COMPARISON OF ROUTES OF FLUMAZENIL ADMINISTRATION TO REVERSE MIDAZOLAM-INDUCED RESPIRATORY DEPRESSION IN A CANINE MODEL

Objective: To determine whether flumazenil, a drug used to reverse ben zodiazepine-induced respiratory depression and approved only for IV us e, is effective by alternative routes, Methods: A randomized, controll ed, nonblinded, crossover canine trial was performed to evaluate rever sal of midazolam-induced respiratory depression by flumazenil when adm inistered by alternative routes. Mongrel dogs were sedated with thiope ntal 19 mg/kg IV, then tracheally intubated, With the dogs spontaneous ly breathing, tidal volume, end-tidal CO2, and O-2 saturation were obs erved until a stable baseline was achieved. Incremental doses of midaz olam were administered until respiratory depression (30% decline in ti dal volume, 10% decrease in O-2 saturation, and 15% increase in end-ti dal CO2) occurred, Flumazenil was administered by a randomly selected route [0.2 mg followed 1 minute later by 0.3 mg IV, sublingual (SL) or intramuscular (IM); or 1 mg followed 1 minute later by 1.5 mg per rec tum (PR)]. Time to return to baseline respiratory functions was record ed (''time to reversal''). Each of 10 dogs was Studied using all 4 rou tes of flumazenil administration with a washout period of at least 7 d ays. An additional dog served as a control (no flumazenil), Results: T he control time to reversal was 1,620 seconds, The IV route was signif icantly faster (mean 120 +/- 24.5 sec) than the other 3 routes (p < 0. 005). The SL route was the second fastest (mean 262 +/- 94.5 sec), the IM route was the third fastest (mean 310 +/- 133.7 sec), and the PR r oute was the slowest (mean 342 +/- 84.4 sec), The SL, IM, and PR route s did not differ significantly from one another. Conclusions: Flumazen il administered by all 4 routes reversed midazolam-induced respiratory depression in a dog model. For the selected dosages used, the IV rout e was significantly faster than all 3 other routes, and SL was the sec ond fastest.