Methods

Randomised, controlled trial. Double‐blinded. No statement on time of randomisation.

The purpose of this pilot study was to compare two regimens of IV remifentanil PCA, along with continuous background infusion, for labour analgesia.

The study was conducted in Mount Sinai Hospital, Toronto, Canada, from September 2005 to December 2006.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: 22

Number randomised: 20 (10/10)

Number receiving treatment: 20 (10/10)

Number analysed: 20 (10/10)

Inclusion criteria:

Term pregnancy, ASA I and II women in active labour, who requested systemic analgesia with or without contraindications to epidural analgesia

Exclusion criteria:

Allergy or hypersensitivity to remifentanil, opioid dependence or addiction, consumption of narcotics within 24 h of the study period, FHR abnormalities, fetal compromise and/or language barrier

Baseline details:

Fixed bolus group (n = 10):

Age (years, mean (SD)): 32.7 (5.9)

Weight (kg, mean (SD)): 85 (30)

ASA I/II (n/n): NA

Type of delivery (n): vaginal (6), CS (4)

Week of gestation: 39.2 ± 1.5

Singleton, twin, multiple pregnancy: NA

Parity (n): Primipara (5)

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Fixed infusion group (n = 10):

Age (years, mean (SD)): 30.4 (5.8)

Weight (kg, mean (SD)): 77.1 (14.1)

ASA I/II (n/n): NA

Type of delivery (n): vaginal (6), CS (4)

Week of gestation: 39.0 ± 1.4

Singleton, twin, multiple pregnancy: NA

Parity (n): Primipara (7)

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Interventions

Initially, all women received a standard regimen of remifentanil with an infusion of 0.025 µg/(kg*min) and a PCA bolus of 0.25 µg/kg. The PCA lockout interval was set at 2 min, and the 4 h limit was 3 mg. As labour progressed and women required additional analgesia, they received higher doses of either the infusion (group: constant bolus) or the PCA boluses (group: constant infusion).

(At the woman’s request, if there was either no change or worsening of pain scores; each step was maintained for at least 15 min before progressing to the subsequent one.)

Fixed bolus group (n = 10):

The infusion rate was increased stepwise from 0.025 µg/(kg*min) to 0.05 µg/(kg*min), 0.075 µg/(kg*min) and 0.1 µg/(kg*min), while the bolus of 0.25 µg/kg was maintained.

Fixed infusion group (n = 10):

The bolus dose was increased stepwise from 0.25 µg/kg to 0.5 µg/kg, 0.75 µg/kg and 1 µg/kg, while the infusion rate of 0.025 µg/(kg*min) was kept constant.

Outcomes

The primary outcome variables were maternal pain and desaturation.

Continuous:

‐ overall satisfaction (VNRS 0 to 10, within 2 h after delivery)

‐ pain intensity (VNRS 0 to 10, at 0, every 30 min until delivery), overall pain score (VNRS 0 to 10, within 2 h of delivery)

‐ umbilical cord BE (artery, vein), umbilical cord pH (artery, vein)

‐ sedation score (observer, 5 to 0, at baseline and lowest sedation)

Dichotomous:

‐ additional analgesia (epidural)

‐ rate of CS

‐ need for neonatal resuscitation

‐ augmented labour (no substance indicated)

‐ women: oxygen desaturation (< 95%, < 90%), hypotension, bradycardia, nausea, vomiting, pruritus, drowsiness, dizziness, confusion

‐ newborns: Apgar score ≥ 7 at 1 and 5 min, non‐reassuring FHR, need for naloxone

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (VNRS pain, n = 10 per group)

Concomitant medication:

Nausea or vomiting was treated with dimenhydrinate, and diphenhydramine was administered for pruritus.

The woman could choose to cross over to epidural analgesia at any time during labour, unless there was a contraindication to a regional technique.

Funding:

NA

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “The patients were randomized, via a computer‐generated randomisation scheme, into one of the two study groups.”

Allocation concealment (selection bias)

Unclear risk

Quote: “The group allocation was blinded via sealed envelopes until the time of PCA administration.”

Not specifically mentioned sequentially numbered, opaque envelopes (SNOSE).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: “The patient and the obstetrician, as well as the registered nurse collecting the data, were all blinded to the study group. The group allocation was known only to the anaesthesiologist who was making changes to the pump settings when needed.”

Blinding for participants and personnel adequate.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: “The patient and the obstetrician, as well as the registered nurse collecting the data, were all blinded to the study group. The group allocation was known only to the anaesthesiologist who was making changes to the pump settings when needed.”, “Fetal heart rate tracings were analysed by an obstetrician (P.B.) who was blinded to the study group.”

Blinding for outcome assessment adequate.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

‐ No missing outcome data after randomisation.

‐ Rate of escape (epidural): 10%/0%

‐ Rate of cross‐over: NA

‐ Data‐analysis: Full‐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.

Methods

Randomised, controlled trial. Single‐blinded. No statement on time of randomisation.

The purpose of this trial was to determine the analgesic efficacy and safety of remifentanil versus pethidine via PCA for women in established uncomplicated labour.

There are no details where or when the study was conducted. The authors’ origin is United Kingdom.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: NA

Number randomised: 40 (20/20)

Number receiving treatment: 40 (20/20)

Number analysed: 39 (20/19)

Inclusion criteria:

Women with ASA I or II, either before the onset of labour in the antenatal ward or in early labour before any analgesia had been requested

Exclusion criteria:

Women were excluded from the study if they planned to use epidural analgesia or had pre‐eclampsia, multiple pregnancy, premature labour or allergy to any agent under investigation.

Baseline details:

Remifentanil group (n = 20):

Age (years, mean (SD)): 29 (5.2)

Weight (kg, mean (SD)): 76 (9)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity (median (IQR [range])): 1 (1 ‐ 2 [0 ‐ 5])

Duration of labour:

‐ before PCA use (min, mean (SD)): 125 (98)

‐ first stage of labour (min, mean (SD)): 260 (97)

‐ second stage of labour (min, mean (SD)): 22 (22)

Pethidine group (n = 19):

Age (years, mean (SD)): 29 (5.4)

Weight (kg, mean (SD)): 76 (12)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous labour (NA)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity (median (IQR [range])): 1 (0 ‐ 2 [0 ‐ 3])

Duration of labour:

‐ before PCA use (min, mean (SD)): 191 (205)

‐ first stage of labour (min, mean (SD)): 296 (158)

‐ second stage of labour (min, mean (SD)): 20 (12)

Interventions

Remifentanil group (n = 20):

Women received a remifentanil PCA using 40 µg remifentanil with a lockout of 2 min. The bolus dose and lockout period for the remifentanil PCA were based on an average maternal weight (80 kg) and a bolus of 0.5 µg/kg.

Pethidine group (n = 19):

Control participants received PCA using pethidine 15 mg with a lockout of 10 min.

Outcomes

The primary endpoint of the study was overall pain.

Continuous:

‐ satisfaction with analgesia (VAS 0 to 10, at 0, 30 min until 120 min, median + IQR + range (symmetric))

‐ pain intensity (VAS 0 to 10, at 0, every 30 min until 120 min, median + IQR (asymmetric)), overall pain score (VAS 0 to 10, at 2 h after delivery)

‐ umbilical cord pH (not specified)

‐ sedation score (observer, 5 to 1, and parturient score, VAS 0 to 10, at 0, 30, 60, 90, 120 min, respectively, median + IQR + range (asymmetric))

‐ women: mean respiratory rate, mean SBP, mean HR, median nausea score (VAS 0 to 10) (at 0, 30, 60, 90, 120 min, respectively)

‐ newborns: mean FHR (at 0, 30, 60, 90, 120 min), Apgar score at 1 and 5 min (median + IQR + range (asymmetric)), NACS at 30 and 120 min (median + IQR + range (symmetric))

Dichotomous:

‐ additional analgesia (Entonox)

‐ women: oxygen desaturation (% total PCA time spent with < 94% and < 90%, diagrammed)

‐ newborns: need for naloxone

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (VAS overall pain, n = 20 per group)

Concomitant medication:

All women were free to change to regional analgesia at any time if so desired. Entonox was available to all women throughout the study.

Funding:

NA

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “The women were randomly allocated to receive PCA using either remifentanil […] or pethidine […].” No method described.

Allocation concealment (selection bias)

Unclear risk

No statement on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “[…] women, who were unaware of which treatment they were receiving.”

No statement on whether key study personnel were blinded. 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 mentioned in the published report for most of the relevant outcomes).

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: “Baseline non‐invasive blood pressure, heart rate, SpO₂, respiratory rate, observer sedation score […] and fetal heart rate were recorded by a blinded investigator. Baseline visual analogue scale (VAS) measurements were also recorded for the pain of contractions, satisfaction with current analgesia, nausea, anxiety and sedation.”, “At delivery, Apgar scores at 1 and 5 min were recorded, cord blood was taken for blood gas analysis and the fetal requirement for naloxone was noted.”, "The cardiotocograph (CTG) was recorded for a minimum of 1 h after starting the PCA and was subsequently analysed by a blinded obstetrician […].”

It is unclear from the description whether assessment for most of the outcomes after treatment (during study) was blinded. The study did address this issue only for the assessment of FHR patterns. We do not know who was responsible for outcome assessment and participants and attending personnel 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

High risk

‐ Dropout rate: 0%/5%

Quote: “There was one protocol violation in the pethidine group and no data were included from this patient.” The protocol violation was not described.

‐ No statement on why 1 woman in the Remifentanil group was not analysed for all outcomes (satisfaction with pain relief, AE for newborn)

‐ Rate of escape (Entonox): 90%/100% (may influence data on AE, satisfaction and pain)

‐ Rate of cross‐over: NA

‐ Data‐analysis: Per‐protocol (protocol violation)

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.

Methods

Randomised, controlled trial. No statement on blinding. No statement on time of randomisation.

The purpose of this trial was to evaluate the effectiveness and security of remifentanil administered by means of elastomeric infusor with PCA IV compared with IM meperidine in obstetric women with contraindication for epidural analgesia.

There are no details where or when the study was conducted. The authors’ origin is Spain.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: NA

Number randomised: 24 (12/12)

Number receiving treatment: 24 (12/12)

Number analysed: 24 (12/12)

Inclusion criteria:

ASA I to III, aged 20 to 40 years, requesting analgesia

Exclusion criteria:

NA

Baseline details:

Remifentanil group (n = 12):

Age (years, mean (SD)): 28 (5)

Weight (kg, mean (SD)): 72 (8)

ASA I/II (n/n): 8/2

Type of delivery (n): spontaneous (NA), instrumental (1), CS (0)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity: NA

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Meperidine group (n = 12):

Age (years, mean (SD)): 30 (3)

Weight (kg, mean (SD)): 75 (6)

ASA I/II (n/n): 7/3

Type of delivery (n): spontaneous (NA), instrumental (2), CS (1)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity: NA

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Interventions

Remifentanil group (n = 12):

An elastomeric infusor with a capacity of 250 mL was filled with 2.5 mg of remifentanil and a 12 mL/h was started (average infusion of 0.025 µg/(kg*min) of remifentanil and boluses of 5 mL with a time of closing of 30 min).

Meperidine group (n = 12):

Women were given 1 mg/kg of meperidine and 2.5 mg of haloperidol every 4 h by IM route.

Outcomes

The primary endpoint of the study was not defined.

Continuous:

‐ overall satisfaction (VAS 0 to 10, time point unclear)

‐ pain intensity (VAS 0 to 100, at 0, every 30 min until 280 min, "expulsivo")

‐ newborns: Apgar score at 1 and 5 min

Dichotomous:

‐ rate of CS, rate of assisted birth (instrumental)

‐ women: nausea + vomiting

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis not performed

Concomitant medication:

NA

Funding:

NA

Intervention:

Lockout time of 30 min seems too long for adequate analgesia.

Contact to the authors:

We contacted Dr. Torres via e‐mail (23 June 2016) to inquire the number of women who reported 'pain intensity at 2 hours'. We did not receive any answer.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “24 patients were randomized […].” No method described.

Allocation concealment (selection bias)

Unclear risk

No statement on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of parturients and personnel did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of outcome assessment did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

‐ No missing outcome data after randomisation

‐ Rate of escape: NA

‐ Rate of cross‐over: NA

‐ Data‐analysis: Full‐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.

Methods

Randomised, controlled trial. Double‐blinded. No statement on time of randomisation.

The purpose of this trial was to compare the analgesic efficacy of remifentanil with meperidine and fentanyl in a patient‐controlled setting (PCA).

There are no details where or when the study was conducted. The authors’ origin is the Netherlands.

Trial Identifier: NTR543

Participants

Participant flow:

Number assessed for eligibility: 180

Number randomised: 180 (60/60/60)

Number receiving treatment: 159 (52/53/54)

Number analysed: 159 (21 excluded, delivery within 1 h after randomisation)

Inclusion criteria:

ASA physical status I or II, singleton cephalic presentation in active labour

Exclusion criteria:

Obesity (BMI (body mass index) ≥ 40 kg/m²), opioid allergy, substance abuse history, and women at high‐risk (pre‐eclampsia, severe asthma, insulin‐dependent diabetes mellitus, hepatic insufficiency, or renal failure)

Baseline details:

Remifentanil group (n = 52):

Age (years, mean (SD)): 33.1 (5.0)

Weight (kg, mean (SD)): 81 (13)

ASA I/II (n/n): NA

Type of delivery: spontaneous (62%), instrumental (22%), CS (16%)

Week of gestation: 40

Singleton, twin, multiple pregnancy: singleton pregnancy

Parity: Primiparity 58%

Duration of labour:

‐ First stage of labour (min, mean (SD)): 363 (191)

‐ Second stage of labour (min, mean (SD)): 36 (30)

Meperidine group (n = 53):

Age (years, mean (SD)): 33.6 (5.5)

Weight (kg, mean (SD)): 84 (14)

ASA I/II (n/n): NA

Type of delivery: spontaneous (69%), instrumental (23%), CS (9%)

Week of gestation: 40

Singleton, twin, multiple pregnancy: singleton pregnancy

Parity: Primiparity 66%

Duration of labour:

‐ First stage of labour (min, mean (SD)): 293 (155)

‐ Second stage of labour (min, mean (SD)): 42 (35)

Fentanyl group (n = 54):

Age (years, mean (SD)): 33.5 (4.1)

Weight (kg, mean (SD)): 79 (12)

ASA I/II (n/n): NA

Type of delivery: spontaneous (85%), instrumental (13%), CS (2%)

Week of gestation: 40

Singleton, twin, multiple pregnancy: just singleton pregnancy

Parity: Primiparity 68%

Duration of labour:

‐ First stage of labour (min, mean (SD)): 348 (175)

‐ Second stage of labour (min, mean (SD)): 38 (26)

Interventions

Remifentanil group (n = 52):

Women received a 40 µg loading dose and remifentanil 40 µg per bolus with a lockout of 2 min and a maximum dose limit of 1200 µg/h.

