Levobupivacaine, the pure S(−) enantiomer of bupivacaine, is the most recent local anaesthetic to be introduced into clinical practice . Both the R(−) and S(−) enantiomers of bupivacaine have anaesthetic activity but preclinical studies demonstrated that levobupivacaine is less cardiotoxic than the racemic mixture [1,2]. Clinical use of levobupivacaine has been extensively evaluated for epidural and spinal anaesthesia [1,3,4]. Initial reports evaluating levobupivacaine for peripheral nerve blocks have suggested that duration of nerve block produced with 0.5% levobupivacaine might be longer than that produced with an equivalent dose of bupivacaine or ropivacaine [5,6]. The aim of this prospective, randomized, double-blind study was to evaluate the onset time and duration of sciatic nerve block produced with 0.75% levobupivacaine and compare them with that provided by 0.5% levobupivacaine and 0.75% ropivacaine.
With Ethics Committee approval and written informed consent, 45 ASA I/II inpatients undergoing sciatic nerve block for elective hallux valgus repair were studied. Patients receiving analgesic therapy for chronic pain syndrome, as well as patients with diabetes or peripheral neuropathies were excluded.
After an 18-G intravenous (i.v.) cannula had been inserted in the forearm, midazolam 0.05 mg kg−1 was given i.v. Standard monitoring was used throughout the study, including non-invasive arterial pressure, heart rate and pulse oximetry.
Nerve blocks were performed with the aid of a nerve stimulator (Plexival, Medival, Italy). The stimulation frequency was set at 2 Hz and the duration of the stimulating pulse at 0.15 ms. The intensity of stimulating current was initially set to deliver 1 mA, and gradually decreased to ≤0.5 mA after the proper motor response was observed. Paraesthesia was never intentionally sought; a multiple injection technique was used eliciting specific twitches on nerve stimulation to confirm exact needle location [7,8]. According to a computer generated sequence of numbers and using a sealed envelopes technique, patients were randomly allocated to receive the sciatic nerve block with levobupivacaine 0.5% (Group Levo-5, n = 15), levobupivacaine 0.75% (Group Levo-7.5, n = 15) or ropivacaine 0.75% 20 mL (Group Ropi-7.5, n = 15). Sterile syringes with the local anaesthetic solution were prepared in a double-blind fashion by one of the authors not involved in further management of studied patients. The sciatic nerve block was performed according to the classic Labat approach modified by Winnie using a double-stimulation technique [7,8]. After eliciting an appropriate stimulation of the tibial (plantar flexion/inversion of the foot) and the common peroneal nerves (dorsiflexion/eversion of the foot) with a stimulating current ≤0.5 mA, 10 mL of the study solution was injected at each site, for a total final volume of 20 mL. Irrespective of the twitch first encountered, we always blocked both the tibial and common peroneal components of the sciatic nerve separately.
An independent blinded observer recorded the onset time of sciatic nerve block. Sensory block was evaluated as complete loss of pinprick sensation in the tibial and common peroneal distributions of the sciatic nerve, while motor block was evaluated by asking the patient to actively contract the posterior and anterior muscles of the leg against resistance. The zero time for clinical assessments was the completion of anaesthetic injection at the sciatic nerve. Surgical anaesthesia was defined as complete loss of pinprick sensation both in the tibial and common peroneal nerve distributions and concomitant inability to move the ankle and the toes of the operated foot. Sensory and motor blocks were evaluated every 5 min until readiness for surgery. If the nerve block was not adequate intraoperatively, 0.1 mg fentanyl was given i.v. with propofol sedation (2-3 mg kg−1 h−1). As surgery was performed in all patients with a thigh tourniquet, according to our surgeons' practice, a femoral nerve block was also performed with mepivacaine 2% 15 mL.
Pain was assessed using a standard 100 mm visual analogue scale (VAS). After surgery, the patients were instructed to ask for postoperative analgesia when a pain score ≥30 mm was reported on the operated foot. Postoperative analgesia consisted of 100 mg ketoprofen i.v. every 8 h and the primary end-point was defined as the time for first administration of ketoprofen. The time for complete recovery of motor and sensory functions on the operated foot was also recorded, as well as the time for the first postoperative pain medication. Rescue analgesia with 100 mg tramadol was also available if required and was infused i.v. over a 30 min period. The acceptance of the anaesthetic technique was assessed 24 h postoperatively using a two-point score: 1 = Good, if necessary I will repeat it; 2 = Bad, I will never repeat it again.
