Ropivacaine (1-propyl-2 prime,6 prime-pipecoloxylidide hydrochloride) is a new, long-acting local anesthetic which is chemically homologous with bupivacaine and mepivacaine. It is the first enantiomerically pure local anesthetic and exists as the S enantiomer. In preclinical studies, ropivacaine produced less cardiac and central nervous system toxicity than bupivacaine [1] [2,3] [4] [5,6]
This study was designed to determine which of three concentrations of epidurally administered ropivacaine, when infused for postoperative analgesia, would attenuate opioid analgesia requirements and minimize motor block.
Methods
With Institutional Human Research Ethics Committee approval and written, informed patient consent, 46 patients from two hospitals were enrolled in the study. Eligible patients were those scheduled for elective major lower abdominal surgery, aged between 18 and 75 yr, ASA status I-III, and weighing 50-110 kg. Patients were not enrolled if there was any contraindication to epidural anesthesia or communication difficulties which would have prevented reliable postoperative assessment.
Patients were block randomized into four treatment groups such that each center had an equal number in each group. All groups had identical intraoperative management. The postoperative epidural infusion solutions for these groups were: Group S, saline; Group 1, 0.1% ropivacaine; Group 2, 0.2% ropivacaine; and Group 3, 0.3% ropivacaine. The study was double-blind.
All patients received benzodiazepine 1 h prior to commencement of anesthesia. On arrival in the anesthetic room, an intravenous infusion was established, and a 19-gauge epidural catheter (Portex Registered Trademark; Boots Australia, Ltd.) was inserted through a 16-gauge Touhy needle into the epidural space for 4-5 cm. The spinal level of epidural insertion was appropriate to the dermatome covering the midpoint of the planned surgical incision. After a 3-mL test dose of 0.5% ropivacaine, an additional 10-15 mL of 0.5% ropivacaine was injected. If the sensory block (to pinprick) had not reached the T8 dermatome by 30 min, an additional 5 mL of 0.5% ropivacaine was administered. General anesthesia was then induced with thiopental, muscle relaxant, and up to 200 micro gram fentanyl. Anesthesia was maintained with muscle relaxant, isoflurane, nitrous oxide, and fentanyl supplements (50 micro gram) as required. During surgery, additional ropivacaine 0.5% could be given via the epidural catheter after 2 h; if required, based on clinical signs.
After surgery, all patients had patient-controlled analgesia (PCA) morphine connected and accessible to them, and an epidural infusion of the study solution commenced which was set to run for 21 h at a rate of 10 mL/h. The PCA regimen was set to a 1-mg patient bolus dose with a 5-min lockout. There was no timelimited maximum dose and no background morphine infusion. Additional 1-mg doses could be administered by an investigator if required. Assessments were made for wound pain at rest and with coughing by visual analog scale (VAS) where 0 = no pain and 100 mm = worst pain possible; sensory block to pinprick; and motor block; modified Bromage scale [7]
Hemodynamic values were recorded hourly postoperatively. Defined events were 1) hypotension, less than 80 mm Hg systolic arterial pressure or over a 30% decrease from preoperative baseline; 2) hypertension, over 180 mm Hg systolic or 110 mm Hg diastolic arterial pressure. Other adverse events were noted, including the occurrence of nausea and vomiting.
Statistical analysis was performed using the SAS (version 6.08; SAS Institute, Cary, NC) program and Statview II program (Abacus Concepts, Berkeley, CA). There were no available data on morphine consumption under similar circumstances, so sample size could not be calculated in advance with respect to statistical power. Continuous data (demographic data) was compared using one-factor analysis of variance. PCA morphine use, VAS, motor block, and quality assessment scores were compared in a pairwise manner using two-tailed Wilcoxon rank sum tests (Wilc.). Fisher's exact test was also used where appropriate. Sensory block data is presented descriptively. The level of significance was set at a P value of 0.05.
