IV ATP Potentiates Midazolam Sedation as Assessed by Bispectral Index

Abstract

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.

Intravenous (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.

METHODS

This study was approved by the Clinical Research Ethics Committee at Tokyo Dental College (approval number 76). Ten healthy male volunteers were randomly assigned on 2 different days with at least 2 weeks' interval to receive (a) IV midazolam + placebo (saline) infusion or (b) IV midazolam + ATP infusion in a double-blind crossover study. The subject was fasted and refrained from smoking or taking caffeine or theophylline for at least 8 hours before each study day. With the subject in a supine position and after local infiltration anesthesia, a 22-gauge catheter was inserted into the left brachiocephalic vein for IV fluid infusion and drug administration.

Assessment of Level of Sedation (BIS Monitoring)

A BIS Plus sensor that was connected to a BIS monitor (Version 2.21, A-2000, Aspect Medical System, Newton, Mass) was placed on the forehead of each subject. The level of sedation (sedation depth) was assessed continuously during the entire study period, and the term consciousness was defined as responsiveness to verbal commands (“open your eyes” and “squeeze my fingers”). A volunteer who obeyed commands positively or negatively was considered conscious (awake) or unconscious (sleep).

Cardiorespiratory Variables

Changes in systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, tidal volume, minute ventilation, pulse oximeter oxygen saturation, and end-tidal carbon dioxide pressure were monitored using noninvasive, automated monitoring equipment (Moneo BP-88R, Nippon Collin, Tokyo, Japan), Capnomac Ultima (Datex Ohmeda), and a Rite flow meter by continuous sampling from the junction of the face mask and the semiclosed anesthesia circle breathing system that provided 6 L/min of air. These variables were recorded, every 5 minutes, before and after administration of midazolam for entire study periods of 60 minutes.

Study Drug Administration

Each subject had 2 separate sessions. After a loading dose of IV midazolam (0.04 mg/kg), subjects received either continuous infusion of placebo (saline) for 40 minutes in one session or ATP infusion at a rate of 100 μg/kg/min for 40 minutes in the other session.

Statistical Analysis

A power analysis based on a preliminary pilot study suggested that a sample size of 10 subjects for each session should be adequate to detect a difference in the BIS values between the 2 sessions with a power of 0.8 (α = .05). Baseline data points were recorded prior to the drug infusion. Data are presented as mean ± SD. Intratrial comparisons of time-dependent variables were made with repeated-measures analysis of variance followed by Dunnett post hoc test. Intertrial comparisons were made with a paired Student's t test for paired samples. P values less than .05 were considered significant.

RESULTS

Changes in BIS Values

After IV bolus injection of midazolam (0.04 mg/kg) alone, BIS value declined, slowly reaching the nadir (BIS = 68 ± 18) at 25 minutes, and then gradually recovered to the baseline level after 60 minutes, without loss of consciousness during entire study period. Coadministration of ATP with midazolam further reduced BIS value to 51 ± 13, indicating the signs of deepening the level of sedation compared to midazolam alone. The significant potentiating effects were seen after 15–30 minutes of ATP in fusion, concomitant with loss of consciousness (loss of responsiveness to verbal command) in all subjects (Figure 1).

Figure 1. .

Intravenous adenosine 5′-triphosphate (ATP) potentiates midazolam sedation in healthy volunteers. Data are presented as mean ± SD, n = 10. *P < .05 midazolam + saline versus midazolam + ATP. BIS indicates bispectral index.

Changes in Cardiorespiratory Effects

IV bolus injection of midazolam (0.04 mg/kg) alone produced significant depressant effects on systolic blood pressure, diastolic blood pressure, tidal volume, minute ventilation, end-tidal carbon dioxide pressure, and pulse oximeter oxygen saturation. However, addition of ATP infusion to midazolam effectively and safely counteracted all the cardiorespiratory depressant effects of midazolam (Figures 2 and 3).

Figure 2. .

Change in hemodynamic variables. Data are presented as mean ± SD, n = 10. *P < .05 versus baseline control. SBP indicates systolic blood pressure; DBP, diastolic blood pressure; and HR, heart rate.

Figure 3. .

A. Change in respiratory variables: respiratory rate (RR), tidal volume (TV), minute ventilation (VE). Data are presented as mean ± SD, n = 10. *P < .05 versus baseline control. B. Change in respiratory variables: oxygen saturation (SpO₂), end-tidal carbon dioxide (ETCO₂). Data are presented as mean ± SD, n = 10. *P < .05 versus baseline control.

Adverse Effects

Coadministration of low-dose ATP with midazolam caused no adverse side effect such as hypotension, bradycardia, headache, chest pain, respiratory depression (hypercapnia, oxygen desaturation), nausea, or vomiting.

DISCUSSION

In this study, we tested the hypothesis that IV ATP infusion would deepen the level of midazolam-induced sedation without adverse side effects. By assessing changes in both BIS and responsiveness to verbal command as well as cardiorespiratory responses simultaneously, we found that ATP infusion significantly potentiates the midazolam sedation with improved cardiorespiratory functions, and that no serious adverse effect was seen. These results are in good agreement with our previous observations in human volunteers as assessed by subjective and objective questionnaires.⁹ Thus, we confirmed that low-dose ATP infusion significantly enhances midazolam sedation.

The water-soluble benzodiazepine midazolam is the most common anesthetic adjuvant during local, regional, and general anesthesia because of its sedative and amnestic properties, and has gained widespread use as an IV agent to provide sedation for short procedures. Thus, it is becoming very common in both medical and dental anesthesiology. However, IV midazolam can often cause profound cardiorespiratory depression if given in higher doses and after repeated administration when deeper levels of sedation are sought.

Meanwhile, a number of animal studies have indicated that administration of adenosine into the brains of rats, cats, dog, and fowl produced behavioral sleep.¹⁰ Similarly, systemic injection of ATP to rabbits or mice caused sedation.¹⁰ Furthermore, systemic injection of adenosine analogs to mice and rats produced marked sedation.¹¹ More recently, Kaputlu et al¹² found in mice that exogenous adenosine or adenosine receptor agonist (2-chloroadenosine, dipyridamole) potentiates hypnosis induced by IV anesthetics (thiopental, propofol, and midazolam). Thus, it is conceivable that stimulation of central adenosine receptors may produce sedation or sleep.

Similarly, adenosine's role in the central actions of the benzodiazepines is well recognized.¹³ Benzodiazepines, including midazolam, potently inhibit adenosine uptake,¹⁴ thereby accumulating extracellular concentration of adenosine, and thus potentiating the actions of adenosine. Also, several effects of benzodiazepines are antagonized by adenosine receptor antagonists caffeine or theophylline.^13,15,16 Thus, the sedative effect of benzodiazepines could be related, in large part, to their inhibition of adenosine uptake.^13,14,16

In the present study, ATP infusion interacted favorably with midazolam, producing significant enhancement of midazolam sedation without further aggravating cardiorespiratory depression. The cardiorespiratory stimulant effects of adenosine appeared to interact favorably with depressant effects of midazolam, thus counteracting the cardiorespiratory depressant effects of midazolam.

We conclude that the use of low-dose ATP infusion safely and significantly enhances midazolam sedation with improved cardiorespiratory functions in healthy human volunteers.