Anaesthesia 2014, 69, 458–467
doi:10.1111/anae.12602
Original Article Fetal effects of combined spinal-epidural vs epidural labour analgesia: a prospective, randomised double-blind study N. P. Patel,1 N. El-Wahab,2 R. Fernando,1 S. Wilson,2 S. C. Robson,3 M. O. Columb4 and G. R. Lyons5 1 Consultant, 2 Research Fellow, Department of Anaesthesia, University College London Hospitals NHS Trust, London, UK 3 Professor, Department of Fetal Medicine, Royal Victoria Infirmary, Newcastle upon Tyne, UK 4 Consultant, Department of Anaesthesia, South Manchester University Hospitals NHS Trust, Wythenshawe, UK 5 Emeritus Consultant, Department of Anaesthesia, St. James’s University Hospital, Leeds, UK
Summary We have compared fetal heart rate patterns, Apgar scores and umbilical cord gas values following initiation of labour analgesia using either combined spinal-epidural or epidural. One hundred and fifteen healthy women requesting neuraxial analgesia in the first stage of labour were randomly assigned to receive either combined spinal-epidural (n = 62) or epidural analgesia (n = 53). Fetal heart rate traces, recorded for 30 min before and 60 min after neuraxial block, were categorised as normal, suspicious or pathological according to national guidelines. Sixty-one fetal heart rate tracings were analysed in the combined spinal-epidural group and 52 in the epidural group. No significant differences were found in fetal heart rate patterns, Apgar scores or umbilical artery and vein acid-base status between groups. However, in both combined spinal-epidural and epidural groups, there was a significant increase in the incidence of abnormal fetal heart rate patterns following neuraxial analgesia (p < 0.0001); two before compared with eight after analgesia in the combined spinal-epidural group and zero before compared with 11 after in the epidural group. These changes comprised increased decelerations (p = 0.0045) (combined spinal-epidural group nine before and 14 after analgesia, epidural group four before and 16 after), increased late decelerations (p < 0.0001) (combined spinal-epidural group zero before and seven after analgesia, epidural group zero before and eight after), and a reduction in acceleration rate (p = 0.034) (combined spinal-epidural group mean (SD) 12.2 (6.7) h 1 before and 9.9 (6.1) h 1 after analgesia, epidural group 11.0 (7.3) h 1 before and 8.4 (5.9) h 1 after). These fetal heart rate changes did not affect neonatal outcome in this healthy population. .................................................................................................................................................................
Correspondence to: R. Fernando Email: [email protected] Accepted: 7 January 2014
Introduction Combined spinal-epidural (CSE) analgesia during labour has been associated with fetal heart rate (FHR) abnormalities with an incidence ranging from 4% to 21% [1–6]. Such changes are reported more frequently with CSE than with epidural analgesia alone [7]. A 458
systematic review demonstrated an increased risk of fetal bradycardia with spinal opioids compared with epidural or intravenous opioids, with an odds ratio of 1.8 (CI 1.0–3.1) [8]. However, the literature is not completely consistent as some publications failed to show a significant increase in fetal bradycardia © 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
following CSE. There are methodological differences in studies, including differences in definitions of FHR abnormalities. Earlier studies compared spinal opioids with epidural bupivacaine 0.25% [1], but more recently, lower dose regimens have been investigated. To date, very few randomised, double-blind studies have compared the incidence of FHR abnormalities between these two neuraxial techniques using the same drug combination [9]. This paper presents secondary outcome data from a study comparing the minimum local analgesic concentration (MLAC) of epidural bupivacaine for analgesic supplementation following establishment of analgesia using either spinal or epidural [10]. We have compared FHR abnormalities and neonatal outcome measures following neuraxial analgesia established either with a spinal or epidural using the same low-dose bupivacaine and fentanyl mixture.
Methods After hospital ethical committee approval (Royal Free Hampstead NHS Trust, London, UK) and written informed consent, 115 parturients requesting neuraxial analgesia were recruited into a prospective, randomised and double-blind study designed primarily to determine epidural bupivacaine requirements for the second dose following initial spinal or epidural initiation of analgesia for labour [10]. The inclusion criteria were ASA physical status 1– 2, singleton pregnancy of > 36 weeks, gestation with vertex presentation, and in active labour between 2 and 6 cm cervical dilatation. The exclusion criteria were pre-eclampsia or administration of opioid medication within the previous 4 h. Upon request for neuraxial analgesia, the women were randomly assigned into two groups by a computer-generated random number table using Excel (Microsoft Corporation, Redmond, WA, USA). Parturients were randomly assigned to one of the two treatment regimens (CSE or epidural labour analgesia) using sealed opaque envelopes that contained details of group allocation. The sequence of treatment was concealed until the interventions were assigned. Three anaesthetists were involved in the study. One anaesthetist who was not involved with clinical care or data collection performed the randomisation procedure. A second anaesthetist performed the neuraxial block on request according to the group © 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 458–467
allocation. A third anaesthetist blinded to the procedure performed measurements at baseline immediately before neuraxial block and at 15 and 30 min after neuraxial block. The patient and third anaesthetist were blinded to group allocation throughout. Analgesic efficacy was assessed using a 100-mm visual analogue pain score (VAPS) where 0 represented ‘no pain’ and 100 represented ‘worst pain possible’, performed at the height of the contraction. Analgesia was ‘effective’ if the VAPS reduced to ≤ 10 mm within 30 min or ‘ineffective’ if the VAPS was > 10 mm at 30 min. Women with ineffective analgesia were given rescue epidural analgesia (20 ml bupivacaine 0.1% with fentanyl 2 lg.ml 1). Hypotension was defined as ≥ 20% decrease in systolic blood pressure from baseline values measured between contractions before commencing the neuraxial procedure. Blood pressure readings were taken from the right arm with the mother in a 45° semirecumbent position. Motor block was recorded using the modified Bromage score where 1 = complete block, unable to move feet or knees; 2 = able to move feet only; 3 = just able to move knees; 4 = detectable weakness of hip flexion; and 5 = full flexion of hips and knees while supine. Adverse effects such as pruritus, sedation, nausea or vomiting and treatment including the use of ephedrine were recorded. All neuraxial procedures were performed in the flexed sitting position at the L3-4 or L4-5 lumbar intervertebral space following an intravenous preload of 500–1000 ml lactated Ringer’s solution. The epidural space was identified using loss of resistance to saline with a 16-G Tuohy needle (Portex; Smiths Medical, Ashford, UK). The CSE was performed using the single interspace, needle-through-needle technique. The spinal was performed using a 27-G, 119-mm Whitacre spinal needle (Becton Dickinson, Franklin Lakes, NJ, USA). In both groups an 18-G, closed-end, multiport epidural catheter (Portex; Smiths Medical) was inserted 4–5 cm into the epidural space. The CSE group received 2.5 ml of a mixture of bupivacaine 0.1% with fentanyl 2 lg.ml 1 injected over 30 s [11]. To ensure that the entire dose was delivered spinally, the syringe was securely attached to the hub of the spinal needle once cerebrospinal fluid (CSF) was seen and CSF was aspirated at the 459
Anaesthesia 2014, 69, 458–467
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
