Epidural clonidine-fentanyl combination for labour analgesia: a comparison with bupivacaine-fentanyl

International Journal of Obstetric Anesthesia (1995) 4, 150 154

© 1995 P . . . . .

Professional Etd

j

,,I

I

International

Obstetric Anesthesia

im

I

Epidural clonidine-fentanyl combination for labour analgesia: a comparison with bupivacaine-fentanyl S. W. Husaini, I. F. Russell

Department of Anaesthesia, Hull Royal Infirmary, North Humberside, UK S U M M A R Y. This open study of 20 women compared epidural clonidine (300 ltg)/fentanyl (100 ltg) with bupivacaine (25 mg)/fentanyl (100 ptg) in the provision of pain relief in labour. Sensory tests in the donidine group revealed slight alterations in the appreciation of pin prick and temperature but motor power was unchanged. Analgesia after the first dose was similar in the two groups, but thereafter the analgesia provided by clonidine/ fentanyl was less than that from bupivacaine/fentanyl. Despite the incomplete pain relief provided by elonidine/ fentanyl, mothers appreciated their essentially normal sensations and muscle power. Midwives also commented favourably on the normal mobility of these labouring mothers. There was no difference between the two groups in the duration of labour or the condition of the infants.

Epidural analgesia with local anaesthetic drugs is used widely to provide pain relief in labour, but often at the expense of unwanted side effects: excessive numbness or motor block, backache, and depending on the obstetric management, an increase in instrumental deliveries. These side effects may be related to the concentration and dose of local anaesthetic drug. L2 Absence of pain per se is not the only determinant of maternal satisfaction and higher levels of maternal satisfaction with epidural analgesia are observed when maternal mobility is preserved. 2 Fentanyl,2-4 sufentanil4 and clonidines have all been used to potentiate the analgesic effects of epidural bupivacaine thus allowing a reduced concentration to provide effective pain relief without profound motor block. Attempts have been made to avoid local anaesthetic drugs completely by using epidural or spinal narcotics alone, but generally such studies have produced poor or indifferent results. 6 Epidural clonidine has analgesic properties 7 and is known to potentiate the effects of epidural opioids administered concomitantly.8 Epidural clonidine has been studied extensively in pregnant sheep and has no deleterious effects on the outcome of labour 9 and oral clonidine has been used in pregnancy for the treatment of hypertension, with no adverse fetal effects.t°-~2

Clonidine modulates pain by effects within both brain and spinal canal. It acts on both ~1 and ~2 receptors although only the latter are believed to be involved in the modulation of painful stimuli. This preliminary investigation examined the effectiveness of epidural analgesia provided by a moderate dose of clonidine added to fentanyl and compared it in an open study with the analgesia and side effects provided by an accepted effective mixture of epidural drugs: fentanyl/bupivacaine.

METHODS Ethics Committee approval was obtained for the study and 20 women were recruited. Only ASA 1 women, in established labour with a full term singleton fetus, who were requesting epidural analgesia for pain relief were recruited into the study. Patients who had previously received parenteral narcotic analgesia were excluded, as were any mothers whose fetal heart trace had shown any deviation from normal before the request for epidural analgesia. Patients were approached and, after discussion, were asked if they would be willing to have the clonidine-fentanyl mixture. If the patient declined she was asked if she would act as a control since she would be having a normal epidural. This non-random approach was felt to be necessary for two reasons: the mixture had never been used in pregnant women before so a high rate of refusal was expected; SWH

Dr S. W. Husaini, MB Bs, MCPS, DA, Registrar, Dr Ian F Russell, MB ChB, B Med Biol, FRCA, Consultant Anaesthetist, Department of Anaesthesia, Hull Royal Infirmary, Anlaby Road, Kingston Upon Hull, North Humberside, HU2 3JZ, UK. Correspondence to: Dr Ian F Russell.

