| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
| ||||||||||||||
| ||||||||||||||
|
|
|
|
||||||||||||
|
||||||||||||||
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Address correspondence and reprint requests to James Crews, MD, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009. Address e-mail to jcrews{at}wfubmc.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
IMPLICATIONS: This study demonstrates the clinical efficacy and equivalence of the pharmacokinetic characteristics of 0.5% levobupivacaine for axillary brachial plexus block in patients with renal disease and normal renal function.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Bupivacaine hydrochloride is a frequently used local anesthetic and has the clinical advantages of long duration of action and favorable ratio of sensory to motor neural block. Bupivacaine has a chiral center and is a racemic mixture of two stereo-enantiomers. Previous studies in animals, volunteers, and patients have demonstrated a significant reduction in symptoms of cardiac or central nervous system (CNS) toxicity with the use of the single (S-)-enantiomer levobupivacaine as compared with equal doses of racemic bupivacaine (1–9). We designed this study to evaluate the pharmacokinetics of 0.5% levobupivacaine, onset of surgical anesthesia, duration of sensory/motor block and postoperative analgesia, and tolerability of doses 
3 mg/kg in a group of patients with normal renal function compared with a group of patients with ESRD.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patients were allowed only clear liquids for the 6 h before the levobupivacaine administration and were premedicated with midazolam (0.5–4.0 mg), fentanyl (25–100 µg), or both. An IV crystalloid (saline drip) solution was administered on admission to the anesthetic room. Continuous electrocardiogram monitoring (Lead II), noninvasive arterial blood pressure monitoring, and pulse oximetry were established, and an additional 18- or 16-gauge IV cannula was used to collect pharmacokinetic samples. A preinjection blood sample (5 mL) was taken from the contralateral arm in the patients included in the pharmacokinetic analysis.
Patients received an axillary block by one of three investigators using 50 mL of 0.5% levobupivacaine without epinephrine. Transarterial (24-gauge, 1-in. needle) and nerve stimulator techniques (23-gauge, 1-in. needle) were used to identify injection into the brachial plexus sheath. A local anesthetic (20–30 mL) was injected in at least two different locations within the axillary sheath after confirmation of needle location. If after 15 min patients required a supplemental local anesthetic to produce anesthesia in a single peripheral nerve distribution, an additional 10 mL of 0.5% levobupivacaine could be administered as a single peripheral nerve block at the axillary level. The maximum total volume of local anesthetic injected did not exceed 60 mL.
Vital signs were recorded at 0 min, 30 min, and hourly until 20 h after the end of the initial 50 mL injection. Sensory and motor block were assessed in each of the four major peripheral nerve distributions. Sensory block was assessed by pinprick using the blunt end of a 27-gauge dental needle at 0, 2, 5, 10, 15, 20, and 30 min and then every hour thereafter. Sensory block was graded according to the following scale: 0 = no block (normal sensation), 1 = partial block (decreased sensation), and 2 = complete block (no sensation). Duration of sensory block, defined as a return of sensation to pinprick in all nerve distributions, was also measured. Motor block was measured at 0, 10, 20, and 30 min by assessing the following motor functions: flexion at the elbow (musculocutaneous nerve), extension of the elbow and the wrist (radial nerve), opposition of the thumb and index finger (median nerve), and opposition of the thumb and small finger (ulnar nerve). Motor block was graded according to the following scale: 0 = no block (full muscle activity), 1 = partial block (decreased muscle activity), and 2 = complete block (no muscle activity). Time to onset of motor block (time to onset of Grade 1 motor block in any nerve distribution), duration of motor block (time from onset to a motor block score of 0 for all activities), and the proportion of patients reaching each grade of motor block were measured. Any analgesic medication requested for pain in the period after surgery was recorded.
Pharmacokinetic analyses were performed for all eight patients with renal disease and 11 with normal renal function. Blood samples were taken preinjection immediately after the administration of the test drug and at 5, 15, 30, 45, and 60 min and 2, 4, 6, 8, 10, 12, 16, 20, and 24 h after the second injection. Plasma samples were analyzed for bupivacaine enantiomers by Inveresk Research (Edinburgh, Scotland).
Demographic differences between the Normal Renal Function and ESRD patients were compared using t-tests and exact 
2 tests as appropriate. Differences in time to onset of block, duration of block, the peak concentration (Cmax), the time to peak concentrations (Tmax), and area under the concentration-time curve were compared between the Normal Renal Function and ESRD patients using the exact Wilcoxon’s ranked sum test. The times to the first request for analgesic medication were compared between the Normal Renal Function and the ESRD patients using survival analysis (log-rank test). Statistical analyses were performed using SAS version 6.12 (SAS Institute, Inc, Cary, NC).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Analysis of the demographic data demonstrated no significant differences in the patients between the ESRD and the Normal Renal Function groups, respectively, with respect to mean age (52.4 yr and 50.7 yr), race, sex, height (168 cm and 169 cm), or body weight (76.4 kg and 78.2 kg). The patients ranged in age from 20–81 yr, and body weight was 50–116 kg. Additional information from the 11 Normal Renal Function and eight ESRD patients included in the pharmacokinetic analysis is listed in Table 1. Doses of 50–60 mL of levobupivacaine in these patients ranged from 2–5 mg/kg. Twenty-six patients had adequate sensory/motor block for surgical anesthesia. In two patients, general anesthesia was required because of inadequate sensory/motor block for surgery at >60 min after the injection. These two patients were considered to have technical failures and were excluded from the analysis of block onset, duration, and pharmacokinetic sampling but were considered in the safety analysis. The efficacy of levobupivacaine, as assessed by the proportion of patients with block adequate for surgery, was 100% of the ESRD group and 90% of the Normal Renal Function group. No patient demonstrated any subjective or objective signs or symptoms of local anesthetic toxicity.
