| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
© 2002 International Anesthesia Research Society
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Levobupivacaine is the isolated S-enantiomer of bupivacaine and may be a favorable alternative to spinal bupivacaine. However, its clinical efficacy relative to bupivacaine and its dose-response characteristics, in spinal anesthesia, must first be known. This double-blinded, randomized, cross-over study was designed to compare the clinical efficacy of hyperbaric levobupivacaine and bupivacaine for spinal anesthesia. Eighteen healthy volunteers were randomized into three equal groups to receive two spinal anesthetics, one with bupivacaine and the other with levobupivacaine, of equal-milligram doses (4, 8, or 12 mg). We assessed blockade quality and duration with pinprick, transcutaneous electrical stimulation, thigh tourniquet, abdominal and quadriceps muscle strength, modified Bromage scale, and time until achievement of discharge criteria. Sensory and motor block were similar between the same doses of levobupivacaine and bupivacaine (P > 0.56 to 0.86). For example, in the 12-mg groups of levobupivacaine versus bupivacaine, mean duration of tolerance to transcutaneous electrical stimulation at T12 was 100 min for both. The duration of motor block at the quadriceps was 71 versus 73 min, and time until achievement of discharge criteria was 164 min for both. Hyperbaric spinal levobupivacaine has equivalent clinical efficacy to racemic bupivacaine for spinal anesthesia in doses from 4 to 12 mg.
IMPLICATIONS: Hyperbaric spinal levobupivacaine has equivalent clinical efficacy to hyperbaric spinal bupivacaine over the 4–12-mg ranges.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Over the past few years, the use of bupivacaine for outpatient spinal anesthesia has increased because of concerns over the potential neurotoxicity of spinal lidocaine. Spinal bupivacaine has a less frequent incidence of postoperative complaints, but doses that provide reliable anesthesia (7.5 mg or larger) may delay patient discharge after outpatient surgery (1,2). Levobupivacaine, an amide local anesthetic which is the isolated S-enantiomer of racemic bupivacaine (henceforth will be referred to as bupivacaine), is commercially available and is less cardiotoxic on a per-milligram basis than bupivacaine because of decreased potency at the sodium channel (3–5). Reports using large doses of levobupivacaine for epidural anesthesia or brachial plexus anesthesia suggest equivalent clinical efficacy to bupivacaine (6,7). We previously determined that the clinical efficacy of spinal ropivacaine was approximately half of bupivacaine (8), despite their being of equal clinical efficacy for epidural and peripheral nerve block anesthesia. Thus, equivalent clinical efficacy in epidural and peripheral nerve block anesthesia does not necessarily translate to equivalent efficacy for spinal anesthesia. However, only one study has evaluated the safety of a single 15-mg isobaric dose of levobupivacaine (9). The relative clinical efficacy of a range dose of intrathecal levobupivacaine has not been determined, and intrathecal levobupivacaine has not been directly compared with racemic bupivacaine.
We performed this randomized, double-blinded volunteer study to address two issues: 1) directly determine the relative clinical efficacy of intrathecal bupivacaine and levobupivacaine in humans to allow direct evaluation of levobupivacaine as a substitute for bupivacaine, and 2) create a dose-response curve for small-dose hyperbaric 0.25% spinal levobupivacaine to determine its suitability for outpatient spinal anesthesia.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
After IRB approval and informed consent were obtained, 18 healthy volunteers (aged 19–57 years; 9 women, 9 men) were enrolled in this randomized, double-blinded, cross-over study. Each volunteer received two spinal anesthetics, separated by at least 24 h, one with bupivacaine and the other with an equal-milligram dose of levobupivacaine. Hyperbaric study solutions were created by combining 0.5% bupivacaine or 0.5% levobupivacaine with an equal volume of 10% dextrose, resulting in final drug and dextrose concentrations of 0.25% and 5%, respectively. The volunteers were randomized (random number generator) into one of three groups of six subjects, with each group receiving one of three doses (4, 8, or 12 mg; 1.6, 3.2, and 4.8 mL, respectively) of both levobupivacaine and bupivacaine. The order of drug administration was balanced and also randomized. All subjects had fasted for 6 h and received no sedatives during the study. Before subarachnoid block, a 20-gauge peripheral IV line was placed and an IV bolus of lactated Ringer’s solution (6 mL/kg) was administered, followed by an infusion of 8 mL · kg-1 · h-1 for the first hour and 2 mL · kg-1 · h-1 thereafter. Vasoactive drugs were administered only if symptoms of hypotension or bradycardia developed.
