This prospective observational study was approved by the Republic of Slovenia National Medical Ethics Committee (Permit No. 91/04/16) and registered at the central database of ClinicalTrials.gov under the trial ID NCT02963337, (https://clinicaltrials.gov/ct2/show/NCT02963337?term=02963337&rank=1) on November 15, 2016. The study was conducted from January 2017 to September 2018 in the labour and delivery unit of the Perinatology Department, Division of Obstetrics and Gynaecology with approximately 6000 deliveries per year, neuraxial and remifentanil analgesia rate of 60% (ratio 1:1) and caesarean section rate of 21%.
Consecutively admitted at the labour and delivery suit, multiparous women with singleton pregnancies in their active phase of first stage labour requesting pain relief were asked to participate in the study. They were informed about the two different analgesic options being studied, i.e. RPCA and CSEA, their advantages and disadvantages. After signing an informed consent, they were allocated either to a RPCA or CSEA group on the basis of their informed choices of labour analgesia. The inclusion criteria were age 18 to 55, American Society of Anaesthesiologists (ASA) physical status 2 or 3, uncomplicated pregnancy at 37 0/7 – 40 6/7 weeks of gestation, absence of known foetal congenital abnormalities, vertex presentation, ongoing uterine contraction, cervical dilation 3 to 6 cm and normal cardiotocography (CTG). Exclusion criteria were preeclampsia, contraindications to CSEA (coagulation and neurological abnormalities, infection/fever) and remifentanil (opioid drug abuse, pethidine given within the two previous hours, known allergic reaction to remifentanil, morbid obesity with body mass index (BMI) >40 and obstructive sleep apnoea).
In the RPCA group, the women were introduced to the PCA pump (Rythmic™ Evolution, Micrel Medical Devices, Athens, Greece) and told to use PCA at the start of each uterine contraction [8]. Remifentanil hydrochloride (Ultiva, GlaxoSmithKline, Oslo, Norway) was diluted in saline to a concentration of 40 µg ml-1 and administered stepwise from 20 to a maximum of 40 µg with a bolus duration of 20 seconds and 2 minutes lockout interval with no background infusion. Dose adjustment was performed by anaesthesiological staff at patients’ request. The bolus dose was increased if pain intensity as assessed by an 11-point numerical rating scale (NRS; 0 is no pain and 10 the worst imaginable pain) increased and a patient’s respiratory rate was > 9 breaths min-1, oxygen saturation (SpO2) ≥ 94%, heart rate > 50min-1 and sedation score ≤ 2 on a five-point categorical scale (scale 1-5: 1=alert, 2=slightly drowsy, 3=drowsy, 4=very drowsy, 5=unarousable) [9–11]. The use of PCA was allowed until 5-10 minutes prior to cord clamping. Women in the RPCA group had one‑to‑one midwifery care. In accordance with the institutional standard operating protocol, women were continuously monitored with Capnostream® capnograph (Oridion®, Jeruzalem, Israel) with an oral‑nasal cannula, sampling from both the nose and mouth (Oridion®). Supplemental oxygen (2 l min-1) was given to all patients via a nasal catheter. The respiratory monitor recorded continuous waveform of end tidal CO2, respiratory rate, SpO2 and heart rate with the alarms being activated by oxygen desaturation (SpO2 < 94 %), bradypnea (respiratory rate < 8 min-1) and apnoea longer than 20 seconds, triggering staged interventions started with a verbal command to take a deep breath or a light tap in case of no response [12]. The anaesthesia provider recorded the triggered alarms from the monitor hourly. Foetal heart rate was continuously monitored with CTG (Hewlett Packard Viridia Series 50IP®, Hewlett Packard, Palo Alto, CA, USA or Philips 50XM®, Amsterdam, Netherlands). Remifentanil was stopped if pathological CTG changes occurred including decreased variability, bradycardia, tachycardia, or late decelerations.
In the CSEA group, all blocks were performed in the sitting position. The epidural space was located with an 18-gauge Touhy needle (PORTEX® CSE cure® Combined Spinal Epidural System, Smiths Medical, Minnesota, USA) inserted in the midline using loss of resistance to air or saline at the L3-L4 or L4-L5 interspace, followed by needle‑through‑needle insertion of 27‑gauge spinal needle. After obtaining a cerebrospinal fluid, 2.5 mg bupivacaine hydrochloride with 25 µg of fentanyl (total volume of 1 ml) was injected, followed by a 20‑gauge multi‑hole catheter insertion into the epidural space. Epidural anaesthesia was managed using patient‑controlled boluses of 6 ml of 0.1 % bupivacaine with 2 µg ml-1 fentanyl every 15 minutes with no background infusion via the PCA pump (Rhythmic™ Evolution, Micrel Medical Devices, Athens, Greece). In accordance with local protocol, 5 mg of ephedrine was injected into all women immediately after the intrathecal analgesic injection to prevent hypotension.
Demographic and medical data were obtained by means of personal interviews before initiation of analgesia and during the labour. Pain intensity was assessed using an 11-point NRS, where 0 is no pain and 10 the worst imaginable pain. NRS scores, sedation level, automatic readings of non‑invasive systolic and diastolic blood pressure, heart rate and SpO2 were recorded immediately before starting the PCA (baseline), every 15 minutes during the first hour and every 30 minutes thereafter. Immediately after delivery, satisfaction with pain relief was evaluated using a five‑point categorical scale (5 = very good, 4 = good, 3 = moderate, 2 = poor, 1 = very poor). At the same time, each parturient was also asked if she would choose the same analgesic technique for her next delivery or recommend it to others.
Data on labour progress (first and second stage labour duration, mean cervical dilation rate) and labour outcome were recorded for each patient, including the use of oxytocin, cumulative dose of oxytocin administered, and mode of delivery (spontaneous vaginal, instrumental vaginal, caesarean section). Cervical dilation was assessed by the midwife, and all changes were recorded until the delivery was completed. The mean cervical dilation rate was defined as 10 minus the cervical dilatation observed at the last examination before the start of analgesia divided by the duration of labour.
The number of epidural boluses as well as the total dose of remifentanil were registered automatically in the PCA pump and recorded for each patient. Data concerning nausea, vomiting and itching were also collected. Oral temperature was measured both at the onset of analgesia and within 1 hour of delivery. After delivery, Apgar scores at 1 and 5 minutes were recorded, and umbilical blood gas analysis performed according to the standard procedures. Neonatal need for naloxone and resuscitation were also noted.
Statistical analysis
The Shapiro-Wilk test was used to evaluate the data for normality. If the normality and equal variance assumptions were met, it was followed by Student’s t test; otherwise the Mann Whitney U test was used. Proportions were compared using Fisher’s exact test. NRS scores at different time points during labour were compared using mixed-effect analysis followed by Sidak post-hoc tests that corrected the p values for the subgroup analyses. Statistical analysis was performed with the GraphPad Prism 8 (GraphPad Software, San Diego CA, USA). The difference was considered statistically significant at p<0.05. The data are presented as frequency (proportion %), mean (standard deviation (SD)) and median [inter-quartile range (IQR)].
The sample size was calculated based on the primary outcome of pain relief during CSEA in multiparous parturients measured on an 11-point scale ranging from 0 to 10. If the true difference between the two studied groups is 1 (on 11-point scale with estimated standard deviation of 2.2), we needed to study 77 subjects in each group to be able to reject the null hypothesis that the population means of the two groups are not equal with probability (power) of 0.8. The Type I error probability associated with the test of this null hypothesis is 0.05 [13].