EFFECT OF FLUMAZENIL ON VENTILATORY DRIVE DURING SEDATION WITH MIDAZOLAM AND ALFENTANIL

Background: Patients who receive a combination of a benzodiazepine and an oploid for conscious sedation are at risk for developing respirato ry depression. While flumazenil effectively antagonizes the respirator y depression associated with a benzodiazepine alone, its efficacy in t he presence of both a benzodiazepine and an opioid has not been establ ished. This study was designed to determine whether flumazenil can rev erse benzodiazepine-induced depression of ventilatory drive in the pre sence of an opioid. Methods: Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to ca rbon dioxide and to isocapnic hypoxia were determined during four trea tment phases: (1) baseline, (2) alfentanil infusion; (3) combined mida zolam and alfentanil infusions, and (4) combined alfentanil midazolam, and ''study drug'' (consisting of either flumazenil or flumazenil veh icle) infusions. Subjects returned 2-6 weeks later to receive the alte rnate study drug. Results: Alfentanil decreased the slope of the carbo n dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 1 . min(- 1). mmHg(-1) (x+/-SE, P < 0.05), and decreased the minute ventilation at PETCO2 = 50 mmHg (V(E)50) from 19.7 +/- 1.2 to 14.8 +/- 0.91 . min( -1)(P < 0.05). Midazolam further reduced these variables to 0.87 +/- 0 .171 . min(-1). mmHg(-1) (P < 0.05) and 11.7 +/- 0.81 . min(-1) (P < 0 .05), respectively. With addition of flumazenil, slope and V(E)50 incr eased to 1.47 +/- 0.37 1 . min(-1). mmHg(-1) (P < 0.05) and 16.4 +/- 2 .01 . min(-1) (P < 0.05); after placebo, the respective values of 1.02 +/- 0.19 1 . min(-1). mmHg(-1) and 12.5 +/- 1.2 1 . min(-1) did not d iffer significantly from their values during combined alfentanil and m idazolam administration. The effect of flumazenil differed significant ly from that of placebo (P < 0.05). Both the slope and the displacemen t of the hypoxic ventilatory response, measured at PETCO2 = 46 +/- 1 m mHg, were affected similarly, with flumazenil showing a significant im provement compared to placebo. Conclusions: Flumazenil effectively rev erses the benzodiazepine component of ventilatory depression during co mbined administration of a benzodiazepine and an opioid.