Spinal anesthesia was administered with the volunteers in the left lateral decubitus position. Under sterile conditions and after local infiltration of the skin with 1% lidocaine, the subarachnoid space was entered at the L2-3 interspace via the midline approach using a 20-gauge introducer and a 25-gauge TV High Flow Whitacre Needle (Becton Dickinson and Co., Franklin Lakes, NJ). With the spinal needle orifice facing cephalad, 0.2 mL of the cerebrospinal fluid was aspirated, followed by injection of the study solution at a rate of 0.25 mL/s. After drug administration, a second 0.2-mL aspiration and reinjection of cerebrospinal fluid was used to confirm intrathecal injection. Subjects were immediately laid supine for the remainder of the study. The duration of blockade was assessed using the following modalities: 1) sensory block to pinprick, 2) tolerance to transcutaneous electrical stimulation (TES), 3) tolerance to thigh tourniquet, and 4) motor block by electromyography (EMG) (abdomen), isometric force dynamometry (quadriceps), and modified Bromage scale (lower extremity).
Bilateral sensory block to pinprick was tested by a blinded assessor in a cephalad-to-caudad direction with a disposable dermatome tester every 5 min after injection for the first 60 min, then at 10-min intervals until complete resolution of sensory anesthesia. The right C5-6 dermatome was used as an unblocked reference point.
Tolerance to TES (1,10) was determined at six common surgical sites: at the lateral ankle (S1) bilaterally, at the medial knee (L3) bilaterally, at the pubis midline (T12), and at the umbilicus midline (T10). TES was performed with a peripheral nerve stimulator (model NS252; Fisher & Paykel, Auckland, New Zealand) using 50-Hz tetanus for 5 s initially at 10 mA and then with increasing increments of 10 mA to a maximum of 60 mA. This maximal limit was chosen because previous studies have shown TES at 60 mA to be equivalent to the intensity of stimulation caused by surgical incision (11,12). Also, volunteers were queried as to their ability to detect a 10-mA stimulus because a previous study has shown TES at 10 mA to be equivalent to the intensity of stimulation caused by surgical incision (10). Testing began in a systematic cephalad-to-caudad order at 4 min after injection and continued at 10-min intervals until the subject could no longer tolerate 60 mA on two successive tests. If the subject was never able to tolerate 60 mA, the testing was terminated at 34 min.
Thirty minutes after injection, duration of the tolerance to left thigh tourniquet was assessed (1) using a 34-in. pneumatic cuff that was inflated to 300 mm Hg after exsanguination by gravity. This is similar to the tourniquet application used in lower extremity orthopedic procedures at our institution. The subjects were instructed to request deflation of the tourniquet when the discomfort level reached a pain score of 5/10 or at a maximal time limit of 120 min.
Motor block of the abdominal and lower extremity muscles was assessed by using EMG, isometric force dynamometry, and modified Bromage scale (1). To test abdominal muscle strength, an EMG lead was placed at the mid-clavicular line to the left of the umbilicus. A restraining strap was placed across the body at the level of the xiphoid, and an isometric maximal contraction of abdominal muscle flexion against the strap was conducted. By using a commercially available surface EMG (MyoTrac2; Thought Technology Ltd., Montreal, and Quebec, Canada), an averaged, rectified measurement was taken during the middle 2 s of a 6-s maximal effort. Muscle strength of the right lower extremity was mea-sured by using a commercially available isometric force dynamometer (Micro FET; Hoggan Health Industries, Draper, UT) during a 5-s maximal force contraction of the right quadriceps muscle (straight leg lift against resistance). Measurements for both tests were performed in triplicate and averaged at baseline and at 10-min intervals after injection until 
90% of baseline strength returned. Modified Bromage scores (no block [0], able to bend the knee [1], able to dorsiflex the foot [2], and complete motor block [3]) were recorded every 10 min after injection until the resolution of the motor block or until 40 min if no motor block was achieved.
Each subject also underwent a simulated clinical discharge pathway. Upon recovery of S2 dermatome to pinprick, the subjects attempted ambulation without assistance. If ambulation was successful, they then attempted to void. If either ambulation or voiding were unsuccessful, then the attempts were repeated at 15-min intervals until these endpoints were achieved. Volunteers were questioned daily for 72 h about the presence of headache, backache, or other residual symptoms.
