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Continuous epidural infusion of ropivacaine for the prevention of postoperative pain after major orthopaedic surgery: A dose-finding study
Original Article
Continuous epidural infusion of ropivacaine for the prevention of postoperative pain after major orthopaedic surgery: A dose-finding study Terry Muldoon, FtLCA (1) Paul McConaghy, FFARCSI (1) Alexander tL Binning, F R C A (2) Charles B Wallis, F1KCA (2) J Dennis 1K Connolly, FFAILCSI 0) Kevin 1K Milligan, MD, PhD, FFARCSI 0) Jonathan Bannister, MD, FtLCA (2) tLoisin A Armstrong, P h D (3)
Abstract The present study investigated the dose relationship of ropivacaine with regard to analgesia and motor block when administered as a continuous 21 hour epidural infusion following major orthopaedic surgery. Forty six patients scheduled for elective total knee or hip arthroplasty were compared in this doubleblind study. Patients were randomly assigned to one of four treatment groups: saline (n=12); ropivacaine 0.1% (n= 11); ropivacaine 0.2% (n= 12); ropivacaine 0.3% (n= 11). Initial epidural analgesia was established with 0.5% ropivacaine and general anaesthesia was then induced for surgery. Within 30 minutes of the end of surgery, epidural infusions were commenced at a rate of 10 ml/hour for 21 hours. All patients had access to PCA morphine. Morphine consumption, VAS pain scores at rest, sensory and motor block and overall quality of treatment were assessed at regular intervals. The morphine consumption and VAS scores were lower overall in the ropivacaine groups than in the group receiving only PCA morphine. The difference was more evident during the first 8 hours of postoperative infusion, when significant differences between the ropivacaine 0.2% and 0.3% groups and the saline group were found. The incidence and degree of motor block were dose dependent. There was significantly higher patient satisfaction in all ropivacaine groups compared to the saline control group. In conclusion, 21 hour epidural infusion of ropivacaine, combined with PCA morphine, provides effective pain relief following major joint surgery and without significant adverse events. Morphine consumption and pain scores were lowest in the 0.3% ropivacaine group but this group had a higher degree of motor block. Pain relief with the combination of ropivacaine and PCA morphine is superior to that of PCA morphine alone. Acute Pain i998; I (2): 13-19. Keywords: anaesthetics, local: ropivacaine; anaesthetic techniques: epidural; postoperative analgesia
Continuous epidural infusion of a low concentration of local anaesthetic, either alone or in combination
with an opioid, is widely used for the prevention of postoperative pain. For optimal analgesia, the epidural block should be established in connection with the surgical procedure.
(1) Department of Anaesthetics, Musg,rave Park Hospital, Belfast, Northern Ireland, UK (2) Department of Anaesthetics, Ninewetls Hospital, Dundee, Scotland, UK (3) Astm Clinical Research Unit, Edinburgh, Scotland, UK.
Ropivacaine (1-propyl-2" 6"-pipecoloxylidide hydrochloride) is a new, long-acting local anaesthetic w h i c h is closely related to amide type local anaesthetics such as bupivacaine and mepivacaine. Ropivacaine is the first agent, however, to be
Introduction
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Ropivacaine: A dose-finding study Muldoon et al commercially available as the pure enantiomer as opposed to a racemate. Although ropivacaine has sensory nerve blocking properties comparable to those ofbupivacaine, 1 clinical and animal studies have shown it to have a lower cardiac toxicity 2,3 and a greater separation of motor and sensory block than bupivacaine.4, s These properties suggest that ropivacaine may offer advantages over bupivacaine w h e n administered as an epidural infusion for postoperative pain relief following surgery. The present study was undertaken to investigate the dose relationship of ropivacaine with regard to analgesia, and motor block when administered as a continuous 21 hour epidural infusion following major o r t h o p a e d i c surgery. Since ropivacaine produces a sensory block comparable to that of bupivacaine, 2 the concentrations and infusion rate chosen were similar to those employed previously for bupivacaine.
Methods Forty six patients (ASA Dill, age range 18-80 years) undergoing elective knee or hip arthroplasty were evaluated in this double-blind study. Eligible patients were those scheduled for total hip arthroplasty or total knee arthroplasty, aged between 18 and 80 years, ASA status I to Ill and weight 50 to 110 kg. Patients were not enrolled if there was any contraindication to epidural anaesthesia or communication difficulties which would have prevented reliable postoperative assessments. The study was conducted at Ninewells Hospital, Dundee, Scotland (centre 1) and the Musgrave Park Hospital, Belfast, Northern Ireland (centre 2). Approval for the study was obtained from the local Ethics Research Committee at both centres. The patients were visited on the day prior to surgery and the purpose of the study was explained. The patients were tutored in the use of a Visual Analogue Scale Ruler (Biomedical Engineering, Flinders Medical Centre, Adelaide, Australia) consisting of a 100 mm horizontal line ungraded with the ends marked 'no pain' (0 mm) and 'worst possible pain' (100 ram). Patients are able to move a pointer along the ruler to mark the distance from the 'no pain' end which corresponds to the intensity of the pain felt. On the reverse side is a line marked with graduations in mm for quick reading. The
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patients were also shown how to use an Abbott LifecareTM PCA pump. After gaining written i n f o r m e d consent, the patients were randomised to one of four postoperative epidural infusion groups: 1. 0.9% saline 2. 0.1% ropivacaine 3. 0.2% ropivacaine 4. 0.3% ropivacaine Temazepam 20 mg was administered as premedication 1 to 2 hours prior to the induction of anaesthesia. O n arrival in the operating theatre an epidural catheter was inserted in the L2-3 or L3-4 interspace. A 3 ml test dose of ropivacaine 0.5% was used to exclude inadvertent dural puncture. On confirming satisfactory placement of the catheter, 10-15 mls of ropivacaine 0.5% was injected in incremental doses over a five minute period. If surgical anaesthesia to T10 was not achieved 30 minutes after the main dose, a further 5 ml ofropivacaine 0.5% was injected. All patients then underwent urinary catheterisation, it being a routine practice in our centres. Once block to T10 was obtained, general anaesthesia was i n d u c e d w i t h intravenous t h i o p e n t o n e , atracurium and fentanyl. General anaesthesia was maintained with isoflurane 1-2%, nitrous oxide 65% in oxygen. Further 5 ml doses of ropivacaine 0.5% could be administered if the patient showed signs of inadequate analgesia. At the end of surgery, defined as the completion of the last suture to the skin incision, the patient was transferred to a dedicated high dependency unit where trained nursing staff" assessed the parameters as shown below. Within 30 minutes of the end of surgery an epidural infusion of study solution was commenced at a rate of 10 ml/hr and continued for 21 hours. The solution was administered in a double-blind manner. All patients had access to intravenous m o r p h i n e delivered by a patientcontrolled analgesia (PCA) device programmed to deliver 1 mg bolus doses of morphine with a five minute lockout. No other analgesic was permitted during the study period. Assessments, timed from the beginning of the epidural infusion, were as follows: • PCA morphine consumption for time intervals 0-4, 4-8 and 8-21 hours.
