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Anesth Analg 2003;97:888-892 © 2003 International Anesthesia Research Society
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Abstract |
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Levobupivacaine is the isolated S(-)-stereoisomer of racemic bupivacaine. Important pharmacodynamic properties of levobupivacaine have not been determined for the femoral three-in-one block. In this randomized, controlled, double-blinded trial, we studied 60 ASA physical status I–III patients scheduled for surgery of the lower limb. A nerve-stimulator-guided three-in-one block was performed as supplemental analgesic therapy with 20 mL of bupivacaine 0.5% (n = 20), levobupivacaine 0.5% (n = 20), or levobupivacaine 0.25% (n = 20). Sensory onset time, quality of blockade, and duration of blockade were assessed by pinprick test in the central sensory innervation region of the femoral nerve (distribution of the anterior femoral cutaneous nerve). A rating scale from 100% (normal sensation) to 0% (no sensation at all) as compared with the contralateral leg was used. No significant difference in sensory onset time among the three local anesthetic solutions was observed (mean [95% confidence interval]): bupivacaine 0.5%, 27 min (20–33 min); levobupivacaine 0.5%, 24 min (18–30 min); and levobupivacaine 0.25%, 30 min (23–36 min) (P = 0.49). The analgesic quality of the blockade was also not significantly different among the three groups, whereas a complete sensory block was achieved in significantly fewer patients in the levobupivacaine 0.25% group (P = 0.02). The duration of blockade was significantly shorter with levobupivacaine 0.25% compared with the other groups: bupivacaine 0.5%, 1053 min (802–1304 min); levobupivacaine 0.5%, 1001 min (844–1158 min); and levobupivacaine 0.25%, 707 min (551–863 min) (P = 0.01). Levobupivacaine 0.5% is recommended instead of bupivacaine 0.5% for the three-in-one block.
IMPLICATIONS: In this randomized, controlled study, we determined important pharmacodynamic variables (onset time, quality of blockade, and duration of blockade) of levobupivacaine 0.5% and 0.25% in the three-in-one block compared with bupivacaine 0.5% by pinprick testing.
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Introduction |
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Levobupivacaine, the isolated S(-)-stereoisomer of the racemic mixture bupivacaine, is a long-acting amino-amide local anesthetic. Previous preclinical studies in animals and volunteers have indicated that levobupivacaine has less cardiac and central nervous system (CNS) toxicity than bupivacaine (1–4). Further studies have shown that levobupivacaine can be regarded as equipotent to bupivacaine (5,6). The clinical application of levobupivacaine has been evaluated for epidural (7) and spinal (8) anesthesia. With regard to peripheral nerve blocks, levobupivacaine has been studied in supraclavicular brachial plexus anesthesia (9), axillary brachial plexus block (10), and sciatic nerve block (11). The three-in-one block, introduced by Winnie et al. in 1973 (12), provides anesthesia for surgical and diagnostic procedures of the lower limbs (13) and is widely used for postoperative analgesia (14–16). We designed this study to investigate the pharmacodynamic properties (time to onset of blockade, quality of blockade, and duration of blockade) of 2 doses of levobupivacaine (0.5% and 0.25%) in comparison with bupivacaine 0.5% in the three-in-one block.
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Methods |
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The study protocol was reviewed and approved by the Research Ethics Committee of the University Hospital of Vienna. Patients were eligible for inclusion when a three-in-one block was indicated for supplemental analgesia because of a fracture or injury of the lower limb, to facilitate positioning for spinal anesthesia, or to prevent painful muscle spasms. Further inclusion criteria were age
18 yr and ASA physical status I–III. Exclusion criteria were inability to follow the study protocol because of a language barrier, allergy or hypersensitivity to local anesthetics, any signs of infection or hematoma at the puncture site, coagulation disorders, neurological or psychiatric disorders, a history of alcohol abuse, a history of epilepsy, and inability to perform the pinprick test because of a dressing or cast. After written informed consent, 60 ASA physical status I–III patients were randomized to 1 of the 3 study groups according to a computer-generated randomization list. In group B 0.5% (n = 20), a three-in-one block was performed with 20 mL of bupivacaine 0.5% (5 mg/mL), in group L 0.5% (n = 20) it was performed with 20 mL of levobupivacaine 0.5% (5 mg/mL), and in group L 0.25% (n = 20) it was performed with 20 mL of levobupivacaine 0.25% (2.5 mg/mL). Syringes with one of the three local anesthetics were prepared by one of three coauthors according to the randomization list. The three-in-one blocks were performed by different staff anesthesiologists, and all examinations and measurements were performed by one observer, who was blinded to the group assignment.