Meperidine group (n = 53):

Women received a 49.5 mg loading dose and 5 mg boluses with a lockout of 10 min and a maximum overall dose limit of 200 mg.

Fentanyl group (n = 54):

Women received a 50 µg loading dose and boluses of 20 µg with a lockout of 5 min and a maximum dose limit of 240 µg/h.

Outcomes

The primary endpoint was not clearly stated but power analysis was performed for average pain score.

Continuous:

‐ overall satisfaction (VRS 1 to 10, at 2 h after delivery)

‐ pain intensity (VAS 0 to 10, at 0 h, every 1 h until 6 h)

‐ umbilical cord BE (not specified), umbilical cord pH (not specified)

‐ sedation score (observer, 1 to 5, at 0, 1, 2, 3 h)

‐ newborns: Apgar score at 1 and 5 min, NACS at 15 and 120 min

Dichotomous:

‐ additional analgesia (epidural)

‐ rate of CS, rate of assisted birth (instrumental)

‐ oxytocin use

‐ women: oxygen desaturation (< 95%), nausea + vomiting, pruritus

‐ newborns: CTG reactive

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (average pain score, n = 60 per group)

Concomitant medication:

All women were free to change to epidural analgesia at any time. The PCA device was discontinued at full cervical dilatation.

Hypotension (systolic arterial pressure < 90 mmHg or > 25% below baseline) was treated with IV fluids and ephedrine 5 mg IV. When oxygen saturation decreased below 95%, oxygen 6 L/min was administered by facemask.

If labour failed to progress (first or second stage), oxytocin was given, according to the hospital protocol.

Funding:

This work was supported by the Bronovo Research Fund.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “Randomization was established by using a computer‐generated random sequence […].”

Allocation concealment (selection bias)

Unclear risk

Quote: “[…] random sequence in numbered envelopes.” Not specifically mentioned opaque and sealed envelopes (SNOSE).

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: “Study medication was prepared and blinded by the hospital pharmacy.”, “Observants and medical personnel attending to the parturient were unaware of the drug assignment.”

We assume that participants and attending personnel might be able to uncover group allocation due to the different pharmacokinetics of the 2 interventions. The used method of blinding may only work for the outcome assessors.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: “Study medication was prepared and blinded by the hospital pharmacy.”, “With the exception of baseline data, all observations and measurements were made by blinded observers. Observants entered the delivery room only after the PCA device had been connected […]. This way the observants were unable to notice time differences in the administration […], which might have jeopardized blinding. Observants had no knowledge of the differences in programming of the PCA devices.”, “Observants and medical personnel attending to the parturient were unaware of the drug assignment.”, “Fetal heart rate patterns were scored as reactive or non‐reactive at regular intervals by an obstetrician who was blinded to the treatment groups.”

An attempt was made and reported in the method section to blind the outcome assessor.

Incomplete outcome data (attrition bias)
All outcomes

High risk

‐ Dropout rate: 15%/12%/10%

Quote: “[…] 21 were excluded due to delivery within 1h after randomisation.” No statement on time of randomisation.

‐ Large amount (up to 50%) of outcome data (satisfaction with pain relief, AE newborn/AE mother, rate of CS, rate of assisted birth, umbilical blood pH/base excess) not reported. No reasons declared.

‐ Rate of escape (epidural): 13%/34%/15% (may influence data on AE, satisfaction and pain)

‐ Rate of cross‐over: NA

‐ Data‐analysis: Per‐protocol (women who delivered within 1 hour were excluded)

Selective reporting (reporting bias)

High risk

The protocol is available (NTR543, ISRCTN12122492) and there are several deviations. In the protocol the primary outcomes were amongst others requirement for naloxone as fetal outcome and presence of opioid substances in umbilical and maternal blood samples. In the published report both outcomes were mentioned within the methods but results were not reported. The observer sedation score was not pre‐specified in the protocol.

The study protocol was retrospectively registered:

Study registration (NTR543): 12/2005

First enrolment: 08/2005

Other bias

Low risk

The study appears to be free of other sources of bias.

Methods

Randomised, controlled trial. No statement on blinding. No statement on time of randomisation.

The purpose of this trial was to compare the efficacy of IV remifentanil PCA with epidural ropivacaine/sufentanil during labour.

There are no details where or when the study was conducted. The authors’ origin is the Netherlands.

Trial Identifiers: NTR1127 or EUCTR2007‐000808‐32‐NL

Participants

Participant flow:

Number assessed for eligibility: 147

Number randomised: 26 (14/12)

Number receiving treatment: 25 (14/11)

Number analysed: 20 (10/10 at 1 h, 9/8 at 2h, 6/6 at 3 h)

Inclusion criteria:

singleton pregnancy, ASA I or II, without prior use of opioid analgesics

Exclusion criteria:

Cervical dilation > 5 cm, pre‐eclampsia, insulin‐dependent diabetes, substance abuse, opioid allergy and morbid obesity (BMI ≥ 40 kg/m²)

Baseline details:

Remifentanil group (n = 10):

Age (years, mean (SD)): 32.7 (5.9)

Weight (kg, mean (SD)): 83.3 (16.7)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (7), instrumental (1), CS (2)

Week of gestation: NA

Singleton, twin, multiple pregnancy: singleton

Parity (n): Primiparity (5)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 488 (277)

‐ Second stage of labour (min, mean (SD)): 71 (40)

Epidural group (n = 10):

Age (years, mean (SD)): 31.0 (5.2)

Weight (kg, mean (SD)): 78.9 (11.9)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (4), instrumental (4), CS (2)

Week of gestation: NA

Singleton, twin, multiple pregnancy: singleton

Parity (n): Primiparity (7)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 410 (173)

‐ Second stage of labour (min, mean (SD)): 32 (14)

Interventions

Remifentanil group (n = 10):

Parturients randomised to the IV remifentanil group received a 40 µg loading dose and boluses of 40 µg with a 2 min lockout time and bolus duration of 36 s using a Graseby 3300 syringe pump (Smiths Medical International, Ashford, Kent, UK). Maximum dose limit was 1200 µg/h.

The PCA device was discontinued when parturients reached full cervical dilation. No further analgesia was provided during the second stage.

Epidural group (n = 10):

Women randomised to receive epidural analgesia were pre‐hydrated with 500 mL IV crystalloid solution before an epidural catheter was placed using a midline paramedian approach with a 17‐gauge Tuohy needle and loss‐of‐resistance to saline at L2–3 or L3–4. A loading dose of 0.2% ropivacaine 12.5 mL was given through the epidural catheter, followed by a continuous infusion of 0.1% ropivacaine with sufentanil 0.5 µg/mL at 10 mL/h. If analgesia was inadequate, additional boluses of the epidural solution were given.

At full cervical dilation the epidural infusion was discontinued according to local hospital policy.

Outcomes

The primary outcome parameter of this study was the VAS pain score.

Continuous:

‐ satisfaction with analgesia (VAS 0 to 10, at 0, 1, 2, 3 h after starting analgesia), overall satisfaction (NRS 1 to 10, at 2 h after delivery)

‐ pain intensity (VAS 0 to 10, at 0, 1, 2, 3 h after starting analgesia)

‐ umbilical cord BE (artery), umbilical cord pH (artery)

‐ sedation score (observer, 1 to 5, at 0, 1, 2, 3 h after starting analgesia)

‐ newborns: Apgar score at 1 and 5 min

Dichotomous:

‐ additional analgesia (conversion remifentanil (PCA) to epidural)

‐ rate of CS, rate of assisted birth (instrumental)

‐ oxytocin use

‐ women: oxygen desaturation (< 95%), hypotension, bradycardia, nausea, vomiting, pruritus

‐ newborns: Apgar score ≤ 7 at 5 min, CTG reactive

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (VAS pain score, n = 10 per group)

Concomitant medication:

If pain relief was inadequate at any time, the woman could request epidural analgesia.

Hypotension (SBP < 90 mmHg or > 25% below baseline) was treated with IV fluids and IV ephedrine 5 mg or phenylephrine 100 µg. Supplemental oxygen was administered if maternal oxygen saturation (SpO₂) levels remained below 95% for more than 60 s.

Funding:

NA

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “[…] numbered envelopes that had been randomised using a computer‐generated random sequence […].”

Allocation concealment (selection bias)

Unclear risk

Quote: “[…] numbered envelopes.” Not specifically mentioned opaque and sealed envelopes (SNOSE).

Blinding of participants and personnel (performance bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of parturients and personnel did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: “Fetal heart rate patterns were scored as reactive or non‐reactive by an obstetrician who was blinded to study allocation.”

The study did not address this issue for most of the relevant outcomes with exception of the assessment of FHR patterns. However, we assume that blinding of outcome assessment did not occurred due to technical reasons and at least all other subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

‐ Dropout rate: 29%/17%

Quote: “Twenty‐six parturients were enrolled of whom 20 completed the study; 10 subjects received remifentanil, 10 received epidural analgesia. Six parturients were excluded because of either delivery within one hour of randomisation (n = 5) or unsuccessful placement of the epidural catheter (n = 1).”

No statement on time of randomisation.

‐ 30%/20% of outcome data were not reported for neonatal outcomes. No reasons declared. One woman in the remifentanil group required an epidural 2 h after initiation of the intervention. Outcome data of this woman were excluded from the analysis for satisfaction, pain, neonatal outcomes. Reason for exclusion may be related to true outcome.

‐ Rate of escape: NA

‐ Rate of cross‐over: 7%/NA, cross‐over participants were analysed as randomised

‐ Data‐analysis: Per‐protocol (women who delivered within 1 h were excluded)

Selective reporting (reporting bias)

High risk

The protocol is available (NTR1127, EUCTR2007‐000808‐32‐NL) and there are several deviations. In the protocol pain scores, woman's satisfaction, and fetal outcome (Apgar scores, umbilical cord pH, NACS, and requirement for naloxone) were defined as primary outcomes. No secondary outcomes were defined. In the published report the only primary outcome was pain score. Woman's satisfaction, sedation score, and SpO₂ were defined as secondary outcomes. NACS and requirement for naloxone were not reported. Sedation, nausea and vomiting, SpO₂ were not pre‐specified in the protocol.

The study protocol was prospectively registered:

Study registration (NTR1127): 17/11/2007

First enrolment: 26/11/2007

Other bias

Low risk

The study appears to be free of other sources of bias.

Methods

2‐arm randomised, controlled trial with a third‐arm observational cohort. Not blinded. Randomisation after onset of labour.

The purpose of this trial was to compare the incidence of maternal fever (temperature ≥ 38°C) in parturients receiving IV remifentanil by PCA, with those receiving either epidural analgesia or no analgesia.

The study was conducted in Leiden University Medical Center (period unknown).

Trial Identifier: NTR1498

Participants

Participant flow:

Number assessed for eligibility: 250

Number randomised: 116 (57/59)

Number receiving treatment: 114 (57/57)

Number analysed: 98 (49/49) + 42 control group

Inclusion criteria:

ASA I or II parturients with a singleton pregnancy, between 37 and 42 weeks of gestation

Exclusion criteria:

BMI ≥ 40 kg/m², insulin‐dependent diabetes, severe pre‐eclampsia (proteinuria ≥ 5 g/24 h), use of antibiotics during delivery, initial maternal SpO₂ < 98%, initial maternal temperature ≥ 38°C, cervical dilation of > 7 cm and ruptured membranes for > 24 h at the time of inclusion.

If delivery occurred within 1 h of starting the study, women were excluded from analysis.

Baseline details:

Remifentanil group (n = 49):

Age (years, mean (SD)): 32 (4.8)

Weight (kg, mean (SD)): 81 (17.2)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (32), instrumental (9), CS (7), missing (1)

Week of gestation: 39

Singleton, twin, multiple pregnancy: singleton

Parity (n): Nulliparous (25)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 355 (179)

‐ Second stage of labour (min, mean (SD)): 35 (29.9)

Epidural group (n = 49):

Age (years, mean (SD)): 31 (5.6)

Weight (kg, mean (SD)): 81 (12.6)

ASA I/II (n/n): NA

Type of delivery(n): spontaneous (29), instrumental (9), CS (10), missing (1)

Week of gestation: 40

Singleton, twin, multiple pregnancy: singleton

Parity (n): Nulliparous (27)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 434 (158)

‐ Second stage of labour (min, mean (SD)): 40 (28.9)

Control group (n = 42):

Age (years, mean (SD)): 33 (4.5)

Weight (kg, mean (SD)): 83 (13.3)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (34), instrumental (3), CS (5)

Week of gestation: 40

Singleton, twin, multiple pregnancy: singleton

Parity (n): Nulliparous (11)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 224 (131)

‐ Second stage of labour (min, mean (SD)): 24 (24.1)

Interventions

Remifentanil group (n = 49):

Women in the remifentanil (PCA) group received a 40 µg bolus (lockout 2 min, bolus duration 36 s) using a Graseby 3300 syringe pump (Smiths Medical Int., Luton, UK). The maximum dose permitted was 1200 µg/h. No background infusion was added. Because of concerns about the potential for neonatal respiratory depression, the pump was stopped when the woman reached full cervical dilatation.

