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Anesth Analg 2005;100:687-696 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000144420.87770.FE
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2-Adrenoceptor for Controlling Convulsions
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Abstract |
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Dexmedetomidine, a highly selective
2-adrenoceptor agonist, is used in combination with local anesthetics for sedation and analgesia. We tested the hypothesis that dexmedetomidine used for sedation alters the convulsive potency of racemic bupivacaine and levobupivacaine in awake, spontaneously breathing rats. In the first experiments, male Sprague-Dawley rats were randomly divided into six groups: bupivacaine with no dexmedetomidine (bupivacaine control; BC), bupivacaine with small-dose dexmedetomidine (BS), bupivacaine with large-dose dexmedetomidine (BL), levobupivacaine with no dexmedetomidine (levobupivacaine control; LC), levobupivacaine with small-dose dexmedetomidine (LS), and levobupivacaine with large-dose dexmedetomidine (LL) (n = 10 for each group). Continuous infusion of dexmedetomidine (Groups BC and LC, 0 µg · kg–1 · h–1; Groups BS and LS, 3.6 µg · kg–1 · h–1; and Groups BL and LL, 10.8 µg · kg–1 · h–1) was started after bolus injection (Groups BC and LC, 0 µg/kg; Groups BS and LS, 0.5 µg/kg; and Groups BL and LL, 1.5 µg/kg). Fifteen minutes after the start of the dexmedetomidine infusion, continuous infusion of bupivacaine (Groups BC, BS, and BL) or levobupivacaine (Groups LC, LS, and LL) at 1 mg · kg–1 · min–1 was started and continued until tonic/clonic convulsions occurred. Dexmedetomidine achieved significantly different sedation levels both in Groups BC, BS, and BL and in Groups LC, LS, and LL (P < 0.05). Convulsive doses of bupivacaine and levobupivacaine were significantly larger in Groups BL and LL than in Groups BC and LC, respectively (P < 0.01 for both). Concentrations of bupivacaine and levobupivacaine in plasma and in brain at the onset of convulsions were also larger in Groups BL and LL than in Groups BC and LC (P < 0.01 for both). In the second experiment, yohimbine (1 mg/kg) administered 10 min before and 5 min after the start of dexmedetomidine infusion completely reversed the sedative effect of dexmedetomidine (bolus 1.5 µg/kg, followed by 10.8 µg · kg–1 · h–1). Convulsive doses and plasma and brain concentrations of bupivacaine and levobupivacaine at the onset of convulsions in rats receiving yohimbine and dexmedetomidine were significantly smaller than in those receiving only dexmedetomidine (P < 0.05 for all) and were similar to those without dexmedetomidine or yohimbine. We conclude that dexmedetomidine used for sedation decreases the convulsive potency of both bupivacaine and levobupivacaine in rats. 2-Adrenoceptor agonism may be involved in this anticonvulsant potency. |
Introduction |
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Large-dose local anesthetics are often used for regional anesthesia and postoperative analgesia. Intravascular injection of local anesthetics can result in central nervous system (CNS) and cardiovascular toxicity. Sedatives and hypnotics used in combination with local anesthetics affect their CNS toxicity and modulate the threshold for convulsions (1,2). Dexmedetomidine is a selective
2-adrenoceptor agonist with analgesic potency and causes minimal respiratory depression. It is a good option for intraoperative sedation under regional anesthesia and for postoperative analgesia. Although there have been numerous studies of the pro- and anticonvulsant effects of dexmedetomidine (3–6), most have examined its effects on chemical-induced convulsions (3–5), and only a few studies have evaluated the effects on local anesthetic-induced CNS toxicity (6). Whittington et al. (6) showed that dexmedetomidine inhibits cocaine-induced convulsions by modulating intracerebral amine levels. However, no studies have examined the effect of dexmedetomidine on the convulsive potency of the amide-type local anesthetics often used in the perioperative period. Because alterations of intracerebral monoamine levels are associated with local anesthetic-induced convulsions and because 2-adrenoceptors play important roles in controlling cerebral monoamines (7,8), dexmedetomidine may affect their CNS toxicity (1,9).
