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© 1999 International Anesthesia Research Society
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Abstract |
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We compared the relative efficacy of the combination of the single-isomer local anesthetic levobupivacaine and the opioid analgesic morphine versus both drugs alone for postoperative epidural analgesia after major abdominal surgical procedures. Thoracic epidural anesthesia was produced and maintained with levobupivacaine 0.75% in combination with general inhaled anesthesia without opioids. Patients were randomized to one of three postoperative treatment groups: 1) a combination of levobupivacaine 0.25% and morphine 0.005%; 2) levobupivacaine 0.25%; or 3) morphine 0.005%. Postoperatively, all epidural infusions were commenced at a rate of 4 mL/h. Patients could receive a 4 mL-bolus dose and an increase in the epidural infusion rate by 2 mL/h on request for supplemental analgesia. Patients were also allowed ketorolac as a supplemental analgesic at any time after the first analgesic request. Patients in the combination group had longer times to request for supplemental analgesia as compared with the levobupivacaine only group (P < 0.05) and a trend toward longer time to request as compared with the morphine only group (P = 0.066). Patients in the combination group had lower visual analog scale pain scores at rest and activity at 4 and 8 h and fewer requests for supplemental ketorolac (P < 0.05). In conclusion, this study demonstrates a significant improvement in postoperative analgesic efficacy with the combination of levobupivacaine and morphine for continuous epidural analgesia after major abdominal surgical procedures.
Implications: A significant improvement in postoperative analgesic efficacy is demonstrated with the thoracic epidural administration of the combination of the single-isomer local anesthetic levobupivacaine 0.25% and morphine 0.005% in patients after major abdominal surgical procedures as compared with either drug used alone.
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Introduction |
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Several studies have supported the conclusion that the combination of bupivacaine and morphine produces superior analgesia when compared with either used alone (1–5). This study was designed to assess the analgesic efficacy of the combination of the single-isomer local anesthetic levobupivacaine 0.25% and morphine 0.005%, as compared with levobupivacaine 0.25% alone or morphine 0.005% alone for the management of postoperative pain in patients after major abdominal surgical procedures.
Bupivacaine is a racemic mixture of two enantiomers [S(-)- and R(+)-] and is widely used as a local anesthetic or analgesic for neuraxial and peripheral nerve blockade. The rationale for the development of levobupivacaine, the S(-)- enantiomer form of bupivacaine, was based on findings indicating that there is stereospecificity of action of the effects on the central nervous system and cardiovascular system. In preclinical in vitro and in vivo animal studies, levobupivacaine had a potency similar to that of bupivacaine while exerting significantly less central nervous system and cardiovascular toxicity (6–9). Clinical trials have also reported the equivalent efficacy of levobupivacaine and the racemate (10–12). With equivalent clinical utility and an enhanced safety profile compared with bupivacaine, levobupivacaine could be an alternative to bupivacaine as a long-acting local anesthetic.
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Methods |
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This double-blinded clinical study was approved by the institutional review boards of the University of Cincinnati College of Medicine and the Emory University School of Medicine. Sixty-four adult male and nonpregnant female patients (ASA physical status I–III) scheduled to undergo major abdominal surgical procedures were recruited for the study. Surgical procedures included gastrectomy, colectomy, pancreatectomy, splenectomy, radical nephrectomy, radical prostatectomy with lymph node dissection, and abdominoperineal resection.
