The addition of adrenaline (3.3 to 5.0 μg mL−1) to local anaesthetics injected into the epidural space prolongs their duration of action [1,2], improves the quality of analgesia [2,3] and might reduce the peak plasma concentration of the local anaesthetics although interpretation of this effect remains controversial particularly for bupivacaine . Adrenaline serves also as a marker for accidental intravenous (i.v.) injection . However, adrenaline may have disadvantages in parturients including tocolytic effects because of its β-agonist properties [6-8]. Side effects of adrenaline given into the epidural space are because of a systemic action, whereas beneficial effects are related to its local action. Therefore, the systemic side effects of epidural adrenaline might be reduced by reducing adrenaline concentration without substantial loss in its beneficial effects. The use of lower concentrations (1.66 μg mL−1) has indeed been shown to retain these beneficial effects during surgical epidural anaesthesia using 2% lignocaine . To date there has been no study assessing the effects of such a low concentration of adrenaline for epidural analgesia for labour. It is likely that a bupivacaine-adrenaline combination would behave in a comparable manner with a lignocaine-adrenaline mixture and that the use of a very low concentration of adrenaline might avoid the untoward effects. This study was designed to assess the effects of adding adrenaline 1.66 μg mL−1 or 5.0 μg mL−1 given with epidural bupivacaine 0.25% during labour and to compare these with those obtained using an adrenaline-free bupivacaine 0.25% solution.
Sixty ASA I or II nulliparous parturients, with uncomplicated pregnancies, in active labour and with cervical dilatation at 2 to 5 cm at the time they requested epidural analgesia, were studied following institutional approval and informed consent from patients. Fetal heart rate (FHR) and uterine activity were monitored using an external doppler device and a tocodynanometer during labour. Prehydration was performed with a 500-mL crystalloid i.v. infusion. With the patients in the sitting position, the epidural space was identified by loss of resistance to saline using a 18-gauge Tuohy needle at the L3-L4 or L4-L5 interspace. Epidural catheters were advanced 3 cm in a cephalad direction. Patients were allocated randomly into one of three groups: Group I received plain bupivacaine 0.25%, Group II received bupivacaine 0.25% with adrenaline 5.0 μg mL−1 and Group III received bupivacaine 0.25% with adrenaline 1.66 μg mL−1. Following negative aspiration of blood and cerebrospinal fluid, a test dose of 3 mL of the test solution was administered and the patients were monitored for 5 min for signs of subarachnoid injection. If there was no evidence of subarachnoid injection, an additional 7 mL of the drug was injected.
Maternal blood pressure and heart rate were monitored using an automated device (Dinamap™) before and at 5 min intervals after injection. Hypotension was defined as a value below 100 mmHg or as a decrease in systolic blood pressure by 30% from the initial blood pressure measurement. The pain level during contractions was noted using a 10-point visual analogue pain score (VAPS), in which zero implies no pain and 10 the worst pain imaginable. The recordings were made before the epidural injection and at 5 min intervals for 30 min and then every 15 min. Onset time was defined as the time from the end of injection to pain relief (VAPS <3, or more than 50% reduction in the VAPS). Duration of action was defined as the time from injection to request for further pain relief. Upper level of sensory analgesia assessed by loss of sensation to cold was evaluated at 15 and 30 min after the injection and then at 30-min intervals until the first additional dose was required. The degree of motor blockade was evaluated using the Bromage scale  (a score of 0-3 was assigned with 0=no block, 1=just able to move the knees, 2=able to move the feet, 3=unable to move the lower extremities) was recorded at the same time intervals. Additional doses were injected during labour according to the mother's needs using the same dose, agent and concentration that had been used for the initial injection.
Maternal height, weight and age, duration of the first and second stages of labour (the second stage was defined as the time from complete cervical dilatation to delivery; the measurements of cervical dilatation were made before epidural analgesia and repeatedly during labour by midwives who did not know which solution had been injected), number of uterine contractions during consecutive 10-min periods from the start of the study until delivery, mode of delivery and neonatal Apgar scores at 1 and 5 minutes were also noted.
Data were analysed for statistical significance using ANOVA and χ2-test when appropriate. The results are expressed as mean ± SD. P<0.05 was considered statistically significant.
