Levobupivacaine is the latest local anesthetic introduced in clinical practice. It is the pure S(-)-enantiomer of the racemic formulation bupivacaine. Whereas both the R- and S-enantiomers of bupivacaine have anesthetic activity, preclinical studies suggested that levobupivacaine might be less cardiotoxic than the racemic mixture (1,2). Levobupivacaine has already been compared with racemic bupivacaine for spinal, epidural, and supraclavicular nerve blocks (1,3), but little is known about the comparative effects of this new anesthetic with another widely used long acting local anesthetic, ropivacaine.
Prolonging interscalene brachial plexus block after surgery has been demonstrated to provide safe and effective pain relief (4,5), with better quality of pain control, decreased incidence of side effects, and higher degree of patient satisfaction than patient-controlled IV analgesia with opioid drugs (6,7). Thus, it may be considered as a new “gold standard” for postoperative analgesia after open shoulder surgery.
The aim of this prospective, randomized, double-blinded study was to compare the onset time and quality of interscalene brachial plexus block produced with 0.5% levobupivacaine or 0.5% ropivacaine in patients undergoing open shoulder surgery. Because in our routine practice we usually provide continuous interscalene nerve block for postoperative pain control, we also evaluated the quality of postoperative analgesia produced by 0.125% levobupivacaine or 0.2% ropivacaine for the first 24 h after surgery.
With ethics committee approval and written informed consent, 50 ASA physical status I–II inpatients undergoing open shoulder surgery with interscalene brachial plexus block were studied (20 patients were enrolled at the IRCCS H San Raffaele and 30 at the IRCCS Istituti Ortopedici Rizzoli). Patients receiving chronic analgesic therapy, as well as patients with severe bronchopulmonary disease, diabetes, neuropathy, or allergy to nonsteroidal antiinflammatory drugs or opioids, were excluded.
Using a computer generated sequence of numbers, patients were randomly assigned to receive interscalene brachial plexus block with 30 mL of 0.5% levobupivacaine (Group levobupivacaine, n = 25) or 0.5% ropivacaine (Group ropivacaine, n = 25). Local anesthetic solutions were prepared by one of the authors not involved in either the care or the monitoring of the patient. The patients, attending anesthesiologists, and research coordinators were blinded to the study drug used.
After an 18-gauge IV cannula was inserted in the forearm, midazolam 0.05 mg/kg IV was given as premedication, and standard monitors were placed, including noninvasive arterial blood pressure, heart rate, and pulse oximetry. After local skin infiltration with 20 mg of 2% lidocaine, the interscalene groove was identified using the landmarks described by Winnie and modified for catheter placement (8) and the plexus located with an 18-gauge, 5-cm-long insulated Tuohy needle (Plexolong™, Pajunk, Geisingen, Germany) connected to a nerve stimulator (stimulation frequency, 2 Hz; duration of the stimulating pulse, 0.1 ms). The intensity of stimulating current was initially set to deliver 1 mA and then gradually decreased to ≤0.5 mA after the proper motor response at the deltoid and/or biceps muscle was observed (8). A 20-gauge catheter was inserted through the introducer needle for 4–5 cm into the plexus sheath and secured to the skin; the study solution was then injected slowly, with multiple negative aspirations for blood.
An independent blinded observer evaluated the evolution of sensory and motor blocks every 5 min until achievement of readiness to surgery. Sensory block was assessed with the pinprick test (22-gauge needle). Motor function was tested by asking the patient to abduct the arm at the shoulder joint against gravity and flex the forearm at the elbow. The zero time for clinical assessments was the completion of anesthetic injection. Surgical anesthesia was defined as complete loss of pinprick sensation (22-gauge) at the skin dermatomes involved in the surgical field (from C4-7) and inability to abduct the arm and flex the forearm against gravity at the shoulder and elbow joints, respectively. If the block was not complete 45 min after the injection, the block was considered as failed. Surgery was performed in awake patients; supplemental sedation with midazolam (2 mg IV) was available if requested by the patient. If the patient complained of pain during surgery, rescue analgesia was provided with IV fentanyl (0.1 mg). If this was not adequate to complete surgery, a propofol infusion was started (a first IV bolus of 1 mg/kg followed by a continuous infusion of 3–5 mg · kg−1 · h−1), and the block was considered as failed.
