BJA Advance Access originally published online on July 18, 2006
British Journal of Anaesthesia 2006 97(3):359-364; doi:10.1093/bja/ael157
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Intermittent vs continuous administration of epidural ropivacaine with fentanyl for analgesia during labour
University Department of Anaesthesia, Ninewells Hospital and Medical School Dundee DD1 9SY, UK
1 Present address: University Department of Anaesthesia, Edinburgh New Royal Infirmary Edinburgh EH16 4SA, UK
2 Present address: Raigmore Hospital Inverness IV2 3UJ, UK
*Corresponding author. E-mail: pdwfettes{at}doctors.org.uk
Accepted for publication May 8, 2006.
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Abstract |
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Background. Many years ago regular intermittent bolus administration of epidural local anaesthetic solution was recognized to produce more effective analgesia than continuous infusion, but only recently has the development of suitable pumps allowed the former technique's wider evaluation.
Methods. In this randomized, double-blind trial, 40 primigravid patients had a lumbar epidural catheter inserted, and plain ropivacaine 0.2% 15–20 ml was titrated until analgesia and bilateral sensory block to T10 were produced (time zero). Patients were then given either an infusion of ropivacaine 2 mg ml–1 with fentanyl 2 µg ml–1 at 10 ml h–1, or hourly boluses of 10 ml of the same solution. Pain, sensory block and motor block were measured frequently. If requested, additional 10 ml boluses of the study mixture were given for analgesia.
Results. There were no differences between the two groups in patient characteristics, obstetric/neonatal outcome, or in sensory or motor block. A total of 12 (60%) patients in the continuous group required one or more additional boluses compared with 4 (20%) patients in the intermittent group (95% CI 9.6–61.7%, P=0.02). Therefore the intermittent group received a lower total drug dose than the infusion group (P=0.02). Duration of uninterrupted analgesia (time to first rescue bolus) was longer in the intermittent group (P<0.02).
Conclusions. The intermittent group required fewer supplementary injections and less drug to maintain similar pain scores, sensory and motor block compared with the continuous group. This represents a more efficacious mode of analgesia.
Keywords: anaesthetic techniques, epidural; analgesia, obstetric; drug delivery, infusion; drug delivery, bolus; regional anaesthesia
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Introduction |
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Regular intermittent bolus administration of epidural local anaesthetic solution was recognized, many years ago, as being more efficacious than continuous infusion in producing postoperative analgesia.1 Despite this observation, continuous infusions became standard, primarily because the infusion pumps available were restricted to that mode of drug delivery. However, more sophisticated devices are now available and have allowed re-evaluation of programmed bolus administration at regular intervals, with confirmation of the earlier observation in postoperative patients.2 Constant infusion tends to result in progressive regression in the block, with resultant failure of pain control and an increase in anaesthetic workload.3 4 This may be a particular problem if the analgesic requirements are increasing, as is the case during labour, so a randomized, double-blind study was devised to compare regular intermittent bolus administration with continuous infusion in patients receiving epidural analgesia during labour.