150

Epidural clonidine-fentanylcombination for labour analgesia: a comparison with bupivacaine-fentanyl 151 had only a limited time in which to perform the trial. After obtaining written maternal consent a 16-gauge cannula (Venflon) was inserted in the non-dominant forearm or wrist and an intravenous preload of 500 ml Ringers fluid was administered during insertion of an 18 gauge epidural catheter (Portex, 3 lateral eyes, bullet tip). The epidural catheter was inserted at either L2/3 or L3/4 using a lateral oblique approach with loss of resistance to air. Hypotension, defined as a fall in maternal systolic pressure to <70% of control was treated with intravenous ephedrine 3-6 mg as required; supplemental oxygen was administered if hypoxia occurred (SPO2<95%); nausea or vomiting was treated with intravenous metoclopramide (10 rag). Group B patients received bupivacaine 0.25% ( 1 0 m l ) with fentanyl 100gg ( 2 m l ) and group C women received clonidine 300 gg (2 ml) and fentanyl 100 gg ( 2 m l ) diluted to 12 ml with normal saline. Top-ups of these mixtures were administered as required throughout labour. The total dose of clonidine was limited to 1200 gg as this was the maximum parenteral dose previously used as an antihypertensive. 1°'11 If this dose limit was reached or if analgesia with the mixture was inadequate then epidural bupivacaine 0.25% was administered. In both groups the initial dose was given as 6 ml in the left lateral position, and after assessing the effect of this over 5 min a further 6 ml was given in the right lateral position. Both groups were monitored in a similar manner: continuous uterine tocography via an abdominal sensor; continuous fetal heart rate, maternal blood pressure, pulse rate and pulse oximetry every 5 rain for 20 rain then every 15 min. M o t o r block (Bromage score 13 none: 4, partial: 3, almost complete: 2, complete: 1), joint position sense (big toe), sensory block to cold, pin prick and touch, were measured immediately before and 15 rain and 30 min after each top-up. At these same time intervals a Visual Analogue Pain Score (VAS) was obtained from the mother by asking her to slide the cursor along a 10 cm line on a ruler (Abbot). The mother could see only the side of the ruler marked 'no pain at all' and 'worst pain imaginable': the investigator noted the

appropriate score from the other side of the ruler. Side effects such as itching and excessive sedation were noted, but not formally assessed. Neonatal assessment was by Apgar scores at 1 and 5 rain, umbilical arterial blood gas analysis (from a length of umbilical cord isolated before the baby's first breath) and Neonatal Adaptive Capacity Score (NACS) 14 at 2 h. Mothers were encouraged to remain in a lateral position throughout labour, but were allowed to assume a supine lithotomy position, with legs supported by midwives, for delivery. All mothers remained in bed for the duration of their labour. At 24 h the mothers were visited by an anaesthetist not involved in the study and were asked about their general wellbeing and degree of satisfaction with the technique used (fully satisfied with the technique, it was some help in relieving pain, it was no help in relieving pain) as well as specific questions regarding potential side effects (headache, backache, urological symptoms, neurological symptoms and motor power). The mothers and midwives were asked whether the babies' feeding and sleeping activities were apparently normal. Non-parametric statistical tests were applied as appropriate: Mann-Whitney, Fisher's exact test, Chi squared.

RESULTS Twenty Caucasian women were recruited, l0 in each group. There were no statistically significant differences in any of the parameters listed in Table 1 between the two groups. However, there were only 2 primiparous women in group B compared with 7 in group C (Fisher's exact test P = 0 . 0 7 ) , a fact which is likely to be medically significant even though not statistically significant. Labour was augmented with oxytocin in 5 women in group B (2 primiparous, 3 multiparous) and 3 women in group C (2 primiparous, t multiparous). There were no significant changes in oxygen saturation (Table 2) in either group following the epidural drugs. The arterial pressure tended to fall in

Table 1. Patient characteristics: Median values (25th, 75th eentiles)

Age (yr) Height (era) Weight (kg) BMI (wt. m -2) Gestation (wk) Prim/Multip (n) Induction/augmentations (n) Cervical dilation at epidural (cm) Duration of labour before epidurals (min) Duration of labour after epidural (min)

BUPIVACAINE n=10

CLONIDINE n=10

30 (26, 34) 164 (153, 167) 72 (69, 80) 27.5 (26.4, 29.8) 40 (40, 41) 2/8 3/5 3 (1.8, 4.3) 120 (54, 186) 250 (153, 406)

27 (22, 31) 162 (159, 165) 74 (65, 85) 27.1 (25.6, 31.1) 40 (39, 40) 7/3 0/3 3 (2, 5) 180 (120, 240) 233 (144, 331)

