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© 2002 International Anesthesia Research Society
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Abstract |
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Levobupivacaine is the pure S(-)-enantiomer of racemic bupivacaine but is less toxic to the heart and central nervous system. Although it has recently been introduced for routine obstetric and nonobstetric epidural anesthesia, comparative clinical studies on its intrathecal administration are not available. We therefore performed this prospective randomized double-blinded study to evaluate the anesthetic potencies and hemodynamics of intrathecal levobupivacaine compared with racemic bupivacaine. Eighty patients undergoing elective hip replacement received either 3.5 mL levobupivacaine 0.5% isobaric or 3.5 mL bupivacaine 0.5% isobaric. Sensory blockade was verified with the pinprick test; motor blockade was documented by using a modified Bromage score. Hemodynamic variables (e.g., blood pressure, heart rate, pulse oximetry) were also recorded. Intergroup differences between levobupivacaine and bupivacaine were insignificant both with regard to the onset time and the duration of sensory and motor blockade (11 ± 6 versus 13 ± 8 min; 10 ± 7 versus 9 ± 7 min; 228 ± 77 versus 237 ± 88 min; 280 ± 84 versus 284 ± 80 min). Both groups showed slight reductions in heart rate and mean arterial pressure, but there was no intergroup difference in hemodynamics. We conclude that intrathecal levobupivacaine is equal in efficacy to, but less toxic than, racemic bupivacaine.
IMPLICATIONS: Levobupivacaine, the pure S(-)-enantiomer of racemic bupivacaine is an equally effective local anesthetic for spinal anesthesia compared with racemic bupivacaine.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Levobupivacaine (S-1-butyl-2-piperidylformo-2',6'-xylidide hydrochloride), the pure S(-)-enantiomer of racemic bupivacaine, is a new long-acting local anesthetic that has recently been introduced in the clinical routine. Because of its significantly decreased cardiovascular (1,2) and central nervous system (3,4) toxicity, levobupivacaine seems to be an attractive alternative to bupivacaine. Comparative clinical studies are available for nonobstetric (5,6) and obstetric epidural anesthesia (7), brachial plexus blockade (8), and infiltration analgesia (9), but not for spinal anesthesia.
Because of their close chemical relationship, levobupivacaine and racemic bupivacaine share many pharmacokinetic properties; therefore, it is not surprising that the preliminary clinical experience shows that both local anesthetics are largely equally effective. One exception was described for lumbar epidural anesthesia, in which the sensory blockade lasted significantly longer with levobupivacaine than with racemic bupivacaine (5), which might be attributable to a greater intrinsic vasoconstrictor potency of levobupivacaine (10).
Only one clinical study is available on intrathecal anesthesia with levobupivacaine (11), suggesting that levobupivacaine achieves satisfactory surgical anesthesia but with an unpredictable spread of sensory blockade. These results were not, however, compared with racemic bupivacaine. This lack of comparative studies and adequate information on the anesthetic potency of intrathecally administered levobupivacaine prompted us to investigate the anesthetic potency and hemodynamic effects of intrathecally administered levobupivacaine compared with intrathecally administered racemic bupivacaine in a prospective randomized double-blinded study.
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Methods |
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Eighty patients aged 35–85 yr with ASA physical status I–III who were scheduled for elective orthopedic hip replacement with spinal anesthesia were enrolled in the study after IRB approval and written informed consent. Exclusion criteria were known hypersensitivity to amide local anesthetics, general contraindications against spinal anesthesia, and morbid obesity (>150% the ideal weight or >130 kg). Patients unable to understand the study protocol because of language problems or other reasons were also excluded.
The patients were randomly allocated to two groups receiving either 3.5 mL levobupivacaine 0.5% isobaric (ChirocaineTM; Antigen Pharmaceuticals, Roscrea, Ireland) or 3.5 mL bupivacaine 0.5% isobaric (CarbostesinTM; Astra, Wedel, Germany) for spinal anesthesia, according to a computer-generated randomization table. The random assignments were prepared outside the study center and delivered in sealed, opaque, sequentially numbered envelopes. After oral premedication with 7.5 mg of midazolam and IV infusion of 500 mL 6% hydroxyethylstarch (12), both drugs were administered intrathecally, under aseptic conditions and with the patients in a sitting position, through a 27-gauge Quincke needle in the midline at L2-3. Immediately after administration, the patients were turned into a supine position.
