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Short-term effects of intravenous benzodiazepines on autonomic neurocardiac regulation in humans: a comparison between midazolam, diazepam, and lorazepam.

Author(s): Agelink MW, Majewski TB, Andrich J, Mueck-Weymann M

Affiliation(s): Department of Neurocardiology, Institute of Biological Psychiatry and Neuroscience, Evangelical Clinics Gelsenkirchen, Ruhr-University of Bochum, Germany.

Publication date & source: 2002-05, Crit Care Med., 30(5):997-1006.

Publication type: Clinical Trial; Randomized Controlled Trial

OBJECTIVES: To evaluate the effects of intravenously applied diazepam, lorazepam, and midazolam on autonomic neurocardiac regulation assessed by standardized measurements of heart rate variability. DESIGN: Prospective, randomized clinical study. SETTING: University teaching hospital. PATIENTS: Forty-five patients, who underwent a gastroscopy, were randomly assigned to intravenous premedication with midazolam (5 mg), diazepam (10 mg), or lorazepam (4 mg). Six subjects refused an injection and served as nonpremedicated controls. INTERVENTIONS: Serial recordings of the 5-min resting heart rate variability were obtained before and 15 and 30 mins after premedication. Seven benzodiazepine-treated patients received intravenous flumazenil (0.5 mg). MEASUREMENTS AND MAIN RESULTS: The average doses applied were 0.07 mg/kg for midazolam, 0.13 mg/kg for diazepam, and 0.06 mg/kg for lorazepam. Fifteen minutes after intravenous benzodiazepines were administered, we found an increase in resting heart rate and a reduction of vagal tone compared with baseline in all three benzodiazepine-treated subgroups. Multivariate analysis (covariate age) of the changes in heart rate variability indices over the experimental course revealed a significant reduction in absolute high-frequency power with midazolam or diazepam compared with nonpremedicated subjects. Moreover, midazolam-treated subjects showed a significantly larger reduction in relative high-frequency power not only compared with nontreated subjects, but also compared with lorazepam- or diazepam-treated subjects. Vagal tone remained reduced compared with baseline even 30 mins after benzodiazepine application, however, the resting heart rate decreased toward baseline levels. After flumazenil administration, there was a linear correlation between an increase in high-frequency power and a corresponding decrease in resting heart rate. CONCLUSIONS: Benzodiazepines can influence autonomic neurocardiac regulation in man, probably through their interaction with the gamma-aminobutyric acidA-receptor chloride ion channel complex. The pattern of findings suggests that intravenous midazolam, diazepam, and lorazepam influence human autonomic neurocardiac regulation in a biphasic way. First, they cause a reduction of central vagal tone, and second, they may decrease the cardiac pacemaker directly. Flumazenil completely abolished the autonomic neurocardiac regulation effects of benzodiazepines.

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