Midazolam-Fentanyl-Emulsified Isofluran Hypnotic Synergism In Rats

Drugs combination during the anesthesia procedures become co-mmon because of its advantages in improving the quality of anesthe-sia. Emulsified isoflurane is a new drug and has unique pharmacolo-gic features that can be administered intravenously. It was reported that midazolam and fentanyl reduced the MAC of isoflurane. How-ever, we do not know whether there is an interaction when combina-tion of above three anesthetics was performed. Therefore, this study was designed to define the hypnotic synergism of midazolam-fentanyl-emulsified isoflurane intravenously used in rats.METHODS: 100 male Sprague-Dawley rats weighing 220-300g were randomly allocated into 4 groups: group M,group F,group E-I and group C. Midazolam, fentanyl and emulsified isoflurane (120mg/ml) were injected into the tail vein in rats of groups M, F and E-I respectively. In group C, above three anesthetics were injected sequentially so that synchronization of the peak effects would occur. Loss of the righting reflex (LRR) was used as an index of the hypnotic action. The up-and-down method was utilized to determine the median effective induction dose (ED₅₀) of anesthetics in each group. The ED₅₀ was compared with algebraic (fractional) and isobolographic analyses.RESULTS: 1. There were no significant differences between the 4 groups in the body weight.2. The single-drug ED₅₀ of midazolam, fentanyl, and emulsified isoflurane was 34.67±1.63 (32.95-36.38) mg/kg, 23.33±2.07 (21.17-25.50)μg/kg, and 0.767±0.l21 (0.640-0.894) ml/kg when used separately. For ternary combina-tions, the ED₅₀ values were 2.50±0.21 (2.28-2.72) mg/kg for midazolam, 2.50±0.21 (2.28-2.72)μg/kg for fentanyl, 0.150±0.021 (0.128-0.171) ml/kg for emulsified isoflurane.3. The ratio (R) of a single-drug fractional dose (ED₅₀=1.0) to a combined fractional dose (in fractions of single-drug ED₅₀ values) which indicated the degree of synergism was 2.69 (p＜0.01) for the midazolam-fentanyl-emulsified isoflurane combination.4. The time of recovery from LRR was 15.3±7.0 (10.6-20.0)s in group E-I, it was significantly shorter than that in other three groups,but there is no significant difference amonge the time in group M,F and C.5. Muscle rigidity was found in all rats of group F. Rats in group E-I showed obvious extremities twisting during the emulsified isolfurane administration. No discernable side effect was observed in group C.CONCLUSION: The midazolam-fentanyl-Emulsified isoflurane interaction results in profound hypnotic synergism...