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Methods |
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In total, 40 ASA I–II primigravid patients with uncomplicated, full-term (
37 weeks) pregnancy were recruited to the study, which was approved by the local medical research ethics committee. A patient information sheet was given to patients when attending the antenatal clinic at 36 weeks gestation. Informed consent was obtained before the start of labour, but patients were not entered into the study until they had requested epidural analgesia, at which time they were randomized to one of two groups. Patients who had received parenteral opioid analgesics within the previous 2 h were excluded, as were those who weighed more than 110 kg, were less than 150 cm in height, or had achieved greater than 5 cm cervical dilation. Age, height, weight and pain were recorded before starting the procedure. Pain was measured using a 0–100 mm visual analogue scale (VAS: 0=no pain and 100=the worst pain imaginable), and a verbal rating score (VRS: 0=no pain, unaware of contraction; 1=aware of contraction, but no pain; 2=contraction painful). The epidural space was identified (by the duty obstetric anaesthetist), using the loss of resistance to the injection of saline technique, with a 16 swg Tuohy needle inserted at the third or fourth lumbar interspace. With the bevel directed cephalad, a three side-hole catheter was advanced 3–5 cm through the needle and secured in place. A 5 ml test dose of ropivacaine 2 mg ml–1 was injected and followed, 5 min later, by a further 10 ml of the same solution. Assessment of the quality of epidural block was made using pain scores and absence of pin prick sensation with a short-bevelled 27 swg dental needle. VAS and VRS pain scores corresponding to the previous contraction, and bilateral sensory block (to pinprick), were measured every 5 min for 45 min. If a bilateral sensory block had not been achieved bilaterally at the T10 level after 30 min, and the patient was still in pain, an additional 5 ml dose of ropivacaine 2 mg ml–1 was administered. If, at 45 min a bilateral block to T10 had not been produced despite this additional bolus, the patient was withdrawn from the study and the epidural was re-sited. The time at which the T10 level was achieved (and the patient was pain free) was defined as ‘zero’. Patients were then randomized (computer generated numbers inserted into opaque envelopes) to receive either a continuous infusion (control group) or intermittent administration (study group) of ropivacaine 2 mg ml–1 with fentanyl 2 µg ml–1. In the control group the infusion was started immediately at a constant rate of 10 ml h–1, whereas in the study group hourly boluses, delivered at 2 ml min–1, were started 30 min after time zero. Both regimens were delivered using a Medfusion 2001 pump (Medex Inc., Duluth, GA, USA). Patients were nursed in the sitting position by staff that were unaware of the treatment used.
Observations were made by an assessor ‘blind’ (the pump was covered) to the mode of drug administration. Pain was assessed using both VAS and VRS obtained at 5 min intervals from the first epidural injection until time zero, at 15 min into the study, and then at 30 min intervals thereafter until delivery (the mode of which was recorded) or to a maximum time of 315 min. Thus the study was primarily designed to measure the efficacy of analgesia during the first stage of labour. If (and only if) pain relief was requested by the patient, additional 10 ml boluses of the study mixture were given (maximum number 2, minimum interval 15 min), without uncovering the pump, and the time of the rescue bolus was noted. Sensory block was assessed bilaterally in the mid-clavicular line using a short-bevelled 27 swg dental needle and a standard dermatome chart. Motor block was assessed bilaterally using both a modified Bromage score (0=lifts leg; 1=knee flexion; 2=ankle flexion; 3=no movement) and a straight-leg raising (SLR) score (0=no contraction; 1=visible contraction; 2=movement, gravity eliminated; 3=movement against gravity; 4=movement against gravity and resistance; 5=normal power). Unilateral motor block was defined as a difference between the two sides of at least two levels on the Bromage or SLR. Sensory and motor block assessments, and maternal heart rate and blood pressure were obtained at the same time as pain scores. Fetal heart rate was monitored continuously by cardiotocograph. Hypotension (30% decrease in systolic blood pressure) was treated with i.v. boluses of ephedrine 6 mg. In the event of technical failure, the study number was reallocated to the next patient, and blinding was maintained.
Using data from a previous study comparing regular intermittent bolus to continuous infusion for administration of epidural drug,2 we calculated that a sample size of 40 patients (20 per group) would give the study a power of >0.9 to detect a statistically significant difference in visual analogue pain scores. This calculation was based on mean (SD) visual analogue pain scores at 4 h of 36 (20) mm in the continuous group and 12 (7) mm in the intermittent group. We considered clinically relevant secondary outcomes to be the number of rescue epidural injections in each group, the total mass of ropivacaine used, worst motor block scores and differences in motor block between each leg.
All results underwent descriptive analysis to measure the central tendency, spread and shape of the data. Comparisons of continuous data with a normal distribution were performed using the t-test, and are presented as mean and SD. Continuous, but not normally distributed data, were analysed using the Mann–Whitney U-test and are presented as median and interquartile range (IQR). Variability of heart rate and blood pressure within (over time) and between groups of patients was analysed using repeat measures ANOVA, one-way ANOVA and Tukey–Kramer post hoc tests. Categorical variables were analysed with contingency-tables using the 
2-test and Fisher's exact test when the number of values was less than 5. Times to first rescue bolus (from time zero) were compared using Kaplan–Meier survival analysis and the log rank test. Statistical significance for two-tailed tests was defined as a P-value <0.05. Cumulative ropivacaine mass (which included initial boluses) against time for the two groups was compared using ANCOVA. Before calculating ANCOVA, a preliminary test was carried out to confirm that the slopes of each group were parallel. Statistical analyses were carried out using Number Cruncher Statistical Systems, Kaysville, UT, USA.
