CLONIDINE PRETREATMENT REDUCES THE SYSTEMIC TOXICITY OF INTRAVENOUS BUPIVACAINE IN RATS

Background: Clonidine prolongs the duration of sensory and motor block induced by bupivacaine, and this association, in constant infusion by the epidural route, is used for postoperative analgesia. After a near -fatal intravenous bolus of bupivacaine in dogs, clonidine improves ve ntricular electrophysiologic parameters, but probably worsens bupivaca ine-induced bradycardia and depression of the myocardial contractility . The current study, using a rodent animal model, evaluated the influe nce of clonidine pretreatment on the systemic toxic effects of bupivac aine overdose induced by a constant intravenous infusion. Methods: Twe nty Wistar male rats were anesthetized with thiopental, and controlled ventilation was started with an equal mixture of O2 and N2O. Electroc ardiogram (ECG), electroencephalogram (EEG), and invasive arterial blo od pressure were continuously recorded. Clonidine (5 mug/kg) or saline was injected intravenously in a randomized fashion. After 15 min, an intravenous infusion of bupivacaine was started at 2 mg . kg-1 . min-1 . The time of occurrence of the bupivacaine-induced toxic events was r ecorded and the doses were calculated. Ten (five in each group) additi onal rats, pretreated according to the same protocol, were killed at t he time of the first dysrhythmia, for blood sampling and plasma bupiva caine concentration measurement. Results. Clonidine reduced heart rate and arterial blood pressure before bupivacaine infusion (P < 0.05). T he threshold doses at the first QRS modification (11.3 +/- 5.6 vs. 2.1 +/- 0.9 mg/kg) and the first dysrhythmia (40.6 +/- 15.3 vs. 8.48 +/- 3.7 mg/kg), the increase in EEG total spectral power (33.3 +/- 21.9 vs . 8.2 +/- 5.1 mg/kg), the 25 and 50% reduction in baseline mean arteri al pressure and heart rate, the isoelectric EEG (58.6 +/- 14 vs. 22 +/ - 6.6 mg/kg), and the final systole (99 +/- 16 vs. 51.8 +/-14.5 mg/kg) were significantly greater in the clonidine group than in the saline group (P < 0.01). The time between the first dysrhthymia and 50% reduc tion of baseline mean arterial blood pressure was not different betwee n the groups. In the additional series, the first dysrhythmia occurred later (10.9 +/- 4.5 vs. 3.2 +/- 1.0 min, P < 0.01) and plasma bupivac aine levels were greater (18.7 +/- 8.0 vs. 7.8 +/- 3.2 mug/ml, P < 0.0 1) in the clonidine group than in the saline group. Conclusions. In th is model, clonidine given prophylactically delays the toxic manifestat ions of bupivacaine overdose and does not accentuate the subsequent hy potension.