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Ropivacaine: A dose-finding study Muldoon et al • W o u n d pain (VAS score) at rest at 4, 8 and 21 hours. • Overall quality o f t r e a t m e n t , w i t h regard to analgesia, as judged by the patient, at 4, 8 and 21 hours. Quality of treatment was assessed using the scale: 1=poor; 2=fair; 3=good; 4=excellent. • Sensory block, determined bilaterally using a short bevelled 27G needle, every 2 hours from the start of the epidural infusion until 22.00 hours on the day o f surgery. Assessments were discontinued during the night to permit the patients to sleep. Assessments were then r e c o m m e n c e d at 08.00 hours the following morning and were performed every hour until return of normal sensation. • Motor block was determined at the same time as sensory block using the modified Bromage scale: 0=no motor block; 1=inability to raise extended legs; 2=inability to flex knees (able to move foot only); 3=inability to flex ankle joints (unable to move foot or knee). Heart rate and blood pressure were m o n i t o r e d throughout the study and recorded at the start of the continuous infusion and thereafter every hour until return o f n o r m a l sensation and m o t o r function. Adverse events, s p o n t a n e o u s l y r e p o r t e d by the patient or observed by the staff, were recorded. An open, standardised question regarding adverse events was asked at the end o f the infusion, at time o f discharge and by phone 2-3 weeks after surgery. This question was 'Have you been bothered by anything (after surgery/after the infusion was stopped/during
the hospital stay and since discharge f r o m the hospital, respectively)'.
Statistical analysis Two approaches to the statistical analysis were used: a per protocol analysis and an all patients treated analysis. Patients were e x c l u d e d f r o m the per protocol analysis in the case of technical failure, if the patient did not receive any study drug, or any major protocol violation which resulted in loss of efficacy data likely to influence the validity of data. M o r p h i n e c o n s u m p t i o n , VAS scores, overall quality of treatment scores, sensory block and motor block were compared by non-parametric Wilcoxon rank sum tests. As there were no available data on morphine consumption under similar circumstances and a sample size could n o t be calculated w i t h consideration to statistical power, 48 patients (12 per treatment group) were to be included in the per protocol analysis. This was considered to be a fair sample size, with a potential to detect a dose response relationship. The four study groups were stratified for centre and comparisons were p e r f o r m e d in a pairwise manner. Tests were two-tailed and performed at a significance level of 0.05.
Results A total of 48 patients received postoperative study treatment, of w h o m 46 were valid for the analysis. For the two patients excluded, violation of the study
Table 1: Patient characteristics (all patients treated)
Saline (n=13)
Ropivacaine 0.1% (n=ll)
Ropivacaine 0.2% (n=12)
Age [yrs] mean (range)
68.5 (64-73)
62 (40-75)
59.5 (33-75)
65.8 (54-75)
Height [cms] mean (SD)
167.8 (145-185)
168.5 (152-185)
165.9 (155-179)
167.8 (158-180)
Weight [kgs] mean (SD)
80.6 (18.1)
75.1 (15.4)
71.3 (16.9)
73.2 (13.5)
ASA Status I II III
4 6 3
4 6 1
3 7 2
4 7 1
Sex - M:F
8:5
6:5
5:7
4:8
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Ropivacaine 0.3% (n=12)
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Ropivacaine: A dose-finding study Muldoon et al inclusion criteria occurred in one (saline) and an inadequate sensory block spread prior to surgery occurred in the second (ropivacaine 0.3%). There were no differences among the groups with regard to age, sex, height, weight and ASA status (Table 1). Duration and type of surgery, time to start of epidural infusion and the total volume and type of intravenous fluids administered were similar across the groups. The ratio of hips to knees was exactly the same in the treatment groups with three knees and nine hips in each. The majority of patients did n o t receive fentanyl but in those that did, the amount administered for induction and maintenance of general anaesthesia was similar in all groups. In addition, the groups were similar with regard to the
mean total dose of 0.5% ropivacaine administered intra-operatively (84.6 mg-91.8mg).
Morphine consumption The median m o r p h i n e c o n s u m p t i o n during the three periods analysed is presented in Table 2. In the 0-4 hour time period, there were 4, 6 and 6 patients in the ropivacaine 0.1%, 0.2% and 0.3% groups respectively who did not take any morphine. In the saline group, all patients t o o k m o r p h i n e except one. M o r p h i n e consumption in the ropivacaine 0.2% group was significantly lower than in the saline group (p=0.01). There were no significant differences between any of the ropivacaine groups.