152 International Journal of Obstetric Anesthesia Table 2. Side-effects. Medianvalues(25tb, 75thcentiles)

Lowest SpO2 Mean arterial pressure (baseline) Mean arterial pressure (lowest) Bronaage motor score

Bupivacaine n = 10

Clonidine n = 10

97 (96, 97) 91 (78, 95)

97 (96, 98) 88 (80, 95)

82 (73, 89)

77 (70, 81)

2 (2, 3)

4 (4, 4)

both groups following initiation of epidural analgesia or after top-ups, but the initial moderate fluid preload prevented any clinically significant fall in blood pressure and no patient in either group required ephedrine at any stage during labour. No specific sedation score was used, but all mothers were easily rousable with normal conversation. A level of sensory block was readily detectable in group B women. In group C, touch and joint position were unaffected but there were discernible changes in the appreciation of pin prick and cold sensations over the lower abdomen: a pin could be easily recognised as sharp and the ethyl chloride as cold, but there was no 'unpleasantness' associated with the sensations. The levels of altered sensation were not recorded. No loss of motor power to the legs occurred in the clonidine group (Table 2) but significant weakness was observed in the bupivacaine group (z2p=0.001). Only the VAS for the first and second doses could be analysed statistically as the groups became too small thereafter due to delivery of some patients. There was no significant difference between the pain scores of the two groups before either the first or second epidural doses (Figure 1). Thirty min after the first dose both groups demonstrated a significant

[ ] GROUP 1 [ ] GROUP 2

80" VISUAL ANALOGUE SCORE

60-

centiles)

MEDIAN

!

I

40-

GROUP

Table3. Top-upsanddrugdoses.Medianvalues(25th,75th

i RANGE(HIGH) UPPERQUARTILE LOWERQUARTILE RANGE(LOW

100--

reduction in pain scores (P=0.02, group B; P = 0.004, group C). After this first dose there was no significant difference between the pain scores of the two groups. However, after the second dose, although there was a reduction in pain scores in both groups this achieved statistical significance only in the bupivacaine group (P=0.02). After the second dose there was a significantly lower pain score in group B compared to group C (P=0.02). Two women in group B and 3 women in group C delivered without the need of any top-ups. Despite the different numbers of primigravid and multigravid women in the two groups there was no statistical difference in the duration of labour, either before or after the epidural was sited, or in the number of top-ups required (Table 3). Operative deliveries were required in 3 women in group B (vacuum, 1; low forceps, 1; caesarean section, 1) and 4 women in group C (vacuum, 1; low forceps, 1; caesarean section, 2). Topping up the epidurals for these operative deliveries presented no problems and general anaesthesia was not required. There was no difference in neonatal outcome between the two groups (Table 4). Itching was present in two patients (a multigravida in the clonidine/fentanyl group who had had a 'rash' on her legs throughout the latter weeks of pregnancy and a multigravida in the bupivacaine group). Neither patient required any specific treatment. After delivery there were no maternal problems such as headache, sedation, urinary difficulties or paraesthesiae and all the babies were normal and alert. There was no difference in NACS between the two groups. Overall, the degree of maternal satisfaction was high in both groups. Two of the 3 multiparous patients in group C had experienced a conventional

2 1 2 FIRST DOSE BEFORE AFTER

2 1 2 SECOND DOSE BEFORE AFTER

Number of top-ups Fentanyl (total dose) nag Fentanyl (mg hr -1) Bup or clon* (total dose) nag Bup or clon* (mghr -1)

Bupivacaine n = 10

Clonidine n = 10

2 (2, 4) 200 (175, 325) 57 (38, 76) 50 (44, 81)

2 (1, 3) 175 (100, 263) 44 (41, 58) 450 (300, 675)

14(11, 19)

136(127, 175)

* Bup or clon = dose of bupivacaine in bupivacaine group; dose of clonidine in clonidine group. Table 4. Infant characteristics. Median values (25th,75thcentiles) Bupivacaine

Clonidine

3.7 (3.5, 4.0) 7.28 (7.22, 7.33) 9 (6, 9) 9 (9, 9) 8

3.4 (3.0, 3.8) 7.27 (7.24, 7.29) 9 (8, 9) 9 (9, 9) 8

1

Figure--Visual Analogue Pain Scores in group 1 (bupivacaine) and group 2 (clonidine) before and after the first two doses of epidural drugs. The whisker box plots represent median values, 25th and 75th centiles, and range.