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Results |
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A total of 47 patients were recruited to the study, but 7 were withdrawn after epidural catheter placement: 3 because of inadequate analgesia at 45 min; and 1 each because of patchy block, epidural filter disconnection, catheter occlusion and study protocol violation. In all, 40 patients, divided equally into two groups, completed the protocol. There were no statistically significant differences between the two groups with regard to patient characteristics (Table 1), obstetric details or fetal outcome (Table 2).
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Pain relief (VRS 0 or 1) and bilateral block to T10 were obtained after the initial bolus of 15 ml ropivacaine 2 mg ml–1 in 19 patients in the continuous group and in 15 patients in the intermittent group (P=0.18). Injection of a further ropivacaine 2 mg ml–1 5 ml to the remaining 6 patients successfully provided pain relief (VRS 0 or 1) and bilateral block to T 10. Good pain relief was maintained equally in both groups throughout the epidural block (Fig. 1). However, patients in the continuous group required over three times more epidural boluses to maintain pain relief compared with the intermittent group (P=0.02). Twelve patients in the continuous group required one rescue bolus, five of them needing two boluses. In contrast, only four patients in the intermittent group required one bolus, and only one of them needed two boluses (Table 3). As a result, the mean total dose of ropivacaine given after insertion of the epidural was greater in the continuous group (124 vs 105 mg; P=0.02). Using ANCOVA the mean dose of ropivacaine adjusted for time was significantly less for the intermittent group than for the continuous group (64.3 mg vs 72.7 mg, P < 0.01; Fig. 2). Before calculating ANCOVA a preliminary test was carried out to confirm that the slopes of each group were parallel (P<0.01). We used Kaplan–Meier graphs and the log rank test to determine the duration of analgesia as indicated by the time to first rescue bolus. This was significantly longer in the intermittent group (P<0.02; Fig. 3).
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Sensory spread (analgesia to pinprick) and motor block (Bromage score and SLR; Fig. 4) were similar in the two groups. The number of patients developing a unilateral block, defined as the difference of at least two levels on the Bromage or SLR scale, was greater in the infusion group, but this did not reach statistical significance. Cardiovascular changes were small with no significant differences between groups, and only one patient (in the continuous group) receiving treatment for hypotension, this shortly after administration of a bolus injection for breakthrough pain.
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Discussion |
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This study has shown that regular intermittent epidural injection is associated with reduced need for epidural rescue medication, and less epidural drug use, but equivalent pain relief when compared with continuous infusion of the same solution of ropivacaine and fentanyl. More effective analgesia is gained without either compromise of cardiovascular stability, or any increase in obstetric complications. We undertook the study because the continuous epidural infusion of local anaesthetic for pain relief during labour is still commonplace in clinical practice. However, despite widespread use, continuous epidural infusion may be problematic. Regression of sensory block over time, need for regular rescue medication and excessive motor block are all well recognized complications of epidural infusions.1–5
Support for the greater efficacy of bolus injection of local anaesthetics comes from both cadaveric dissection and clinical study. Cryomicrotome sectioning has shown more uniform spread of liquid in the epidural space, through the intervertebral foraminae, and along nerve sheaths when using large volumes of injectate, and a high injection pressure.6 This supports the theory that intermittent boluses of local anaesthetic will result in a more uniform spread than that produced by continuous infusion. Furthermore, a clinical study comparing continuous and intermittent administration of epidural bupivacaine after major abdominal gynaecological surgery showed that regular intermittent bolus administration resulted in a lower requirement for rescue medication (and therefore total drug used), better pain scores and better maintenance of sensory block.2 More recently a similar study, albeit in a smaller number of patients, found that regular intermittent bolus produced a more extensive block than continuous infusion, although the investigators failed to demonstrate any difference in pain scores or rescue medication.7 Two recent studies from a group in Singapore showed that regular bolus administration of epidural local anaesthetic prolonged the analgesic effect of intrathecal fentanyl in labour for longer than continuous infusion.8 9 Although these studies could not exclude the possibility that this effect was a result of the passage of infusate into the intrathecal space, their finding of lower pain scores and higher patient satisfaction scores adds weight to our argument that intermittent bolus provides more effective analgesia than continuous infusion.
