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4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine
1Department of Anesthesiology, University-Hospital Eppendorf, Hamburg, Germany. wappler@uke.uni-hamburg.de
Background:
4-Chloro-m-cresol (4-CmC) induces marked contractures in skeletal 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 commercially available drug-preparations (e.g., insulin, heparin, succinylcholine), and it has been suggested that 4-CmC might trigger malignant hyperthermia. This study was designed to investigate the effects of 4-CmC in vivo and in vitro in 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 intramuscularly and metomidate 10 mg/kg intraperitoneally. After endotracheal intubation, lungs were mechanically ventilated (inspired oxygen fraction 0.3) and anesthesia was maintained with etomidate 2.5 mg x kg(-1) x h(-1) and fentanyl 50 microg x kg(-1) x 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 specimens were excised for in vitro contracture tests with 4-CmC in concentrations of 75 and 200 microM. Subsequently, pigs were exposed to cumulative administration 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 dioxide concentration > or = 70 mmHg, pH < or = 7.25, and an increase of temperature > or = 2 degrees C, the animals were treated with dantrolene, 3.5 mg/kg.
Results:
All MHS swine developed malignant hyperthermia after administration of 4-CmC in doses of 12 or 24 mg/kg. Venous carbon dioxide concentration significantly increased and pH significantly decreased. Temperature increased in all MHS animals more than 2 degrees C. Blood lactate concentrations and creatine kinase levels were significantly elevated. All MHS swine were treated successfully with dantrolene. In contrast, no MHN swine developed signs of malignant hyperthermia. After receiving 4-CmC in a concentration of 48 mg/kg, however, all MHN animals died by ventricular fibrillation. The in vitro experiments showed that both concentrations of 4-CmC produced significantly greater contractures in MHS than in MHN specimens.
Conclusions:
4-CmC is in vivo 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-CmC concentrations within clinically used preparations.
Insights
4-Chloro-m-cresol (4-CmC) triggers malignant hyperthermia in susceptible swine. Doses required in vivo were significantly higher than concentrations found in clinical drug preparations, suggesting a low risk for triggering malignant hyperthermia in patients.
Area of Science:
- Veterinary Anesthesiology and Pharmacology
- Malignant Hyperthermia Research
- Pharmacology and Toxicology
Background:
- 4-Chloro-m-cresol (4-CmC) causes significant muscle contractures in malignant hyperthermia-susceptible (MHS) individuals, but not in normal (MHN) individuals.
- 4-CmC is a common preservative in various pharmaceutical preparations, raising concerns about its potential to trigger malignant hyperthermia (MH).
- This study aimed to correlate in vivo and in vitro responses to 4-CmC in the same animal models.
Purpose of the Study:
- To investigate the in vivo and in vitro effects of 4-Chloro-m-cresol (4-CmC) on malignant hyperthermia (MH) in swine.
- To compare the responses of malignant hyperthermia-susceptible (MHS) swine and normal (MHN) swine to 4-CmC exposure.
- To assess the potential of 4-CmC to trigger MH in a controlled animal model.
Main Methods:
- Six MHS and six MHN swine were anesthetized and surgically prepared for hemodynamic monitoring.
- Muscle specimens were tested in vitro for contracture responses to 75 and 200 μM 4-CmC.
- Animals received escalating intravenous doses of 4-CmC (3–48 mg/kg) to assess in vivo MH triggering, with MH diagnosis based on specific physiological criteria.
Main Results:
- All MHS swine developed malignant hyperthermia (MH) following 12 or 24 mg/kg 4-CmC administration, characterized by increased CO2, decreased pH, elevated temperature, lactate, and CK.
- MHN swine did not exhibit MH signs, but all died from ventricular fibrillation at the highest dose (48 mg/kg).
- In vitro studies confirmed significantly greater contractures in MHS muscle specimens compared to MHN specimens at both 4-CmC concentrations.
Conclusions:
- 4-Chloro-m-cresol (4-CmC) acts as an in vivo trigger for malignant hyperthermia (MH) in susceptible swine.
- The doses of 4-CmC required to induce MH in vivo (12–24 mg/kg) are approximately 150-fold higher than concentrations found in clinical preparations.
- These findings suggest that 4-CmC, despite its preservative role, poses a relatively low risk for triggering MH in clinical settings.