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From the Department of Anesthesiology, Gunma University Graduate School of Medicine, Maebashi City, Japan.
Address correspondence to: Dr. Koichi Nishikawa, Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi City 371-8511, Japan. Phone: +81-27-220-8454; Fax: +81-27-220-8473; E-mail: nishikaw{at}med.gunma-u.ac.jp
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Abstract |
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Methods: General anesthesia was administered to 36 patients with a continuous infusion of propofol to maintain a BIS value of 40 ± 5. After baseline recordings, patients were randomly assigned to receive either midazolam, isoflurane, or aminophylline. Bispectral index values, rSO2 using near-infrared spectroscopy, and hemodynamic parameters were recorded for 60 min.
Results: Midazolam (0.05 mg·kg–1) significantly decreased the BIS from 47.8 ± 5.4 to 35.0 ± 4.5 at five minutes after injection (P < 0.001 vs control) during propofol anesthesia, whereas the rSO2 was unchanged. Similarly, isoflurane (1.1% end-tidal) decreased the BIS from 42.5 ± 7.5 to 27.8 ± 6.9 (P < 0.001) without affecting rSO2. In contrast, aminophylline (3 mg·kg–1) was associated with an increase in BIS from 41.6 ± 2.1 to 48.3 ± 9.2 at five minutes after injection (P < 0.05) without affecting rSO2.
Conclusions: Midazolam or isoflurane-induced decreases in the BIS during propofol anesthesia were not accompanied by a decrease in rSO2. Aminophylline significantly increased the BIS score during propofol anesthesia, suggesting that aminophylline can antagonize, at least in part, the sedative actions of propofol.
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Introduction |
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Volatile anesthetics or analgesics are often co-administered during propofol anesthesia in various clinical settings. It is therefore important to understand the impact of the interaction between these drugs in terms of anesthetic depth. For example, Iselin-Chaves et al.5 examined the effects of the interaction of propofol and alfentanil on recall or loss of consciousness, and found that the sedation and changes in memory function produced by propofol, but not by alfentanil, correlate well with changes in BIS. However, one side effect of co-administered general anesthetics is hypotension, which may result in decreased cerebral blood flow. To examine this influence, cerebral oximetry based on near-infrared spectroscopy (NIRS) has also been used for non-invasive monitoring of regional cerebral oxygen saturation (rSO2) during general anesthesia. The changes of rSO2 may reflect changes of cerebral blood flow relative to metabolic rate in the brain. The interaction between propofol and volatile anesthetics on rSO2 remains unclear.
Several lines of evidence suggest aminophylline may antagonize the sedative action of diazepam and change the depth of anesthesia.6–8 Stirt6 first reported the possibility of antagonistic actions of aminophylline on diazepam sedation. Niemand et al.7,8 suggested the possibility of the involvement of an adenosine receptor blockade of GABA(A) receptors in the antagonistic actions of aminophylline. In addition, as observed during diazepam sedation, Taylor et al.9 presented a case report of a patient with asthma for whom the infusion rate of propofol required for sedation apparently decreased after disconnection of aminophylline. This case suggests that aminophylline may have similar antagonistic actions on propofol. However, the effects of aminophylline on the BIS and cerebral oxygenation during propofol anesthesia have not been described.
We therefore undertook a study to compare the effects of midazolam, isoflurane, and aminophylline (which may modulate the GABA receptor function leading to the changes in anesthetic depth during propofol anesthesia) on BIS scores and rSO2. We also examined whether or not aminophylline would antagonize propofol action on the BIS, and further, tested the hypothesis that drug-induced changes in the BIS score are accompanied by a change in the rSO2 during propofol anesthesia.