Single-shot three-in-one blocks were performed for supplemental analgesia in addition to spinal or general anesthesia or in combination with a sciatic nerve block. Patients were placed supine, and after disinfection and the administration of local anesthesia (2 mL of lidocaine 2%), three-in-one blocks were done with the help of a nerve stimulator (Stimuplex HNS11; B. Braun, Melsungen, Germany) and a 22-gauge, 40-mm, short-bevel, insulated, unipolar needle (Pajunk, Geisingen, Germany). The needle was introduced 1 cm lateral to the femoral artery and 1.5 cm below the inguinal ligament and was advanced cephalad at an angle of 45° to the skin. When a current of 0.3 mA over 0.3 ms at 2 Hz elicited contractions of the quadriceps femoris muscle with clearly visible impulse-synchronous cephalic movement of the patella and after negative aspiration, 20 mL of the local anesthetic was injected slowly, with a repeated aspiration test after 10 mL.
The onset time and the quality of the nerve blocks were evaluated by pinprick test with a 27-gauge needle at 5, 10, 20, 30, 40, 50, and 60 min after performance of the block (16). Sensory assessment of blockade was performed in the central sensory region (area propria) of the femoral nerve (distribution of the anterior femoral cutaneous nerve), in the middle of the anterior aspect of the thigh. Patients were requested to compare the pinprick on the anesthetized leg with that of the contralateral leg as a reference. A scale from 100% (normal sensation) to 0% (no sensation) was used. A reduction of sensibility to 
30% (compared with the contralateral leg) was defined as sensory onset of blockade (16). When this reduction to 30% was not reached within the first 60 min of observation because of technical failure of the block, patients were excluded from further investigation and statistical analysis. To avoid painful stimuli and possible further dislocation of fractures, motor block was not assessed. During the first 60 min after the injection, three-lead electrocardiogram, heart rate, noninvasive blood pressure, and peripheral oxygen saturation were recorded, continuously monitored (Hewlett-Packard Corp., Palo Alto, CA), and documented at the above-mentioned points in time. After the last measurement at 60 min after the injection, further anesthetic and surgical management started. After surgery, patients were seen hourly in the recovery room and on the ward, and the nerve blocks were again evaluated by pinprick test. The individual end point of each patient’s study period was defined as the first time there was no difference between sensation in the previously anesthetized leg and in the contralateral leg. Duration of the block was calculated as the time interval from injection of the local anesthetic to complete recovery of normal sensation. On the first day after the intervention, all patients were examined for signs of infection at the puncture site, and they were asked whether they experienced paresthesia in the previously anesthetized leg.
Demographic data and clinical characteristics of the participants, onset time, quality of blockade, and duration of blockade were compared by means of analysis of variance (ANOVA), the 
2 test, the Kruskal-Wallis test, and the median test, where appropriate. Multiple measurements in individual patients were analyzed by repeated-measurements ANOVA. The sample size of this trial was calculated to show a 10-min difference in onset time or a 10% difference in quality of blockade with a power of 90% and an 
level of 5%. Statistical computation was performed with SPSS Version 11.0 (SPSS Inc., Chicago, IL). A two-tailed P value 0.05 was considered statistically significant.
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Results |
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Participants for this study were recruited between October 2001 and May 2002. Demographic data and clinical characteristics of the patients are shown in Table 1. No significant differences with respect to age, sex, ASA physical status, weight, type of surgery, or type of anesthesia were observed among the three groups.