Bupivacaine is one of the most commonly used local anesthetics. It is a racemic mixture of dextro- and levorotatory stereoisomers. As noted with other amide-type local anesthetics, these isomers have different pharmacokinetic profiles and CNS and cardiovascular toxicities (10), and the less toxic S(–) isomer, levobupivacaine, has been introduced clinically. Despite numerous studies of the anesthetic potency and toxicity of these isomers (10–12), none has examined the effect of concomitantly administered drugs on the CNS toxicity of stereoisomers of bupivacaine. Because one drug may have different effects on the pharmacokinetics and pharmacodynamics of the stereoisomers of another (13,14), dexmedetomidine may have differential effects on the CNS toxicity of bupivacaine and levobupivacaine. In this study, we tested the hypothesis that dexmedetomidine used for sedation decreases the CNS toxicity of bupivacaine and examined differences in the effects on racemic bupivacaine and levobupivacaine in awake, spontaneously breathing rats. We also examined the involvement of 2-adrenoceptors for controlling convulsions by using yohimbine, an 2-adrenoceptor antagonist.
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Methods |
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Effect of Dexmedetomidine on Bupivacaine- and Levobupivacaine-Induced Convulsions (Protocol 1)
Dexmedetomidine and levobupivacaine were supplied by Abbott Laboratories Inc. (North Chicago, IL) and Maruishi Pharmaceutical Co., Ltd. (Osaka, Japan), respectively. Other reagents are commercially available. After approval from the Institutional Animal Care and Use Committee, 60 male Sprague-Dawley rats aged 9 wk and weighing 320–360 g (CLEA Japan, Inc., Tokyo, Japan) were included in the study. Under general anesthesia with sevoflurane, the carotid artery and cervical and femoral veins were cannulated as described previously (15). Before emergence from anesthesia, the animals were placed in a semidark, closed cardboard box to recover for at least 4 h before the experiment. Rectal temperature was maintained at 37°C with an infrared lamp. The animals were allowed to acclimatize to the new environment for at least 1 h before the study and were randomly divided into six groups: bupivacaine with no dexmedetomidine (bupivacaine control; BC), bupivacaine with small-dose dexmedetomidine (BS), bupivacaine with large-dose dexmedetomidine (BL), levobupivacaine with no dexmedetomidine (levobupivacaine control; LC), levobupivacaine with small-dose dexmedetomidine (LS), and levobupivacaine with large-dose dexmedetomidine (LL) (n = 10 in each group) (Fig. 1, Protocol 1). After baseline measurements, a continuous infusion of dexmedetomidine was started (Groups BS and LS, 3.6 µg · kg–1 · h–1; Groups BL and LL, 10.8 µg · kg–1 · h–1) after bolus injection of an initial dose (Groups BS and LS, 0.5 µg/kg; Groups BL and LL, 1.5 µg/kg) via the femoral vein by an infusion pump (ATOM 1235; Nipro, Japan) until the end of the study. The same amount of saline was administered to rats in Groups BC and LC. Doses of dexmedetomidine were determined on the basis of the pharmacokinetic variables reported previously (16) and on preliminary experiments we performed to determine doses yielding adequate levels of sedation. Fifteen minutes after the bolus injection of saline or dexmedetomidine, continuous IV infusion of bupivacaine (Groups BC, BS, and BL) or levobupivacaine (Groups LC, LS, and LL) via the cervical vein was started at 1 mg · kg–1 · min–1 until tonic/clonic convulsions occurred.
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Observation of rats was performed by one of the authors (YO), who was unaware of group allocation. Levels of sedation were evaluated every minute during the infusion of dexmedetomidine according to a method reported by Lee et al. (2), with modifications: Grade 0, resting quietly, intermittent spontaneous activity; Grade 1, sedated and arousable with difficulty, with diminished whisker reflex but with intact righting reflex; and Grade 2, never arousable, with diminished righting reflex. We used these grades because all the rats were at Grade 0 before the administration of dexmedetomidine in a dark environment, and higher levels of sedation induced apnea after the start of bupivacaine infusion. Arterial blood (0.3 mL) was drawn before injection of saline or dexmedetomidine (baseline), before the beginning of local anesthetic infusion, and at the onset of convulsions to determine blood gas tensions and pH. An additional 0.3 mL of blood was obtained at 5, 10, and 15 min after the start of dexmedetomidine infusion to determine its concentration. At the onset of convulsions, an additional 2.5 mL of blood was obtained to measure the plasma concentrations of dexmedetomidine and local anesthetics. Immediately after blood sampling, rats were killed with IV thiopental (100 mg/kg). A catheter was inserted in the thoracic aorta, and the brain was removed after perfusion with 40 mL of ice-cold saline via the catheter to determine the concentrations of racemic bupivacaine or levobupivacaine in the brain. Appropriate placement of catheters into the carotid arteries and cervical and femoral veins was verified by injecting indocyanine green and examining its extravasation. Blood gases and pH were measured immediately after sampling with a blood gas analyzer (ABL4; Radiometer, Copenhagen, Denmark). The remaining blood samples were centrifuged, and plasma and brain samples were frozen and kept at –80°C until analysis.
