Adenosine is a central nervous system neuromodulator.1 The hypnotic effects of adenosine were first described in animals,2,3 and the soporific effects of systemic and central administration of adenosine have also been demonstrated in humans.4,5 Increases in neuronal activity related to waking augment extracellular adenosine concentrations.6 Microdialysis of adenosine into the basal forebrain promotes sleepiness, whereas perfusion of A1 receptor-selective antagonists such as caffeine or theophylline increases wakefulness.7
The methylxanthine derivative aminophylline, which is clinically used as a bronchodilator, centrally antagonizes adenosine.8 Several clinical studies and case reports suggest that aminophylline antagonizes the effects of diazepam,9 barbiturates,10 sevoflurane,11 morphine,12 and propofol.13 However, the available results from uncontrolled clinical settings make it difficult to quantify the specific effects of aminophylline on hypnotics and anesthetics. Our primary hypothesis was that aminophylline delays the time to loss of consciousness (LOC) and decreases the time to recovery of consciousness (ROC) during propofol anesthesia. Of secondary interest was total propofol dose at LOC as well as estimated plasma propofol concentrations at LOC and ROC.
To the extent that aminophylline produces a generalized arousal effect, it might be expected to increase the minimum alveolar concentration (MAC) of volatile anesthetics. However, the effect of aminophylline on MAC remains controversial. There have been 2 studies in animals, and the results conflict.14,15 A secondary hypothesis was that aminophylline increases the MAC of desflurane.
The study was conducted with IRB approval from the University of Louisville, and with written informed consent from participating volunteers. Volunteers were recruited by advertisements in the local newspapers, flyers posted at local universities, and word of mouth.
Ten healthy male volunteers, 18–40 yr old, who were not taking any medicine were enrolled in this randomized, double-blind, placebo-controlled, 2-day crossover study. Exclusion criteria were obesity (body mass index >30 kg/m2), recent history of infection or recent fever, and habitual coffee consumption exceeding 2 cups per day.
Each subject was studied on 2 separate days at least 1 wk apart. Each fasted and refrained from smoking for at least 8 h before each study day. Studies were conducted in a quiet room that was maintained at a comfortable ambient temperature. Each study started near 7:00 am to minimize circadian effects.
On arrival at the laboratory on the first study day, subjects were randomly assigned to either aminophylline or saline placebo groups. Randomization was based on computer-generated codes that were maintained in sequentially numbered opaque envelopes. Randomly assigned study drug administration was done in a double-blind manner. Neither the investigators nor the volunteers knew whether aminophylline or saline was given on any particular study day. When volunteers were assigned to aminophylline, the drug was given with an initial loading dose of 6 mg/kg over 10 min, followed by continuous infusion of 1.5 mg · kg−1 · h−1 throughout the study day. On the alternate study day, a corresponding amount of normal saline was given instead of aminophylline.
After at least an hour of continuous study drug administration, propofol 200 mg was infused at a rate of 20 mg/min. After complete recovery from propofol, as determined by bispectral index (BIS) and Observer's Assessment of Alertness and Sedation (OAA/S) score16 (and at least 20 min), general anesthesia was induced with sevoflurane and oxygen. Succinylcholine 1 mg/kg was given, and the trachea was intubated. Sevoflurane was discontinued, and anesthesia was subsequently maintained solely with desflurane at an initial end-tidal concentration of 5.0%. MAC determination (described below) started 1 h after sevoflurane induction to allow sufficient time for the effects of propofol to dissipate. Normothermia was maintained throughout with forced-air warming. After MAC determination, desflurane was discontinued, the trachea was extubated, and volunteers were discharged home after an appropriate observation period.
Body weight and height were recorded. Noninvasive monitoring included oscillometric arterial blood pressure, electrocardiogram, oxygen saturation, exhaled carbon dioxide partial pressure, and BIS (BIS XP 3.4 monitor, Aspect Medical Systems, Norwood, MA). Core body temperature was measured from the tympanic membrane using Mon-a-therm thermocouples (Tyco-Mallinckrodt, St. Louis, MO).
