COMPARATIVE ANAESTHETIC PROPERTIES OF VARIOUS LOCAL ANAESTHETIC AGENTS IN EXTRADURAL BLOCK FOR LABOUR

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1 Br.J. Anaesth. (1977), 49, 75 COMPARATIVE ANAESTHETIC PROPERTIES OF VARIOUS LOCAL ANAESTHETIC AGENTS IN EXTRADURAL BLOCK FOR LABOUR D. G. LITTLEWOOD, D. B. SCOTT, J. WILSON AND B. G. COVINO SUMMARY Various concentrations of lignocaine, etidocaine and bupivacaine in 10-ml doses of plain solutions were studied in a double-blind manner as agents for extradural analgesia to relieve the pain of labour. In 67 patients in established labour the onset time and duration of analgesia were assessed by the abolition and recurrence of the pain of uterine contractions, motor block on a 0-2 scale, dermatomal spread by pinprick testing, and arterial pressure by standard sphygmomanometry. Increasing the drug concentration reduced the onset times and increased both tie duration of analgesia and the degree of motor block, but had little effect on dermatomal spread or on the frequency of hypotension. Based on the results the agents have been classified with regard to onset and duration of analgesia and degree of motor blockade. The introduction of new local anaesthetic drugs such as bupivacaine and etidocaine has made available agents whose properties are sufficiently different to enable the anaesthetist to select the drug most suitable for an individual patient (Engberg, Holmdahl and Edstrom, 1974). It is not possible to describe the relative anaesthetic properties of the various agents in general terms. For example, the amide-types of local anaesthetic agent have been classified according to their relative duration of activity. Lignocaine, prilocaine and mepivacaine are considered to be of moderate duration of analgesia, and bupivacaine and etidocaine of long duration. However, anaesthetic agents vary, not only as a result of their own intrinsic pharmacological properties, but also according to the type of procedure being performed, the dose and concentration of drug administered, and the presence or absence of adrenaline (Downing, 1969; Bridenbaugh et al., 1973; Lund, Cwik and Pagdanganan, 1973; Abdel-Salam and Scott, 1975; Poppers, Covino and Boyes, 1975; Moir et al., 1976). Moreover, there is considerable variation in the methods by which anaesthetic properties are evaluated. One area of discrepancy is extradural blockade for the relief of pain associated with labour and delivery (Phillips, 1975; Poppers, Covino and Boyes, 1975; Wilson, 1975), since the anaesthetic requirement for relieving the pain of uterine contractions is not identical with that required for vaginal delivery. D. G. LITTLEWOOD, F.F.A.R.C.S.; D. B. SCOTT, M.D., M.R.C.P.E., F.F.A.R.C.S.; J. WlLSON, F.F.A.R.C.S.; B. G. COVINO, PH.D., M.D.; Department of Anaesthetics, Royal Infirmary, Edinburgh. The present study was designed to evaluate the anaesthetic properties of lignocaine, bupivacaine and etidocaine in various concentrations such that seven different solutions were compared in alleviating the pain of uterine contractions during labour. METHOD Sixty-seven patients, aged from 17 to 35 yr, participated in the study, which was designed to allow three different anaesthetic solutions to be given to each patient during her labour. In every case, two of the solutions were 1.5% lignocaine and 0.5% bupivacaine, which were selected as standards. All ampoules were coded and given in a randomized, double-blind fashion. All the injections were of the same volume (10 ml). This is more than is used by many anaesthetists, but we wished to ensure that any deficiency in the effectiveness of the injection was a result of the drug or its concentration rather than inadequate spread. Injections were made through an indwelling catheter inserted into the lumbar extradural space at L 2/3. Established labour was present in every patient, each of whom experienced discomfort during uterine contractions before the first injection. The following were noted after each injection: (a) Onset time: from injection to the first painless contraction. (b) : from injection to recurrence of painful contractions. This was not recorded if delivery intervened. (c) Dermatomal spread: extent of anaesthesia to pinprick 20 min after injection.

