Effect of Flumazenil on Ventilatory Drive during Sedation with Midazolam and Alfentanil

Abstract

Flumazenil effectively reverses the benzodiazepine component of ventilatory depression during combined administration of a benzodiazepine and an opioid.

Effects of Anesthetics, Sedatives, and Opioids on Ventilatory Control

“…The slope of the HVR at PetCO 2 of 55 mmHg was decreased by alfentanil and further decreased by midazolam. As expected, the effects of midazolam were completely reversed by the benzodiazepine antagonist flumazenil (1 mg) (232).…”

“…In contrast, Gross et al (232) found that sedative doses of midazolam (repeated doses of 10 μg/kg every minute until loss of response to voice command) added to a low-dose alfentanil infusion (loading infusions plus 0.05 μg/kg/min) further depressed the slope of the CO 2 response (assessed by the steady-state method), that was already depressed and right shifted by the opioid [for details see figure 1 in Gross et al 1996 (232)]. The slope of the HVR at PetCO 2 of 55 mmHg was decreased by alfentanil and further decreased by midazolam.…”

“…However, such combinations frequently also cause synergy in terms of the respiratory depressant effects of the drugs, and therefore controlled or assisted mechanical ventilation is a common feature of modern anesthesia. The number of drug combinations are almost limitless but some drug combinations that are more frequently used by anesthesiologists are volatile anesthetic-opioid (105), midazolamopioid (23,232), propofol-opioid (113), ketamine-hypnotic (19,464), and ketamine-opioid (64) combinations. The respiratory effects of some of these combinations have been reviewed by Gross (231).…”

Daily titration of neurally adjusted ventilatory assist using the diaphragm electrical activity

“…Consequently, elimination of sedative drugs between day 1 and 3 may be associated with an improvement of respiratory drive and thus EAdi maxSBT values [18]. Flumazenil could have been tested at day 1 in order to quantify EAdi modification [19]. It is also a common observation that surface electromyographic (EMG) amplitude, thus net neural drive to a muscle, increase within days of training using isometric, concentric, or other forms of contraction (more motor units could be recruited or firing faster) [20].…”

Ability to Reverse Deeper Levels of Unintended Sedation

“…As a result, flumazenil blocks midazolam- (alone or with opiates) induced sedation and respiratory depression [10,11]. In the oversedated individual, flumazenil is administered through intravenous boluses of 0.2–0.5 mg. A common practice is to administer 0.2 mg over 30 s, and increase to 0.3 mg in the absence of response.…”