Postoperative analgesia consisted of 100 mg of IV ketoprofen every 8 h with the first administration before the end of surgery, and a patient-controlled interscalene analgesia (PCIA) was started 4 h after the initial interscalene injection (basal infusion rate, 6 mL/h; bolus, 2 mL; lockout period, 15 min; maximum number of boluses per hour, three). Patients of Group levobupivacaine received 0.125% levobupivacaine, whereas patients of Group ropivacaine received 0.2% ropivacaine. In addition, rescue analgesia with 100 mg of IV tramadol was available on demand.
Pain intensity was assessed with a 10-cm visual analog scale (0 cm = no pain; 10 cm = worst possible pain) while asking the patients to move the hand and flex the elbow joint. The degree of pain was recorded when starting the PCIA and then every 8 h for the first 24 h after surgery. At the same time, sensory and motor functions of the operated arm were recorded. To evaluate motor function of the operated arm, the patient was asked to squeeze with both hands the hands of the blinded observer, who scored motor function using a three-point scale: 1 = no motor block, similar strength in both hands; 2 = partial motor block, operated hand weaker than the nonoperated one; 3 = complete motor block, unable to squeeze with the operated hand. Total consumption of local anesthetic solution, as well as the number of incremental doses asked and received by the patient, and the amount of rescue tramadol given during the first 24 h were recorded. At the end of the 24-h study period, the interscalene catheter was removed and patients discharged from the hospital with oral analgesics, as routine in our institutions.
Patient’s satisfaction was evaluated 24 h after surgery with a two-point score: 1 = satisfied; if operated on again in the future, I’ll ask for the same procedure; 2 = unsatisfied; if operated on again in the future, I’ll ask for a different anesthesia/analgesia technique. The presence of persistent neurological symptoms was evaluated 1 wk after surgery by the orthopedic surgeon, who was blinded to the drug used.
The sample size was calculated taking into account the results of a previous study on interscalene brachial plexus block performed with 0.5% ropivacaine (9). Nineteen patients per group were required to detect a 10-min difference in the onset time of surgical block between the two groups accepting a two-tailed α error of 5% and a β error of 20%(10). A preliminary review of the data was performed after the first 20 subjects were enrolled at the San Raffaele Hospital (results of this preliminary review have been presented at the 2002 annual meeting of the European Society of Anesthesia in Nice), and a potential difference in postoperative consumption of the studied local anesthetic solution was noted at this time. Based on this potential difference, the sample-size for the second hospital was increased from 20 patients to 30 patients. This increase in the sample size of the whole study provided an 80% power to detect a 30-mL difference in the volume of local anesthetic solution infused after surgery between the two groups with a two-tailed α error of 5% and a β error of 20%(10); in the meantime, this also increased the power of detecting a 10-min difference in the onset time of surgical block from 80% to 90%. We therefore added a further 10-patient randomization block (five patients in each group) to the initial 20 patients that were going to be enrolled at the second hospital (the Istituti Ortopedici Rizzoli) before they completed their patient enrollment. The physicians and research coordinator taking care of the study protocol at the Istituti Ortopedici Rizzoli were kept blinded to the reasons for such an increase in the sample size.
Statistical analysis was performed using the program Systat 7.0 (SPSS Inc, Chicago, IL). Data distribution was first evaluated using the Kolmogorov-Smirnov test. The Mann-Whitney U-test was used to compare continuous variables, whereas categorical data were analyzed using the contingency table analysis and the Fisher’s exact test. Results are presented as median (range) or as number (percentage). A P value ≤ 0.05 was considered as statistically significant.
A center effect was first excluded by comparing the cases enrolled in the two participating hospitals. No differences in demographic variables as well as type and duration of surgical procedure were reported between the two groups (Table 1).