Epidural group (n = 49):

A catheter was inserted at the L2–3 or L3–4 interspace using a 17‐gauge Tuohy needle. Parturients received a loading dose of ropivacaine 25 mg (0.2% ropivacaine 12.5 mL), followed by a continuous infusion of 0.1% ropivacaine and sufentanil 0.5 µg/mL at 10 mL/h. In case of inadequate analgesia, additional 10 mL boluses could be given. In case of epidural catheter dislodgement, the catheter was replaced.

Control group (n = 42):

No intervention

Outcomes

The primary outcome variable was the proportion of women who developed a temperature ≥ 38°C before delivery.

Continuous:

‐ overall satisfaction (NRS 1 to 10, after delivery)

‐ pain intensity (VAS 0 to 10, at 0, 1, 2, 3, 4 h after starting analgesia, diagrammed)

‐ umbilical cord BE (venous), umbilical cord pH (venous)

‐ sedation score (observer, 1 to 5, at 0, 1, 2, 3, 4 h after starting analgesia)

‐ newborns: Apgar score at 1 and 5 min

Dichotomous:

‐ additional analgesia (escape analgesia)

‐ rate of CS, rate of assisted birth (instrumental)

‐ oxytocin use

‐ women: oxygen desaturation (< 92%, < 90%, for 1, 2 or 5 min), nausea, vomiting, pruritus

‐ newborns: Apgar score ≤ 7 at 5 min, CTG reactive

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (incidence of fever, n = 175 in total)

Concomitant medication:

When parturients were dissatisfied with analgesia, an epidural was offered as alternative.

When SpO₂ dropped < 92% for more than 60 s, oxygen was administered by facemask.

Intrapartum fever was defined as maternal tympanic temperature ≥ 38°C. In cases of fever, antibiotics could be administered to the parturient.

Hypotension (SBP < 90 mmHg or > 25% below pre‐analgesia values) was treated with IV fluids and/or IV ephedrine or phenylephrine.

Funding:

NA

Contact to the authors:

We contacted Dr. Douma via e‐mail (15 March 2016) to inquire the number of women who reported 'satisfaction with pain relief' and 'pain intensity at 1, 2, 3, and 4 hours'. We received the missing data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “Randomisation was performed using a computer‐ generated randomisation list and treatments (RPCA or EA) […]”

Allocation concealment (selection bias)

Low risk

Quote: “…were presented in a numbered opaque sealed envelope that was opened upon the request for analgesia.”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “The study was not blinded.” No blinding and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: “The study was not blinded.” No blinding and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

‐ Dropout rate: 14%/17%

Quote: “We assessed the eligibility of 250 women, of whom 164 were enrolled in the study […]. After excluding women who delivered within one hour, [2 failed epidural, 2 withdrawals, 13 delivered within 1 hour, 5 exclusion criterion] 140 women were analysed, 49 received RPCA, 49 received EA and 42 were in the observational control group."

No reasons declared for exclusion of the 5 women (exclusion criterion).

‐ Quote: “Due to technical difficulties, continuous saturation data were not always available and this information is reported for only 114 women.”; Data on type of delivery from one woman each group were missing with no reasons declared.

‐ Rate of escape: NA

‐ Rate of cross‐over: 16%/2%, cross‐over participants were analysed as randomised

‐ Data‐analysis: Per‐protocol (women who delivered within 1 h were excluded)

Selective reporting (reporting bias)

High risk

2 protocols are available (NTR1498 and EUCTR2008‐002792‐28‐NL) and there are several deviations. In the protocol maternal temperature and maternal saturation were defined as primary outcomes. In the published report, however, maternal saturation was reported as a secondary outcome. The secondary outcomes pain and overall satisfaction were not pre‐specified in the protocol. The pre‐specified outcomes NACS and requirement for naloxone were not reported in the published report.

The study protocol was prospectively registered:

Study registration (NTR1498): 10/2008.

First enrolment: 11/2008

Other bias

Low risk

The study appears to be free of other sources of bias.

Methods

Randomised, controlled trial. No statement on blinding. No statement on time of randomisation.

The study was planned to compare the use of remifentanil patient‐controlled IV analgesia (PCIA) to epidural bupivacaine plus fentanyl for labour analgesia in pre‐eclamptic women.

There are no details where or when the study was conducted. The authors’ origin is Egypt/Saudi Arabia.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: NA

Number randomised: NA

Number receiving treatment: NA

Number analysed: 30 (15/15)

Inclusion criteria:

≥ 32 weeks of gestation, normal cephalic presentation, < 5 cm cervical dilatation, clinical diagnosis of pre‐eclampsia

Exclusion criteria:

Remifentanil allergy, progression to eclampsia, evidence of increased intracranial pressure or focal neurologic deficit, platelet count of less than 80*10⁹/L, evidence of pulmonary oedema, non‐reassuring FHR tracing requiring imminent delivery

Baseline details:

Remifentanil group (n = 15):

Age (years, mean (SD)): 26 (8)

Weight (kg, mean (SD)): 79 (22)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (10), instrumental (0), CS (3)

Week of gestation: 36 ± 4

Singleton, twin, multiple pregnancy: NA

Parity: NA

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Epidural group (n = 15):

Age (years, mean (SD)): 28 (9)

Weight (kg, mean (SD)): 84 (37)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (8), instrumental (3), CS (4)

Week of gestation: 35 ± 3

Singleton, twin, multiple pregnancy: NA

Parity: NA

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Interventions

Remifentanil group (n = 15):

The remifentanil hydrochloride concentration used was 50 µg/mL (3 mg diluted to 60 mL of normal saline). The PCA was set to deliver 0.5 µg/kg as a loading bolus infused over 10 s, lockout time of 5 min, PCA bolus of 0.25 µg/kg, continuous background infusion of 0.05 µg/(kg*min), and maximum dose was 3 mg in 4 h. Women were advised to start the PCA bolus when they felt the signs of a coming uterine contraction.

Epidural group (n = 15):

An epidural catheter was placed under complete aseptic technique at the L3‐L4 or L4‐L5 interspaces. A test dose of 0.25% bupivacaine was administered, and epidural analgesia was established with initial bolus of 10 mL to 15 mL of 0.25% bupivacaine plus 1 µg/kg fentanyl. Analgesia was maintained by continuous infusion of 0.125% bupivacaine plus 2 µg/mL fentanyl at a rate of 10 mL to 12 mL per hour aiming to obtain a T‐10 sensory level.

Outcomes

The primary endpoint of the study was not defined.

Continuous:

‐ overall satisfaction (NRS 1 to 4, 24 h after delivery)

‐ pain intensity (VAS 0 to 10, at 0, 1 h and after delivery)

‐ umbilical cord pH (artery, vein)

‐ sedation score (observer, 1 to 4, 0, 1 h and after delivery)

‐ women: mean respiratory rate, mean SpO₂, mean HR (at 0, 1 h and after delivery, respectively)

Dichotomous:

‐ rate of CS, rate of assisted birth (instrumental)

‐ need for neonatal mechanical ventilation

‐ women: hypotension (at 0, 1 h and after delivery), nausea, vomiting, pruritus

‐ newborns: Apgar score ≤ 7 at 1 and 5 min, need for naloxone, FHR abnormalities 1 h after analgesia

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis not performed

‐ Satisfactory analgesia was considered if VAS ≤ 3

Concomitant medication:

If the assigned analgesia was inadequate for the woman at any time, an alternative was offered and further study recording was discontinued.

Hypotension (defined as reduction of > 25% of baseline level) was treated by either additional IV crystalloid or IV bolus doses (e.g. 2.5 to 5.0 mg) of ephedrine.

Funding:

NA

Intervention:

Lockout time of 5 min seems too long for adequate analgesia.

Ethics:

The study did not report that the study protocol was approved by the local Ethics committee.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “30 preeclamptic patients were randomly assigned….” No method described.

Allocation concealment (selection bias)

Unclear risk

No statement on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of parturients and personnel did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of outcome assessment did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

‐ No missing outcome data after randomisation

‐ Rate of escape: NA

‐ Rate of cross‐over: NA

‐ Data‐analysis: NA

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.

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.

Methods

Randomised, controlled trial. Single‐blinded. Randomisation after onset of labour (VAS pain score ≥ 30 mm).

The purpose of this trial was to test the hypothesis whether labour can induce hyperthermia during epidural analgesia, and to assess the effects of analgesic doses of the IV opioid remifentanil or antipyretic doses of acetaminophen in the prevention of hyperthermia during labour.

The study was conducted in Wolfson Medical Center affiliated to Tel‐Aviv University (period unknown).

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: NA

Number randomised: 213

Number receiving treatment: 201 (12 women which did not receive any analgesia were excluded)

Number analysed: 192 (44/50/49/49), only women with at least 2 h of labour

Inclusion criteria:

Healthy women with singleton cephalic presentation at term, spontaneous active labour

Exclusion criteria:

Fever (oral temperature ≥ 38°C), signs of infection, ruptured membranes for more than 24 h, CS

Baseline details:

IV Remifentanil group (n = 44):

Age (years, mean (SD)): 29 (7)

Weight (kg, mean (SD)): 75 (11)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), forceps (1), CS (4)

Week of gestation: NA

Singleton, twin, multiple pregnancy: singleton

Number of birth (n)(1/2/3/≥ 4): 20/7/11/11

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Epidural ropivacaine group (n = 50):

Age (years, mean (SD)): 28 (5)

Weight (kg, mean (SD)): 79 (14)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), forceps (3), CS (5)

Week of gestation: NA

Singleton, twin, multiple pregnancy: singleton

Number of birth (n) (1/2/3/≥ 4): 28/12/5/5

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Epidural ropivacaine and IV Remifentanil group (n = 49):

Age (years, mean (SD)): 27 (5)

Weight (kg, mean (SD)): 78 (10)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), forceps (3), CS (11)

Week of gestation: NA

Singleton, twin, multiple pregnancy: singleton

Number of birth (n) (1/2/3/≥ 4): 25/9/4/7

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Epidural ropivacaine and IV acetaminophen group (n = 49):

Age (years, mean (SD)): 27 (4)

Weight (kg, mean (SD)): 74 (14)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), forceps (3), CS (3)

Week of gestation: NA

Singleton, twin, multiple pregnancy: singleton

Number of birth (1/2/3/≥ 4): 29/13/4/3

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Interventions

Remifentanil group (n = 44):

Parturients randomised to PCIA with remifentanil initially received a basal infusion of 0.025 µg/(kg*min) combined with 20 µg bolus doses with a lockout of 3 min. The dose was increased by 25% every 15 to 20 min as required. Acetaminophen was administered by continuous infusion 30 min after the initiation of epidural analgesia with the PCIA machine device at a rate of 0.47 mg/(kg*min) to a maximal dose of 2 g.

Epidural ropivacaine group (n = 50):

Epidural analgesia was administered after pre‐hydration with 500 mL Ringer’s lactate solution. A test dose of 3 mL lidocaine (2% without epinephrine) was followed by increments of 5 mL to 10 mL of 0.2% ropivacaine; maintenance was provided with the same solution via patient‐controlled epidural analgesia (PCEA) with a background infusion of 10 mg/h and a 10 mg patient‐activated bolus with 20 min lockout. The maximal dose of ropivacaine was 20 mL/h. The same ropivacaine dose was administered to women in all epidural groups.

Epidural ropivacaine and IV Remifentanil group (n = 49):

Epidural analgesia was administered after pre‐hydration with 500 mL Ringer’s lactate solution. A test dose of 3 mL lidocaine (2% without epinephrine) was followed by increments of 5 mL to 10 mL of 0.2% ropivacaine; maintenance was provided with the same solution via PCEA with a background infusion of 10 mg/h and a 10 mg patient‐activated bolus with 20 min lockout. The maximal dose of ropivacaine was 20 mL/h.

Parturients initially received a basal infusion of 0.025 µg/(kg*min) combined with 20 µg bolus doses with a lockout of 3 min. The dose was increased by 25% every 15 to 20 min as required.

Epidural ropivacaine and IV acetaminophen group (n = 49):

Epidural analgesia was administered after pre‐hydration with 500 mL Ringer’s lactate solution. A test dose of 3 mL lidocaine (2% without epinephrine) was followed by increments of 5 mL to 10 mL of 0.2% ropivacaine; maintenance was provided with the same solution via PCEA with a background infusion of 10 mg/h and a 10 mg patient‐activated bolus with 20 min lockout. The maximal dose of ropivacaine was 20 mL/h.

Acetaminophen was administered by continuous infusion 30 min after the initiation of epidural analgesia with the PCIA machine device at a rate of 0.47 mg/(kg*min) to a maximal dose of 2 g.

Outcomes

The primary outcome was the incidence of hyperthermia.

Continuous:

‐ pain intensity (VAS 0 to 100 mm, averaged over study period)

Dichotomous:

‐ additional analgesia (conversion remifentanil (PCA) to epidural)

‐ rate of CS, rate of assisted birth (forceps)

Notes

‐ Power analysis not described

Concomitant medication:

Women with breakthrough pain (VAPS > 30 mm) were given rescue analgesia: women in the ropivacaine or ropivacaine and acetaminophen groups were given up to 4 additional boluses of 8 mL ropivacaine (0.2%), even if they had reached the maximum dose specified above; and women in either remifentanil group had their baseline infusion and bolus doses increased, as necessary, in 25% increments. If 4 increases proved insufficient, women assigned to IV remifentanil were switched to epidural analgesia.

Oxytocin augmentation was applied when the rate of cervical dilatation was less than 1 cm/h.

Funding:

Supported by NIH Grant GM 061655 (Bethesda, MD), the Gheens Foundation (Louisville, KY), the Joseph Drown Foundation (Los Angeles, CA), and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY). Mallinckrodt Anesthesiology Products, Inc (St. Louis, MO) donated the thermocouples. Exergen, Inc (Boston, MA) donated the infrared skin‐temperature thermometer.

