Wappler F, Scholz J, Fiege M, Kolodzie K, Kudlik C, Weisshorn R, Schulte am Esch J
Department of Anesthesiology, University-Hospital Eppendorf, Hamburg, Germany.
Anesthesiology. 1999 Jun;90(6):1733-40. doi: 10.1097/00000542-199906000-00031.
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.
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.
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.
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.
4-氯间甲酚（4-CmC）可使恶性高热易感者（MHS）的骨骼肌标本产生明显挛缩。相比之下，4-CmC仅使正常（MHN）患者的标本产生轻微挛缩。4-CmC是大量市售药物制剂（如胰岛素、肝素、琥珀胆碱）中的一种防腐剂，有人认为4-CmC可能引发恶性高热。本研究旨在探讨4-CmC在同一动物体内和体外的作用。
经动物护理委员会批准后，6头皮特兰MHS猪和6头对照（MHN）猪用4 mg/kg阿扎哌隆肌肉注射和10 mg/kg美托咪酯腹腔注射麻醉。气管插管后，肺部进行机械通气（吸入氧分数0.3），并用2.5 mg·kg⁻¹·h⁻¹依托咪酯和50 μg·kg⁻¹·h⁻¹芬太尼维持麻醉。通过手术为动物留置动脉和中心静脉导管，以测量血流动力学参数并采集血样。在体内暴露于4-CmC之前，切除肌肉标本进行体外挛缩试验，4-CmC浓度分别为75和200 μmol/L。随后，猪静脉内累积给予3、6、12、24和48 mg/kg 4-CmC。如果出现明确的恶性高热发作，表现为静脉二氧化碳浓度≥70 mmHg、pH≤7.25且体温升高≥2℃，则用3.5 mg/kg丹曲林治疗动物。
所有MHS猪在给予12或24 mg/kg剂量的4-CmC后均发生恶性高热。静脉二氧化碳浓度显著升高，pH显著降低。所有MHS动物体温升高超过2℃。血乳酸浓度和肌酸激酶水平显著升高。所有MHS猪均用丹曲林成功治疗。相比之下，没有MHN猪出现恶性高热迹象。然而，在接受48 mg/kg浓度的4-CmC后，所有MHN动物均死于心室颤动。体外实验表明，两种浓度的4-CmC在MHS标本中产生的挛缩均明显大于MHN标本。
4-CmC在体内是猪恶性高热的触发因素。然而，诱导恶性高热所需的4-CmC剂量在12至24 mg/kg之间，这比临床使用制剂中的4-CmC浓度高约150倍。
