Levobupivacaine is the latest local anaesthetic introduced in clinical practice. It is the pure S(−)-enantiomer of the racemic formulation, bupivacaine. While both the R- and S-enantiomers of bupivacaine have anaesthetic activity, preclinical studies suggested that levobupivacaine might be less cardiotoxic than the racemic mixture [1,2].
Although it has been already compared with racemic bupivacaine for spinal , epidural  and peripheral nerve blockade [5-7], little is known about the comparative efficacy of epidural levobupivacaine with another widely used long-acting local anaesthetic, ropivacaine. Studies evaluating the minimum local anaesthetic concentration for epidural analgesia during labour demonstrated that levobupivacaine and bupivacaine were nearly equipotent , while ropivacaine was 40-60% less potent than racemic bupivacaine . In a study comparing similar concentrations of levobupivacaine, ropivacaine and bupivacaine for epidural anaesthesia in orthopaedic patients, we recently reported that levobupivacaine 0.5% produced an epidural block of similar onset, quality and duration as that produced by bupivacaine 0.5%, and the motor block was more profound than that produced by the same volume of ropivacaine 0.5% . We, therefore, conducted a prospective, randomized, observer-blinded study to compare the onset time and duration of epidural anaesthesia, produced by levobupivacaine 0.5% and ropivacaine 0.75%.
Ethics approval was obtained from our institutional Ethics Committee and our patients' gave their written informed consent. We prospectively studied 65 patients receiving epidural anaesthesia for elective lower limb procedures, including orthopaedic and vascular surgery. Patients with severe renal, hepatic, respiratory, cardiovascular or neurological diseases, diabetes mellitus or ASA >III, as well as patients weighting <45 kg with a contraindication for an epidural block, or a history of drug or alcohol abuse were excluded. Patients enrolment was performed at the anaesthesia departments of six hospitals: Policlinico Monteluce (Perugia), Policlinico S. Orsola Malpighi (Bologna), Policlinico Universitario (Messina), Università Cattolica del Sacro Cuore (Rome), CTO (Rome) and Ospedale Policlinico II (Naples). A centralized computer-generated randomization sequence was provided by the study sponsor. Randomization was performed in blocks of 10 patients and concealed in sealed envelopes. Participating centres received blocks of 20 sealed and numbered envelopes (from 1 to 20). In each hospital a physician, who was not involved in further patient care, opened the envelope and prepared sterile syringes. The statistician, who performed the statistical analyses was unaware of patients' group assignment until the end of the study.
A routine physical examination of each patient was performed the day before surgery. In the operating theatre, an 18-G intravenous (i.v.) cannula was inserted. Then, midazolam 0.05 mg kg−1 i.v. and atropine 0.01 mg kg−1 intramuscularly (i.m.) were given as a standard premedication. Standard monitoring was used throughout the study, including non-invasive arterial pressure, heart rate (HR) and pulse oximetry. All patients received 20 mL kg−1 of lactate Ringer's solution, to increase their circulating fluid volume, before the block was undertaken.
The 1:1.5 equipotency ratio between levobupivacaine and ropivacaine was extrapolated from two different studies describing the equipotency ratio between racemic bupivacaine and levobupivacaine , and between racemic bupivacaine and ropivacaine . Patients were allocated to receive epidural anaesthesia with levobupivacaine 0.5% 15 mL (group Levobupivacaine) or ropivacaine 0.75% 15 mL (group Ropivacaine). The patients were placed in the sitting position, and skin infiltration with lidocaine 2% 3 mL was performed. Then, the epidural space was located at the L2-L3 or L3-L4 interspaces with a 17-G Tuohy needle using the mid-line approach and a loss of resistance technique. After negative aspiration for blood, 3 mL of the study drug was injected as a test dose to exclude intrathecal injection. Then, after a 5 min period, the remaining 12 mL was injected slowly with repeated aspirations every 5 mL, to exclude intravascular injection.
An independent, blinded observer recorded the evolution of sensory block every 5 min until complete loss of pinprick sensation at T10 (readiness to surgery), and then every 15 min until regression of the sensory block at T12. When the sensory block reached T10, motor block was also assessed using a modified Bromage score by asking the patient to flex the hip, knee and ankle joints against gravity (0: no block; 1, unable to flex the hip; 2: unable to flex the hip and extend the leg with the hip passively flexed; 3: unable to flex the hip, extend the leg with the hip passively flexed hip and flex the ankle). After surgery started, the evaluation of sensory block was performed on the non-operated side, while no further evaluation of motor block was performed. At the same time, non-invasive arterial pressure and HR were also recorded. During surgery, patients were sedated with further boluses of midazolam (2 mg i.v.) according to patient needs. If the patient complained of pain during surgery, supplemental analgesia with 0.1 mg fentanyl i.v. was given, and the need recorded. If this proved to be ineffective, general anaesthesia was provided to complete surgery.
Clinically relevant hypotension (systolic arterial pressure >30% from baseline) was treated with boluses of phenylephrine (3 mg i.v.). Bradycardia (HR < 45 beats min−1) was treated with atropine 0.5 mg i.v. Occurrence of any adverse effects, including nausea, vomiting or shivering, during the first 24 h after surgery was also recorded at our visit on the first postoperative day. Patient acceptance of the anaesthesia procedure was evaluated the day after surgery using a two-point scale: (1) 'Satisfied, if operated on again in the future, I would accept the same procedure'; (2) 'Unsatisfied, if operated on again in the future, I would prefer a different anaesthesia procedure'.