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Sensory onset times (mean [95% confidence interval]) were 27 min (20–33 min) in the B 0.5% group, 24 min (18–30 min) in the L 0.5% group, and 30 min (23–36 min) in the L 0.25% group. Statistical analysis of the onset times showed no significant difference among the three groups (ANOVA; P = 0.49).
Sensory blockade in the first 60 min after performance of the block (in percentages, as compared with the contralateral leg) is shown in Figure 1. In the first hour after the completion of the injection, there was no statistically significant difference in the analgesic quality of blockade among the three study groups. Nevertheless, not all patients reached a depth of anesthesia of 0% (no sensation to pinprick test; anesthetic blockade). At 60 min, 16 (80%) of 20 patients in the B 0.5% group, 16 (80%) of 20 patients in the L 0.5% group, and 9 (45%) of 20 patients in the L 0.25% group had no sensation (2 test; P = 0.02).
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, •, and 
= means; bars = 95% confidence interval; x axis = minutes after performance of the three-in-one block; y axis = sensation in response to the pinprick test on the anesthetized leg, as a percentage of that in the contralateral leg. *Analgesic levels of blockade (%) did not differ among the three groups, although the rate of patients who reached an anesthetic block (0% sensation to pinprick) was significantly different among the three groups (P = 0.02).All three-in-one blocks persisted after patient recovery from general anesthesia or after spinal anesthesia. The duration of the blocks is presented in Figure 2. The duration of the three-in-one blocks (mean [95% confidence interval]) in the B 0.5% group was 1053 min (802–1304 min), was 1001 min (844–1158 min) in the L 0.5% group, and was 707 min (551–863 min) in the L 0.25% group (Kruskal-Wallis test; P = 0.01). Analysis of distribution of block duration around the median showed that 12 (60%) of 20 blocks in the B 0.5% group, 13 (65%) of 20 blocks in the L 0.5% group, and 5 (25%) of 20 blocks in the L 0.25% group lay above the median (median test; P = 0.02).
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Heart rate, noninvasive blood pressure, and peripheral oxygen saturation showed no statistically significant inter- or intragroup differences during the entire study period. In the 60 patients involved in this clinical trial, no signs of cardiac or CNS toxicity were observed. On the first day after the intervention, none of the participants reported paresthesia in the sensory innervation region of any of the three nerves possibly affected by the three-in-one block. No signs of infection at the puncture site were found.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This is the first study that describes the pharmacodynamic properties of levobupivacaine for the three-in-one block. Our results show that the onset times and analgesic quality of blockade of levobupivacaine 0.5% and 0.25% are not significantly different from those of bupivacaine 0.5% when three-in-one blocks with 20 mL of local anesthetic are performed. The anesthetic quality of blockade was significantly less in the levobupivacaine 0.25% group, with fewer patients reaching a complete sensory blockade. The duration of three-in-one blocks was shorter with levobupivacaine 0.25% than with bupivacaine 0.5% or levobupivacaine 0.5%. These results indicate that levobupivacaine 0.5% may replace bupivacaine 0.5% when three-in-one blocks are performed as supplemental analgesic therapy. Levobupivacaine 0.25% offers a similar onset time and analgesic quality of blockade over the first 60 minutes, but the proportion of patients with a complete sensory block is smaller and the duration of blockade is shorter.
The local anesthetic equipotency of levobupivacaine and bupivacaine was shown in the rat sciatic nerve block model (5) and clinically in epidural anesthesia (6). Vladimirov et al. (5) observed no differences in stereopotency between R(+)- and S(-)-bupivacaine in the in vivo rat sciatic nerve block model. Lyons et al. (6) demonstrated equipotency of bupivacaine and levobupivacaine for epidural anesthesia with the up-down sequential allocation method, which is considered the standard clinical technique for the determination and comparison of local anesthetic potency. The comparison of the pharmacodynamic variables of bupivacaine 0.5% and levobupivacaine 0.5% in our study strongly suggests equipotency of bupivacaine and levobupivacaine for the three-in-one block.
