Anesth Analg 1999;89:1497
© 1999 International Anesthesia Research Society
REGIONAL ANESTHESIA AND PAIN MANAGEMENT
A Comparison of Levobupivacaine 0.125%, Fentanyl 4 µg/mL, or Their Combination for Patient-Controlled Epidural Analgesia After Major Orthopedic Surgery
Dan J. Kopacz, MD*,
Nigel E. Sharrock, MB, ChB
, and
Hugh W. Allen, MD*
Departments of Anesthesiology,
*Virginia Mason Medical Center, Seattle, Washington; and
The Hospital for Special Surgery, New York, New York
Address correspondence to Dan J. Kopacz, MD, Virginia Mason Medical Center, Department of Anesthesiology, 1100 Ninth Ave., Mailstop B2-AN, Seattle, WA 98111. Address e-mail to anedjk{at}vmmc.org
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Abstract
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Levobupivacaine, the isolated S(-) isomer of bupivacaine, is less cardiotoxic than racemic bupivacaine in animal studies. We studied the effectiveness of patient-controlled epidural analgesia (PCEA) with either levobupivacaine 0.125% or fentanyl 4 µg/mL alone, or a combination of levobupivacaine and fentanyl in 65 patients after total joint arthroplasty in a prospective, random, double-blinded fashion. Intraoperatively, all patients received 20 mL of 0.75% levobupivacaine. Study medication was infused at an initial rate of 4 mL/h, with additional medication available on patient demand (2 mL/10 min). The combination of levobupivacaine and fentanyl produced better analgesia (longer time to first PCEA request; P = 0.007 combination versus fentanyl and P = 0.006 combination versus levobupivacaine) than either drug alone. Patients in the levobupivacaine groups had appreciable sensory blockade to pinprick with minimal motor impairment. Resting and dynamic visual analog scale pain scores were lower in the combination group than in the plain fentanyl group at 6 (P = 0.022 and 0.036) and 12 h (P = 0.002 and 0.001). The 24-h overall patient- and investigator-rated visual analog scale pain scores were also lower in the combination group (resting P = 0.007, dynamic P = 0.005). There was no significant difference among the groups in the incidence of postoperative nausea (26.2%), pruritus (9.2%), hypotension (23.1%), or sedation (0%). We conclude that the analgesic effects of levobupivacaine 0.125% and fentanyl (4 µg/mL) are additive and beneficial for the management of orthopedic surgical pain by the PCEA method. Patients in this study began demand-dosing later, reported lower pain scores, and had no greater risk of adverse events than those who were given either levobupivacaine or fentanyl alone.
Implications: We demonstrated a significant additive effect of the combination of levobupivacaine (0.125%) and fentanyl (4 µg/mL), compared with either drug alone, when using patient-controlled epidural analgesia in patients after total joint arthroplasty.
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Introduction
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Racemic bupivacaine has been an ideal local anesthetic for use in the management of postoperative pain because of its long duration of action and its beneficial ratio of sensory to motor blockade when used for epidural analgesia. A potential concern with bupivacaine, however, is reports of death in patients after accidental intravascular injection attributable to bupivacaine-induced cardiotoxicity (1). Although the incidence of death is very low, the concern is sufficient that the Food and Drug Administration has not approved the use of 0.75% bupivacaine in obstetrical anesthesia practice, and it prohibits bupivacaine from being used in IV regional anesthesia (2). An area of further theoretical concern is postoperative epidural analgesia, in which bupivacaine is continuously infused into the epidural space for long periods of time, which could allow potentially toxic amounts of bupivacaine to accumulate.
Levobupivacaine, the isolated S(-)-isomer of bupivacaine, is less cardiotoxic according to animal studies (3,4). Initial studies with levobupivacaine are now appearing in the literature, and they confirm its equivalent clinical potency with racemic bupivacaine (5,6). It is currently being developed for clinical use in anesthesia and postoperative pain management.
The addition of bupivacaine to postoperative epidural opiate infusions is controversial. Some authors have shown benefits, including improved analgesia or a reduction in the amounts of one or both of these drugs (7,8). Others have failed to demonstrate any benefit (9,10).