beginning and end of the injection. If analgesia was inadequate following CSE, women were given an epidural bolus of the same mixture. The epidural group received 20 ml bupivacaine 0.1% with fentanyl 2 lg.ml 1 over 3 min. A test dose was not used. Following neuraxial block, women were positioned 45° semirecumbent with left uterine displacement using a wedge, and routine maternal and fetal monitoring was continued. Continuous electronic FHR monitoring was performed by cardiotocography (CTG) for 30 min before initiating the neuraxial block and for 60 min afterwards. The CTGs were analysed retrospectively by an obstetrician (SCR) who was blinded to the method of analgesia. Fetal heart rate traces were categorised overall as normal, suspicious or pathological according to a national guideline [12] (Appendix 1). Maternal data included age, height, weight, gestation, parity, cervical dilatation at time of neuraxial labour analgesia, use of prostaglandin for induction of labour and oxytocin for augmentation of uterine contractions, use of pethidine before neuraxial analgesia, and time from first epidural or spinal injection until delivery. Neonatal data included mode of delivery, Apgar score at 1 and 5 min, umbilical artery and vein pH and base excess. Any admissions to the neonatal intensive care unit were recorded. Monitoring was continued for 60 min in all recruited women, whether additional rescue epidural analgesia was required or not and regardless of exclusion from the primary study [10]. All women received routine obstetric care throughout the study and thereafter. Differences in groups were analysed using the two-sided Student’s t-test and Fisher exact test. Within-group analyses included repeated measures ANOVA and McNemar’s exact chi-squared test. Multiple logistic regression was used to identify independent factors associated with suspicious or pathological FHR patterns on an intention-to-treat basis. Analyses were carried out using Excel 2000 (Microsoft Corporation), Number Crunching Statistical System (NCSS) 2000 (NCSS Inc, Kaysville, UT, USA) and GraphPad Prism 4.0 (GraphPad Software Inc, San Diego, CA, USA). Statistical significance was defined as an overall p value of 0.05. 460
Results The CONSORT recruitment diagram is shown in Fig. 1. Patient and obstetric characteristics were similar between groups (Table 1). Effective analgesia was achieved in 88 women following the first injection, 43 in the CSE group and 45 in the epidural group. The remainder received rescue epidural analgesia within 30 min. All patients were comfortable following rescue analgesia except for two; one delivered shortly after having the epidural sited and one refused rescue analgesia after the first injection. Mode of delivery was similar between groups (Table 2). No emergency caesarean sections were performed in the hour following neuraxial analgesia. There were two failed attempts at topping up the epidural catheter for emergency caesarean section in the CSE group and these women received general anaesthesia. The indications for caesarean section are summarised in Table 2. There was no difference in neonatal Apgar scores at 1 or 5 min or in umbilical artery or vein pH or base excess between groups (Table 3). There were no admissions to the neonatal intensive care unit. Of the 115 women recruited, 113 FHR traces were analysed by intention-to-treat. One FHR trace from each group was missing from the patient’s notes and could not be located. Table 4 gives a breakdown of FHR pattern in the epidural and CSE groups before and after injection. There were no differences in FHR patterns between groups. There was a significant reduction in the acceleration rate and increase in decelerations after neuraxial analgesia. The time interval between neuraxial anaesthesia and the first deceleration was non-significantly shorter in the epidural group (p = 0.053). There were no overall differences between groups in the incidences of normal, suspicious or pathological FHR traces either before or after injection (Table 5). All FHR traces, except two in the CSE group, were categorised as normal before injection. After spinal injection, one improved from pathological to suspicious and one deteriorated from suspicious to pathological. Within groups, there was a significant increase in the number of abnormal (suspicious or pathological) FHR traces after neuraxial analgesia (two before and eight after in the © 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
Anaesthesia 2014, 69, 458–467
Assessed for eligibility (n = 124)
Excluded (n = 9) Not meeting inclusion criteria (n = 0) Declined to participate (n = 9) Other reasons (n = 0)
Randomised (n = 115)
CSE GROUP
EPIDURAL GROUP
Allocated to intervention (n = 62) Received allocated intervention (n = 62) Did not receive allocated intervention (n = 0)
Allocated to intervention (n = 53) Received allocated intervention (n = 53) Did not receive allocated intervention (n = 0)
Lost to follow-up (n = 0)
Lost to follow-up (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Analysed (n = 61) Excluded from analysis (n = 1, CTG missing from notes)
Analysed (n = 52) Excluded from analysis (n = 1, CTG missing from notes)
Figure 1 CONSORT recruitment diagram. Table 1 Patients’ characteristics and obstetric data in 115 women receiving combined spinal-epidural (CSE) or epidural analgesia. Values are mean (SD) or number (proportion).
Age; years Height; cm Weight; kg Gestation; weeks Cervical dilatation; cm Nulliparous Previous use of prostaglandin E2 Oxytocin infusion Previous use of pethidine
CSE (n = 62)
Epidural (n = 53)
30.3 163.5 73.9 40.4 3.6 44 15
31.0 162.6 77.7 40.1 3.6 35 9
(5.2) (6.9) (11.7) (1.2) (1.0) (71%) (24%)
9 (15%) 6 (10%)
(5.3) (7.2) (15.1) (1.1) (0.9) (66%) (17%)
12 (23%) 2 (4%)
Table 2 Mode of delivery, indication for caesarean section and elapsed time until delivery in 115 women receiving combined spinal-epidural (CSE) or epidural analgesia. Values are number (proportion) or median (IQR [range]). CSE (n = 62) Spontaneous Instrumental Caesarean section Failure to progress (dystocia) Fetal distress/ abnormal FHR pattern Time to delivery; min
Epidural (n = 53)
41 (66%) 7 (11%) 14 (23%) 6 (10%)
32 (60%) 12 (23%) 9 (17%) 6 (11%)
8 (13%)
3 (6%)
462 (291–611 [81–966])
431 (283–589 [100–1025])
FHR, fetal heart rate.
CSE group, zero before and 11 after in the epidural group; p < 0.0001). There was a non-significant increase in the number of pathological FHR traces after neuraxial analgesia (one before and three after in the CSE group, zero before and four after in the epidural group; p = 0.07). Sub-analysis of those patients with effective analgesia after the first injection © 2014 The Association of Anaesthetists of Great Britain and Ireland
(n = 88) showed no differences in FHR abnormalities, Apgar scores or umbilical acid-base status between groups. Table 6 summarises the incidence of adverse effects. There was no difference in the incidence and severity of hypotension between groups, although 461
Anaesthesia 2014, 69, 458–467
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
Table 3 Neonatal outcome data for 115 women receiving combined spinal-epidural (CSE) or epidural analgesia. Values are median (IQR [range]) or mean (SD). CSE (n = 62) Apgar; 1 min Apgar; 5 min Umbilical artery pH Umbilical artery base excess; mmol.l 1 Umbilical vein pH Umbilical vein base excess; mmol.l 1
Table 5 Fetal heart rate pattern in women before and after the start of combined spinal-epidural (CSE) or epidural analgesia. Values are number (proportion). CSE (n = 61)
Epidural (n = 53)
9 (9–9 [4–10]) 10 (10–10 [9–10]) 7.23 (0.08), n = 31 7.87 (3.14), n = 22
9 (9–9 [6–10]) 10 (10–10 [8–10]) 7.25 (0.07), n = 24 8.22 (3.64), n = 23
7.31 (0.07), n = 31 7.11 (3.20), n = 31
7.31 (0.08), n = 29 7.06 (4.07), n = 27
Epidural (n = 52)
Before Suspicious Pathological
After
1 (2%) 1 (2%)
5 (8%) 3 (5%)
Before 0 0
After 7 (13%) 4 (8%)
Significant increase within both groups in total number of cases with suspicious or pathological fetal heart rate pattern following neuraxial analgesia p < 0.0001.
severe hypotension occurred more frequently than mild/moderate hypotension in both groups. Two women in the CSE group required ephedrine (6 mg each) compared with one woman in the epidural group (12 mg). The maximum motor weakness recorded during the study period in any woman was a modified Bromage score of 4. This motor weakness occurred exclusively in the CSE group (10 women after CSE vs 0 after epidural; p = 0.0017), although the effect was transient and recovered by 30 min. Using multiple logistic regression analysis, hypotension, parity and efficacy of analgesia were not found to be associated with suspicious or pathological
Table 6 Maternal adverse effects in women receiving combined spinal-epidural (CSE) or epidural. Values are number (proportion). CSE (n = 62) Nausea and/or vomiting Sedation Modified Bromage score 4 Pruritus Decrease of SBP 20–24.9% Decrease of SBP 25–30% Decrease of SBP > 30%
Epidural (n = 53)
p value
1 (2%)
2 (4%)
NS
1 (2%) 10 (16%)
1 (2%) 0
NS 0.0017
14 (22%) 1 (2%)
6 (11%) 2 (4%)
NS NS
0
1 (2%)
NS
3 (5%)
5 (9%)
NS
SBP, systolic blood pressure.
Table 4 Summary of fetal heart rate (FHR) changes before and after initiation of combined spinal-epidural (CSE) or epidural analgesia. Values are mean (SD), number (proportion) or median (IQR [range]). CSE (n = 61)
1
Baseline FHR; beats.min Reduced variability; < 5 beats.min 1 for > 40 min Accelerations; n.h 1* Decelerations† Early Variable Late‡ Time to deceleration (variable or late); min
Epidural (n = 52)
Before
After
Before
After
135 0 12.2 9 7 3 0
136 2 9.9 14 7 4 7 36
134 0 11.0 4 3 1 0
135 1 8.4 16 6 7 8 17
(9) (6.7) (15%) (11%) (5%)
(9) (3%) (6.1) (23%) (11%) (7%) (11%) (17–50 [7–56])
(8) (7.3) (8%) (6%) (2%)
(10) (2%) (5.9) (31%) (12%) (13%) (15%) (12–29 [2–42])
*p = 0.034 within group. †p = 0.0046 within group. ‡p < 0.0001 within group. 462
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
FHR traces. Only the use of oxytocin was found to be independently significant (p < 0.01).
