Maternal and neonatal side-effects of remifentanil patient-controlled analgesia in labour

I. Volikas1,*, A. Butwick2, C. Wilkinson3, A. Pleming4 and G. Nicholson2

1 Department of Anaesthesia, St Helier Hospital, Surrey, UK. 2 Department of Anaesthesia, St George's Hospital Medical School, London, UK. 3 Department of Chemical Pathology, Epsom Hospital Laboratories, West Park Hospital, Surrey, UK. 4 Department of Obstetrics and Gynaecology, Glan Clwyd Hospital, North Wales, UK

* Corresponding author. E-mail: ivolikas{at}hotmail.com

Accepted for publication April 12, 2005.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Remifentanil has been suggested as an ideal opioid for patient-controlled analgesia (PCA) in labour, but the safety profile has not been established. The aims of this preliminary prospective observational study were to investigate the maternal side-effects and early neonatal effects, and to assess the placental transfer of remifentanil PCA during labour.

Methods. Women with no known obstetric complications or contraindication to remifentanil were recruited (n=50). Remifentanil was administered at a bolus dose of 0.5 µg kg–1 and a lockout period of 2 min. A visual analogue scale was used to assess pain, nausea and itching. Maternal observations were recorded hourly and fetal heart rate trace was assessed every 2 h. Umbilical cord gases, 1 and 5 min Apgar scores and neurological evaluation of the neonate were recorded. Maternal venous blood and umbilical artery and vein cord blood samples were collected for analysis of remifentanil concentration.

Results. Fifty women enrolled in the study (24 multiparous, 26 primiparous). There was no evidence of cardiovascular instability or respiratory depression. Pain scores decreased significantly, but there was no significant change in nausea after initiating the PCA. A statistically significant increase in itching was found to be clinically mild and 22 women were slightly drowsy (95% confidence interval [CI], 30–58.7%) but alert to voice. Ten fetal heart rate traces demonstrated changes in the first 20 min, but did not require intervention (95% CI, 10–33.7%). The median 1 and 5 min Apgar scores were 9. The mean umbilical cord gases and neurological examination were within normal limits. Maternal vein and umbilical vein cord samples demonstrated placental transfer of remifentanil, and small amounts were detected in umbilical artery samples.

Conclusions. At the bolus dose used remifentanil PCA has an acceptable level of maternal side-effects and minimal effect on the neonate. Remifentanil crosses the placenta and appears to be either rapidly metabolized or redistributed in the neonate.

Keywords: analgesia, obstetric ; analgesia, patient-controlled ; analgesics, opioid, remifentanil


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
It has been suggested that remifentanil may be the opioid analgesia of choice for women in labour.1 2 The lack of analgesic efficacy of more traditional opioids in labour has necessitated the need for an alternative, especially for those women with a contraindication for epidural analgesia.3 5

Remifentanil has µ-specific activity antagonized by naloxone. It has a fast onset of effect and undergoes rapid hydrolysis by non-specific tissue and blood esterases to almost completely inactive metabolites, which are eliminated in the urine. The context-sensitive half-time is only 3 min.6 These pharmacokinetic characteristics suggest that remifentanil is ideally administered as patient-controlled analgesia (PCA).7

Remifentanil PCA has been successfully administered to provide pain relief during labour. Comparative studies have demonstrated that it has a greater analgesic efficacy than intramuscular and intravenous meperidine.8 9 A dosing regimen of a 0.5 µg kg–1 bolus and a 2 min lockout period has been proposed.5 10

All previous studies of remifentanil PCA in labour have included a small group of women, restricted duration of analgesia or permitted increasing doses of remifentanil.4 5 814 Placental transfer of remifentanil to the neonate has only been assessed in patients during Caesarean section with a continuous remifentanil infusion supplementing epidural anaesthesia.7

In this preliminary prospective observational study we aimed to investigate a large group of women receiving remifentanil PCA (bolus of 0.5 µg kg–1 and a 2 min lockout period) for maternal and neonatal side-effects during the first and second stages of labour. We also aimed to assess the placental transfer of remifentanil.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Approval was obtained from the Merton and Sutton Local Research Ethics Committee. All healthy women with singleton pregnancies received an information leaflet in the antenatal clinic at 36–40 weeks gestation. Written informed consent was obtained in early labour on the delivery suite.

The inclusion criteria were ASA I or II, with no known obstetric complications, and requesting meperidine or remifentanil analgesia. The exclusion criteria were any contraindication to remifentanil and a request for early epidural analgesia.

