Efficacy and kinetics of extradural ropivacaine: comparison with bupivacaine

British Journal of Anaesthesia 1994; 72: 164-169

Efficacy and kinetics of extradural ropivacaine: comparison with bupivacaine L. M. M. MORRISON, B. M. EMANUELSSON, J. H. MCCLURE, A. J. POLLOK, D. W. MCKEOWN, M. BROCKWAY, H. JOZWIAK AND J. A. W. WILDSMITH

Ninety-one patients were allocated randomly to three groups to receive 1 % ropivacaine 10 ml, 0.5% ropivacaine 20 ml or 0.5% bupivacaine 20 ml extradurally. Intermittent sensory (pinprick) and motor (Bromage scale) assessments of the block produced were recorded, with an assessment of the quality of the block and the requirement for supplementary analgesia. There was little difference between the groups in frequency, onset, duration or spread of sensory block. However, the motor block produced by 0.5 % ropivacaine was less intense and of shorter duration than that with bupivacaine. The block produced by the smaller volume of ropivacaine was less reliable clinically than the larger, more dilute, solution and more anaesthetic supplements were required in that group. Cardiovascular changes were similar in all three groups. The peak plasma concentration of ropivacaine was significantly greater and T$ significantly shorter than those of bupivacaine, a/though no patient showed any features of systemic toxicity. The systemic kinetics of ropivacaine were not influenced significantly by varying the concentration or volume administered. (Br. J. Anaesth. 1994; 72: 164-169) KEY WORDS Anaesthetics, local, bupivacaine, ropivacaine. Pharmacokinetics: ropivacaine. Anaesthetic techniques' extradural.

Ropivacaine is a new local anaesthetic drug which has been developed as a possible alternative to bupivacaine [1]. Early clinical studies after extradural injection suggested that the sensory block produced by ropivacaine was similar to that of bupivacaine, although the motor block was less profound and of shorter duration [2, 3]. However, the majority of studies to date have involved a catheter technique and prior administration of lignocaine as a test dose. The influence of the test dose may have obscured other differences between the two drugs, such as rate of onset or quality of block, and this study was designed to avoid this complicating factor. The availability of ropivacaine in a wide range of concentrations allowed an assessment of the influence of volume and concentration on the profile of extradural block obtained with a constant dose of

drug. This allowed testing of the hypothesis proposed by Duggan and colleagues, that a small volume of a high concentration of drug might produce a less variable block than a large volume of a low concentration [4]. The final aim of this study was the evaluation of the influence of drug concentration on the kinetics of ropivacaine and to compare the kinetics with those of bupivacaine. PATIENTS AND METHOD

We studied 91 patients (ASA I—II, age range 19-70 yr) undergoing elective varicose vein or inguinal hernia surgery under extradural anaesthesia; the study was approved by the local Ethics Committee. After giving written informed consent, patients were allocated randomly to receive ropivacaine or bupivacaine 100 mg in divided doses. There were three treatment groups: 30 patients received 20 ml of ropivacaine 5 mg ml"1, 30 received 10 ml of ropivacaine 10 mg ml"1 and 31 received 20 ml of bupivacaine 5 mg ml"1. The extradural injections were performed by one of four anaesthetists and a series of boxed, numerically coded ampoules was used so that each anaesthetist performed the same number of blocks with each test solution. Ampoules of identical appearance containing 20 ml of 0.5 % ropivacaine or 0.5% bupivacaine or 10 ml of 1 % ropivacaine were used. The administration of 20-ml volumes of ropivacaine or bupivacaine was performed doubleblind, but clearly the anaesthetist performing the block knew when a 10-ml volume of 1 % ropivacaine was injected. However, all assessments were performed by an investigator who did not know which solution had been used. Approximately 1 h after premedication with oral temazepam 10-20 mg, the patient was transferred to the anaesthetic room and a vein was cannulated. No

L. M. M. MORRISON, B.SC. (HONS), F.F.A.R.C.S.I.; J. H. MCCLURE, B.SC. (HONS), F.R.C.A.; A. J. POLLOK, F.R.C.A.; D . W. McKEOWN, F.R.C.A.; M. BROCKWAY, F.R.C.A.; J. A. W. WILDSMITH, M.D.,

F.R.C.A.; Department of Anaesthetics, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh. B. M. EMANUELSSON, M.SC.PHARM., PH.D.; H. JOZWIAK, B.A.; Department of Clinical

Pharmacology, Astra Pain Control AB, Sodertalje, Sweden. Accepted for Publication: August 19, 1993. Correspondence to L.M.M.M.

Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on July 9, 2015

SUMMARY

EXTRADURAL ROPIVACAINE

Kinetic study Ten patients in each treatment group were recruited to the kinetic part of the study. Blood (5 ml) was obtained from a forearm vein on the side opposite to that used for i.v. injections before insertion of the extradural, and then 0,10,20,30,45, 60, 90 min and 2, 4, 6, 8, 10, 24, 26 and 28 h after administration of the test drug. The samples were centrifuged as soon as practicable (within 2 h of collection) and the separated plasma was stored at — 20 °C until required for measurement of drug concentration using a gas chromatographic technique [5]. This was performed by the Department of Bioanalysis at Astra Pain Control in Sodertalje, Sweden. The limit of determination was set at 15 ug litre"1 and the interassay precision (based on three different concentrations, one close to the limit of determination and two greater) was 5 % and 4 % for ropivacaine and bupivacaine, respectively. To compare the pharmacokinetics of ropivacaine

and bupivacaine bases, the following variables were derived from the individual plasma concentration time profiles: peak plasma concentration (Cmax), time to peak (rCmax) and area under the plasma concentration-time curve (AUClot). The terminal phase half-life (7p was calculated from the terminal slope by linear regression. Apparent plasma clearance was calculated assuming a bioavailability of 100% and using the dose of ropivacaine and bupivacaine base [6]. Statistical analysis Groups were compared pairwise. The null hypothesis of equal treatment effects was tested by use of a two-tailed Wilcoxon rank sum test. For qualitative variables, the hypothesis of equal proportions of the responses for the two treatments was tested by use of chi-square test. When the expected frequency in any cell was less than 5, Fisher's exact test was used. A repeated measurements analysis was performed on the % change from baseline of the cardiovascular variables heart rate, systolic and diastolic arterial pressure, mean arterial pressure and rate—pressure product. A significant treatment effect indicated that mean responses over time were different for the two groups. For all statistical tests performed, an outcome with a two-tailed P value less than or equal to 0.05 was considered statistically significant. The sample size was chosen so that any difference in mean duration of analgesia at T12 would be detected with a power of 80 %, if the true difference was at least 1 h, and a difference in the mean onset time to T12 would be detected with a power of at least 90%, if the true difference was at least 5 min. RESULTS

The mean weight was greater in the bupivacaine group (72 (SD 11.1) kg) than in the 1 % ropivacaine group (66 (13.9) kg). There were fewer women in the bupivacaine group (14) than in each ropivacaine group (20 and 19) (table I). These differences were statistically significant, but were not considered to have any effect on evaluation of the efficacy of each drug. The distribution of surgical diagnoses was similar between groups. One patient in the bupivacaine group was initially withdrawn from the study because of violation of procedure, but was later included (before the code was broken) because the violation was considered to be of minor importance (needle inserted at the fourth lumbar interspace). Onset, spread and duration of anaesthesia

All three solutions produced extradural block which was largely effective within 30 min. The median onset times for pinprick analgesia at the various dermatomal levels varied between 5 and 20 min in the 0.5 % ropivacaine group, 5 and 19 min in the 1 % ropivacaine group and 5 and 20 min in the 0.5% bupivacaine group (fig. 1). There were no significant differences in onset times for the three groups except at the L5 dermatome, where 1 % ropivacaine was significantly faster in onset than 0.5% ropivacaine (P = 0.0416) (table II). The segmental spread of pinprick analgesia with

Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on July 9, 2015

fluids were given. With the patient in the lateral position, the skin was infiltrated with 1 % lignocaine 1-2 ml and the extradural space was identified at the second or third lumbar interspace using a 16-gauge Tuohy needle and a midline loss of resistance to injection of saline, in a volume not exceeding 2-3 ml. After negative aspiration for blood and CSF, the patient received a test dose of 25 % (5 or 2.5 ml) of the test solution through the needle over 5 s. One minute after the test dose, and in the absence of any adverse sequelae, additional 25 % increments were delivered over 5 s at 55-s intervals, so that the total injection time was 3 min 5 s. After completion of the injection (time 0), the needle was removed and the patient placed supine. Surgery was not commenced until at least 30 min after the extradural injection. The upper and lower levels of analgesia were tested with a 27-gauge, short-bevel dental needle, 2 and 5 min after the injection was completed and at 5min intervals for 30 min. Thereafter, the block was assessed at 30-min intervals until it was judged to have regressed completely. Lower limb motor block was recorded using a modified Bromage scale (0 = able to raise extended leg; 1 = unable to raise extended leg, but able to flex knees; 2 = unable to flex knees, but able to flex ankles; 3 = unable to move leg), at the intervals stated above. For the first 3 h, arterial pressure and heart rate were recorded at the time of each assessment using an automatic sphygmomanometer. Episodes of hypotension (defined as a greater than 30% decrease in systolic arterial pressure) or bradycardia (heart rate less than 50 beat min"1) were recorded and treated according to the standard hospital practice. An evaluation of the quality of surgical anaesthesia and neuromuscular block was made by the investigator before surgery and judged as satisfactory or unsatisfactory. If the patient experienced any discomfort or if limb movement interfered with surgery, the block was deemed unsatisfactory. Sedation with propofol, midazolam, or both, was administered at the discretion of the anaesthetist. General anaesthesia (enflurane and nitrous oxide in oxygen) was given if the block was inadequate.

165

166

BRITISH JOURNAL OF ANAESTHESIA TABLE I. Patient data {mean {SD) [range]). * Significantly less than buptvacaine group; f Significantly fewer women than in ropivacatne groups

0.5% Ropivacaine Age (yr)

48.9 [25-70] 168.0 (8.0) [152-183] 68.4 (9.7) [51-92] 10:20

Height (cm) Weight (kg) Sex(M:F) Surgical diagnosis Varicose veins Inguinal hernia

0.5% Bupivacaine

1% Ropivacaine

42.8 [19-68] 170.5(9.7) [152-188] 72.0(11.1) [52-103]

46.9 [20-68] 167.4(9.7) [140-183] 66.0(13.9)* [39-98] 11:19

17:14t

24 6

24 6

26

5

30-,

10 -

S5

S3

SI

L5

L2

T12

T10

T8

T6

T4

FIG. 1. Median times (Ql, Q3) to onset of sensory analgesia at various dermatomal levels. • = 0.5 % Bupivacaine; 0 = 0.5% ropivacaine; • = 1 % ropivacaine. TABLE II. Summary of sensory and motor block {median [range] or No.). {95% Confidence intervals for all data are available from the authors.) Significant differences compared with: * 1 % ropivacaine, L5 (P = 00416); \1% ropivacaine, L5 (P = 0.0126); $1% ropivacaine, SI (P = 0.0194); %0.5% bupivacaine; § / % ropivacaine and 0.5% bupivacaine

0.5% Ropivacaine (n = 30)

1

/o

Ropivacaine (n = 30)

0.5% Bupivacaine (" = 31)

Sensory analgesia Onset (min) T12 L2 L5 SI

5.0 [2.0-25.0] 5.0 [2.0-12.5] 12.3 [2.0-25.0]* 15.0 [2.0-60.0]

5.0 [2.0-30.0] 5.0 [2.0-15.0] 10.0 [2.0-23.5] 7.9 [2.0-25.0]

6.3 [2.0-20.0] 5.0 [2.0-15.0] 10.0 [2.0-50.0] 10.0 [2.0-70.0]

