DOI: 10.1213/ane.0000000000008333 ISSN: 0003-2999

Influence of Hypothermia on Triggering of Malignant Hyperthermia in a Mouse Model Expressing Type I Ryanodine Receptor-p.R2509C

Tsuyoshi Ikeda, Keiko Mukaida, Kenshiro Kido, Guoqiang Xia, Tomomi Ishii, Ayako Sumii, Yuko Noda, Sachiko Otsuki, Koji Ikegami, Yusuke Sotomaru, Satoru Noguchi, Toshimichi Yasuda, Yasuo M. Tsutsumi, Hirotsugu Miyoshi
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BACKGROUND:

Although hyperthermia exacerbates the pathophysiology of malignant hyperthermia (MH), the response to hypothermia remains poorly understood. MH susceptible-swine studies suggested that hypothermia prevents MH, yet clinical cases occur during hypothermic cardiopulmonary bypass. This study aimed to elucidate whether hypothermia inhibits the MH trigger or merely decelerates the progression of the lethal metabolic cascade.

METHODS:

Pharmacological sensitivity of type 1 ryanodine receptor was evaluated in myotubes from heterozygous p.R2509C knock-in mice and wild-type (WT) mice by measuring the half-maximal effective concentration of caffeine at 30 °C and 40 °C. Intracellular calcium dynamics were also assessed during temperature changes. In vivo, anesthetized male and female mice were exposed to 2.5% sevoflurane at rectal temperatures of 34 °C or 36 °C. Survival time, heart rate, arterial blood gas analysis, and muscle ultrastructure were compared.

RESULTS:

Compared with WT myotubes, R2509C myotubes showed a leftward shift in the caffeine dose–response curve and a lower half-maximal effective concentration at both 30 °C (estimated treatment effects = 2.0 mM, 95% confidence interval [CI], 0.5–3.6 mM, P = .020) and 40 °C (estimated treatment effects = 2.1 mM, 95% CI, 0.5–3.7 mM, P = .029). Cooling myotubes from 36 °C to 34 °C significantly reduced relative intracellular Ca 2 + fluorescence in R2509C myotubes. In vivo, all mutant mice developed MH and went into cardiac arrest regardless of temperature. Survival time was significantly longer at 34 °C compared to 36 °C (mean difference = 45.0 minutes, 95% CI, 20.9–69.1 minutes, P = .002). Typical signs such as tachycardia were absent at 34 °C. Despite masked clinical signs, progressive hypercapnia, metabolic acidosis, hyperkalemia, and characteristic mitochondrial swelling occurred in hypothermia.

CONCLUSIONS:

Hypothermia decelerates the clinical progression of MH but does not prevent triggering or lethality in mouse models. The caffeine-hypersensitivity of R2509C myotubes was detectable even under the lower-temperature assay condition. Mitochondrial swelling was identified as an ultra-early pathological change, suggesting that muscle damage is not solely driven by thermal injury. Clinicians should be aware that hypothermia may mask tachycardia and body temperature elevation, leaving hypercapnia and acidosis as critical early indicators.

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