The calculation of the required sample size was based on mean and standard deviation of duration of postoperative analgesia reported in previous investigations [6,9]. Fifteen patients per group were required to detect a 3 h difference in the first request for postoperative pain medication, accepting a two-tailed α error of 5% and a β error of 20% . Statistical analysis was performed using the program Systat 7.0 (SPSS Inc, Chicago, IL, USA). Normal distribution of data was first determined with the Kologmorov-Smirnov test. Continuous variables were analysed using the Kruskal-Wallis test. The U-test with the Bonferroni's correction was used for post hoc comparison. Categorical data were analysed using the contingency table analysis and the Fisher's exact test. Results are presented as median (range or 95% confidence intervals, CI) or as number. A P-value ≤0.05 was considered as statistically significant.
No differences in patient characteristic parameters were seen among the three groups (Table 1). The onset time of surgical block was shorter in patients of Group Levo-7.5 [5 (5-40) min] than in patients of Group Levo-5 [30 (5-60) min] (P = 0.02), but no differences were reported as compared to Group Ropi-7.5 [20 (5-50) min] (P = 0.12). Four patients (two in Group Levo-5 and two in Group Ropi-7.5) required fentanyl and propofol sedation to complete surgery because of pain at the surgical site (P = 0.33); however, in no case was general anaesthesia required.
Complete regression of sensory and motor blocks occurred later in Group Levo-7.5 as compared to the other two groups (Fig. 1). The time from block placement to first request for pain medication was shorter in Group Ropi-7.5 (13: 11-14 h) than in Groups Levo-7.5 (18: 15-19 h) and Levo-5 (16: 13-20 h) (mean: 25-75 percentiles; P = 0.002 and P = 0.002, respectively). The log-rank curves representing the Kaplan-Meier estimation of time to the first analgesic request were significantly different (Fig. 2). The intensity of pain assessed with the VAS was lower in Group Levo-7.5 at the 8 h observation time, but no further differences in pain intensity were reported among the three groups at further observation times (Fig. 3). Rescue tramadol was required to control postoperative pain by three patients of Group Levo-7.5, eight patients of Group Levo-5 and nine patients of Group Ropi-7.5 (P = 0.05). Patient acceptance was similarly good in the three groups and all studied patients indicated a willingness to accept the same anaesthesia procedure for future operations. No severe complications were reported during the study.
This prospective, randomized, double-blind study provides original data related to the clinical use of 0.75% levobupivacaine for lower extremity nerve block, demonstrating that 0.75% levobupivacaine provides a shorter onset time than 0.5% levobupivacaine and a longer duration of postoperative analgesia than both 0.5% levobupivacaine and 0.75% ropivacaine with reduced need for rescue analgesia after surgery.
The onset time of nerve block reported in this study is longer than that reported when using levobupivacaine for different nerve blocks  but similar to that reported by other authors evaluating sciatic nerve block performed with other long-acting agents [6,9,11-13]. Both the reduction in the onset time and increase in duration of nerve block demonstrated with 0.75% levobupivacaine as compared to the 0.5% concentration are reasonably related to the increase in the total dose injected and similar findings have been already reported [9,14]. Interestingly, levobupivacaine also produced a longer duration of nerve block and postoperative analgesia as compared with the same dose of 0.75% ropivacaine . A possible explanation of this finding could be related to a different potency ratio between levobupivacaine and ropivacaine. In fact, the minimum local anaesthetic concentration of levobupivacaine and bupivacaine providing effective epidural analgesia during labour are similar , while ropivacaine has been demonstrated to be 40-60% less potent than racemic bupivacaine with the same experimental model . However, results coming from other studies cannot be easily extrapolated to surgical block where much higher concentrations of local anaesthetic were used and further studies should be considered to evaluate this interesting point.
As compared to racemic bupivacaine, ropivacaine and levobupivacaine have been demonstrated to be less toxic [18-20]. This is particularly important for lower limb nerve blocks, where a combination of different blocks is usually required with an increased risk for local anaesthetic overdosing. Although our data suggest that levobupivacaine is safe both at 0.5% and 0.75% concentrations, the study was not powered to evaluate the relative safety of levobupivacaine as compared with ropivacaine. Properly powered studies with a much larger sample size are required to confirm that levobupivacaine may increase patient safety and compare its toxic potential with that of ropivacaine. In conclusion, results of this prospective, randomized, double-blind study demonstrate that 0.75% levobupivacaine provides a shorter onset time than 0.5% levobupivacaine and a longer duration of postoperative analgesia than both 0.5% levobupivacaine and 0.75% ropivacaine, with reduced need for rescue analgesia after surgery.
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