The use of patient-controlled epidural analgesia (PCEA) to provide postoperative analgesia is increasing. Its postulated benefits are the avoidance of potential overdosage, elimination of the "waiting time" and "peaks and valleys" of nurse-administered analgesics, and the involvement of the patient in his/her own healthcare (11). The purpose of this study was to examine the amount and timing of epidural analgesic requirements, the quality of pain relief, and the incidence of side effects with the new local anesthetic, levobupivacaine, during PCEA. Levobupivacaine 0.125% alone, or in combination with fentanyl (4 µg/mL), was compared with fentanyl (4 µg/mL) alone in a random, double-blinded fashion in patients after joint replacement surgery.
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Methods
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After institutional review board approval and written, informed consent were obtained, ASA physical status I–III patients aged 18–80 yr who were scheduled to undergo primary total hip (THR) or total knee arthroplasty (TKR) with intraoperative epidural anesthesia were enrolled in this prospective, double-blinded study of postoperative PCEA. Sample size was determined based on estimates of the primary efficacy end point of "time to first patient request" for rescue analgesia, assuming a population mean difference of 2 h and a standard deviation of 2 h for all groups. Sixteen patients per group was considered necessary to detect statistical significance (
= 0.05, two-sided) with power (1 - ß) = 80%.
All patients were premedicated with IV midazolam (0.5–4.0 mg). The L2-3 or L3-4 epidural space was identified with patients in the lateral decubitus position using an 18-gauge Tuohy needle and a loss-of-resistance to saline technique. After negative aspiration, 3 mL of 0.75% levobupivacaine plus 15 µg of epinephrine was administered as a test dose. If, after 2 min, there was no evidence of intravascular or subarachnoid injection (tachycardia 
100 bpm or hypotension [systolic blood pressure <90 mm Hg]), an additional 17 mL of 0.75% levobupivacaine without epinephrine was incrementally administered over a 5-min period (6-mL injection, wait 1 min, 6-mL injection, wait 1 min, final 5 mL administered). The first four patients were given these injections through a 20-gauge catheter that had been advanced 3–4 cm into the epidural space. After the fourth patient showed signs of intravascular injection (see Results), the protocol was changed so that, in all subsequent patients, the initial 20-mL injection was made through the epidural needle before placement of the epidural catheter.
Patients were then randomized, with separate stratification for patients undergoing THR or TKR surgery, to receive one of three postoperative epidural solutions: 1) fentanyl 4 µg/mL; 2) 0.125% levobupivacaine; 3) levobupivacaine 0.125% combined with fentanyl 4 µg/mL.
The epidural catheter was immediately connected to a PCEA pump, and the double-blinded infusion was begun at 4 mL/h (time 0) and continued for 24 h postoperatively.
Sensory block was assessed using a blunted 27-gauge dental needle at 0, 2, 5, 10, 15, 20, 25, and 30 min (or until appropriate block for surgery [T10-L4] was achieved) and postoperatively at 6-h intervals up to 24 h. Patients with any evidence of venous or dural puncture, or those requiring any subsequent epidural injections, were discontinued from the study. Blood pressure, heart rate, and the degree of lower extremity motor blockade (modified Bromage scale) were assessed during surgery and 6, 12, 18, and 24 h after the start of the PCEA infusion. Additional doses of midazolam (1–10 mg total) and/or propofol (0–50 µg · kg-1 · min-1) were used intraoperatively for sedation, per patient request. No other nonstudy opiates or local anesthetics were allowed. Supplemental oxygen was used at the discretion of the attending anesthesiologist.
In the postoperative period, the time to first analgesic request was recorded. The patient was allowed to self-administer (PCEA) 2-mL doses every 10 min (14 mL/h maximum). If analgesia became inadequate, an additional 5-mL "loading dose" of study medication was given, and the infusion rate was increased by 2 mL to 6 mL/h (20 mL/h maximum). If the patient was still experiencing pain 30 min after this initial infusion adjustment, another loading dose of 5 mL of study medication was given, and the infusion rate was increased by another 2 mL to 8 mL/h (24 mL maximal volume in 1 h).
If pain relief from these additional amounts of study drug (loading doses and patient pump activations) remained inadequate, the epidural infusion was discontinued, and alternative analgesia measures were used (epidural bolus with higher concentrations of lidocaine or racemic bupivacaine, IV morphine, or a racemic bupivacaine femoral nerve block [TKR patients]). At this point, further study assessments were discontinued.
Pain assessments using a standard 100-mm visual analog scale (VAS; 0 = no pain and 100 = worst pain ever), at rest and with lower extremity movement, were made at 6, 12, 18 and 24 h. A global VAS rating for overall pain satisfaction was completed by both the patient and the investigator at the end of the 24-h trial.
