ABSTRACT
BACKGROUND: The pathophysiology of the serotoninergic system in malignant hyperthermia (MH) is not completely understood. The serotonin-2 (5HT(2A)) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) induces typical MH symptoms, including skeletal muscle rigidity, an increase in body temperature, hyperventilation and acidosis in conscious MH-susceptible (MHS) pigs. Whether these symptoms are directly generated in skeletal muscle, result from central serotonergic overstimulation or from a porcine stress syndrome remains unresolved. In this study the in vivo effects of DOI on anaesthetized (and thus stress-protected) MHS and MH-normal (MHN) pigs were investigated. METHODS: and results. DOI 1 mg kg(-1) was administered three times at 40-min intervals to five MHS and five MHN anaesthetized pigs. Body temperature, heart rate, muscle tone, arterial carbon dioxide pressure (Pa(CO(2))), pH and creatine kinase concentrations were measured. The clinical occurrence of MH was defined by Pa(CO(2)) above 70 mm Hg and an increase in body temperature of more than 2 degrees C. Intragroup differences were analysed with the Friedman test as an overall non-parametric ANOVA and, in case of significance, with the Wilcoxon test. Intergroup comparisons were performed with the Mann-Whitney U-test (statistical significance P<0.05). MHS and MHN pigs developed muscle fasciculations, significant increases in body temperature and Pa(CO(2)) and a significant decrease in pH after the administration of DOI. These changes were comparable in both groups until the third dose of DOI, when in MHS pigs heart rate and Pa(CO(2)) rose significantly and pH fell significantly compared with MHN pigs. All MHS pigs fulfilled the MH criteria. Body temperature increased by more than 2 degrees C in all MHN pigs and Pa(CO(2)) exceeded 70 mm Hg in two. Thus, two MHN pigs fulfilled the criteria of MH. CONCLUSIONS: The comparability of the clinical presentation following DOI administration in MHS and MHN animals and the order of the development of MH-like symptoms favour the hypothesis of a central serotonergic overstimulation, leading to a serotonin syndrome.
Subject(s)
Malignant Hyperthermia/etiology , Receptors, Serotonin/physiology , Serotonin Receptor Agonists/adverse effects , Amphetamines/adverse effects , Animals , Carbon Dioxide/blood , Disease Susceptibility , Malignant Hyperthermia/physiopathology , Partial Pressure , Serotonin Syndrome/chemically induced , SwineABSTRACT
UNLABELLED: A multicenter, randomized, comparative phase III study evaluating the effect of sevoflurane versus isoflurane in adult outpatients was performed. The aim of the study was to compare (1) maintenance of anaesthesia and (2) how rapidly and easily the patients emerge from the anaesthetic and recover. METHODS: Outpatients were included who underwent scheduled surgical procedures of an anticipated duration of up to 3 h and an anticipated length of hospitalization of less than 24 h post-anaesthesia. Five hundred patients were randomly selected to receive either sevoflurane (n = 247) or isoflurane (n = 253), each administered with oxygen (30-50%) in nitrous oxide. Efficacy was evaluated through the measurement of times of recovery parameters and tests like the objective pain-discomfort scale, the visual analogue scale, and the digit symbol substitution test. Safety was evaluated by monitoring adverse experience, clinical laboratory and non-laboratory testing and physical assessments. RESULTS: No statistical differences were observed between the two treatment groups with respect to demographics and ASA class. All study drug concentrations during each anaesthetic phase were statistically lower in the sevoflurane (average concentration 0.61 MAC) compared to the isoflurane (average concentration 0.70 MAC) group. The mean time to emergence was statistically shorter in the sevoflurane group (8.2 min) than in the isoflurane group (9.3 min). The mean time to response to commands (8.5 min vs 9.8 min) and the mean time to orientation (10.6 min vs 13.0 min) were also statistically shorter in the sevoflurane than in the isoflurane group. The EEG results showed a faster decrease in delta activity and a faster increase in alpha activity in the sevoflurane group than in the isoflurane group, indicating faster awakening. No statistical differences were observed between the two treatment groups for the mean time to any of the remaining post-anaesthesia events. Bradycardia was observed in a statistcally higher percentage of patients in the sevoflurane group (6%) than in the isoflurane group (2%). No other statistical differences were observed between the two treatment groups concerning the incidence of study drug-related adverse experience. The most common adverse experiences were nausea and vomiting. At all post-anaesthesia time points, higher serum inorganic fluoride concentrations were observed in the sevoflurane (maximum 30.2 mumol/l) than in the isoflurane group. No clinical or laboratory renal insufficiency was noted. Eighty-seven percent of patients in the sevoflurane group would request the same anaesthetic technique compared to only 79% of patients in the isoflurane group. CONCLUSIONS: Sevoflurane was as safe as isoflurane for anaesthesia in adult outpatients. Patients who received sevoflurane had statistically significantly shorter recovery parameters than isoflurane patients.
