Bupivacaine is the standard agent for epidural analgesia in labour. Epinephrine or opioids, or both, are often added to improve analgesia in order to reduce the dose of bupivacaine and to minimize the side-effects, but both additions have disadvantages. Addition of epinephrine to local anaesthetics is not universally accepted because it may cause fetal and maternal tachycardia and can reduce uterine blood flow [1-3]. Fentanyl may cause pruritus, urinary retention, delayed gastric emptying and respiratory depression [4,5].
Clonidine as an α2-agonist may be a useful adjuvant. It has analgesic properties when administered epidurally alone and acts synergistically with epidural opioids and local anaesthetics [6,7]. Clonidine does not interfere with proprioception and does not cause motor block, nausea or vomiting. When large doses of clonidine have been used respiratory depression may occur only secondary to sedation [8,9]. Eisenach and his colleagues suggested that clonidine may offer advantages as an analgesic in pregnancy . It modulates, but does not abolish, sympathetic response. Intrathecal and epidural clonidine have been studied in pregnant ewes and there were only minor changes in maternal and fetal physiology and biochemistry at concentrations of clonidine anticipated to be effective in human beings [7,10].
The aim of our study was to evaluate 75 μg clonidine added to 0.125% bupivacaine solution and compare it with 50 μg fentanyl added to 0.125% bupivacaine. We investigated differences in the duration of analgesia, reduction in the number of injections or total bupivacaine requirement and observed the side-effects in mother and fetus.
Patients and methods
This double-blind randomized study was approved by the Hospital Ethics Committee. After obtaining informed consent, we studied 41 women, ASA I or II with a singleton vertex pregnancy of at least 36 weeks gestation who were candidates for epidural analgesia for labour. We excluded patients younger than 18 years, patients receiving antihypertensive drugs, those with baseline heart rates < 55 beats min−1 and patients who had already received opioid analgesia during this labour. Parity was not a selection criterion.
All the patients received continuous cardiotocograph (CTG) monitoring using an external transducer while arterial pressure was measured using a Dinamap® (Model 1846 SX, Critikon, FL, USA) on the non-dependent arm. Each parturient received intravenous (i.v.) infusion of 0.9% saline 10 mL kg−1 during the 20 min before induction of epidural anaesthesia and was then placed in the left lateral position. The epidural space was cannulated via a mid-line approach and loss of resistance to normal saline at L2-3 or L3-4; a 3-4 cm length of catheter left in place. The patient was then turned into the supine position with a left lateral tilt.
One investigator prepared the local anaesthetic solution while the other blinded investigator assessed the patient. Baseline observations of maternal heart rate, arterial pressure, sedation, motor power and fetal heart rate (FHR) were recorded. Pain was assessed by asking the patient to complete a 10-cm visual analogue scale (VAS) at the peak of contractions.
All patients received 3 mL of 0.5% plain bupivacaine as a test dose when cervical dilatation reached 4 cm or more and were allocated randomly to receive either 0.125% bupivacaine 10 mL with 50 μg fentanyl or 0.125% bupivacaine 10 mL with 75 μg clonidine. A second injection of the same solution was given for any pain relief subsequently. Patients in both groups received further 10 mL injections of 0.125% bupivacaine without fentanyl or clonidine if more than two doses were necessary.
Maternal heart rate, arterial pressure and FHR were recorded at 5-min intervals for 30 min and thereafter at 15-min intervals. Hypotension was defined as a decrease in systolic arterial pressure at least 20% of the baseline values. It was treated by turning the patient into the left lateral position, administering oxygen, i.v. saline, and ephedrine 5 mg i.v. repeated as necessary. Bradycardia was defined as the occurrence of a maternal heart rate < 60 beats min−1 and treated with atropine i.v.
The sensory level was assessed by response to bilateral pinprick at the mid-clavicular line downwards every 5 min for 30 min and every 15 min thereafter. The patient was asked to complete a VAS in approximately 15-min intervals to coincide with the peak of a contraction. Onset of analgesia was assessed by time to achieve sensory block of T10 and time to reach maximum decrease in VAS. The duration of analgesia was taken as the time from the onset of the initial dose to the time the patient requested additional analgesia (VAS > 5).