Monitored variables included continuous electrocardiogram (lead II), heart rate, arterial blood pressure (by noninvasive means), and pulse oximetry (SpO2). Sensory blockade was monitored with the pinprick test, motor blockade was assessed based on a modified Bromage scale (0 = no paralysis, able to flex hips/knees/ankles; 1 = able to move knees, unable to raise extended legs; 2 = able to flex ankles, unable to flex knees; 3 = unable to move any part of the lower limb). These tests were performed every 2 min for up to 30 min after spinal anesthesia and every 30 min postoperatively until the sensory and motor variables were back to normal. In the postanesthesia care unit (PACU), the patients were asked to assess their level of pain based on a visual analog scale (VAS) ranging from 0 (no pain) to 10 (maximal pain). All tests (i.e., sensory/motor block and VAS) were performed by a staff anesthesiologist not otherwise involved in the study.
The surgical procedure was started 20 min after initiation of spinal anesthesia. If the level of analgesia was inadequate, the regimen was switched to general anesthesia. Intraoperatively, the patients received 10 mL · kg-1 · h-1 lactated Ringer solution.
The hemodynamic variables and SpO2 were recorded before spinal anesthesia and thereafter every 2 min for up to 30 min, then every 5 min until the end of the procedure. Postoperatively, the recordings were repeated every 30 min until the patient was transferred to the ward. A decrease >25% from baseline, or to <60 mm Hg, in mean arterial pressure, was defined as hypotension and treated with etilephrine bolus 2 mg; a heart rate <50 bpm was defined as bradycardia and treated with 0.5 mg of atropine; and a decrease in SpO2 to <93% was defined as hypoxia and treated with supplemental oxygen via face mask. In such cases, only the pretherapeutic data were included in the statistical analysis.
The onset time of sensory or motor blockade was defined as the interval between intrathecal administration and maximal spread of the sensory block, or a Bromage score of 3, respectively. The duration of sensory or motor blockade was defined as the interval from intrathecal administration to the point of a 2-segment regression and the first 
1 VAS score, or to the point in which the Bromage score was back to zero.
In the PACU, the patients were attached to a patient-controlled analgesia pump (Pharmacia BiosystemsTM, Freiburg, Germany) using piritramide 3 mg bolus and a 15-min lockout interval. No continuous background infusion was used, and there was no upper dose limit. Patients in whom adequate pain relief could not be achieved with this patient-controlled analgesia setup were accepted for rescue analgesia with additional piritramide. First use and total supply of piritramide were documented over 10 h. The patients were monitored in the PACU for 12 h and were then discharged to the ward.
Group size was estimated based on a pilot study using Machin and Campbell tables. After data collection, calculation of the power revealed a 77% power of the study for detecting a difference in duration of sensory block and 83% power in detecting a difference in maximal spread of the sensory block. Data were expressed as mean values ± SD except for peak block height in which the range of values is also indicated and the upper and lower 95% confidence intervals. Intergroup differences in onset time and duration of sensory/motor blockade were evaluated by using an unpaired t-test on first VAS scores as well as piritramide, etilephrine, and atropine requirements. Intragroup and intergroup differences in hemodynamic data were evaluated by using analysis of variance for repeated measurements. Results were considered to be statistically significant at P < 0.05.
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Results |
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Demographic data and the mean duration of surgery are compiled in Table 1. One patient in the Levobupivacaine group required supplemental anesthesia during skin incision because of a failed block for technical reasons and was not evaluated further. All statistical analyses were therefore based on 39 patients in the Levobupivacaine and 40 patients in the Bupivacaine group.
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Table 2 gives an overview of onset times and durations of sensory/motor blocks. There were no significant differences between groups except for the fact that the transition from Bromage scale 0 to 2 was significantly faster in the Levobupivacaine (4 ± 3 min) than in the Bupivacaine group (6 ± 5 min; P = 0.03). By comparison, there was no significant difference in first VAS scores at the PACU (2.6 ± 1.5 in the Levobupivacaine versus 3.4 ± 2.4 in the Bupivacaine group).
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There was a slight decrease in mean heart rates and arterial blood pressures over 30 min after anesthesia (Fig. 1), which however was not associated with significant intergroup differences in hemodynamics. SpO2 remained stable throughout the observation period. None of the patients with sufficient spinal anesthesia required supplemental oxygen. Hemodynamic and respiratory variables remained stable from skin incision throughout the surgical procedure. No patient required blood replacement.