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)

Low risk

Quote: “Randomization was based on computer‐generated codes that were maintained in sequentially numbered opaque envelopes until just prior to use. The randomisation envelopes were opened and the designated treatment started when the visual analogue pain score (VAPS) reached 30 mm.”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “The treatment regimen was blinded for the evaluator anaesthesiologist by using two patient‐controlled analgesia machine devices (PCIA and PCEA) for every patient. A “dummy” IV saline infusion (PCIA) was attached to parturients with patient‐controlled epidural analgesia (PCEA) and the other was a “dummy” epidural catheter attached superficially to the skin and connected to a PCEA syringe in the group with patient‐controlled IV analgesia (PCIA) with remifentanil.”

The study seemed to be not blinded for parturients and personnel and we assume that at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: “The treatment regimen was blinded for the evaluator anaesthesiologist by using two patient‐controlled analgesia machine devices (PCIA and PCEA) for every patient. A “dummy” IV saline infusion (PCIA) was attached to parturients with patient‐controlled epidural analgesia (PCEA) and the other was a “dummy” epidural catheter attached superficially to the skin and connected to a PCEA syringe in the group with patient‐controlled IV analgesia (PCIA) with remifentanil.”

An attempt was made and reported in the method section to blind the outcome assessor.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

‐ Dropout rate: 10% (overall)

Reasons for missing outcome data were described (12 women delivered quickly without requirement for analgesia and nine women with labour < 2 h were excluded). Reasons may be unlikely to be related to true outcome.

‐ Rate of escape: NA

‐ Rate of cross‐over: 0% (remifentanil (PCA) to epidural)

‐ Data‐analysis: Per‐protocol (women without requirement for analgesia or with labour < 2 h were excluded)

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.

Methods

Multicentre randomised, controlled equivalence trial. No blinding. Randomisation before start of actual labour.

The purpose of this trial was to determine women’s satisfaction with pain relief using PCA with remifentanil compared with epidural analgesia during labour.

The study was conducted in three academic hospitals, 11 teaching hospitals, and one general hospital in the Netherlands from 30 May 2011 to 24 October 2012.

Trial Identifier: NTR2551

Participants

Participant flow:

Number assessed for eligibility: NA

Number randomised: 1414 (709/705)

Number receiving treatment (of interest): 698 (402/296)

Number analysed: 1358 (687/671)

Inclusion criteria:

Healthy women or those who have a mild systemic disease (ASA I or II), aged 18 or older, scheduled to deliver vaginally after 32 weeks

Exclusion criteria:

Contraindications for epidural analgesia or hypersensitivity to one of the drugs used

Baseline details:

Remifentanil group (n = 687):

Age (years, mean (SD)): 31.5 (5.1)

BMI (kg/m², median (IQR)): 23.7 (21.5‐26.9)

ASA I/II (n/n): 491/196

Type of delivery (n): spontaneous (518), instrumental (63), CS (106)

Week of gestation (median (IQR)): 37.8 (35.5 ‐ 39.2)

Singleton, twin, multiple pregnancy (n): multiple pregnancy (24)

Parity (n): 0 (323), ≥ 1 (364)

Duration of labour:

‐ First stage of labour (min, mean (IQR)): 236 (128 ‐ 376)

‐ Second stage of labour (min, mean (IQR)): 20 (10 ‐ 46)

Epidural group (n = 671):

Age (years, mean (SD)): 31.7 (4.8)

BMI (kg/m², median (IQR)): 23.8 (21.4 ‐ 27.6)

ASA I/II (n/n): 461/210

Type of delivery (n): spontaneous (501), instrumental (70), CS (100)

Week of gestation (median (IQR)): 37.1 (35.3 ‐ 39.0)

Singleton, twin, multiple pregnancy (n): multiple pregnancy (30)

Parity (n): 0 (329), ≥ 1 (342)

Duration of labour:

‐ First stage of labour (min, mean (IQR)): 309 (181 ‐ 454)

‐ Second stage of labour (min, mean (IQR)): 24 (10 ‐ 53)

Interventions

Remifentanil group (n = 687):

The patient‐controlled device was programmed to deliver 30 µg remifentanil (solution 20 µg/mL) on request with a lockout time of 3 min. The dose could be increased to 40 µg in case of insufficient pain relief or decreased to 20 µg in case of excessive side effects. No background infusion was allowed.

Women who were treated with patient‐controlled remifentanil were instructed on how to use the device and to maximise analgesia by pressing the device’s button in anticipation of the next contraction.

Epidural group (n = 671):

Women randomised to epidural analgesia received this when they requested pain relief, according to local protocol.

Outcomes

The primary outcome measure was satisfaction with pain relief measured on a VAS ranging from 0 to 100 mm.

Continuous:

‐ satisfaction with pain relief (VAS scale unclear, during active labour, after pain relief, at request, averaged), overall satisfaction (NRS 0 to 10, after birth)

‐ pain intensity (VAS scale unclear, during active labour, after pain relief, at request, averaged)

Dichotomous:

‐ additional analgesia (escape analgesia)

‐ rate of CS, rate of assisted birth (instrumental)

‐ need for neonatal admission

‐ oxytocin use

‐ umbilical cord pH (artery), pH < 7.1 (twin 1)

‐ women: respiratory depression (< 8 breaths/min), oxygen desaturation (< 95%, < 92%), hypotension (< 90 mmHg), nausea, vomiting, pruritus, postpartum haemorrhage (≥ 1000 mL)

‐ newborns: Apgar score ≤ 7 at 5 min (twin 1)

Notes

‐ Power analysis performed (satisfaction with pain relief, n = 102 per group)

Concomitant medication:

If pain relief was inadequate, women could request epidural analgesia. They were advised to discontinue using the device during the second stage of labour to minimise the risk of neonatal side effects.

If pain relief after epidural analgesia was judged inadequate by the woman, she could receive patient‐controlled remifentanil instead of epidural analgesia. No advice was given regarding continuing epidural analgesia during the second stage of labour.

Funding:

This study was funded by a grant from ZonMW (Dutch Organization for Health Care Research and Development) project No 80‐82310‐97‐11039.

Intervention:

Lockout time of 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: “Randomisation was performed through a web based randomisation program. We randomised in fixed blocks of three, stratified for centre and parity.”

Allocation concealment (selection bias)

High risk

Quote (full‐text publication): “The allocation code appeared after a patient’s initials were entered into the randomisation program.”

Quote (protocol: BMC Pregnancy and Childbirth 2012, 12: 63): "The consent form must be signed before performance of any study‐related activity. After obtaining informed consent women will be randomized and will be informed on the assigned method of pain relief before labour starts (as in usual care). They are only given pain relief during labour at their request or if a medical reason should arise."

Allocation concealment was uncovered for participants and personnel before the start of treatment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “Blinding was not possible because of the nature of the two interventions.” No blinding and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: “Blinding was not possible because of the nature of the two interventions.” No blinding and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

‐ Dropout rate: 3%/5%

‐ Large amount (5.5% to 41.5%) of data for maternal side effects and neonatal data were missing. No reasons reported.

‐ Randomisation occurred before onset of labour and only 65% and 52% received an analgesic intervention in the remifentanil and epidural group, respectively. Only 57% of women in the remifentanil group and only 42% in the epidural group received the allocated intervention.

‐ Rate of women with other pain relief (not escape, immediate use): 10%/15%

‐ Rate of cross‐over (insufficient pain relief): 13%/1%

‐ Rate of cross‐over (protocol violation): 9%/10%

‐ Data analysis: A partial ITT analysis with all women (including those without pain relief) was performed for rate of CS, assisted vaginal birth, postpartum haemorrhage, Apgar score < 7 at 5 min, and neonatal admission. A partial‐ITT with only women received pain relief (cross‐over participants as randomised) was performed for satisfaction, pain, cross‐over rate, and maternal side effects (SpO₂, BP, respiratory depression, PONV, pruritus).

‐ Study design: equivalence study (per‐protocol analysis recommended)

‐ Multiple imputation was used to correct missing primary outcome data

Selective reporting (reporting bias)

High risk

A published protocol (BMC Pregnancy and Childbirth 2012, 12: 63) and a registered protocol (NTR2551) are available and there are several deviations. In the registered protocol cost‐effectiveness was defined as the primary outcome and pain relief, woman's satisfaction, pain scores, and maternal and neonatal side effects were defined as secondary outcomes. In the published report, however, the authors stated: “Our published protocol stated that both effectiveness and cost effectiveness were primary outcome measures. Satisfaction with pain relief was the primary outcome measure for effectiveness from the start of the study [which was not reported in the protocol]. We planned to perform a cost effectiveness analysis as well, taking into account the primary outcome for effectiveness. Because this was not made clear enough in the original protocol and registry it was changed in the last amended protocol. This last amended protocol was submitted before the last randomised woman delivered and as a result we did not have access to the data.”

The first protocol (NTR2551) was prospectively registered:

Study registration: 10/2010

First enrolment: 05/2011

The second protocol (BMC Pregnancy and Childbirth 2012, 12: 63) was retrospectively registered:

Protocol received: 04/2012

First enrolment: 05/2011

Other bias

Low risk

The study appears to be free of other sources of bias.

Methods

Randomised, controlled trial. No statement on blinding. Randomisation after onset of labour.

The purpose of this trial was to assess if there is a difference in duration of labour, the mode of delivery, average VAS pain scores, maternal overall satisfaction with analgesia, side effects and neonatal outcomes in nulliparous women who received early labour analgesia with either epidural, PCIA with remifentanil or combined spinal–epidural (CSE) techniques.

The study was conducted in TAIBA Hospital in Kuwait during the period from September 2009 to August 2011.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: 1460

Number randomised: 1140 (380/380/380), 320 women were excluded due to cervical dilation of 4 cm or more

Number receiving treatment: 1140 (380/380/380)

Number analysed: 1140 (380/380/380)

Inclusion criteria:

Spontaneous labour (with at least two painful uterine contractions in 10 min and the cervix is at least 80 % effaced and up to 3 cm dilated) and requesting labour analgesia

Exclusion criteria:

Allergy to opioids, a history of the use of centrally‐acting drugs of any sort, chronic pain, psychiatric diseases records, participants younger than 18 years or older than 40 years, not willing to, or could not finish the whole study, alcohol‐ or opioid‐dependent women, non‐vertex presentation or scheduled induction of labour, diabetes mellitus and pregnancy‐induced hypertension, twin gestation and breech presentation, any contraindication to neuraxial or systemic opioid analgesia, cervical dilation of 4 cm or more, estimated fetal weight above 4000 g and abnormal FHR tracing on admission

Baseline details:

Remifentanil group (n = 380):

Age (years, mean (SD)): 28.35 (5.54)

Weight (kg, mean (SD)): 81 (13)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (250), instrumental (35), CS (95)

Week of gestation (mean (SD)): 39.2 (1.1)

Singleton, twin, multiple pregnancy: singleton

Parity: NA

Duration of labour:

‐ First stage of labour (h, mean (SD)): latent phase: 7.7 (0.8), active phase: 1.80 (0.6)

‐ Second stage of labour (h, mean (SD)): 0.95 (0.4)

Epidural group (n = 380):

Age (years, mean (SD)): 28.6 (5.49)

Weight (kg, mean (SD)): 83 (15)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (249), instrumental (36), CS (95)

Week of gestation (mean (SD)): 39.0 (1.3)

Singleton, twin, multiple pregnancy: singleton

Parity: NA

Duration of labour:

‐ First stage of labour (h, mean (SD)): latent phase: 7.8 (0.9), active phase: 1.88 (0.7)

‐ Second stage of labour (h, mean (SD)): 1.0 (0.5)

Spinal‐epidural group (n = 380):

Age (years, mean (SD)): 28.8 (5.50)

Weight (kg, mean (SD)): 82 (14)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (255), instrumental (38), CS (87)

Week of gestation (mean (SD)): 39.1 (1.2)

Singleton, twin, multiple pregnancy: singleton

Parity: NA

Duration of labour:

‐ First stage of labour (min, mean (SD)): latent phase: 6.6 (0.7), active phase: 1.55 (0.4)

‐ Second stage of labour (h, mean (SD)): 0.80 (0.3)

Interventions

Remifentanil group (n = 380):

The PCIA device was set to deliver 0.1 µg/kg of Ultiva (remifentanil hydrochloride, Glaxo Operations UK Ltd, Barnard Castle, Durham, UK), diluted with saline and given as a solution of 25 µg/mL as a bolus infused during a period of 1 min, with a lockout time of 1 min, into an IV catheter attached to a 1‐way line providing continuous infusion of saline at approximately 100 mL/h. During the study, the IV PCIA bolus was increased following a dose escalation scheme (0.1 – 0.2 – 0.3 – 0.5 – 0.7 – 0.9 µg/kg) after every second contraction until the parturient answered ‘no’ to the question whether she would like to get more efficient pain relief or until a maximum dose of 0.9 µg/kg was achieved.

Epidural group (n = 380):

Blocks were performed in the sitting position. The epidural space was located at the L3–L4 interspace using loss of resistance to air (an 18‐gauge Tuohy needle was used). A 3 mL epidural test dose of 2% lidocaine was given through the epidural catheter. After the test dose, an 8 mL dose of 0.125% levobupivacaine with 2 µg/mL fentanyl was administered through the epidural catheter. Then the catheter was connected to an electronic pump set to deliver a continuous infusion of 8 mL/h of 0.125% levobupivacaine and 2 µg/mL fentanyl. Further boluses of 5 mL to 10 mL of 0.125% levobupivacaine were given by the attending anaesthesiologist upon request.

Spinal‐epidural group (n = 380):

Blocks were performed in the sitting position. The epidural space was located at the L3–L4 interspace using loss of resistance to air (an 18‐gauge Tuohy needle was used). A 3 mL epidural test dose of 2% lidocaine was given through the epidural catheter. A needle‐through‐needle technique was performed with 2 mg levobupivacaine and 15 µg fentanyl (total volume of 2 mL) was injected intrathecally and the spinal needle was removed. Then the epidural catheter was inserted and connected to an electronic pump set to deliver the same previously mentioned mixture.