The number of animals per group was determined according to previous experiments (15) and the data we obtained for 10 animals. In the previous study, a convulsive dose of racemic bupivacaine was 6.2 ± 1.5 mg/kg. We assumed that a 35% increase of the convulsive dose of racemic bupivacaine by dexmedetomidine would be expected. On the basis of analysis of variance (ANOVA) sample size calculations and assuming a Type I error protection of 0.05 and a power of 0.80, 10 animals were required in each of the 6 groups.
Effect of Pretreatment with Yohimbine on Bupivacaine- and Levobupivacaine-Induced Convulsions (Protocol 2)
After preparation as described previously, 30 Sprague-Dawley rats were divided into 6 groups: bupivacaine without dexmedetomidine or yohimbine (Group B); bupivacaine with dexmedetomidine, but not yohimbine (Group BD); bupivacaine with both yohimbine and dexmedetomidine (Group BYD); levobupivacaine without dexmedetomidine or yohimbine (Group L); levobupivacaine with dexmedetomidine, but not yohimbine (Group LD); and levobupivacaine with both yohimbine and dexmedetomidine (Group LYD) (n = 5 per group) (Fig. 1, Protocol 2). Dexmedetomidine (bolus of 1.5 µg/kg, followed by 10.8 µg · kg–1 · h–1; Groups BD, BYD, LD, and LYD) or the same volume of saline (Groups B and L) was administered. A bolus dose of yohimbine (1 mg/kg; Groups BYD and LYD) or the same volume of saline (Groups B, BD, L, and LD) was administered 10 min before and 5 min after the start of dexmedetomidine infusion. Fifteen minutes after the start of dexmedetomidine infusion, bupivacaine or levobupivacaine was started in Groups B, BD, and BYD and in Groups L, LD, and LYD, respectively. The dose of yohimbine to antagonize the effect of dexmedetomidine was determined on the basis of previous studies (4). Subsequent experiments were performed as described above. Cumulative dose and total plasma and brain concentrations of bupivacaine and levobupivacaine at the onset of convulsions were compared among Groups B, BD, and BYD and among Groups L, LD, and LYD, respectively. The number of rats in each group was determined on the basis of the results of the preceding study. Five rats were required in each group to detect a 30% decrease of the convulsive dose of bupivacaine by yohimbine administered with dexmedetomidine, with a Type I error protection of 0.05 and a power of 0.80.
Plasma concentrations of total and free bupivacaine and levobupivacaine were determined by high-performance liquid chromatography (HPLC), as reported previously (15). Plasma concentrations of free local anesthetics were measured after treatment by using an ultrafiltration system (Centricon YM-30; Amicon, Inc., Beverly, MA). Concentrations of local anesthetics in homogenate of whole brain were measured by using a method described previously (15). Regression coefficients of the calibration curves for plasma and brain were more than 0.99. The lower limits of quantitation were 0.1 µg/mL in plasma and 0.3 µg/g tissue in the brain. Intraassay and interassay coefficients of variation were <7% throughout the range of testing. Concentrations of local anesthetics in plasma were the mean of duplicate measurements, whereas concentrations of those in the brain were the mean of triplicate measurements. The active metabolite of bupivacaine and levobupivacaine, 2,6-pipecoloxy-lidide (17), was not detected in plasma or brain in this study.