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None of the 79 patients required supplemental analgesics during surgery. One patient in the Levobupivacaine and two patients in the Bupivacaine group received etilephrine within a few minutes of spinal anesthesia. One patient in the Levobupivacaine group received atropine (8 min after spinal anesthesia) to treat hypotension and bradycardia. There were no episodes of perioperative nausea and vomiting.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study demonstrates that levobupivacaine, the pure S(-)-enantiomer of racemic bupivacaine, is an effective local anesthetic for spinal applications. Onset time and duration of the sensory and motor blocks, peak block height, and hemodynamics are similar to those obtained with racemic bupivacaine.
Ropivacaine is another enantiomer whose potency in intrathecal administration has been investigated. Wahedi et al. (13) reported that 0.5% spinal ropivacaine only achieved sufficient surgical anesthesia in 75% of cases, 30% being characterized by subtotal motor blockade. This result was since confirmed by Malinovsky et al. (14), who suggested an anesthetic ratio between spinal ropivacaine and bupivacaine of 2:3, with lower anesthetic potency achieved by 15 mg of spinal ropivacaine than by 10 mg of bupivacaine in patients undergoing endoscopic urological surgery. Aside from being evidently inferior to bupivacaine, ropivacaine is not approved for intrathecal use.
Although levobupivacaine has very similar pharmacokinetic properties to those of racemic bupivacaine, several studies involving humans as well as animals support the notion that its faster protein-binding rate reflects a decreased degree of toxicity (15). The decreased cardiovascular and central nervous system toxicity make levobupivacaine an interesting alternative to racemic bupivacaine, despite the fact that spinal anesthesia is achieved with small-dose regimens. Levobupivacaine is also worth considering for its anesthetic potency and hemodynamic effects in the event of inadvertent intrathecal administration during epidural anesthesia.
Levobupivacaine has been investigated in epidural anesthesia, brachial plexus blocks, peripheral nerve blocks, and in infiltration anesthesia. Kopacz et al. (5) compared 0.75% levobupivacaine and bupivacaine for epidural anesthesia in lower abdominal surgery and observed similar onset times, but a significantly longer duration of sensory blockade when levobupivacaine was used. Their report includes no figures on the onset time of motor blockade but indicates that its maximal degree and duration was similar regardless of which drug was used. Cox et al. (8) reported that 0.5% levobupivacaine compared with bupivacaine for supraclavicular plexus blocks generally resulted in longer-lasting sensory (1039 versus 896 minutes) and motor (1050 versus 933 minutes) blocks, the analgesic potencies as such being similar. Finally, Bay-Nielsen et al. (9) observed similar analgesic potencies of 0.25% levobupivacaine and bupivacaine for infiltration analgesia in inguinal hernia repair.
To summarize, the currently available data on levobupivacaine and racemic bupivacaine for epidural anesthesia and brachial plexus blocks show a similar analgesic potency whereas levobupivacaine tends to induce more sustained sensory and motor blocks.
Previous to our own study, Burke et al. (11) have been the only authors to report on levobupivacaine for spinal anesthesia. In their noncomparative study involving a relatively small sample of 18 patients, 3.0 mL 0.5% intrathecal levobupivacaine achieved satisfactory surgical anesthesia. There were mean intervals of 25 minutes (2–30 minutes) until maximal cephalic spread and of 15 minutes (10–30 minutes) until maximal motor blockade, the sensory blocks were sustained for 388 minutes (295–478 minutes), and the motor blocks for 266 minutes (170–415 minutes). The patients in that study revealed slightly reduced heart rates and significantly reduced blood pressures, without, however, requiring prespinal fluid administration.
Our own results, which were obtained in the first prospective comparative clinical study on the subject, indicate that levobupivacaine and bupivacaine are equi-effective for spinal anesthesia, both with regard to the onset time and the duration of sensory and motor blockade. The requirements for postoperative supplemental analgesia were also similar in both groups. Even the 95% upper and lower confidence intervals indicate equal effectiveness of these two local anesthetics. As in the study by Burke et al. (11), there were slight reductions in heart rate and mean arterial pressure, but there were no significant intergroup differences in hemodynamics. Considering the finding of Carpenter et al. (16) that peak height is the main variable for bradycardia and hypotension during spinal anesthesia, the similar intergroup hemodynamics in our study are consistent with the fact that both study groups showed a mean peak block height of Th8.