Weight (kg) UApH* Apgar score (1 min) Apgar score (5 rain) NACS <35 (n) * Umbilical artery pH.

Epidural clonidine--fentanyl combination for labour analgesia: a comparison with bupivacaine-fentanyl

epidural in their first pregnancy and indicated a preference for the new epidural.

DISCUSSION The difference in the ratio of primigravid to multigrarid women in the two groups has the potential to confound inter-group comparisons. However, it was fortunate that the excess of primigravidae occurred in the clonidine group as this provided a more stringent test of the analgesia provided by the clonidine/fentanyl drug combination. Despite the higher VAS found in group C women 30 min after the second dose, no local anaesthetic drugs were required at any time except for surgical interference (two caesarean sections, one forceps delivery and a retained placenta following a vacuum delivery). Maternal satisfaction with the clonidine/fentanyl mixture was high, but this finding needs to be interpreted with care. The preponderance of primigravidae in group C may give a false impression of the effectiveness of analgesia. Our local experience of fentanyl via a spinal catheter for pain relief in labour suggests that primigravid women have a greater appreciation of even limited pain relief than do women with previous experience of effective epidural analgesia: for the inexperienced primigravida anything may be better than nothing (Russell & Toomey, unpublished results). The similarity in the duration of labour between the groups coupled with the excess of primigravid women in the clonidine group suggests that, in comparison to bupivacaine/fentanyl, epidural clonidine/fentanyl does not inhibit the progress of labour. A similar more rapid progress of labour in the absence of bupivacaine is suggested from preliminary observations of spinal fentanyl v conventional epidural analgesia (Russell & Toomey unpublished). The principal side effects associated with epidural clonidine are sedation and hypotension and these can affect both baby and mother. 12 While there was no overt indication of neonatal depression at 2 and 24 h only two neonates in each group attained a NACS score in the range 35-40, the score arbitrarily chosen to indicate a vigorous infant) 4 Mothers tended to be more sedated in the clonidine group, but no formal assessment of sedation was made. The sedation was not seen as a problem by either the patient or the midwife and it was not uncommon to find mothers asleep with a conventional epidural. All patients in both groups were easily roused by conversation and played an active role in the delivery process. In human volunteers epidural clonidine (700 gg) produces a fall in blood pressure which may be related to systemic absorption. T M In the current study hypotension was not a problem. Whether the

153

smaller dose of epidural clonidine used limited hypotensive side effects 16 or labouring women are less susceptible to these hypotensive effects is unknown. To the investigators, it appeared that clonidine/ fentanyl did not provide the quality of analgesia found in the bupivacaine/fentanyl group and this was borne out statistically for the second dose. Despite the fact that relief of uterine contraction pain may not have been complete in the clonidine group, other significant analgesic effects were noted in several individual instances. A primigravida who had been undergoing a trial of labour was noted to have difficulty walking shortly after a normal delivery; a wide separation of the symphysis pubis was diagnosed (in retrospect, the mother stated that she was aware of a 'click' at some time during the second stage but there was no pain associated with this). A primigravida underwent a vacuum delivery with no discomfort. Following emergency caesarean section with epidurai lignocaine 400 mg and bupivacaine 50 mg, some 2 h after a single dose of the clonidine/ fentanyl mixture, a patient required no postoperative analgesia for over 24 h. It is unknown if these analgesic effects are merely chance occurrences or are due to the clonidine itself, or to a potentiation of the effects of fentanyl. While the trial was under way a patient with a history of allergy to local anaesthetic drugs requested epidural analgesia during labour. Her epidural was inserted with ethyl chloride skin spray and nitrous oxide inhalation, but although she was managed very successfully with fentanyl and clonidine she is not included in these results as her subsequent epidural management was not strictly according to the trial protocol. With the exception of the patient with separation of the symphysis pubis all mothers in the clonidine/ fentanyl group who achieved a vaginal delivery were rapidly mobile after delivery and capable of resuming normal activities. This mobility was not accompanied by hypotension and since sense of joint position was well preserved there was no unsteadiness of gait nor any need for support. The ease of mobility, both during labour and in the immediate puerperium was commented upon favourably by the midwives and by two of the three multigravid women with previous experience of a 'normal' epidural. The women receiving bupivacaine and fentanyl had to wait for the block to wear off before they could mobilise. Limited as these results are, they provide further evidence that women in labour do not always seek complete pain relief. Provided mothers find the pain bearable and they retain near normal sensation and motor power, very high levels of satisfaction can be obtained. With a conventional epidural, reduced mobility and limited ability to bear down during delivery confer a much more passive role on the

