Abstract

Objective

Epidural patient-controlled analgesia (EPCA) with a mixture of low-concentration levobupivacaine (0.0625% or 0.1%) plus fentanyl, with basal infusion, has been extensively used for postoperative analgesia in our allied institutions. To elucidate whether these two EPCA regimens provide satisfactory analgesia, we compared the analgesia efficacy and incidence of drug-related side effects for both EPCA regimens with those of the most widely used postoperative analgesia regimen, intra-venous PCA (IVPCA) with morphine.

Methods

Data collection was performed through retrospective chart review. A total of 335 patients who underwent colorectal surgery were included. Patients received IVPCA (n = 200), EPCA with 0.0625% levobupivacaine/fentanyl (n = 45), or EPCA with 0.1% levobupivacaine/fentanyl (n = 90). The analgesia efficacy and side effects were compared.

Results

Pain scores with 0.0625% and 0.1% EPCA were significantly lower than those with IVPCA. Most patients were satisfied with their postoperative analgesia, and the satisfaction scores of these three groups were comparable. No patients developed respiratory depression or over-sedation. The incidence of nausea and vomiting was significantly higher with 0.1% EPCA (16.7% and 7.8%, respectively) compared with IVPCA (6.1% and 3.5%, respectively) and 0.0625% EPCA (9.3% and 2.3%, respectively). Moreover, the incidence of sensory and motor blockade was significantly higher with 0.1% EPCA (13.5% and 5.6%, respectively) than with 0.0625% EPCA (4.7% and 0%, respectively).

Conclusion

Epidural analgesia with low-concentration levobupivacaine plus fentanyl provides satisfactory postoperative analgesia with few side effects for patients after colorectal surgery.

Keywords

colorectal surgery; epidural analgesia; fentanyl; levobupivacaine; patient-controlled analgesia;

1. Introduction

Levobupivacaine, the pure S(−)enantiomer of bupivacaine, possesses similar local anesthetic potency to the racemic parent bupivacaine, but with reduced cardiac and central nervous system toxicity.¹⁻³ Epidural infusion of levobupivacaine provides excellent anesthesia and analgesia in clinical practice. ⁴⁻⁷ For example, continuous epidural infusion of levobupivacaine, with or without morphine, has been shown to provide adequate postoperative analgesia in patients undergoing major abdominal surgery.⁷

  In a previous study conducted to compare the postoperative analgesia efficacy of three different concentrations of levobupivacaine (0.0625%, 0.125% and 0.25%), given via epidural continuous infusion, 0.25% levobupivacaine provided better analgesia than 0.125% or 0.0625% levobupivacaine in patients after orthopedic surgery.⁸ However, epidural continuous infusion of 0.25% levobupivacaine could result in a higher incidence of untoward effects, particularly motor block, than 0.125% or 0.0625% levobupivacaine.⁸

  Decreasing the concentration of levobupivacaine can reduce the incidence of side effects.⁸ However, decreasing the concentration of levobupivacaine might also decrease the efficacy of analgesia and increase the consumption of narcotic agents for postoperative pain management. The ideal combination of levobupivacaine and narcotic agent should balance these two extremes and provide satisfactory analgesia with few side effects. Continuous epidural infusion combined with patient-controlled boluses of a mixture of low-concentration levobupivacaine (0.0625% or 0.1%) and fentanyl (2 μg/mL) delivered by a patient-controlled analgesia (PCA) device has been used in our institutions to provide postoperative analgesia after colorectal surgery. However, it has not been reported whether these two epidural PCA (EPCA) regimens provide satisfactory analgesia without side effects. Therefore, we compared the analgesia efficacy and incidence of analgesia-related side effects of these EPCA regimens with those of the most widely used postoperative analgesia regimen, intravenous PCA (IVPCA) with morphine.⁹

2. Methods

This retrospective study (MMH-I-S-651) was approved by the Human Research Review Committee and conducted at Mackay Memorial Hospital in Taipei, Taiwan. Data were collected from chart review.

  We reviewed the records of 335 patients who underwent elective colorectal surgery under general anesthesia, followed by epidural anesthesia for postoperative analgesia using continuous epidural infusion of 0.0625% or 0.1% levobupivacaine (Abbott Laboratories Ltd., Abbott Park, IL, USA) plus 2 μg/mL fentanyl (Janssen Pharmaceutica, Beerse, Belgium). The concentration of levobupivacaine (i.e. 0.0625% or 0.1%) was chosen by the anesthesiologist in charge. Patients who received procedures in addition to colorectal surgery, such as hepatectomy, were excluded.