All patients were premedicated with midazolam (0.5–4.0 mg). For upper abdominal surgery, the catheter was sited at T8-10 and for lower abdominal surgery, T10-12. A 17-gauge Tuohy needle and a 19-gauge end-hole catheter were used for epidural catheterization and drug administration. All epidural catheters were advanced 3–4 cm into the epidural space. Any evidence of needle or catheter entry to an epidural vein or cerebrospinal fluid excluded the patient from the study. A test dose of 3 mL of 1.5% lidocaine with 15 g of epinephrine was given. If after 5 min there was no evidence of intravascular or subarachnoid injection, levobupivacaine 0.75% was incrementally administered in an initial volume of 6–12 mL. Sensory block was assessed using the blunt end of a 27-gauge dental needle at Time 0, 2, 5, 10, 15, 20, 25, 30, 40, 50, and 60 min or until an appropriate block was achieved for surgery. An appropriate sensory block to pinprick for upper abdominal procedures was defined as T4-L1, and for lower abdominal procedures as T6-L4. If adequate sensory block was not achieved 15 min after injection of the primary dose, one or two additional injections of 5 mL of 0.75% levobupivacaine could be administered. If adequate sensory block was not achieved 45 min after the additional injections as above, the patient was withdrawn from the study. Blood pressure, heart rate, and lower extremity motor block (Bromage scale) were also determined at each time point outlined above.
General anesthesia was induced with either propofol or etomidate with dose titration to loss of consciousness. Inhaled anesthetics (sevoflurane or isoflurane) were administered for maintenance of general anesthesia. All patients were endotracheally intubated per routine clinical practice. Neuromuscular blocking drugs (rocuronium, vecuronium, or pancuronium) were used to facilitate endotracheal intubation and to provide intraoperative muscle relaxation at the discretion of the investigator. For surgical procedures with an extended duration (>2 h), patients received additional doses of 5–8 mL of levobupivacaine 0.75% as required to maintain surgical anesthesia, at the discretion of the investigator. Hypotension, defined as a decrease in systolic pressure >30% of baseline or the patient’s developing symptomatic hypotension, was treated with vasopressors and/or IV fluid at the discretion of the investigator. General anesthesia was maintained until skin closure at the end of the surgical procedure, and patients were allowed to emerge from general anesthesia and were tracheally extubated when they met routine clinical indicators of readiness.
Patients were randomized to one of three postoperative treatment groups in a double-blinded, three-arm, parallel-group, two-center study design using a 1:1:1 patient allocation. The three treatment groups were as follows: a combination group, which received a continuous epidural infusion of levobupivacaine 0.25% (2.5 mg/mL) combined with morphine 0.005% (0.05 mg/mL); a levobupivacaine group that received a continuous epidural infusion levobupivacaine 0.25% (2.5 mg/mL); and a morphine group that received a continuous epidural infusion of morphine 0.005% (0.05 mg/mL).
All patients received a 2-mL dose of drug via a coded syringe after skin closure. For patients in the morphine and the combination groups, this syringe contained 2 mL of morphine-preservative free 0.1% (1.0 mg/mL). For patients in the levobupivacaine group, the syringe contained saline-preservative free only. The epidural infusion was commenced in all patients at the end of surgery after administration of this 2-mL epidural drug dose. The start of postoperative epidural drug administration at the end of the surgical procedure was defined as Time 0. The infusion was commenced in all patients at a rate of 4 mL/h and was maintained throughout the 24-h postoperative study period.
The patient’s pain was assessed every 4 h, while awake, at rest, and with activity (movement to sitting position or deep cough), by using a visual analog scale (VAS). If at any time during the 24-h study period the patient’s pain was not adequately controlled by the epidural infusion, the patient was allowed to receive a loading dose of 4 mL of the epidural infusion, and the infusion rate was increased to 6 mL/h. If within 1 h, the patient’s pain was not adequately controlled, an additional loading dose of 6 mL could be administered, and the epidural infusion was increased to 8 mL/h. If within 1 additional h the patient’s pain was not adequately controlled, an additional loading dose of 8 mL could be administered, and the infusion rate was increased to 10 mL/h.
At the investigator’s discretion, at any time after a supplemental dose of 4 mL and increase in the epidural infusion rate to 6 mL/h, ketorolac could be administered IV at a dose of 15–30 mg as a supplemental analgesic while additional changes were made in the epidural infusion. If the patient’s pain was not controlled by the concomitant administration of ketorolac and per protocol adjustments in the epidural infusion, the patient was withdrawn from the study.