Using Kaplan–Meier analysis we have shown that the duration of uninterrupted analgesia (as indicated by the time to first rescue bolus) was longer in the intermittent bolus group. While this may in part be because more of the intermittent group needed 20 ml rather than 15 ml to achieve analgesia at the start of the study (Table 3), this difference was not statistically significant. Furthermore, the continuous infusion group had an ongoing requirement for rescue analgesia long after any initial effect would have regressed (Fig. 3). However, we failed to show any difference in pain scores (our primary outcome measure) between the two groups although we had expected to find one. This is probably because the majority of patients in the continuous infusion group received sufficient rescue medication to mask any difference between the groups (but to withhold such relief would have been inappropriate). Thus a tendency to increased pain score in the continuous infusion group (seen as an increase in the area under the curve for VAS in Table 3, and early increases in IQRs for VAS in Fig. 1) was not allowed to reach significance. In addition to this, pain relief was very good in both groups. At least 50% of patients had a VAS score of 0 at any measured time, representing a level of analgesia better than in the previous postoperative study used to power this one. Improved pain relief may be attributable to the use of local anaesthetic (ropivacaine) and opioid (fentanyl) rather than local anaesthetic alone.
Unlike the previous study investigating the application of intermittent bolus for hysterectomy,2 we failed to demonstrate any difference in sensory spread. Nor was there any significant difference in overall motor block, or unilateral motor block although such differences might be expected. It seems likely that the duration of the study was too short to allow any difference to develop. Again any difference between the groups may have been masked by the additional rescue boluses given to the continuous infusion group. One potential criticism of the study is that the mean duration of the epidural in the intermittent group was 25 min less than in the continuous group. This difference was not statistically significant, and when the mean ropivacaine doses for the two groups were adjusted for time, and compared using ANCOVA, the intermittent group required significantly less drug (Fig. 2). Another potential criticism is that the incidences of instrumental delivery and Caesarean section in the study were very high (they are substantially higher than the normal incidences in our hospital), and we cannot deny the possibility that the doses used in the study may have contributed to this. However, we chose to investigate a particularly challenging group of patients—primigravid women requesting an epidural in early labour—and the high intervention rate needs to be considered in that context. Finally, no comment can be made about efficacy of analgesia for the second stage of labour because this study was designed primarily to examine the efficacy of analgesia for the first stage, and because the majority of patients delivered after the study was completed.
Our most significant findings were the reduction in number of boluses and overall reduction in local anaesthetic use in the intermittent group. Local anaesthetic sparing by a magnitude of 15–20% is also characteristic of patient-controlled epidural analgesia (PCEA) whereby patients self-administer local anaesthetic according to their level of pain.6 However, a potential criticism of the PCEA system is that patients will only demand a bolus when developing pain as the sensory block regresses. This is compounded by the lag time between administration and action of epidural drugs. In contrast, regular intermittent bolus administration endeavours to prevent pain by injecting local anaesthetic at time intervals chosen so that the majority of patients remain pain free. It was disappointing that there was no statistically significant difference in motor block, although the trend was towards less motor block in the intermittent group. The high incidence of motor block found in both groups may indicate that we used an excessive dose of local anaesthetic mixture. Further investigation of the optimal volume and concentration of local anaesthetic, and the optimal mix of local anaesthetic and opioid are needed to guide clinical practice, particularly in regard to reducing motor block.
In conclusion, in this study the intermittent bolus group required significantly less rescue medication and less total drug than the continuous infusion group, to maintain similar pain scores, sensory and motor block. Duration of analgesia as indicated by time to first rescue bolus was also longer in the intermittent group. This represents a more efficacious mode of analgesia and should lead to a reduction in workload for the anaesthetist. These findings are consistent with current understanding of the nature of spread of solution within the epidural space. It is thought that intermittent boluses of local anaesthetic solution result in more uniform spread, therefore giving more reliable analgesia than infused solution.
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Footnotes |
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Declaration of interest. P.D.W.F., C.S.M. and J.B.W. received salaries from AstraZeneca while working as research fellows at Ninewells Hospital, Dundee, UK. 
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