Discussion We found that CSE did not increase the incidence of FHR abnormalities when compared with epidural analgesia. There was no difference in the incidence of suspicious or pathological FHR traces, neonatal outcome as assessed by Apgar scores or umbilical artery and vein pH and base excess or obstetric outcome between the two neuraxial techniques. This is in contrast to the results of a systematic review [8], although it should be noted that only two of the studies included in that analysis are directly comparable to ours, which may explain the difference in our findings. Most studies comparing CSE and epidural labour analgesia have not recorded umbilical artery base excess. Base excess is probably a better indicator of neonatal metabolic status than pH, which can be affected by maternal breathing [13]. Other studies demonstrating an increase in FHR abnormalities following neuraxial analgesia have shown no association with umbilical artery acidaemia [1, 14, 15]. We collected paired umbilical arterial and venous samples, as ideally they should be interpreted together [12, 13]. Fetal heart rate pattern analysis was performed by an independent blinded obstetrician using national guidelines to minimise bias. The original study was not powered to detect differences in FHR abnormalities, but it is reassuring that there was no difference in FHR and neonatal outcome between the groups. This study does, however, demonstrate that there are increased incidences of non-reassuring and pathological FHR patterns after neuraxial analgesia. It is only pathological FHR patterns that require obstetric intervention [12]; although we demonstrated a non-significant tendency to an increased incidence of pathological FHR following neuraxial analgesia, inclusion of a control group would be required in order to evaluate a causal link fully. There were no emergency caesarean deliveries during the first hour after neuraxial analgesia was established. One of the suggested mechanisms of fetal bradycardia is that rapid onset of analgesia can lead to an imbalance of plasma adrenaline and noradrenaline, which can lead to uterine hypertonus [7, 16]. This is supported by laboratory work on the rat uterus that © 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 458–467
demonstrated increased myometrial tone and uterine vascular resistance following a decrease in adrenaline concentration [17]. A recent study in humans using intrauterine pressure measurements provides further evidence, demonstrating that a faster onset of pain relief after regional analgesia led to a higher incidence of uterine hypertonus and resultant FHR changes [7]. We would have expected FHR decelerations to have occurred sooner in the CSE group, as this has a faster speed of onset than epidural, but this was not the case in our study. However, an explanation may be as follows: although four of seven women in the CSE group had decelerations between 30 and 60 min, three of these had ineffective analgesia from the spinal injection and required epidural rescue medication, hence increasing the time until effective analgesia was achieved. In the epidural group, six of seven women who had decelerations between 30 and 60 min had effective analgesia after the first injection. None of our patients exhibited clinical hypertonus, defined as ≥ 6 contractions 10 min 1. Uterine hypertonus may be one of a number of factors involved in precipitating FHR abnormalities. Other proposed mechanisms include hypotension and aortocaval compression. Although hypotension was implicated in the past [18], most studies have shown no relation with FHR abnormalities [5, 15, 16, 19, 20]. In this setting, hypotension results from one or more of pain relief, sympathetic block and inferior vena caval compression. In our study, there was no difference in the incidence and severity of hypotension between groups; very few participants had severe hypotension requiring treatment. All women were given a fluid preload and positioned to reduce inferior vena caval compression. A fall in uterine perfusion pressure may occur in the absence of maternal hypotension due to aortic compression, with resultant placental hypoperfusion and FHR abnormalities. It has been suggested that milder degrees of aortocaval compression may remain concealed until after neuraxial analgesia, when the onset of sympathetic block inhibits the normal compensatory mechanisms that act to maintain maternal blood pressure, particularly vasoconstriction [21]. Interestingly, multiple logistic regression analysis showed no significant association between hypotension and a suspicious or pathological FHR pattern in this 463
Anaesthesia 2014, 69, 458–467
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
study. It did, however, show that oxytocin independently increased the likelihood of FHR pattern deterioration in combination with neuraxial analgesia. This has also been suggested by others [16], as have other factors such as lack of fetal head engagement [22], presence of variable FHR decelerations before neuraxial blockade [22], contraction pain scores [23] and increased maternal age [23]. Evaluation of these factors was beyond the scope of this study, but it is clear that FHR pattern deterioration has a multifactorial causation that warrants further investigation. The dose of analgesics that we used represents approximately 3.69 the ED50 of spinal bupivacaine and 29 the EC50 of epidural bupivacaine as estimated in previous MLAC studies [24, 25]. As such, it was anticipated that these first doses would provide effective analgesia to all. If we had administered a higher dose of spinal fentanyl, we might have seen a difference in FHR abnormalities between the groups. Many institutions give fentanyl 25 lg combined with bupivacaine 2.5 mg. We used fentanyl 5 lg because previous work at our institution demonstrated a similar significant degree of sparing of spinal bupivacaine with 5, 15 and 25 lg of fentanyl [24]. Using a pre-mixed solution of 2.5 ml bupivacaine 0.1% with fentanyl 2 lg.ml 1 is standard practice at our institution because it is effective, convenient, saves time and reduces the potential for drug errors and contamination. Spinal sufentanil appears to have a dose-dependent effect, with 7.5 lg producing a greater incidence of fetal bradycardia compared with 1.5 lg in one retrospective study [15]. The same authors confirmed this finding in a recent prospective, randomised study involving 300 parturients, finding an increased incidence of FHR abnormalities and uterine hypertonus in women receiving 7.5 lg spinal sufentanil alone compared with those receiving either 1.5 lg spinal sufentanil with 2.5 mg bupivacaine and 2.5 lg adrenaline, or epidural analgesia [20]. In another prospective study of patients receiving spinal analgesia, 7.5 lg sufentanil produced more FHR abnormalities compared with either 5 lg sufentanil with 1 mg bupivacaine or 1.05 lg sufentanil with 1.75 mg bupivacaine [14]. A randomised study of 84 patients investigating the dose–response relation of spinal fentanyl for labour analgesia showed no difference in FHR between a range of doses between 5–25 lg, although FHR monitoring was only performed at baseline and 464
30 min after injection [24]. A recent study showed no difference in FHR abnormalities between six groups receiving between 0 and 25 lg spinal fentanyl combined with 2.5 mg bupivacaine, although it did not have sufficient power to assess this outcome [26]. Therefore, whether fentanyl is similar to sufentanil in this regard remains to be established. In conclusion, these secondary outcome data from a prospective, randomised, double-blind study confirm the findings of others that CSE analgesia during the first stage of labour does not increase FHR abnormalities or have an adverse effect on neonatal or obstetric outcomes when compared with epidural analgesia. It also confirms that FHR abnormalities increase after institution of neuraxial analgesia and that oxytocin rather than hypotension may be an important associated factor. A larger prospective study randomly assigning women to CSE, epidural and parenteral opioid is required, using standard guidelines to interpret FHR traces and measuring neonatal umbilical artery and vein pH and base excess.
Acknowledgements We thank the labour ward staff at the Royal Free Hospital NHS Trust, London, UK.
Competing interests NP was supported by a research fellowship grant from the Obstetric Anaesthetists’ Association (OAA), UK. RF was supported by the University College London Hospitals/University College London (UCLH/UCL) Comprehensive Biomedical Research Centre, which receives a proportion of funding from the UK Department of Health’s National Institute of Health Research (NIHR) Biomedical Research Center’s funding scheme. NE and SW undertook research fellowships as salaried posts employed by University College London Hospitals NHS Foundation Trust.