Plasma concentrations of dexmedetomidine were measured by using a method reported previously, with slight modifications (18). Briefly, 4 mL of ethyl acetate, 500 pg of midazolam (an internal standard), and 200 µL of 1 M Na2CO3 were added to 100 µL of plasma, vortexed, and centrifuged at 3000 rpm for 20 min. The aqueous layer (3.6 mL) was transferred to another tube, evaporated to dryness under reduced pressure at room temperature, and reconstituted in 120 µL of HPLC mobile phase. One hundred microliters of the reconstituted residue was injected into a HPLC system (Waters Alliance 2690; Waters, Milford, MA) fit with a Tosoh TSK-OSD 120T column (4.6 x 150 mm; 5-µm particle size; Tosoh Corp., Tokyo, Japan) and a TSK-OSD 120T guard column (4.6 x 15 mm; 5-µm particle size) with an isocratic mobile phase of 65% methanol in 100 mM ammonium acetate. The mass spectrometer (Finnigan LCQ; Thermo Finnigan Corporation, San Jose, CA) was equipped with an atmospheric positive chemical ionization interface and was operated in the positive ionization mode. The vaporizer temperature was maintained at 450°C with a nitrogen nebulization pressure of 13.8 N/cm2, and the fragmentation voltage was 12.0 V. Detection was performed at m/z 200.1 and 326.2 for dexmedetomidine and midazolam, respectively. The retention times of dexmedetomidine and midazolam were 4.4 and 5.5 min, respectively. The peak dexmedetomidine/midazolam area ratio was used to calculate concentrations on the basis of least-squares regression of the calibrators (50–5000 pmol/mL) included in each run. The lower limit of quantitation of dexmedetomidine was 50 pmol/mL, and the intraassay and interassay variations were <8% throughout the range. Values are means of duplicate measurements.
Values are mean ± sd. Differences in levels of sedation among Groups BC, BS, and BL; Groups LC, LS, and LL; Groups B, BD, and BYD; and Groups L, LD, and LYD were examined by the Kruskal-Wallis test, followed by the Tukey honestly significant difference test. Overall differences in plasma concentrations of dexmedetomidine among groups were examined by one-way ANOVA for repeated measures with Bonferroni’s correction. In addition, comparisons among the values at 5, 10, and 15 min after initiation of the dexmedetomidine infusion and at the onset of convulsions were examined by one-way ANOVA for repeated measures with Bonferroni’s correction to determine which time points had values significantly different from those of baseline. Comparisons of hemodynamic variables, convulsive doses, and plasma and brain concentrations of local anesthetics between pairs of groups receiving the same dose of dexmedetomidine (Groups BC versus LC, BS versus LS, and BL versus LL) were performed with the unpaired Student’s t-test. Comparisons among three groups receiving the same anesthetic (Groups BC, BS, and BL; Groups LC, LS, and LL; Groups B, BD, and BYD; and Groups L, LD, and LYD) were performed with one-way ANOVA for repeated measures with Bonferroni’s correction. Differences were considered significant when P < 0.05.
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Results |
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All of the animals were included in the study. Dexmedetomidine achieved significantly different sedation levels both in Groups BC, BS, and BL and Groups LC, LS, and LL (P < 0.05) (Fig. 2). The righting reflex was diminished in most in Groups BL and LL, but a response to painful stimulation (clamping of the tail) was maintained in all rats. There were no differences in mean arterial blood pressure (MAP), pH, Paco2, or Pao2 among Groups GC, BS, and BL or among Groups LC, LS, and LL at baseline, before infusion of bupivacaine or levobupivacaine, or at the onset of convulsions (Tables 1 and 2). Before the infusion of local anesthetics, there were no differences in MAP compared with baseline in any group. Heart rate (HR) was significantly slower in Groups BL and LL compared with baseline (P < 0.01) and compared with Groups BC and LC, respectively (P < 0.05). At the onset of convulsions, MAP was significantly higher and HR was significantly slower than baseline in each group (P < 0.01); Paco2 was significantly less than baseline in all groups except Groups BS and BL. Pao2 was maintained within the normal range in all groups during experiments (Tables 1 and 2). Overall plasma dexmedetomidine concentrations were significantly larger in Groups BL and LL than in Groups BS and LS (P < 0.01), whereas no differences were observed between Group BS and LS or between Group BL and LL. Although there were no significant within-group differences in plasma concentrations of dexmedetomidine at 5, 10, and 15 min after initiation of infusion in any group, they were significantly larger at the onset of convulsions than at 5 min after the initiation of infusion in Groups BL, LS, and LL (Fig. 3).