Determination of dose-response relationships for TES tolerance, EMG, isometric force dynamometry, Bromage scores, and achievement of discharge criteria were initially attempted with multiple and linear regression analysis. However, because a plateau occurred at the 8-mg dose, the data are not consistent with a linear model. Subsequent statistical analysis of parametric data were performed with analysis of variance, examining both drug and dose as independent factors, with Bonferroni/Dunn used for post hoc analysis. All bilateral measurements were averaged for each subject. In addition, all dermatome levels blocked to pinprick were averaged for each dose of each drug to determine estimated time course of sensory anesthesia to pinprick. Significance was defined as P < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subject demographics were similar in the three dosage groups (Table 1), and spinal anesthesia was successful in all groups. No volunteers required vasoactive drugs. Assessments of all subjects with both levobupivacaine and bupivacaine included pinprick, tolerance to TES, ability to detect TES at 10 mA, tolerance to tourniquet, motor block, and time until achievement of discharge criteria, and are reported as minutes of duration per-milligram dose (Table 2). Dose-response relationships were unable to be determined by linear regression for levobupivacaine and bupivacaine because of a plateau at the8-mg dose (P > 0.063) (Table 2). For each dose of levobupivacaine and bupivacaine, duration of sensory and motor blockade (Figs. 1–4) were not clinically or statistically different (P > 0.1). Tolerance to TES and loss of ability to detect TES at 10 mA were not achieved for the smallest dose of levobupivacaine or bupivacaine at the ankle, pubis, and umbilicus (Table 2).
|
|
|
|
|
|
Three volunteers reported mild postdural puncture headaches after each of their two anesthetics. None required treatment and all resolved within 24–72 h. Two volunteers reported mild backaches, one after levobupivacaine and one after bupivacaine. No symptoms were felt radiating into the buttocks or legs. Neither subject required treatment and all symptoms resolved within 48–72 h.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The dose-response data for bupivacaine and levobupivacaine within this study suggest an approximate relative clinical efficacy of 1:1. This equivalent efficacy is well illustrated by the dermatome regression curves (Fig. 1) and from the duration per milligram information in Table 2. In Figure 1, the resolution of the two local anesthetics at all dose levels is similar. Table 2 illustrates that the duration of anesthesia per-milligram dose for levobupivacaine and bupivacaine are consistently near a 1:1 ratio for multiple measures of sensory and motor block. Thus, levobupivacaine should be clinically similar to bupivacaine for outpatient subarachnoid block and offers no obvious clinical advantage.
Our findings complement our previous study determining relative clinical efficacies of subarachnoid block with bupivacaine and ropivacaine (8). In our previous study, we used the same model and determined a 2:1 ratio of relative clinical efficacy for subarachnoid block with bupivacaine/ropivacaine. This relative clinical efficacy of bupivacaine and ropivacaine was then confirmed in the outpatient setting in arthroscopy patients by other authors (13). Thus, the results indicate a 2:2:1 relative clinical efficacy for outpatient subarachnoid block for levobupivacaine/bupivacaine/ ropivacaine.
We were unable to determine a statistically significant dose-response relationship because of the unusual plateau in effects at the middle (8 mg) dose. This unusual response between the 8-mg and 12-mg groups may be explained in several ways. Subarachnoid blocks have highly variable results and a two- to three-fold variation is not unusual among subjects given the same dose (8). Our sample size was small (n = 6) and likely exaggerated the chance greater effect of subarachnoid block in the 8-mg versus 12-mg groups because of this inter-subject variability. Because previous studies in the same dose range (4–15 mg) of bupivacaine and ropivacaine have clearly demonstrated a dose-response effect (2,8,13), we suspect a larger study would also clearly demonstrate a dose-response effect for levobupivacaine versus bupivacaine. We note that our findings do support our use of a cross-over design. Each dose group of levobupivacaine and bupivacaine used the same individual for both drugs (e.g., each subject in the 12-mg groups received both levobupivacaine and bupivacaine) which would minimize random differences between drugs. The parallel plateaus in dose response to levobupivacaine and bupivacaine nicely demonstrate the need for use of only intra-individual differences to control for comparison of levobupivacaine versus bupivacaine.
In conclusion, we determined that the relative clinical efficacy of bupivacaine to levobupivacaine in spinal anesthesia is approximately 1:1. Equal milligram doses of spinal levobupivacaine provide a similar profile to bupivacaine for sensory and motor block as well as time until achievement of discharge criteria. Levobupivacaine is an alternative to bupivacaine in outpatient spinal anesthesia, but does not offer any specific advantages.
|
Acknowledgments |
|---|
This study was supported by the Department of Anesthesiology, Virginia Mason Medical Center.
|
Footnotes |
|---|
Presented in part at the International Anesthesia Research Society 75th Clinical and Scientific Congress, March 19, 2001, Ft. Lauderdale, FL.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Liu S, Ware P, Allen H, et al. Dose-response characteristics of spinal bupivacaine in volunteers: clinical implications for ambulatory anesthesia. Anesthesiology 1996; 85: 729–36.[Web of Science][Medline]
- Liu S, Pollock J, Mulroy M, et al. Comparison of 5% with dextrose, 1.5% with dextrose, and 1.5% dextrose-free lidocaine for solutions for spinal anesthesia in human volunteers. Anesth Analg 1995; 81: 697–702.[Abstract]
- 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]
- Huang Y, Pryor M, Mather L, Veering B. Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep. Anesth Analg 1998; 86: 797–804.[Abstract]
-
Morrison S, Dominguez J, 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] -
Cox C, Faccenda K, Gilhooly C, et al. Extradural S(-)-bupivacaine: comparison with racemic RS-bupivacaine. Br J Anaesth 1998; 80: 289–93.
