Effect of midazolam infusion and flumazenil administration on epinephrine arrhythmogenicity in dogs anesthetized with halothane

Abstract

Background: Midazolam is being selected increasingly for use in patients with cardiovascular compromise. Although clinical doses of midazolam have minimal effects on cardiac function, the influence of midazolam (and other benzodiazepine sedatives) on cardiac arrhythmogenesis has yet to be elucidated fully. Methods: In this study, we investigated the effect of midazolam, with and without flumazenil, on the arrhythmogenic serum concentration of epinephrine (ACE) in six halothane-anesthetized dogs. Midazolam was administered as a loading dose (1.5 mg/kg over 5 min) followed by a 4.5-h infusion at two rates (10 and 40 μg · kg-1 · min-1) to achieve and maintain predetermined clinical and supraclinical plasma midazolam concentrations. The arrhythmogenic serum concentration of epinephrine determinations were made prior to midazolam infusion, following 2 h of midazolam infusion and following 3.5 h of midazolam infusion and 1 mg flumazenil/kg iv. Saline control studies were also performed in four of the six dogs. Results: Plasma midazolam concentrations ranged from 363 to 855 ng/ml in the low-dose infusion study, essentially spanning the clinically effective range for humans. In the high-dose infusion study, plasma midazolam concentrations were up to four times greater, ranging from 1168 to 3563 ng/ml. The arrhythmogenic serum concentration of epinephrine values were unchanged following low-dose midazolam infusion and saline. In the high-dose study, ACE increased from baseline values of 68 ± 13 (SEM) ng/ml to 112 ± 25 ng/ml (P = .03) following midazolam infusion and decreased to 79 ± 13 ng/ml with flumazenil administration. Plasma midazolam concentrations, however, were poorly correlated with ACE values normalized for control ACE (ACE ratio). Diastolic arterial pressure was significantly depressed following both low-dose (-14%) and high-dose (-19%) midazolam infusion. This decrease in blood pressure was unaffected by flumazenil administration. Other hemodynamic parameters were unaffected by drug treatment. Conclusions: This study has demonstrated that midazolam infusion results in either no effect (with clinical plasma midazolam concentrations) or flumazenil-reversible suppression (with supraclinical concentrations) of halothane-epinephrine arrhythmogenesis.