2 76 BRITISH JOURNAL OF ANAESTHESIA (d) Motor blockade of the lower limbs: graded on a 0-2 scale 20min after injection: 0 = no motor impairment, 1 = partial impairment, 2 = inability to move the legs. (e) Mean arterial pressure: measured by sphygmomanometry frequently during the first 20 min after injection. The maximum decrease in mean pressure (diastolic+l pulse pressure) was recorded. Although 67 patients participated in the study, it was possible to administer all three designated solutions to only 36 patients. Sixteen received only two injections and 15 received only one injection before delivery. The data obtained on all 67 patients were subjected to an analysis of variance and group mean Student's t test where appropriate. In the group of 52 patients who received more than one drug, using the paired t test it was possible to compare the standard solutions (1.5% lignocaine and 0.5% bupivacaine) with the test solutions: 0.25% bupivacaine, 0.375% bupivacaine, 0.75% bupivacaine, 0.75% etidocaine and 1% etidocaine. All solutions were administered without adrenaline. RESULTS The results are summarized in table I. The values represent the means of all injections of the various solutions. The onset time varied from a mean of 5.6 min with 1% etidocaine to 14.7 min with 0.375% bupivacaine. There was no significant difference in onset time between 1.5% lignocaine, 0.5 and 0.75% bupivacaine and 0.75% etidocaine. Bupivacaine 0.25 and 0.375% had significantly longer onset times, while 1 % etidocaine caused a significantly more rapid onset of action than any of the other anaesthetic solutions (P<0.01). The mean duration of analgesia varied from 65 min with 0.375% bupivacaine to 117 min with 0.75% bupivacaine. There was no significant difference in duration between 1.5% lignocaine, 0.25 and 0.375% bupivacaine and 0.75% etidocaine. The solutions containing 0.5% bupivacaine, 0.75% bupivacaine and 1% etidocaine, however, provided significantly longer durations of analgesia than any of the other agents (P<0.05, 0.01, 0.05). No significant difference in duration of analgesia existed between 0.5 and 0.75% bupivacaine and 1% etidocaine. The smallest spread of anaesthesia (approximately 10 dermatomes) was with 0.25 and 0.375% bupivacaine. The spread with all of the other solutions involved dermatomes. The dermatomal extent of analgesia was significantly less for 0.25 and 0.375% bupivacaine as compared with the other anaesthetic solutions (P< 0.05). The mean degree of motor block expressed on a 0-2 basis and the percentage of patients exhibiting complete lower limb is shown in table I. None of the patients treated with 0.25 or 0.375% bupivacaine was paralysed completely, whereas three of eight patients treated with 1% etidocaine were unable to move their lower limbs. The other anaesthetic solutions caused complete motor block in one or two patients in each group. The average decrease in mean arterial pressure varied from 6 to 18 mm Hg (table I). No statistically significant difference in the degree of hypotension was observed between the various drugs. In addition, there was no trend towards a greater degree of hypotension as the anaesthetic concentration was increased. The use of the paired t test in patients receiving more than one injection allowed a comparison TABLE I. Properties of various anaesthetic solutions employed for extradural analgesia during labour Agent Lignocaine 1.5% Bupivacaine 0.25% 0.375% 0.5% 0.75% Etidocaine 0.75% 1% Onset 9.2 ± 1.03(56) 11.8 ± 1.48(12) (9) 9.0 ± 0.53 (67) 8.9 ± 1.00(10) (10) 5.6 ± 0.50 (8) 68.6 ± 2.92(50) (11) (9) ± 5.8(57) ± 12.03(10) (10) (8) Mean motor score 0-2 scale 0.99 ± 0.07 (56) 0.83 ± 0.11(12) (9) (67) 1.2 ±0.13(10) (10) 1.4 ± 0.18(8) Mean values + SEM of all 67 patients; (number of observations). % patients with severe lower limb 12 (56) 0(12) 0(9) 11(67) 20 (10) 10 (10) 38(8) No. dermatomes of skin anaesthesia 12.9 ± 0.45 (56) 11.1 ± 1.02(12) (9) (67) 13.5 ± 1.49(10) (10) 14.3 ± 1.41 (8) Mean reduction in mean arterial pressure (mmhg) 12.1 ± 2.1 (56) (12) 18.3 ± 9.0 (9) (67) 10.5 ± 5.4 (10) (10) (8)