4.5 [0.1-6.9] 4.9 [1.6-6.6] 5.8[1.5-8.0]t 5.4 [0-6.2]$ T7 [L3-T2] 25 [5-240]

4.3 [0.8-6.8] 5.0 [1.0-8.9] 6.3 [4.3-7.9] 6.3 [2.6-8.9] T7 [L2-T2] 25 [2-180]

4.8 [1.3-8.0] 5.4 [2.3-8.9] 6.6 [0.2-8.9] 5.5 [1.0-8.9] T7 [L5-T2] 25 [10-120]

26

21

27

21/30 4/30* 0/30

20/30 6/30 0/30

25/31 11/31 1/31

25(10-100] 90 [30-120]

15 [5-100] 90 [20-120]

Duration (h) T12 L2 L5 SI

Max cephalad level Time to max cephalad level (min) Satisfactory for surgery (No.) Motor block Frequency (No.) Degree 1 Degree 2 Degree 3 Onset (min) Degree 1 Degree 2 Degree 3 Duration (h) Degree 1 Degree 2 Degree 3 Satisfactory (No.)

—

—

2.6 [0 5-4.3]f 1 0 [0.5-2 0]

3.4 [0.5-6.3] 1.7 [0 5-3 7]

—

26/29

—

24/30*

20 [5-120] 90 [15-160] 120 [120] 3.7 [0.5-6.4] 1.3 [0.5-^1.0] 1.0 [1.0] 29/29

Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on July 9, 2015

20 -

EXTRADURAL ROPIVACAINE

167 TABLE III. Summary of adverse events

T4-, T5T6T7T8_ T9f T10 « Til "5 T12 c L1 0) L2 E L3-

0.5% Ropivacaine (n = 30)

1.0% Ropivacaine (n = 30)

0.5% Bupivacaine (n = 31)

8 6 4 1 0 2 0 0 0

10 2 5 0 5 2 1 1 0

4

Hypotension Backache Nausea Vomiting Bradycardia Headache Sweating Diarrhoea Difficulty in micturition

S1 S2S3S4S50

1

2

3

4 5 Time (h)

6

7

5

1 1 2, 7 0 0 1

8

time for each treatment group was broadly similar (fig. 2). The median maximum cephalad level of sensory block was T7 (table II) and the median time to reach this level was 25 min in all three groups. Although there was no statistically significant difference between each ropivacaine group and the bupivacaine group in the offset of analgesia, duration was significantly longer in the 1 % ropivacaine group than the 0.5% group at the L5 and SI derma tomes (P = 0.0126 and P = 0.0194, respectively) (table II).

0.9•T 0.8" £ = 0.7 CD

I 0.5-1 CD

c 0.4 • O

0 0.3-1

1 0-2 1 CO

£ o. H hr

1.0

Motor block

Analysis of motor block revealed no significant difference in onset times (table II). However, the duration of grade 1 motor block was significantly longer with 0.5 % bupivacaine (P = 0.0004) and 1 % ropivacaine (P = 0.0082) than with 0.5% ropivacaine (table II). The intensity of motor block also was significantly greater in the bupivacaine group, 11 patients having a grade 2 motor block, compared with only four in the 0.5 % ropivacaine group (P = 0.045). Quality of block

Global assessment of the block obtained and its adequacy for surgery revealed that the quality of block was unsatisfactory in nine patients in the 1 % ropivacaine group, compared with only four in each of the two other groups. In these patients, general anaesthesia was required before or during surgery. Analysis of the block pattern in these patients revealed that five of the nine patients in the 1 % group had missed segments which rendered the block inadequate for surgery. Although neuromuscular block was satisfactory for surgery in all the bupivacaine-treated patients, it was judged to be unsatisfactory in three patients treated with 0.5% ropivacaine and six treated with 1 % ropivacaine. The difference in block between 1 % ropivacaine and 0.5 % bupivacaine was statistically significant. Adverse events

The adverse sequelae which occurred are presented in table III. The most common events were

2 4 8 Time (h)