Table 2: Summary of morphine consumption, VAS scores at rest, sensory block spread and motor block Ooerprotocol patients * Significant differencefiom saline (p
Saline n=12
Ropivacaine 0.1% n=11
Ropivacaine 0.2% n=12
Ropivacaine 0.3% n=11
Morphine consumption [mg] (PCA) median (SD) 0-4 hours 4-8hours 8-21 hours
9.0 (8) 10.5 (5.7) 17.5 (10.9)
2.0 6.2) 3.0 (6.7) 12.6 (9.5)
0.5 (3.2)* 1.5 (6.4)* 25.8 (15.2)
0.0 (14.5) 0.0 (2.6)* 4.0 (6.2)**
Pain scores (VAS) at rest [mm] median (SD) 4 hours 8 hours 21 hours
33 (23) 2t (27) 29 (22.8)
0 (23.9) 2 (20) 0 (31.7)
0 (19.5)* 0 (25.3)* 6.8 (21.5)
0 (18.4)* 0 (25.1) 10 (20.0)
L1-L2
T10 T12 L2
T12 T12-L1 L2
T10 T10 T12
$1 L4-L3 L3
$1 L5 L5
$1 L5 L5
64 27 0 9 82 18 0 0 82 18 0 0
25 17 41 17 42 8 42 8 42 49 9 0
36 19 36 9 46 9 36 9 45 19 27 9
Sensory block pin-prick Upper spread 4 hours 8 hours 21 hours Lower spread
4 hours 8 hours 21 hours
Motor block Bromage score (% of patients) 4 hours
8 hours
21 hours
16
0 1 2 3 0 1 2 3 0 1 2 3
67 25 8 0 92 8 0 0 100 0 0 0
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Ropivacaine: A dose-finding study Muldoon et al In the 4-8 hour time period, there were 4, 4 and 6 patients in the ropivacaine 0.1%, 0.2% and 0.3% groups respectively who did not take any morphine. In the saline group, all patients took morphine except one. Morphine consumption was significantly lower in both the ropivacaine 0.2% and 0.3% groups than in the saline group (p=0.022 and p=0.006 respectively). There were no significant differences between any of the ropivacaine groups. In the 8-21 hour time period, there were 1, 1 and 3 patients in the ropivacaine 0.1%, 0.2% and 0.3% groups respectively who did not take any morphine. During the same interval, morphine was taken by all patients in the saline group. Morphine consumption in the 0.3% group was significantly lower than both the saline group (p=0.032) and the ropivacaine 0.2% group (1o=0.045). Pain at rest The groups were compared at 4, 8 and 21 hours after commencing the epidural infusion (Table 2). At 4 hours, significantly l o w e r VAS scores occurred in the ropivacaine 0.2% and 0.3% groups than in the saline group (p=0.015 and p=0.044 respectively). At 8 hours, only the difference between the ropivacaine 0.2% group and the saline group was statistically significant (p=0.045). At 21 hours there were no statistically significant differences between the four treatment groups. Sensory block Upper and lower sensory block spread during the 21 hour epidural infusion, as determined by pin-prick, is presented in Table 2. Sensory block spread decreased in all groups during the infusion. In the saline group, the block had c o m p l e t e l y resolved by 6 hours. In the ropivacaine groups, the sensory block decreased from T8 to T l l at 2 hours after infusion start to between T10 and L2 at 10 hours. At 21 hours the median upper spread was T12 for the ropivacaine 0.3% group and L2 for the 0.1% and 0.2% groups. The lower spread decreased to a median of L3 for the 0.1% group and to L5 for the other two groups. M o t o r block The results of the m o t o r block assessments are presented in Table 2.
Acute Pain
There was a significant difference in motor block between the ropivacaine 0.2% group and both the saline (p=0.01) and ropivacaine 0.1% (p=0.042) groups at 4 hours. At 8 hours, in comparison to the saline group, there was significantly more motor block in the ropivacaine 0.2% (p=0.005) and 0.3% (17=0.018) groups. There were no patients in the saline group and two patients in the ropivacaine 0.1% group with residual motor block after 21 hours. At this time point the difference in intensity of motor block between the ropivacaine 0.3% group and the saline (p=0.066) and ropivacaine 0.1% (p=0.050) groups were statistically significant. Quality o f treatment The great majority of the parents in the ropivacaine groups rated the treatment as excellent or good at all three assessments. In the saline group only 33% of patients rated the treatment as excellent or good at 4 hours but at 8 and 21 hours, 67% of patients rated treatment as excellent or good. The quality of treatment was significantly higher (p<0.05) in the ropivacaine groups than in the saline group at 4 hours whereas no statistically significant differences were found at 8 or 21 hours. It is likely that the lower satisfaction rating in the saline group at 4 hours was due to the fact that at this time the residual analgesia from the initial epidural injection was wearing off and the patients had not yet had sufficient time to titrate their PCA morphine dose to produce satisfactory analgesia. Adverse events Most adverse events were of mild or moderate intensity. The most common adverse events during the epidural infusion were nausea and vomiting (Table 3). Serious adverse events were reported for five patients and the causal relationship to ropivacaine was judged unlikely in each. In the ropivacaine 0.1% group, one patient sustained a pulmonary embolus and one patient experienced nausea and vomiting resulting in p r o l o n g e d hospitalisation. In the ropivacaine 0.3% group, congestive cardiac failure developed in one patient and deep vein thrombosis occurred in another. Deep vein thrombosis also occurred in one saline treated patient.
