The impact of 4-chloro-m-cresol in heparin formulas on malignant hyperthermia: in vitro and in vivo

Abstract

Background: The preservative 4-chloro-m-cresol (4CmC) is a specific activator of sarcoplasmic Ca2- release and induces contractures in skeletal muscles of malignant hyperthermia susceptible (MHS) patients in vitro. Clinical formulas of heparin contain 4CmC. We studied whether (a) these heparin formulas induce contractures in isolated MHS and normal (MHN) human skeletal muscles and whether (b) significant serum levels of 4CmC are reached after heparinization in cardiopulmonary bypass patients.

Methods: (a) In vitro, muscle bundles of 16 MHS and 22 MHN patients were exposed to the heparin formula Liquemin (containing 4CmC 0.08 mg/500 IU), to chlorocresol and to preservative-free heparin in the in vitro contracture test. (b) In vivo, serum 4CmC levels of 12 patients receiving Liquemin 500 IU/ kg before cardiopulmonary bypass were determined at 1, 5 and 60 min by high-pressure liquid chromatography.

Results: (a) For Liquemin and 4CmC, significant contractures were measured with MHS muscles compared to MHN muscles at 61.4 microM 4CmC. (b) In control sera, the detection threshold for 4CmC was 4 microM. Concentrations of 4CmC in all patients' serum samples were below this threshold.

Conclusion: Heparin formulas, containing 4CmC, induce dose-dependent contractures in vitro in MHS human skeletal muscle at about 60 microM 4CmC. However, in vivo, 4CmC serum concentrations with therapeutic heparinization are less than 1/15 of the in vitro concentration. The lipophilicity of 4CmC with a high volume of distribution may account for these findings. MHS patients seem not to be at risk from clinical heparin formulas containing chlorocresol.