Motor impairment was assessed at 15-min intervals using the Bromage scoring system  (0 = ability to move hips, ankles and knees, 1 = inability to raise extended leg, 2 = inability to flex knee, 3 = inability to flex ankle, foot or knee). Sedation was evaluated on a five-point scale (0 = wide awake, 1 = drowsy, 2 = dozing, eyes shut intermittently, 3 = asleep, 4 = unrousable) at 15-min intervals. Side-effects such as hypotension, bradycardia, pruritus, nausea or dryness of mouth were noted (Table 1). The mode of delivery, neonatal birth weight and Apgar scores at 1 and 5 min were recorded. All patients were examined the next day and asked for an overall global rating of the treatment (0 = poor, 1 = fair, 2 = good, 3 = very good).
Patient data were compared using Student's t-test. The Mann-Whitney test was used to compare the time to sensory block of T10, duration of analgesia, sedation and VAS between groups. The chi-square (with Yates correction) and Wilcoxon tests were used for non-parametric data. P < 0.05 was considered as statistically significant.
There were 21 patients in the bupivacaine-fentanyl group and 20 in the bupivacaine-clonidine group. There were no differences between groups in age, weight, height, parity or gestation and cervical dilatation before insertion of epidural catheter (Table 2).
There was no difference between groups in initial VAS, onset of sensory block to T10, maximal height of block. Duration of analgesia after the first injection was longer in the bupivacaine-clonidine group when compared with the bupivacaine-fentanyl group with 139.4 ± 31 and 127.9 ± 48 min respectively. The difference was not significant (P = 0.42). The duration of labour and mode of delivery were also similar in both groups (Table 3).
The number of epidural injections (2.47 ± 1.0 injections vs. 1.8 ± 1.0 injections) (P = 0.04) and the total bupivacaine requirements were higher in the bupivacaine-fentanyl group when compared with the bupivacaine-clonidine group (30.9 ± 12.8 mg vs. 22.5 ± 12.5 mg) (P = 0.04). Fifty percent of patients (10 patients) in the bupivacaine-clonidine group needed only one dose of epidural analgesic until delivery whereas the number of patients who needed one dose was only 14.2% (three patients) in the bupivacaine-fentanyl group (Fig. 1).
There were no differences between groups in systolic (SAP), or diastolic arterial pressure initially or over the next 120 min. But in both groups, SAP was less than baseline from 5 to 20 min (P = 0.04). Two patients in each group with more than 20% decrease of SAP from baseline required rapid fluid infusion and ephedrine treatment.
Baseline heart rate was similar in both groups. After 20 min of the epidural injection, there was no clinically significant decrease in heart rate in the clonidine group. Fetal heart rate showed no difference between the two groups during the whole period. Apgar scores were also similar in both groups with no Apgar score lower than seven at 1 min and lower than nine at 5 min. Sedation scores and adverse effects showed no significant difference (P = 0.46) between the groups (Table 1).
The overall global rating of the treatment on the next day was better in the clonidine group. In this group, 85% of patients said that it was good or very good. Seventy-five percent of patients in the fentanyl group had the same opinion (P = 0.26).
The addition of clonidine to bupivacaine provided longer duration of analgesia after the first epidural injection. This was not significant statistically but analgesic requirement thereafter and total bupivacaine administration was significantly less in the bupivacaine-clonidine group, where 10 patients had delivery after only a single epidural dose of bupivacaine-clonidine combination. However, this is also a limitation of this study because the conclusion is based on the other 10 patients. This may arise from the fact that both nulliparae and multiparae were in the study.
Clonidine is a highly lipid-soluble alpha2-adrenergic agonist which acts via a non-opioid mechanism involving alpha2-receptors at the dorsal horn [8,9,12]. When it is used alone, large doses are necessary to obtain pain relief but side-effects of hypotension and sedation may occur [8,13]. However, combination with other drugs acting on different sites of pain transmission pathways allows the dose of each component to be decreased. Clonidine alone prolongs the sensory block of local anaesthetics and has an additive effect with epidural opioids [7-9]. During pregnancy, systemic clonidine is safe: doses in the range of 150-900 μg orally or i.v. have been shown to be safe for the treatment of pregnancy-induced hypertension and withdrawal symptoms during pregnancy [14,15]. In a patient with intractable labour pain, epidural clonidine 300 μg was used and complete pain relief was achieved within a few minutes. No adverse effects were seen in the mother and newborn .
Epidural clonidine during pregnancy has been studied in a sheep model; a minor decrease in heart rate in ewes and fetal lambs was observed, without changes in maternal and fetal blood pressure, intrauterine pressure or uterine blood flow .
