Effect of flumazenil on ventilatory drive during sedation with midazolam and alfentanil.
BACKGROUND
Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine-induced depression of ventilatory drive in the presence of an opioid.


METHODS
Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and "study drug" (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2-6 weeks later to receive the alternate study drug.


RESULTS
Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 l.min-1.mmHg-1 (x +/- SE, P < 0.05), and decreased the minute ventilation at P(ET)CO2 = 50 mmHg (VE50) from 19.7 +/- 1.2 to 14.8 +/- 0.9l.min-1 (P < 0.05). Midazolam further reduced these variables to 0.87 +/- 0.17 l.min-1.mmHg-1 (P < 0.05) and 11.7 +/- 0.8 l.min-1 (P < 0.05), respectively. With addition of flumazenil, slope and VE50 increased to 1.47 +/- 0.37 l.min-1.mmHg-1 (P < 0.05) and 16.4 +/- 2.0l.min-1 (P < 0.05); after placebo, the respective values of 1.02 +/- 0.19 l.min-1.mmHg-1 and 12.5 +/- 1.2 l.min-1 did not differe significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P < 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at P(ET)CO2 = 46 +/- 1 mmHG, were affected similarly, with flumazenil showing a significant improvement compared to placebo.


CONCLUSIONS
Flumazenil effectively reverses the benzodiazepine component of ventilatory depression during combined administration of a benzodiazepine and an opioid.
Gross
J B
JB
Department of Anesthesiology, University of Connecticut School of Medicine, Farmington 06030-2015, USA. GROSS@SUN.UCHC.EDU
Blouin
R T
RT
Zandsberg
S
S
Conard
P F
PF
Häussler
J
J
D000328:Adult; D015760:Alfentanil / Q000008:administration & dosage*; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000931:Antidotes / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000037:antagonists & inhibitors; D002245:Carbon Dioxide; D016292:Procedural Sedation / Q000009:adverse effects / Q000379:methods*; D003243:Consciousness / Q000187:drug effects; D018592:Cross-Over Studies; D003864:Depression, Chemical; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D005442:Flumazenil / Q000008:administration & dosage*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage*; D000860:Hypoxia / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage*; D012119:Respiration / Q000187:drug effects*
D000701:Analgesics, Opioid; D000931:Antidotes; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D002245:Carbon Dioxide; D015760:Alfentanil; D005442:Flumazenil; D008874:Midazolam