COMPARISON OF EXTRADURAL ROPIVACAINE AND BUPIVACAINE

Transcription

1 British Journal of Anaesthesia 99; : -7 COMPARISON OF EXTRADURAL ROPIVACAINE AND BUPIVACAINE M. S. BROCKWAY, J. BANNISTER, J. H. McCLURE, D. McKEOWN AND J. A. W. WILDSMITH SUMMARY Ropivacaine, a new long acting amide type local anaesthetic, was compared with bupivacaine in a randomized double-blind study. One hundred and ten patients undergoing extradural anaesthesia received a test dose of ml of % lignocaine with adrenaline which was followed by 5 ml of one of five solutions:.5,.75 or.% ropivacaine or.5 or bupivacaine. There was little difference between the groups with respect to speed of onset or sensory block. The duration of analgesia was increased by increasing the concentration of both drugs, but this had minimal effect on onset time or extent of block. When the same concentration of each drug was administered, there were inconsistent differences in duration of sensory block, none of which was statistically significant. Increasing concentration of both drugs resulted in greater degree and longer duration of motor block. Ropivacaine produced a slower onset, shorter duration and less intense motor block than the same concentration of bupivacaine. The cardiovascular changes were similar in all groups. KEY WORDS Anaesthetic techniques: extradural. Anaesthetics, ropivacaine. bupivacaine. local: Ropivacaine (S-( )- -propyl-','-pipecoloxylidide hydrochloride monohydrate) is a new, long acting, amide type local anaesthetic agent which has a chemical structure similar to that of bupivacaine, the butyl group being replaced by a propyl group []. It also differs in that it is prepared as the S isomer rather than as a racemic mixture. Ropivacaine is less lipid soluble than bupivacaine and in vitro comparisons [.] have shown it to be slightly less potent. However, in vivo animal studies have suggested that the central administration of both drugs produces similar patterns of onset and extent of sensory block, but that ropivacaine has a shorter duration of action [] and causes less motor block []. The vasoconstrictor properties of ropivacaine [5] were perhaps responsible for the longer duration of action seen when it was used for infiltration or peripheral nerve block [, 5, ]. In man, ropivacaine has been used successfully for both brachial plexus [7] and extradural block [8, 9]. These open studies indicated that the drug produced effective analgesia and that motor block appeared to regress considerably more rapidly than sensory. The duration of sensory analgesia provided by ropivacaine has been shown to be increased with greater concentration [9]. In addition, ropivacaine at similar plasma concentrations has been shown to be less cardiotoxic than bupivacaine in both animals [] and man []. Thus ropivacaine would have a better therapeutic ratio, if the drugs are of equivalent potency. This study was designed to provide a double-blind comparison of ropivacaine with bupivacaine in extradural block. PATIENTS AND METHODS After Ethics Committee approval, we studied patients (ASA I II, ages 8-7 yr) undergoing elective urological, gynaecological, orthopaedic or M. S. BROCKWAY, F.F.A.R.C.S.; J. BANNISTER*, F.F.A.R.C.S.; J. H. MCCLURE, B.SC, F.F.A.R.C.S. ; D. MCKEOWN, F.F.A.R.C.S. ; J. A. W. WILDSMITH, M.D., F.F.A.R.C.S. ; Department of Anaesthesia, Royal Infirmary, Lauriston Place, Edinburgh EH 9YW. Accepted for Publication: April 7, 99. Correspondence to J.A.W.W. * Present address: Department of Anaesthesia, Ninewells Hospital and Medical School, Dundee.