During propofol administration, volunteers were evaluated with the OAA/S score every 10 s until ROC. BIS was continuously recorded electronically and the lowest value determined. Times to LOC and ROC were recorded. LOC was defined as an OAA/S score <2 (loss of responsiveness to light tapping on shoulder or mild shaking with voice command to open eyes), and ROC was defined as the first eyes opening in response to verbal command.
The total dose of propofol required for LOC was recorded. Effect-site propofol concentrations at LOC and ROC were estimated using the pharmacokinetic model TIVA Trainer version 8 (http://www.eurosiva.org) using the Schnider model to simulate the time course of the effect-site concentration of propofol. Because we did not actually measure plasma propofol concentrations, the values we report are termed “estimated.” Blood for aminophylline analysis was obtained before propofol administration, upon completion of the propofol infusion, and at the end of study before drug administration stopped. Aminophylline concentrations were determined with a COBAS Integra 400 analyzer (Roche Diagnostic GmbH, Mannheim, Germany). The analytical sensitivity of this method is 0.18 μg/mL.
Anesthetic requirement was defined as the average partial pressure of desflurane required to prevent movement in response to noxious electrical stimulation 50% of the time. Electrical stimulation was administered via two 25-gauge needles inserted intradermally into the upper abdomen. The noxious stimulus was provided by a bilateral 70-mA, 100-Hz electrical current that was maintained for 10 s. To prevent desensitization at the insertion site, the electrodes were moved 1 cm after each stimulation.
Desflurane MAC was determined using the Dixon “up-and-down” method, which is the standard paradigm.17 After maintaining the designated end-tidal desflurane concentration for 20 min to ensure alveolar-brain equilibration, noxious stimulation was applied. If the subject moved, the anesthetic concentration was subsequently increased by 0.5%. In contrast, the desflurane concentration was reduced by the same amount when the subject did not move.
Movement was determined by an independent investigator who was blinded to the vaporizer dial, and values were displayed on the gas analyzer. This investigator was brought into the study room just before each noxious stimulation, and left within a few minutes after each stimulus. A positive response was defined as gross purposeful movement of the legs or arms within the first minute after stimulation. Grimacing and head movement were not considered purposeful responses. The new steady end-tidal desflurane partial pressure was maintained for 20 min, and the process was repeated. The study was stopped when volunteers “crossed over” from movement to no movement 4 times.18
All statistical analyses were performed using SPSS for Windows version 16.0 (SPSS, Chicago, IL) and R software version 2.8.1 (Vienna, Austria). Our analyses assume no carryover and order effects in this crossover design, and a constant volunteer state in regard to response to anesthetic treatment from the first to second observation period, which were at least 1 wk apart.
Our primary study hypothesis, namely that aminophylline alters time to LOC and/or time to ROC in a volunteer relative to the saline control, was evaluated using paired t-tests. Analysis was conditional on the fact that volunteers lost (and regained) consciousness, which is to say we did not analyze those who did not lose consciousness.
The propofol dose at LOC, effect-site propofol concentrations at LOC and ROC, and BIS at desflurane MAC for those volunteers who experienced LOC were each tested for mean difference (aminophylline minus control) unequal to 0 using a paired t-test. In addition, the time-weighted average BIS was analyzed in a similar manner, but for all volunteers completing both study days (i.e., not excluding those who did not lose consciousness).
Heart rate was analyzed using repeated-measures analysis of variance, adjusting for baseline heart rate as a covariable as well as the degree of correlation among repeated measures within a subject (intrasubject correlation).
Assuming a standard deviation of LOC difference scores of 1 min and a paired design with a significance criterion of 0.05, at least 7 volunteers would provide approximately 90% power to detect a mean difference of 1.5 min or more (in either direction), which we believe to be the smallest clinically meaningful effect.