Excessive distribution of sensory or motor block in the postoperative period beyond 8 h after the last dose administration of 0.75% levobupivacaine was managed by withholding the epidural infusion for a period of 1 h and recommencing the infusion at 4 mL/h at the discretion of the investigator.
Other variables measured at 4-h intervals throughout the 24-h postoperative study period included the patients’ blood pressure, heart rate, respiratory rate, oxygen saturation, level of sensory block to pinprick, lower extremity motor blockade, and adverse events. A global pain assessment was obtained from both the patient and the investigator at the end of the 24-h study period.
Statistical analysis was performed using the statistical package SAS version 6.07 (SAS Institute, Cary, NC). Sample size was based on the variable of time to first request for supplementation of postoperative analgesia with the key comparison groups being those patients receiving morphine only and combination therapy. It was assumed that the standard deviation would be 2 h, and a difference of 2 h was expected between the treatment means of the morphine only and the combination groups. Twenty patients per group were considered necessary to detect a statistical significance with 80% power (1-ß) and assuming a population mean difference of 2 h in time to rescue medication using a two-sided 0.05-level including compensation for normal approximation. The main patient population was the intent-to-treat population, defined as all patients who received epidural infusions. Time to first request for supplemental postoperative analgesia was analyzed by survival analysis using the product-limit (Kaplan-Meier) approach with the study drug as a treatment factor. The study center was a stratification factor in the Kaplan-Meier model. No significance-level adjustment was made for multiple comparisons.
Pair-wise comparisons were used for between-group analysis. The volume of rescue medication, the degree of postoperative motor blockade, and VAS at rest and with activity were analyzed by using a one-way analysis of variance with treatment as the independent factor. Usage of ketorolac and the proportion of patients who requested rescue medication were analyzed by using a Cochran-Mantel-Haenzel test controlling for study center.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There were no between-group or between-center differences in patient age, gender, or body mass. Table 1 summarizes the demographic characteristics of the patients included in the study. The mean time to adequate onset of surgical anesthesia was 11.0 ± 12.5 min after administration of the initial dose of levobupivacaine 0.75%. There were no differences in total dose administered or the time of administration of levobupivacaine 0.75% during the surgical procedure and no difference in the distribution of patients undergoing upper versus lower abdominal surgical procedures with respect to randomization to postoperative treatment group.
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The mean time to first request for supplemental analgesia was 16.0, 4.3, and 10.9 h for the combination, levobupivacaine, and morphine groups, respectively. The difference in time to first request for supplemental analgesia for the combination group approached statistical significance as compared with that of the morphine group (P = 0.066), the primary study endpoint, and was significantly different for the combination group as compared with the levobupivacaine only group (P < 0.001). Of the patients in the combination group, 10 (48%) requested rescue analgesia during the 24-h postoperative period compared with 15 (73%) in the morphine group and 21 (95%) in the levobupivacaine only group. A Kaplan-Meier survival curve of time to first request for each patient is shown in Figure 1. Pair-wise comparisons of the proportion of patients requesting rescue analgesia were significantly different for combination versus levobupivacaine (48% vs 95%; P < 0.001) and approached significance for combination versus morphine (48% vs 73%; P = 0.062).
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The mean volume of rescue medication administered did not differ significantly among the treatment groups; however, this was clearly dependent on how long the patient remained in the study. Hence, the rate of rescue medication per hour was calculated and was found not to differ significantly for the primary comparison.
The difference in the proportion of patients requesting ketorolac between the combination group and both the morphine group and the levobupivacaine group was statistically significant (P = 0.040 and P < 0.001, respectively). These data are presented in Figure 2. For those requesting ketorolac, the amount of ketorolac administered did not differ significantly across the treatment groups.
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Four hours after the start of the postoperative epidural infusion, the sensory block levels were similar in each of the three groups. The spread of block gradually decreased over time in the combination group; however, in the levobupivacaine alone group it decreased, then increased in response to the increase in infusion rate. In those patients receiving morphine, although the spread of sensory anesthesia to pinprick was reasonably extensive at 4 h, the block had almost completely disappeared by 12 h. Motor block was assessed as 0 on the Bromage scale at all postoperative time points for all patients except for two in the levobupivacaine group who had moderate lower extremity weakness (1–2 on the Bromage scale).