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Ropivacaine: A dose-finding study Muldoon et al morphine consumption was highest in the saline (n=12) group. A dose dependent relationship for PCA Nausea 3 5 3 morphine was evident Vomiting 3 2 3 for the 0-4 and 4-8 Hypotension 2 2 0 hour intervals. Although this did not extend to Table 3: Adverse events during the extradural infusion (alt patients treated). the 8-21 hour interval, it is conceivable that this Discussion is due to the marked variation in the PCA morphine In the present study, continuous epidural infusion of requirement of the ropivacaine 0.2% group which ropivacaine produced well-tolerated postoperative has been described above. pain relief following major orthopaedic surgery. Pain Comparison of VAS scores confirmed the efficacy relief from epidural ropivacaine combined with PCA of continuous epidural infusion of ropivacaine. The morphine was superior to PCA morphine alone. highest median score among the ropivacaine groups
Saline 0.1% (n=13)
Ropivacaine 0.2% (n=11)
Ropivacaine 0.3% (n=12)
The results of other studies have been variable, Turner et al, 6 using various infusion rates of 0.2% ropivacaine found that motor blockade and urinary retention increased with higher infusion rates but that the analgesia did not improve. Badner et al, 7 using 0.1, 0.2 and 0.3% ropivacaine infusions could not demonstrate any differences in the analgesic properties of the three concentrations. This is in agreement with Stienstra's findings, 8 but the latter commented that the 0.2% ,solution was superior in view of a lower incidence of complete motor block and fewer high sensory blocks. PCA opioid consumption is widely used as an indicator of efficacy o f postoperative analgesic regimens. The process is a dynamic one in which analgesic administration is titrated to provide optimal pain relief according to the patient's o w n requirements. One constraint to the use of PCA in this manner, however, is inter-patient variability in analgesic demand. 9 This observation was apparent in the present study. In particular, there was a marked variation in m o r p h i n e c o n s u m p t i o n in the ropivacaine 0.2% group during the 8-21 hour interval. One patient in this group appears to have had a non-functional block, in which case PCA morphine would have been the patient's only source of pain relief. A second patient in the 0.2% group was also n o t e d to have an e x c e p t i o n a l l y high morphine consumption, these two accounting for the difference in overall consumption of the 0.2% group. At the end o f the 21 h o u r infusion p e r i o d ,
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Ropivacaine
was 10 mm. This was recorded in the 0.3% group during the 8-21 hour interval. There were no statistically significant differences b e t w e e n the ropivacaine groups. In the saline group, the median VAS score was 0 mm at 2 hours. At this time, sensory block from the ropivacaine administered for surgery was still evident. The median VAS score then increased to between 33 mm and 14 mm during the rest of the study period. No statistically significant differences in the degree of sensory block was apparent between the ropivacaine groups. Sensory block regression, however, tended to be dose dependent. In the saline group, sensory block had completely resolved by 6 hours. With the infusion rate fixed at 10 ml/hr, motor block tended to be of longer duration and of greater intensity in the ropivacaine 0.2% and 0.3% groups. Moreover, motor block in patients of the ropivacaine 0.2% and 0.3% groups was significantly greater when compared to motor block in patients of the saline and ropivacaine 0.1% groups. The motor block evident in a small percentage of the saline treated patients at 4 hours, as with the sensory block, probably reflects a residual effect o f the intraoperative ropivacaine. The quality of treatment scores were higher in patients who received epidural ropivacaine infusion than in the saline group and were independent of the incidence and degree of motor block. There were no significant differences b e t w e e n the ropivacaine groups. Nausea and vomiting, which are commonly experienced after major, surgery, were the most
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Ropivacaine: A dose-finding study Muldoon et al common adverse events in the present study and were not related to study treatment.
References
T h e results o f the present study show that morphine consumption and pain scores were lower in the ropivacaine groups than in the saline control group. The difference was more apparent in the first 8 hours of postoperative infusion, when significant differences between the ropivacaine 0.2% and 0.3% groups and the saline group were detected.
1. Brockway MS, Bannister J, McClure JH, McKeown D, et al. Comparison of epidural ropivacaine and bupivacaine. BrJ Anaesth 1991; 66:31-37. 2. Pitkanen M, Covino BG, Feldman HS, Arthur GR. Chronotropic and inotropic effects of ropivacaine, bupivacaine and lidocaine in the spontaneously beating and electrically paced isolated, perfused rabbit heart. Reg Anesth 1992; 17: 183-192. 3. Scott DB, Lee A, Fagan D, Bowler GM1K, et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 1989; 69: 563-569. 4. Bader AM, Datta S, Flanaghan H, Covino BG. Comparison of bupivacaine and ropivacaine induced conduction blockade in the isolated rabbit vagus nerve. Anesth Analg 1989; 68: 724-727. 5. Morrison LMM, Emanuelsson BM, McClure JH, Pollock AJ, et at. Efficacy and kinetics of extradural ropivacaine: Comparison with bupivacaine. B r J Anaesth 1994; 72: 164-169. 6. Turner G, Blake D, Buckland M, Chamley P, et al. Continuous extradural infusion of ropivacaine for the prevention of postoperative pain after major orthopaedic surgery. BrJAnaesth 1996; 76: 606-610. 7. Badner NH, Reid D, Sullivan P, Ganapathy S, et al. Continuous epidural infusion of ropivacaine for the prevention of postoperative pain after major orthopaedic surgery: A dose finding study. Can J Anaesth 1996; 43: 17-22. 8. Stienstra R, van KleefJW, Brouwer RP, Burm AGL, et al. Postoperative epidural analgesia with ropivacaine 0.2% versus 0.3% after major orthopaedic surgery: A double-blind clinical evaluation. Reg Anesth 1997; 22: 80. 9. Ferrante M. Commentary: Patient-controlled analgesia. In: Max M B, Portenoy R K, Laska E M, (Eds). Aduances in pain researcl7 and therapy. The design of analgesic clinical trials. New York: Raven Press, 1991; 18: 525-532.
Following orthopaedic surgery, it is important for patients to be able to comply with mobilisation regimes from an early stage. It would therefore be of interest to evaluate pain scores on mobilisation when ropivacaine is administered for surgery and as a continuous epidural infusion for postoperative pain relief. A further area of interest would be to evaluate infusions o f a single s o l u t i o n o f ropivacaine combined with an opioid. It may be postulated that this strategy would facilitate lower concentrations of ropivacaine while still providing optimal analgesia with minimal motor block. In conclusion, c o n t i n u o u s 21 h o u r epidural infusion o f ropivacaine, c o m b i n e d w i t h P C A morphine, provides efficacious and well-tolerated postoperative pain relief following major orthopaedic surgery. Pain relief w i t h the c o m b i n a t i o n o f ropivacaine and PCA morphine is superior to that of P C A morphine alone. The results of this study demonstrate that for major orthopaedic surgery, using a range of concentrations, epidural infusions of 0.3% ropivacaine were associated with a lower postoperative morphine consumption but the pain scores were no better than in the other ropivacaine groups. The 0.3% group had the highest degree of motor blockade.
