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Effects of pretreatment with etomidate, ketamine, phenytoin, and phenytoin/midazolam on acute, lethal cocaine toxicity

Abstract Objective: To evaluate the effects of etomidate, ketamine, phenytoin, and phenytoin/midazolam in a mouse model of acute cocaine toxicity. Methods: We performed a randomized controlled study consisting of five groups (n = 25 each) of rats that received intraperitoneal injections of normal saline solution, 5 mg/kg ketamine, 7·5 mg/kg etomidate, 40 mg/kg phenytoin, and 40 mg/kg phenytoin and 2 mg/kg midazolam 10 minutes before cocaine hydrochloride (105 mg/kg). Following cocaine administration, a blinded observer watched the animals for 30 minutes to assess seizures (popcorn jumping, tonic-clonic activity, or loss of righting reflex), and lethality for 30 minutes. Results: The number of animals with seizures was lower in the etomidate (60%), phenytoin (40%), and phenytoin/midazolam (40%) groups (P<0·001). The etomidate (24%) and phenytoin/midazolam (16%) treatments were most effective in preventing lethality (P<0·001). Conversely, compared to the vehicle group (72%), cocaine-induced lethality was higher in the ketamine (84%) and phenytoin (92%) groups. All treatments prolonged the time to seizure, but this effect was most pronounced in the etomidate and phenytoin/midazolam groups, which also had the longest average time to lethality. Discussion: The present study provides the first experimental evidence supporting the use of etomidate to treat cocaine-induced seizures. Notably, ketamine and phenytoin were ineffective. Our findings suggest that premedication with etomidate, phenytoin, and phenytoin/midazolam reduced seizure activity in an acute cocaine toxicity mouse model.