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Convulsive doses of bupivacaine and levobupivacaine were larger in Groups BL and LL than in Groups BC and LC (7.2 ± 1.0 mg/kg versus 5.0 ± 1.2 mg/kg and 8.9 ± 1.7 mg/kg versus 6.3 ± 1.4 mg/kg, respectively; P < 0.01 for both). Convulsive doses of levobupivacaine in Groups LC and LL were significantly larger than those of bupivacaine in Groups BC and BL (P < 0.05 for both) (Fig. 4). Plasma concentrations of total (protein-bound and free) bupivacaine and levobupivacaine in Groups BL and LL at the onset of convulsions were significantly larger than those in Groups BC and LC (7.9 ± 2.0 µg/mL versus 5.3 ± 1.0 µg/mL and 8.9 ± 2.2 µg/mL versus 6.7 ± 1.4 µg/mL, respectively; P < 0.01 for both). Plasma concentrations of total levobupivacaine in Group LC at the onset of convulsions were significantly larger than those of bupivacaine in Group BC (P < 0.05) (Fig. 5, left). However, no significant differences were detected in plasma concentrations of free bupivacaine among Groups BC, BS, and BL (0.8 ± 0.3 µg/mL, 0.9 ± 0.4 µg/mL, and 1.0 ± 0.3 µg/mL, respectively) or of free levobupivacaine among Groups LC, LS, and LL (1.2 ± 0.4 µg/mL, 1.3 ± 0.4 µg/mL, and 1.5 ± 0.4 µg/mL, respectively). In Groups LC, LS, and LL, plasma concentrations of free levobupivacaine were significantly larger than those of free bupivacaine in Groups BC, BS, and BL (P < 0.01, 0.05, and 0.01, respectively) (Fig. 5, right). The protein-binding ratios of bupivacaine and levobupivacaine calculated from (total – free)/total plasma concentrations in Groups BC, BS, and BL and Groups LC, LS, and LL were 0.86 ± 0.04, 0.86 ± 0.04, and 0.87 ± 0.02 and 0.81 ± 0.06, 0.81 ± 0.06, and 0.83 ± 0.03, respectively (P > 0.05). Concentrations of bupivacaine and levobupivacaine in the brain in Groups BL and LL were significantly larger than in Groups BC and LC (15.8 ± 3.1 µg/g versus 10.9 ± 3.1 µg/g and 20.8 ± 4.2 µg/g versus 14.6 ± 3.6 µg/g, respectively; P < 0.01 for both). Brain concentrations of levobupivacaine in Groups LC, LS, and LL were significantly larger than those of bupivacaine in Groups BC, BS, and BL (14.6 ± 3.6 µg/g versus 10.9 ± 3.1 µg/g, P < 0.05; 16.6 ± 2.6 µg/g versus 12.0 ± 2.9 µg/g, P < 0.01; and 20.8 ± 4.2 µg/g versus 15.8 ± 3.1 µg/g, P < 0.01, respectively) (Fig. 6, left). No significant differences were detected in the brain/plasma concentration ratio between any pairs of groups (BC, 2.1 ± 0.7; BS, 2.0 ± 0.4; BL, 2.1 ± 0.6; LC, 2.3 ± 0.7; LS, 2.4 ± 0.8; and LL, 2.5 ± 0.7) (Fig. 6, right).
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P < 0.05 compared with those receiving bupivacaine and the same dose of dexmedetomidine (Groups BC and BL, respectively). BC = bupivacaine control; BS = bupivacaine with small-dose dexmedetomidine; BL = bupivacaine with large-dose dexmedetomidine; LC = levobupivacaine control; LS = levobupivacaine with small-dose dexmedetomidine; LL = levobupivacaine with large-dose dexmedetomidine.