12

16 20 24

28

FIG. 3. Variation in mean plasma concentrations of the three test drugs with time. = 0.5% Ropivacaine 20 ml; = 1% ropivacaine 10 ml; =0.5% bupivacaine 20 ml.

hypotension (22 of 91 patients) during anaesthesia and backache and headache in the postoperative period. I.v. ephedrine was required infivepatients in the 0.5 % ropivacaine group, eight in the 1 % group and three in the 0.5% bupivacaine group and was effective in restoring arterial pressure in each one. None of the adverse events reported was severe and all patients reported complete recovery. There were no statistically significant differences between the groups in the incidence of these side effects. Kinetic results

All results were expressed as mean (SD); units " m g " represent milligrams of drug base per litre of plasma. Figure 3 shows the mean plasma concentrations of ropivacaine and bupivacaine as a function of time (no drug was detected beyond 28 h after administration) and mean values for various pharmacokinetic variables are presented in table IV. Similar values of Cmax and rCmax were obtained when ropivacaine was administered in either the 0.5 % or the 1 % form (Cmax 0.76 (0.24) mg litre"1 and 0.93 (0.30) mg litre"1; tCmax 27 (12) min and 24 (11) min, respectively); tCmax for bupivacaine was similar to values for ropivacaine (26 (11) min), but Cmax for bupivacaine was significantly smaller (0.55 (0.11) mg litre"1) (P < 0.02 compared with ropiv-

Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on July 9, 2015

FIG. 2. Median (Ql, Q3) segmental levels of sensory analgesia. = 0.5% Bupivacaine; •• •• =0.5% ropivacaine; = 1 % ropivacaine.

BRITISH JOURNAL OF ANAESTHESIA

168

TABLE IV. Pharmacokinetic data derived from analysis of plasma ropivacaine and bupivacaine concentrations (mean (SD) or median [range]). Cmax = mean peak plasma concentration; xCmax = time to occurrence of Cmax; T ^ = half-life estimations based upon the terminal slope of total concentrations of ropivacaine and bupivacaine ; Cl = apparent clearance, assuming bioavailability is 100%. Significant differences compared with bupivacaine: * P < 0.05; **P < 0.001 0.5% Ropivacaine Cmax (mg litre"1) tCmax (min) 7j (h) Cl (ml min"1)

0.76 (0.24)* 27(12) 30 [10-45] 5.5 (0.8)** 314(140)

DISCUSSION

The results of this study show that, in equal doses and concentrations, ropivacaine and bupivacaine produced a comparable, long acting sensory block. We were unable to confirm the impression of earlier studies [2, 7] that bupivacaine might produce a slightly longer duration of block. However, in both of those earlier studies a catheter technique or a lignocaine test dose, or both, were used. We found no significant differences in the duration of sensory block at any dermatomal level when 0.5 % ropivacaine and bupivacaine were compared. In spite of the quantitative limitations of the Bromage scale [8], we have been able to confirm that the motor block produced by ropivacaine was of less intensity and shorter duration than that with bupivacaine. Unlike one earlier study [2], we found no significant difference in the onset of motor block produced by ropivacaine or bupivacaine but, again, the use of lignocaine test dose in the earlier study may have influenced the results. In an analysis of the influence of volume and concentration on the types of extradural block obtained with bupivacaine, Duggan and colleagues [4] found that the range in the upper sensory level of block was narrower in patients who received 10-ml than in those who received 15-ml injections, although the difference was not significant. In spite of a larger difference in volume in our study, we were not able to confirm this trend. The onset, duration and maximum cephalad level of sensory block were similar when ropivacaine was administered in the more concentrated form. Although the objective assessment of the block revealed no statistically significant differences between the two, the more concentrated solution produced blocks which were less reliable clinically. The explanation for this is

0.93 (0.30)* 24(11) 20 [10-^15] 5.3 (2.7)* 282 (92)