3 COMPARISON OF LOCAL ANAESTHETICS IN LABOUR 77 TABLE II. Influence of order of administration on anaesthetic properties of 1.5% Ugnocaine. Mean + SEM (number of observations) Onset time Motor block % severe First injection Second injection Third injection 8.8 ± 1.02(22) 7.9 ± 0.73(20) 9.2 ± 1.71(14) 0.6 ± ± ± (22) 20 (20) 21 (14) 60.0 ± 4.7 (22) (19) 79.4 ± 7.6 (8) between the test solutions and the two standard drugs (1.5% Ugnocaine and 0.5% bupivacaine). This analysis did not show any difference between the agents which was not shown by the group mean t tests (table I). Table II shows the onset and duration of sensory analgesia and degree of motor block for 1.5% Ugnocaine when given as the initial, second or third injection. No difference in onset time was observed. However, the duration of sensory analgesia increased from a mean of 60 min for the first injection to 79 min when Ugnocaine was administered as the third agent. Moreover, the intensity of motor block appeared to increase with subsequent injections; none of the patients who received Ugnocaine as the first injection showed complete motor, compared with a frequency of 20% in the patients who received Ugnocaine as the second or third injection. A similar analysis was conducted with 0.5% bupivacaine given as the first, second or third injection (table III). Onset time increased progressively from 6.4 min when the drug was given as the first injection to 9.5 and 10.2 min for the second and third administration. The onset time for the first injection was significantly shorter than that for the second or third injection (P<0.05). The duration of analgesia also appeared to become shorter when bupivacaine was given as the second or third drug: 123 min following the first injection of bupivacaine and 96 and 92 min respectively when administered as the second or third drug. As with Ugnocaine, the degree of motor block appeared to increase when bupivacaine was given as the second or third injection. Thus, only 4% of patients showed total motor when bupivacaine was given first, compared with 13 and 17% when given as the second or third agent. One other interesting aspect of this study was the possibiuty of plotting dose-duration and dose-onset time curves for the four different concentrations of bupivacaine. Since the volume was kept constant at 10 ml, the total dosage of bupivacaine administered varied from 25 to 75 mg. As shown in figure 2, a decrease in onset time and a prolongation of duration of sensory analgesia occurred as the dose of bupivacaine was increased. The maximum improvement in onset and duration occurred at a dose of 50 mg (10 ml of 0.5%). No significant enhancement of onset or duration was observed at a dose of 75 mg. DISCUSSION It is difficult to evaluate accurately the onset and duration of analgesic activity of local anaesthetic solutions in a clinical setting, and to compare results from different studies, since the clinical situation and the method of evaluation vary from one centre to another (PhilUps, 1975; Poppers, Covino and Boyes, 1975; Wilson, 1975; Moir et al., 1976). In most studies in which onset and duration of sensory analgesia have been determined, the method of pinprick has been employed, but the values obtained for the same anaesthetic agent may vary widely, even when this apparently simple technique is employed by different investigators (Covino and Bush, 1975). In obstetrics the situation is even more confusing, since the analgesic property of various drugs may be evaluated before the onset of labour, during labour or during deuvery. For example, PhilUps (1975) found TABLE III. Influence of order of administration on anaesthetic properties of 0.5% bupivacaine. Mean ± SEM (number of observations) First injection Second injection Third injection Onset time 6.4 ± 0.41 (26) 9.5 ± 0.73(24) 10.2 ± 1.25(16) Motor block 1.0 ± ± ± 0.13 % severe 4(26) 17(24) 13 (16) ± 9.5(26) 96.0 ± 8.5 (18) 92.8 ± 8.5 (12)

