Effect of Midazolam and Diazepam Premedication on Central Nervous System and Cardiovascular Toxicity of Bupivacaine in Pigs

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Abstract
To determine the effect of benzodiazepine premedication on central nervous system and cardiovascular effects of bupivacaine, the authors administered toxic doses of bupivacaine to awake spontaneously breathing pigs after intravenous premedicaton with midazolam (0.06 mg/kg), diazepam (0.15 mg/kg), or saline. Five minutes after administration of one of these solutions, they began an infusion of bupivacaine at 2 mg .cntdot. kg-1 .cntdot. min-1. The bupivacaine infusion was continued until cardiovascular collapse. They then attempted to resuscitate the animals via open chest cardiac massage and a standard resuscitation protocol. Premedication with midazolam or diazepam significantly delayed the onset of ventricular dysrhythmias (P < 0.05), decreased the incidence of seizures (P < 0.05), and prevented the increase in blood pressure and heart rate following bupivacaine infusion (P < 0.05). Benzodiazepine premedication did not affect the dose of bupivacaine or the blood concentration required to produce cardiovascular collapse. The ability to resuscitate animals premedicated with midazolam did not differ from control; however, significantly fewer animals premedicated with diazepam were resuscitated (P < 0.05). A clinically relevant observation was the almost all animals premedicated with a benzodiazepine progressed directly to cardiovascular collapse without first manifesting seizures.