Anesth Analg 2002;94:886-891
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Interaction Between Propofol and Clonidine for Loss of Consciousness
Hideyuki Higuchi, MD*,
Yushi Adachi, MD
,
Albert Dahan, MD, PhD
,
Erik Olofsen, MSc,
Shinya Arimura, MD*,
Tomohisa Mori, MD*, and
Tetsuo Satoh, MD
*Department of Anesthesia, Self Defense Force Central Hospital, Tokyo; Departments of Anesthesiology, National Defense Medical College, Saitama, Japan; and Leiden University Medical Center, Leiden, The Netherlands
Address correspondence and reprint requests to Hideyuki Higuchi, MD, Department of Anesthesia, Self Defense Force Hanshin Hospital, 4-1-50 Kushiro, Kawanishi, Hyogo 666-0024, Japan. Address e-mail to higu-chi{at}ka2.so-net.ne.jp
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Abstract
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Clonidine premedication reduces the intraoperative requirement for opioids and volatile anesthetics. Clonidine also reduces the induction dose of IV anesthetics. There is no information, however, regarding the effect of oral clonidine premedication on the propofol blood concentrations required for loss of consciousness, and the interaction between propofol and clonidine. We randomly administered target effect-site concentrations of propofol ranging from 0.5 to 5. 0 µg/mL by using computer-assisted target-controlled infusion to 3 groups of healthy male patients: Control (n = 35), 2.5 µg/kg Clonidine (n = 36), and 5.0 µg/kg Clonidine (n = 36) groups. Nothing was administered to the Control group. Clonidine (2.5 or 5.0 µg/kg) was administered orally 90 min before the induction of anesthesia in the Clonidine groups. After equilibration between the blood and effect-site for 15 min, a verbal command to open their eyes was given two times to the patients. Arterial blood samples for analysis of the serum propofol and clonidine concentrations were taken immediately before verbal commands were given. Measured serum propofol concentrations in equilibrium with the effect-site at which 50% of the patients did not respond to verbal commands (EC50 for loss of consciousness) were determined by logistic regression. The EC50 ± SE values in the Control, 2.5 µg/kg Clonidine, and 5.0 µg/kg Clonidine groups were 2.67 ± 0.18, 1.31 ± 0.12, and 0.91 ± 0.13 µg/mL, respectively. The EC50 in the 2.5 and 5.0 µg/kg clonidine groups was significantly smaller than that in the Control group (P < 0.001). The use of a response surface modeling analysis indicated that there was an additive interaction between measured arterial propofol and clonidine concentrations in relation to loss of consciousness. These results indicate that propofol and clonidine act additively for loss of consciousness.
IMPLICATIONS: Oral clonidine 2.5 and 5.0 µg/kg premedication decreases the propofol concentration required for loss of consciousness.
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Introduction
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Clonidine, an 
2-adrenergic receptor agonist, is a useful drug for premedication because it produces anxiolysis and sedation (1). Its effects, however, are not limited to the preoperative period. Clonidine premedication reduces the intraoperative requirement for opioids and volatile anesthetics (2,3). Clonidine also reduces the induction dose of IV anesthetics, such as thiamylal and propofol (4–6). There are, however, some limitations in the previous studies (4–6). IV anesthetics were administered in dose increments, which might lead to overestimation of the dose required to produce loss of consciousness (4,6). In addition, because the responses were investigated after a bolus dose of anesthetics, the biophase (effect-site compartment) had not reached equilibrium at the time of testing for hypnosis (4–6). Such confounding factors can only be eliminated by maintaining stable effect-site concentrations of the IV drug using computer-assisted target-controlled infusion (TCI). Furthermore, there is no information on the pharmacokinetics and pharmacodynamic interaction between propofol and clonidine for loss of consciousness. Therefore, the aim of the present study was to investigate the effects of oral clonidine premedication on the requirement of propofol for loss of consciousness by using TCI. We compared the EC50 of propofol for loss of consciousness (the measured propofol blood concentration in equilibrium with the effect-site at which 50% of the patients did not respond to a verbal command) between a control group and groups receiving 2.5 or 5.0 µg/kg oral clonidine. Similarly, we measured the arterial clonidine concentration. In addition, we investigated the nature of the interaction between propofol and clonidine for loss of consciousness.