Data are presented as means ± sds, unless otherwise noted. Two of the volunteers completed only 1 of the 2 study days, and results reflect the 8 volunteers who completed the study, unless otherwise noted. They were 27 ± 6 yr old, weighed 76 ± 15 kg, and were 178 ± 5 cm tall. Aminophylline blood concentrations were within the therapeutic range for treatment of bronchospasm before propofol administration (11.4 ± 2.2 μg/mL), upon completion of propofol administration (12.7 ± 1.9 μg/mL), and at the end of the study (16.7 ± 3 μg/mL). (Most studies find that serum theophylline concentrations >10 μg/mL are necessary to produce clinically important symptom control and improvement in pulmonary function.)
Our principal results are provided in Table 1. One volunteer did not lose consciousness on the aminophylline day. Time to LOC was 2.6 ± 1.9 min prolonged and ROC was 6.0 ± 5.9 min shortened with aminophylline.
During propofol administration, period time-weighted average BIS did not differ between aminophylline and saline treatments (mean difference, aminophylline minus control, of 6 ± 9, P = 0.08), but the minimum BIS values were higher in the aminophylline group (13 ± 14, P = 0.038). During desflurane MAC determination, BIS values were only analyzed during stable unstimulated periods and at the end of the study. BIS values at desflurane MAC were significantly higher with aminophylline than with saline (mean difference of 7 ± 6, P = 0.013).
Total propofol dose at LOC was 2.2 ± 0.9 mg/kg with aminophylline and 1.4 ± 0.4 mg/kg with saline; the within-volunteer difference in total propofol dose (aminophylline minus control), estimated at 0.8 ± 0.6 mg/kg, was statistically significant (P = 0.015). The estimated effect-site plasma concentrations were significantly higher with aminophylline than saline at LOC (P = 0.015) and at ROC (P = 0.025).
The MAC of desflurane was identical to aminophylline and saline in 6 volunteers, whereas it decreased by 0.5% for the other 2 volunteers when going from saline to aminophylline (Fig. 1); the corresponding mean difference in desflurane MAC on the aminophylline and saline days was −0.12% ± 0.23% (95% confidence interval for mean of −0.31 to +0.06, paired t-test, P = 0.17). There were no differences in mean arterial blood pressure, oxygen saturation, or core body temperature between groups (not reported). However, heart rate increased significantly during aminophylline administration (Fig. 2).
Stirt19 reported in 1981 that aminophylline antagonizes the hypnotic action of diazepam. The mechanism for the antihypnotic effect of aminophylline is thought to be suppression of central adenosine receptors. There are 4 subtypes of adenosine receptors expressed in the central nervous system: A1, A2A, A2B, and A3.20 Several lines of evidence indicate that both A1R and A2AR subtypes promote sleep, although the subtype of adenosine receptor responsible for sleep regulation remains a matter of debate.7
Nonetheless, the duration and depth of sleep seem to be profoundly modulated by the elevated concentrations of adenosine.4 In addition to its effect in the basal forebrain, adenosine exerts soporific effects in the lateral hypothalamus by inhibiting hypocretin/orexin neurons.21 Systemic administration of adenosine enhances hypnosis induced by IV anesthetics22 and reduces intraoperative anesthetic requirements.15 Basal forebrain administration of the adenosine A1 receptor antagonist 8-cyclopentyltheophylline increases the discharge rate of cholinergic neurons involved in arousal.23 Halothane decreases pontine acetylcholine release,24 and pontine administration of an adenosine A1 agonist both decreases acetylcholine release and slows recovery from halothane anesthesia.25 The effect of adenosine on brain cholinergic activity may moderate the effects of volatile anesthetics, but as in the animal studies of Nicholls et al.,14 we found that MAC was similar with and without aminophylline at therapeutic concentrations.