There is convincing evidence from studies on the molecular and cellular level (1), from animal studies (2,3), and from volunteer studies (4) that the probability of an adverse event (17) related to the cardiac and CNS toxicity of local anesthetics can be reduced when levobupivacaine is used instead of bupivacaine. This arises primarily from the higher toxicity of the R(+)-stereoisomer of bupivacaine (1).
Studies on sensory onset time, quality of sensory block, and duration of peripheral nerve blocks with levobupivacaine showed different results. The onset times of levobupivacaine 0.5% ranged from a mean of 6 ± 5 minutes in supraclavicular brachial plexus block with 0.4 mL/kg (9) to a median of 13 minutes (range, 0–60 minutes) in axillary brachial plexus block with 50 mL (10) and to a median of 30 minutes (range, 5–60 minutes) in sciatic nerve block with 20 mL (11). The onset time of supraclavicular brachial plexus blocks with 0.4 mL/kg of levobupivacaine 0.25% was 7 ± 6 minutes (9). The duration of sensory blockade with levobupivacaine 0.5% was 1039 ± 317 minutes (9) and 1200 minutes (range, 840–1440 minutes) (10) and was 892 ± 250 minutes for levobupivacaine 0.25% (9). In contrast to our study, in which only 45% of patients reached a complete anesthetic blockade with 0.25% levobupivacaine, Cox et al. (9) found 68% of patients with a "satisfactory block" after a supraclavicular brachial plexus block in a surgical setting. This more frequent rate may be explained by differences in the local anesthetic volume (20 mL vs 0.4 mL/kg) or by slight methodological differences in the assessment of blockade. For bupivacaine 0.5%, we found sensory onset times of 32 ± 10 minutes (16) and 27 ± 12 minutes (18) in 2 earlier studies with the same methodology and definition.
The clinical effect is not known of the significant difference between the local anesthetics at the 0.5% level and that at the 0.25% level in the proportion of patients who achieve a sensory block of 0% at 60 minutes after blockade of the femoral nerve. With respect to this finding, future trials will have to concentrate on the question of whether three-in-one blocks with 20 mL of levobupivacaine 0.25% are able to provide anesthesia (as opposed to analgesia) satisfactorily in a surgical setting. Additionally, studies with primary outcome variables that reflect clinical efficacy (such as visual analog scale score and morphine consumption) would be of great interest when the three-in-one block is studied with levobupivacaine or ropivacaine. The absence of such outcome variables may be a potential limitation of our study.
The clinical effectiveness of the three-in-one block (12) has continued to be controversial (19). However, when a nerve stimulator is used with the three-in-one block, the femoral nerve is targeted for injection of the local anesthetic solution (20). Because the aim of this study was the evaluation of clinically relevant pharmacodynamic variables when three-in-one blocks are performed with levobupivacaine 0.5% and 0.25%, compared with bupivacaine 0.5%, we did not measure the extent of the blockade of the lateral femoral cutaneous and obturator nerves.
In this trial, we have shown that in three-in-one blocks, sensory onset times and analgesic quality of blockade are not significantly different among bupivacaine 0.5%, levobupivacaine 0.5%, and levobupivacaine 0.25%. The proportion of patients with a complete sensory block and the duration of blockade are comparable between levobupivacaine 0.5% and bupivacaine 0.5%. With levobupivacaine 0.25%, fewer patients reach a complete anesthetic blockade, and the duration of blockade is shorter. Levobupivacaine 0.5% can be recommended instead of bupivacaine 0.5% for three-in-one blocks because of its similar pharmacodynamic profile and because of its reported decreased toxicity.
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Acknowledgments |
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The authors would like to thank Jane Neuda for editorial assistance.
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References |
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- Lyons G, Columb M, Wilson RC, Johnson RV. Epidural pain relief in labour: potencies of levobupivacaine and racemic bupivacaine. Br J Anaesth 1998; 81: 899–901.
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