Results
Of the 46 patients enrolled, six were not eligible for analysis, two because of protocol violation and one each due to equipment failure, surgery cancellation, consent withdrawal (prior to infusion), and initial block failure. This left 10 patients in each group. There were no demographic differences between groups, including the level of catheter insertion Table 1 . The duration of surgery and the time until commencement of infusion were also similar Table 2 .
Table 1: Demographic Data
Table 2: Duration of Surgery and Time from end of Surgery to Start of Infusion
Total PCA morphine use was more over the 21-h period in Group S than all the ropivacaine groups, being significantly so for Group 2. Groups 2 and 3 had significantly lower cumulative values than Group S at 8 h Figure 1 . During the 0- to 4-h time period, the number of patients using any PCA morphine was significantly lower in Group 2 compared with Group S, and at 4 to 8 h in both Groups 2 and 3 compared to Group S Table 3 .
Figure 1: Cumulative patient-controlled analgesia (PCA) morphine consumption. Median values and interquartile ranges at the times shown. Group S = saline infusion; Group 1 = 0.1% ropivacaine, Group 2 = 0.2% ropivacaine, Group 3 = 0.3% ropivacaine. * P < 0.05 compared to Group S.
Table 3: Patient-Controlled Analgesia Use
Pain VAS scores at rest and with coughing were significantly lower compared with Group S for all ropivacaine groups at 4 h, and at rest for Group 3 at 8 h. With coughing, a dose-related separation of VAS scores occurred, with significantly lower scores for Groups 2 and 3 at 8 h, and Group 3 at 21 h compared with Group S Figure 2 and Figure 3 .
Figure 2: Pain visual analog scale (VAS) scores at rest at the end of each time period (median values and interquartile range). * P < 0.05 compared to Group S. Group S = saline infusion, Group 1 = 0.1% ropivacaine, Group 2 = 0.2% ropivacaine, Group 3 = 0.3% ropivacaine. All data points were for 10 patients unless otherwise indicated by a digit adjacent to the data point.
Figure 3: Pain visual analog scale (VAS) scores with coughing at the end of each time period (median values and interquartile range). * P < 0.05 compared to Group S. Group S = saline infusion, Group 1 = 0.1% ropivacaine, Group 2 = 0.2% ropivacaine, Group 3 = 0.3% ropivacaine. All data points were for 10 patients unless otherwise indicated by a digit adjacent to the data point.
Quality ratings for the three sample times were grouped together. Quality ratings were significantly higher for patients receiving ropivacaine in association with PCA than for PCA alone (P < 0.01, Wilc.). There were no differences between ropivacaine groups, however Figure 4 .
Figure 4: Quality of analgesia ratings by patients. Cumulative scores over 21 h. For Groups 1, 2 and 3, P < 0.01 compared to Group S. Group S = saline infusion, Group 1 = 0.1% ropivacaine, Group 2 = 0.2% ropivacaine, Group 3 = 0.3% ropivacaine. Rating 1 = poor, 2 = fair, 3 = good, 4 = excellent.
Sensory block was not different between groups until after 2 h from commencement of epidural infusion. It then regressed rapidly in Group S, with little difference between Groups 1, 2, and 3 over the infusion period, except for earlier regression of the lower extent of the sensory block in Group 1 Figure 5 .
Figure 5: Sensory block to pinprick from start of infusion until normal sensation had returned (median levels). Upper and lower block limits for each group are shown. Group S = saline infusion, Group 1 = 0.1% ropivacaine, Group 2 = 0.2% ropivacaine, Group 3 = 0.3% ropivacaine.
There was a dose-related increase in the amount of motor block Figure 6 . Group 3 had significantly more motor block than both Group S and Group 1 at 4 h (P < 0.01, Wilc.), and Group 3 had significantly more motor block than all other groups at 8 h (P < 0.05, Wilc.). No patients had Bromage level 3 block during the infusion.
