Effect of midazolam on transfer function between beat-to-beat arterial pressure and inter-beat interval length

Arterial pressure (AP) and inter-beat interval (IBI) length are under autonomic nervous system control. The control mechanisms can be investigated by transfer function analysis. It is not known if this type of analysis may be helpful in monitoring depth of sedation. In an open-label, uncontrolled investigation, the effect of midazolam on the transfer function between AP and IBI, and on spectral indices of AP and heart rate (HR) variability (APV, HRV) were assessed in the absence and presence of the benzodiazepine antagonist flumazenil. We studied 11 healthy male volunteers. After an initial control period of 60 min, we studied three consecutive periods, each of 60 min duration, with progressively increasing concentrations of midazolam (0.02, 0.06, 0.14 mg kg-1 h-1). A final 60-min period during administration of flumazenil 0.004 mg kg-1 h-1 and while the agonist was still present was also studied. To confirm midazolam-induced central nervous system effects, electroencephalography was performed and Ramsay sedation scores were determined. With increasing dose of midazolam, the high frequency (0.15-0.4 Hz) component of the transfer function between AP and IBI decreased progressively (mean 26.5 (SEM 3.7), 19.2 (2.9), 12.8 (1.7), 8.4 (1.6) ms mm Hg-1). This effect was antagonized by flumazenil (21.5 (3.2) ms mm Hg-1). Other indices (e.g. HRV, APV) did not reveal such a clear response to midazolam dose and flumazenil application. Thus in healthy male volunteers, the transfer function between AP and IBI in the parasympathetically dominated high frequency range varies according to benzodiazepine agonism and antagonism. This finding has potential implications for monitoring the effects of benzodiazepines.