154 International Journal of Obstetric Anesthesia

mother. Nevertheless, there are some mothers who wish to feel nothing at all and are willing to accept a significant degree of immobility to achieve this. From these preliminary results it would appear that epidural clonidine may have a role in the relief of labour pains and as such it deserves further investigation in a larger randomised trial. References 1. Thorburn J, Moir D D. Extradural analgesia; the influence of volume and concentration of bupivacaine on the mode of delivery, analgesic efficacy and motor block. Br J Anaesth 1981; 53: 933-939. 2. Murphy J D, Henderson K, Bowden M I, Lewis M, Cooper G M. Bupivacaine versus bupivacalne plus fentanyl for epidural analgesia: the effect on maternal satisfaction. Br Med J 1991; 302: 564-567. 3. Chestnut D H, Owen C L, Bates J N, Ostman L G, Choi W W, Geiger M W. Continuous infusion epidural analgesia during labor: randomized, double blind comparison of 0.0625% bupivacaine/0.0002% fentanyl versus 0.125% bupivacaine. Anesthesiology 1988; 68: 754-759. 4. Russell R, Reynolds F. Epidural infusions for nulliparous women in labour. Anaesthesia 1993; 48: 856-861. 5. O'Meara M E, Gin T. Comparison of 0.125% bupivacaine with 0.125% bupivacaine and clonidine as extradural analgesia in the first stage of labour. Br J Anaesth 1993; 71: 651-656. 6. Naulty J S. Epidural and spinal opiates in labour. In: F Reynolds, ed. Epidural and spinal blockade in obstetrics. London: Bailliere Tindall, 1990; pp 171-182.

7. Bonnet F, Boico O, Rostaing S, Saada M, Loriferne J F, Touboul C, Abhay K, Ghignone M. Postoperative analgesia with extradural clonidine. Br J Anaesth 1989; 63: 465-469. 8. Motsch J, Gr~tber E, Ludwig K. Addition of clonidine enhances post operative analgesia from epidural morphine: a double blind study. Anesthesiology 1990; 73: 1067-1073. 9. Eisenach J C, Castro M I, Dewan D W, Rose J C. Epidural clonidine analgesia in obstetrics: Sheep studies. Anesthesiology 1989; 70: 51-56. 10. Henderson-Smart D J, Horvarth J S, Phippard A, Korda A, Child A, Duggin G C, Hall B M, Storey B, Tiller D J. Effect of antihypertensive drugs on neonatal blood pressure. Clin Exp Pharmacol Physiol 1984; 11: 351-354. l 1. Horvarth J S, Phippard A, Korda A, HendersonSmart D J, Child A, Tiller D J. Clonidine hydrochloride - A safe and effective antihypertensive agent in pregnancy. Obstet Gynecol 1985; 66: 634-638. 12. Hartikainen-Sorri A L, Heikkinen J E, Koivisto M. Pharmacokinetics of clonidine during pregnancy and nursing. Obstet Gynecol 1987; 69: 598-600. 13. Bromage P. Epidural Analgesia. Philadelphia: WB Saunders 1978; 144. 14. Amiel-Tison A, Barrier G, Shnider S M, Levinson G, Hughes S C, Stefani S J. A new neurologic and adaptive capacity scoring system for evaluating obstetric medications in full term newborns. Anesthesiology 1982; 56: 340-350. 15. Eisenach J C, Tong C. Site of hemodynamic effects of intrathecal c~2-adrenergic agonists. Anesthesiology 1991; 74: 766-771. 16. Eisenach J, Detweiller D, Hood D. Hemodynamic and analgesic actions of epidurally administered clonidine. Anesthesiology 1993; 78: 277-287.