The women received PCA with a remifentanil bolus of 0.5 µg kg–1 and a lockout period of 2 min, with no maximum hourly limit. A 16 gauge cannula was inserted with local anaesthesia and the PCA was connected using an IVAC PCAM® model P5000 pump (ALARIS Medical Systems, UK). The women also received metoclopramide 10 mg intravenously. The investigator (an anaesthetist) remained on the delivery suite for the duration of use of PCA to provide continuous monitoring and attended to the mother throughout the entire labour. The women used the PCA from institution until after delivery of the placenta. If they decided to withdraw from the study because of inadequate pain relief, the remifentanil PCA was used until an epidural had been sited.

A visual analogue scale (VAS) scoring system was used to assess the average level of pain, nausea and itching hourly throughout the first and second stages of labour. This consisted of a 100 mm horizontal line with a verbal description at either end (‘no pain’ and ‘worst pain imaginable’). VAS scores were recorded immediately before the PCA was started (baseline VAS scores). VAS scores for the subject's level of pain, nausea and itching overall throughout labour were also recorded within 30 min of delivery (post-delivery scores). Maternal non-invasive blood pressure, pulse oximetry, radial pulse and ventilatory frequency were recorded hourly. The hourly sedation score was noted using a four-point scale (1=alert; 2=slightly drowsy but alert to voice; 3=drowsy but responds to gentle stimulus; 4=very drowsy).

The fetal heart rate (FHR) was monitored with a cardiotocograph (Hewlett Packard 9040 A) for the first 20 min after starting the PCA and for a subsequent 20 min period every 2 h throughout labour, or more often if indicated. The FHR tracings were analysed by an obstetrician and categorized as normal, suspicious or pathological, according to current NICE guidelines. The category was determined by assessing baseline, variability, decelerations and accelerations in each FHR trace. Umbilical artery (UA) and umbilical vein (UV) cord blood samples were obtained for analysis of blood gases and lactate measurement at the time of delivery. Apgar scores at 1 and 5 min were noted and a neurological evaluation of the neonate was performed within 12 h of delivery. This consisted of 12 tests to assess resting posture, state, motor activity, integrated reflexes and phasic and postural tone.

At the time of delivery, maternal venous blood (MV), UA and UV cord blood samples were collected for analysis of remifentanil concentrations. The UA and UV blood samples were taken from a double-clamped segment of umbilical cord, and all samples were placed into tubes containing citrate. These were mixed and stored immediately in a freezer below –18°C before transporting in dry ice to the laboratory for remifentanil assays. The assay was based on that of Grosse and colleagues.15 Whole blood was mixed with fentanyl as an internal standard, denatured with acetonitrile and extracted with dichloromethane. The dried extract was reconstituted in ethyl acetate and analysed by gas chromatography–mass spectrometry using selected ion monitoring. Concentrations were estimated by comparing response ratios with the internal standard and reference remifentanil standards. The samples were analysed in duplicate where possible.

Patient characteristics and obstetric data were collected and these results are summarized separately for primiparous and multiparous women. Statistical analysis was carried out using the SPSS® 12.0 package for Windows XP. Pain scores are presented as mean (SD), and changes over time for the first 3 h after initiating PCA were analysed by repeated measures analysis of variance (ANOVA). Where significant changes were found, the post hoc Bonnferroni correction was used to compensate for multiple comparisons and P<0.017 was considered statistically significant. No assumption was made regarding normality for nausea and itching scores; hence Friedman two-way ANOVA for within-group testing was used for the first 3 h after initiating PCA. Where significant differences were found, the Wilcoxon signed rank test was used with corrections for multiple comparisons and again P<0.017 was considered statistically significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Fifty women (24 multiparous and 26 primiparous) were enrolled in this study. More primiparous women than multiparous women received syntocinon (18/26 compared with 7/24). The primiparous women also had a longer duration of labour and lower spontaneous delivery rate (Table 1).


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Table 1 Patient characteristics and obstetric data. Data are mean (range) or mean (SD)

 
Remifentanil PCA provided adequate pain relief for 43 of the 50 women. Two women were advised to have an epidural because of obstetric indications, and five primiparous women requested an epidural because of inadequate pain relief. The baseline, mean hourly and post-delivery VAS scores for pain were 69 (SD 17.4), 46 (18.7) and 49 (23.1), respectively. The mean hourly VAS pain scores for all subjects are presented in Figure 1. Pain scores decreased significantly from baseline for the first 2 h in primiparous and the first hour in multiparous women, and were also significantly less post-delivery.



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Fig 1 Mean (SD) hourly VAS pain scores for multiparous women (**P<0.017) and primiparous women (*P<0.017) receiving remifentanil PCA.

 
Nausea VAS scores did not change significantly after initiating the remifentanil PCA. There was a statistically significant increase in itching scores from baseline for the first 2 h and post-delivery, but clinically this was considered mild and no treatment was required (Table 2).


