Key points.
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The usage of neuraxial and opioid analgesia for labour varies widely in different countries.
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Remifentanil has been shown to be an effective analgesic for labour with good maternal satisfaction ratings, but less so than neuraxial analgesia.
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Serious respiratory complications are a concern with remifentanil patient-controlled analgesia for labour.
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Careful monitoring is required to ensure maternal and neonatal safety in women receiving remifentanil during labour.
Learning objectives.
By reading this article, you should be able to:
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Explain the indications for the use of remifentanil in labour.
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Compare the effectiveness of remifentanil with other common practices for analgesia in labour.
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Discuss the safety profile of remifentanil for mother and neonate.
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Describe the precautions and monitoring required when giving remifentanil in labour.
Current practice
Neuraxial analgesia (epidural and combined spinal–epidural) is the gold standard for pain relief in labour. Rates of use vary considerably worldwide (Fig. 1). In the UK, in 2014, the rate of using epidural analgesia for labour was 30%. Despite the advantages of neuraxial analgesia, there may be contraindications to its use in some women, such as significant coagulopathy or ongoing use of anticoagulant medication, local infection, or uncorrected maternal hypovolaemia. Some women may choose not to receive it or prefer to use alternative analgesia.
Fig 1.
Percentage usage of epidurals in vaginal deliveries worldwide. Nigeria, 0.3; Croatia, 2.3; Japan, 2.6; South Africa, 5.6; Turkey, 11.4; Czech Republic and Slovakia, 12.5; Hong Kong, 15; Greece, 19.1; Denmark, 22; Norway, 28; UK, 29; Sweden, 31; Iceland, 43; Finland, 47; Ireland, 49.7; Israel, 50; Canada, 58.6; USA, 63; Belgium, 68; and France, 77.3.
There is an assortment of alternative pharmacological forms of analgesia for use during labour, including inhaled nitrous oxide (N2O), and opioids administered i.m. or i.v. via PCA (patient controlled analgesia). In 2014, 25% of labouring women in the UK received an opioid analgesic.1 There are global variations in the use of i.v. opioid analgesia for labour (Fig. 2). Because of its unique pharmacology, remifentanil may be a plausible alternative to both pethidine and neuraxial analgesia. A commentary in the British Medical Journal in 2018 suggested that labour epidural rates could be halved by the use of remifentanil.2
Fig 2.
Percentage availability of i.v. analgesia in vaginal deliveries worldwide. Nigeria, 17.3; Belgium, 22; USA, 25; Israel, 30; UK, 49; and France, 53.
Remifentanil
Remifentanil is an ultrashort-acting synthetic opioid. It has a rapid onset of effect of approximately 1 min. It is uniquely degraded by non-specific tissue and plasma esterases, and does not accumulate, with a context-sensitive half-time of approximately 3 min.
A study in 1997 measured the concentrations of remifentanil and its metabolite (remifentanil acid) in the maternal circulation (MA), umbilical vein (UV), and umbilical artery (UA) of pregnant women undergoing elective Caesarean delivery. The authors found high rates of placental transfer of remifentanil (mean [sd] UV:MA ratio: 0.88 [0.78]); this incidence is to be expected, as remifentanil is highly lipophilic and the placenta is well perfused. However, the drug undergoes rapid metabolism or redistribution in the fetus, as evident by a low mean (sd) UA:UV ratio of 0.29 (0.07).3 This finding suggests that remifentanil may be safer than other opioids for the fetus.
The first study that reported the use of remifentanil in labour was published in 2000. Only four women were included, and the study was terminated early because of the incidence of maternal adverse effects (sedation, desaturation, airway obstruction, and facial and generalised pruritis) and lack of efficacy as an analgesic as labour progressed.4 A subsequent study of 21 labouring women demonstrated a reduction of visual analogue scale (VAS) pain score by 3 cm from a baseline median pain score of 8 cm.5 This sets the stage for remifentanil as a labour analgesic. The RemiPCA SAFE Network (Switzerland, initiated in 2009) collated reports of remifentanil PCA use in labour with information about maternal satisfaction and adverse effects. Amongst more than 10,000 reported uses of remifentanil PCA recorded on the network, 82% of women reported that they were either satisfied or very satisfied with their labour analgesia.6
Over the past two decades, many dosage regimens have been described. Currently used bolus doses range from 10 to 50 μg, with a 2 min lockout period.6, 7 Background infusions are rarely used because of an increase incidence of severe adverse events.