2 BRITISH JOURNAL OF ANAESTHESIA varicose vein surgery under extradural block. After giving written, informed consent the patients were allocated randomly in a doubleblind manner to one of the following five groups:.5 % Ropivacaine 5 ml (75 mg) Ropivacaine 5 ml (.5 mg).% Ropivacaine 5 ml (5 mg) 5 ml (75 mg) 5 ml (.5 mg) A series of boxed coded ampoules was used, so that each solution group contained similar numbers of patients undergoing each type of surgery and so that each anaesthetist performed the same number of blocks with each test solution. The patients were premedicated with temazepam mg orally approximately h before anaesthesia. I.v. administration of fluids was restricted to a maximum of 5 ml before operation. With the patient in the lateral position, the skin over the rd (or nd) lumbar interspace was infiltrated with % lignocaine and the extradural space located with a -gauge Tuohy needle using midline loss of resistance to saline injection. An end-hole catheter was inserted cm in a cephalad direction. After negative aspiration for blood and CSF, a test dose of ml of % lignocaine with adrenaline : was injected and the catheter flushed with saline ml. The patient was then turned supine. Five minutes after the test dose, in the absence of any adverse sequelae, 5 ml of the study solution was injected at. ml s" with a 5-s pause between each 5 ml, so that the total injection time was min 5 s. Surgery was not commenced until at least min after injection. Sedation with propofol or midazolam, or general anaesthesia (usually with propofol and enflurane and nitrous oxide in oxygen), were used if desired or required. All assessments were related to the end of injection of the study solution (time zero). The height of sensory block was assessed on the right side using analgesia to pinprick with a 7-gauge short-bevelled dental needle. Lower limb motor block was recorded using a modified Bromage scale ( = able to straight leg raise, full flexion of knees and feet; = inability to raise leg, able to flex knees; = inability to flex knees, able to flex ankles; = inability to flex ankles). Assessments were made at, 5,, 5,, 5 and min and every min thereafter until the block had regressed completely, unless sedation, anaesthesia or restricted access during surgery prevented it. If assessments were precluded FIG. r R R LR.%. B B. The multiple group analysis: eight pairwise comparisons. B = bupivacaine; R = ropivacaine. during surgery, one was performed as soon as possible after the end of the procedure. The patient's arterial pressure and heart rate were recorded also at the time of each assessment for the first h. Analgesia and muscle relaxation during surgery were judged as satisfactory or unsatisfactory. If the patients experienced any discomfort or moved their limbs so as to interfere with surgery, the blocks were deemed unsatisfactory. If there were any obvious technical problems with the extradural injection, the patient was excluded and another recruited to the same study group; the double-blind nature of the trial was maintained. Eight pairwise comparisons were performed (fig. ) using the non-parametric techniques of Wilcoxon rank sum and Fischer's exact test as appropriate. To compensate for the multiple comparisons, a sequentially rejective Bonferroni- Holm method [] was used. This involved arranging the P values for each comparison in order and relating them to the Bonferroni-Holm rejection criteria, which for a significance of 5 % are:.5,.7,.8,.,.5,.7,.5 and.5. The smallest value of P was considered to be significant if it was less than or equal to.5. If the first was significant, the next smallest value was deemed significant if it was less than.7, and so on until one value was insignificant. A further stratified analysis using Wilcoxon rank sum test for stratified data (a test that does not presume parallel dose-response curves) was performed. This analysis involved combining the data for the.5 % and.75 % groups of each drug and comparing ropivacaine with bupivacaine (P <.5 considered significant). Two-tailed tests were used. RESULTS The groups were similar in regard to age, weight, height or gender (table I). In addition to the valid study entries, a further patients were

3 EXTRADURAL ROPIVACAINE AND BUPIVACAINE TABLE I. Patient characteristics (mean (SD)), maximum block heights and unsatisfactory blocks (in terms of other analgesia (Analg.) or muscle relaxation (Relax.) and numbers requiring general anaesthesia (GA)) Ropivacaine Group.% Age (yr) Weight (kg) Height (cm) Sex (F:M) Maximum block heights Mean (SD) Median Range Unsatisfactory blocks (n/) Number Analg. Relax. GA 55() 9 () 9 () :8 T() T T-T () 7 () 7 (9) 9: T(5) T L-C 8 () 7(9) 7 (8) : T() T T-C 8 () 8() 9 () : T() T5 T-C8 9 () 7 () 7() : T() T5 T-C Group Ropivacaine.%.5 % TABLE II. Exclusions on technical grounds n Reason I.v. injection Anatomical abnormality I.v. injection Two i.v. injection Anatomical abnormality excluded for several technical reasons (table II) after they had given informed consent. The programme did not allow continued inclusion in the study when such an event had occurred. Multiple group analysis Sensory block. All five solutions produced rapidly effective extradural block. There were no significant differences between the groups with regard to onset time at any dermatomal level (table III, fig. ). The mean upper level of block was T in each group, but the range of blocks was very wide (table I). There was a tendency towards a longer duration of sensory block at most dermatomal levels with increasing concentration of both drugs. This reached statistical significance when.75 % and.% ropivacaine were compared with at L5 and SI, and T-S5, and when bupivacaine was compared with.5 % ropivacaine between T and SI (table III, fig. ). Motor block. Onset of level motor block was significantly faster with.75 % bupivacaine than with.5 % or.75 % ropivacaine and there was a tendency towards more intense motor block with bupivacaine and with increasing concentration of each drug (table III). This was significant when.% ropivacaine was compared with at motor block level. There was also a tendency towards increased duration of motor block with increasing concentration of each drug and with bupivacaine compared with ropivacaine. However, statistical significance was obtained only when level block with.75 % bupivacaine was compared with.5 % ropivacaine (table III). Stratified analysis At T, but at no other level, ropivacaine had a significantly slower onset (P =.) and shorter duration (P =.5) of sensory block. Ropivacaine had a slower onset of levels and motor block (P =. and., respectively), less intense degree of motor block after min (P =.), and shorter duration of motor block