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Table 2 VAS scores for itching and nausea. Data are presented as median (interquartile range) for baseline, 1–3 h and post-delivery scores. Raw data are presented for 4–12 h (n<17).

 
Cardiovascular, respiratory and sedation data are presented in Table 3. A decrease in systolic blood pressure of >15% was demonstrated in three women in the first hour after initiating the PCA but did not require any intervention. A decrease in maternal heart rate of >15% was also demonstrated in five women in the first hour, but again did not require any intervention. There was no evidence of maternal muscle rigidity or ventilatory frequency <12 bpm, and the lowest oxygen saturation recorded was 93%. On the four-point sedation scale, 22 women were ‘slightly drowsy but alert to voice’ (95% confidence interval [CI], 30–58.7%) for ≥2 h, but this was the highest level of sedation.


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Table 3 Maternal cardiovascular and respiratory data presented as mean (SD). Sedation scores are presented as median ([interquartile range] range)

 
All subjects had a 20 min FHR trace every 2 h in the first and second stages of labour. Twenty were categorized as normal throughout, as all the features (baseline, variability, decelerations, and accelerations) were reassuring. Fifteen women had a suspicious trace, where one of the four features was classed as non-reassuring (Table 4). Fifteen women had a pathological trace, where two or more features were classed as non-reassuring or there were one or more abnormal features (Table 5). The FHR traces were also assessed for changes in the first 20 min after commencing PCA and compared with the trace pre-PCA for 48 of the 50 subjects. Ten of these demonstrated changes in the first 20 min (95% CI, 10–33.7%) (Table 6).


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Table 4 Summary of cardiotocographs with suspicious changes following NICE guidelines

 

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Table 5 Summary of cardiotocographs with pathological changes following NICE guidelines

 

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Table 6 Summary of 10 cardiotocographs which demonstrated fetal heart rate changes in the first 20 min after starting remifentanil PCA.

 
The median 1 and 5 min Apgar score was 9, and one neonate scored 7 at 5 min. UV and UA cord blood gases were not recorded for all subjects as insufficient blood sample was obtained from the umbilical cord. The mean UA pH was 7.24, and seven of the 37 subjects had an arterial pH <7.2. The mean umbilical artery base excess was –5.19 mEq litre–1, and two of the 34 subjects had a value greater than –10 mEq litre–1 (Table 7). Neonatal neurological evaluation was performed on 45 neonates: 35 of these were normal for term in all tests, seven failed to demonstrate a normal response in one test and two failed to demonstrate a normal response in two tests. One neonate failed to demonstrate a normal response in three tests.


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Table 7 Neonatal data. Apgar scores are presented as median (range) and umbilical cord blood gases as mean (SD)

 
Remifentanil assays were measured for nine subjects, although two samples clotted. The results are summarized in Table 8. The mean total dose of remifentanil was 2.39 (0.38–7.3) mg over a mean period of 306 (165) min.


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Table 8 Remifentanil assays for umbilical cord artery, umbilical cord vein and maternal vein.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In our study, 26 primiparous and 24 multiparous women received remifentanil PCA during labour. We had originally intended to recruit 100 subjects, but because of the time constraints of the anaesthetist observing the mother throughout the entire labour, the study was terminated after 50 subjects. All women demonstrated an initial decrease in VAS pain scores in the first hour of receiving remifentanil PCA. This was followed by an increase in VAS pain scores but at a decreased level compared with baseline (Fig. 1). This pattern of pain scoring in women in labour receiving remifentanil PCA has been demonstrated previously, and differs from the results obtained in women receiving meperidine as the pain scores continue to increase as labour progresses.9 Labour pain and its assessment is complex, but if one makes the assumption that the pain increases as labour progresses and a reduction in VAS pain score of 1 cm is clinically significant, then remifentanil at this dose provides analgesia during labour.16

Primiparous labours are often more complicated, which is demonstrated in our study. An increased number of primiparous women required syntocinon infusion and the duration of labour was longer, with a higher rate of instrumental and Caesarean section delivery. This may provide an explanation for the request for an epidural by five primiparous women because of inadequate pain relief as labour progressed. In the study by Blair and colleagues10 primiparous women receiving remifentanil PCA requested epidural analgesia as labour became more complicated. It is interesting to note that our withdrawal rate of 10% crossover to epidural analgesia is the same as that in the study by Evron and colleagues,13 in which increasing doses of remifentanil PCA were permitted. In our study, two women who requested an epidural required bupivacaine 0.25% for analgesia, as the low-dose epidural (bupivacaine 0.1% and fentanyl 2 µg kg–1) was inadequate for lower back pain because of a confirmed occipitoposterior fetal position.