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Methods |
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Study protocol
Patients were randomly allocated by random number tables into one of three groups: the midazolam group, the isoflurane group, and the aminophylline group. No sedative premedication was given before general anesthesia. In the operating room, two 18-G cannulae were inserted into a large forearm vein under local anesthesia; one for drug administration and the other for fluid or blood infusion. Lactated Ringer’s solution was infused at a rate of 5 to 10 mL·kg–1·hr–1. Routine physiological monitoring was initiated including an electrocardiogram, non-invasive arterial blood pressure, heart rate, SpO2, end-tidal CO2 concentration, end-tidal isoflurane concentration, and body temperature. A radial artery catheter was inserted with local anesthesia for monitoring arterial blood pressure. In some cases, an epidural catheter was also inserted before induction of anesthesia for postoperative analgesia, but epidural injection of local anesthetics or opioids occurred only after the study was complete.
The BIS index was monitored and recorded continuously using the Aspect EEG monitor (A-1050, Aspect Medical Systems, Newton, MA, USA) containing software revision 1.30 in the standard montage. Following alcohol cleaning, disposable BIS sensor electrodes (BIS sensor plus, Aspect Medical Systems, Newton, MA, USA) were applied to the forehead of patients to record the pre-induction value. Impedance of the electrodes was confirmed to be less than 500 
. In addition, continuous, non-invasive monitoring of rSO2 was also performed using NIRS (OM-200 version 3.17, Shimadzu Corporation, Kyoto, Japan). Changes of oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) were measured using wavelengths of 780 and 830 nm. The reflected beam of light was analyzed and data stored continuously on a personal computer. A sampling interval of 0.5 sec was used and rSO2 = oxy-Hb/(oxy-Hb ± deoxy-Hb) were calculated. A previous study10 reported that, among many factors, patient age, hemoglobin concentration, and sensor location may affect rSO2 values, and thus in all patients the rSO2 sensors were applied on the right forehead, 3 cm away from the midline to avoid distortion from the sagittal sinus.
Routine physiological monitoring was started and baseline values recorded while the patient breathed 100% oxygen. After breathing 100% oxygen for at least three minutes through a facemask, general anesthesia was induced with a single dose of propofol (2 mg·kg–1 iv). To facilitate tracheal intubation, vecuronium bromide (0.1 mg·kg–1) was injected immediately after loss of consciousness (eyelash reflex) occurred. Tracheal intubation was attempted only when the BIS value reached < 40; if the BIS score did not reach 40, an additional single dose of propofol (0.2 mg·kg–1 iv) was injected. After intubation, general anesthesia was maintained with oxygen (33%), nitrous oxide (67%), and a continuous infusion of propofol using an infusion pump to maintain mean values of the BIS within the target range 40 ± 5 before the study period. The propofol infusion was allowed to run at a constant level throughout the study period. Ventilation was controlled to maintain end-tidal PaCO2 at approximately 35 mmHg. The studies were conducted immediately following induction or after the surgical procedure, to avoid the effects of surgical stimuli on the drug-induced changes of the BIS score. During surgery, supplemental fentanyl and vecuronium were administered as required, but both drugs were avoided during the period of data collection to minimize their effects on the BIS.
After recording baseline values, midazolam (0.05 mg·kg–1 iv), or aminophylline (3 mg·kg–1, iv) was administered. The selected drug doses were considered standard doses for sedation or anti-asthmatic treatment, respectively. In the isoflurane group, application began when the end-tidal concentration of 1.1% (1.0 MAC) was attained. Physiological data and BIS values were recorded and analyzed before injection, at one minute, and every five minutes after injection. No vasopressor or vasodilator medications were administered during the study period. However, when systolic blood pressure increased above 140 mmHg or decreased below 80 mmHg during the study period, nicardipine or phenylephrine were administered to treat hemodynamic changes, and the case was excluded from further analysis. All BIS values reflect the mean of three consecutive measurements taken at each data point. All measurements were made by the investigator blinded to the study drugs.