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Methods
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Written informed consent was obtained from each patient after explanation of the study, which was approved by the Local Clinical Research Ethics Committee. Healthy male patients (n = 107) were recruited. Patients were eligible for the study if they were classified as ASA physical status I, aged 18–53 yr, and had no known contraindication to using propofol. Patients were excluded if they were taking any medications, or were significantly obese (body mass index >35). Patients were randomly assigned to one of three groups: Control (n = 35), 2.5 µg/kg Clonidine (n = 36), and 5.0 µg/kg Clonidine (n = 36). Nothing was administered to the Control group. Clonidine (2.5 or 5.0 µg/kg) was administered orally 90 min before arrival at the operating room in the Clonidine groups. Because clonidine is available only in tablets of 75 or 150 µg in Japan, doses were determined by choosing the dose closest to half, one-third, and a quarter of a tablet.
Upon arrival of the patient in the operating room, an 18-gauge venous cannula was inserted and then acetated Ringer’s solution was administered. A 20-gauge radial artery catheter was inserted for blood sampling and for measuring arterial pressure. Heart rate, blood pressure, and oxyhemoglobin saturation were monitored continuously during the study. After preoxygenation, computer-controlled TCI was started, targeting the effect-site concentration. Propofol was administered via a Graseby 3500 syringe pump (SIMS Graseby Ltd., Herts, England) using the infusion program RUGLOOP (written by T. De Smet and M. Struys, Ghent University, Gent, Belgium) (7). Effect compartment controlled administration was used. A three-compartment model (8) with an enlarged effect-site compartment was used. The effect-site equilibration constant, ke0, was computed to yield a time to peak effect of 1.6 min after bolus injection, yielding a t1/2 ke0 of 34 s (9,10).
Within each group, patients were randomized to receive predetermined target concentrations of propofol ranging from 0.5 to 5.0 µg/mL (Fig. 1). These values were selected on the basis of our preliminary research. Each patient received only one predetermined target concentration of propofol. To ensure equilibration between the blood and effect-site, the predetermined target concentration (Fig. 1) was maintained for 15 min before giving the verbal command. All patients breathed spontaneously or with manual assistance when necessary and received oxygen via a face mask. Arterial blood samples for analysis of the serum propofol concentration were taken at 9 and 14 min after equilibration between the blood and effect-site concentrations. Simultaneously, arterial blood samples for analysis of the serum clonidine concentration were taken at 9 and 14 min. After a 15-min equilibration period of the predetermined propofol serum concentration (set by TCI), a verbal command to open their eyes was given two times to the patients. Patients who did not open their eyes were recorded as "unresponsive" (loss of consciousness), and patients who opened their eyes were recorded as "responsive." The responses were identified by one of the authors (SA), who was blinded to the predetermined propofol serum concentration. For determination of the EC50 for loss of consciousness, we used only the data of responses at the predetermined equilibrated propofol concentration, as shown in Figure 1: Only paired samples with concentrations within ±35% of each other were analyzed (11). From these samples, only the postassessment propofol concentrations were used for analysis (12). The EC50 for loss of consciousness of the three groups and the reduction of EC50 by clonidine were calculated by logistic regression or by using the following multiple independent variable logistic regression model (13):
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Figure 1. Target concentrations of propofol to which patients were randomized for assessment of response. The bars represent individual patients.
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equation
equation
where X1 is the measured propofol concentration, X2 is the measured clonidine concentration, X3 is the age of the patient, ß0 is the regression intercept constant, ß1 is the coefficient for propofol, ß2 is the coefficient for clonidine, and ß12 is the coefficient for the product of propofol and clonidine concentration (interaction coefficient). ß3 is the coefficient for age (Statview 5.0; SAS Institute, Cary, NC). Each EC50 value of propofol in the three groups was determined by setting the probability of no response to be 0.5 and the clonidine concentration to be zero. To investigate the relation between the clonidine dose and EC50 values, the clonidine dose at which 50% of the patients had no responses to a verbal command was calculated by applying the following formula (12):
equation
where variables A and B were estimated for the remaining patients, in which paired samples had concentrations within ±35% of each other.