References 1. Nielsen PE, Erickson JR, Abouleish EI, Perriatt S, Sheppard C. Fetal heart rate changes after intrathecal sufentanil or epidural bupivacaine for labor analgesia: incidence and clinical significance. Anesthesia and Analgesia 1996; 83: 742–6. 2. Palmer CM, Maciulla JE, Cork RC, Nogami WM, Gossler K, Alves D. The incidence of fetal heart rate changes after intrathecal fentanyl labor analgesia. Anesthesia and Analgesia 1999; 88: 577–81. © 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia 3. Carvalho B, Fuller AJ, Brummel C, Durbin M, Riley ET. Fetal oxygen saturation after combined spinal-epidural labor analgesia: a case series. Journal of Clinical Anesthesia 2007; 19: 476–8. 4. Collis RE, Davies DWL, Aveling W. Randomised comparison of combined spinal-epidural and standard epidural analgesia in labour. Lancet 1995; 345: 1413–6. 5. Eberle RL, Norris MC, Eberle AM, Naulty JS, Arkoosh VA. The effect of maternal position on fetal heart rate during epidural or intrathecal labor analgesia. American Journal of Obstetrics and Gynecology 1998; 179: 150–5. 6. Nageotte MP, Larson D, Rumney PJ, Sidhu M, Hollenbach K. Epidural analgesia compared with combined spinal-epidural analgesia during labor in nulliparous women. New England Journal of Medicine 1997; 337: 1715–9. 7. Abrao KC, Francisco RPV, Miyadahira S, Cicarelli DD, Zugaib M. Elevation of uterine basal tone and fetal heart rate abnormalities after labor analgesia: a randomized controlled trial. Obstetrics and Gynecology 2009; 113: 41–7. 8. Mardirosoff C, Dumont L, Boulvain M, Tramer MR. Fetal bradycardia due to intrathecal opioids for labour analgesia: a systematic review. British Journal of Obstetrics and Gynaecology 2002; 109: 274–81. 9. Van de Velde M, Mignolet K, Vandermeersch E, Van Assche A. Prospective, randomized comparison of epidural and combined spinal epidural analgesia during labour. Acta Anaesthesiologica Belgica 1999; 50: 129–36. 10. Patel NP, Armstrong SL, Fernando R, et al. Combined spinal epidural vs epidural labour analgesia: does initial intrathecal analgesia reduce the subsequent minimum local analgesic concentration of epidural bupivacaine? Anaesthesia 2012; 67: 584–93. 11. Davies J, Fernando R, McLeod A, Verma S, Found P. Postural stability following ambulatory regional analgesia for labor. Anesthesiology 2002; 97: 1576–81. 12. National Institute for Health and Care Excellence. Intrapartum care: care of healthy women and their babies during childbirth (clinical guideline 55). 2007. htpp://www.nice.org.uk/ CG55 (accessed 07/01/2014). 13. Reynolds F. Regional Analgesia in Obstetrics: a Millennium Update. London: Springer, 2000. 14. Vercauteren M, Bettens K, Van Springel G, Schols G, Van Zundert J. Intrathecal labor analgesia: can we use the same mixture as is used epidurally? International Journal of Obstetric Anesthesia 1997; 6: 242–6.
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 458–467
15. Van de Velde M, Vercauteren M, Vandermeersch E. Fetal heart rate abnormalities after regional analgesia for labor pain: the effect of intrathecal opioids. Regional Anesthesia and Pain Medicine 2001; 26: 257–62. 16. Clarke VT, Smiley RM, Finster M. Uterine hyperactivity after intrathecal injection of fentanyl for analgesia during labor: a cause of fetal bradycardia? Anesthesiology 1994; 81: 1083. 17. Segal S, Csavoy AN, Datta S. The tocolytic effect of catecholamines in the gravid rat uterus. Anesthesia and Analgesia 1998; 87: 864–9. 18. D’Angelo R, Eisenach JC. Severe maternal hypotension and fetal bradycardia after a combined spinal epidural anesthetic. Anesthesiology 1997; 87: 166–8. 19. Norris MC. Intrathecal opioids and fetal bradycardia: is there a link? International Journal of Obstetric Anesthesia 2000; 9: 264–9. 20. Van de Velde M, Teunkens A, Hanssens M, Vandermeersch E, Verhaeghe J. Intrathecal sufentanil and fetal heart rate abnormalities: a double-blind, double placebo-controlled trial comparing two forms of combined spinal epidural analgesia with epidural analgesia in labor. Anesthesia and Analgesia 2004; 98: 1153–9. 21. Preston R, Crosby ET, Kotarba D, Dudas H, Elliott RD. Maternal positioning affects fetal heart rate changes after epidural analgesia for labour. Canadian Journal of Anesthesia 1993; 40: 1136–41. 22. Gaiser RR, McHugh M, Cheek TG, Gutsche BB. Predicting prolonged fetal heart rate deceleration following intrathecal fentanyl/bupivacaine. International Journal of Obstetric Anesthesia 2005; 14: 208–11. 23. Nicolet J, Miller A, Kaufman I, Guertin MC, Deschamps A. Maternal factors implicated in fetal bradycardia after combined spinal epidural for labour pain. European Journal of Anaesthesiology 2008; 25: 721–5. 24. Stocks GM, Hallworth SP, Fernando R, England AJ, Columb MO, Lyons G. Minimum local analgesic dose of intrathecal bupivacaine in labor and the effect of intrathecal fentanyl. Anesthesiology 2001; 94: 593–8. 25. Lyons G, Columb M, Hawthorne L, Dresner M. Extradural pain relief in labour: bupivacaine sparing by extradural fentanyl is dose dependent. British Journal of Anaesthesia 1997; 78: 493–7. 26. Wong CA, Scavone BM, Slavenas JP, et al. Efficacy and side effect profile of varying doses of intrathecal fentanyl added to bupivacaine for labor analgesia. International Journal of Obstetric Anesthesia 2004; 13: 19–24.
465
Anaesthesia 2014, 69, 458–467
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
Appendix 1: Fetal heart rate trace analysis [12]. Classification of fetal heart rate (FHR) trace features Baseline FHR; beats.min 1
Variability; beats.min 1
Reassuring Non-reassuring
110–160 100–109 161–180
≥5 < 5 for 40–90 min
Abnormal
< 100
< 5 for ≥ 90 min
> 180 Sinusoidal pattern
Parameters defined as follows:
• • • •
Baseline – mean level of the FHR when this is stable, excluding accelerations and decelerations, determined over a 5–10 min period. Normal is 110–160 beats.min 1. Variability – minor fluctuations in baseline FHR, the difference between the highest peak and lowest trough in a 1-min segment of the trace. Normal is ≥ 5 beats.min 1. Number of accelerations per hour – transient FHR increases of ≥ 15 beats.min 1 lasting ≥ 15 s. Number of decelerations – transient episodes of FHR slowing by ≥ 15 beats.min 1 below baseline lasting ≥ 15 s.
Decelerations None Early deceleration Variable deceleration Single prolonged deceleration ≤ 3 min Atypical variable deceleration
• •
466
Early (uniform, repetitive decelerations with onset early in contraction and return to baseline at the end of the contraction). Late (uniform, repetitive decelerations with onset mid to end of the contraction, nadir > 20 s after peak of the contraction and ending after the contraction). Variable (variable, intermittent decelerations with rapid onset and recovery. Time relations with the contraction cycle are variable and may occur in isolation).
Present The absence of accelerations with an otherwise normal FHR trace are of uncertain significance
Late decelerations Single prolonged deceleration > 3 min
•
Prolonged (abrupt decrease in FHR to below baseline lasting at least 60–90 s, becoming pathological if > 3 min).
Further information about classifying FHR traces is given below:
• • • •
Types of deceleration:
•
Accelerations
•
If repeated accelerations are present with reduced variability, the FHR trace should be regarded as reassuring. True early uniform decelerations are rare and benign, and therefore they are not significant. Most decelerations in labour are variable. If a bradycardia occurs in the baby for more than 3 min, urgent medical aid should be sought and preparations should be made to urgently expedite the birth of the baby, classified as a category 1 birth. This could include moving the woman to theatre if the fetal heart has not recovered by 9 min. If the fetal heart recovers within 9 min, the decision to deliver should be reconsidered in conjunction with the woman if reasonable. A tachycardia in the baby of 160–180 beats.min 1, where accelerations are present and no other adverse features appear, should not be regarded as suspicious. However, an increase in the baseline heart rate, even within the normal range, with other non-reassuring or abnormal features should increase concern.