In summary:
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(i)
Remifentanil is an ultrashort-acting synthetic opioid with a context sensitive time of approximately 3 min.
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(ii)
Remifentanil undergoes degradation by non-specific tissue and plasma esterases.
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(iii)
Remifentanil readily crosses the placenta, but undergoes rapid fetal elimination.
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(iv)
The use of remifentanil in labour is off-label, but may be suitable when neuraxial analgesia is either contraindicated (coagulopathy, anticoagulant use, and infection at site) or when not wanted.
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(v)
There is high maternal satisfaction when using remifentanil in labour.
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A typical dose of remifentanil is 40 μg bolus with a 2 min lockout.
Remifentanil compared with neuraxial analgesia
Efficacy
A 2014 meta-analysis of five RCTs, including 886 healthy labouring women, compared remifentanil PCA with epidural analgesia (bupivacaine, ropivacaine or levobupivacaine with an opioid: fentanyl or sufentanil), and found that epidural analgesia provided superior analgesia, with a mean difference between the groups of 1.9 cm for the VAS score at 1 h. At 2 h, the superiority of epidural analgesia became more pronounced with a mean difference of 3 cm.8
A multicentre equivalence trial performed in 2015 studied 1,358 women who received either remifentanil (n=687) or epidural analgesia (n=671).9 Of the 402 labouring women who initially received remifentanil PCA, 53 (13%) converted to epidural analgesia, and amongst the 296 women who initially received epidural analgesia, three (1%) converted to remifentanil PCA. The primary study outcomes were VAS scores to measure both pain intensity and pain relief. Remifentanil achieved poorer pain relief scores (–2.8) and worse pain intensity scores (3.8) compared with epidural analgesia. When comparing the modes of delivery, there were no significant differences between groups, with similar rates for spontaneous, instrumental, or Caesarean deliveries.10
Safety
Overall, adverse-effect profiles (nausea, vomiting and pruritus) were not significantly different. Apgar scores did not differ between remifentanil PCA and epidural analgesia, although UA pH was unexpectedly higher in women receiving remifentanil analgesia.
In summary:
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(i)
Remifentanil provides inferior analgesia compared with epidural analgesia in the first hour.
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(ii)
After the first hour, the efficacy of epidural analgesia becomes even more pronounced compared with remifentanil.
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(iii)
Modes of delivery were similar with both remifentanil and neuraxial analgesia.
Remifentanil compared with N2O
Efficacy
One RCT compared the use of remifentanil PCA with inhaled N2O.11 In this small study (15 women), pain was assessed using a verbal 11-point pain score (0=no pain; 10=worst pain imaginable). Pain intensity difference scores were calculated and significantly favoured remifentanil (1.5 vs 0.5 for N2O).
Safety
There were higher subjective sedation scores (using a 4-point system) for remifentanil.
Remifentanil compared with i.v. or i.m. pethidine
Efficacy
Pethidine is currently the most commonly prescribed opioid in UK labour wards. Douma and colleagues compared remifentanil PCA with pethidine PCA, and reported two main findings.12 They found that the rate of crossover to epidural analgesia was higher for pethidine than for remifentanil. Furthermore, remifentanil was associated with greater decreases in mean VAS scores from baseline at 1 h (3.2 compared with 0.8 for remifentanil and pethidine, respectively), but this difference disappeared after 1 h.12 The effect of remifentanil on VAS scores in the first hour was confirmed by a meta-analysis of seven RCTs with a total of 349 women.13 Three RCTs compared i.v. remifentanil to i.m. pethidine, and the other four compared i.v. remifentanil to i.v. pethidine. In another RCT, i.v. remifentanil was compared with i.m. pethidine (34 women in each arm); again, remifentanil reduced pain scores by a greater degree than pethidine.14
The largest study to date comparing remifentanil PCA with i.m. pethidine for pain relief in labour, the RESPITE trial, reported that significantly fewer women requested epidural analgesia, (19% compared with 41%).7 However, as most women approached (1,797/2,950 [61%]) declined to participate, a significant non-enrolment bias of women who desired an epidural or who a priori preferred remifentanil cannot be ruled out. In fact, 22 out of 200 (11%) women randomised to receive pethidine immediately requested an epidural (compared with none in the remifentanil group).7 A prespecified secondary outcome looking at mode of delivery revealed that a higher proportion of women in the remifentanil group had a spontaneous vaginal delivery and fewer required instrumental delivery, but the rates of Caesarean deliveries were the same.