Outcomes

The primary outcome was the rate of caesarean delivery.

Continuous:

‐ overall satisfaction (VRS 1 to 4, 24 h after delivery)

‐ pain intensity (VAS 0 to 100, averaged)

‐ umbilical cord pH (artery, vein)

‐ women: mean respiratory rate, mean systolic and diastolic blood pressure, mean HR (averaged, respectively)

Dichotomous:

‐ rate of CS, rate of assisted birth (instrumental)

‐ umbilical cord pH (artery), pH < 7.2

‐ oxytocin use after analgesia

‐ women: nausea, vomiting, pruritus

‐ newborns: Apgar score < 7 at 1 and 5 min, non‐reassuring fetal status (indication for CS), need for naloxone

Notes

‐ Power analysis not performed

Concomitant medication:

NA

Funding:

NA

Intervention:

Maximum dose might be too high (might cause adverse effects).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “[…] the participants were randomized (in 3 blocks of 380 participants per block) through a computer‐generated, random‐number list […]”

Allocation concealment (selection bias)

Unclear risk

Quote: “The group assignment numbers were sealed in an envelope and kept by the study supervisor.” Not specifically mentioned sequentially numbered, opaque envelopes (SNOSE).

Blinding of participants and personnel (performance bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of parturients and personnel did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of outcome assessment did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

‐ No missing outcome data after randomisation

‐ Rate of escape: NA

‐ Rate of cross‐over: NA

‐ Data‐analysis: Full‐ITT

Selective reporting (reporting bias)

Unclear risk

There is no reference to a trial registry and no published study protocol.

The study reported only significant positive results in the abstract. The non‐significant primary outcome was not there reported.

Other bias

Low risk

The study appears to be free of other sources of bias.

Methods

Randomised, controlled trial. Single‐blinded. Randomisation after onset of labour.

The purpose of this trial was to compare the efficacy and adverse maternal and neonatal effects of remifentanil given by bolus PCA versus continuous IV infusion for labour analgesia.

The study was conducted at the Department of Anesthesiology of Ali Ebn‐e Abitaleb Hospital, Zahedan, Iran from January 2010 to March 2013.

Trial Identifier: IRCT2012100811020N2

Participants

Participant flow:

Number assessed for eligibility: NA

Number randomised: 82 (41/41)

Number receiving treatment: 82 (41/41)

Number analysed: 82 (41/41)

Inclusion criteria:

Aged 18 to 35 years, gestational ages of 37 to 40 weeks

Exclusion criteria:

BMI > 30 or < 20 kg/m², pre‐eclampsia, using psychiatric drugs, opioid or alcohol consumption, occurrence of antenatal haemorrhage, fetal distress and requesting epidural analgesia

Baseline details:

Remifentanil infusion group (n = 41):

Age (years, mean (SD)): 24.83 (4.67)

BMI (kg/m², mean (SD)): 24.07 (2.21)

ASA I/II (n/n): NA

Type of delivery: NA

Week of gestation (mean (SD)): 38.61 (1.16)

Singleton, twin, multiple pregnancy: NA

Parity: NA

Duration of labour:

‐ First stage of labour (min, mean (SD)): 165.3 (38.7)

‐ Second stage of labour (min, mean (SD)): 42.1 (12)

Remifentanil bolus group (n = 41):

Age (years, mean (SD)): 24.83 (4.67)

BMI (kg/m², mean (SD)): 24.07 (2.21)

ASA I/II (n/n): NA

Type of delivery: NA

Week of gestation (mean (SD)): 38.49 (1.23)

Singleton, twin, multiple pregnancy: NA

Parity: NA

Duration of labour:

‐ First stage of labour (min, mean (SD)): 153.2 (34.2)

‐ Second stage of labour (min, mean (SD)): 40 (10.3)

Interventions

Remifentanil infusion group (n = 41):

Remifentanil was incrementally infused with the starting dosage of 0.025 µg/(kg*min) and as required the infusion rate was increased to reach the doses of 0.05, 0.075 and 0.1 µg/(kg*min).

Remifentanil bolus group (n = 41):

Remifentanil was given by bolus PCA using an IVAC PCAM model P5000 pump, with the starting dosage of 0.25 µg/kg and as required increased to reach the dose of 0.4 µg/kg with a lockout time of 4 min.

Outcomes

The primary endpoint of the study was reduction of labour pain.

Continuous:

‐ pain intensity (VNRS 0 to 10, at baseline, averaged at stage 1 (every 15 min) and at stage 2 (every 15 min))

‐ averaged oxytocin use

‐ sedation score (observer, MOAA/S 1 to 5, after remifentanil administration)

Dichotomous:

‐ overall satisfaction (good to excellent, time point unclear)

‐ women: respiratory depression (< 8 breaths/min), oxygen desaturation (< 90 %), hypotension (< 90 mmHg), bradycardia (< 50 beats/min), nausea + vomiting

‐ newborns: Apgar score < 7 at 1 min, need for naloxone

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis not performed

Concomitant medication:

Remifentanil dosage was increased when VNRS was ≥ 7.

Remifentanil was discontinued if any of the following criteria were detected: HR < 50 beats/min, SBP < 90 mmHg, SPO₂ < 90% and respiratory rate (RR) < 8 breaths/min.

Based on the standard protocols, oxytocin was infused in cases with inappropriate labour progress.

Funding:

Zahedan University of Medical Sciences

Intervention:

Lockout time 4 min (bolus group) seems too long for adequate analgesia.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “A computerized random number generator was used for sequence generation. Simple randomisation with a 1:1 allocation ratio was used in this study.”

Allocation concealment (selection bias)

Unclear risk

Quote: “We used the consecutive opaque envelopes for the allocation concealment. The envelopes were opaque when held to the light and opened sequentially and only participant’s name and other details were written on the appropriate envelope.”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “This randomized, single‐blind clinical trial…”

The authors did not describe how they have blinded the parturients and personnel. We assume from the description of the intervention that blinding was not possible since a PCA pump was used only in the remifentanil PCA group.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No statement on blinding of outcome assessors. However, we assume from the description of the intervention that blinding was not possible since a PCA pump was used only in the remifentanil PCA group.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

‐ No missing outcome data after randomisation

‐ Rate of escape: NA

‐ Rate of cross‐over: NA

‐ Data‐analysis: Full‐ITT

Selective reporting (reporting bias)

Unclear risk

The study protocol (IRCT2012100811020N2) is available and all pre‐specified primary and secondary outcomes have been reported in the final report. However, the outcomes remifentanil dose, maternal satisfaction, and maternal and neonatal side effects have not been pre‐specified in the protocol.

The protocol was retrospectively registered:

Protocol registration: 02/2013

First enrolment: 01/2012

Other bias

Low risk

The study appears to be free of other sources of bias.

Methods

Randomised, controlled trial. Double‐blinded. Randomisation after onset of labour.

The purpose of this trial was to compare the efficacy of PCA remifentanil with IM pethidine for labour analgesia.

There are no details where or when the study was conducted. The authors’ origin is China.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: 69

Number randomised: 68 (34/34)

Number receiving treatment: 68 (34/34)

Number analysed: 68 (34/34)

Inclusion criteria:

Full term (36 to 40 weeks' gestation) parturients, ASA I and II, in the first stage of spontaneous labour, who requested parenteral opioid for labour analgesia

Exclusion criteria:

Complicated obstetric history (such as gestational diabetes, pregnancy induced hypertension or antepartum haemorrhage), multiple pregnancies, non‐cephalic presentation

Baseline details:

Remifentanil group (n = 34):

Age (years, mean (SD)): 28 (5)

Weight (kg, mean (SD)): 68.2 (11.1)

ASA I/II (n/n): 24/10

Type of delivery: NA

Week of gestation (median (IQR [range])): 39 (38 ‐ 40 [37 ‐ 41])

Singleton, twin, multiple pregnancy: singleton

Parity (n): 0 (30), ≥ 1 (4)

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Pethidine group (n = 34):

Age (years, mean (SD)): 29 (5)

Weight (kg, mean (SD)): 68.0 (8.9)

ASA I/II (n/n): 27/7

Type of delivery: NA

Week of gestation (median (IQR [range])): 39 (39 ‐ 40 [37 ‐ 41])

Singleton, twin, multiple pregnancy: singleton

Parity (n): 0 (28), ≥1 (6)

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Interventions

Remifentanil group (n = 34):

All parturients were provided with a PCA device (Omnifuse PCA, Smiths Medical, Kent, UK).

The machine was loaded with a 50 mL syringe of study drug containing remifentanil 20 µg/mL. For each successful PCA demand, an IV bolus of 1.25 mL study drug (remifentanil 25 µg) was delivered to parturients weighing < 60 kg and 1.5 mL (remifentanil 30 µg) for those weighing ≥ 60 kg. The bolus was delivered at a rate of 20 mL/h. The effective lockout interval was 3.75 – 4.50 min with an hourly limit of 25 mL. A background infusion was not used.

Parturients in the remifentanil group received an IM injection of 1.5 mL saline 0.9%.

Parturients were then instructed to press the PCA demand button as soon as they felt the start of uterine contraction.

Pethidine group (n = 34):

All parturients were provided with a PCA device (Omnifuse PCA, Smiths Medical, Kent, UK).

The machine was loaded with a 50 mL syringe of study drug containing 0.9% saline. For each successful PCA demand, an IV bolus of 1.25 mL study drug (saline) was delivered to parturients weighing < 60 kg and 1.5 mL (saline) for those weighing ≥ 60 kg. The bolus was delivered at a rate of 20 mL/h. The effective lockout interval was 3.75 to 4.50 min with an hourly limit of 25 mL. A background infusion was not used. Parturients were then instructed to press the PCA demand button as soon as they felt the start of uterine contraction.

A single IM injection of pethidine 50 mg diluted to 1.5 mL with saline was given to parturients weighing < 60 kg and pethidine 75 mg in 1.5 mL to those weighing ≥ 60 kg.

Outcomes

The primary endpoint of the study was VAS pain score during the entire duration of the study.

Continuous:

‐ overall satisfaction (NRS 0 to 10, after delivery, median + IQR + range (symmetric))

‐ pain intensity (VAS 0 to 100, at 0 h, every hour until 4 h, > 5 h, diagrammed)

‐ women: mean highest respiratory rate, oxygen saturation, SBP and pulse rate

‐ newborns: Apgar score at 1 and 5 min (median + IQR + range (symmetric)), mean FHR

Dichotomous:

‐ additional analgesia (Entonox, pethidine IM)

‐ rate of CS, rate of assisted birth (ventouse)

‐ syntocinon use

‐ women: nausea, vomiting, pruritus (women reporting VAS ≥ 30 mm or requiring treatment, respectively), dizziness, sedation score = 1 = alert

‐ newborns: fetal distress with impaired CTG

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (VAS pain, n = 34 per group)

Concomitant medication:

Rescue analgesia with IM pethidine and Entonox was offered to parturients with VAS > 50 mm or upon request. The time from the start of the study to the first request for rescue analgesia was recorded.

Funding:

NA

Intervention:

Bolus application time seems too slow (0.11 µg/s).

Contact to the authors:

We contacted Dr. Ng via e‐mail (23 June 2016) to inquire the number of women who reported 'pain intensity at 2 hours'. We received the missing data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “parturients were randomly assigned to receive either PCA remifentanil or intramuscular pethidine for labour analgesia according to a computer‐generated code […].”

Allocation concealment (selection bias)

Unclear risk

Quote: “[…] code concealed in an opaque envelope.” Not specifically mentioned sequentially numbered, sealed envelopes (SNOSE).

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: “All parturients were provided with a PCA device (Omnifuse PCA, Smiths Medical, Kent, UK). The machine was loaded with a 50‐ml syringe of study drug containing either remifentanil 20 µg/ml or 0.9% saline.”, “Parturients in the remifentanil group received an intramuscular injection of 1.5 ml saline 0.9%.”, “Study drugs were prepared by an anaesthetist not otherwise involved in the study.”, “The parturient, the attending obstetricians, midwives and research staff responsible for data collection and outcome assessment were blinded to the group identity.”

Blinding was attempted to achieve by application of both a PCA pump and an IM injection. 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.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: “All parturients were provided with a PCA device (Omnifuse PCA, Smiths Medical, Kent, UK). The machine was loaded with a 50‐mL syringe of study drug containing either remifentanil 20 µg/mL or 0.9% saline.”, “The parturient, the attending obstetricians, midwives and research staff responsible for data collection and outcome assessment were blinded to the group identity.”

An attempt was made and reported in the method section to blind the outcome assessor.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

‐ No missing outcome data after randomisation

‐ Rate of escape (pethidine IM or Entonox): 50%/85% (may influence data on AE, satisfaction and pain)

‐ Rate of cross‐over: NA

‐ Data‐analysis: Full‐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.

Methods

Randomised, controlled trial. Double‐blinded. Randomisation after onset of labour.

The purpose of this trial was to compare the maternal and neonatal effects of remifentanil given by PCA or continuous infusion for labour analgesia.

The study was conducted in China from July 2008 and September 2009.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: 60

Number randomised: 60 (30/30)

Number receiving treatment: 60 (30/30)

Number analysed: 53 (27/26)

Inclusion criteria:

ASA I to II, singleton term pregnancy, a cervical dilation of 1 to 3 cm, healthy fetus with a cephalic presentation, normal FHR pattern

Exclusion criteria:

Inability to understand PCA and VAS score, age less than 18 years or more than 45 years, morbid obesity, prior administration of regional or systemic analgesia, alcohol abuse, diabetes mellitus, pregnancy‐induced hypertension, pre‐eclampsia, severe disease of brain, heart, lung, liver or kidney

Baseline details:

Remifentanil bolus group (n = 27):

Age (years, mean (SD)): NA

Weight (kg, mean (SD)): NA

ASA I/II (n/n): NA

Type of delivery: NA

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity: NA

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Remifentanil infusion group (n = 26):

Age (years, mean (SD)): NA

Weight (kg, mean (SD)): NA

ASA I/II (n/n): NA

Type of delivery: NA

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity: NA

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Interventions

Remifentanil bolus group (n = 30):

Two syringe pumps (Graseby 3300; Graseby Medical Ltd., Watford, UK) were connected, one set up for PCA and the other for continuous infusion. A nurse made up two labelled syringes, one with remifentanil and the other with 0.9% saline. Remifentanil (Yichang Humanwell Pharmaceutical Co., Ltd., Yichang, Hubei, China) was diluted to 10 µg/mL with saline 0.9%.