  The epidural catheter (Arrow International Inc., Asheboro, NC, USA) was placed before surgery. To facilitate the insertion of the epidural catheter, a Tuohy needle (18 gauge; Arrow International Inc.) was inserted via a median or paramedian approach through an interspace between T11 and L5, depending on the dermatome affected by the surgical site. Using the loss of resistance technique, the entry to the epidural space was identified and the epidural catheter was inserted in a cranial direction to a distance of 5−6 cm. The catheter was affixed with skin adhesive tape along the back bone. After surgery, a PCA device (APM II; Abbott Laboratories Ltd.) was used to facilitate continuous epidural infusion and patientcontrolled bolus doses of low-concentration levobupivacaine (0.0625% or 0.1%) and fentanyl (2 μg/ mL). Epidural infusion was commenced within 30 minutes after surgery at a rate of 4−6 mL/hr together with a PCA bolus of 3−5 mL. The lockout interval for the PCA bolus was 10−15 minutes and the 4-hour limit was 35−50 mL.

  Because IVPCA with morphine is one of the most widely used regimens for postoperative analgesia,⁹ we also evaluated the records of 200 patients who underwent colorectal surgery under general anesthesia only and who received PCA with intravenous morphine (1 mg/mL; National Bureau of Controlled Drugs Pharmaceutical Plant, Taipei, Taiwan) plus droperidol (2.5−5 mg in 100 mL of morphine solution; Excelsior Biopharma Inc., Taipei, Taiwan) for postoperative pain management as a control group. For IVPCA, the infusion rate was 0 mL/hr and the bolus dose was 3−5 mL. The lockout interval for PCA boluses was 5−8 minutes and the 4-hour limit was 20−30 mL. All patients could receive supplemental intravenous analgesics with either ketorolac (15− 30 mg every 6 hours; Yung Shin Pharmaceutical, Taichung, Taiwan) or meperidine (0.5−1 mg/kg every 4 hours; National Bureau of Controlled Drugs Pharmaceutical Plant) if analgesia was inadequate. As intravenous morphine can cause nausea and vomiting, ⁹ some patients received a single dose of intravenous dexamethasone (4 mg; Union Chem & Pharm Co. Ltd., Taipei, Taiwan) before starting IVPCA to decrease the incidence of nausea and vomiting,¹⁰ at the anesthesiologist’s discretion.

  All patients were visited daily by clinical staff within the PCA team in the morning, and whenever necessary. The daily consumption of levobupivacaine/ fentanyl solution or morphine was documented on charts until 72 hours after surgery. Pain scores at rest, during activity (defined as changing body position), and during coughing were assessed using a visual analog scale (VAS), with scores ranging from 0 to 100, where 0 = no pain and 100 = worst pain possible. Supplemental intravenous analgesic consumption was also recorded. Patient’s daily satisfaction was also assessed using a VAS, with scores ranging from 1 to 5, where 1 = poor and 5 = excellent. The occurrence of side effects related to postoperative pain management, including respiratory depression, over-sedation, dizziness, nausea, vomiting, sensory block and motor block were documented.

2.1. Statistical analysis

Continuous data with normal distributions were evaluated by one-way analysis of variance with post hoc least significant difference tests. Continuous data with non-normal distributions were evaluated by Kruskal-Wallis H tests with post hoc Mann-Whiney U tests and Bonferroni’s correction. Categorical data were evaluated by χ2 tests. The significance level was set at p < 0.05, or p < 0.0167 with Bonferroni’s correction. Numeric data are presented as means ± standard errors. Cate gorical data are presented as percentages. SPSS version 11.5 (SPSS Inc., Chicago, IL, USA) was used for all analyses.

3. Results

A total of 335 patients were included in this study. The demographic data and clinical characteristics (including locations of neoplasm, operation time, and surgical blood loss volume) for patients who received IVPCA (n = 200), 0.0625% EPCA (n = 45), and 0.1% EPCA (n = 90) were comparable (Table 1). In addition, 66.7% of patients given IVPCA received dexamethasone.