Safety
One study found higher rates of sedation amongst women receiving remifentanil, as measured by an observer (1: awake; 2: sleepy; 3: eyes closed, but rousable by vocal stimulus; 4: eyes closed, but rousable by physical stimulus; and 5: unrousable). There were no differences in haemodynamic stability or ventilatory frequency.12 Other studies found no differences in opioid-related adverse outcomes, including cardiovascular status, respiration, gastrointestinal adverse effects, and neonatal Apgar in the two groups.14
In summary:
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(i)
Remifentanil PCA results in less crossover to epidural analgesia compared with pethidine.
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(ii)
There is greater reduction in pain scores, especially after 1 h, when using remifentanil PCA.
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(iii)
There are higher rates of spontaneous delivery (compared with instrumental) when using remifentanil PCA compared with pethidine.
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(iv)
Maternal non-respiratory adverse-effect profiles appear similar for remifentanil and pethidine, with potentially more sedation using remifentanil.
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(v)
Apgar scores were similar for remifentanil and pethidine.
Remifentanil compared with fentanyl
Efficacy
In one study, remifentanil PCA showed greater reduction in VAS after 1 h compared with fentanyl PCA (a mean reduction of 3.2 cm compared with 1.4 cm from baseline for remifentanil and fentanyl, respectively), with no difference thereafter.12 In another study, the reductions in VAS pain scores were not significantly different between fentanyl and remifentanil, but there was greater crossover to epidural analgesia in the fentanyl arm, suggesting less effective analgesia.15
Safety
There were significantly higher sedation scores and a higher frequency of maternal desaturations amongst women receiving remifentanil compared with fentanyl. The neonatal Apgar scores were lower (<7 at 1 min for 39% compared with 18%) and the need for resuscitation (bag-and-mask ventilation or tracheal intubation) was greater (59% compared with 25%).15
In summary:
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(i)
Evidence suggests that remifentanil provides better pain relief than fentanyl.
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(ii)
More frequent desaturations and respiratory depression, and greater sedation occurs using remifentanil compared with fentanyl.
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There are lower Apgar scores and greater need for positive-pressure ventilation with fentanyl.
Remifentanil PCA compared with remifentanil infusion
One study of 53 women compared the use of a continuous infusion of remifentanil (at a rate of 0.05 μg kg−1 min−1) with PCA (starting bolus 0.1 μg kg−1, increasing up to 0.4 μg kg−1). The VAS pain scores were significantly lower at 30, 60, and 90 min in the remifentanil PCA group.16
Maternal side respiratory depression
Remifentanil is associated with maternal respiratory depression. More apnoea events (described as either >20 s of zero ventilatory frequency or hypoventilation of <8 bpm) and a higher incidence of oxygen desaturation (below 94%) are reported with remifentanil compared with neuraxial analgesia.9 Data from the RemiPCA SAFE Network reported an incidence of hypoxaemia of 26% (defined as oxygen saturations under 94%).6 Life-threatening respiratory complications have been reported in the literature, although the reported events are likely to be an under-representation.17 In a survey of remifentanil use in the USA, respiratory depression (defined as hypoventilation or brief periods of apnoea) was reported in nine women, and two of these cases involved a cardiac arrest, albeit with ‘good outcomes’.18 Of concern, these cases would never have come to light without the survey specifically targeted to seek them.
