The optimal dose of oral midazolam with or without intranasal S-ketamine for premedication in children: a randomised, double blinded, sequential dose-finding trial

BACKGROUND: Oral administration of midazolam syrup is one of the most favorable methods of premedication, the optimal dose of midazolam and midazolam with S-ketamine for preschool children has not been determined. This prospective, double-blind, randomized, sequential dose-finding study was designed to estimate the 90% effective doses of oral midazolam with and without intranasal S-ketamine in a grade III child medical center. METHODS: Eighty successive children were recruited and randomly allocated to midazolam group and midazolam with S-ketamine group. The initial oral doses of midazolam were 0.25 mg/kg in both groups, and the dose of midazolam for the next child was based on the response of the preceding child as the biased coin up-and-down designed. The primary outcome was parental separation anxiety score = 1 throughout the period of transferring from premedication center to the operation room 30 min after premedication. Secondary outcomes were the preoperative and post-operative observations. Finally, the 90% effective dose and 95% confidence intervals were estimated by isotonic regression. RESULTS: The 90% effective dose of oral midazolam or oral midazolam with intranasal S-ketamine was 0.461 mg/kg (95% confidence interval: 0.425–0.488) and 0.253 mg/kg (95% confidence interval: 0.242–0.278), respectively. Oral midazolam with intranasal S-ketamine was quicker onset (8.9±3.8 vs. 19.7±7.4 min, P<0.001), had less incidence of behavioral changes (7.5% vs. 32.5%, P=0.010) and faster recovery (21.6±14.1 vs. 31.6±13.5 min, P=0.002) than solely oral midazolam. CONCLUSIONS: A suggestion of oral midazolam 0.3 mg/kg with intranasal small dose of S-ketamine could be used as premedication for preschool children. TRIAL REGISTRATION: Chinese Clinical Trial Registry.