Plasma concentrations of flumazenil following intranasal administration in children

Abstract

Purpose: A pharmacokinetic study in children to determine plasma flumazenil concentrations after the intranasal administration of 40 µg·kg -1 .Methods: Following institutional approval and informed written consent, 11 ASA physical status I-II patients, aged two to six years, undergoing general anesthesia for dental surgery were recruited. After induction, 40 µg·kg -1 flumazenil Anexate®, Roche, 0.1 mg·mL -1 (0.4 mL·kg -1 )) were administered via a syringe as drops, prior to nasal intubation. Venous plasma samples were drawn prior to administration of flumazenil (t=0), and then at 2, 4,6,8,10,15, 20, 30, 40, 60, and 120 min thereafter. The plasma samples were immediately processed by the onsite laboratory and then stored at -70°C, before batch analysis via high performance liquid chromatography assay. Pharmacokinetic data calculations were performed using WinNonLin software (Scientific Consulting Inc.).Results: Eleven patients were studied, but data for one patient were discarded due to insufficient sampling. The median age was 4.3 yr (range 3 to 6), with a median weight of 18.9 kg (range 14.9 to 22.2). There were seven boys and three girls. Mean C max was 67.8 ng·mL -1 (SD 41.9), with T max at two minutes. The calculated half-life was 122 min (SD 99). Conclusion:The mean plasma concentrations of flumazenil attained were similar to those reported after intravenous administration, and may be sufficient to antagonize the side-effects of benzodiazepines. This route of administration may be useful when the intravenous route is not readily available.

Dental Sedation in Children

“…Intranasal flumazenil [35] achieves therapeutics blood levels in 2 min facilitating reversal of the effects of midazolam. Intranasal naloxone is now used routinely by many EMT's with a positive response in greater than 80 % of patients with suspected opioid overdoses [36].…”

Flumazenil Reversal of Sublingual Triazolam

“…The intravenous (IV) titration of the drug is capable of completely reversing any of the sedative effects of benzodiazepines; albeit, the length of action after reversal may be shorter than the drug effect being treated 19. While flumazenil is to be administered intravenously, there are reports of it being effective when administered nasally,20 rectally, 21 or via an endotracheal tube 22. Submucosal (SM) injections have been studied in dogs 23…”

Rectal Flumazenil can save the day

“…Nasal Flumazenil administration has been studied by L. Scheeperts (2) in 11 children of age 2–6 years old but all of these patients were anesthetized, paralyzed and nasotracheally intubated so that the large amount of fluid given through the nose did not produce adverse reactions (aspiration or laryngospasm). We were concerned about putting any drops in the nose of a child with an unprotected airway and no intravenous access.…”