To calculate the study sample size, we took into account the mean and standard deviations (SD) reported in previous investigations for the regression of sensory block with the two considered agents [4,11,12]. Twenty-five patients per group were required to detect a 30 min difference in the time of regression of sensory level at T12 between the two anaesthetic solutions accepting a two-tailed α error of 5% and a β error of 10% . The statistical analysis was performed using the program SPSS® (SPSS, Chicago, IL, USA). Normal distribution of considered data was first evaluated using the Kolmogorov-Smirnov test. Continuous variables were evaluated with the analysis of variance (ANOVA) or with the Kruskal-Wallis test. The Tukey's and Scheffé's tests were used for post hoc comparisons. A two-way ANOVA for repeated measures was used to analyse changes over time. Ordinal data were analysed using the contingency table analysis and the χ2-test with the appropriate corrections. P ≤ 0.05 was considered significant. Continuous variables are presented as mean (±SD) or as median (range), while categorical variables are presented as number (%).
Since a total of six hospitals participated in patient enrolment, a 'centre effect' was first excluded before starting the statistical analysis. No differences in patient characteristics and duration of surgery were reported between the two groups (Table 1). Table 1 also shows the distribution of surgical procedures in the two treatment groups.
Readiness to surgery (loss of pinprick sensation at T10) was achieved after 29 ± 24 min in group Levobupivacaine and 25 ± 22 min in group Ropivacaine (P = 0.41). No difference in the degree of motor blockade was observed between the two groups, when sensory block reached T10 (Fig. 1). Supplemental analgesia with i.v. fentanyl (0.1 mg) was required in one patient of group Levobupivacaine (3.5%) and in two of group Ropivacaine (5.7%) (P = 0.99). No patient required general anaesthesia to complete surgery.
Clinically relevant hypotension was reported in two patients of group Levobupivacaine (3%), and in eight of group Ropivacaine (12%) (P = 0.16). Bradycardia was observed in three patients of group Ropivacaine (8%) (P = 0.24). Figure 2 shows the times for complete regression of motor block, and regression of sensory level at T12. No differences were reported between the groups.
No severe adverse events were reported in either group. Postoperative nausea and vomiting was reported in one patient of group Levobupivacaine (3.5%), while two patients of group Ropivacaine (5.5%) reported shivering. Patient acceptance was similarly good in the two groups, and all patients accepted the same anaesthesia procedure for future operations.
Although levobupivacaine has already been compared to racemic bupivacaine for spinal [1,3], epidural [1,4] and peripheral nerve blocks [5-7], little information is available on the comparative clinical profile of epidural levobupivacaine and ropivacaine. This prospective, randomized, observer-blinded study demonstrated that the epidural injection of levobupivacaine 0.5% 15 mL induces a surgical block of similar onset, intensity and duration as by the same volume of ropivacaine 0.75%.
Even though no comparative studies were available to choose the equipotency ratio between ropivacaine and levobupivacaine, data coming from different studies comparing ropivacaine with bupivacaine and levobupivacaine with bupivacaine for epidural [1,4,8,10] and spinal [12,14-16] anaesthesia suggested the use of a 1:1.5 concentration ratio between levobupivacaine and ropivacaine. Results of the present study indirectly confirmed this hypothesis, since no clinically or statistically significant differences in the evolution of epidural block were found between identical volumes of levobupivacaine 0.5% and ropivacaine 0.75%.
The onset time of sensory block observed in this study is longer than that reported in previous investigations. Cox and colleagues  reported onset times of sensory block ranging between 6 and 8 min with 0.5% or 0.75% concentrations of levobupivacaine, respectively. Kopacz and colleagues  observed a sensory block at T10 within 13 min after injecting levobupivacaine 0.75% 20 mL while the addition of epinephrine at different concentrations did not result in relevant changes of onset time or duration of nerve block . However, our findings are similar to those reported by others [18,19]. According to the study design, motor blockade was assessed when sensory block reached T10, and then evaluated after the end of surgery only because of a possible interference with the surgeon during the procedure. This may explain, why up to 45% of our patients had an inadequate motor block before surgery; however, no problems were reported by the surgeons during the procedure, and no differences in times for complete resolution of motor block after surgery were reported between the two groups. These results are similar to those reported by other authors evaluating the same volumes and concentrations of ropivacaine and bupivacaine in similar clinical settings [17-19].
In conclusion, results of this prospective, randomized, observer-blinded study demonstrate that for lower limb surgery an epidural block produced by levobupivacaine 0.5% 15 mL has the same clinical profile as the one produced by the same volume of ropivacaine 0.75%. Similar to ropivacaine, levobupivacaine also has the interesting potential for reduced toxicity [20-23]; this may be especially advantageous when large volumes of local anaesthetic are to be used, such as for epidural anaesthesia and analgesia.
This study was supported by a grant by Abbott Italy, Spa (Campoverde, Latina). The authors thank Dr Pascale Chevallier and Dr Simona Lotito (Medical Direction, Abbott, Italy) for their support in designing and conducting the study. Statistical analyses were performed by Dr Stefano Omboni (Vanasia, Spa).
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