Liv Freeman For the RAVEL study group SMFM February 7 th 2014

1. Remifentanil patient controlled Analgesia Versus Epidural analgesia in Labor.A randomized multicenter equivalence trial. Liv Freeman For the RAVEL study group SMFM February 7th 2014

2. Disclosure • Grants: ZonMW (the Netherlands organization for • health research and development) • No other potential conflicts of interest

3. Background: RPCA • Synthetic opioid with direct agonist action on µ-opioid receptors. • Rapid onset of action: 1-3 min to peak effect. • Context sensitive half time 3.5 min. • Placental transfer; rapidly metabolized and/or redistributed. • Side effects.

4. Background: RPCA, pain appreciation • Epidural analgesia provides superior pain relief (pain scores) to remifentanil PCA. • Pain appreciation may be comparable. Douma et al. Int J ObstAnesth 2011. Volmanen et al. ActaAnaesthesiol. Scand 2008

5. Hypothesis • Remifentanil PCA is equivalent to epidural • analgesia with respect to pain appreciation.

6. Design 15 hospitals Dutch Obstetric Consortium

7. In- and exclusion criteria • Inclusion criteria • Age ≥ 18 years • ASA classification 1-2 • Labor between 32 and 42 weeks

8. In- and exclusion criteria Exclusion criteria • Allergy for used medication • Contra-indication for epidural analgesia

9. Intervention • Remifentanil PCA • Intravenous: bolus 30 µgram, lockout time 3 minutes. • No background infusion. • Optional ↑ to 40 µgram or↓ to 20 µgram. • Epidural analgesia • According to local protocol.

10. Primary outcome • Pain appreciation • Measured on a visual analogue scale (VAS). • Every hour from the start of labor. • Expressed as area under the pain appreciation curve.

11. Area under the curve • AUC is a time-weighted measure of total pain appreciation. • Calculated for the total duration of labor and for the time pain relief was administered. • A higher AUC represents higher satisfaction with pain relief.

12. Secondary outcomes • Pain score • Measured on a VAS scale • Expressed as area under the curve • Overall satisfaction • With pain during labor • Maternal side effects • Mode of delivery • Maternal mortality and morbidity • Neonatal mortality and morbidity

13. Statistics • To exclude a clinically relevant difference of 10% • We needed to enroll 1136 patients (α 0.05, β 0.10) • Increased to 1400 • Intention to treat analysis, repeated for women who received analgesia. • Multiple imputation to correct for missing data.

14. Flow chart 1414 women randomised 709 Remifentanil PCA 705 Epidural analgesia • 22 elective cesarean • 29 elective cesarean • 3 patients lost to follow up • 2 withdrew consent after randomization 687 cases analyzed 671 cases analyzed

15. Results: baseline

16. Intervention 709 Remifentanil PCA 705 Epidural analgesia • 240 (35%) no pain relief • 402 (59%) RPCA • 53 (13%) conversion to EA • 41 (6%) EA • 4 (<1%) other opioids • 324 (48%) no pain relief • 296 (44%) EA • 3 (1%) conversion to RPCA • 33 (5%) RPCA • 2 conversion to EA • 18 (3%) other opioids

17. Results: pain appreciation

18. Results: labor characteristics

19. Results: labor characteristics

20. Maternal and neonatal outcome

21. Conclusion • Remifentanil PCA is not equivalent to epidural • analgesia. • Pain appreciation scores (AUC) in women, with a • request for pain relief during labor, randomized to • epidural analgesia, are significantly better.

22. All women who participated in the RAVEL study The RAVEL study group Dr. J.M. Middeldorp Dr. K.W.M. Bloemenkamp Prof. Dr. B.W. Mol Prof. Dr. A. Dahan Prof. Dr. M.M.R.F Struys Prof. Dr. J.M.M. van Lith Dr. E. Lopriore Dr. M.E. van den Akker-vanMarle Dr. S. le Cessie K. Oude Rengerink, MSc S.L.M. Logtenberg, MSc Prof. Dr. P.M.M. Bossuyt Research nurses/midwives Clara Kolster-Bijdevaate Marjolein Verhart Birgit van der Goes Jannet Bakker Sieta Kleiterp Sabine Logtenberg Angelique de Vos-Brouwer Corine Verhoeven LidewijdeJongmans Marianne van der Hel Gerard Zijderveld Lida Ulkeman Ineke Hamming José Keurentjes Ina van der Wal Edwin Lubbers Joyce Cantineau David Borman Kathy van den Berg-Swart Coby van Dam-Bouwens Lucie Poppens Maartje de Reus The Obstetric Consortium Board Trial desk Researchers Maya Kruijt Marijke van Nispen Obstetricians, residents, midwives, nursing staff and outpatient clinic staff of all participating hospitals Cluster Leiden LUMC - Leiden HagaZiekenhuis - Den Haag Cluster Amsterdam AMC - Amsterdam VUMC - Amsterdam OLVG - Amsterdam St Lucas Andreas hospital- Amsterdam ZaansMedisch Centrum- Zaandam Cluster Groningen UMCG - Groningen Cluster Utrecht Diakonessenhuis- Utrecht St. Antonius ziekenhuis - Nieuwegein Meander Medisch Centrum - Amersfoort Cluster Nijmegen Radboud UMC - Nijmegen Cluster Oost ZGT - Almelo Cluster Brabant Maxima Medisch Centrum - Veldhoven Cluster Rotterdam Amphia ziekenhuis - Breda Manythanksto: Contact: L.M. Freeman l.m.freeman@lumc.nl

23. Results: pain score

24. Results: overall score

25. Pain appreciation: multipara

26. Pain appreciation: nullipara

27. Outcome • Most important difference between total group and pain relief only: • Pain relief nullivs multi • Duration second stage

28. Maternal outcome

29. Maternal outcome

30. Maternal outcome