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 auton omic 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 in vestigation, the effect of midazolam on the transfer function between AP an d IBI, and on spectral indices of AP and heart rate (HR) variability (APV, HRV) were assessed in the absence and presence of the benzodiazepine antago nist flumazenil. We studied 11 healthy male volunteers. After an initial co ntrol period of 60 min, we studied three consecutive periods, each of 60 mi n 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 effe cts, electroencephalography was performed and Ramsay sedation scores were d etermined. With increasing dose of midazolam, the high frequency (0.15-0.4 Hz) component of the transfer function between AP and IBI decreased progres sively (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 i ndices (e.g. HRV, APV) did not reveal such a clear response to midazolam do se and flumazenil application. Thus in healthy male volunteers. the transfe r function between AP and IBI in the parasympathetically dominated high fre quency range varies according to benzodiazepine agonism and antagonism. Thi s finding has potential implications for monitoring the effects of benzodia zepines.