To investigate the nature of the interaction between propofol and clonidine, the data sets were analyzed by response surface modeling, as reported by Minto et al. (14) and Dahan et al. (15). In brief, we used the following model of the probability of no response to verbal commands (14,15):
equation
equation
where UP is the normalized concentration of propofol, UC is the normalized concentration of clonidine, and C50,P and C50,C denote the concentration at which P = 50% with either propofol or clonidine present, respectively. The dependence of U50(Q) and 
(Q) on Q allows the assessment of the type of interaction between the two drugs. U50(Q) is the relative potency of the drug combination at ratio Q, and denotes the steepness of the concentration-effect curve. For U50(Q) and (Q), any smooth function of Q can be used; here, splines I(Q) were tested with three knots viz. Q = 0, Q = Qmax, and Q = 1 with the constraints dI(Q)/ dQ || Q=Qmax = I(1) - I(0) and U50(0) = U50(1) = 1 (15). Initially, the splines were constrained to be the constant functions U50(Q) = 1 and (Q) = .
The blood samples were allowed to clot and were then centrifuged at 3000 rpm for 10 min, and the serum was frozen at -4°C until assayed. The serum concentration of propofol was determined by using a high-performance liquid chromatograph with a fluorescence detection wavelength of 310 nm and excitation wavelength of 276 nm (RF550; Shimadzu, Kyoto, Japan), as described previously (16). The area under the chromatographic peak was measured by using an integrator (PowerChrom; ADInstruments, Tokyo, Japan). The propofol concentration was estimated from a peak-area ratio to the internal standard, thymol. Linear relationships were obtained between propofol and the internal standard peak-area ratios. The correlation coefficient was >0.997 in the range of 50 ng/mL to 10 µg/mL. The detection limit of propofol was 10 ng/mL using this assay. The repeatability coefficients of the variation in serum were 4.6% and 2.1% at concentrations of 1 and 10 µg/mL, and 2.2% between days (10 µg/mL). The serum concentration of clonidine was measured in an outside laboratory by using a radioimmunoassay with [3H]-clonidine according to the modified method described previously (17). Linear relationships were obtained in the Scatchard plot against the concentration of labeled plus unlabeled bound ligand. The correlation coefficient was >0.993 in the range of 10 to 1000 pg/mL. The detection limit of clonidine was 10 pg/mL using this assay. The coefficient of variation did not exceed 4.3% for any of 7 standard determinations with 5 replicates.
For each pair of predicted and measured propofol values, the median prediction error and absolute prediction error (18) were calculated. Results were presented as mean ± SD, or EC50 and EC95 ± SE (95% confidence interval). Analyses of patients’ demographic data and the values of EC50 or EC95 for loss of consciousness within each group were performed with one-way analysis of variance followed by Tukey’s post hoc test. A P value < 0.05 was considered to be statistically significant. In the analysis by response surface modeling, logistic regression analysis was performed with NONMEM (University of California, San Francisco, CA) (19). Improvement of the fit by removing the restriction of the splines to be constant was assessed by the likelihood ratio test with P < 0.01 considered to be significant.
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Results
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All 107 patients completed the study without adverse effects, such as bradycardia, or hypotension. Of the 107 patients, 15 patients (5 per group) were excluded from analysis because pre- and postassessment paired samples did not give concentrations within ±35% of each other: the data from 92 patients were analyzed. There was no significant difference in age, weight, or height among the groups.
The measured serum clonidine concentration in the 5.0 µg/kg Clonidine group was 1.31 ± 0.25 (ng/mL), significantly larger than that in the 2.5 µg/kg Clonidine group, 0.75 ± 0.11 (ng/mL) (P < 0.001; Table 1). The median prediction error and median absolute prediction error for TCI administration of propofol in the Control group were -7.3% and 11.0%, respectively. Corresponding values in the 2.5 and 5.0 µg/kg Clonidine groups were -20.0% and 20.0%, -20.0% and 20.0%, respectively (Table 1). The EC50 and EC95 are presented in Table 1. The concentration-response to verbal command curve is shown in Figure 2. The EC50 ± SE (95% confidence interval) of propofol for loss of consciousness in the Control group was 2.67 ± 0.18 (2.30–3.04), whereas the corresponding values in the 2.5 and 5.0 µg/kg Clonidine groups were 1.31 ± 0.12 (1.07–1.55) and 0.91 ± 0.13 (0.66–1.17). The EC50 in the 2.5 and 5.0 µg/kg Clonidine groups was significantly smaller than that in the Control group (P < 0.001). There were significant differences between the EC95 of the 2.5 or 5.0 µg/kg (P < 0.01) Clonidine groups and the Control group (Table 1). The EC50 was calculated to be EC50 = 2.51 - 0.34 · dose. Coefficient estimates for a multiple independent variable logistic regression model are presented in Table 2. Although the coefficients ß2 and ß3 were not significantly different from zero, the interaction coefficient ß12 was significantly different from zero (P < 0.05). Accordingly, a multiple independent variable logistic regression was reanalyzed by excluding the age factor (Table 2). In that case, the interaction coefficient ß12 was also significantly different from zero, although coefficient ß2 was not significantly different.
