4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine

Background: 4-Chloro-m-cresol (4-CmC) induces marked contractures in skelet al muscle specimens from individuals susceptible to malignant hyperthermia (MHS). In contrast, 4-CmC induces only small contractures in specimens from normal (MHN) patients. 4-CmC is a preservative within a large number of co mmercially available drug-preparations (e.g., insulin, heparin, succinylcho line), and it has been suggested that 4-CmC might trigger malignant hyperth ermia. This study was designed to investigate the effects of 4-CmC in vivo and in vitro Ln the same animals. Methods: After approval of the animal care committee, six Pietrain MHS and six control (MHN) swine were anesthetized with azaperone 4 mg/kg intramuscu larly and metomidate 10 mg/kg intraperitoneally. After endotracheal intubat ion, lungs were mechanically ventilated (inspired oxygen fraction 0.3) and anesthesia was maintained with etomidate 2.5 mg . kg(-1) . h(-1) and fentan yl 50 mu g . kg(-1) . h(-1). Animals were surgically prepared with arterial and central venous catheters for measurement of hemodynamic parameters and to obtain blood samples. Before exposure to 4-CmC in vivo, muscle specimen s were excised for in vitro contracture tests with 4-CmC in concentrations of 75 and 200 mu M. Subsequently, pigs were exposed to cumulative administr ation of 3, 6, 12, 24, and 48 mg/kg 4-CmC intravenously. If an unequivocal episode of malignant hyperthermia occurred, as indicated by venous carbon d ioxide concentration greater than or equal to 70 mmHg, pH less than or equa l to 7.25, and an increase of temperature greater than or equal to 2 degree s C, the animals were treated with dantrolene, 3.5 mg/kg, Results: All MHS swine developed malignant hyperthermia after administratio n of 4-CmC in doses of 12 or 24 mg/kg, Venous carbon dioxide concentration significantly increased and pH significantly decreased Temperature increase d in all MHS animals more than 2 degrees C, Blood lactate concentrations an d creatine kinase levels were significantly elevated. All MHS swine were tr eated successfully with dantrolene, In contrast, no MHN swine developed sig ns of malignant hyperthermia After receiving 4-CmC in a concentration of 48 mg/kg, however, all MHN animals died by ventricular fibrillation, The in v itro experiments showed that both concentrations of 4-CmC produced signific antly greater contractures In MHS than in MHN specimens. Conclusions: 4-CmC is in vitro a trigger of malignant hyperthermia in swine , However, the 4-CmC doses required for induction of malignant hyperthermia were between 12 and 24 mg/kg, which is about 150-fold higher than the 4-Cm C concentrations within clinically used preparations.