 5%, 2.5% or 0.6% sevoflurane. The time at maximum temperature, maximum temperature, time at maximum heart rate, maximum heart rate, and time to asystole in the first experiment were measured. In the second experiment, blood samples were obtained from mice after the administration of 5% or 0.6% sevoflurane. In this experiment, the pH, base excess, and electrolyte and lactate levels were measured. Among the 16 mutant mice used, all showed elevation of heart rate and body temperature and went into asystole. The 0.6% group showed longer time at maximum temperature than the 5% group (68.0 [67.0, 72.0] min vs 43.5 [18.3, 47.8] min, p = 0.046); while, maximum temperature was higher in the 0.6% group than the other groups (40.2 [38.2, 40.8] °C in the 5% group, 42.4 [42.2, 42.6] °C in the 2.5% group, and 44.7 [43.6, 45.3] °C in the 0.6% group); maximum heart rate was lower in the 5% group (480 [465, 503] bpm in the 5% group, 630 [570, 630] bpm in the 2.5% group, and 630 [630, 660] bpm in the 0.6% group). In the second experiment, the 5% group showed lower base excess (-23.4 [-24.4, -22.3] mmol/L vs -5.3 [-7.2, -4.3] mmol/L, p = 0.043) and higher lactate levels than the 0.6% group (20.00 [19.90, 20.00] mmol/L vs 4.80 [4.35, 7.88] mmol/L, p = 0.022). Potassium was relatively higher in the 5% group than in the 0.6% group. When exposed to high concentrations of sevoflurane, MH developed and progressed rapidly; however, the maximum temperature was lower than that in cases of low-concentration exposure, likely due to the rapid progression of electrolyte abnormalities.