Comparisons of remifentanil with pethidine report varying rates of major adverse effects. Some studies suggested a higher incidence of sedation and desaturation with remifentanil.12 Another study reported the greater use of supplementary oxygen to treat desaturation, with remifentanil PCA compared with i.m. pethidine (46% and 1%, respectively).7
Giving supplemental oxygen may not prevent hypoxia. Stocki and colleagues found episodes of apnoea despite giving oxygen to all women.19 Routine oxygen supplementation during remifentanil infusion has been recommended by some investigators.20, 21 Using pulse oximetry to monitor respiratory function remains as the most popular method. However, the use of 1:1 nursing or capnography increases the chance of identifying respiratory depression.7, 19 Because apnoea can occur before oxygen desaturation, the use of capnography in addition to pulse oximetry has been advocated.22
In the USA, the Food and Drug Administration requires monitored anaesthesia care during remifentanil administration, with a trained clinician to manage potential airway complications. Interestingly, only two-thirds of centres in the USA who responded to a survey reported 1:1 patient-to-nurse ratios. In addition, 1:1 ratios are recommended by Hill, whose Belfast unit introduced remifentanil in 2005.23 Mandatory 1:1 nursing decreased the likelihood of serious adverse events in the RESPITE study.7
Some adverse effects may be mild (nausea or pruritus), requiring little or no intervention. When compared with neuraxial analgesia, no differences were found in the rate of minor adverse effects, including nausea, vomiting, or pruritus, using remifentanil (Table S1).
In summary:
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(i)
Data should be routinely collected at a national level on the use of remifentanil PCA in labour and occurrence of adverse outcomes.
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(ii)
Respiratory depression is a common finding over a wide dose range, with great variation in rates reported (5–93%).
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(iii)
Respiratory depression is more common with remifentanil than neuraxial analgesia or pethidine.
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(iv)
Supplemental oxygen should be given to keep saturations over 94–95%, but may not prevent apnoea.
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(v)
The ratio of 1:1 nursing care should be mandatory and pulse oximetry should be used.
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Capnography may recognise apnoea before desaturation.
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(vii)
No significant haemodynamic effects are seen using remifentanil PCA.
Neonatal Apgar scores and respiratory depression
When Apgar scores at 1 and 5 min were compared, no difference was found between remifentanil and epidural analgesia.8 Compared with pethidine, no significant differences were found in neonatal Apgar scores at 1 and 5 min.13 However, neurological and adaptive capacity scores (NACS) were higher, and there was a lower incidence of non-reassuring fetal HRs (NRFHRs) requiring interventional delivery with remifentanil.7
Given the potential for neonatal adverse effects, oxygen, naloxone, a neonatal resuscitation trolley, and a paediatrician should all be readily available.
In summary:
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(i)
There are no differences in Apgar scores with remifentanil PCA compared with neuraxial analgesia.
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(ii)
Compared with pethidine, remifentanil PCA was associated with better neonatal outcomes measured by NACS and the incidences of NRFHR.
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(iii)
Safety measures must include availability of oxygen, naloxone, and a paediatrician.
Conclusions
Historically, pethidine has been the opioid of choice for many UK obstetric units. The avaiability of systemic opioid analgesics for labour expands the options for women.24 Remifentanil PCA appears to provide the most effective non-neuraxial labour analgesia, with high levels of maternal satisfaction and favourable delivery and neonatal outcomes. However, because of the incidence of maternal respiratory depression with remifentanil, illustrated by reports of maternal hypoxia, respiratory arrest, and maternal cardiac arrest, safety consideration is paramount. Not all units will be able to provide the levels of supervision required. At a minimum, a 1:1 ratio of woman to nurse or midwife capable of identifying and managing maternal apnoea is essential. A nurse or midwife should be present continuously in the room with the woman. Respiratory monitoring, including capnography, cannot be viewed as an alternative to the presence of a trained clinician. Such issues currently limit the widespread adoption of remifentanil PCA as a routine choice for labour analgesia.
Declaration of interest
The authors declare that they have no conflicts of interest.
MCQs
The associated MCQs (to support CME/CPD activity) will be accessible at www.bjaed.org/cme/home by subscribers to BJA Education.
Biographies
Ilai Ronel BMBS BMedSci is a final-year trainee in anaesthesia at Tel Aviv Sourasky Medical Center, Israel.
Carolyn Weiniger is an associate professor of anaesthesia and director of obstetric anaesthesia at Tel Aviv Sourasky Medical Center, Israel. She is chair of the Israeli Society of Obstetric Anaesthesia of the Israel Society of Anesthesiologists, and is an editor of the International Journal of Obstetric Anesthesia.
Matrix codes: 1A02, 2B01, 3B00
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.bjae.2019.07.002.
Supplementary data
The following is the Supplementary data to this article:
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