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
Anaesthesia 2014, 69, 458–467
Definition of FHR abnormalities Normal Suspicious Pathological
An FHR where all four features fall into the reassuring category An FHR whose features fall into one of the non-reassuring categories and the remainder of the features are reassuring An FHR whose features fall into two or more non-reassuring categories or one or more abnormal categories
© 2014 The Association of Anaesthetists of Great Britain and Ireland
467
doi:10.1111/anae.12602
Original Article Fetal effects of combined spinal-epidural vs epidural labour analgesia: a prospective, randomised double-blind study N. P. Patel,1 N. El-Wahab,2 R. Fernando,1 S. Wilson,2 S. C. Robson,3 M. O. Columb4 and G. R. Lyons5 1 Consultant, 2 Research Fellow, Department of Anaesthesia, University College London Hospitals NHS Trust, London, UK 3 Professor, Department of Fetal Medicine, Royal Victoria Infirmary, Newcastle upon Tyne, UK 4 Consultant, Department of Anaesthesia, South Manchester University Hospitals NHS Trust, Wythenshawe, UK 5 Emeritus Consultant, Department of Anaesthesia, St. James’s University Hospital, Leeds, UK
Summary We have compared fetal heart rate patterns, Apgar scores and umbilical cord gas values following initiation of labour analgesia using either combined spinal-epidural or epidural. One hundred and fifteen healthy women requesting neuraxial analgesia in the first stage of labour were randomly assigned to receive either combined spinal-epidural (n = 62) or epidural analgesia (n = 53). Fetal heart rate traces, recorded for 30 min before and 60 min after neuraxial block, were categorised as normal, suspicious or pathological according to national guidelines. Sixty-one fetal heart rate tracings were analysed in the combined spinal-epidural group and 52 in the epidural group. No significant differences were found in fetal heart rate patterns, Apgar scores or umbilical artery and vein acid-base status between groups. However, in both combined spinal-epidural and epidural groups, there was a significant increase in the incidence of abnormal fetal heart rate patterns following neuraxial analgesia (p < 0.0001); two before compared with eight after analgesia in the combined spinal-epidural group and zero before compared with 11 after in the epidural group. These changes comprised increased decelerations (p = 0.0045) (combined spinal-epidural group nine before and 14 after analgesia, epidural group four before and 16 after), increased late decelerations (p < 0.0001) (combined spinal-epidural group zero before and seven after analgesia, epidural group zero before and eight after), and a reduction in acceleration rate (p = 0.034) (combined spinal-epidural group mean (SD) 12.2 (6.7) h 1 before and 9.9 (6.1) h 1 after analgesia, epidural group 11.0 (7.3) h 1 before and 8.4 (5.9) h 1 after). These fetal heart rate changes did not affect neonatal outcome in this healthy population. .................................................................................................................................................................
Correspondence to: R. Fernando Email: [email protected] Accepted: 7 January 2014
Introduction Combined spinal-epidural (CSE) analgesia during labour has been associated with fetal heart rate (FHR) abnormalities with an incidence ranging from 4% to 21% [1–6]. Such changes are reported more frequently with CSE than with epidural analgesia alone [7]. A 458
systematic review demonstrated an increased risk of fetal bradycardia with spinal opioids compared with epidural or intravenous opioids, with an odds ratio of 1.8 (CI 1.0–3.1) [8]. However, the literature is not completely consistent as some publications failed to show a significant increase in fetal bradycardia © 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
following CSE. There are methodological differences in studies, including differences in definitions of FHR abnormalities. Earlier studies compared spinal opioids with epidural bupivacaine 0.25% [1], but more recently, lower dose regimens have been investigated. To date, very few randomised, double-blind studies have compared the incidence of FHR abnormalities between these two neuraxial techniques using the same drug combination [9]. This paper presents secondary outcome data from a study comparing the minimum local analgesic concentration (MLAC) of epidural bupivacaine for analgesic supplementation following establishment of analgesia using either spinal or epidural [10]. We have compared FHR abnormalities and neonatal outcome measures following neuraxial analgesia established either with a spinal or epidural using the same low-dose bupivacaine and fentanyl mixture.
Methods After hospital ethical committee approval (Royal Free Hampstead NHS Trust, London, UK) and written informed consent, 115 parturients requesting neuraxial analgesia were recruited into a prospective, randomised and double-blind study designed primarily to determine epidural bupivacaine requirements for the second dose following initial spinal or epidural initiation of analgesia for labour [10]. The inclusion criteria were ASA physical status 1– 2, singleton pregnancy of > 36 weeks, gestation with vertex presentation, and in active labour between 2 and 6 cm cervical dilatation. The exclusion criteria were pre-eclampsia or administration of opioid medication within the previous 4 h. Upon request for neuraxial analgesia, the women were randomly assigned into two groups by a computer-generated random number table using Excel (Microsoft Corporation, Redmond, WA, USA). Parturients were randomly assigned to one of the two treatment regimens (CSE or epidural labour analgesia) using sealed opaque envelopes that contained details of group allocation. The sequence of treatment was concealed until the interventions were assigned. Three anaesthetists were involved in the study. One anaesthetist who was not involved with clinical care or data collection performed the randomisation procedure. A second anaesthetist performed the neuraxial block on request according to the group © 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 458–467
allocation. A third anaesthetist blinded to the procedure performed measurements at baseline immediately before neuraxial block and at 15 and 30 min after neuraxial block. The patient and third anaesthetist were blinded to group allocation throughout. Analgesic efficacy was assessed using a 100-mm visual analogue pain score (VAPS) where 0 represented ‘no pain’ and 100 represented ‘worst pain possible’, performed at the height of the contraction. Analgesia was ‘effective’ if the VAPS reduced to ≤ 10 mm within 30 min or ‘ineffective’ if the VAPS was > 10 mm at 30 min. Women with ineffective analgesia were given rescue epidural analgesia (20 ml bupivacaine 0.1% with fentanyl 2 lg.ml 1). Hypotension was defined as ≥ 20% decrease in systolic blood pressure from baseline values measured between contractions before commencing the neuraxial procedure. Blood pressure readings were taken from the right arm with the mother in a 45° semirecumbent position. Motor block was recorded using the modified Bromage score where 1 = complete block, unable to move feet or knees; 2 = able to move feet only; 3 = just able to move knees; 4 = detectable weakness of hip flexion; and 5 = full flexion of hips and knees while supine. Adverse effects such as pruritus, sedation, nausea or vomiting and treatment including the use of ephedrine were recorded. All neuraxial procedures were performed in the flexed sitting position at the L3-4 or L4-5 lumbar intervertebral space following an intravenous preload of 500–1000 ml lactated Ringer’s solution. The epidural space was identified using loss of resistance to saline with a 16-G Tuohy needle (Portex; Smiths Medical, Ashford, UK). The CSE was performed using the single interspace, needle-through-needle technique. The spinal was performed using a 27-G, 119-mm Whitacre spinal needle (Becton Dickinson, Franklin Lakes, NJ, USA). In both groups an 18-G, closed-end, multiport epidural catheter (Portex; Smiths Medical) was inserted 4–5 cm into the epidural space. The CSE group received 2.5 ml of a mixture of bupivacaine 0.1% with fentanyl 2 lg.ml 1 injected over 30 s [11]. To ensure that the entire dose was delivered spinally, the syringe was securely attached to the hub of the spinal needle once cerebrospinal fluid (CSF) was seen and CSF was aspirated at the 459
Anaesthesia 2014, 69, 458–467
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