Acknowledgement This study was supported by a grant from Astra Pain Control AB, S6dert~lje, Sweden.
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Continuous epidural infusion of ropivacaine for the prevention of postoperative pain after major orthopaedic surgery: A dose-finding study Terry Muldoon, FtLCA (1) Paul McConaghy, FFARCSI (1) Alexander tL Binning, F R C A (2) Charles B Wallis, F1KCA (2) J Dennis 1K Connolly, FFAILCSI 0) Kevin 1K Milligan, MD, PhD, FFARCSI 0) Jonathan Bannister, MD, FtLCA (2) tLoisin A Armstrong, P h D (3)
Abstract The present study investigated the dose relationship of ropivacaine with regard to analgesia and motor block when administered as a continuous 21 hour epidural infusion following major orthopaedic surgery. Forty six patients scheduled for elective total knee or hip arthroplasty were compared in this doubleblind study. Patients were randomly assigned to one of four treatment groups: saline (n=12); ropivacaine 0.1% (n= 11); ropivacaine 0.2% (n= 12); ropivacaine 0.3% (n= 11). Initial epidural analgesia was established with 0.5% ropivacaine and general anaesthesia was then induced for surgery. Within 30 minutes of the end of surgery, epidural infusions were commenced at a rate of 10 ml/hour for 21 hours. All patients had access to PCA morphine. Morphine consumption, VAS pain scores at rest, sensory and motor block and overall quality of treatment were assessed at regular intervals. The morphine consumption and VAS scores were lower overall in the ropivacaine groups than in the group receiving only PCA morphine. The difference was more evident during the first 8 hours of postoperative infusion, when significant differences between the ropivacaine 0.2% and 0.3% groups and the saline group were found. The incidence and degree of motor block were dose dependent. There was significantly higher patient satisfaction in all ropivacaine groups compared to the saline control group. In conclusion, 21 hour epidural infusion of ropivacaine, combined with PCA morphine, provides effective pain relief following major joint surgery and without significant adverse events. Morphine consumption and pain scores were lowest in the 0.3% ropivacaine group but this group had a higher degree of motor block. Pain relief with the combination of ropivacaine and PCA morphine is superior to that of PCA morphine alone. Acute Pain i998; I (2): 13-19. Keywords: anaesthetics, local: ropivacaine; anaesthetic techniques: epidural; postoperative analgesia
Continuous epidural infusion of a low concentration of local anaesthetic, either alone or in combination
with an opioid, is widely used for the prevention of postoperative pain. For optimal analgesia, the epidural block should be established in connection with the surgical procedure.
(1) Department of Anaesthetics, Musg,rave Park Hospital, Belfast, Northern Ireland, UK (2) Department of Anaesthetics, Ninewetls Hospital, Dundee, Scotland, UK (3) Astm Clinical Research Unit, Edinburgh, Scotland, UK.
Ropivacaine (1-propyl-2" 6"-pipecoloxylidide hydrochloride) is a new, long-acting local anaesthetic w h i c h is closely related to amide type local anaesthetics such as bupivacaine and mepivacaine. Ropivacaine is the first agent, however, to be
Introduction
Acute Pain
Volume 1 (2) March 1998
13
Ropivacaine: A dose-finding study Muldoon et al commercially available as the pure enantiomer as opposed to a racemate. Although ropivacaine has sensory nerve blocking properties comparable to those ofbupivacaine, 1 clinical and animal studies have shown it to have a lower cardiac toxicity 2,3 and a greater separation of motor and sensory block than bupivacaine.4, s These properties suggest that ropivacaine may offer advantages over bupivacaine w h e n administered as an epidural infusion for postoperative pain relief following surgery. The present study was undertaken to investigate the dose relationship of ropivacaine with regard to analgesia, and motor block when administered as a continuous 21 hour epidural infusion following major o r t h o p a e d i c surgery. Since ropivacaine produces a sensory block comparable to that of bupivacaine, 2 the concentrations and infusion rate chosen were similar to those employed previously for bupivacaine.
Methods Forty six patients (ASA Dill, age range 18-80 years) undergoing elective knee or hip arthroplasty were evaluated in this double-blind study. Eligible patients were those scheduled for total hip arthroplasty or total knee arthroplasty, aged between 18 and 80 years, ASA status I to Ill and weight 50 to 110 kg. Patients were not enrolled if there was any contraindication to epidural anaesthesia or communication difficulties which would have prevented reliable postoperative assessments. The study was conducted at Ninewells Hospital, Dundee, Scotland (centre 1) and the Musgrave Park Hospital, Belfast, Northern Ireland (centre 2). Approval for the study was obtained from the local Ethics Research Committee at both centres. The patients were visited on the day prior to surgery and the purpose of the study was explained. The patients were tutored in the use of a Visual Analogue Scale Ruler (Biomedical Engineering, Flinders Medical Centre, Adelaide, Australia) consisting of a 100 mm horizontal line ungraded with the ends marked 'no pain' (0 mm) and 'worst possible pain' (100 ram). Patients are able to move a pointer along the ruler to mark the distance from the 'no pain' end which corresponds to the intensity of the pain felt. On the reverse side is a line marked with graduations in mm for quick reading. The
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patients were also shown how to use an Abbott LifecareTM PCA pump. After gaining written i n f o r m e d consent, the patients were randomised to one of four postoperative epidural infusion groups: 1. 0.9% saline 2. 0.1% ropivacaine 3. 0.2% ropivacaine 4. 0.3% ropivacaine Temazepam 20 mg was administered as premedication 1 to 2 hours prior to the induction of anaesthesia. O n arrival in the operating theatre an epidural catheter was inserted in the L2-3 or L3-4 interspace. A 3 ml test dose of ropivacaine 0.5% was used to exclude inadvertent dural puncture. On confirming satisfactory placement of the catheter, 10-15 mls of ropivacaine 0.5% was injected in incremental doses over a five minute period. If surgical anaesthesia to T10 was not achieved 30 minutes after the main dose, a further 5 ml ofropivacaine 0.5% was injected. All patients then underwent urinary catheterisation, it being a routine practice in our centres. Once block to T10 was obtained, general anaesthesia was i n d u c e d w i t h intravenous t h i o p e n t o n e , atracurium and fentanyl. General anaesthesia was maintained with isoflurane 1-2%, nitrous oxide 65% in oxygen. Further 5 ml doses of ropivacaine 0.5% could be administered if the patient showed signs of inadequate analgesia. At the end of surgery, defined as the completion of the last suture to the skin incision, the patient was transferred to a dedicated high dependency unit where trained nursing staff" assessed the parameters as shown below. Within 30 minutes of the end of surgery an epidural infusion of study solution was commenced at a rate of 10 ml/hr and continued for 21 hours. The solution was administered in a double-blind manner. All patients had access to intravenous m o r p h i n e delivered by a patientcontrolled analgesia (PCA) device programmed to deliver 1 mg bolus doses of morphine with a five minute lockout. No other analgesic was permitted during the study period. Assessments, timed from the beginning of the epidural infusion, were as follows: • PCA morphine consumption for time intervals 0-4, 4-8 and 8-21 hours.