Adverse events were recorded throughout the 24-h study period and followed for up to 7 days after patients were discharged from the hospital. Assessments of hypotension (defined as systolic blood pressure decrease >30% from preoperative value) were made every 6 h after surgery with the patient in the supine position. Other adverse events were recorded as they occurred or when voluntarily mentioned by the patient.
Statistical analyses were performed using data from the intent-to-treat population using the statistical package SAS® v6.09 (SAS Institute, Cary, NC). Time to first use of rescue medication by PCEA was analyzed by using Kaplan-Meier survival analysis. Statistical comparisons among the three groups were performed by using a two-way analysis of variance with subsequent comparisons of pairwise differences, where appropriate. Recurrent measures of motor blockade and VAS pain scores were analyzed by using repeated-measures analysis of variance with post hoc analysis using the Bonferroni/Dunn correction. The proportion of patients that requested rescue medication was analyzed using the Cochran-Mantel-Haenszel test. Post hoc analysis of the proportion of patients completing the 24-h study period was performed by using 
2 analysis. Unless otherwise specified, data are mean ± SD, and a P value <0.05 was defined as significance.
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Results
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Sixty-eight patients from two centers were enrolled and randomized. Two patients were discontinued before receiving any medication. The remaining 66 patients (44 THR/22 TKR) were included in the safety population. One THR patient was withdrawn after the administration of 19 mL of the initial 0.75% levobupivacaine dose because of suspected accidental intravascular injection (12). This patient recovered without significant morbidity and underwent an uneventful surgical procedure 1 h later with tetracaine spinal anesthesia. The remaining 65 patients were included in the efficacy evaluation. There were no between-group or between-center differences in demographic variables (Table 1), and no patient required additional epidural bolus injections.
The time to first request for rescue analgesia by PCEA during the first 24 h postoperatively was the primary efficacy end point. This time was significantly longer for the combination group (Table 2). The Kaplan-Meier survival curve for this variable demonstrates the superiority of the combination of levobupivacaine and fentanyl relative to either drug alone (P = 0.007 combination versus fentanyl and P = 0.006 combination versus levobupivacaine) (Figure 1). Of the 21 patients in the levobupivacaine/fentanyl combination group, 2 (9.5%) did not self-administer rescue analgesia during the 24-h postoperative study period, using a total of 96 mL (4 mL x 24 h) of study solution. This compares with 1 (4.5%) of 22 patients in the levobupivacaine group and no patients in the fentanyl group. Figure 1 also demonstrates the similarity of the single-drug therapies (levobupivacaine or fentanyl). Nearly all patients in these groups started to self-administer PCEA doses at a time (6–9 h) when it would be anticipated that sensory blockade from the initial 0.75% levobupivacaine injection was resolving. In contrast, approximately 40% of the patients in the combination group did not request additional amounts of medication until later.
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Figure 1. Kaplan-Meier survival curve for time to first request for additional epidural analgesia solution by patient-controlled epidural analgesia. % Survival = the proportion of patients in a given group that had not yet had to self administer any additional epidural medication. The time to first request was significantly longer for the combination than for either levobupivacaine or fentanyl alone (P = 0.007). There was no difference between 0.125% levobupivacaine or plain fentanyl.
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The amount of rescue medication by volume was compared across treatment groups at 6, 12, 18, and 24 h (Figure 2). Although there were no significant differences at any time point, at 12 h, a pairwise comparison of the levobupivacaine/fentanyl combination group versus the fentanyl alone group approached significance (P = 0.063). Clinically, this correlates to that point in the study at which blockade from the initial 0.75% levobupivacaine had most recently resolved. Although there were no intergroup differences in the mean volume of rescue medication given over the 24-h period, the highest volume was in the levobupivacaine group, and the lowest volume was in the combination group (Table 2). More patients in the combination group completed the full 24-h infusion period. The amount of PCEA rescue medication was significantly smaller for the combination group compared with the levobupivacaine group when expressed as volume infused per hour.
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Figure 2. Mean cumulative volumes of patient-controlled epidural analgesia (PCEA) solution administered for each group. P = 0.149, 0.123, 0.493, and 0.762 at 6, 12, 18, and 24 h, respectively.
