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Comparison of Routes of Flumazenil Administration to Reverse Midazolam‐induced Respiratory Depression in a Canine Model
Author(s) -
Heniff Melanie S.,
Moore Gregory P.,
Trout Anne,
Cordell William H.,
Nelson David R.
Publication year - 1997
Publication title -
academic emergency medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.221
H-Index - 124
eISSN - 1553-2712
pISSN - 1069-6563
DOI - 10.1111/j.1553-2712.1997.tb03692.x
Subject(s) - flumazenil , medicine , midazolam , anesthesia , respiratory system , respiratory rate , tidal volume , crossover study , benzodiazepine , heart rate , sedation , blood pressure , receptor , alternative medicine , pathology , placebo
Objective : To determine whether flumazenil, a drug used to reverse benzodiazepine‐induced respiratory depression and approved only for IV use, is effective by alternative routes. Methods : A randomized, controlled, nonblinded, crossover canine trial was performed to evaluate reversal of midazolam‐induced respiratory depression by flumazenil when administered by alternative routes. Mongrel dogs were sedated with thiopental 19 mg/kg IV, then tracheally intubated. With the dogs spontaneously breathing, tidal volume, end‐tidal CO 2 , and O 2 saturation were observed until a stable baseline was achieved. Incremental doses of midazolam were administered until respiratory depression (30% decline in tidal volume, 10% decrease in O 2 saturation, and 15% increase in end‐tidal CO 2 ) 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 rectum (PR)]. Time to return to baseline respiratory functions was recorded (“time to reversal”). Each of 10 dogs was studied using all 4 routes of flumazenil administration with a washout period of at least 7 days. An additional dog served as a control (no flumazenil). Results : The control time to reversal was 1,620 seconds. The IV route was significantly 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 route was the slowest (mean 342 ± 84.4 sec). The SL, IM, and PR routes did not differ significantly from one another. Conclusions : Flumazenil administered by all 4 routes reversed midazolam‐induced respiratory depression in a dog model. For the selected dosages used, the IV route was significantly faster than all 3 other routes, and SL was the second fastest.