There was an increase in itching, although this was generally mild and no treatment was required. One woman had severe itching from obstetric cholestasis, but her recorded VAS score for itching did not increase from baseline. Itching has previously been reported as a side-effect of remifentanil PCA during labour, and in a preliminary investigation generalized itching resulted in one patient being withdrawn from the study.10 12

Nausea and vomiting are common during labour, but in our study remifentanil PCA resulted in no statistically significant change in the level of nausea from baseline. This is consistent with a previous study administering the same dose of remifentanil.10

There was no evidence of haemodynamic instability or respiratory depression, but monitoring was intermittent and there was no assessment of depth of respiration. Remifentanil by bolus injection in healthy volunteers has been demonstrated to produce a dose-related increase in respiratory adverse effects, with oxygen desaturation occurring at bolus doses of 25 or 50 µg, although not requiring intervention.17 Oxygen desaturation requiring oxygen supplementation has been demonstrated in the parturient receiving remifentanil PCA, but at a dose of 0.5 µg kg–1 and 2 min lockout the desaturation period was self-limiting.10 11 Oxygen desaturation may occur in the non-medicated parturient or if she is breathing entonox during labour.18 Mild sedation was common in our study, but all women were alert to voice and none of the subjects requested withdrawal of PCA because of any side-effects experienced.

The cardiotocographs were analysed according to NICE guidelines and categorized as normal, suspicious or pathological.19 These guidelines are similar to previous methods of analysis of cardiotocograph interpretation, but are mainly applicable during the first stage of labour.20 21 Most of the suspicious and pathological traces were recorded during the second stage of labour, when analysis can be difficult. There was no association between commencement of PCA and any deterioration in the cardiotocograph requiring intervention or investigation, such as fetal blood sampling. A transient decrease in variability was noted in three traces after starting PCA, but was still within reassuring parameters. These changes are consistent with a previous study, but the effects are much less frequent than those observed during systemic administration of other opioids.11 22

The neonatal Apgar scores at 1 and 5 min and the neurological examination were within normal limits for all neonates. The mother of the neonate who failed to demonstrate a normal response in three neurological tests had received 150 mg meperidine. This had been administered on the antenatal ward before she was in established labour, 4 h before commencing remifentanil PCA. The good neonatal outcome is consistent with previous studies, and Apgar scores have been demonstrated to be significantly higher following remifentanil PCA than after meperidine PCA.9 Fentanyl PCA in labour for those women with a contraindication to epidural analgesia has been shown to be associated with a 44% incidence of moderately depressed neonates.23

The mean umbilical cord gases were within normal range. Base deficit and lactate measurements are known to correlate significantly and are good indicators of neonatal outcome.24 The two UA cord samples with base excess values greater than –10 mEq litre–1 were both obtained following spontaneous delivery of a vigorous neonate with 1 and 5 min Apgar scores of 9.

The MV and UV cord samples demonstrate that remifentanil crosses the placenta. The remifentanil assays were below the detection limit in 50% of our UA samples which may suggest that the drug is either rapidly metabolized or redistributed in the neonate. Although this blood sampling only represents drug concentrations at one point in time, it does support the failure to demonstrate drug effects within the neonate following maternal administration of remifentanil PCA during labour.

In conclusion, remifentanil PCA at a bolus dose of 0.5 µg kg–1 and a lockout period of 2 min provided acceptable pain relief in labour with minimal side-effects for both multiparous and primiparous women. If labour becomes complicated, epidural analgesia may be required. The results of this study indicate placental transfer of remifentanil following bolus administration during labour, but we have failed to demonstrate any adverse effects on the fetus or neonate.

We suggest that remifentanil PCA is an option for pain relief in labour for those women with a contraindication to epidural analgesia or requesting opioid analgesia. An information sheet can be given to mothers antenatally and provisional consent obtained. Although we did not demonstrate any respiratory depression, our assessment of respiratory function was limited, and the potential for this always exists with any opioid analgesia. Therefore we would recommend the presence of a member of staff trained in Basic Life Support, who is able to detect and manage any respiratory compromise. The respiratory effect of remifentanil in pregnancy requires further study.


    Acknowledgments
 
The authors gratefully acknowledge Elan Pharma for sponsorship.


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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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18 Arfeen Z, Armstrong PJ, Whitfield A. The effects of entonox and epidural analgesia on arterial oxygen saturation of women in labour. Anaesthesia 1994; 49: 32–4[ISI][Medline]

19 National Institute for Clinical Excellence. The Use of Electronic Fetal Monitoring. London: NICE, 2001. Available online at: http://www.nice.org.uk

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