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Patients in the combination group consistently reported lower VAS pain scores than patients in either of the other two treatment groups, both at rest and with movement (Figure 3, A and B). There were statistically significant differences between the combination group and the fentanyl group at 6 and 12 h, both at rest and with movement. At 12 h, VAS scores with movement in the combination group were lower than the VAS scores at rest in the other two groups.
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Figure 3. A, Mean visual analog scale (VAS) pain scores at rest for the three treatment groups. Scores at 6 and 12 h for patients in the combination group were significantly lower than those for patients in the fentanyl group at rest (P = 0.02 and 0.002). There were no differences among groups at 18 and 24 h. B, Mean VAS pain scores with activity for the three treatment groups. Activity is defined as lifting the operative extremity 6 in. off the bed. Scores at 6 and 12 h for patients in the combination group were significantly lower than those for patients in the fentanyl group (P = 0.04 and 0.001). There were no differences among groups at 18 and 24 h.
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The 24-h overall patient-rated (17, 28, and 38 mm) and investigator-rated (14, 29, and 37 mm) mean VAS pain assessments for the combination, levobupivacaine, and fentanyl groups, respectively (Figure 4), reinforce the results of measurements taken at 6-h intervals. There was excellent correlation between ratings made by the patient and the investigator. The difference between the combination and fentanyl groups was statistically significant. The combination group patients had significantly lower overall investigator pain assessment scores than the fentanyl group patients. There were no statistically significant differences between the combination group and the levobupivacaine group, although the assessments were consistently lower for the combination group.
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Figure 4. Overall assessment of pain (visual analog scale [VAS]) at the end of the 24-h period. Global pain ratings were significantly lower for the combination group compared with the fentanyl group by the patient (P = 0.007) and by the investigator (P = 0.005). Correlation between patient and investigator ratings was excellent (r2 = 0.927, P = 0.0001). PCEA = patient-controlled epidural analgesia.
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Sensory block followed an expected and predictable pattern. Patients in the levobupivacaine groups had appreciable sensory blockade (levobupivacaine/fentanyl 6 (0–16), 6 (0–10), and 3 (0–8) dermatomes [median (range)]; levobupivacaine 6 (0–13), 6 (0–12), and 5 (0–9) dermatomes at 12, 18, and 24 h, respectively) and to a significantly greater degree than patients in the fentanyl only group (Figure 5, top; levobupivacaine/fentanyl versus fentanyl; P = 0.017; levobupivacaine versus fentanyl; P = 0.01). At 6 h from the start of the infusion, the patients in the combination group had the greatest number of blocked dermatomes. By 24 h, there was no residual sensory block in patients receiving fentanyl only, whereas the other two groups had their sensory block maintained by the continued administration of levobupivacaine.
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Figure 5. Time courses of sensory (A) and motor (B) blockade during patient-controlled epidural analgesia. Levobupivacaine-containing groups had more sensory blockade than the fentanyl only group throughout the 24-h period (P = 0.02) but a greater degree of motor blockade only at the 6-h time point (P = 0.013).
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After surgery, patients in the levobupivacaine group had more residual motor block than patients in the fentanyl group (Figure 5; levobupivacaine versus fentanyl; P = 0.004; levobupivacaine/fentanyl versus fentanyl; P = 0.085). By 12 h postsurgery, only a few patients continued to have residual Bromage grade 1 blockade (levobupivacaine/fentanyl one patient; levobupivacaine three patients); the rest had regained full movement of their lower limbs. Despite the presence of sensory block, motor block had resolved sufficiently in all patients to allow physical therapy.
No patients became excessively sedated. Because most patients had a urinary catheter for 24 h, we are unable to comment on urinary retention. Nausea (26.2%) and hypotension (44.6%) were the most common side effects noted, and all side effects were evenly spread across the groups (Table 3).
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Discussion
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Previous clinical studies of levobupivacaine have demonstrated equipotency with racemic bupivacaine when used in equal volumes and concentrations in the epidural space or for brachial plexus blockade to provide surgical anesthesia (5,6). Although we did not directly compare levobupivacaine and racemic bupivacaine, we did specifically evaluate the use of a high concentration of levobupivacaine (0.75%) for intraoperative anesthesia, and we comparatively investigated the continued infusion of levobupivacaine into the postoperative period for epidural analgesia.
We demonstrated the postoperative analgesic efficacy and tolerability of adding 0.125% levobupivacaine to fentanyl 4 µg/mL in patients after THR and TKR. The VAS pain scores and average hourly amounts of study medication used by the patients are comparable to those of previous studies using either PCEA or continuous infusion epidural analgesia with racemic bupivacaine and fentanyl.