beginning and end of the injection. If analgesia was inadequate following CSE, women were given an epidural bolus of the same mixture. The epidural group received 20 ml bupivacaine 0.1% with fentanyl 2 lg.ml 1 over 3 min. A test dose was not used. Following neuraxial block, women were positioned 45° semirecumbent with left uterine displacement using a wedge, and routine maternal and fetal monitoring was continued. Continuous electronic FHR monitoring was performed by cardiotocography (CTG) for 30 min before initiating the neuraxial block and for 60 min afterwards. The CTGs were analysed retrospectively by an obstetrician (SCR) who was blinded to the method of analgesia. Fetal heart rate traces were categorised overall as normal, suspicious or pathological according to a national guideline [12] (Appendix 1). Maternal data included age, height, weight, gestation, parity, cervical dilatation at time of neuraxial labour analgesia, use of prostaglandin for induction of labour and oxytocin for augmentation of uterine contractions, use of pethidine before neuraxial analgesia, and time from first epidural or spinal injection until delivery. Neonatal data included mode of delivery, Apgar score at 1 and 5 min, umbilical artery and vein pH and base excess. Any admissions to the neonatal intensive care unit were recorded. Monitoring was continued for 60 min in all recruited women, whether additional rescue epidural analgesia was required or not and regardless of exclusion from the primary study [10]. All women received routine obstetric care throughout the study and thereafter. Differences in groups were analysed using the two-sided Student’s t-test and Fisher exact test. Within-group analyses included repeated measures ANOVA and McNemar’s exact chi-squared test. Multiple logistic regression was used to identify independent factors associated with suspicious or pathological FHR patterns on an intention-to-treat basis. Analyses were carried out using Excel 2000 (Microsoft Corporation), Number Crunching Statistical System (NCSS) 2000 (NCSS Inc, Kaysville, UT, USA) and GraphPad Prism 4.0 (GraphPad Software Inc, San Diego, CA, USA). Statistical significance was defined as an overall p value of 0.05. 460
Results The CONSORT recruitment diagram is shown in Fig. 1. Patient and obstetric characteristics were similar between groups (Table 1). Effective analgesia was achieved in 88 women following the first injection, 43 in the CSE group and 45 in the epidural group. The remainder received rescue epidural analgesia within 30 min. All patients were comfortable following rescue analgesia except for two; one delivered shortly after having the epidural sited and one refused rescue analgesia after the first injection. Mode of delivery was similar between groups (Table 2). No emergency caesarean sections were performed in the hour following neuraxial analgesia. There were two failed attempts at topping up the epidural catheter for emergency caesarean section in the CSE group and these women received general anaesthesia. The indications for caesarean section are summarised in Table 2. There was no difference in neonatal Apgar scores at 1 or 5 min or in umbilical artery or vein pH or base excess between groups (Table 3). There were no admissions to the neonatal intensive care unit. Of the 115 women recruited, 113 FHR traces were analysed by intention-to-treat. One FHR trace from each group was missing from the patient’s notes and could not be located. Table 4 gives a breakdown of FHR pattern in the epidural and CSE groups before and after injection. There were no differences in FHR patterns between groups. There was a significant reduction in the acceleration rate and increase in decelerations after neuraxial analgesia. The time interval between neuraxial anaesthesia and the first deceleration was non-significantly shorter in the epidural group (p = 0.053). There were no overall differences between groups in the incidences of normal, suspicious or pathological FHR traces either before or after injection (Table 5). All FHR traces, except two in the CSE group, were categorised as normal before injection. After spinal injection, one improved from pathological to suspicious and one deteriorated from suspicious to pathological. Within groups, there was a significant increase in the number of abnormal (suspicious or pathological) FHR traces after neuraxial analgesia (two before and eight after in the © 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
Anaesthesia 2014, 69, 458–467
Assessed for eligibility (n = 124)
Excluded (n = 9) Not meeting inclusion criteria (n = 0) Declined to participate (n = 9) Other reasons (n = 0)
Randomised (n = 115)
CSE GROUP
EPIDURAL GROUP
Allocated to intervention (n = 62) Received allocated intervention (n = 62) Did not receive allocated intervention (n = 0)
Allocated to intervention (n = 53) Received allocated intervention (n = 53) Did not receive allocated intervention (n = 0)
Lost to follow-up (n = 0)
Lost to follow-up (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Analysed (n = 61) Excluded from analysis (n = 1, CTG missing from notes)
Analysed (n = 52) Excluded from analysis (n = 1, CTG missing from notes)
Figure 1 CONSORT recruitment diagram. Table 1 Patients’ characteristics and obstetric data in 115 women receiving combined spinal-epidural (CSE) or epidural analgesia. Values are mean (SD) or number (proportion).
Age; years Height; cm Weight; kg Gestation; weeks Cervical dilatation; cm Nulliparous Previous use of prostaglandin E2 Oxytocin infusion Previous use of pethidine
CSE (n = 62)
Epidural (n = 53)
30.3 163.5 73.9 40.4 3.6 44 15
31.0 162.6 77.7 40.1 3.6 35 9
(5.2) (6.9) (11.7) (1.2) (1.0) (71%) (24%)
9 (15%) 6 (10%)
(5.3) (7.2) (15.1) (1.1) (0.9) (66%) (17%)
12 (23%) 2 (4%)
Table 2 Mode of delivery, indication for caesarean section and elapsed time until delivery in 115 women receiving combined spinal-epidural (CSE) or epidural analgesia. Values are number (proportion) or median (IQR [range]). CSE (n = 62) Spontaneous Instrumental Caesarean section Failure to progress (dystocia) Fetal distress/ abnormal FHR pattern Time to delivery; min
Epidural (n = 53)
41 (66%) 7 (11%) 14 (23%) 6 (10%)
32 (60%) 12 (23%) 9 (17%) 6 (11%)
8 (13%)
3 (6%)
462 (291–611 [81–966])
431 (283–589 [100–1025])
FHR, fetal heart rate.
CSE group, zero before and 11 after in the epidural group; p < 0.0001). There was a non-significant increase in the number of pathological FHR traces after neuraxial analgesia (one before and three after in the CSE group, zero before and four after in the epidural group; p = 0.07). Sub-analysis of those patients with effective analgesia after the first injection © 2014 The Association of Anaesthetists of Great Britain and Ireland
(n = 88) showed no differences in FHR abnormalities, Apgar scores or umbilical acid-base status between groups. Table 6 summarises the incidence of adverse effects. There was no difference in the incidence and severity of hypotension between groups, although 461
Anaesthesia 2014, 69, 458–467
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
Table 3 Neonatal outcome data for 115 women receiving combined spinal-epidural (CSE) or epidural analgesia. Values are median (IQR [range]) or mean (SD). CSE (n = 62) Apgar; 1 min Apgar; 5 min Umbilical artery pH Umbilical artery base excess; mmol.l 1 Umbilical vein pH Umbilical vein base excess; mmol.l 1
Table 5 Fetal heart rate pattern in women before and after the start of combined spinal-epidural (CSE) or epidural analgesia. Values are number (proportion). CSE (n = 61)
Epidural (n = 53)
9 (9–9 [4–10]) 10 (10–10 [9–10]) 7.23 (0.08), n = 31 7.87 (3.14), n = 22
9 (9–9 [6–10]) 10 (10–10 [8–10]) 7.25 (0.07), n = 24 8.22 (3.64), n = 23
7.31 (0.07), n = 31 7.11 (3.20), n = 31
7.31 (0.08), n = 29 7.06 (4.07), n = 27
Epidural (n = 52)
Before Suspicious Pathological
After
1 (2%) 1 (2%)
5 (8%) 3 (5%)
Before 0 0
After 7 (13%) 4 (8%)
Significant increase within both groups in total number of cases with suspicious or pathological fetal heart rate pattern following neuraxial analgesia p < 0.0001.
severe hypotension occurred more frequently than mild/moderate hypotension in both groups. Two women in the CSE group required ephedrine (6 mg each) compared with one woman in the epidural group (12 mg). The maximum motor weakness recorded during the study period in any woman was a modified Bromage score of 4. This motor weakness occurred exclusively in the CSE group (10 women after CSE vs 0 after epidural; p = 0.0017), although the effect was transient and recovered by 30 min. Using multiple logistic regression analysis, hypotension, parity and efficacy of analgesia were not found to be associated with suspicious or pathological
Table 6 Maternal adverse effects in women receiving combined spinal-epidural (CSE) or epidural. Values are number (proportion). CSE (n = 62) Nausea and/or vomiting Sedation Modified Bromage score 4 Pruritus Decrease of SBP 20–24.9% Decrease of SBP 25–30% Decrease of SBP > 30%
Epidural (n = 53)
p value
1 (2%)
2 (4%)
NS
1 (2%) 10 (16%)
1 (2%) 0
NS 0.0017
14 (22%) 1 (2%)
6 (11%) 2 (4%)
NS NS
0
1 (2%)
NS
3 (5%)
5 (9%)
NS
SBP, systolic blood pressure.
Table 4 Summary of fetal heart rate (FHR) changes before and after initiation of combined spinal-epidural (CSE) or epidural analgesia. Values are mean (SD), number (proportion) or median (IQR [range]). CSE (n = 61)
1
Baseline FHR; beats.min Reduced variability; < 5 beats.min 1 for > 40 min Accelerations; n.h 1* Decelerations† Early Variable Late‡ Time to deceleration (variable or late); min
Epidural (n = 52)
Before
After
Before
After
135 0 12.2 9 7 3 0
136 2 9.9 14 7 4 7 36
134 0 11.0 4 3 1 0
135 1 8.4 16 6 7 8 17
(9) (6.7) (15%) (11%) (5%)
(9) (3%) (6.1) (23%) (11%) (7%) (11%) (17–50 [7–56])
(8) (7.3) (8%) (6%) (2%)
(10) (2%) (5.9) (31%) (12%) (13%) (15%) (12–29 [2–42])
*p = 0.034 within group. †p = 0.0046 within group. ‡p < 0.0001 within group. 462
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
FHR traces. Only the use of oxytocin was found to be independently significant (p < 0.01).