Statistics
Using an expected difference of 5% for the BIS value at five minutes following injection, a variability of 17.7 for BIS values with a power of 0.8 (ß = 0.8) and assuming an 
= 0.05, it was estimated that 12 patients per group would be required to demonstrate a clinically important difference (Sample Power 2.0, SPSS Inc., Chicago, IL, USA). These figures were based on results of our preliminary study. All data are expressed as mean ± standard deviation. Statistical analysis was performed using StatMate version III for Windows (ATMS Co., Ltd., Tokyo, Japan). Statistical difference was analyzed by one-factor repeated measures ANOVA followed by the Tukey’s method as a post hoc test for each group. P < 0.05 was considered statistically significant.
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Results |
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. Two patients in the isoflurane group were excluded from analysis, since phenylephrine was used to treat hemodynamic changes. As a result, the data from 34 patients was analyzed for this study. No significant differences were observed with respect to age, weight, and other parameters among groups. The base-line, non-medicated BIS values of the three groups were between 97–98, with no significant differences amongst groups. The mean infusion rate of propofol before administration of the study drug was 6.9 ± 1.3 mg·kg–1·hr–1 (n = 34). There was no significant difference in the infusion rates of propofol in the three groups.
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) during propofol anesthesia. A significant decrease in the BIS was observed for 30 min after injection. As shown in Table II, rSO2 was not affected by midazolam injection during propofol anesthesia, i.e., 70.3 ± 7.9 before midazolam and 68.8 ± 7.0 at 20 min after injection. No changes in other parameters such as systolic blood pressure, heart rate, SpO2, body temperature, or EtCO2 after midazolam injection were detected (Table II).
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) whereas rSO2 was unchanged (Table II
). The BIS returned to baseline level within ten minutes after isoflurane discontinuation. Systolic blood pressure was also significantly decreased after the introduction of 1 MAC isoflurane at five, ten, 15, and 20 min (Table II). No changes in other parameters such as heart rate, SpO2, body temperature, or EtCO2 during isoflurane application were detected (Table II).
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). In addition, heart rate was significantly increased at five minutes (P < 0.01 vs control, Table II). During these procedures, no significant changes in rSO2, systolic blood pressure, or other parameters were observed (Table II).
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Discussion |
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There have been few studies examining the interaction of anesthetics on BIS and rSO2. Lovell et al.11 previously compared cerebral oxygenation by NIRS during induction of anesthesia with etomidate, propofol, or thiopental. They reported that etomidate (0.31 mg·kg–1) was associated with a decrease in cerebral oxygenation, whereas propofol (3.1 mg·kg–1) and thiopental (6.4 mg·kg–1) were associated with an increase in cerebral oxygenation. The different effects of iv anesthetics on oxygen saturation may be due to the different actions on cerebral blood flow and oxygen consumption; both propofol and thiopental maintain flow-metabolism coupling12 whereas etomidate is associated with a rapid reduction in cerebral blood flow accompanied by a slower reduction in oxygen consumption.13 Iwasaki et al.14 compared the effects of higher doses of sevoflurane (8%) on cerebral blood volume with 5% sevoflurane and propofol on cerebral volume using BIS and NIRS during induction of anesthesia. Only vital capacity inhalation with 8% sevoflurane produced an increase in cerebral blood volume, suggesting that high concentrations of sevoflurane may be dangerous in patients with elevated intracranial pressure. We found that a single dose of midazolam or 1.1% isoflurane induced changes in BIS during continuous propofol anesthesia are not accompanied by a significant change of rSO2, suggesting the favourable effects of these drugs with respect to cerebral oxygenation and hemodynamic changes.
Historically, Stirt6 first reported in 1981 that aminophylline antagonizes the action of diazepam. Others have reported similar actions of aminophylline on diazepam sedation.7,8 In this context, Taylor and Collins9 reported a possible interaction between aminophylline and propofol. They described a 24-yr-old patient who required respiratory support in the intensive care unit for the treatment of asthma and persistent intense bronchospasm, using propofol sedation. However, she frequently became agitated during aminophylline administration and, after the discontinuation of aminophylline, the infusion requirements for propofol decreased. These observations suggested that aminophylline may have an antagonistic interaction with propofol. Recently, Turan et al.15 examined the effects of aminophylline on BIS during clinical recovery in patients anesthetized with sevoflurane. They found that the BIS scores were significantly higher after aminophylline (5 mg·kg–1) injection than in the control group, and that recovery time variables such as eye opening time and extubation times were slightly shorter in the aminophylline group.