Although not all patients did achieved uniformly low (i.e., VAS score <20 mm) pain scores particularly in the fentanyl only group early in the study—the PCEA technique was generally well accepted by all patients. In designing studies comparing the combination of local anesthetics and opiates versus either drug alone, a clear, prospectively defined end point is critical. Many other PCEA studies find a difference in pain scores (8,13). Some studies, however, find a difference in the amount of medication used because patients titrate themselves to comfort (7,14,15). Only occasionally are both lower pain scores and a reduction in medication found (16).
Many of the present results compare quite favorably to a previous study of PCEA in orthopedic patients using the same concentration of racemic bupivacaine (0.125%) and a similar concentration (5 µg/mL) of fentanyl. In that study (7), the bupivacaine was actually shown to decrease opioid requirements. Although we were able to show improved analgesia, we were unable to demonstrate a statistically significant opiate-sparing effect. This difference can be explained by differences in methodology or sample size.
Methodological differences between this study using levobupivacaine and previous studies in which racemic bupivacaine was used must be emphasized. Because clinical data have shown an added margin of safety of levobupivacaine relative to racemic bupivacaine, 0.75% levobupivacaine was used in the present study. Previous studies of this type most often used 0.5% racemic bupivacaine, a shorter-acting drug (lidocaine), or no epidural local anesthetic (general anesthesia) for the intraoperative time period. Because levobupivacaine 0.75% was used for intraoperative anesthesia, its effects are obviously prolonged into the initial postoperative period, and one can only assume that these effects were balanced among the groups. However, we designed the present study with this condition in mind, for when time to first analgesic request is used as a primary end point, it is mandatory that all patients start the initial postoperative period at the same pain-free baseline (VAS score 0 mm). This methodology also allows for the avoidance of any other intraoperative opiates (epidural or IV), which can confound the results of studies of postoperative analgesia. In fact, this may be the main explanation for the minor differences between our study and that of Cooper and Turner (7), in which up to 200 µg of IV fentanyl was given during the intraoperative general anesthetic for joint replacement surgery.
PCEA regimens themselves can also be a source of variability; we used what could more appropriately be called "patient-assisted epidural analgesia," as it is a hybrid of a background continuous infusion (4–8 mL/h) with additional patient-activated boluses (2 mL/10 min). Theoretically, the continuous infusion maintains satisfactory anesthesia with the patient at rest; when mobilization begins, the patient-demand feature can be used.
Our results corroborate those reported by Dahl et al. (17) comparing epidural morphine with or without bupivacaine in abdominal surgical patients. The addition of a local anesthetic to an epidural opiate may not show differences with the patient at rest, but an appreciable benefit is realized when the patient is actively mobilized, particularly for the first time in the postoperative period.
The absence of demonstrable sensory blockade after 12 hours in most of our patients is not surprising. First, the concentration of levobupivacaine (0.125%) is low enough that sensory blockade may not be consistently produced. A concentration of 0.2%–0.25% is usually necessary before a consistent percentage of patients develop sensory anesthesia, often with some degree of accompanying motor blockade (8,17,18). Furthermore, epidural infusions of bupivacaine as high as 0.5% at 8 mL/h are unpredictable in their ability to maintain a broad dermatomal band of sensory blockade (19).
This study design was not specifically powered to show differences in adverse events. Although tendencies toward a reduction in adverse events (less nausea and pruritus in nonopiate groups, more hypotension and sensory block in local anesthetic-containing groups) are seen in many studies, few actually attain statistical significance, presumably because of the limited number of patients in most of these studies, which are powered to determine analgesia differences.
In conclusion, because of concerns of cardiotoxicity, past recommendations have discouraged the use of 0.75% racemic bupivacaine, particularly in obstetrics. In this study, we demonstrated the efficacy and tolerability of the intraoperative use of 0.75% levobupivacaine in patients undergoing THA and TKA. Finally, we showed that the addition of 0.125% levobupivacaine to fentanyl (4 µg/mL) for postoperative PCEA provides improved analgesia over either drug alone.
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Acknowledgments
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This study was supported by a grant from Chiroscience Ltd.
We thank George Go, BS; Carol Stephenson, RN; Shirley Klakken, RN; and Jane Kreider, RN, for their dedication and assistance.
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Accepted for publication August 17, 1999.
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Abstract
Introduction