Two patients in the levobupivacaine group (8%) and one patient in the ropivacaine group (4%) failed to achieve surgical block within 45 min after the first injection. In these patients, the block was supplemented with a further 10-mL bolus of 2% lidocaine and surgery performed uneventfully, but the patients were withdrawn from the study (P = 0.60). The onset time of surgical block was 20 min (10–40 min) with levobupivacaine and 20 min (5–45 min) with ropivacaine (P = 0.53). No differences in intraoperative midazolam consumption were observed between Group levobupivacaine (2 mg [2–4 mg]) and Group ropivacaine (2 mg [2–6 mg]) (P = 0.85). Eight patients in each group (34%) received rescue intraoperative analgesia with 0.1 mg of fentanyl to complete surgery (P = 0.99), but in no case was general anesthesia with propofol required to complete surgery.
In one patient of Group ropivacaine, the interscalene catheter was dislodged 18 h after starting the PCIA. According to our Institutions’ policy, patients undergoing these surgical procedures are usually discharged from the hospital the day after surgery. For this reason, four patients receiving surgery in the afternoon were discharged home before completing the 24 h of postoperative PCIA infusion: one in Group levobupivacaine (4%) was discharged after 12 h of PCIA infusion, and three in Group ropivacaine (11%) were discharged after 16, 20, and 22 h of PCIA infusion, respectively (P = 0.61). In all these patients, data recording were stopped with the end of the interscalene infusion, and patients were removed from the analysis of postoperative efficacy. No differences in the intensity of pain were reported between the two groups at the given observation times (Fig. 1).
Table 2 shows the volume of local anesthetic solution administered in those patients completing the 24-h PCIA infusion; data of this end-point are also presented for each of the two participating hospitals. As explained in the Methods section, the preliminary review performed at the San Raffaele Hospital revealed a trend toward an increase in total volume of local anesthetic solution infused during the first 24 h after surgery in the ropivacaine group as compared with the levobupivacaine group (P = 0.084). This finding was confirmed by data collected at the Istituti Ortopedici Rizzoli (P = 0.024), with a final consumption of local anesthetic solution during the first 24 h of infusion nearly 10% larger in patients receiving ropivacaine than in those treated with levobupivacaine (P = 0.019). Table 2 also shows the number of incremental doses requested and received in the two groups as well as the ratio between them, which can be considered as an index of efficacy.
Rescue tramadol was given in 11 patients of the levobupivacaine group (47%) and 11 patients of the ropivacaine group 55%) (P = 0.77) without differences in total consumption during the observation period (100 mg [0–200 mg] in Group levobupivacaine and 100 mg [0–200 mg] in Group ropivacaine;P = 0.34).
Figure 2 shows the evolution of motor block on the operated limb during the study period. When starting the PCIA infusion, 4 h after the initial induction bolus, motor blockade was more profound in patients of Group levobupivacaine than ropivacaine (P = 0.003); however, no further differences in the recovery of motor function were observed between the two groups at the given observation times.
No severe complications were reported in either group. Three patients in Group ropivacaine only (12%) reported nausea, and one of them (4%) vomited during the postoperative period, whereas no patient in the levobupivacaine group complained of nausea or vomiting (P = 0.23 and P = 0.99, respectively).
All patients stated they would accept the same anesthesia procedure for future operation. No case of persistent neurological dysfunction was reported at the routine postoperative visit 1 wk after surgery.
Although levobupivacaine has been already compared with racemic bupivacaine for spinal (1,11), epidural (1,12), and peripheral nerve blocks (3,13,14), little information is still available comparing the clinical profile of levobupivacaine with that of another widely used long-acting anesthetic, ropivacaine. This prospective, randomized, double-blinded study provides original data related to the clinical use of levobupivacaine for interscalene brachial plexus anesthesia and compares its clinical use with that of ropivacaine, demonstrating that 30 mL of 0.5% levobupivacaine injected into the brachial plexus sheath at the interscalene level induces a surgical block of similar onset and intensity than the one produced by the same volume and concentration of ropivacaine. The present findings also demonstrate that the use of levobupivacaine 0.125% provides similar postoperative analgesia and recovery of motor block than that produced by 0.2% ropivacaine, with a reduced volume of local anesthetic solution infused during the first 24 hours after surgery.
No previous studies have reported evaluating levo-bupivacaine for interscalene brachial plexus block. When comparing 0.4 mL/kg of 2 concentrations of levobupivacaine (0.25% and 0.5%) for supraclavicular brachial plexus block, Cox et al. (3) reported a mean onset time of six to eight minutes. In the present investigation, the onset time observed with nearly the same volume of levobupivacaine was much longer than that reported by Cox et al. (3). However, the onset time observed in the ropivacaine group was similar to other previous clinical studies evaluating 0.5% ropivacaine for interscalene brachial plexus block (9,14,15).