0.5% Bupivacaine 0.55(0.11) 26(11) 30 [10-45] 10.6 (4.3) 301(133)

unclear, although Paul and Wildsmith's study on the influence of volume on extradural pressure may lend some support to the suggestion that a small volume of local anaesthetic may not generate sufficient pressure to allow effective distribution of solution throughout the extradural space [9], especially with the relatively slow incremental injection technique used here. Regardless of the volume administered, the Cmax of ropivacaine 100 mg (0.8-0.9 mg litre"1) was significantly greater than that of bupivacaine 100 mg (0.6 mg litre"1). The Cmax is determined by the rate of its absorption from the extradural space, its volume of distribution and its rate of elimination. In addition to the dose of drug and the site of injection (which were constant in this study), the main factors which affect the rate of uptake of a local anaesthetic are the lipid solubility and vasoactivity of the drug administered. It may be that the adipose tissue in the lumbar extradural space acted as a depot, especially for the more lipid-soluble bupivacaine, and retarded its systemic absorption to a greater degree than that of ropivacaine. Dahl and colleagues suggested that ropivacaine decreases extradural blood flow, which would be expected to result in smaller systemic concentrations [10]. However, Lee and colleagues reported a greater volume of distribution for bupivacaine (66 litre) than for ropivacaine (42 litre) after i.v. infusion in volunteers [11]. Thus the influence of the greater lipid solubility of bupivacaine on the extradural depot effect and volume of distribution would seem to outweigh the effect of ropivacaine on local blood supply. In this study rCmax was similar in all groups, but this is a poor measure of rate of absorption from the extradural space because it is dependent on both absorption and elimination rates. It has been shown repeatedly that the elimination rate of bupivacaine is greater than the absorption rate and that elimination is absorption-dependent [6, 12]. The consequence of absorption rate-limited elimination is that the 7} calculated from the terminal slope is not a true estimate of the elimination rate, but a reflection of the absorption rate. The true elimination is difficult to estimate, unless disposition data after i.v. administration are available. The value of 5 h for the 7} of ropivacaine is much greater than that described by Lee and colleagues [11] after i.v. administration (1.9 h) and was presumably related to the slow systemic absorption of ropivacaine from the extradural space. The explanation for the prolonged 7j of bupivacaine compared with ropivacaine may

Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on July 9, 2015

acaine 20 ml; P < 0.001 compared with ropivacaine 10 ml). The terminal phase 7J was 5.3 (2.7) h for 1 % ropivacaine, 5.5 (0.8) h for 0.5 % ropivacaine and 10.6 (4.3) h for 0.5 % bupivacaine (P < 0.001 bupivacaine compared with ropivacaine 20 ml; P < 0.005 bupivacaine compared with ropivacaine 10 ml). However, the 7J estimated is not a true elimination 7j, but a reflection of the absorption. No statistically significant differences were seen between the apparent clearance of 0.5 % ropivacaine and 1 % (314 (140)mlmin- 1 and 282 (92) ml min"1, respectively) or 0.5 % bupivacaine (301 (133) ml min"1).

1.0% Ropivacaine

EXTRADURAL ROPIVACAINE

ACKNOWLEDGEMENTS Dr Morrison was in receipt of a research fellowship from Astra Pain Control AB and the study was supported by Astra Pain Control AB Sodertalje, Sweden. Dr T. Arvidsson, Department of Bioanalysis and Mrs Anna Torrang, Department of Biostatistics, Astra Pain Control, Sweden are thanked for their contributions.