The initial PCA set‐up was with a bolus of 0.1 µg/kg given over 30 s with a 2‐min lockout interval. The parturients were advised to press the PCA button at the start of a uterine contraction. No additional training was given to parturients in respect of how to recognise the beginning of a contraction, and the decision of whether to press the PCA button depended on the parturient alone. The initial continuous infusion was with a dose of 0.05 µg/(kg*min).

The PCA bolus dose was increased in increments of 0.1 µg/kg from 0.1 to 0.4 µg/kg. The continuous infusion pump was increased stepwise from 0.05 to 0.2 µg/(kg*min) with an increment of 0.05 µg/(kg*min). The two pumps were disconnected at the time of delivery, and the final dose of remifentanil was recorded.

Remifentanil infusion group (n = 30):

Two syringe pumps (Graseby 3300; Graseby Medical Ltd., Watford, UK) were connected, one set up for PCA and the other for continuous infusion. A nurse made up two labelled syringes, one with remifentanil and the other with 0.9% saline.

The continuous infusion pump was increased stepwise from 0.05 to 0.2 µg/(kg*min) with an increment of 0.05 µg/(kg*min). The two pumps were disconnected at the time of delivery, and the final dose of remifentanil was recorded.

Outcomes

The primary endpoint of the study was not explicitly stated but power analysis was performed for pain score.

Continuous:

‐ overall satisfaction (NRS 0 to 10, 1 h after delivery, median + IQR + range (asymmetric))

‐ pain intensity (VAS 0 to 10, 0, every 30 min until 120 min, delivery, diagrammed), median pain relief score (NRS 0 to 5, 0, every 30 min until 120 min, delivery, diagrammed) (median + IQR + range, respectively (symmetric))

‐ sedation score (observer, Ramsey sedation score, at 0, 30, 60, 120 min and after delivery, median + IQR + range (symmetric))

Dichotomous:

‐ additional analgesia (epidural)

‐ need for neonatal resuscitation

‐ women: respiratory depression (< 8 breaths/min), oxygen desaturation (< 95%), hypotension, bradycardia, nausea, vomiting, pruritus

‐ newborns: non‐reassuring FHR/transient fetal bradycardia, need for naloxone, respiratory depression

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (pain score, n = 30 per group)

Concomitant medication:

During labour, if the parturient requested a higher dose of analgesia then both pumps were adjusted simultaneously.

To avoid potential hypoxaemia, parturients received oxygen by nasal catheter with 2 L/min oxygen flow when there was an episode of desaturation, which was defined as SpO₂ < 95%, and the dose of remifentanil was not increased. The bolus or the infusion was discontinued in the following circumstances: HR < 50 beats/min, respiratory rate < 8 breaths/min, SpO₂ < 90%, mean arterial pressure > 25% decrease from baseline, FHR < 110 beats/min, or sedation score > 4.

When these variables returned to a normal level, the remifentanil administration was restarted at a dose one step lower than that preceding the event. If any adverse reactions persisted, the trial was stopped, the parturient was excluded and the appropriate treatment was followed. For adverse reactions, unsatisfactory analgesia, or unwillingness to continue the trial, epidural analgesia was provided unless there was a contraindication. The decision to cross‐over to epidural analgesia was made by the parturient in collaboration with the anaesthesiologist. Adverse reactions were recorded throughout the labour.

Funding:

This study was supported by grant YKK08119 and YKK11058 from Medical Science and Technology Development Foundation, Nanjing Department of Health, Nanjing, Jiangsu, China, grant CSZ00838 from Wuxi Municipal Science and Technology Projects, Wuxi, Jiangsu, China and grant 08NMUM063 from the Science & Technology Development Foundation of Nanjing Medical University, Nanjing, Jiangsu, China.

Intervention:

Application time of remifentanil seems too long (0.003 µg/(kg*s).

Contact to the authors:

We contacted Dr. Shen via e‐mail (23 June 2016) to inquire the number of women who reported 'pain intensity at 2 hours'. We received the missing data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “The randomisation code was generated by computer […].”

Allocation concealment (selection bias)

Low risk

Quote: “[…] and then sealed in sequentially numbered, opaque envelopes before the beginning of the trial.”, “Only one investigator who selected the envelope knew the grouping.”

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: “The anaesthesiologists who set up the analgesia and recorded the data, the nurses who prepared the medication, midwives, obstetricians and mothers were all blinded to the group allocation. Only one investigator who selected the envelope knew the grouping.”, “Two syringe pumps […] were connected to the cannula, one set up for PCA and the other for continuous infusion. A nurse made up two labelled syringes, one with remifentanil and the other with 0.9% saline. Remifentanil […] was diluted to 10 µg/ml with saline 0.9%. The investigator opened the randomisation envelope and then put the syringes into the appropriate pumps according to the group allocation. The syringe label was then covered with black paper.”

Blinding for participants and personnel adequate.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: “The anaesthesiologists who set up the analgesia and recorded the data, the nurses who prepared the medication, midwives, obstetricians and mothers were all blinded to the group allocation. Only one investigator who selected the envelope knew the grouping.”, “Two syringe pumps […] were connected to the cannula, one set up for PCA and the other for continuous infusion. A nurse made up two labelled syringes, one with remifentanil and the other with 0.9% saline. Remifentanil … was diluted to 10 µg/ml with saline 0.9%. The investigator opened the randomisation envelope and then put the syringes into the appropriate pumps according to the group allocation. The syringe label was then covered with black paper.”

Blinding for outcome assessment adequate.

Incomplete outcome data (attrition bias)
All outcomes

High risk

‐ Dropout rate: 10%/13%

Quote: “Two women in the PCA group and four subjects in the infusion group chose to cross over to epidural analgesia because of inadequate analgesia despite using the maximum dose, and there was one protocol violation in the PCA group. These mothers delivered their babies spontaneously, with Apgar scores > 9 at 1 min and 10 at 5 min, and no data were included from these subjects.”

The protocol violation was not described. Reasons for missing outcome data likely to be related to true outcome.

‐ Rate of escape (epidural): 7%/13%

‐ Rate of cross‐over: NA

‐ Data‐analysis: Per‐protocol

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.

Methods

Randomised, controlled trial. Not blinded. Randomisation after onset of labour.

The purpose of this trial was to compare the analgesia efficacy and maternal satisfaction of remifentanil labour analgesia with standard treatment (epidural analgesia).

The study was conducted in a Jerusalem tertiary hospital labour and delivery suite from February 2010 to August 2010.

Trial Identifier: NCT00801047

Participants

Participant flow:

Number assessed for eligibility: 144

Number randomised: 40 (20/20)

Number receiving treatment: 39 (19/20)

Number analysed: 39 (19/20)

Inclusion criteria:

Healthy, ASA I or II, age 18 to 40 years, body weight < 110 kg, gestational age > 36 completed weeks, with singleton pregnancy and vertex presentation

Exclusion criteria:

Contraindication to epidural analgesia, opioid administration in the previous 2 h, previous uterine surgery, pre‐eclampsia, inability to understand the consent form, nasal obstruction for any reason, medical indication for epidural analgesia (e.g. cardiac disease, suspected difficult airway), or non‐reassuring FHR tracing

Baseline details:

Remifentanil group (n = 19):

Age (years, mean (SD)): 31 (5)

Weight (kg, mean (SD)): 72 (10)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), vacuum delivery (2), CS (0)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity (median (IQR) or n): 1 (1‐1), Nulliparous (4)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 329 (215)

‐ Second stage of labour (min, mean (SD)): 35 (41)

Epidural group (n = 20):

Age (years, mean (SD)): 30 (6)

Weight (kg, mean (SD)): 73 (13)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), vacuum delivery (1), CS (4)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity (median (IQR) or n): 1 (0‐1), Nulliparous (6)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 404 (259)

‐ Second stage of labour (min, mean (SD)): 69 (81)

Interventions

Remifentanil group (n = 19):

PCA: The bolus dose was titrated to effect from 20 µg up to a maximum of 60 µg as required; the lockout interval was initially set at 2 min, without a background infusion. The PCIA bolus/lockout interval was titrated to an endpoint of either woman's comfort or a maximal bolus dose of 60 µg/minimal lockout interval of 1 min by the recruiting anaesthesiologist at any time during labour. The PCIA pump tubing was “piggybacked” into the distal most port of the mainline IV fluid tubing. The mainline tubing contained an antireflux valve designed to prevent remifentanil inadvertently backing up in the IV line during administration.

Epidural group (n = 20):

A 17‐gauge Tuohy needle was inserted by the midline approach using loss of resistance to air at intervertebral space L3‐4 or L2‐3. An incremental initial loading dose of 15 mL of 0.1% bupivacaine with 50 µg fentanyl was administered followed by patient‐controlled epidural analgesia infusion of 0.1% bupivacaine with 2 µg/mL fentanyl: basal infusion of 5 mL/h, patient‐controlled bolus 10 mL, and lockout interval 20 min. Additional epidural bolus doses (either 0.1% bupivacaine 10 mL during the first stage of labour or 1% lidocaine 8 mL during the second stage of labour) were administered by the anaesthesiologist to treat breakthrough pain. If epidural analgesia failed, the epidural catheter was reinserted.

Outcomes

The primary endpoint of the study was to demonstrate non‐inferiority of remifentanil labour analgesia compared with epidural analgesia in labouring women, measured by hourly assessment of NRS for pain throughout the duration of labour and maternal satisfaction.

Continuous:

‐ satisfaction with pain relief (NRS 0 to 10, at 10 min and postpartum)

‐ pain intensity (NRS 0 to 10, at 0, 30 min, 1, 2, 3, 4, 5, 6 h)

‐ newborns: Apgar score at 1 and 5 min (median + IQR + range (symmetric), data for Apgar score at 5 min dichotomised: all newborn had an Apgar score of 10 at 5 min)

Dichotomous:

‐ additional analgesia after 1 h (rescue), additional analgesia (cross‐over to the other treatment arm)

‐ rate of CS, rate for assisted birth (vacuum)

‐ need for neonatal resuscitation

‐ umbilical cord BE (artery), umbilical cord pH (artery)

‐ oxytocin use

‐ sedation score (observer, awake or easily arousable at 1 h)

‐ women: apnoea (> 20 s of zero respiratory rate), respiratory depression (< 8 breaths/min), oxygen desaturation (< 94%), nausea (at 1 h and postpartum), pruritus (at 1 h and postpartum)

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (NRS pain, n = 17 per group)

Concomitant medication:

Women were informed before study enrolment that conversion to the other treatment would be possible at any time during labour beginning 30 min after analgesia initiation with the study technique.

All women received continuous supplementary oxygen (2 L/min) through an oral‐nasal cannula.

Funding:
Hadassah Medical Organisation

Contact to the authors:

We contacted Dr. Weiniger via e‐mail (16 March 2016) to inquire the number of women who reported 'pain intensity at 30 min, 1, and 2 hours'. We received the missing data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “Randomization and group allocation were determined: cards were divided into groups of 8 cards. Each group contained 4 allocation cards for remifentanil and 4 allocation cards for epidural analgesia (ratio 1:1), and 8 opaque envelopes numbered in groups from 1 – 8, 9 – 16, etc. were assigned to each group of cards. The cards were placed face down, manually shuffled, randomly selected, and then inserted into the numbered, opaque envelopes by a person not involved in the study. These envelopes were then sealed. Treatment assignment was revealed by breaking the seal of an envelope in consecutive order from number 1.”

Allocation concealment (selection bias)

Low risk

Quote: “…inserted into the numbered, opaque envelopes by a person not involved in the study. These envelopes were then sealed. Treatment assignment was revealed by breaking the seal of an envelope in consecutive order from number 1.”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “This randomized nonblinded controlled noninferiority study […].”

The study was not blinded due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: “The investigator inquired whether opioid side effects (i.e., pruritus and/or nausea and vomiting) were present or absent.”, “After delivery, face‐to‐face follow‐up was performed on the first postpartum day for both mother and child by one of the investigators”, “Hence, the mathematician was not blinded to group allocation. However, she was blinded to our study hypothesis that remifentanil was noninferior to epidural analgesia and that remifentanil may have respiratory effects different from those seen with epidural analgesia.”

The study did not adequately report on blinding of outcome assessors. Therefore, we assume that the study was not blinded due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

‐ Dropout rate: 5%/0%

One woman was excluded after enrolment but before analgesia due to obstetrician request. Reasons for missing outcome data unlikely to be related to true outcome.

‐ Rate of escape (other pain relief after 1 h): 0%/17% (may influence data on AE, satisfaction and pain)

‐ Rate of cross‐over: 16%/5%

‐ Data‐analysis: Partial‐ITT

‐ Study design: non‐inferiority study (per‐protocol analysis recommended)

Selective reporting (reporting bias)

High risk

A registered protocol (NCT00801047) is available and there are several deviations. The VAS pain score was defined as primary outcome and no other primary or secondary outcomes were defined in the protocol. In the published report, however, the authors defined maternal satisfaction as another primary endpoint, and incidence of apnoea was defined as secondary outcome. The primary outcome pain score was reported on a 11‐point NRS scale in the final report. The authors further reported on SpO₂, sedation, pruritus, nausea, and adverse effects on the newborn.