In contrast to Burke et al. (11), who reported an unpredictable spread of levobupivacaine, we found that the spread of spinal anesthesia with levobupivacaine was just as predictable as with bupivacaine. Likewise, we observed considerably shorter onset times for sensory/motor blockade (11 ± 6/10 ± 7 minutes) than Burke et al. (25/15 minutes). Given our sample size of 40 patients compared with the 18 patients in the study by Burke et al., we are confident that our own figures are more realistic.
To summarize, the results of this study indicate that levobupivacaine and racemic bupivacaine show equally effective potencies for spinal anesthesia, both with regard to the onset time and the duration of sensory and motor blockade. Indeed, levobupivacaine generally showed a more sustained sensory and motor blockade. Intrathecal administration resulted in similar hemodynamic changes regardless of whether levobupivacaine or racemic bupivacaine was used. Based on these data, levobupivacaine seems to be an interesting alternative to bupivacaine for spinal anesthesia.
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Acknowledgments |
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The authors thank Mag. Christine Kasper from Abbott Austria Ltd. for providing patients with insurance.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- Bardsley H, Gristwood R, Baker H, et al. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol 1998; 46: 245–9.[Web of Science][Medline]
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Morrison SG, Dominguez JJ, Frascarolo P, Reiz S. A comparison of the electrocardiographic cardiotoxic effects of racemic bupivacaine, levobupivacaine, and ropivacaine in anesthetized swine. Anesth Analg 2000; 90: 1308–14.
[Abstract/Free Full Text] - Huang YF, Pryor ME, Mather LE, et al. Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep. Anesth Analg 1998; 86: 797–804.[Abstract]
- Gristwood RW, Greaves JL. Levobupivacaine: a new safer long acting local anaesthetic agent. Expert Opin Invest Drug 1999; 8: 861–76.
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Kopacz DJ, Allen HW, Thompson GE. A comparison of epidural levobupivacaine 0.75% with racemic bupivacaine for lower abdominal surgery. Anesth Analg 2000; 90: 642–8.
[Abstract/Free Full Text] -
Cox CR, Faccenda KA, Gilhooly C, et al. Extradural S(-)-bupivacaine: comparison with racemic (RS)-bupivacaine. Br J Anaesth 1998; 80: 289–93.
[Abstract/Free Full Text] - Bader AM, Tsen LC, Camann WR, et al. Clinical effects and maternal and fetal plasma concentrations of 0.5% epidural levobupivacaine versus bupivacaine for cesarean delivery. Anesthesiology 1999; 90: 1596–601.[Web of Science][Medline]
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Cox CR, Checketts MR, MacKenzie N, et al. Comparison of S(-)-bupivacaine with racemic (RS)-bupivacaine in supraclavicular brachial plexus block. Br J Anaesth 1998; 80: 594–8.
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Bay-Nielsen M, Klarskov B, Bech K, et al. Levobupivacaine vs bupivacaine as infiltration anaesthesia in inguinal herniorrhaphy. Br J Anaesth 1999; 82: 280–2.
[Abstract/Free Full Text] - Foster RH, Markham A. Levobupivacaine: a review of its pharmacology and use as a local anaesthetic. Drugs 2000; 59: 551–79.[Web of Science][Medline]
- Burke D, Kennedy S, Bannister J. Spinal anesthesia with 0.5% S(-)-bupivacaine for elective lower limb surgery. Reg Anesth Pain Med 1999; 24: 519–23.[Web of Science][Medline]
- Marhofer P, Faryniak B, Oismüller C, et al. Cardiovascular effects of six percent hetastarch and lactated Ringer’s solution during spinal anesthesia. Reg Anesth Pain Med 1999; 24: 399–404.[Web of Science][Medline]
- Wahedi W, Nolte H, Klein P. Ropivacaine in spinal anaesthesia. Anaesthesist 1996; 45: 737–44.[Web of Science][Medline]
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[Abstract/Free Full Text] - Burm AGL, Van der Meer AD, Van Kleef JW et al. Pharmacokinetics of the enantiomers of bupivacaine following intravenous administration of the racemate. Br J Clin Pharmacol 1994; 38: 125–9.[Web of Science][Medline]
- Carpenter RL, Caplan RA, Brown DL, et al. Incidence and risk factors for side effects of spinal anesthesia. Anesthesiology 1992; 76: 906–16.[Web of Science][Medline]
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