REFERENCES 1. Akerman B, Hellberg IB, Trossvik C. Primary evaluation of the local anaesthetic properties of the aminoamide agent ropivacaine [LEA 103]. Acta Anaesthesiologica Scandinavica 1988; 32: 571-578. 2. Brockway MS, Bannister J, McClurc JH, McKeown DW, Wildsmith JAW. Comparison of extradural ropivacaine and bupivacaine. British Journal of Anaesthesia 1991; 66: 31-37. 3. 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 1988; 67: 1047-1052. 4. Duggan J, Bowler GMR, McClure JH, Wildsmith JAW. Extradural block with bupivacaine: influence of dose, volume, concentration and patient characteristics. British Journal of Anaesthesia 1988; 63: 324-331. 5. Bjork M, Peterson KJ, Ostcrlof G. Capillary gas chromatographic method for the simultaneous determination of local anaesthetic in plasma samples. Journal of Chromatography 1990; 533: 229-234. 6. Burm AGL, Vermeulcn NPE, Van Kleef JW, Dc Boer AG, Spierdijk J, Breimer DD. Phannacokinetics of lignocaine and bupivacaine in surgical patients following epidural administration. Simultaneous investigation of absorption and disposition kinetics using stable isotopes. Clinical Phannacokinetics 1987; 13: 191-203. 7. Brown DL, Carpenter RL, Thompson GE. Comparison of 0.5% ropivacaine and 0.5% bupivacaine for epidural anesthesia in patients undergoing lower-extremity surgery. Ancsthesiology 1990; 72: 633-636. 8. Zaric D, Axelsson K, Nydahl PA, Philipsson L, Larsson P, Jansson JR. Sensory and motor blockade during cpidural analgesia with 1 %, 0.75 %, and 0.5 % ropivacaine—a doublcblind study. Anesthesia and Analgesia 1991; 72: 509-515. 9. Paul DL, Wildsmith JAW. Extradural pressure following the injection of two volumes of bupivacaine. British Journal of Anaesthesia 1989; 62: 368-372. 10. Dahl JB, Simonson L, Mogenson T, Henriksen JH, Kehlet H. The effect of 0.5 % plain ropivacaine on epidural blood flow. Acta Anaesthesiologica Scandinavica 1990; 34: 308—310. 11. Lee A, Fagan D, Lamont M, Tucker GT, Halldin M, Scott DB. Disposition kinetics of ropivacaine in humans. Anesthesia and Analgesia 1989; 69: 736-738. 12. Tucker GT, Mather LE. Phannacokinetics of local anaesthetic agents. British Journal of Anaesthesia 1975; 47: 213-224. 13. Burm AGL, De Boer AG, Van Kleef JW, Vermeulen NPE, De Leede LGJ, Spierdijk J, Breimer DD. Pharmacokinetics of lignocaine and bupivacaine and stable isotope labelled analogues: a study in healthy volunteers. Biopharmacology and Drug Disposition 1988; 9: 85-95. 14. Burm AGL, van Kleef JW, Gladines MPRR, Olthof G, Spierdijk J. Epidural anaesthesia with lidocaine and bupivacaine: Effects of epinephrine on the plasma concentration profiles. Anesthesia and Analgesia 1986; 65: 1281-1284.

Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on July 9, 2015

again lie in its greater lipid solubility, which may slow the systemic absorption. Because the 7} for ropivacaine was virtually the same after administration of 100 mg in 0.5 % or 1 % solutions, there is further evidence for the general view that it is the total dose of a local anaesthetic that governs drug kinetics. The values of about 300 ml min~l for the apparent plasma clearance of both ropivacaine and bupivacaine are smaller than those reported by Lee and colleagues (500 ml min"1) [11] and Burm and colleagues (610 ml min"1) [13] after i.v. infusion in healthy volunteers. The reason for the smaller values presented here is unclear, and may simply reflect the difference between healthy volunteers and patients undergoing surgery. Burm and colleagues [14] reported a plasma clearance of 525 ml min"1 for bupivacaine administered extradurally to healthy patients. One reason for this difference may be that a short sampling time resulted in failure to reach the terminal linear phase and inaccurate estimates of AUC and, consequently, clearance. In conclusion, we have shown that the single-shot technique of extradural administration of ropivacaine produced an effective and well tolerated local anaesthetic block. In equal concentrations, ropivacaine produced a sensory block virtually identical to that with bupivacaine, but the administration of the same dose of ropivacaine in a more concentrated form produced poorer quality surgical anaesthesia. The motor block produced by ropivacaine was less intense and shorter in duration than that produced by bupivacaine. The systemic kinetics of ropivacaine in man were not influenced significantly by drug concentration in die injected solution, although they differed from those of bupivacaine. Greater peak concentrations occurred after administration of ropivacaine and the calculated 7j was shorter than that of bupivacaine.

169