There were no statistical differences in age, height or weight between groups (Table 1). Onset time of analgesia seemed slightly quicker when adrenaline was added, but the difference was not statistically significant. There were no significant differences between groups in regard to the duration of analgesia, upper level of sensory analgesia, intensity of motor blockade, frequency of uterine contractions or mode of delivery (Table 2). However, the first stage of labour was prolonged significantly in group II compared with group I. In contrast, the second stage was comparable in the three groups (Table 2). The groups were comparable with regard to base-line pain score (Fig. 1). Epidural analgesia induced a decrease in VAPS in all groups but without any significant difference between the three groups (Fig. 1). Systolic blood pressure decreased significantly below base-line values and to the same extent in all groups, although no changes were observed in maternal heart rate (Fig. 2). Fetal heart rate (FHR) and Apgar scores were also similar in all the groups and no neonate had a 1-min Apgar score of less than seven.
Findings in the present study demonstrate that the addition of 5 μg mL−1 of adrenaline to bupivacaine 0.25% for epidural analgesia prolongs the duration of the first stage of labour without any significant effect on the frequency of uterine contractions. This suggests that labour is slowed by adrenaline given by epidural injection by a negative effect on the intensity rather than the frequency of uterine contractions. This suggestion cannot be confirmed as intraamniotic pressure was not measured in this study. The results presented here are in agreement with those of Gunther et al. who also observed a prolonged duration of the first stage of labour during continuous caudal anaesthesia, although adrenaline doses used at that time were twice those used here in group II [11,12]. Garrett et al. in a study published in 1954, also demonstrated that low doses of i.v. adrenaline (2.5 to 5 μg) reduced uterine activity. The presence of α and β-adrenergic receptors in uterine muscle has been previously demonstrated and their mechanisms of action have been identified: α-receptor stimulation leads to uterine hypertonus, whereas β-receptor stimulation causes a decrease in uterine tone and contractility . When small doses of adrenaline are used, β-adrenergic responses predominate . The prolonged duration of the first stage of labour reported in the present study with adrenaline 50 μg administered with the epidural local anaesthetic is in agreement with these β-adrenergic responses; however, two other studies using similar doses showed adrenaline not to have tocolytic effects [2,16]. Dose differences seem to be insufficient to explain this discrepancy. In fact, there are some methodological differences between these studies and the present study. In the present study, all parturients were nulliparous and epidural analgesia was performed when cervical dilation was between 2 to 5 cm. Grice et al. and Eisenach et al. performed epidural analgesia up to 7 cm cervical dilatation and this may have been too late to study the effects of epidural analgesia on the duration of the first stage of labour. Moreover, in the latter study comparing plain bupivacaine 0.25% vs. bupivacaine 0.25% with adrenaline 3.3 μg mL−1, there was also a significant difference in parity between the two groups.
Epidural adrenaline administration produces analgesia probably by an α2-adrenergic mechanism in the spinal cord dorsal horn  and thus addition of adrenaline to local anaesthetics may be expected to enhance analgesia. However, neither the present study nor others  have been able to confirm this effect. Possible explanations include: (1) plain bupivacaine 0.25% induced analgesia may be maximal and thus adrenaline cannot provide any additional benefit, as in the case of opiates ; (2) bupivacaine, in contrast with lignocaine, has little vasodilatatory effect and therefore adrenaline-induced vasoconstriction does not increase substantially the local concentration of bupivacaine.
Profound motor blockade was rare and was not intensified by the addition of adrenaline in the present study. These results confirm those of Abboud et al. obtained using plain bupicacaine 0.25% vs. bupivacaine 0.25% with 3.3 μg mL−1 of adrenaline .
Adrenaline administered by epidural injection produces β-adrenergic effects: in the study by Bonica et al., epidural anaesthesia with 2% lignocaine (18 to 22 mL) produced small (5 to 10%) and clinically non-significant changes in cardiac output, total peripheral resistance (TPR) and mean arterial pressure (MAP). In contrast, when combined with adrenaline 5 μg mL−1 a 49% increase in cardiac output and a 37% decrease in TPR was obtained, resulting in a 10% decrease in MAP . Another study has confirmed these findings during anaesthesia for Caesarean section . However, no significant difference in the haemodynamic effects because of the addition of adrenaline to bupivacaine was found. This may be because of the lower doses used for labour and the haemodynamic changes already induced by pregnancy and labour. The same results have been reported by others who added adrenaline to bupivacaine for epidural analgesia in obstetrics .
On the basis of FHR and Apgar scores, the present study has shown that the addition of either adrenaline 1.66 or 5 μg mL−1 does not affect neonatal well-being: these results are in agreement with previous studies [1,2,16].
In conclusion, in the labouring patient, this study has shown that the addition of adrenaline 1.66 μg mL−1 to bupivacaine 0.25% did not produce any recorded beneficial effect. Moreover, adrenaline 5 μg mL−1 prolongs the first stage of labour. These findings do not support the addition of adrenaline, even at a low dose, to bupivacaine during epidural analgesia during labour.
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