The protocol was prospectively registered:

Protocol registration: 12/2008

First enrolment: 02/2010

Other bias

Low risk

The study appears to be free of other sources of bias.

Methods

Randomised, controlled trial. No statement on blinding. Randomisation after onset of labour.

The purpose of this trial was to compare the analgesic efficacy of parturient‐controlled IV remifentanil administration with epidural analgesia during first stage of labour with regard to maternal and early neonatal side effects.

The study was conducted in Czech Republic from March 2010 to May 2010.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: 81

Number randomised: 28 (13/15)

Number receiving treatment: 28 (13/15)

Number analysed: 24 (12/12)

Inclusion criteria:

No comorbidity (ASA I), singleton head‐down full term pregnancy, spontaneous or induced labour, request for labour analgesia

Exclusion criteria:

NA

Baseline details:

Remifentanil group (n = 12):

Age (years, mean (SD)): 27.9 (2.95)

Weight (kg, mean (SD)): 84 (16.75)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (2), induced (10)

Week of gestation (weeks + days, mean (SD)): 39 + 3 (1 + 3)

Singleton, twin, multiple pregnancy: singleton

Parity (n): 1 (10), 2 (2), 3 (0)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 260.8 (65.5)

‐ Second stage of labour (min, mean (SD)): 11.25 (10.01)

Epidural group (n = 12):

Age (years, mean (SD)): 29.4 (2.05)

Weight (kg, mean (SD)): 85.83 (16.75)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (4), induced (8)

Week of gestation (weeks + days, mean (SD)): 40 + 0 (1 + 0)

Singleton, twin, multiple pregnancy: singleton

Parity (n): 1 (8), 2 (3), 3 (1)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 246.7 (76.3)

‐ Second stage of labour (min, mean (SD)): 13.75 (13.51)

Interventions

Remifentanil group (n = 13):

After the parturient's consent, her peripheral vein was cannulated and infusion of normal saline up to 2 mL/(kg*h) was started. The PCA device was connected to the same cannula. Remifentanil (Ultiva, Glaxo‐Smith‐Kline, Great Britain) was then administered via the PCA device (Technic 1, AMV Technics, Czech Republic) from a 50 mL syringe in a concentration of 20 µg/mL. On demand, the parturient received an IV bolus of 20 µg (1 mL) of remifentanil. Lockout interval was set to 3 min. The significant analgesic effect was set to a minimal VAS score decrease of 2, based on existing evidence. In case of inadequate analgesic VAS decrease (< 2), it was possible for the anaesthesiologist to increase the dose in 10 µg steps.

Epidural group (n = 15):

The parturients undergoing EA had an epidural catheter inserted into the epidural space by an anaesthesiologist. The dosage regimen of bupivacaine and sufentanil in the EA group was rigidly set to induction dose of 12.5 mg of bupivacaine and 5 µg of sufentanil in 10 mL of normal saline; top‐up boluses of half‐size dose were repeated in 60‐min to 90‐min intervals. The epidural catheter was extracted after the delivery, at least 2 hours before the parturient's transport to post‐natal care ward.

Outcomes

The primary endpoint of the study was not defined.

Continuous:

‐ overall satisfaction (mean % score + range, at 2 ‐ 24 h after delivery)

‐ pain intensity (VAS 0 to 10, 0, 30 min, until delivery (4 h), median + IQR (symmetric))

‐ umbilical cord pH (not specified)

‐ newborns: Apgar score at 1, 5 and 10 min

Dichotomous:

‐ rate of CS

‐ women: hypotension (> 25% decrease from baseline), bradycardia (< 50 beats/min), nausea + vomiting, drowsiness + dizziness

‐ newborns: pathological CTG (conversion to CS)

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis not performed

Concomitant medication:

If any signs of sedation (drowsiness), dizziness, muscle rigidity or bradypnoea (< 10 breaths/min) were observed, the lockout interval could be extended by 1 min.

Funding:

NA

Contact to the authors:

We contacted Dr. Stourac via e‐mail (29 June 2016) to inquire details on the method used for randomisation. We received the missing information.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Women who had asked for obstetric analgesia and met the inclusion criteria were offered the PCA using remifentanil (randomisation by the parturient)." On request the trial author offered the following information on the randomisation method: "Then she rolled the dice and based on the result she was assigned into remi (even) or epi (odd) groups".

Allocation concealment (selection bias)

Low risk

Participants and investigators enrolling participants could not foresee assignment because of the method used for randomisation (throwing dice).

Blinding of participants and personnel (performance bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of parturients and personnel did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of outcome assessment did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

High risk

‐ Dropout rate: 8%/20%

Quote: “The data of the parturients whose pregnancies were terminated by Caesarean Section were excluded from statistical evaluation. Four pregnancies were terminated by Caesarean Section (2 of them due to labour progress stagnancy, 2 because of a pathological cardiotocography (CTG) record (1 in each branch)).”

Reasons for missing outcome data likely to be related to true outcome.

‐ Rate of escape: NA

‐ Rate of cross‐over: NA

‐ Data‐analysis: Per‐protocol

Selective reporting (reporting bias)

Unclear risk

There is no reference to a trial registry and no published study protocol.

Other bias

Unclear risk

Early stopping.

Quote: “28 parturients met the requirements to take part in this prospective randomised trial. This low count was caused by high parturient refusal to participate in the study (N=53) despite agreement with labour analgesia. We are aware of the decreased power with the lower sample size; nevertheless the 95% confidence interval for endpoint estimate in the groups showed clinically non‐significant results within its whole range which supports our findings from the statistical testing. Therefore we decide to terminate the enrolment.”

Methods

Randomised, controlled trial. No statement on blinding. No statement on time of randomisation.

The purpose of this trial was to compare the analgesic effect of remifentanil given as PCA with IM meperidine during labour.

There are no details where or when the study was conducted. The authors’ origin is the UK.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: 36

Number randomised: 36 (18/18)

Number receiving treatment: 36 (18/18)

Number analysed: 36 (18/18)

Inclusion criteria:

Aged between 18 and 40 years, between 38 to 42 weeks of gestation in early labour

Exclusion criteria:

< 50 kg or >100 kg

Baseline details:

Remifentanil group (n = 18):

Age (years, median (IQR)): 28 (22 ‐ 32)

Weight (kg, median (IQR)): 66.5 (58 ‐ 78)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (11), ventouse (4), CS (3)

Week of gestation (median (IQR)): 40.1 (39.25 ‐ 41)

Singleton, twin, multiple pregnancy: NA

Parity (n): 1 (13), 2 (0), 3 (3), 4 + (2)

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Meperidine group (n = 18):

Age (years, median (IQR)): 29 (25 ‐ 30)

Weight (kg, median (IQR)): 64 (58 ‐ 76)

ASA I/II (n/n): NA

Type of delivery (n/n): spontaneous (16/17), ventouse (1/17), CS (0/17)

Week of gestation (median (IQR)): 39.6 (39 ‐ 40)

Singleton, twin, multiple pregnancy: NA

Parity (n): 1 (13), 2 (0), 3 (2), 4 + (0)

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Interventions

Remifentanil group (n = 18):

PCA: starting with a 5 µg bolus, an increasing dose of remifentanil was given at the beginning of each painful contraction until the contraction was pain‐free, and the next painful contraction was noted.

Meperidine group (n = 18):

IM Meperidine 100 mg

Outcomes

The primary endpoint of the study was not explicitly defined but power analysis was performed for pain score.

Continuous:

‐ midwives' and mother's assessment of overall effective analgesia (VRS 1 to 5, within 2 h after delivery, individual patient data)

‐ pain intensity (VAS 0 to 100, at 0 and 1 h), max. pain score over 2 h (VAS 0 to 100) (median + IQR, respectively (asymmetric))

‐ sedation score (unclear assessor, VAS 0 to 100, at baseline, median + IQR)

Dichotomous:

‐ additional analgesia (Entonox, epidural)

‐ rate of CS, rate of assisted birth (ventouse)

‐ syntocinon use

‐ women: respiratory depression (< 8 breaths/min), oxygen desaturation (< 94%), nausea + vomiting

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (pain score, n = 30 in total)

‐ Abstract: fewer number of women

‐ The exact intervention in the remifentanil group remains unclear (“20 µg bolus over 20 s, 3 min lockout and no background infusion”)

Concomitant medication:

If the assigned analgesia was inadequate for the woman at any time, an alternative was offered (epidural analgesia) and further study recordings were discontinued.

All women had access to Entonox at all times.

Remifentanil group: No antiemetic was given unless indicated clinically.

Meperidine group: antiemetic was given (promethazine 25 mg or prochlorperazine 12.5 mg)

Funding:

NA

Intervention:

Lockout time of 3 min seems too long for adequate analgesia (borderline).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “[…] women were assigned randomly to one of two groups by sequentially numbered, sealed opaque envelopes prepared by an independent practitioner.”

The method used for randomisation was not described.

Allocation concealment (selection bias)

Low risk

Quote: “[…] sequentially numbered, sealed opaque envelopes…”

Blinding of participants and personnel (performance bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of parturients and personnel did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

The study did not address this issue. However, we assume that blinding of outcome assessment did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

‐ Dropout rate: 0%

‐ There were no withdrawals. However, there are some outcome data (additional analgesia, mode of delivery) incomplete (missing from notes) without reasons.

‐ Rate of escape (Entonox): 55%/81% (may influence data on AE, satisfaction and pain)

‐ Rate of escape (epidural): 39%/17%

‐ 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.

Methods

Randomised, controlled trial. Not blinded. Randomisation after onset of labour.

The purpose of this trial was to compare the analgesic efficacy and side effects of remifentanil (PCA) with walking epidural analgesia during labour, with regard to maternal and early neonatal side effects.

There are no details where or when the study was conducted. The authors’ origin is Norway.

Trial Identifier: NCT00202722

Participants

Participant flow:

Number assessed for eligibility: 62

Number randomised: 39 (19/20)

Number receiving treatment: 39 (19/20)

Number analysed: 37 (17/20)

Inclusion criteria:

Mixed parity, ASA I or II with normal singleton pregnancies, regular uterine contractions, cervical dilatation more than 2 cm, anticipated vaginal delivery, fetus without suspected abnormality, normal fetal cardiotocographic pattern, no complications during pregnancy, gestation age 37 to 40 weeks

Exclusion criteria:

Request for an epidural, had received pethidine less than 8 h before the study period, contraindications to remifentanil

Baseline details:

Remifentanil group (n = 17):

Age (years, mean (range)): 26 (20 ‐ 33)

Weight (kg, mean (SD)): 79 (13.7)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), forceps/ventouse (2), CS (1)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity (n): Primiparous (12), Multiparous (5)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 360 (185.9)

‐ Second stage of labour (min, mean (SD)): 51 (33.5)

Epidural group (n = 20):

Age (years, mean (range)): 27 (20 ‐ 37)

Weight (kg, mean (SD)): 80 (8.7)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), forceps/ventouse (3), CS (3)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity (n): Primiparous (11), Multiparous (9)

Duration of labour:

‐ First stage of labour (min, mean (SD)): 359 (165.5)

‐ Second stage of labour (min, mean (SD)): 42 (32.2)

Interventions

Remifentanil group (n = 17):

Those randomised to the RA group received remifentanil hydrochloride (Ultiva, GlaxoSmithKline, Oslo, Norway) diluted in physiological saline to a concentration of 50 µg/mL, given as stepwise bolus doses with no background infusion.

The starting bolus dose was 0.15 µg/kg, with increasing dose steps of 0.15 µg/kg and no maximum limit. The dose was allowed to be increased or decreased every 15 min according to the woman’s request for dose adjustment, VAS pain score and side effects.

The lockout period was 2 min. Remifentanil was administered using a PCA pump (Baxter 6060 Multi‐Therapy infusion pump, Baxter Healthcare Corporation, Kista, Sweden) with a bolus infusion speed of 2 mL/min (100 µg/min). Calculation of PCA doses was based on estimated bodyweight using the following formula: body height in centimetres ‐ 100 = estimated weight (kg).

Epidural group (n = 20):

Parturient women randomised to the epidural group had an epidural catheter inserted in the midline at L2–3/L3–4 by the investigator. They received a continuous epidural infusion of ropivacaine 1 mg/mL and fentanyl 2 µg/mL (‘walking epidural’). An initial bolus dose of 10 mL, followed by a 5 mL top‐up after 5 min (total 15 mL) was given before the start of infusion (10 mL/h). Thereafter, the midwife was allowed to adjust the infusion dose (5 mL/h to 15 mL/h) and give rescue doses (5 mL) if needed.

If pain relief was inadequate, the position of the epidural catheter was adjusted or a new catheter was placed if necessary.

Outcomes

The primary endpoint of the study was not defined but power analysis was performed for VAS pain reduction.

Continuous:

‐ pain intensity (VAS 0 to 100, at 0, 30 min, until 240 min)

‐ sense of control in labour (VRS 1 to 5, within 24 h after delivery, median + range)

‐ umbilical cord BE (artery, vein), umbilical cord pH (artery, vein)

‐ newborns: Apgar score at 1, 5 and 10 min (median + range)

Dichotomous:

‐ satisfaction with pain relief (very satisfied, recommend analgesia, same analgesia next time)

‐ additional analgesia (rescue, epidural group: additional bolus), additional analgesia (conversion to EA)

‐ rate of CS, rate of assisted birth (ventouse, forceps)

‐ neonatal abnormalities

‐ oxytocin use

‐ sedation score (parturient, sedated or very sedated, discomfort by sedation, amnesia from labour)

‐ women: respiratory depression (< eight breaths/min), oxygen desaturation (< 92%, supplemental oxygen), nausea, vomiting, pruritus, drowsiness

‐ newborns: Apgar score < 8 at 1 min, pathological FHR changes

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (VAS pain reduction, n = 26 per group)

‐ If delivery took place within 30 min of analgesia, the woman was excluded.

Concomitant medication:

Oxytocin, metoclopramide, ephedrine and IV fluids were available if needed.