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Figure 2. Relation between the serum concentration and response to verbal command in the three groups. The diagrams show the measured arterial propofol concentration of every patient associated with (x = positive response) or without (open circles = negative response) the response. The concentration-effect curves were defined from the data shown in the upper diagrams of the three groups using logistic regression. The straight line indicates ± SE of EC50.
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The parameterestimates of the response surface model are shown in Table 3. Figure 3 presents the three-dimensional response surface model relating propofol and clonidine concentrations with the probability of no response to verbal command. Extending the pharmacodynamic model with splines for the interaction terms did not result in a statistically significant improvement of the fit. Values for the U50 spline were U50(Qmax) = 0.67 at Qmax = 0.71 with P = 0.08 (decrease in log likelihood was 5.1 U). The drug interaction can therefore be described as purely additive.
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Figure 3. Response surface modeling of the influence of propofol and clonidine on loss of consciousness. Inlet, The raw data from every patient associated with (x = positive response) or without (open circles = negative response) the response to verbal command are shown with 10% (dashed line), 50% (thick line), and 95% (thin line) isoeffect lines. These findings indicate additive interaction.
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Discussion
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The main purpose of the present study was to determine the reduction of the EC50 of propofol for loss of consciousness by oral clonidine administration. Premedication with 2.5 and 5.0 µg/kg oral clonidine successfully reduced the EC50 of propofol for loss of consciousness by approximately 50% and 65%, respectively. Furthermore, there was a significant interaction between propofol and clonidine in relation to loss of consciousness.
Gan et al. (20) reported that gender is an important variable in recovery from general anesthesia (propofol- alfentanil-nitrous oxide) and that including gender as a variable was necessary in pharmacokinetic and pharmacodynamic studies of anesthetic drugs. Therefore, only male patients were included in the present study.
The EC50 of propofol for loss of consciousness in the Control group was 2.67 µg/mL, which was comparable with that obtained in previous studies, 2.2–4.4 µg/mL (11,12,21). The extent of reduction of the EC50 of propofol by 2.5 and 5.0 µg/kg oral clonidine premedication was more than that obtained in the previous studies (4–6). The larger reduction in the present study than those in these studies may be attributable to methodologic differences. Nishina et al. (4) reported that 2 and 4 µg/kg oral clonidine premedication decreased the dose of thiamylal required for the induction of anesthesia in children by 16% and 27%, respectively. Goyagi et al. (6) also reported that 4 µg/kg oral clonidine premedication decreased the induction dose of propofol in female patients by 26%. These two studies (4,6) compared incremental doses of anesthetics up to loss of consciousness, which might cause overestimation of the true requirement of anesthetics. Kulka et al. (5) reported that 4 µg/kg IV clonidine pretreatment reduced the ED50 of propofol for loss of consciousness, which was evaluated after a bolus infusion, by 45%. However, we compared the EC50 of propofol for loss of consciousness after a 15-min equilibration between blood and effect-site by using computer- assisted TCI.
The propofol concentration-response curve of the 2.5 µg/kg Clonidine group was greatly shifted to the left and overlapped with that of the 5.0 µg/kg group in the upper portions of the curve (Fig. 2). The confidence intervals of EC95 in both groups overlapped with each other (Table 1). This might be attributable to the larger clonidine concentrations in the 2.5 µg/kg Oral Clonidine group than in half of those in the 5.0 µg/kg Oral Clonidine group (0.75 versus 1.31 ng/mL; Table 1).