4 78 BRITISH JOURNAL OF ANAESTHESIA A ONSET B DURATION % BUPIVACAINE 0.75 FIG. 2. A: Onset time v. dosage for bupivacaine. B: of analgesia v. dosage for bupivacaine. little difference in duration of anaesthesia between and 0.5% bupivacaine, but the patients were not in established labour, and the endpoint selected to determine duration was two segment regression of pinprick anaesthesia. In the present study we attempted to standardize the conditions under which the various anaesthetic solutions were evaluated. Administration occurred only following establishment of active labour, and no attempt was made to utilize data on duration if delivery intervened. Onset and duration of analgesia were measured solely in terms of relief of the pain of uterine contractions. Pinprick testing was reserved for the determination of spread of analgesia. It is appreciated that the assessment of onset depended upon the frequency of contractions, but it was felt that differences in the frequency from patient to patient following injection would be equally divided among the groups. The results of this study have revealed certain interesting aspects of the analgesic activity of the various solutions employed. Adequate analgesia for pain relief during labour was obtained with all the solutions. In only two instances (both with 0.25% bupivacaine) out of more than 200 injections was the degree of analgesia considered to be unsatisfactory because of a lack of anaesthetic potency. Thus, the efficacy of these various solutions was similar in terms of the relief of pain during labour. However, the anaesthetic profile of the various solutions varied considerably with regard to onset, duration, degree of motor blockade and spread of analgesia. For example, bupivacaine has been studied extensively in recent years in obstetrical extradural anaesthesia (Duthie, Wyman, and Lewis, 1968; Bromage, 1969; Phillips, 1975; Wilson, 1975). In general, this agent has been considered to provide a long duration of analgesia relative to lignocaine, which had been the standard anaesthetic agent for obstetric analgesia for many years. Our results indicate that there is no difference between 0.25 and 0.375% bupivacaine and 1.5% lignocaine in respect of duration of pain relief during labour. However, bupivacaine 0.5 and 0.75% cause a duration of analgesia which is significantly longer than that of 1.5% lignocaine. On the basis of the results obtained, it should be possible to select an agent for use in labour depending on the criteria of the clinical situation. If rapid onset of analgesia is considered desirable, 1% etidocaine would be the drug of choice. However, if long duration of analgesia is the prime requirement, 0.5 or 0.75% bupivacaine are preferable. If onset or duration is not important compared with freedom from motor blockade, 0.25 or 0.375% bupivacaine and 1.5% lignocaine solutions would seem most appropriate. It is possible to classify the agents employed in this study as follows (table IV): (1) Agents of moderate duration (approximately 1 h): 1.5% lignocaine, 0.25 and 0.375% bupivacaine and 0.75% etidocaine. Within this group, etidocaine shows the most rapid onset and greatest degree of motor block. The two solutions of bupivacaine demonstrate the slowest onset and least motor blockade. Lignocaine is intermediate in terms of onset time. (2) Agents of long duration (approximately h): 0.5 and 0.75% bupivacaine and 1% etidocaine. Within this group, etidocaine is the most rapidly acting agent and produces the most intense motor blockade, whereas the bupivacaine solutions provide a longer duration of action and less motor block, but a slower onset time. It is difficult to explain the discrepancy observed between lignocaine and bupivacaine when these agents were administered as the first, second or third agent. The progressive increase in onset time and