Table 1 Demographic data and clinical characteristics*

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3.1. Pain scores

The postoperative pain scores at rest in the 0.0625% and 0.1% EPCA groups were significantly lower than those in the IVPCA group (Day 1: p = 0.004 and p < 0.001, respectively; Day 2: p = 0.011 and p < 0.001, respectively; Day 3: both p < 0.001; Figure 1A). The postoperative pain scores during activity with 0.0625% and 0.1% EPCA were also significantly lower than those with IVPCA (Day 1: both p < 0.001; Day 2: both p < 0.001; Day 3: both p < 0.001; Figure 1B). Moreover, the postoperative pain scores during coughing were significantly lower with 0.0625% and 0.1% EPCA than with IVPCA (Day 1: both p < 0.001; Day 2: both p < 0.001; Day 3: both p < 0.001; Figure 1C). In contrast, the postoperative pain scores at rest, during activity and during coughing were comparable between 0.0625% and 0.1% EPCA (Figure 1). The daily consumption of levobupivacaine/fentanyl was also comparable between patients given 0.0625% and 0.1% EPCA (Table 2).

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Figure 1 Daily pain scores at: (A) rest; (B) during activity (defined as changes in body position); and (C) during coughing. Scores were assessed using a visual analog scale, with scores ranging from 0 to 100, where 0 = no pain and 100 = worst pain possible. Data were evaluated by Kruskal-Wallis H test with post hoc Mann-Whitney U tests and Bonferroni’s correction. Data are presented as mean ± standard error. *p < 0.0167 vs. IVPCA. IVPCA = intravenous patientcontrolled analgesia (PCA) with morphine (1 mg/mL); EPCA = epidural PCA with 0.0625% or 0.1% levobupivacaine plus fentanyl (2 μg/mL).

Table 2 Daily consumption of levobupivacaine/fentanyl solution*

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3.2. Patient satisfaction

The daily satisfaction scores revealed that most patients were satisfied with their postoperative pain management. Moreover, the mean daily satisfaction scores were comparable among the three groups (Figure 2).

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Figure 2 Daily patient satisfaction scores assessed using a visual analog scale, with scores ranging from 0 to 5, where 0 = poor and 5 = excellent. Data were evaluated by Kruskal- Wallis H test with post hoc Mann-Whitney U tests and Bonferroni’s correction. Data are presented as mean ± standard error. IVPCA = intravenous patient-controlled analgesia (PCA) with morphine (1 mg/mL); EPCA = epidural PCA with 0.0625% or 0.1% levobupivacaine plus fentanyl (2 μg/mL).

3.3. Supplemental analgesics

Most patients did not require supplemental intravenous analgesics for postoperative pain management (Table 3). Moreover, the incidence and frequency of supplemental analgesic administration were comparable among the three groups (Table 3).

Table 3 Frequency of administration of supplemental analgesic agents*

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3.4. Side effects

No patients included in this study developed respiratory depression or over-sedation (Table 4). Differences in the incidence of dizziness among the three groups of patients were not statistically significant (Table 4). However, the incidence of nausea and vomiting was significantly higher with 0.1% EPCA than with IVPCA or 0.0625% EPCA (nausea: p < 0.001 and p = 0.018, respectively; vomiting: p = 0.002 and p = 0.011, respectively; Table 4). However, the differences in the incidence of nausea and vomiting between 0.0625% EPCA and IVPCA were not statistically significant (Table 4). Moreover, the incidence of sensory block and motor block was significantly higher with 0.1% EPCA than with 0.0625% EPCA (both p = 0.001; Table 4).

Table 4 Incidence of side effects related to postoperative pain management* IVPCA

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4. Discussion

This study revealed that EPCA with low-concentration levobupivacaine (0.0625% or 0.1%) plus fentanyl provided better postoperative analgesia than IVPCA with morphine after colorectal surgery. These data were similar to those in the earlier study by Carli et al11 who reported that colorectal surgery patients given epidural analgesia with a mixture of bupivacaine and fentanyl had better quality of postoperative analgesia than those who received IVPCA with morphine. Our results, together with those reported by Carli et al,¹¹ indicate that levobupivacaine and bupivacaine possess similar local anesthetic potency. Moreover, these data support the concept that EPCA with a mixture of local anesthetic agents and narcotic agents is more appropriate for postoperative analgesia than IVPCA with morphine in colorectal surgery patients. 