In the present study, we used identical volumes and concentrations of levobupivacaine and ropivacaine to induce the block and demonstrated a similar quality of surgical anesthesia. On the contrary, the concentration of levobupivacaine used for postoperative analgesia was nearly 40% less than that of ropivacaine. When used for epidural analgesia, levobupivacaine has the same potency of racemic bupivacaine (16), whereas ropivacaine has demonstrated nearly 40% less potency than bupivacaine in the same experimental model (17). For this reason we used a concentration of levobupivacaine 40% smaller than that of ropivacaine for postoperative analgesia, reporting results similar to those previously described by Borgeat et al. (18), who reported on the use of 0.2% ropivacaine in a similar clinical setting.
Interestingly, despite the smaller concentration of local anesthetic used for postoperative analgesia, patients receiving levobupivacaine also required a reduced total volume during the 24 hours of PCIA infusion, with a better ratio between incremental dose received from and asked to the patient-controlled anesthesia pump. This finding might be related to the difference in the potency ratio between levobupivacaine and ropivacaine extrapolated by previous minimum local analgesic concentration studies with the two drugs (16,17). Another possible explanation for this finding could be a different profile of nerve block resolution between the two drugs. This may be also in agreement with the deeper motor block observed in patients receiving levobupivacaine when PCIA infusion was started. Because the interscalene PCIA infusion was started before complete resolution of the nerve block induced with the first bolus, our results do not provide adequate information on the time for complete resolution of nerve block with the two studied drugs; however, previous experiences with sciatic nerve block failed to demonstrate a different profile of nerve block resolution between 0.5% levobupivacaine and 0.5% ropivacaine (19).
The use of 0.2% ropivacaine has been reported to better preserve motor function than 0.15% bupivacaine (18). In the present investigation, motor block was assessed with a semi-quantitative scale because we only compared the strength of the operated hand with that of the nonoperated one. However, no difference in the recovery profile of motor function was reported between 0.2% ropivacaine and a concentration of levobupivacaine as small as 0.125%, suggesting that this concentration of levobupivacaine can result in an adequate differentiation between sensory and motor blocks.
Ropivacaine is often preferred because of its reduced toxic potential as compared with bupivacaine, not only at equivalent, but also at equipotent doses (20). The reduced toxic potential of ropivacaine is particularly important when continuous peripheral nerve blocks are planned because of the increased risk for drug accumulation (21). In animal studies, levobupivacaine has been associated with a reduced depressant effect on cardiovascular function than both dex- and racemic bupivacaine (22,23), whereas in healthy volunteers, levobupivacaine produced significantly less depression of cardiac output than bupivacaine (24). Although our data suggest that levobupivacaine is safe, 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.
The present findings only apply to interscalene brachial plexus block, whereas additional studies should be done to better evaluate the clinical use of levobupivacaine for both single-shot and continuous peripheral nerve blocks with other approaches. Nonetheless, results of this study demonstrate that 30 mL of 0.5% levobupivacaine produces an interscalene brachial plexus block of similar onset and quality as the one produced by the same volume of 0.5% ropivacaine. When prolonging the block with a PCIA infusion, 0.125% levobupivacaine provides adequate pain relief after major open shoulder surgery, with a reduced volume of local anesthetic infused during the first postoperative day and no differences in the recovery of motor function as compared with 0.2% ropivacaine.
The study was supported by the Vita-Salute University of Milano and the IRCCS Istituti Ortopedici Rizzoli of Bologna. The authors thank Drs Marco Berti, Giorgio Danelli, Roberta Santorsola, and the staff of anesthesia nurses of the Acute Pain Service of the Department Anesthesiology, San Raffaele Hospital. We also thank Dr Valeria Sassoli and Dr Massimiliano Luppi (pharmacists) and Mrs Pina Gallerani and Tiziana Risi (nurses) of the Istituti Ortopedici Rizzoli for their valuable help in conducting the study. Finally, we thank Abbott SpA (Campoverde, Latina, Italy) for supplying levobupivacaine free of charge.
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