Evron 2005.

Methods	Randomised, controlled trial. Double‐blinded. Randomisation after onset of labour. The purpose of this trial was to compare the analgesic effect of remifentanil in PCIA during labour and delivery with the effect of an IV infusion of meperidine. There are no details where or when the study was conducted. The authors’ origin is Israel. Trial Identifier: NA
Participants	Participant flow: Number assessed for eligibility: NA Number randomised: 88 (43/45) Number receiving treatment: 88 (43/45) Number analysed: 88 (43/45) Inclusion criteria: Term parturients with singleton cephalic presentation requesting systemic analgesia, ASA I or II, active labour (cervical dilation of 3 cm to 6 cm) Exclusion criteria: ASA III or more, obesity (more than 100 kg or BMI ≥ 40kg/m²), history of drug (including analgesic chronic use or large doses) or alcohol abuse, smoking more than 10 cigarettes per day, and abnormal liver, renal, or haematological function Baseline details: Remifentanil group (n = 43): Age (years, mean (SD)): 29.5 (5.3) Weight (kg, mean (SD)): 75.1 (16) ASA I/II (n/n): NA Type of delivery (n): spontaneous (40), vacuum extraction (1), forceps delivery (0), CS (2) Week of gestation: NA Singleton, twin, multiple pregnancy: NA Parity (n): Primiparity (22) Duration of labour: ‐ First stage of labour (min, mean (SD)): active phase 245.2 (150.8) ‐ Second stage of labour (min, mean (SD)): 38.0 (32.2) Meperidine group (n = 45): Age (years, mean (SD)): 29.2 (5.2) Weight (kg, mean (SD)): 74.8 (11.27) ASA I/II (n/n): NA Type of delivery (n): spontaneous (38), vacuum extraction (2), forceps delivery (0), CS (5) Week of gestation: NA Singleton, twin, multiple pregnancy: NA Parity (n): Primiparity (19) Duration of labour: ‐ First stage of labour (min, mean (SD)): active phase 251.4 (118.8) ‐ Second stage of labour (min, mean (SD)): 42.2 (45.6)
Interventions	Remifentanil group (n = 43): Participants randomised to receive remifentanil were connected to PCIA by a 1‐way infusion line (PCAM Syringe Pump Model P500; IVAC Medical Systems, NH) with patient‐controlled boluses of 20 µg each as a starting dose, regardless of parturient weight, and a 3 min lockout interval without basal infusion. The dose was increased by the attending anaesthesiologist every 15 to 20 min by 5 µg increments, on woman's request, to a maximum dose limit of 1500 µg/h. If any parturient had reached the maximum dose, a single bolus would have had 70 µg (0.93 µg/kg). Meperidine group (n = 45): Parturients in the control group received 75 mg of meperidine in 100 mL of normal saline over 30 min (approximately 1 mg/kg in a single bolus). In case of insufficient analgesia, another dose of 75 mg, followed by 50 mg when necessary, was administered, to a maximum dose of 200 mg of meperidine.
Outcomes	The primary endpoint of the study was not explicitly stated but power analysis was performed for pain score. Continuous: ‐ overall satisfaction (NRS 1 to 4, within 24 h after delivery) ‐ pain intensity (VAS 0 to 100, at 0, 1 h and end of first stage of labour) ‐ umbilical cord pH (not specified) ‐ sedation score (observer, Ramsey sedation score, at 1 h and end oft 1st stage of labour) ‐ women: mean respiratory rate, mean SBP, mean HR (at 0, 1 h and end oft 1st stage of labour, respectively) Dichtomous: ‐ additional analgesia (epidural) ‐ rate of CS, rate of assisted birth (vacuum, forceps) ‐ feeding difficulties ‐ oxytocin use ‐ women: oxygen desaturation (< 95%), nausea + vomiting, pruritus ‐ newborns: Apgar score < 7 at 1 and 5 min, opioid‐induced loss of FHR, FHR reactive
Notes	‐ Small trial sample size (< 200 participants) ‐ Power analysis performed (VAS pain scores, n = 88 in total) Concomitant medication: For inadequate analgesia, adverse effects due to opioids, or failure of the technique (VAS > 40), epidural analgesia was offered. The decision to cross‐over from systemic opioids to epidural analgesia was made by the parturient in corroboration with the anaesthesiologist and after an additional trial of increasing the dose of the analgesic and a repeat VAS score of > 40. A VAS of 40 was considered an indication for cross‐over to epidural analgesia. To avoid possible hypoxaemia, supplemental oxygen was administered to the parturients whenever SpO2 decreased to less than 95%. Funding: NA Intervention: Lockout time 3 min seems too long for adequate analgesia (borderline).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomization was based on computer‐generated codes […]”
Allocation concealment (selection bias)	Unclear risk	Quote: “[…] kept in sequentially numbered opaque envelopes until just before use.” Not specifically mentioned sealed envelopes (SNOSE).
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: “For blinding, PCIA remifentanil parturients were connected to a dummy IV saline bag, and IV meperidine parturients were connected to a dummy saline PCIA.”, “A senior anaesthesiologist, not involved in data recording, attended each parturient throughout labor.” Blinding was attempted to achieve by insertion of both an IV catheter and a PCA pump. However, we assume that participants and attending personnel might be able to uncover group allocation due to the different pharmacokinetics of the two interventions. The used method of blinding may only work for the outcome assessors (which was not explicitly mentioned in the published report for all outcomes).
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: “For blinding, PCIA remifentanil parturients were connected to a dummy IV saline bag, and IV meperidine parturients were connected to a dummy saline PCIA.”, “A senior anaesthesiologist, not involved in data recording, attended each parturient throughout labor.”, "Patient satisfaction [...] was assessed 24 h after delivery by an anaesthesiologist blinded to the mode of labor analgesia." The study did not address this issue for most of the relevant outcomes with exception of the assessment of woman's satisfaction. We do not know who was responsible for other outcome assessment and attending personnel and parturients may be able to uncover group allocation. The subjective1 outcomes or outcome measurements are likely to be influenced by lack of blinding. Therefore, insufficient information exists to judge "yes" or "no".
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	‐ Dropout rate: 0% ‐ Large amount (2%/22%) of outcome data (AE for women: SpO2) not reported and imbalanced between groups. No reasons declared. ‐ Rate of escape (epidural): 12%/38% (may influence data on AE, satisfaction and pain) ‐ Rate of cross‐over: NA ‐ Data‐analysis: Partial‐ITT
Selective reporting (reporting bias)	Unclear risk	There is no reference to a trial registry and no published study protocol.
Other bias	Low risk	The study appears to be free of other sources of bias.