  The results reported by Murdoch et al⁸ suggest that reducing the concentration of levobupivacaine could provide less motor block but might impair pain control, necessitating greater consumption of rescue analgesics in patients undergoing orthopedic surgery. This concept was partially supported by our data, because we found that the incidence of sensory and motor block was lower in patients who received EPCA with 0.0625% levobupivacaine plus fentanyl compared with patients who received EPCA with 0.1% levobupivacaine plus fentanyl. However, unlike the earlier study,⁸ we found that the postoperative analgesic efficacy of EPCA with 0.0625% levobupivacaine plus fentanyl was similar to that of 0.1% levobupivacaine plus fentanyl in colorectal surgery patients. The discrepancy between our findings and the earlier findings⁸ may be due to differences in the analgesic regimen. Murdoch et al used levobupivacaine alone for postoperative analgesia8 whereas we administered a mixture of levobupivacaine plus fentanyl. It is likely that the addition of fentanyl significantly increased the analgesia efficacy compared with levobupivacaine alone. Therefore, reducing the concentration of levobupivacaine in the presence of fentanyl did not result in worse pain control or increased consumption of rescue analgesics in patients undergoing colorectal surgery, as observed in our study. Moreover, our data indicate that EPCA with 0.0625% levobupivacaine plus fentanyl could be a better postoperative analgesia regimen than EPCA with 0.1% levobupivacaine plus fentanyl in colorectal surgery patients.

  It has been postulated that the quality of epidural analgesia depends on the total mass of the local anesthetic rather than on the volume or concentration. ¹² This concept is supported by Dernedde et al,¹³ who reported similar analgesia efficacy, local anesthetic (i.e. levobupivacaine) consumption, and rescue morphine consumption in two groups of abdominal surgery patients who received two different concentrations of levobupivacaine (1.5 mg/ mL and 5 mg/mL) given as an equal milligram-bolus dose (5 mg) via EPCA for postoperative analgesia. According to this concept, we would expect the daily consumption of levobupivacaine/fentanyl with 0.1% EPCA to be lower than that with 0.0625% EPCA. However, we found that the daily consumption of levobupivacaine/fentanyl in the two groups was actually comparable. Again, the discrepancy between our results and those reported by Dernedde et al¹³ may be related to the analgesic efficacy of the drugs used, because we used levobupivacaine plus fentanyl whereas they used levobupivacaine alone.

  Nausea and vomiting are the most common side effects in patients given intravenous morphine for postoperative analgesia.^9,10 Cheung et al reported that a substantial proportion of patients who experienced nausea (47%) and vomiting (18.5%) used intravenous morphine for postoperative analgesia.⁹

  Some studies have revealed that the administration of droperidol and/or dexamethasone could reduce the incidence of nausea and vomiting induced by intravenous morphine.^10,14 Based on these reports,^10,14 some of our colleagues at our institutions administer droperidol and/or dexamethasone to patients who are given intravenous morphine for postoperative analgesia. The results of this study confirm the beneficial effects of these strategies, because the incidence of nausea and vomiting in patients given IVPCA with morphine was much lower than that reported in earlier studies.^9,10 Moreover, this intervention may also explain why the incidence of nausea and vomiting was significantly lower with IVPCA than with 0.1% EPCA.

  Most of the patients included in this study were satisfied with their postoperative analgesia. We also found that two EPCA regimens provided better postoperative analgesia than an IVPCA regimen in colorectal surgery patients. According to these results, one would expect that patients given an EPCA regimen would report higher satisfaction scores than those who received the IVPCA regimen. Surprisingly, the patient satisfaction scores were comparable among the three groups, which may be related to the above-mentioned differences in analgesia-related side effects.

  We found that the incidence of motor and sensory block was significantly higher with 0.1% EPCA than with 0.0625%. Previous studies have revealed that motor and sensory block may cause significant decreases in blood pressure.¹⁵ Of note, a decrease in blood pressure is strongly associated with postoperative nausea and vomiting.¹⁶ Unfortunately, changes in blood pressure, except for hypotension, were not recorded in the medical charts and could not be evaluated in this retrospective study. However, we speculate that the blood pressure in patients given 0.1% EPCA may be lower than those given 0.0625% EPCA. Accordingly, we speculate that the higher incidence of motor and sensory block with 0.1% EPCA was responsible for the higher incidence of nausea and vomiting in this group of patients. This is supported by our results showing that the incidence of nausea and vomiting was significantly higher with 0.1% EPCA than with 0.0625% EPCA. 

  Our study has several limitations. First, this was a retrospective study rather than a prospective one. Second, the sample size of this study was relatively small. Third, the daily evaluations were conducted at a fixed time in the morning (i.e. 08:00− 10:00 hours) and/or whenever necessary, rather than at times appropriate for the patient’s condition (e.g. at 24, 48 and 72 hours after surgery). Fourth, it remains to be seen whether these EPCA regimens provide satisfactory analgesia with low incidence of side effects for patients undergoing other major surgeries. More studies are needed before further conclusions can be drawn.

  In summary, epidural analgesia with lowconcentration levobupivacaine combined with fentanyl provides satisfactory postoperative analgesia with few side effects for patients undergoing colorectal surgery.