Many studies demonstrated that the propofol requirements for induction and maintenance of anesthesia are reduced in the elderly (10–12,16). This can be explained by age-related changes in pharmacokinetics, pharmacodynamics, or both. By using electroencephalogram measures and responsiveness to verbal command, Schnider et al. (10) demonstrated that age increases the sensitivity of the brain to propofol. The present study, however, failed to demonstrate a significant effect of age on the EC50 of propofol for loss of consciousness (P = 0.10). This failure might have resulted from the narrow age range in the present study. In the present study, approximately 60% of all patients were in their 20s.
Although anesthetic drug interactions have traditionally been characterized by using isobolographic analysis or multiple logistic regressions, both approaches have significant limitations. Response surface modeling analysis enables us to construct three-dimensional representations of the concentration-response relation among combinations of propofol and clonidine and to assess the nature of the interaction (additive, synergistic, or antagonistic) over the whole surface area (14,15). In the present study, the interaction was modeled by splines, in contrast to polynomials as in the study by Minto et al. (14). An advantage of the splines is their flexibility, but each time a spline is extended with a knot, two additional parameters are needed. It is unlikely, however, that a parabola (described by "ß2" in the approach used by Minto et al.) (15) would yield different results; a decrease of 5.1 with one parameter would give P = 0.02, whereas the use of a parabola is similar to constraining Qmax at 0.5.
The hypnotic synergism was demonstrated between propofol and midazolam in female patients (22,23). In the present study, the analysis by response surface modeling revealed that the interaction between propofol and clonidine for loss of consciousness was additive. Our failure to demonstrate the synergistic interaction between propofol and clonidine might be related to the small sample size and/or the narrow clonidine concentration range in the present study, because the interaction tended to be synergistic (P = 0.08). We investigated the dose of clonidine within clinical use. It is unlikely, however, that the different site of action of each drug (propofol and clonidine) accounts for the absence of synergism. Propofol and benzodiazepines exert anesthetic action by enhancement of -aminobutyric acid-A receptors (24,25). However, although 2-adrenergic agonists such as clonidine produce clinical effects after binding to 2-adrenergic receptors (1), clonidine also increases the release of -aminobutyric acid in rats (26). Indeed, the hypnotic synergistic interaction was reported between dexmedetomidine, a highly selective 2-adrenergic agonist, and midazolam in rats (27).
In summary, 2.5 and 5.0 µg/kg oral clonidine premedication significantly reduced the EC50 and EC95 of propofol for loss of consciousness in male patients. Response surface modeling analysis revealed that there was an additive interaction between propofol and clonidine for loss of consciousness.
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Acknowledgments
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This study was supported by funding from institutional and department resources only.
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References
|
|---|
-
Kamibayashi T, Maze M. Clinical uses of 2-adrenergic agonists. Anesthesiology 2000; 93: 1345–9.[ISI][Medline]
-
Ghignone M, Calvillo O, Quintin L. Anesthesia and hypertension: the effect of clonidine on perioperative hemodynamics and isoflurane requirements. Anesthesiology 1987; 67: 3–10.[ISI][Medline]
-
Ghignone M, Quintin L, Duke PC, et al. Effects of clonidine on narcotic requirements and hemodynamic response during induction of fentanyl anesthesia and endotracheal intubation. Anesthesiology 1986; 64: 36–42.[ISI][Medline]
-
Nishina K, Mikawa K, Maekawa N, et al. Clonidine decreases the dose of thiamylal required to induce anesthesia in children. Anesth Analg 1994; 79: 766–8.[Abstract/Free Full Text]
-