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Immediately before the infusion of bupivacaine or levobupivacaine, levels of sedation of rats in Groups BYD and LYD were significantly less than those in Groups BD and LD (P < 0.05 for both) and were comparable with those in Groups B and L, respectively (Fig. 7). Convulsive doses and plasma and brain concentrations of bupivacaine and levobupivacaine at the onset of convulsions in Groups BYD and LYD were significantly smaller than those in Groups BD and LD (P < 0.05 for all) and were comparable with those in Groups B and L, respectively (convulsive doses: B, 6.6 ± 1.2 mg/kg; BD, 9.2 ± 1.2 mg/kg; BYD, 6.6 ± 1.3 mg/kg; L, 5.4 ± 2.2 mg/kg; LD, 9.7 ± 2.0 mg/kg; LYD, 5.4 ± 2.6 mg/kg; plasma concentrations: B, 5.3 ± 0.8 µg/mL; BD, 8.3 ± 1.9 µg/mL; BYD, 5.6 ± 1.3 µg/mL; L, 6.2 ± 1.8 µg/mL; LD, 10.2 ± 3.3 µg/mL; LYD, 4.6 ± 0.9 µg/mL; brain concentrations: B, 12.9 ± 1.2 µg/g tissue; BD, 21.2 ± 2.9 µg/g; BYD, 12.8 ± 3.2 µg/g; L, 14.0 ± 2.7 µg/g; LD, 23.8 ± 2.9 µg/g; LYD, 14.2 ± 5.7 µg/g; Fig. 8).
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Discussion |
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We have shown that dexmedetomidine decreases the CNS toxicity of bupivacaine and levobupivacaine by increasing the convulsive dose and threshold plasma concentrations for convulsions. The effect of dexmedetomidine was reversed by concomitant administration of yohimbine, suggesting that dexmedetomidine exerts its anticonvulsant effect via
2-adrenoceptor agonism. In the large-dose dexmedetomidine groups (BL and LL), local anesthetic concentrations were increased in the brain at the onset of convulsions; however, it did not affect brain/plasma concentration ratios of either bupivacaine or levobupivacaine. This demonstrates that dexmedetomidine did not affect entry of these local anesthetics into the brain. Although plasma concentrations of the free fractions were not significantly different at the onset of convulsions, there was insufficient power to detect a difference if one existed. Because more than 80% of dexmedetomidine in plasma is bound to protein (16), it may affect the protein binding of bupivacaine, an anesthetic with a high rate of protein binding. However, protein binding of bupivacaine or levobupivacaine was comparable in all groups, suggesting that dexmedetomidine did not affect the protein binding of these anesthetics. The convulsive dose and brain concentration of levobupivacaine in Group LL were approximately 20% larger than those of bupivacaine in Group BL, and this is consistent with the findings obtained without dexmedetomidine in Groups BC and LC, thus suggesting that dexmedetomidine exerts anticonvulsant effects with use of dextroisomers and levoisomers of bupivacaine. Although the reason for this is not clear, dexmedetomidine may exert its anticonvulsant effect on both stereoisomers of other local anesthetics with pipecoloxylidines such as mepivacaine and ropivacaine.
In this study, animals were sedated with a continuous infusion of dexmedetomidine at a constant rate after bolus injection based on pharmacokinetic variables reported previously (16). Although the mean plasma concentrations of dexmedetomidine tended to increase during the infusion in all groups, there were no significant within-group differences before bupivacaine infusion. Because most rats in Groups BL and LL lost their righting reflex before the infusion of bupivacaine or levobupivacaine and because the mean plasma concentrations of dexmedetomidine in Groups BL and LL were approximately 1.5 ng/mL, the plasma concentration of dexmedetomidine required for sedation in rats might be similar to that in humans (19).
Few animal studies have examined the effects of dexmedetomidine on hemodynamic variables (16). In this study, dexmedetomidine alone did not affect MAP and decreased HR in Groups BL and LL. In combination with the finding of a lack of effect on blood gas data, these results suggest that dexmedetomidine may be an ideal sedative for animals and humans. At the onset of convulsions, plasma pH was increased secondary to hyperventilation and a decrease of Paco2. Because the extraction ratio of dexmedetomidine is approximately 70% and systemic clearance is dependent on hepatic blood flow rather than hepatic metabolic activity (20), the significant increase in the plasma concentration of dexmedetomidine compared with that at five minutes after initiation of infusion could be the result of a decrease in hepatic blood flow caused by hyperventilation.
If the results of this study in rats can be applied to humans, dexmedetomidine used for sedation may reduce the convulsive potency of simultaneously administered bupivacaine. Because dexmedetomidine may exert its anticonvulsant effect via 2-adrenoceptor and 2-adrenoceptor agonists have an anticonvulsant effect on other local anesthetics (6,9), dexmedetomidine might reduce the convulsive potency of these local anesthetics. However, careful monitoring for cardiovascular toxicity is needed, because manifestations of CNS toxicity—such as excitation and convulsions—may be prevented by dexmedetomidine.
