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 19.7±7.4 min, P<0.001), had less incidence of behavioral changes (7.5% 32.5%, P=0.010) and faster recovery (21.6±14.1 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.