Kulka PJ, Tryba M, Sczepanski U, Zenz M. Does clonidine modify the hypnotic effect of propofol? Anaesthesist 1993; 42: 630–7.[ISI][Medline]
-
Goyagi T, Tanaka M, Nishikawa T. Oral clonidine premedication reduces induction dose and prolongs awakening time from propofol-nitrous oxide anesthesia. Can J Anaesth 1999; 46: 894–6.[Abstract/Free Full Text]
-
Struys MM, De Smet T, Depoorter B, et al. Comparison of plasma compartment versus two methods for effect compartment: controlled target-controlled infusion for propofol. Anesthesiology 2000; 92: 399–406.[ISI][Medline]
-
Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991; 67: 41–8.[Abstract/Free Full Text]
-
Shafer SL, Gregg KM. Algorithms to rapidly achieve and maintain stable drug concentrations at the site of drug effect with a computer-controlled infusion pump. J Pharmacokinet Biopharm 1992; 20: 147–69.[ISI][Medline]
-
Schnider TW, Minto CF, Shafer SL, et al. The influence of age on propofol pharmacodynamics. Anesthesiology 1999; 90: 1502–16.[ISI][Medline]
-
Smith C, McEwan AI, Jhaveri R, et al. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994; 81: 820–8.[ISI][Medline]
-
Kazama T, Takeuchi K, Ikeda K, et al. Optimal propofol plasma concentration during upper gastrointestinal endoscopy in young, middle-aged, and elderly patients. Anesthesiology 2000; 93: 662–9.[ISI][Medline]
-
Katoh T, Uchiyama T, Ikeda K. Effect of fentanyl on awakening concentration of sevoflurane. Br J Anaesth 1994; 73: 322–5.[Abstract/Free Full Text]
-
Minto CF, Schnider TW, Short TG, et al. Response surface model for anesthetic drug interactions. Anesthesiology 2000; 92: 1603–16.[ISI][Medline]
-
Dahan A, Nieuwenhuijs D, Olofsen E, et al. Response surface modeling of alfentanil-sevoflurane interaction on cardiorespiratory control and bispectral index. Anesthesiology 2001; 94: 982–91.[ISI][Medline]
-
Adachi Y, Watanabe K, Higuchi H, Satoh T. The determinants of propofol induction of anesthetic dose. Anesth Analg 2001; 92: 656–61.[Abstract/Free Full Text]
-
Arndts D, Stahle H, Struck CJ. A newly developed precise and sensitive radioimmunoassay for clonidine. Arzneimittelforschung 1979; 29: 532–8.[Medline]
-
Varvel JR, Donoho DL, Shafer SL. Measuring the predictive performance of computer-controlled infusion pumps. J Pharmacokinet Biopharm 1992; 20: 63–94.[ISI][Medline]
-
Beal SL, Sheiner LB. NONMEN user’s guide. San Francisco: University of California, 1998.
-
Gan TJ, Glass PS, Sigl J, et al. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999; 90: 1283–7.[ISI][Medline]
-
Kazama T, Ikeda K, Morita K. Reduction by fentanyl of the Cp50 values of propofol and hemodynamic responses to various noxious stimuli. Anesthesiology 1997; 87: 213–27.[ISI][Medline]
-
Short TG, Chui PT. Propofol and midazolam act synergistically in combination. Br J Anaesth 1991; 67: 539–45.[Abstract/Free Full Text]
-
McClune S, McKay AC, Wright PM, et al. Synergistic interaction between midazolam and propofol. Br J Anaesth 1992; 69: 240–5.[Abstract/Free Full Text]
-
Hara M, Kai Y, Ikemoto Y. Enhancement by propofol of the gamma-aminobutyric acidA response in dissociated hippocampal pyramidal neurons of the rat. Anesthesiology 1994; 81: 988–94.[ISI][Medline]
-
Macdonald R, Barker JL. Benzodiazepines specifically modulate GABA-mediated postsynaptic inhibition in cultured mammalian neurones. Nature 1978; 271: 563–4.[Medline]
-
Pittaluga A, Raiteri M. Clonidine enhances the release of endogenous gamma-aminobutyric acid through alpha-2 and alpha-1 presynaptic adrenoceptors differentially located in rat cerebral cortex subregions. J Pharmacol Exp Ther 1988; 245: 682–6.[Abstract/Free Full Text]
-
Salonen M, Reid K, Maze M. Synergistic interaction between alpha 2-adrenergic agonists and benzodiazepines in rats. Anesthesiology 1992; 76: 1004–11.[ISI][Medline]
Accepted for publication December 11, 2001.
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J. F. A. Hendrickx, E. I. Eger II, J. M. Sonner, and S. L. Shafer
Is Synergy the Rule? A Review of Anesthetic Interactions Producing Hypnosis and Immobility
Anesth. Analg.,
August 1, 2008;
107(2):
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[Abstract]
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Abstract
Introduction