We performed experiments in awake, spontaneously breathing rats. This experimental condition is useful for examining levels of sedation. In addition, the convulsive dose of bupivacaine is increased by general anesthesia (2). In awake animals, physiological changes such as acidosis and decreases of carbon dioxide tension may affect the CNS toxicity of local anesthetics (21). In this study, although overall arterial blood pH was increased because of the decrease in carbon dioxide tensions at the onset of convulsions compared with baseline, there were no differences in these values among the groups at baseline or at the onset of convulsions, thus suggesting that changes in blood gases did not differentially affect the convulsive potency of bupivacaine or levobupivacaine among groups. Continuous infusion of bupivacaine or levobupivacaine alone significantly increased MAP in Groups BC and LC, as noted previously (10). Inhibition of 
-aminobutyric acid (GABA)-ergic neurons in the brain, resulting in increased sympathetic activity and peripheral vasoconstriction, is responsible for this hypertension (22,23). Although dexmedetomidine exerts sympatholytic effects through 2a-adrenergic receptors in the CNS and facilitates the release of GABA in the CNS (24,25), continuous infusion of dexmedetomidine did not prevent an increase in MAP in any group. Vasoconstriction via activation of peripheral 2-adrenoceptors (26) or insufficient release of GABA by dexmedetomidine (required to counteract the inhibitory effect of bupivacaine and levobupivacaine) would also be responsible for this hypertension.
Several studies have demonstrated the proconvulsant effect of dexmedetomidine (3,4). Mirski et al. (3) showed that IV dexmedetomidine 100 and 500 µg/kg decreased the convulsive dose of pentylenetetrazol. Miyazaki et al. (4) also showed that IV dexmedetomidine 10 and 100 µg/kg increased the convulsive potency of electrical stimulation during 3.5% enflurane anesthesia. In these studies, however, the dose of dexmedetomidine was relatively large, and plasma concentrations of dexmedetomidine were not measured; neither hemodynamic variables nor blood gas data were presented. Dexmedetomidine may lose some of its selectivity for 2-adrenoceptors, and 1-adrenoceptor activation may thus occur. Indeed, 1-adrenoceptor agonist activity appears to reverse the anticonvulsant effects of these 2-adrenoceptor agonist compounds (27). General anesthesia affects convulsive potency, and enflurane induces convulsions, as determined electroencephalographically (28). Moreover, the mechanisms of the induction of convulsions by pentylenetetrazol are fundamentally different from those of local anesthetics, as shown by the differential effect of manipulation of intracerebral monoamine levels on local anesthetic- and pentylenetetrazol-induced convulsions (8,29).
However, some investigators have demonstrated that 2-adrenoceptor agonists such as clonidine and tizanidine, as well as dexmedetomidine, have anticonvulsant properties (1,6,9,27). This also protects against neuronal injury by kainic acid (5). Of importance, Whittington et al. (6) showed that dexmedetomidine increases the threshold for convulsions by cocaine via inhibition of increases in central dopamine concentrations. Several studies have shown that dopaminergic neurons are also involved in the CNS toxicity of local anesthetics such as lidocaine (8), suggesting that there are common mechanisms between cocaine- and bupivacaine-induced convulsions.
Because the 2-adrenoceptor antagonist yohimbine reversed the effect of dexmedetomidine in this study, modulation of monoamine levels via activation of 2-adrenoceptors by dexmedetomidine might be responsible for its anticonvulsant effect. Further study will be needed to elucidate the role of monoamines such as dopamine in bupivacaine-induced convulsions.
In summary, we have shown that dexmedetomidine administered for sedation in doses comparable to those for humans decreased the convulsive potency of bupivacaine and levobupivacaine in awake, spontaneously breathing rats, probably by 2-adrenoceptor agonism.
We thank Mrs. Masako Tanaka for preparing the manuscript.
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References |
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- De Kock M, Le Polain B, Henin D, et al. Clonidine pretreatment reduces the systemic toxicity of intravenous bupivacaine in rats. Anesthesiology 1993;79:282–9.[Web of Science][Medline]
- Lee VC, Moscicki JC, DiFazio CA. Propofol sedation produces dose-dependent suppression of lidocaine-induced seizures in rats. Anesth Analg 1998;86:652–7.[Abstract]
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