A multicenter study of 4-chloro-m-cresol for diagnosing malignant hyperthermia susceptibility

Standardization of the in vitro contracture test (IVCT) for malignant hyper thermia (MH) susceptibility has resulted in very rare false negative tests. However, false positive results stigmatizing the patient seem to be more f requent than false negative results and make supplementary tests desirable. This multicenter approach studied the usefulness of an IVCT with 4-chloro- m-cresol (4-CmC), a ryanodine receptor-specific agonist for a better defini tion of MH susceptibility. Diagnosis made by the standard IVCT was compared with the results of this 4-CmC test on muscle specimens of 202 individuals from 6 European MH centers. In the 4-CmC test, the results of the MH susce ptible group differed significantly from both the MH normal and the MH equi vocal group. 4-CmC revealed a qualitatively dose response-curve similar to caffeine. A correlation index of r = 0.79 for the concentration thresholds underlined the strong concordance of the caffeine and the 4-CmC effects. Th e optimal threshold concentration was determined to be 75 mu M in the poole d data of all centers and is much lower than that of caffeine (2 mM), sugge sting a more than 25-fold higher affinity of 4-CmC. The predictive value of 4-CmC is as high as that of caffeine and consequently higher than that of halothane. 4-CmC seems to be a suitable drug to refine diagnosis of MH susc eptibility and could be used as an additional test substance. Implications: Although in vitro contracture testing for malignant hyperthermia diagnosis is well standardized, with a relatively high sensitivity and specificity, false test results cannot be excluded and may be associated with serious di sabilities for the concerned individuals. In this multicenter study, 4-chlo ro-m-cresol was evaluated as a new test substance for the in vitro contract ure testing. Its use improves the accuracy of in vitro diagnosis of maligna nt hyperthermia susceptibility.