Antagonism of the Hypnotic Effect of Midazolam in Children: A Randomized, Doubleblind Study of Placebo and Flumazenil Administered After Midazolam-Induced Anaesthesia

Abstract

In a randomized, double-blind study, we administered placebo and flumazenil to 40 healthy Chinese boys, aged 3-12 yr, undergoing circumcision. The children received midazolam 0.5 mg kg-1 orally for premedication and 0.5 mg kg-1 i.v. during induction. After operation the patients were given 0.1 ml kg-1 of a blinded solution followed by 0.05 ml kg-1 min-1 until either they awoke or the 10-ml ampoule of solution was empty. Efficacy of antagonism of midazolam was assessed by times to eye opening and self identification, modified Steward coma scale, a post-box toy completion-time ratio and qualitatively by an independent observer. The difference between flumazenil and placebo was both clinically and statistically different in the first 2 h. Children receiving flumazenil awoke approximately four times faster and identified themselves nearly three times sooner; 65% of this group could complete the post-box toy at 10 min, compared with none of the placebo group. There were no cases of resedation, but one child did not awaken for 30 min after i.v. administration of flumazenil 1.0 mg. The mean total dose of flumazenil administered was 0.024 (SD 0.019) mg kg-1. Flumazenil rapidly antagonized midazolam-induced hypnosis in children and was associated with minimal change in cardiorespiratory variables.

Effect of flumazenil on recovery from sevoflurane anesthesia in children premedicated with oral midazolam before undergoing herniorrhaphy with or without caudal analgesia

“…Flumazenil induces rapid recovery in children who receive midazolam 0.5 mg · kg -1 orally as premedication and intravenous injection of midazolam 0.5 mg · kg -1 during induction [8]. In that study, the mean total dose of flumazenil administered to achieve awakening was 0.024 mg · kg -1 , whereas other investigators used flumazenil 0.017-0.027 mg · kg -1 to antagonize the effect of midazolam [9,16].…”

“…Flumazenil, a potent benzodiazepine antagonist, reverses the sedative effect of midazolam used for premedication or induction with no significant adverse effects on children [8,9]. Moreover, midazolam occasionally precipitates hostility and violence instead of tranquility, and this paradoxical phenomenon can also be reversed by flumazenil [10,11].…”

A comparison of intramuscular ketamine with high dose intramuscular midazolam with and without intranasal flumazenil in children before suturing

“…Jones et al 19 in a randomised, double blind study involving 40 children found that intravenous flumazenil rapidly antagonised midazolam induced hypnosis in children and was not associated with any episodes of resedation. The anxiety concerning resedation can be tackled after reviewing the pharmacokinetics of midazolam and flumazenil.…”

Flumazenil and midazolam in anaesthesia

“…Another randomized, double-blind, placebo-controlled study on Chinese males aged 3-12 years undergoing circumcision who received midazolam 0.5 mg/kg orally for premedication followed by 0.5 mg/kg i.v. for the induction of anaesthesia, with subsequent reversal by flumazenil, commented on the lack of resedation (39).…”