Discussion We found that CSE did not increase the incidence of FHR abnormalities when compared with epidural analgesia. There was no difference in the incidence of suspicious or pathological FHR traces, neonatal outcome as assessed by Apgar scores or umbilical artery and vein pH and base excess or obstetric outcome between the two neuraxial techniques. This is in contrast to the results of a systematic review [8], although it should be noted that only two of the studies included in that analysis are directly comparable to ours, which may explain the difference in our findings. Most studies comparing CSE and epidural labour analgesia have not recorded umbilical artery base excess. Base excess is probably a better indicator of neonatal metabolic status than pH, which can be affected by maternal breathing [13]. Other studies demonstrating an increase in FHR abnormalities following neuraxial analgesia have shown no association with umbilical artery acidaemia [1, 14, 15]. We collected paired umbilical arterial and venous samples, as ideally they should be interpreted together [12, 13]. Fetal heart rate pattern analysis was performed by an independent blinded obstetrician using national guidelines to minimise bias. The original study was not powered to detect differences in FHR abnormalities, but it is reassuring that there was no difference in FHR and neonatal outcome between the groups. This study does, however, demonstrate that there are increased incidences of non-reassuring and pathological FHR patterns after neuraxial analgesia. It is only pathological FHR patterns that require obstetric intervention [12]; although we demonstrated a non-significant tendency to an increased incidence of pathological FHR following neuraxial analgesia, inclusion of a control group would be required in order to evaluate a causal link fully. There were no emergency caesarean deliveries during the first hour after neuraxial analgesia was established. One of the suggested mechanisms of fetal bradycardia is that rapid onset of analgesia can lead to an imbalance of plasma adrenaline and noradrenaline, which can lead to uterine hypertonus [7, 16]. This is supported by laboratory work on the rat uterus that © 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 458–467
demonstrated increased myometrial tone and uterine vascular resistance following a decrease in adrenaline concentration [17]. A recent study in humans using intrauterine pressure measurements provides further evidence, demonstrating that a faster onset of pain relief after regional analgesia led to a higher incidence of uterine hypertonus and resultant FHR changes [7]. We would have expected FHR decelerations to have occurred sooner in the CSE group, as this has a faster speed of onset than epidural, but this was not the case in our study. However, an explanation may be as follows: although four of seven women in the CSE group had decelerations between 30 and 60 min, three of these had ineffective analgesia from the spinal injection and required epidural rescue medication, hence increasing the time until effective analgesia was achieved. In the epidural group, six of seven women who had decelerations between 30 and 60 min had effective analgesia after the first injection. None of our patients exhibited clinical hypertonus, defined as ≥ 6 contractions 10 min 1. Uterine hypertonus may be one of a number of factors involved in precipitating FHR abnormalities. Other proposed mechanisms include hypotension and aortocaval compression. Although hypotension was implicated in the past [18], most studies have shown no relation with FHR abnormalities [5, 15, 16, 19, 20]. In this setting, hypotension results from one or more of pain relief, sympathetic block and inferior vena caval compression. In our study, there was no difference in the incidence and severity of hypotension between groups; very few participants had severe hypotension requiring treatment. All women were given a fluid preload and positioned to reduce inferior vena caval compression. A fall in uterine perfusion pressure may occur in the absence of maternal hypotension due to aortic compression, with resultant placental hypoperfusion and FHR abnormalities. It has been suggested that milder degrees of aortocaval compression may remain concealed until after neuraxial analgesia, when the onset of sympathetic block inhibits the normal compensatory mechanisms that act to maintain maternal blood pressure, particularly vasoconstriction [21]. Interestingly, multiple logistic regression analysis showed no significant association between hypotension and a suspicious or pathological FHR pattern in this 463
Anaesthesia 2014, 69, 458–467
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
study. It did, however, show that oxytocin independently increased the likelihood of FHR pattern deterioration in combination with neuraxial analgesia. This has also been suggested by others [16], as have other factors such as lack of fetal head engagement [22], presence of variable FHR decelerations before neuraxial blockade [22], contraction pain scores [23] and increased maternal age [23]. Evaluation of these factors was beyond the scope of this study, but it is clear that FHR pattern deterioration has a multifactorial causation that warrants further investigation. The dose of analgesics that we used represents approximately 3.69 the ED50 of spinal bupivacaine and 29 the EC50 of epidural bupivacaine as estimated in previous MLAC studies [24, 25]. As such, it was anticipated that these first doses would provide effective analgesia to all. If we had administered a higher dose of spinal fentanyl, we might have seen a difference in FHR abnormalities between the groups. Many institutions give fentanyl 25 lg combined with bupivacaine 2.5 mg. We used fentanyl 5 lg because previous work at our institution demonstrated a similar significant degree of sparing of spinal bupivacaine with 5, 15 and 25 lg of fentanyl [24]. Using a pre-mixed solution of 2.5 ml bupivacaine 0.1% with fentanyl 2 lg.ml 1 is standard practice at our institution because it is effective, convenient, saves time and reduces the potential for drug errors and contamination. Spinal sufentanil appears to have a dose-dependent effect, with 7.5 lg producing a greater incidence of fetal bradycardia compared with 1.5 lg in one retrospective study [15]. The same authors confirmed this finding in a recent prospective, randomised study involving 300 parturients, finding an increased incidence of FHR abnormalities and uterine hypertonus in women receiving 7.5 lg spinal sufentanil alone compared with those receiving either 1.5 lg spinal sufentanil with 2.5 mg bupivacaine and 2.5 lg adrenaline, or epidural analgesia [20]. In another prospective study of patients receiving spinal analgesia, 7.5 lg sufentanil produced more FHR abnormalities compared with either 5 lg sufentanil with 1 mg bupivacaine or 1.05 lg sufentanil with 1.75 mg bupivacaine [14]. A randomised study of 84 patients investigating the dose–response relation of spinal fentanyl for labour analgesia showed no difference in FHR between a range of doses between 5–25 lg, although FHR monitoring was only performed at baseline and 464
30 min after injection [24]. A recent study showed no difference in FHR abnormalities between six groups receiving between 0 and 25 lg spinal fentanyl combined with 2.5 mg bupivacaine, although it did not have sufficient power to assess this outcome [26]. Therefore, whether fentanyl is similar to sufentanil in this regard remains to be established. In conclusion, these secondary outcome data from a prospective, randomised, double-blind study confirm the findings of others that CSE analgesia during the first stage of labour does not increase FHR abnormalities or have an adverse effect on neonatal or obstetric outcomes when compared with epidural analgesia. It also confirms that FHR abnormalities increase after institution of neuraxial analgesia and that oxytocin rather than hypotension may be an important associated factor. A larger prospective study randomly assigning women to CSE, epidural and parenteral opioid is required, using standard guidelines to interpret FHR traces and measuring neonatal umbilical artery and vein pH and base excess.
Acknowledgements We thank the labour ward staff at the Royal Free Hospital NHS Trust, London, UK.
Competing interests NP was supported by a research fellowship grant from the Obstetric Anaesthetists’ Association (OAA), UK. RF was supported by the University College London Hospitals/University College London (UCLH/UCL) Comprehensive Biomedical Research Centre, which receives a proportion of funding from the UK Department of Health’s National Institute of Health Research (NIHR) Biomedical Research Center’s funding scheme. NE and SW undertook research fellowships as salaried posts employed by University College London Hospitals NHS Foundation Trust.