4 BRITISH JOURNAL OF ANAESTHESIA TABLE III. Numbers (n of ) of patients achieving sensory block and mean (SD) onset and duration times, at SI, LI and T. Numbers (n of ) of patients achieving levels, or motor block and mean {SD) onset and duration limes. * P <.5 Ropivacaine Group.% Sensory block SI LI T Motor block Level Level Level () 5 () 8() (5) () (5) (9) 8 () 5 9 () (5) * 5 () (-) () 8 (7) 8(9) 7 (9) (5) 9 (9) (5) 9 (85) (8) (8) 7 7 () 9 (5) () 7 () () (8) (5) 5 () (7) (97) 9 () 89 (7) * 8(7) () (5) () (5) () (7) 9 (55) (9) 9 (5) 9 (5) 5 (59) 79 (5) (7) (7) (87) (5) (8) 5 8() 79 (89) (5) (8) (9) 7 (9) 9(57) 5 (5) at levels and (P =. and., respectively) than bupivacaine. Miscellaneous results Cardiovascular effects. The cardiovascular changes in the first min were similar in all groups and were of the order expected with the block heights achieved. Generally, the systolic, diastolic and mean arterial pressures decreased by about % from baseline values over the first min, whereas the heart rate tended to increase over the first 5 min and thereafter decrease to slightly less than the baseline figure. There were no significant differences between any of the five groups in the five cardiovascular variables recorded. Quality of block. Subjective assessment of the suitability of the blocks for surgery revealed no significant differences between the groups, but there were more unsatisfactory blocks and general anaesthetics required with.5 % ropivacaine (table I). Plasma concentrations. Peripheral venous blood samples were taken from four patients (all exclusions) after suspected i.v. administration of the study drug. Ropivacaine base was determined in plasma using gas chromatography and a nitrogen sensitive detector at Astra Pain Control AB, Sodertalje, Sweden (Monica Bjork) (table IV). Side effects. There were similar numbers of minor side effects in each group, the commonest being backache, which was reported spontaneously by patients (%) when questioned the day after anaesthesia. For the purposes of this study, bradycardia was defined as a decrease in heart rate warranting treatment, rather than an arbitrary value. The overall incidence was 8.%, with no significant differences between groups. Nausea was reported by % of the patients, of whom % also vomited. Among the patients who did not have a urinary catheter for surgical reasons, there were only two cases of urinary retention requiring such intervention.

5 EXTRADURAL ROPIVACAINE AND BUPIVACAINE 5 (mm) (h) Tune FIG.. Segmental spread of analgesia (mean,.9 SEM) of ( ), (O) and.% ropivacaine, and ( ) and (O) bupivacaine. ( ) TABLE IV. Plasma concentrations of local anaesthetic in four patients in whom accidental i.v. administration was suspected. Drug administered, and time of withdrawal of sample Plasma Patient Time concn Drug (min) (mg litre" ) 5 Ropivacaine ml 77 Ropivacaine 5 ml 8 ml 9 5 ml DISCUSSION We have confirmed that ropivacaine administered extradurally was an effective long acting local anaesthetic. The duration of sensory block was similar to that produced by the same concentration of bupivacaine and the results have confirmed those obtained in a previous open study [9]. There were no significant differences in duration of sensory block at any dermatomal level when equal concentrations of the two drugs were compared. There was a significant prolongation of sensory block with bupivacaine (P =.5) at the T dermatome, but at no other level, when the pooled data for both drugs were compared. Duration of analgesia was increased, frequently significantly, with increasing concentration of both drugs.

