Intravenous midazolam significantly enhances the lethal effect of thiopental but not that of ketamine in mice

Intravenous (i.v.) drug combinations are used in clinical anaesthesia in order to combine the desired effects and minimize toxicity from large doses of single agents. This fundamental assumption has not been systematically evaluated. We examined its validity by testing the influence of midazolam on the lethal effect of i.v. thiopental and ketamine in mice. Dose-response curves were constructed for the lethal effect of i.v. thiopental and ketamine, and for the loss of righting reflex effect by midazolam, in sexually mature male ICR mice weighing 20-40 g. For each curve, six or seven groups of eight to 10 mice each were used. A quarter of the median effective dose (ED₅₀) for loss of righting reflex by midazolam was combined with the two other drugs to deduce dose-response curves for the lethal effect of the combinations. The ED₅₀ for loss of righting reflex by i.v. midazolam was 43.5 mg kg^-1 (95% confidence interval [CI], 40.4-46.5). The median lethal dose (LD₅₀) of i.v. thiopental was 50.6 mg kg^-1 (95% CI, 50.0-54.9) and that of ketamine 42.9 mg kg^-1 (95% CI, 32.3-52). In the presence of 10 mg kg^-1 midazolam, the LD₅₀ of thiopental was reduced to 20 mg kg^-1 (17.7-22.2), but that of ketamine remained 44.4 mg kg^-1 (37.7-54.9). Midazolam increased the lethal effect of thiopental 2.5-fold, but did not affect that of ketamine. Interactions at the toxic level between commonly used anaesthetic agents may differ from those at the hypnotic or analgesic levels, which should prompt evaluation of such combinations before their introduction to routine clinical use.