When comparing the VAS scores both at rest and with activity (Figure 3), the combination group maintained a consistently low VAS score with the patients’ having excellent analgesia throughout the trial. The VAS scores were highest in the levobupivacaine only group; however, these scores declined as the sensory block spread increased with the increased dosage of study medication. Patients in the morphine group also exhibited relatively high VAS scores particularly at 4 and 8 h; however, these scores decreased and became more consistent as the analgesia was maintained over time.
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All patients experienced at least one adverse event during the study period with the most common adverse events being hypotension (67%–77% of patients), pain (32%–48%), pruritus (19%–48%), oliguria (14%–19%), nausea (5%–19%), and vomiting (0%–14%). The combination group had significantly fewer patients withdrawn as a result of the occurrence of adverse events (P < 0.05) as compared with either of the single-drug groups. Of the 18 patients withdrawn from the study as a result of an adverse event, 1 was from the combination group, 10 from the levobupivacaine group, and 7 from the morphine group. Two patients were withdrawn for postoperative hypotension, both in the morphine only group.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Racemic bupivacaine in concentrations of 0.0625%–0.25% is often used in combination with opioid analgesics for continuous postoperative epidural analgesia. Concentrations of bupivacaine exceeding 0.125% may be associated with excessive lower extremity motor blockade when used in epidural infusions in the lumbar region. The efficacy of the combination of thoracic epidural bupivacaine 0.25% and morphine 0.005% has been previously reported (1). Studies have demonstrated significantly better postoperative analgesic efficacy with the combination of bupivacaine and morphine (1–5) or diamorphine (13) as compared with either bupivacaine or morphine used alone.
We used levobupivacaine 0.25% with continuous epidural infusions at the thoracic level. This concentration was selected to maximize the analgesic effects of the local anesthetic in the thoracoabdominal somatosensory distribution where motor effects are not clinically significant.
Patients in the combination group reported better analgesia at rest and with activity at the four- and eight-hour time points. VAS scores at and beyond the 12-hour time point reflect an improvement in analgesia caused by supplementation of the epidural infusion and doses of rescue medications, especially for patients in the morphine group and the levobupivacaine group. By 12 hours postoperatively, greater than 55% of the patients in the morphine group and 90% of the patients in the levobupivacaine group had requested supplementation of analgesia, as compared with 40% of the patients in the combination group.
Although the postoperative epidural infusion of levobupivacaine or morphine alone produced reasonable analgesia in some patients, the improvement seen with a combination of the two drugs was significant. The difference in time to first analgesic request between the combination group and the morphine only group was somewhat less than expected. All patients received levobupivacaine 0.75%, which produced a dense sensory neural blockade throughout the surgical procedure. Perhaps the intraoperative neural blockade with levobupivacaine in this study produced a preemptive analgesic effect in all groups, making the differences in postoperative analgesic efficacy between the combination group and the morphine only group less profound.
Our results indicate better postoperative analgesic efficacy with the combination of levobupivacaine and morphine for continuous epidural analgesia in patients after major abdominal surgical procedures as compared with either drug alone. The use of continuous levobupivacaine 0.25% in addition to morphine via a thoracic epidural catheter produced a segmental sensory block and excellent postoperative analgesia without rehabilitation-limiting lower extremity motor blockade. The combination of a potentially enhanced toxicity/safety profile and similar anesthetic use of the single-isomer local anesthetic levobupivacaine, as compared with racemic bupivacaine, indicates that levobupivacaine may be a useful analgesic for postoperative epidural neural blockade.
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Acknowledgments |
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This study was supported by CHIROSCIENCE R&D, Ltd., Cambridge Science Park, Cambridge, Cambridgeshire, UK.
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References |
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