A study of intravenous sedation using midazolam and reversal of sedation using flumazenil

Key Points

• Individuals appear more alert when their midazolam sedation is reversed with flumazenil and this improvement is matched by objective measurement of reaction time but is not matched by objective measurement of stability.

• Individuals vary in psychomotor response to midazolam and flumazenil.

• Patients should not be discharged earlier following reversal of midazolam sedation with flumazenil according to their subjective alertness.

Abstract

Objective

To investigate the effect of midazolam and flumazenil on psychomotor function and alertness in human volunteers.

Design

Randomised, double-blind, cross over study.

Methods

Intravenous flumazenil was administered to sedated and non-sedated healthy human volunteers, in doses typical of those used clinically to induce sedation with midazolam and for reversal with flumazenil. Subjective assessment of alertness and objective measures of psychomotor function using light reaction time and the Maddox wing were made over a 1 hour period.

Results

Seven males and seven females each attended four experimental sessions. Psychomotor function was impaired by midazolam but there was some individual variation to this response. All sedated subjects receiving flumazenil had significantly improved alertness and psychomotor function when compared with those subjects who received placebo. Mean alertness (P < 0.01) and light reaction time (P < 0.05) showed significant improvement and returned to baseline by 60 minutes. Stability also showed significant improvement (P < 0.05) but did not return to baseline by 60 minutes. There was no significant effect on psychomotor function or alertness when the antagonist flumazenil was administered in the absence of the agonist midazolam.

Conclusion

An earlier discharge time based on subjective assessment of alertness is not advocated for patients whose intravenous midazolam sedation is reversed with flumazenil.

Main

The effects of midazolam and flumazenil on psychomotor function and alertness in human volunteers Coulthard P., Sano K., Thomson P. J., and Macfarlane T. V. Br Dent J 2000; 188: 325–328

Commentary

Intravenous sedation is increasingly employed in dentistry, not just to enable extremely anxious patients to tolerate treatment, but also to reduce psychological stress and associated physiological responses during unpleasant episodes of treatment.

The introduction of midazolam with its short elimination half-life was a significant development. Most patients, who are sedated satisfactorily, using doses usually within the range recommended in the product information sheet, recover smoothly and the majority are sufficiently recovered to be discharged with an escort about 1 hour after the drug was administered. Patient responses and recovery rates vary, so a formal assessment of fitness for discharge is always required. The product information literature recommends that patients should remain under medical supervision for at least 1 hour.

It is essential to have flumazenil available in case of inadvertent over-sedation, although if midazolam is administered appropriately, this is highly unlikely to occur. The temptation to reverse sedation exists, but this is undesirable, as many patients are alarmed and uneasy when rapidly roused. Natural, slow recovery from the sedative effects of midazolam is usually a pleasant experience.

This paper is valuable in demonstrating that, although the more obvious effects of midazolam may be reversed 1 hour after administering flumazenil, stability (and possibly other effects) are not. The authors recognise that the very short half-life of flumazenil could lead to the later emergence of 'residual' sedative effects (although a return to a completely sedated state would not occur) — so that patients could become more sleepy and unsteady as the effects of flumazenil wane after the 1 hour period documented in this study.

This investigation was carried out on volunteers. It is acknowledged by these authors that a previous study from the same unit involving patients revealed that spontaneous recovery was more complete and reliable than recovery after flumazenil reversal.

An important conclusion from this investigation is that patients receiving flumazenil should not be discharged home earlier because they appear to be alert. Additionally, escorts should be advised of the possibility of patients becoming increasingly sleepy or unsteady after discharge.

As reversal is sometimes alarming to patients, recovery might not be as complete and the assessment of patients' state of recovery might be more difficult, the routine use of flumazenil should be considered undesirable.