|
No differences were found in the time to resolution of motor block between Normal Renal Function patients at 18 h (range, 14–24 h) and the ESRD patients at 22 h (range, 14–24 h). All ESRD patients reported complete motor block. In the Normal Renal Function group, 90% of the patients reported a complete block. Although, fewer patients required rescue analgesic medication during the study period in the ESRD group (63%) as compared with the Normal Renal Function group (92%). This difference was not significant. However, survival analysis found the time to first rescue medication to be shorter in the Normal than in the ESRD patients (P = 0.013) with median rescue times of 13.0 h and 35.2 h, respectively.
The noncompartmental pharmacokinetic data are summarized in Table 2. From these data, it is apparent that there are no significant differences in the Cmax, Tmax, and area under the concentration-time curve0-t between the two groups.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
No significant differences in the noncompartmental plasma pharmacokinetic variables of levobupivacaine were noted after axillary block in patients with ESRD as compared with patients with normal renal function. The clinical characteristics of time to onset of sensory block, duration of block, and quality of surgical anesthesia were also similar between the two groups. These results are consistent with the results of a study of supraclavicular brachial plexus block in patients with normal renal function and ESRD in which no significant differences in plasma pharmacokinetic variables, or in block latency or duration, were noted for racemic bupivacaine (10).
The observed differences in time to first request for supplemental analgesics between the two groups may be explained on the basis of the type of surgical procedures performed on the patients in the two groups. Patients in the Normal Renal Function group generally underwent orthopedic surgical procedures, whereas patients in the ESRD group underwent more superficial soft tissue (vascular shunt creation or revision) procedures. Differences in times to first request for supplemental analgesics could be explained on the basis that the orthopedic surgical procedures would be expected to be associated with more intense postoperative pain than the more superficial soft tissue vascular access procedures.
There are several clinical characteristics of patients with ESRD that may predict differences in the systemic uptake and distribution of local anesthetics as compared with patients with normal renal function, most notably a hyperdynamic circulatory status, alterations in plasma protein concentrations, and acidemia. Although plasma protein levels were not measured in the present study, increased levels of 
-1-acid glycoprotein, the major binding protein for bupivacaine, have been demonstrated in patients with ESRD (10–12). This suggests that plasma concentrations of free drug would be smaller at any given total drug concentration in patients with ESRD as compared with patients with normal renal function.
The influence of block technique and the investigator performing the block were also analyzed. It is interesting that no differences in systemic absorption of local anesthetic could be detected based on the technique of axillary brachial plexus block (i.e., transarterial versus nerve stimulator). There may be some concern that the systemic absorption of a local anesthetic may be increased by the use of the transarterial technique, although no such correlation could be demonstrated in this study.
The volume of the local anesthetic used in this study was 50–60 mL. An injection volume of 40–50 mL is usually required to ensure a reliable spread of local anesthetic within the axillary brachial plexus sheath, especially if a single injection technique is used. Even with injection volumes of 50 mL, the brachial plexus sheath is not completely filled (13). In patients in whom a total volume of 60 mL was used (50 mL for the initial injection and an additional 10 mL, if required, to block a single nerve distribution), the additional 10 mL dose was most often used to block the musculocutaneous nerve outside the brachial plexus sheath.
The use of bupivacaine for brachial plexus block has proved attractive because of its relatively long duration of sensory block, which produces adequate anesthesia for more lengthy surgical procedures as well as providing analgesia well into the postoperative period. However, bupivacaine has the potential for severe cardiovascular and CNS toxicity in cases of rapid systemic uptake, relative overdose, or unintentional intravascular injection. Previous studies have shown levobupivacaine to have a greater margin of clinical safety with respect to both cardiovascular and CNS effects compared with racemic bupivacaine (1). In a comparison study of levobupivacaine and bupivacaine for supraclavicular brachial plexus block, no differences in onset time or duration of sensory or motor block were demonstrated (14). The present study further demonstrates the clinical efficacy of levobupivacaine 0.5% for axillary brachial plexus block. Although no generalized conclusions on the safety of levobupivacaine can be made from the results of this relatively small study, no patient demonstrated any signs or symptoms of local anesthetic toxicity with doses of 2–5 mg/kg and a Cmax of up to 4.0 mg/L.
This study demonstrates the clinical efficacy and equivalence of the pharmacokinetic characteristics of 0.5% levobupivacaine for axillary brachial plexus block in patients with ESRD and normal renal function. In those clinical situations where relatively large volumes and concentrations of local anesthetics are indicated, such as brachial plexus neural block, the use of local anesthetics, such as levobupivacaine, with the combination of good clinical efficacy and a greater margin of cardiovascular and CNS safety, has significant advantages.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  A. Duma, B. Urbanek, C. Sitzwohl, A. Kreiger, M. Zimpfer, and S. Kapral Clonidine as an adjuvant to local anaesthetic axillary brachial plexus block: a randomized, controlled study Br. J. Anaesth., January 1, 2005; 94(1): 112 - 116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Urbanek, A. Duma, O. Kimberger, G. Huber, P. Marhofer, M. Zimpfer, and S. Kapral Onset Time, Quality of Blockade, and Duration of Three-in-One Blocks with Levobupivacaine and Bupivacaine Anesth. Analg., September 1, 2003; 97(3): 888 - 892. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
