Hypnotic and anesthetic interactions between ketamine and midazolam in female patients

Midazolam, if used with ketamine for induction and maintenance of anesthesia, may attenuate hyperdynamic circulatory effects and prevent undesirable emergenic reactions. The nature of the interaction between midazolam and ketamine used for anesthesia induction was studied in female patients.

Quantal dose-response curves were determined in 170 female patients for the drugs, individually and in combination. Two endpoints were assessed, loss of response to verbal command (hypnosis) and loss of response to a 5-s transcutaneous tetanus (anesthesia). At the hypnotic endpoint, interactions were analyzed by fitting the data to a mathematical model in which the response was analyzed in terms of the doses of the two drugs, and an additional term was included to describe nonadditive interactions. At the anesthetic endpoint, the decrease in ED50 of ketamine in the presence of midazolam was assessed because dose-related effects could not be demonstrated for midazolam alone.

At the hypnotic endpoint, the ED50s were: 0.15 mg/kg midazolam (95% CIs 0.11-0.38 mg/kg), 0.37 mg/kg ketamine (95% CIs 0.08-0.44 mg/kg), and the combination of 0.086 mg/kg midazolam and 0.27 mg/kg ketamine (95% CIs 0.07/0.22-0.10/0.31 mg/kg), respectively. The hypnotic effects were found to be additive, and there was no evidence of an interaction. At the anesthetic endpoint, the ED50 of ketamine alone was 0.57 mg/kg (95% CIs 0.47-0.69) and the ED50 for ketamine in the presence of midazolam was also 0.57 mg/kg (95% CIs 0.48-0.79); 0.18 mg/kg midazolam was given at this point. Midazolam had no influence on the anesthetic dose of ketamine.

When using the combination, doses employed should be adjusted according to the depth of central nervous system depression that is required.