Figure 6: Motor block at the end of each time period. Group S = saline infusion, Group 1 = 0.1% ropivacaine, Group 2 = 0.2% ropivacaine, Group 3 = 0.3% ropivacaine. Modified Bromage scale: 0 = no motor block, 1 = inability to raise extended leg, 2 = inability to flex knee, 3 = inability to flex ankle. The number of patients (n) included for each column is indicated above the column.
The commonest adverse events during infusion were hypotension, nausea, and vomiting. There was a higher incidence of hypotensive episodes in all ropivacaine groups compared with Group S (Group S, one patient; Group 1, six patients; Group 2, five patients; Group 3, six patients; P < 0.05 in Groups 1 and 3 compared with Group S, Fisher's exact test). Nausea or vomiting occurred in similar numbers of patients in each group (Group S, eight patients; Group 1, four patients; Group 2, six patients; Group 3, six patients).
Discussion
This study demonstrates that ropivacaine is effective and well tolerated when used in combination with intravenous opiate PCA for postoperative analgesia after major lower abdominal surgery. All concentrations of ropivacaine, when compared with PCA alone (Group S), showed decreased morphine consumption and improved quality of analgesia.
Ropivacaine is of interest for postoperative epidural infusion because of the lower toxicity it has demonstrated compared with bupivacaine [1-3] [5,6]
It is important to assess postoperative pain during activity. When pain scores were measured at rest, the median VAS scores in the ropivacaine groups were all below 20 mm. After coughing, a dose-related reduction in pain VAS scores with increasing ropivacaine concentration is evident, as is the inability of PCA opiates alone to control such pain. Local anesthetic alone was adequate for analgesia in almost half the patients in Groups 2 and 3 up to 8 h postoperatively. The use of PCA as an indicator of efficacy is not without its problems because most patients will at some stage press the button for reasons unrelated to the quality of analgesia at the surgical site. Keeping these effects in mind, PCA still provides a convenient and quantitative index of patient analgesic needs.
There was a dose-dependent degree of motor block. With the rate of infusion fixed at 10 mL/h, 0.3% ropivacaine maintained a moderate degree of motor block, compared with 0.1% and 0.2% ropivacaine patients who demonstrated very little motor block. The intensity of motor block did not increase with time. The residual motor block in a small percentage of the epidural saline infusion group reflects either some residual effect from the intraoperative ropivacaine dose or possibly a reluctance to flex the hip due to abdominal discomfort. Minimal motor block is important for ambulation and physiotherapy, and selection of the most suitable solution concentration and rate of infusion is important in order to achieve "ambulatory analgesia."
Hypotension was, not surprisingly, more common in the ropivacaine groups than in Group S. There was no relationship of hypotension to dose and no patient had to have his or her postoperative infusion discontinued because of hypotension. Nausea or vomiting occurred in 60% of all patients and was not related to PCA morphine use. Any reduction in nausea or vomiting related to the opiate sparing effect of epidural local anesthesia may be difficult to demonstrate in the first 24 h after abdominal surgery with general anesthesia and would be better studied over a 2- or 3-day period.
The process of administering a local anesthetic infusion at a constant rate for postoperative pain relief is somewhat artificial, in that it does not allow adjustment of the dose administered to compensate for individual requirements. This may have contributed to the wide spread of VAS scores obtained. In this study, PCA was available to all patients and provided the flexibility required for clinical pain control. It is possible that by adjusting ropivacaine infusion rates, considerably less PCA use would have been required and side effects may have been reduced. Future studies are planned to assess the ability of ropivacaine to be titrated to effect during postoperative analgesic infusion over longer periods.
In conclusion, ropivacaine epidural infusions of 0.2% and 0.3% with PCA provided superior postoperative analgesia to PCA alone in this patient population. Motor block was greater in the 0.3% group and of low frequency and intensity in the 0.1% and 0.2% groups. For postoperative analgesia, the epidural infusion of 0.2% ropivacaine provided the best balance of analgesia with minimal motor block.
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