IV ATP Potentiates Midazolam Sedation as Assessed by Bispectral Index

In this study, by measuring bispectral index (BIS), we tested the hypothesis that intravenous adenosine 5′-triphosphate (ATP) infusion would deepen the level of midazolam-induced sedation. Ten healthy volunteers underwent 2 experiments with at least 2 weeks'' interval: immediately after intravenous bolus administration of midazolam (0.04 mg/kg), they received continuous infusion of either ATP infusion (100 μg/kg/min) or placebo (saline) for 40 minutes in a double-blind, randomized, crossover manner. Changes in BIS values and responsiveness to verbal command as well as cardiorespiratory variables were observed throughout the study periods. Administration of midazolam alone reduced BIS value from control: 97 ± 1 to 68 ± 18 at 25 minutes, which was accompanied by significant cardiopulmonary depressant effects, while maintaining responsiveness to verbal command (consciousness) throughout the study period. Coadministration of ATP with midazolam further reduced BIS value to 51 ± 13, associated with complete loss of consciousness without adverse effect on the cardiorespiratory systems. We conclude that the addition of ATP infusion to midazolam significantly enhances midazolam sedation without disturbing cardiorespiratory functions.Key Words: Midazolam sedation, ATP, Central adenosine receptorsIntravenous (IV) adenosine 5′-triphosphate (ATP) infusion has been used for various clinical indications.¹ However, when ATP is infused intravenously, it is rapidly broken down into adenosine. Thus, we assumed that ATP would act in a similar fashion to adenosine. Adenosine is an endogenous neuromodulator that is capable of inducing sedation and sleep. There is good evidence that adenosine is an endogenous sleep-promoting molecule.^2,3 Further, a low dose of adenosine infusion (80–140 μg/kg/min) in humans has been shown to stimulate cardiorespiratory systems.^4–6 Meanwhile, the bispectral index (BIS) was reported to provide a reliable measure of the hypnotic effect of midazolam, and BIS analysis can indicate the depth of midazolam sedation.^7,8 Previously, we have shown that coadministration of ATP with midazolam significantly enhanced the hypnotic effect of midazolam in humans, as assessed by subjective and objective questionnaire.⁹ In this study, we examined the effect of ATP infusion on midazolam-induced sedation by continuous measurement of BIS and responsiveness to verbal command as well as cardiorespiratory responses. Furthermore, we sought to find the potential beneficial and/or adverse effects of ATP infusion when combined with midazolam in healthy human volunteers.