There were no clinically apparent differences between MH triggered by sevoflurane and isoflurane, and thus no evidence to support the postulate that sevoflurane is a weak or weaker MH triggering agent.
We investigated the transition of clinical signs of fulminant-type malignant hyperthermia (f-MH) by analyzing a database consisting of 383 cumulative cases of f-MH from 1961 to 2004. The cases were divided by time period into group 1 (1961-1984), group 2 (1985-1994), and group 3 (1995-2004). The variables considered were age, sex, type of agents used (succinylcholine and volatile anesthetics), dantrolene administration, clinical signs, laboratory data, and mortality. The level of statistical significance was considered to be less than 5%. Groups 1, 2, and 3 consisted of 196, 127, and 60 cases, respectively. In groups 1, 2, and 3, the rates of dantrolene administration were 18.4%, 93.6%, and 86.7%; the rates of occurrence of ventricular arrhythmia were: 75.2%, 55.6%, and 35.0%; and the rates of generalized muscle rigidity were 64.7%, 60.9%, and 23.9%, respectively. The mortality rate decreased over time, from 42.3% in group 1, to 15.0% in group 2 and group 3. We considered that this decrease occurred because of the increased use of dantrolene and the early diagnosis of malignant hyperthermia in the latter two groups.
Malignant hyperthermia is a pharmacogenetic skeletal muscle disorder of intracellular calcium (Ca 2+) homeostasis with an autosomal dominant inheritance. The objective of this study was to investigate the safety of propofol by investigating its effects on calcium homeostasis and its effect sites in human skeletal muscles. Muscle specimens were obtained from 10 individuals with predisposition to malignant hyperthermia. In skinned fibre experiments, we measured the effects of propofol on the Ca 2+-induced Ca 2+ release and the uptake of Ca 2+ into the sarcoplasmic reticulum. Ca 2+ imaging in primary myotubes was employed to analyse propofol-mediated alternations in the Ca 2+ regulation and propofol-induced Ca 2+ responses in the presence of Ca 2+ channel blocker or Ca 2+-induced Ca 2+ release inhibitor. Increased Ca 2+ release from the sarcoplasmic reticulum and inhibition of Ca 2+ uptake into the sarcoplasmic reticulum were not observed with 100 μM propofol. A rise of Ca 2+ was not seen under 100 μM propofol and the EC 50 value for propofol was 274.7±33.9 μM, which is higher than the clinical levels for anaesthesia. Propofolinduced Ca 2+ responses were remarkably attenuated in the presence of Ca 2+ channel blocker or Ca 2+-induced Ca 2+ release inhibitor compared with the results obtained with caffeine. We conclude firstly that propofol is safe for individuals with predisposition to malignant hyperthermia when it is used within the recommended clinical dosage range, and secondly that its mode of action upon ryanodine receptors is likely to be different from that of caffeine.
Malignant hyperthermia is a pharmacogenetic disorder caused by autosomal dominant mutations in the ryanodine receptor type 1 gene. Propofol has been reported as a safe anaesthetic for malignant hyperthermia susceptible patients but has not been tested on cultured cells from patients with the ryanodine receptor type 1 mutation. The aim of this study was to determine whether propofol could trigger abnormal calcium fluxes in human myotubes isolated from malignant hyperthermia susceptible patients harbouring the native ryanodine receptor type 1 mutation. Muscle specimens were obtained from the patients to diagnose malignant hyperthermia disposition and the calcium-induced calcium release test and molecular genetic analyses were performed. Using the calcium sensitive probe Fura 2, we determined the 340/380 nm wavelength ratios by measuring alterations in calcium homeostasis in isolated myotubes from cultured skeletal muscle specimens. Two patients, one with ryanodine receptor type 1 R2508C and one with the L4838V mutation had accelerated calcium-induced calcium release rates. The 340/380 nm ratios increased when the propofol concentration exceeded 100 µM. The half-maximal activation concentrations (EC 50) for propofol from patients 1 and 2 were 181.1 and 420.5 µM, respectively. Increases in calcium concentrations in response to propofol dosage were limited to doses at least 100-fold greater than those used in clinical settings. These observations correlate well with clinical observations that propofol does not trigger malignant hyperthermia in susceptible humans.
We demonstrated that the transfected RYR1 mutant was more sensitive to caffeine and 4CmC than wildtype RYR1. These findings suggest that the p.R2508C mutation may be pathogenetic for susceptibility to MH.
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