5 COMPARISON OF LOCAL ANAESTHETICS IN LABOUR 79 TABLE IV. Classification of local analgesic agents for relief ofbridenbaugh, P. O., Tucker, G. T., Moore, D. C, Bridenbaugh, of pain in labour L. D., and Thompson, G. E. (1973). Etidocaine: Agent Onset Motor block a clinical evaluation for intercostal nerve block and lumbar epidural block. Anesth. Analg. (.Cleve.), 52,407. Bromage, P. R. (1969). An evaluation of bupivacaine in (A) Moderate duration (approximately 1 h) epidural analgesia for obstetrics. Can. Anaesth. Soc. J., Lignocaine 1.5% Moderate Minimal 16,46. Bupivacaine 0.25% Slow Minimal Pettigrew, R. T., and Crowell, D. E. (1969). Tachyphylaxis in epidural analgesia. I: Augmentation and decay Bupivacaine 0.375% Slow Minimal Etidocaine 0.75% Rapid Moderate of local anesthesia. J. Clin. Pharmacol., 9, 30. (B) Long duration (approximately h) Catchlove, R. F. H. (1972). The influence of CO 2 and ph on Bupivacaine 0.5% Moderate Moderate local anesthetic action. J. Pharmacol. Exp. Ther., 181, Bupivacaine 0.75% Moderate Moderate 298. Etidocaine 1.0% Rapid Intense Covino, B. G., and Bush, D. F. (1975). Clinical evaluation of local anaesthetic agents. Br. J. Anaesth. (Suppl.), 47, decrease in duration of bupivacaine between the first and subsequent injections is suggestive of tachyphylaxis 289. Downing, J. W. (1969). Bupivacaine: a clinical assessment in lumbar epidural block. Br. J. Anaesth., 41, 427. (Bromage, Pettigrew and Crowell, 1969). Duthie, A. M., Wyman, J. B., and Lewis, G. A. (1968). The ph of plain bupivacaine solutions ( units) Bupivacaine in labour. Its use in lumbar extradural analgesia. Anaesthesia, 23, 20. is significantly less than that of plain lignocaine Engberg, G., Holmdahl, M. H:son, and Edstrom, H. H. solutions ( units). Therefore, the repeated (1974). A comparison of the local anaesthetic properties injection of acidic solutions into the extradural space of bupivacaine and two new long-acting compounds, will result in a greater proportion of the anaesthetic HS 37 and etidocaine in epidural analgesia. Ada Anaesthesiol. Scand., 18, 277. agent being available in the cationic form, which Lund, P. C, Cwik, J. C, and Pagdanganan, R. T. (1973). diffuses across the dural sheath to the spinal roots Etidocaine a new long acting local anesthetic agent. A less effectively, resulting in a slower onset and shorter clinical evaluation. Anesth. Analg. (Cleve.), 52, 482. duration of action (Catchlove, 1972). Since the ph of Moir, D. D., Slater, P. J., Thorburn, J., McLaren, R., and bupivacaine solutions is low, this agent may be Moodie, J. (1976). Extradural analgesia in obstetrics: a affected to a greater degree by repeated injections than controlled trial of carbonated lignocaine and bupivacaine hydrochloride with or without adrenaline. Br. J. is lignocaine which is prepared in solutions of a higher Anaesth., 48, 129. ph. This would not explain the longer duration of Phillips, G. (1975). A double-blind trial of bupivacaine and lignocaine when administered as the third injection. etidocaine in extradural block for surgical induction of However, this longer duration may simply reflect the labour. Br. J. Anaesth., 47, small sample size (eight) in this group. Poppers, P., Covino, B. G., and Boyes, N. (1975). Epidural block with etidocaine for labour and delivery. Ada Anaesthesiol. Scand., 60, 89. REFERENCES Wilson, J. (1975). A double-blind comparison of single Abdel-Salam, A., and Scott, D. B. (1975). Bupivacaine and doses of etidocaine 1 per cent and bupivacaine 0.5 per etidocaine in epidural block for post-operative relief of cent during lumbar epidural block in obstetrics. Acta pain. Ada Anaesthesiol. Scand. (Suppl.), 60, 80. Anaesthesiol. Scand. (Suppl.), 60, 97.