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Ropivacaine: A dose-finding study Muldoon et al • W o u n d pain (VAS score) at rest at 4, 8 and 21 hours. • Overall quality o f t r e a t m e n t , w i t h regard to analgesia, as judged by the patient, at 4, 8 and 21 hours. Quality of treatment was assessed using the scale: 1=poor; 2=fair; 3=good; 4=excellent. • Sensory block, determined bilaterally using a short bevelled 27G needle, every 2 hours from the start of the epidural infusion until 22.00 hours on the day o f surgery. Assessments were discontinued during the night to permit the patients to sleep. Assessments were then r e c o m m e n c e d at 08.00 hours the following morning and were performed every hour until return of normal sensation. • Motor block was determined at the same time as sensory block using the modified Bromage scale: 0=no motor block; 1=inability to raise extended legs; 2=inability to flex knees (able to move foot only); 3=inability to flex ankle joints (unable to move foot or knee). Heart rate and blood pressure were m o n i t o r e d throughout the study and recorded at the start of the continuous infusion and thereafter every hour until return o f n o r m a l sensation and m o t o r function. Adverse events, s p o n t a n e o u s l y r e p o r t e d by the patient or observed by the staff, were recorded. An open, standardised question regarding adverse events was asked at the end o f the infusion, at time o f discharge and by phone 2-3 weeks after surgery. This question was 'Have you been bothered by anything (after surgery/after the infusion was stopped/during
the hospital stay and since discharge f r o m the hospital, respectively)'.
Statistical analysis Two approaches to the statistical analysis were used: a per protocol analysis and an all patients treated analysis. Patients were e x c l u d e d f r o m the per protocol analysis in the case of technical failure, if the patient did not receive any study drug, or any major protocol violation which resulted in loss of efficacy data likely to influence the validity of data. M o r p h i n e c o n s u m p t i o n , VAS scores, overall quality of treatment scores, sensory block and motor block were compared by non-parametric Wilcoxon rank sum tests. As there were no available data on morphine consumption under similar circumstances and a sample size could n o t be calculated w i t h consideration to statistical power, 48 patients (12 per treatment group) were to be included in the per protocol analysis. This was considered to be a fair sample size, with a potential to detect a dose response relationship. The four study groups were stratified for centre and comparisons were p e r f o r m e d in a pairwise manner. Tests were two-tailed and performed at a significance level of 0.05.
Results A total of 48 patients received postoperative study treatment, of w h o m 46 were valid for the analysis. For the two patients excluded, violation of the study
Table 1: Patient characteristics (all patients treated)
Saline (n=13)
Ropivacaine 0.1% (n=ll)
Ropivacaine 0.2% (n=12)
Age [yrs] mean (range)
68.5 (64-73)
62 (40-75)
59.5 (33-75)
65.8 (54-75)
Height [cms] mean (SD)
167.8 (145-185)
168.5 (152-185)
165.9 (155-179)
167.8 (158-180)
Weight [kgs] mean (SD)
80.6 (18.1)
75.1 (15.4)
71.3 (16.9)
73.2 (13.5)
ASA Status I II III
4 6 3
4 6 1
3 7 2
4 7 1
Sex - M:F
8:5
6:5
5:7
4:8
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Ropivacaine: A dose-finding study Muldoon et al inclusion criteria occurred in one (saline) and an inadequate sensory block spread prior to surgery occurred in the second (ropivacaine 0.3%). There were no differences among the groups with regard to age, sex, height, weight and ASA status (Table 1). Duration and type of surgery, time to start of epidural infusion and the total volume and type of intravenous fluids administered were similar across the groups. The ratio of hips to knees was exactly the same in the treatment groups with three knees and nine hips in each. The majority of patients did n o t receive fentanyl but in those that did, the amount administered for induction and maintenance of general anaesthesia was similar in all groups. In addition, the groups were similar with regard to the
mean total dose of 0.5% ropivacaine administered intra-operatively (84.6 mg-91.8mg).
Morphine consumption The median m o r p h i n e c o n s u m p t i o n during the three periods analysed is presented in Table 2. In the 0-4 hour time period, there were 4, 6 and 6 patients in the ropivacaine 0.1%, 0.2% and 0.3% groups respectively who did not take any morphine. In the saline group, all patients t o o k m o r p h i n e except one. M o r p h i n e consumption in the ropivacaine 0.2% group was significantly lower than in the saline group (p=0.01). There were no significant differences between any of the ropivacaine groups.