Supplemental oxygen (4 L/min) was given immediately via nasal cannula if SaO₂ was less than 92%. Remifentanil analgesia was temporarily stopped if SaO₂ less than 92% persisted or respiratory frequency was less than nine breaths/min, SBP was less than 90 mmHg or HR was less than 50 beats/min. When physiological variables returned to normal, pain therapy was continued on a dose 1 step lower.

Funding:

The work was funded by Sørlandet Hospital HF, Sørlandets Kompetansefond and Helse Sør‐Øst, Norway.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “Randomisation was based on a computer‐generated list [...].”

Allocation concealment (selection bias)

Unclear risk

Quote: “[…] codes were kept in sealed envelopes until recruitment..” Not specifically mentioned sequentially numbered, opaque envelopes (SNOSE).

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: “Our study has some limitations; it was not blinded, […].”

The study was not blinded due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Quote: “[…] for observer sedation score […] the anaesthesiologist and attending midwife scored independently.”, “After the study, two additional obstetricians, blinded to the analgesia method and neonatal outcome, independently evaluated FHR recordings.”

The study was not blinded due to technical reasons and at least all other subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding. However, the authors attempted to minimise bias by duplicate outcome assessment for the outcomes observer sedation score and FHR.

Incomplete outcome data (attrition bias)
All outcomes

High risk

‐ Dropout rate: 10%/0%

Two women (10%) were excluded (per‐protocol analysis) from the remifentanil group due to cross‐over to the epidural group (reasons: suspicious FHR changes and inadequate analgesia). However, there are five women in the epidural group who received an extra bolus dose (rescue medication) due to unsatisfactory analgesia and were not excluded.

‐ There were missing outcome data (15% to 70%) regarding neonatal outcomes without reasons.

‐ Rate of escape (additional epidural bolus): NA/25%

‐ Rate of cross‐over: 10%/NA,

‐ Data‐analysis: Per‐protocol

Selective reporting (reporting bias)

High risk

A registered protocol (NCT00202722) is available. However, there are large discrepancies between the protocol and the published study report. The protocol deals only with a single group assignment (remifentanil PCA) and 41 enrolled women (39 within the published report), whereupon we contacted the study author. The author confirmed on request by mail that this protocol matches the published study.

The protocol was retrospectively registered:

Protocol registration: 09/2005

First enrolment: 01/2004

Other bias

Unclear risk

Early stopping.

Quote: “We had a technical problem with our infusion pumps after inclusion of 39 patients, and were not able to find new pumps with exactly the same technical specifications. Therefore, we closed the study at this point, leaving us with a number of participants close to the estimation from the power calculation.”

Methods

Randomised, controlled trial. Double‐blinded. Randomisation after onset of labour.

The purpose of this trial was to compare the efficacy of analgesia and side effects of a remifentanil PCA and pethidine PCA, using a VAS scoring system, throughout the first and second stages of labour.

There are no details where or when the study was conducted. The authors’ origin is the UK.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: 17

Number randomised: 17 (9/8)

Number receiving treatment: 17 (9/8)

Number analysed: 17 (9/8)

Inclusion criteria:

Healthy women at 36 to 40 weeks’ gestation, ASA I or II, with no known obstetric complications, and requesting pethidine analgesia

Exclusion criteria:

Any contraindication to pethidine or remifentanil and a request for early epidural analgesia in labour

Baseline details:

Remifentanil group (n = 9):

Age (years, mean (SD)): 28.6 (4.7)

Weight (kg, mean (SD)): 81.1 (24.1)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (5), forceps/ventouse (2), CS (2)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity (n): primiparous (5), multiparous (4)

Duration of labour (min, mean (SD)): 362 (300)

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Pethidine group (n = 8):

Age (years, mean (SD)): 28.9 (4.6)

Weight (kg, mean (SD)): 67.2 (14.3)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (5), forceps/ventouse (2), CS (1)

Week of gestation: NA

Singleton, twin, multiple pregnancy: NA

Parity (n): primiparous (4), multiparous (4)

Duration of labour (min, mean (SD)): 348 (283)

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Interventions

Remifentanil group (n = 9):

PCA (IVAC PCAM model P5000 pump (ALARIS Medical Systems, UK)) with a remifentanil bolus of 0.5 µg/kg, a lockout period of 2 min and no hourly maximum limit.

The remifentanil bolus was calculated using the maternal weight recorded at the antenatal booking clinic.

Pethidine group (n = 8):

PCA (IVAC PCAM model P5000 pump (ALARIS Medical Systems, UK)) with a pethidine bolus 10 mg, a lockout period of 5 min and a maximum limit of 100 mg per h.

Outcomes

The primary endpoint of the study was not defined but power analysis was performed for VAS pain.

Continuous:

‐ pain intensity (VAS 0 to 100, at 0 h, every hour until 5 h, diagrammed)

‐ women: mean nausea and pruritus (VAS 0 to 100, initial and mean hourly)

‐ newborns: Apgar score at 1 and 5 min (median + range)

Dichotomous:

‐ additional analgesia (Entonox and epidural)

‐ rate of CS, rate of assisted birth (forceps/ventouse)

‐ need for neonatal admission

‐ syntocinon use before and after PCA

‐ women: respiratory depression (< 12 breaths/min), hypotension, bradycardia

‐ newborns: Apgar score < 7 at 5 min, need for naloxone

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (VAS pain, n = 17 in total)

Concomitant medication:

All the women in both groups were given metoclopramide 10 mg IV every 8 h.

They received IV ondansetron 8 mg for persisting nausea and vomiting. The use of Entonox for any period during labour was noted. The PCA was stopped if epidural analgesia was requested but the VAS scores to that point were included in the analysis.

Funding:

NA

Intervention:

high bolus starting dose (0.5 mg/kg)

Contact to the authors:

We contacted Dr. Volikas via e‐mail (23 June 2016) to inquire the number of women who reported 'pain intensity at 2 hours'. We did not receive any answer.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: “The women were randomly allocated to one of two groups by selecting the next in a series of sealed envelopes prepared by our pharmacy department.”

It is not specifically mentioned that the envelopes were opaque. Therefore, it might be possible that sequence generation is influenced by specifically selecting the preferred group.

Allocation concealment (selection bias)

Unclear risk

Quote: “…in a series of sealed envelopes prepared by our pharmacy department.”

Not specifically mentioned sequentially numbered, opaque envelopes (SNOSE).

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: “The women and observer were blind to the treatment. This was achieved by having two investigators. One investigator selected the envelope and prepared the PCA pump with the appropriate drug. The pump was covered so that the other investigator, the observer, was unable to see which drug the woman was receiving.”

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.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: “The women and observer were blind to the treatment. This was achieved by having two investigators. One investigator selected the envelope and prepared the PCA pump with the appropriate drug. The pump was covered so that the other investigator, the observer, was unable to see which drug the woman was receiving. The observer, who was an anaesthetist, stayed on the delivery suite at all times to record the visual analogue scale (VAS) scores and provide continuous monitoring of the individual under study. The observer did not have any other commitments on the labour ward.”

An attempt was made to blind the outcome assessor. However, we assume, that the outcome assessor who stayed on the delivery suite all the time might be able to uncover group allocation due to the different pharmacokinetics of the two interventions.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

‐ No missing outcome data after randomisation.

‐ Rate of escape (Entonox): 44%/63% (may influence data on AE, satisfaction and pain)

‐ Rate of escape (epidural): 11%/13%

‐ Rate of cross‐over: NA

‐ Data‐analysis: Full‐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.

Methods

Randomised, controlled trial. Double‐blinded. Randomisation after onset of labour.

The purpose of this trial was to evaluate if IV PCA with remifentanil could provide as satisfactory pain relief for labour as epidural analgesia.

There are no details where or when the study was conducted. The authors’ origin is Finland.

Trial Identifier: NA

Participants

Participant flow:

Number assessed for eligibility: 52

Number randomised: 52 (27/25)

Number receiving treatment: 51 (27/24)

Number analysed: 45 (24/21)

Inclusion criteria:

Healthy term parturients with uncomplicated singleton pregnancies, normal cephalic presentation, no prior administration of opioid analgesia for at least 4 h or regional analgesia

Exclusion criteria:

NA

Baseline details:

Remifentanil group (n = 24):

Age (years, median (IQR)): 27 (24 ‐ 32)

Weight (kg, median (IQR)): 80 (73 ‐ 86)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), vacuum extraction (4), CS (1)

Week of gestation: NA

Singleton, twin, multiple pregnancy: singleton

Parity (n): primiparous (17), multiparous (7)

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Epidural group (n = 21):

Age (years, median (IQR)): 28 (27 ‐ 31)

Weight (kg, median (IQR)): 79 (75 ‐ 87)

ASA I/II (n/n): NA

Type of delivery (n): spontaneous (NA), vacuum extraction (1), CS (1)

Week of gestation: NA

Singleton, twin, multiple pregnancy: singleton

Parity (n): primiparous (16), multiparous (5)

Duration of labour:

‐ First stage of labour (min, mean (SD)): NA

‐ Second stage of labour (min, mean (SD)): NA

Interventions

Remifentanil group (n = 24):

The PCA (Graseby 3300, Graseby Medical Ltd, Watford, UK) device was set to deliver 0.1 mg/kg of Ultiva (remifentanil hydrochloride, Glaxo Operations UK Ltd, Barnard Castle, Durham, UK), diluted with saline and given as a solution of 25 µg/mL as a bolus infused during a period of 1 min, with a lockout time of 1 min, into an IV catheter attached to a 1‐way line providing continuous infusion of saline at approximately 100 mL/h. In order to mimic a normal clinical situation, the subjective signs of anticipating the next uterine contraction were not specified, and no attempts were made to train the parturient in early recognition of the onset of contractions. The decision as to whether to start the PCA dose was left solely to the woman.

Epidural saline was used for blinding during remifentanil administration.

The first epidural bolus was given simultaneously with the first PCA bolus. During the study, the IV PCA bolus was increased following a dose escalation scheme (0.1 – 0.2 – 0.33 – 0.5 – 0.7 – 0.9 µg/kg) after every second contraction until the parturient answered ‘no’ to the question whether she would like to get more efficient pain relief or until a maximum dose of 0.9 mg/kg was achieved. If she answered ‘no’ and her pain score was higher than what she had estimated before as acceptable for herself, she was asked why she did not want to get more efficient pain relief.

The study period was terminated if the parturient answered ‘yes’ when she was asked whether she wanted more efficient pain relief although the 0.9 µg/kg bolus had been reached, if the parturient wished to stop participation for any reason, or if the midwife noted that the parturient had reached full cervical opening.

Epidural group (n = 21):

An epidural catheter was sited at the L2/3 lumbar interspace. The parturient received epidurally 20 mL of levobupivacaine (0.625 mg/mL) and fentanyl 2 µg/mL in saline divided into 2 10 mL boluses given by the researcher manually with a 5‐min interval.

IV saline was used for blinding in the epidural group.

The first epidural bolus was given simultaneously with the first PCA bolus.

After the study period was over, an epidural bolus was given when the parturient requested more efficient pain relief.

Outcomes

The primary endpoint of the study was not defined but power analysis was performed for pain score.

Continuous:

‐ pain relief score (NRS 0 to 4, every 10 min until 60 min), median pain relief score (NRS 0 to 4, averaged, median + IQR (symmetric))

‐ pain intensity (NRS 0 to 10, every 10 min until 60 min, median + IQR (asymmetric))

‐ umbilical cord pH (artery, median + IQR (asymmetric))

‐ sedation score (VRS 0 to 3, average over 60 min every 10 min)

‐ women: mean blood pressure, mean HR

‐ newborns: Apgar score at 1 min (median + IQR (asymmetric))

Dichotomous:

‐ rate of CS, rate of assisted birth (vacuum)

‐ oxytocin use (started or increased during the study)

‐ women: oxygen desaturation (< 95%, supplemental oxygen), nausea (before and during the study)

‐ newborns: abnormal FHR (during and 30 min after the study period)

Notes

‐ Small trial sample size (< 200 participants)

‐ Power analysis performed (Pain score, n = 20 per group)

‐ The parturients were requested to use sunglasses in order to hide the miosis peculiar to systemic opioid treatment.

‐ The women used the study medicines during a 60‐min study period, which was thought to be long enough for a complete dose escalation for the IV PCA medication.

Concomitant medication:

SaO₂ < 95% was treated with supplemental oxygen at a rate of 2 L/min via nasal cannula.

Funding:

NA

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: “The patients were randomly allocated to two groups using sealed envelopes numbered according to a computer‐generated list that was stratified according to parity.”

Allocation concealment (selection bias)

Unclear risk

Quote: “[…] using sealed envelopes numbered according to a computer‐generated list.” Not specifically mentioned opaque envelopes (SNOSE).

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: “[…] epidural saline was used for blinding during remifentanil administration. IV saline was used for blinding in the epidural group.”, “Midwives and nurses not involved in the study prepared the medications and placebo syringes. Both the parturient and all the personnel present during the study were blinded as to which medication was used during the study. The parturients were requested to use sunglasses in order to hide the miosis peculiar to systemic opioid treatment.”

Blinding was attempted to achieve by insertion of both an epidural 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 mentioned in the published report).

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Quote: “The FHR tracings were analysed afterwards by an obstetrician who was blinded to the method of analgesia and the outcome of the newborn.”

The study did not address this issue for most of the relevant outcomes with exception of the assessment of FHR patterns. We do not know who was responsible for outcome assessment and attending personnel 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

High risk

‐ Dropout rate: 11%/16%

It is unclear from the description why and how many women in each group were excluded: two vs. four (flow diagram: three vs. three) women discontinued the intervention due to insufficient pain relief (flow diagram: due to entering second stage of labour); one woman (epidural) did not receive allocated intervention (dural tap). Exclusion of parturients due to insufficient pain relief is likely to be related to true outcome.

‐ Rate of escape: NA

‐ Rate of cross‐over: NA

‐ Data‐analysis: Per‐protocol

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.