MAC has been an important measure of anesthesia effect for several decades but it measures primarily a spinal response to noxious stimulation. In recent years, the BIS, which is derived from the frontal cortical electroencephalogram (EEG), has been used extensively for quantifying the hypnotic component of anesthesia. BIS is not a consistent measure across different hypnotic drugs, and anesthetics and drugs vary in their relative analgesic and hypnotic potentials.26 We found that the effects of aminophylline on BIS and MAC as determined by the response to a tetanic noxious stimulus differed. As in a previous study, we found that aminophylline increased BIS values during volatile anesthesia.27
Aminophylline seems to have prolonged the time required and increased the propofol dose needed for LOC, and shortened the time to ROC. Propofol dose and estimated effect-site concentration for LOC were increased 36% and 30%, respectively, with aminophylline. Our results are consistent with those of Sakurai et al.13 who reported that prolonged postoperative effects of propofol were rapidly reversed in 2 patients given aminophylline.
Aminophylline also decreased the anesthetic effects of propofol as determined by BIS. Aminophylline promotes epileptic discharges28 and has been used to increase seizure length during electroconvulsive therapy,29 an effect that may have artifactually increased BIS scores during aminophylline treatment, although we never observed epileptiform EEG activity. Given the LOC and ROC results, it seems likely that higher BIS values during aminophylline administration reflect an antihypnotic effect of aminophylline. Another possibility is that aminophylline produced hemodynamic changes that altered the rate and amount of propofol transfer between the blood and brain.
Aminophylline increases mean arterial blood pressure, left ventricular systolic pressure, velocity of myocardial fiber shortening, and heart rate, and reduces left ventricular end-diastolic diameter.30 As expected, heart rates were increased with aminophylline in our study. A combination of halothane and aminophylline results in serious cardiac arrhythmias31; however, with other volatile anesthetics, aminophylline use seems to be safe and does not cause cardiac arrhythmias,32 and none were observed in our young healthy volunteer population.
Asthma is among the most common chronic diseases and urbanization is expected to increase its incidence over the next 2 decades.33,34 The National Asthma Education and Prevention Program and the Global Initiative for Asthma guidelines specify that sustained-release theophylline is a choice treatment for moderate and severe asthma.33–36 Aminophylline is a complex of theophylline-ethylenediamine, in which theophylline is the main component. Since Ito et al.37 identified antiinflammatory actions of theophylline in 2002, use of aminophylline has increased. Anesthesiologists will thus encounter more patients taking theophylline and aminophylline. Our results suggest that patients taking either drug may require higher than normal propofol doses to prevent awareness. Similarly, sedated critical care patients taking the drugs may need additional propofol.
We evaluated only a single dose of aminophylline. However, we chose a dose that produced therapeutic plasma concentrations, presumably similar to doses that patients taking aminophylline on a regular basis constantly will have. The dose we used thus seems to be the relevant one. One limitation of our study is that it was conducted in 8 healthy volunteers under controlled conditions; results may differ in patients with some diseases or in a critical care setting. Stimulation of the patient such as calling out, prodding, or shaking to evaluate neurological status can affect the responsiveness when sedation is insufficient. A difference in our study is that MAC was estimated by the response to noxious electrical stimulation rather than the traditional response to surgical skin incision. Nonetheless, responses to electrical stimulation have been used in many studies and have proven a reliable substitute. A major advantage of our approach is that it allows individual determination of anesthetic requirement rather than just obtaining a single population average. Of note, it is not critical that we determined MAC per se because our interest was the relative effect of placebo and aminophylline.
In summary, aminophylline prolonged the time required and increased the propofol dose needed to induce LOC; similarly, it shortened the time for ROC. The depth of propofol anesthesia, as determined with BIS-processed EEG monitoring, was reduced by aminophylline; however, aminophylline did not affect the MAC of the volatile anesthetic desflurane as determined by response to a tetanic electrical stimulus.
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© 2010 International Anesthesia Research Society
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