Table 2: Summary of morphine consumption, VAS scores at rest, sensory block spread and motor block Ooerprotocol patients * Significant differencefiom saline (p
Saline n=12
Ropivacaine 0.1% n=11
Ropivacaine 0.2% n=12
Ropivacaine 0.3% n=11
Morphine consumption [mg] (PCA) median (SD) 0-4 hours 4-8hours 8-21 hours
9.0 (8) 10.5 (5.7) 17.5 (10.9)
2.0 6.2) 3.0 (6.7) 12.6 (9.5)
0.5 (3.2)* 1.5 (6.4)* 25.8 (15.2)
0.0 (14.5) 0.0 (2.6)* 4.0 (6.2)**
Pain scores (VAS) at rest [mm] median (SD) 4 hours 8 hours 21 hours
33 (23) 2t (27) 29 (22.8)
0 (23.9) 2 (20) 0 (31.7)
0 (19.5)* 0 (25.3)* 6.8 (21.5)
0 (18.4)* 0 (25.1) 10 (20.0)
L1-L2
T10 T12 L2
T12 T12-L1 L2
T10 T10 T12
$1 L4-L3 L3
$1 L5 L5
$1 L5 L5
64 27 0 9 82 18 0 0 82 18 0 0
25 17 41 17 42 8 42 8 42 49 9 0
36 19 36 9 46 9 36 9 45 19 27 9
Sensory block pin-prick Upper spread 4 hours 8 hours 21 hours Lower spread
4 hours 8 hours 21 hours
Motor block Bromage score (% of patients) 4 hours
8 hours
21 hours
16
0 1 2 3 0 1 2 3 0 1 2 3
67 25 8 0 92 8 0 0 100 0 0 0
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Ropivacaine: A dose-finding study Muldoon et al In the 4-8 hour time period, there were 4, 4 and 6 patients in the ropivacaine 0.1%, 0.2% and 0.3% groups respectively who did not take any morphine. In the saline group, all patients took morphine except one. Morphine consumption was significantly lower in both the ropivacaine 0.2% and 0.3% groups than in the saline group (p=0.022 and p=0.006 respectively). There were no significant differences between any of the ropivacaine groups. In the 8-21 hour time period, there were 1, 1 and 3 patients in the ropivacaine 0.1%, 0.2% and 0.3% groups respectively who did not take any morphine. During the same interval, morphine was taken by all patients in the saline group. Morphine consumption in the 0.3% group was significantly lower than both the saline group (p=0.032) and the ropivacaine 0.2% group (1o=0.045). Pain at rest The groups were compared at 4, 8 and 21 hours after commencing the epidural infusion (Table 2). At 4 hours, significantly l o w e r VAS scores occurred in the ropivacaine 0.2% and 0.3% groups than in the saline group (p=0.015 and p=0.044 respectively). At 8 hours, only the difference between the ropivacaine 0.2% group and the saline group was statistically significant (p=0.045). At 21 hours there were no statistically significant differences between the four treatment groups. Sensory block Upper and lower sensory block spread during the 21 hour epidural infusion, as determined by pin-prick, is presented in Table 2. Sensory block spread decreased in all groups during the infusion. In the saline group, the block had c o m p l e t e l y resolved by 6 hours. In the ropivacaine groups, the sensory block decreased from T8 to T l l at 2 hours after infusion start to between T10 and L2 at 10 hours. At 21 hours the median upper spread was T12 for the ropivacaine 0.3% group and L2 for the 0.1% and 0.2% groups. The lower spread decreased to a median of L3 for the 0.1% group and to L5 for the other two groups. M o t o r block The results of the m o t o r block assessments are presented in Table 2.
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There was a significant difference in motor block between the ropivacaine 0.2% group and both the saline (p=0.01) and ropivacaine 0.1% (p=0.042) groups at 4 hours. At 8 hours, in comparison to the saline group, there was significantly more motor block in the ropivacaine 0.2% (p=0.005) and 0.3% (17=0.018) groups. There were no patients in the saline group and two patients in the ropivacaine 0.1% group with residual motor block after 21 hours. At this time point the difference in intensity of motor block between the ropivacaine 0.3% group and the saline (p=0.066) and ropivacaine 0.1% (p=0.050) groups were statistically significant. Quality o f treatment The great majority of the parents in the ropivacaine groups rated the treatment as excellent or good at all three assessments. In the saline group only 33% of patients rated the treatment as excellent or good at 4 hours but at 8 and 21 hours, 67% of patients rated treatment as excellent or good. The quality of treatment was significantly higher (p<0.05) in the ropivacaine groups than in the saline group at 4 hours whereas no statistically significant differences were found at 8 or 21 hours. It is likely that the lower satisfaction rating in the saline group at 4 hours was due to the fact that at this time the residual analgesia from the initial epidural injection was wearing off and the patients had not yet had sufficient time to titrate their PCA morphine dose to produce satisfactory analgesia. Adverse events Most adverse events were of mild or moderate intensity. The most common adverse events during the epidural infusion were nausea and vomiting (Table 3). Serious adverse events were reported for five patients and the causal relationship to ropivacaine was judged unlikely in each. In the ropivacaine 0.1% group, one patient sustained a pulmonary embolus and one patient experienced nausea and vomiting resulting in p r o l o n g e d hospitalisation. In the ropivacaine 0.3% group, congestive cardiac failure developed in one patient and deep vein thrombosis occurred in another. Deep vein thrombosis also occurred in one saline treated patient.