We found that a single dose of aminophylline (3 mg·kg–1) during propofol anesthesia significantly increased BIS and heart rate. These data suggest that aminophylline can antagonize, at least in part, propofol effects on EEG parameters used for BIS score production. Although the mechanism of aminophylline’s antagonistic action is unknown, one hypothesis relates to the hemodynamic effects of the drug. Generally, as a drug with an extraction ratio approaching 1, propofol clearance is directly proportional with liver blood flow. The addition of aminophylline would be expected to increase cardiac output due to an increase in heart rate and liver blood flow, and thus reduce propofol concentration. This hypothesis may explain, in part, the observed increase in BIS associated with aminophylline administration. In this context, Ishiyama et al.16 reported that ephedrine 0.1 mg·kg–1, but not phenylephrine 2 µg·kg–1, increases BIS values during general anesthesia with sevoflurane combined with epidural anesthesia. These data support the hypothesis that an increase in heart rate may affect the BIS score.
The dose of aminophylline chosen for the present study was relatively small compared to a previous study15 for several reasons. The first was to avoid significant tachycardia. Second, aminophylline has been shown to cause epileptic discharges at higher doses. Third, aminophylline is mainly metabolized by the hepatic cytochrome P450 system, thus hepatic dysfunction and heart failure reduce the elimination of aminophylline. Care must be taken with the plasma level of aminophylline in patients with such co-existing disease. Turan et al.15 used a higher bolus dose of aminophylline (5 mg·kg–1) to examine its effects on recovery time from sevoflurane anesthesia. However, they used aminophylline after inhalational anesthetic discontinuation, which was a different protocol from the present study. Finally, intraoperative awareness is one of the most serious considerations, since aminophylline has been reported to reverse diazepam’s sedative/hypnotic action.6,7 Fortunately, no patient showed evidence, or complained of this complication postoperatively in the present study.
Cerebral oxygen saturation using NIRS has been used widely to monitor the relative change in oxidative status of the brain. However, the data requires careful interpretation, since the rSO2 value may be affected by many factors such as age, hemoglobin concentration, bleeding and transfusion.10,17 The patients included in the present study experienced minimal bleeding and required no blood transfusion during the study period, and thus we can exclude the effects of such factors on rSO2. Thus, our data suggest that administration of 1 MAC isoflurane during propofol anesthesia has little effect on regional cerebral oxygen status.
One might question the use of nitrous oxide in the present study, since nitrous oxide may affect electroencephalographic variables, including the BIS. We do not know the interaction of nitrous oxide with aminophylline, although evidence to date indicates that N2O induces endogenous opioid peptide release in the periaqueductal gray area of the midbrain leading to the activation of the descending inhibitory pathways, resulting in modulation of the pain/nociceptive processing in the spinal cord.18 On the other hand, some studies have shown that the use of N2O had little influence on the BIS score. For example, Rampil et al.2 reported in human volunteers that 50% N2O/O2 had no effect on the BIS and spectral edge frequency, although it significantly increased theta, beta 40–50 Hz, and 70–110 Hz band powers. Similar observations that up to 66% N2O does not alter the BIS have also been reported.19 Studies have shown that opioids,20 as well as nitrous oxide, do not affect BIS values when correlated with drug concentrations and clinical responses.
In conclusion, we have shown that midazolam or isoflurane-induced decreases in BIS during propofol anesthesia are not accompanied by a decrease in rSO2. A single dose of aminophylline interfered with propofol effects on EEG parameters and increased the BIS score, suggesting that aminophylline can antagonize, at least in part, the sedative actions of propofol.