[Abstract/Free Full Text] -
Kopacz D, Allen H, Thompson G. Comparison of epidural levobupivacaine 0.75% with racemic bupivacaine for lower abdominal surgery. Anesth Analg 2000; 90: 642–8.
[Abstract/Free Full Text] - McDonald S, Liu S, Kopacz D, Stephenson C. Hyperbaric spinal ropivacaine. Anesthesiology 1999; 90: 971–7.[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]
-
Sakura S, Sakaguchi Y, Shinzawa M, et al. The assessment of dermatomal level of surgical anesthesia after spinal tetracaine. Anesth Analg 2000; 90: 1406–10.
[Abstract/Free Full Text] - Petersen-Felix S, Zbinden A, Fischer M, Thomson D. Isoflurane minimum alveolar concentration decreases during anesthesia and surgery. Anesthesiology 1993; 79: 959–65.[Web of Science][Medline]
- Zbinden A, Maggiorini M, Petersen-Felix S, et al. Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia. Anesthesiology 1994; 80: 253–60.[Web of Science][Medline]
- Gautier P, DeKock M, Van Steenberge A, et al. Intrathecal ropivacaine for ambulatory surgery. Anesthesiology 1999; 91: 1239–45.[Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  J. de Santiago, J. Santos-Yglesias, J. Giron, F. Montes de Oca, A. Jimenez, and P. Diaz Low-Dose 3 mg Levobupivacaine Plus 10 {micro}g Fentanyl Selective Spinal Anesthesia for Gynecological Outpatient Laparoscopy Anesth. Analg., November 1, 2009; 109(5): 1456 - 1461. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. J. Umbrain, M.-H. Lauwers, L. Shi, I. Smolders, Y. Michotte, and J. Poelaert Comparison of the effects of intrathecal administration of levobupivacaine and lidocaine on the prostaglandin E2 and glutamate increases in cerebrospinal fluid: a microdialysis study in freely moving rats Br. J. Anaesth., April 1, 2009; 102(4): 540 - 545. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Luck, P. D. W. Fettes, and J. A. W. Wildsmith Spinal anaesthesia for elective surgery: a comparison of hyperbaric solutions of racemic bupivacaine, levobupivacaine, and ropivacaine Br. J. Anaesth., November 1, 2008; 101(5): 705 - 710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Cappelleri, G. Aldegheri, G. Danelli, C. Marchetti, M. Nuzzi, G. Iannandrea, and A. Casati Spinal Anesthesia with Hyperbaric Levobupivacaine and Ropivacaine for Outpatient Knee Arthroscopy: A Prospective, Randomized, Double-Blind Study Anesth. Analg., July 1, 2005; 101(1): 77 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Casati, E. Moizo, C. Marchetti, and F. Vinciguerra A Prospective, Randomized, Double-Blind Comparison of Unilateral Spinal Anesthesia with Hyperbaric Bupivacaine, Ropivacaine, or Levobupivacaine for Inguinal Herniorrhaphy Anesth. Analg., November 1, 2004; 99(5): 1387 - 1392. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hocking and J. A. W. Wildsmith Intrathecal drug spread Br. J. Anaesth., October 1, 2004; 93(4): 568 - 578. [Full Text] [PDF]
|
|
|
|
|
|
A. Casati, F. Vinciguerra, G. Cappelleri, G. Aldegheri, C. Grispigni, M. Putzu, and P. Rivoltini Levobupivacaine 0.2% or 0.125% for Continuous Sciatic Nerve Block: A Prospective, Randomized, Double-Blind Comparison with 0.2% Ropivacaine Anesth. Analg., September 1, 2004; 99(3): 919 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kokki, P. Ylonen, M. Heikkinen, and M. Reinikainen Levobupivacaine for Pediatric Spinal Anesthesia Anesth. Analg., January 1, 2004; 98(1): 64 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Gautier, M. De Kock, L. Huberty, T. Demir, M. Izydorczic, and B. Vanderick Comparison of the effects of intrathecal ropivacaine, levobupivacaine, and bupivacaine for Caesarean section Br. J. Anaesth., November 1, 2003; 91(5): 684 - 689. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