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Ropivacaine: A dose-finding study Muldoon et al morphine consumption was highest in the saline (n=12) group. A dose dependent relationship for PCA Nausea 3 5 3 morphine was evident Vomiting 3 2 3 for the 0-4 and 4-8 Hypotension 2 2 0 hour intervals. Although this did not extend to Table 3: Adverse events during the extradural infusion (alt patients treated). the 8-21 hour interval, it is conceivable that this Discussion is due to the marked variation in the PCA morphine In the present study, continuous epidural infusion of requirement of the ropivacaine 0.2% group which ropivacaine produced well-tolerated postoperative has been described above. pain relief following major orthopaedic surgery. Pain Comparison of VAS scores confirmed the efficacy relief from epidural ropivacaine combined with PCA of continuous epidural infusion of ropivacaine. The morphine was superior to PCA morphine alone. highest median score among the ropivacaine groups
Saline 0.1% (n=13)
Ropivacaine 0.2% (n=11)
Ropivacaine 0.3% (n=12)
The results of other studies have been variable, Turner et al, 6 using various infusion rates of 0.2% ropivacaine found that motor blockade and urinary retention increased with higher infusion rates but that the analgesia did not improve. Badner et al, 7 using 0.1, 0.2 and 0.3% ropivacaine infusions could not demonstrate any differences in the analgesic properties of the three concentrations. This is in agreement with Stienstra's findings, 8 but the latter commented that the 0.2% ,solution was superior in view of a lower incidence of complete motor block and fewer high sensory blocks. PCA opioid consumption is widely used as an indicator of efficacy o f postoperative analgesic regimens. The process is a dynamic one in which analgesic administration is titrated to provide optimal pain relief according to the patient's o w n requirements. One constraint to the use of PCA in this manner, however, is inter-patient variability in analgesic demand. 9 This observation was apparent in the present study. In particular, there was a marked variation in m o r p h i n e c o n s u m p t i o n in the ropivacaine 0.2% group during the 8-21 hour interval. One patient in this group appears to have had a non-functional block, in which case PCA morphine would have been the patient's only source of pain relief. A second patient in the 0.2% group was also n o t e d to have an e x c e p t i o n a l l y high morphine consumption, these two accounting for the difference in overall consumption of the 0.2% group. At the end o f the 21 h o u r infusion p e r i o d ,
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Ropivacaine
was 10 mm. This was recorded in the 0.3% group during the 8-21 hour interval. There were no statistically significant differences b e t w e e n the ropivacaine groups. In the saline group, the median VAS score was 0 mm at 2 hours. At this time, sensory block from the ropivacaine administered for surgery was still evident. The median VAS score then increased to between 33 mm and 14 mm during the rest of the study period. No statistically significant differences in the degree of sensory block was apparent between the ropivacaine groups. Sensory block regression, however, tended to be dose dependent. In the saline group, sensory block had completely resolved by 6 hours. With the infusion rate fixed at 10 ml/hr, motor block tended to be of longer duration and of greater intensity in the ropivacaine 0.2% and 0.3% groups. Moreover, motor block in patients of the ropivacaine 0.2% and 0.3% groups was significantly greater when compared to motor block in patients of the saline and ropivacaine 0.1% groups. The motor block evident in a small percentage of the saline treated patients at 4 hours, as with the sensory block, probably reflects a residual effect o f the intraoperative ropivacaine. The quality of treatment scores were higher in patients who received epidural ropivacaine infusion than in the saline group and were independent of the incidence and degree of motor block. There were no significant differences b e t w e e n the ropivacaine groups. Nausea and vomiting, which are commonly experienced after major, surgery, were the most
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Ropivacaine: A dose-finding study Muldoon et al common adverse events in the present study and were not related to study treatment.
References
T h e results o f the present study show that morphine consumption and pain scores were lower in the ropivacaine groups than in the saline control group. The difference was more apparent in the first 8 hours of postoperative infusion, when significant differences between the ropivacaine 0.2% and 0.3% groups and the saline group were detected.
1. Brockway MS, Bannister J, McClure JH, McKeown D, et al. Comparison of epidural ropivacaine and bupivacaine. BrJ Anaesth 1991; 66:31-37. 2. Pitkanen M, Covino BG, Feldman HS, Arthur GR. Chronotropic and inotropic effects of ropivacaine, bupivacaine and lidocaine in the spontaneously beating and electrically paced isolated, perfused rabbit heart. Reg Anesth 1992; 17: 183-192. 3. Scott DB, Lee A, Fagan D, Bowler GM1K, et al. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 1989; 69: 563-569. 4. Bader AM, Datta S, Flanaghan H, Covino BG. Comparison of bupivacaine and ropivacaine induced conduction blockade in the isolated rabbit vagus nerve. Anesth Analg 1989; 68: 724-727. 5. Morrison LMM, Emanuelsson BM, McClure JH, Pollock AJ, et at. Efficacy and kinetics of extradural ropivacaine: Comparison with bupivacaine. B r J Anaesth 1994; 72: 164-169. 6. Turner G, Blake D, Buckland M, Chamley P, et al. Continuous extradural infusion of ropivacaine for the prevention of postoperative pain after major orthopaedic surgery. BrJAnaesth 1996; 76: 606-610. 7. Badner NH, Reid D, Sullivan P, Ganapathy S, et al. Continuous epidural infusion of ropivacaine for the prevention of postoperative pain after major orthopaedic surgery: A dose finding study. Can J Anaesth 1996; 43: 17-22. 8. Stienstra R, van KleefJW, Brouwer RP, Burm AGL, et al. Postoperative epidural analgesia with ropivacaine 0.2% versus 0.3% after major orthopaedic surgery: A double-blind clinical evaluation. Reg Anesth 1997; 22: 80. 9. Ferrante M. Commentary: Patient-controlled analgesia. In: Max M B, Portenoy R K, Laska E M, (Eds). Aduances in pain researcl7 and therapy. The design of analgesic clinical trials. New York: Raven Press, 1991; 18: 525-532.
Following orthopaedic surgery, it is important for patients to be able to comply with mobilisation regimes from an early stage. It would therefore be of interest to evaluate pain scores on mobilisation when ropivacaine is administered for surgery and as a continuous epidural infusion for postoperative pain relief. A further area of interest would be to evaluate infusions o f a single s o l u t i o n o f ropivacaine combined with an opioid. It may be postulated that this strategy would facilitate lower concentrations of ropivacaine while still providing optimal analgesia with minimal motor block. In conclusion, c o n t i n u o u s 21 h o u r epidural infusion o f ropivacaine, c o m b i n e d w i t h P C A morphine, provides efficacious and well-tolerated postoperative pain relief following major orthopaedic surgery. Pain relief w i t h the c o m b i n a t i o n o f ropivacaine and PCA morphine is superior to that of P C A morphine alone. The results of this study demonstrate that for major orthopaedic surgery, using a range of concentrations, epidural infusions of 0.3% ropivacaine were associated with a lower postoperative morphine consumption but the pain scores were no better than in the other ropivacaine groups. The 0.3% group had the highest degree of motor blockade.
Acknowledgement This study was supported by a grant from Astra Pain Control AB, S6dert~lje, Sweden.
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