References 1. Nielsen PE, Erickson JR, Abouleish EI, Perriatt S, Sheppard C. Fetal heart rate changes after intrathecal sufentanil or epidural bupivacaine for labor analgesia: incidence and clinical significance. Anesthesia and Analgesia 1996; 83: 742–6. 2. Palmer CM, Maciulla JE, Cork RC, Nogami WM, Gossler K, Alves D. The incidence of fetal heart rate changes after intrathecal fentanyl labor analgesia. Anesthesia and Analgesia 1999; 88: 577–81. © 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia 3. Carvalho B, Fuller AJ, Brummel C, Durbin M, Riley ET. Fetal oxygen saturation after combined spinal-epidural labor analgesia: a case series. Journal of Clinical Anesthesia 2007; 19: 476–8. 4. Collis RE, Davies DWL, Aveling W. Randomised comparison of combined spinal-epidural and standard epidural analgesia in labour. Lancet 1995; 345: 1413–6. 5. Eberle RL, Norris MC, Eberle AM, Naulty JS, Arkoosh VA. The effect of maternal position on fetal heart rate during epidural or intrathecal labor analgesia. American Journal of Obstetrics and Gynecology 1998; 179: 150–5. 6. Nageotte MP, Larson D, Rumney PJ, Sidhu M, Hollenbach K. Epidural analgesia compared with combined spinal-epidural analgesia during labor in nulliparous women. New England Journal of Medicine 1997; 337: 1715–9. 7. Abrao KC, Francisco RPV, Miyadahira S, Cicarelli DD, Zugaib M. Elevation of uterine basal tone and fetal heart rate abnormalities after labor analgesia: a randomized controlled trial. Obstetrics and Gynecology 2009; 113: 41–7. 8. Mardirosoff C, Dumont L, Boulvain M, Tramer MR. Fetal bradycardia due to intrathecal opioids for labour analgesia: a systematic review. British Journal of Obstetrics and Gynaecology 2002; 109: 274–81. 9. Van de Velde M, Mignolet K, Vandermeersch E, Van Assche A. Prospective, randomized comparison of epidural and combined spinal epidural analgesia during labour. Acta Anaesthesiologica Belgica 1999; 50: 129–36. 10. Patel NP, Armstrong SL, Fernando R, et al. Combined spinal epidural vs epidural labour analgesia: does initial intrathecal analgesia reduce the subsequent minimum local analgesic concentration of epidural bupivacaine? Anaesthesia 2012; 67: 584–93. 11. Davies J, Fernando R, McLeod A, Verma S, Found P. Postural stability following ambulatory regional analgesia for labor. Anesthesiology 2002; 97: 1576–81. 12. National Institute for Health and Care Excellence. Intrapartum care: care of healthy women and their babies during childbirth (clinical guideline 55). 2007. htpp://www.nice.org.uk/ CG55 (accessed 07/01/2014). 13. Reynolds F. Regional Analgesia in Obstetrics: a Millennium Update. London: Springer, 2000. 14. Vercauteren M, Bettens K, Van Springel G, Schols G, Van Zundert J. Intrathecal labor analgesia: can we use the same mixture as is used epidurally? International Journal of Obstetric Anesthesia 1997; 6: 242–6.
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia 2014, 69, 458–467
15. Van de Velde M, Vercauteren M, Vandermeersch E. Fetal heart rate abnormalities after regional analgesia for labor pain: the effect of intrathecal opioids. Regional Anesthesia and Pain Medicine 2001; 26: 257–62. 16. Clarke VT, Smiley RM, Finster M. Uterine hyperactivity after intrathecal injection of fentanyl for analgesia during labor: a cause of fetal bradycardia? Anesthesiology 1994; 81: 1083. 17. Segal S, Csavoy AN, Datta S. The tocolytic effect of catecholamines in the gravid rat uterus. Anesthesia and Analgesia 1998; 87: 864–9. 18. D’Angelo R, Eisenach JC. Severe maternal hypotension and fetal bradycardia after a combined spinal epidural anesthetic. Anesthesiology 1997; 87: 166–8. 19. Norris MC. Intrathecal opioids and fetal bradycardia: is there a link? International Journal of Obstetric Anesthesia 2000; 9: 264–9. 20. Van de Velde M, Teunkens A, Hanssens M, Vandermeersch E, Verhaeghe J. Intrathecal sufentanil and fetal heart rate abnormalities: a double-blind, double placebo-controlled trial comparing two forms of combined spinal epidural analgesia with epidural analgesia in labor. Anesthesia and Analgesia 2004; 98: 1153–9. 21. Preston R, Crosby ET, Kotarba D, Dudas H, Elliott RD. Maternal positioning affects fetal heart rate changes after epidural analgesia for labour. Canadian Journal of Anesthesia 1993; 40: 1136–41. 22. Gaiser RR, McHugh M, Cheek TG, Gutsche BB. Predicting prolonged fetal heart rate deceleration following intrathecal fentanyl/bupivacaine. International Journal of Obstetric Anesthesia 2005; 14: 208–11. 23. Nicolet J, Miller A, Kaufman I, Guertin MC, Deschamps A. Maternal factors implicated in fetal bradycardia after combined spinal epidural for labour pain. European Journal of Anaesthesiology 2008; 25: 721–5. 24. Stocks GM, Hallworth SP, Fernando R, England AJ, Columb MO, Lyons G. Minimum local analgesic dose of intrathecal bupivacaine in labor and the effect of intrathecal fentanyl. Anesthesiology 2001; 94: 593–8. 25. Lyons G, Columb M, Hawthorne L, Dresner M. Extradural pain relief in labour: bupivacaine sparing by extradural fentanyl is dose dependent. British Journal of Anaesthesia 1997; 78: 493–7. 26. Wong CA, Scavone BM, Slavenas JP, et al. Efficacy and side effect profile of varying doses of intrathecal fentanyl added to bupivacaine for labor analgesia. International Journal of Obstetric Anesthesia 2004; 13: 19–24.
465
Anaesthesia 2014, 69, 458–467
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
Appendix 1: Fetal heart rate trace analysis [12]. Classification of fetal heart rate (FHR) trace features Baseline FHR; beats.min 1
Variability; beats.min 1
Reassuring Non-reassuring
110–160 100–109 161–180
≥5 < 5 for 40–90 min
Abnormal
< 100
< 5 for ≥ 90 min
> 180 Sinusoidal pattern
Parameters defined as follows:
• • • •
Baseline – mean level of the FHR when this is stable, excluding accelerations and decelerations, determined over a 5–10 min period. Normal is 110–160 beats.min 1. Variability – minor fluctuations in baseline FHR, the difference between the highest peak and lowest trough in a 1-min segment of the trace. Normal is ≥ 5 beats.min 1. Number of accelerations per hour – transient FHR increases of ≥ 15 beats.min 1 lasting ≥ 15 s. Number of decelerations – transient episodes of FHR slowing by ≥ 15 beats.min 1 below baseline lasting ≥ 15 s.
Decelerations None Early deceleration Variable deceleration Single prolonged deceleration ≤ 3 min Atypical variable deceleration
• •
466
Early (uniform, repetitive decelerations with onset early in contraction and return to baseline at the end of the contraction). Late (uniform, repetitive decelerations with onset mid to end of the contraction, nadir > 20 s after peak of the contraction and ending after the contraction). Variable (variable, intermittent decelerations with rapid onset and recovery. Time relations with the contraction cycle are variable and may occur in isolation).
Present The absence of accelerations with an otherwise normal FHR trace are of uncertain significance
Late decelerations Single prolonged deceleration > 3 min
•
Prolonged (abrupt decrease in FHR to below baseline lasting at least 60–90 s, becoming pathological if > 3 min).
Further information about classifying FHR traces is given below:
• • • •
Types of deceleration:
•
Accelerations
•
If repeated accelerations are present with reduced variability, the FHR trace should be regarded as reassuring. True early uniform decelerations are rare and benign, and therefore they are not significant. Most decelerations in labour are variable. If a bradycardia occurs in the baby for more than 3 min, urgent medical aid should be sought and preparations should be made to urgently expedite the birth of the baby, classified as a category 1 birth. This could include moving the woman to theatre if the fetal heart has not recovered by 9 min. If the fetal heart recovers within 9 min, the decision to deliver should be reconsidered in conjunction with the woman if reasonable. A tachycardia in the baby of 160–180 beats.min 1, where accelerations are present and no other adverse features appear, should not be regarded as suspicious. However, an increase in the baseline heart rate, even within the normal range, with other non-reassuring or abnormal features should increase concern.
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Patel et al. | Fetal effects of combined spinal-epidural vs epidural labour analgesia
Anaesthesia 2014, 69, 458–467
Definition of FHR abnormalities Normal Suspicious Pathological
An FHR where all four features fall into the reassuring category An FHR whose features fall into one of the non-reassuring categories and the remainder of the features are reassuring An FHR whose features fall into two or more non-reassuring categories or one or more abnormal categories
© 2014 The Association of Anaesthetists of Great Britain and Ireland
467