6 BRITISH JOURNAL OF ANAESTHESIA The multiple group comparisons revealed that the speed of onset of analgesia was similar in all groups, at all dermatomal levels. The onset times were similar also after stratified analysis of the data, although that for bupivacaine was significantly faster at one level (T). The mean maximum block height was the same in all five groups a somewhat surprising finding, in view of the differences in dose and concentration of drug used. This result conflicts with that of the open study [9] in which after the injection of ml of solution, it was found that the maximum height was significantly lower with.5 % ropivacaine than with.75 or.%. The present study has also provided further evidence that ropivacaine produces a greater degree of differential block than bupivacaine. This is in keeping with in vitro prediction [] and early animal and clinical work [,, 9], The motor block produced by ropivacaine was slower in onset, shorter in duration and less intense. The degree of motor block and its duration increased with concentration of both drugs, although onset times were not significantly different. Analysis of the quality of block revealed no significant differences between the groups, although the ropivacaine group had more unsatisfactory blocks than the others. Despite the random allocation, the average duration of surgery was longer in this group than in any other except.75 % ropivacaine, a factor which may explain the finding. There were also more knee replacement patients in the.5 % ropivacaine group who, because of the duration of the procedure and the use of a tourniquet, experienced more unsatisfactory blocks. The plasma concentrations of drug in the four patients in whom i.v. injection was suspected were consistent with such an event, although not at a level that would cause concern. This promotes two observations. First, that the injection of ml of % lignocaine with adrenaline did not provide unequivocal evidence of i.v. catheter placement in any case; and second that the slow, incremental injection technique used for the main dose did indicate that i.v. injection had occurred without harming the patient. This method may thus be preferable to the use of a test dose. In conclusion, the results of this study confirm the suitability of ropivacaine for extradural anaesthesia in man. It appears to induce a sensory block similar to that obtained with bupivacaine, although perhaps with a slightly shorter duration of action. The motor block induced by ropivacaine was less than that of bupivacaine a finding which, when combined with its known lesser cardiotoxicity, makes ropivacaine a drug worthy of continued investigation. The finding that the rate of onset and extent of sensory block were the same in all groups was surprising in view of the range of drug and dose used. The prior administration of a small dose of lignocaine may have influenced the onset particularly, and obscured any differences. There is a need for a comparison of the two drugs in the absence of such prior medication. ACKNOWLEDGEMENTS Dr G. Bowler, Dr A. S. Buchan, Dr Colette Clark, Denise Fagan, Carol Fowler and Dr D. G. Littlcwood contributed to this studyj as did Dr D. B. Scott of Astra Pharmaceuticals. Dr Brockway was in receipt of a research fellowship from Astra Pharmaceuticals and the study was supported by Astra Alab AB, Sodertalje, Sweden. REFERENCES. Wildsmith JAW, Brown DT, Paul D, Johnson S. Structure-activity relationships in differential nerve block at high and low frequency stimulation. British Journal of Anaesthesia 989; : -5.. Bader AM, Datta S, Flanagan H, Covino BG. Comparison of bupivacaine and ropivacaine induced conduction blockade in the isolated rabbit vagus nerve. Anesthesia and Analgesia 989; 8: Akerman B, Hellberg IB, Trossvik C. Primary evaluation of the local anaesthetic properties of the amino amide agent ropivacaine (LEA ). Acta Anaesthesiologica Scandinavica 988; : Feldman HS, Covino BG. Comparative motor blocking effects of bupivacaine and ropivacaine, a new amino amide local anesthetic, in the rat and dog. Anesthesia and Analgesia 988; 7: Kopacz DJ, Carpenter RL, Mackey DC. Effect of ropivacaine on cutaneous capillary blood flow in pigs. Aneslhesiology 989; 7: Akerman B, Sandbcrg R, Covino BG. Local anesthetic efficacy of LEA an experimental xylidide agent. Aneslhesiology 98; 5: A7. 7. Winnie AP, Raza SM, Candido MD, Masters RW, Durrani Z. An exploratory study of ropivacaine with epinephrine and.55 % ropivacaine without epinephrine when used for brachial plexus anesthesia in patients undergoing surgery of the upper limb. Regional Anesthesia 989; : 7(S). 8. Thompson GE, Brown MD, Carpenter RL. Ropivacaine epidural anesthesia: An initial study in humans. Regional Anesthesia 989; : (S). 9. Whitehead E, Arrigoni B, Bannister J. An open study of

7 EXTRADURAL ROPIVACAINE AND BUPIVACAINE 7 ropivacaine in extradural anaesthesia. British Journal of Anaesthesia 99; : Arthur GR, Feldman HS, Norway SB, Doucette BA, Covino BG. Acute i.v. toxicity of LEA-, a new local anesthetic, compared to lidocaine and bupivacaine in the awake dog. Anesthesiology 98; 5: A8.. Scon DB, Lee A, Fagan D, Bowler G, Bloomfield P, Lundh R. Acute toxicity of ropivacaine compared to bupivacaine. Anesthesia and Analgesia 989; 9: Holm S. A simple sequentially rejective multiple test procedure. Scandinavian Journal of Statistics 979; : 5-7.