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Acknowledgments |
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Footnotes |
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A part of the present study was presented at the Annual Meeting of the American Society of Anesthesiologists, October 23-27, 2004 in Las Vegas, Nevada, USA.
Assessed April 8, 2005. Accepted for publication September 1, 2005. Revision accepted October 31, 2005.
Competing interests: None declared.
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References |
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2 Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998; 89: 980–1002.[Medline]
3 Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997; 86: 836–47.[Medline]
4 Ibrahim AE, Taraday JK, Kharasch ED. Bispectral index monitoring during sedation with sevoflurane, midazolam, and propofol. Anesthesiology 2001; 95: 1151–9.[Medline]
5 Iselin-Chaves IA, Flaishon R, Sebel PS, et al. The effect of the interaction of propofol and alfentanil on recall, loss of consciousness, and the Bispectral Index. Anesth Analg 1998; 87: 949–55.
6 Stirt JA. Aminophylline is a diazepam antagonist. Anesth Analg 1981; 60: 767–8.
7 Arvidsson SB, Ekstrom-Jodal B, Martinell SA, Niemand D. Aminophylline antagonises diazepam sedation. Lancet 1982; 2: 1467.[Medline]
8 Niemand D, Martinell S, Arvidsson S, Svedmyr N, Ekstrom-Jodal B. Aminophylline inhibition of diazepam sedation: is adenosine blockade of GABA-receptors the mechanism? Lancet 1984; 1: 463–4.[Medline]
9 Taylor BL, Collins C. Aminophylline and propofol: apparent antagonism. Anaesthesia 1988; 43: 508.[Medline]
10 Kishi K, Kawaguchi M, Yoshitani K, Nagahata T, Furuya H. Influence of patient variables and sensor location on regional cerebral oxygen saturation measured by INVOS 4100 near-infrared spectrophotometers. J Neurosurg Anesthesiol 2003; 15: 302–6.[Medline]
11 Lovell AT, Owen-Reece H, Elwell CE, Smith M, Goldstone JC. Continuous measurement of cerebral oxygenation by near infrared spectroscopy during induction of anesthesia. Anesth Analg 1999; 88: 554–8.
12 Michenfelder JD. Anesthesia and the Brain. New York: Churchill Livingstone; 1988.
13 Milde LN, Milde JH, Michenfelder JD. Cerebral functional, metabolic, and hemodynamic effects of etomidate in dogs. Anesthesiology 1985; 63: 371–7.[Medline]
14 Iwasaki K, Nomoto Y, Ishiwata M, Yokota T, Ogawa R. Vital capacity induction with 8% sevoflurane and N2O causes cerebral hyperemia. J Anesth 2003; 17: 3–7.[Medline]
15 Turan A, Memis D, Karamanlyodthlu B, Pamukcu Z, Sut N. Effect of aminophylline on bispectral index. Acta Anaesthesiol Scand 2004; 48: 408–11.[Medline]
16 Ishiyama T, Oguchi T, Iijima T, Matsukawa T, Kashimoto S, Kumazawa T. Ephedrine, but not phenylephrine, increases bispectral index values during combined general and epidural anesthesia. Anesth Analg 2003; 97: 780–4.
17 Torella F, Haynes SL, McCollum CN. Cerebral and peripheral oxygen saturation during red cell transfusion. J Surg Res 2003; 110: 217–21.[Medline]
18 Fujinaga M, Maze M. Neurobiology of nitrous oxide-induced antinociceptive effects. Mol Neurobiol 2002; 25: 167–89.[Medline]
19 Barr G, Jakobsson JG, Owall A, Anderson RE. Nitrous oxide does not alter bispectral index: study with nitrous oxide as sole agent and as an adjunct to i.v. anaesthesia. Br J Anaesth 1999; 82: 827–30.
20 Johansen JW, Sebel PS. Development and clinical application of electroencephalographic bispectrum monitoring. Anesthesiology 2000; 93: 1336–44.[Medline]
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