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Background and objective: The in vitro contracture test with halothane and caffeine is the current gold standard for diagnosis of malignant hyperthermia. This test has a sensitivity of 99.0% but a specificity of only 93.6%. Therefore, an alternative drug is desirable which distinguishes between malignant hyperthermia-susceptible and malignant hyperthermia-normal subjects with a higher specificity and sensitivity.
Methods: 4-chloro-3-ethylphenol has recently been shown to trigger Ca2+-induced Ca2+-release in skeletal muscle terminal cisternae and to increase the myoplasmic free Ca2+ concentration in skeletal muscle fibres. The purpose of this study was to investigate the ability of 4-chloro-3-ethylphenol to distinguish between malignant hyperthermia-susceptible and malignant hyperthermia-normal porcine muscle specimen in the in vitro contracture test. Ten malignant hyperthermia-susceptible and 14 malignant hyperthermia-normal swine were anaesthetized and muscle biopsies were taken. For the in vitro contracture test muscle specimens were exposed to cumulative concentrations of 4-chloro-3-ethylphenol (12.5 to 200 µmol L−1).
Results: 4-chloro-3-ethylphenol produced contractures in a concentration-dependent manner in the malignant hyperthermia-susceptible muscle bundles. In contrast, cumulative 4-chloro-3-ethylphenol did not generate contractures in malignant hyperthermia-normal specimens. Contractures were significantly greater (P < 0.05) in the malignant hyperthermia-susceptible compared to the malignant hyperthermia-normal preparations in all 4-chloro-3-ethylphenol concentration steps from 50 µmol L−1 to 200 µmol L−1. There was no overlap between the two groups above a concentration of 75 µmol L−1 in cumulative 4-chloro-3-ethylphenol in vitro contracture tests.
Conclusions: It remains to be verified whether an in vitro contracture test with 4-chloro-3-ethylphenol can also discriminate between malignant hyperthermia-susceptible and malignant hyperthermia-normal humans. Since no prior tested agent revealed a clear differentiation in contracture development without overlap, the 4-chloro-3-ethylphenol test might be a promising new approach to the diagnosis of malignant hyperthermia.
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