Because it was recognized that the dose of epidural clonidine alone necessary to provide effective labour analgesia would be accompanied by unwanted sedation and hypotension, clinical experience has been restricted to combinations of clonidine with bupivacaine. For this double-blind study, we chose a control solution known to be effective and used routinely in our institution (bupivacaine 0.125% 10 mL with 50 μg fentanyl) and compared the same solution with 75 μg clonidine instead of fentanyl. A bolus injection was performed because it is used commonly in our unit and we had not enough patient-controlled analgesia (PCA) devices at the time this study was undertaken. The dose of clonidine 75 μg was chosen because it is suggested that 75 μg may be an appropriate dose to combine with bupivacaine as a single bolus for analgesia in labour . These data are supported by comparison of the effects of clonidine to sufentanil, when added to bupivacaine. For example, Cigarini and his colleagues  observed longer lasting analgesia during labour when 75 μg clonidine was added to 12.5 mg bupivacaine than from either bupivacaine 12.5 mg alone or with 10 μg sufentanil added; the duration was similar to another group receiving 10 μg sufentanil, 12.5 μg epinephrine (1:80 000) and bupivacaine 12.5 mg. Le Polain and his colleagues  confirmed that a small clonidine dose (30 μg) was ineffective in increasing the duration or intensity of the bupivacaine-sufentanil-epinephrine combination in labour.
In a study comparing sufentanil and clonidine in obstetric analgesia, Le Polain and his colleagues limited the mixture of 30 μg clonidine to a local anaesthetic-epinephrine combination for two doses . Further doses were given without clonidine or sufentanil in order to avoid possible side-effects caused by cumulative doses of epidural clonidine. We also restricted the total dose of clonidine up to a maximum of 150 μg, because of this statement in that study and the long eliminitation half-life of clonidine . After the first two injections, no more clonidine was added to the solution. The maximum dose of fentanyl was also limited up to 100 μg to avoid side-effects of opioids. After two doses of study solutions, only plain bupivacaine 0.125% was given to both groups. Additional dose requirement was less in the clonidine group. The addition of clonidine instead of fentanyl improved the quality and the duration of analgesia. This finding is similar to other studies comparing opioids and clonidine for analgesia in labour [11,18,20]. O'Meara and his colleagues added 120 μg clonidine to 0.125% bupivacaine (8 mL) which provided greater analgesia but caused marked sedation .
In our study, we observed more sedation in the clonidine group, but it was taken as a positive finding and the difference was not statistically significant (P > 0.46). Clonidine is believed to act supraspinally, in particular at the locus coeruleus where there is a high concentration of α2-receptors . Some of the sedation may be a consequence of effective analgesia which allows the mother to rest. Neonatal sedation was not observed but it is known that Apgar scores are insensitive measures of neonatal depression compared with neurobehavioural testing.
Two patients in each group had significant hypotension which responded satisfactorily to fluid replacement and injection of ephedrine, while modest hypotension occurred during the follow-up period in both groups. A decrease in arterial pressure may occur as a result of effective epidural analgesia. The effects of epidural clonidine on cardiovascular variables are dose related. Epidurally administered clonidine has a U-shaped dose response [7,8] on arterial pressure and may explain the decrease in systolic arterial pressure observed in our study. Clonidine decreases the arterial pressure and heart rate by enhancing parasympathetic nervous system activity at brainstem sites and by inhibiting sympathetic outflow in the spinal cord. Clonidine also affects the myocardium directly and can influence heart rate through this mechanism ; however, in our study no patient suffered serious bradycardia.
Approximately 20% of normal gravidas develop abnormal fetal heart rate patterns which place the fetus 'at risk' during labour. Most frequently, these patterns can occur as a result of either umbilical, maternal or uteroplacental circulatory problems . Fetal heart rate abnormalities such as variable or late decelerations, bradycardia or change in baseline variability may occur. Chassard and his colleagues  found that epidural clonidine, particularly clonidine 150 μg added to 0.0625% bupivacaine with 10 μg sufentanil, was associated with such fetal heart rate abnormalities. In our study, there was no adverse effects on the fetal heart rate, e.g. the studies of Celleno and his colleagues and those of O'Meara and Gin showed no effect of clonidine 150 or 120 μg on fetal heart rate abnormalities when given epidurally [21,23].
There were no differences between groups in the mode of delivery or Apgar scores, and the results were not inconsistent with obstetric practice in this hospital.
In conclusion, 75 μg clonidine added to 0.125% bupivacaine 10 mL was associated with less additional analgesic requirement when compared with the 'traditional' bupivacaine-fentanyl combination in pregnant women during labour.
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