ORIGINAL ARTICLE
Effect of high-volume systematic local infiltration analgesia in Caesarean section: a randomised, placebo-controlled trial K. R. Larsen1, B. B. Kristensen1, M. A. Rasmussen1, Y. H. Rasmussen1, T. Weber2, B. Kristensen3 and H. Kehlet4 1
Department of Anaesthesiology, Hvidovre University Hospital, Hvidovre, Denmark Department of Gynaecology and Obstetrics, Hvidovre University Hospital, Hvidovre, Denmark 3 Department of Clinical Physiology, Hillerød Hospital, Hilleroed, Denmark 4 Section of Surgical Pathophysiology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark 2
Correspondence B. B. Kristensen, Department of Ambulatory Surgery 141, Hvidovre University Hospital, Kettegård Allé 30, DK-2650 Hvidovre, Denmark E-mail: [email protected] Conflicts of interest Katrine Rose Larsen: no conflict of interest. Billy B. Kristensen: has received an independent research grant from AstraZeneca to study local infiltration analgesia. AstraZeneca had no influence on study protocol. Marianne A. Rasmussen: no conflict of interest. Yvonne H. Rasmussen: no conflict of interest. Tom Weber: no conflict of interest. Bent Kristensen: no conflict of interest. Henrik Kehlet: has received an independent research grant from AstraZeneca to study local infiltration analgesia. AstraZeneca had no influence on study protocol. Funding None. Submitted 31 January 2015; accepted 5 February 2015; submission 3 May 2014. Citation Larsen KR, Kristensen BB, Rasmussen MA, Rasmussen YH, Weber T, Kristensen B, Kehlet H. Effect of high-volume systematic local infiltration analgesia in Caesarean section: a randomised, placebo-controlled trial. Acta Anaesthesiologica Scandinavica 2015
Background: Pain after Caesarean section is often treated with opioids with a risk of side effects. Wound infiltration with local anaesthetics is effective and has few side effects, but volume vs. dose concentration has not been examined. Methods: Ninety patients scheduled for elective Caesarean section included in a randomised, double-blinded, placebo-controlled trial receiving infiltration with 50 ml ropivacaine 0.5% or 125 ml ropivacaine 0.2% or 50 ml 0.9% saline (placebo) during surgery. Surgery was performed under lumbar spinal anaesthesia. Primary endpoint was post-operative pain. Secondary endpoints were rescue analgesic, post-operative nausea and vomiting, time spent in the postanesthesia care unit (PACU) and time to first mobilisation. Results: No difference in pain response between groups, but time until maximum pain score was prolonged in the ropivacaine 0.5% group compared with the placebo group (P = 0.0493). The administration of ketobemidone at 24 h post-operatively in the ropivacaine 0.5% group was reduced compared with the placebo group (P = 0.020), and between the ropivacaine 0.2% group and the ropivacaine 0.5% group (P = 0.044). No significant differences between groups were found concerning time spent in the PACU, to first mobilisation or in number of women with nausea/vomiting (P ≥ 0.05). No complications related to ropivacaine were observed. Conclusions: Systematic infiltration with a high concentration, low volume compared with low concentration, high volume showed no significant effect on post-operative pain intensity. However, a statistically significant, but clinically limited opioid sparing effect was demonstrated compared with placebo in the high concentration, low volume group.
doi: 10.1111/aas.12509
Editorial comment: what this article tells us This study assessed the analgesic effect of wound infiltration with 50 ml ropivacaine 0.5% (high concentration – low volume), 125 ml ropivacaine 0.2% (low concentration – high volume) vs. placebo in patients undergoing Caesarean section. No significant effect of ropivacaine on post-operative pain was found. A limited opioid sparing effect was demonstrated in the high concentration, low volume ropivacaine group. Acta Anaesthesiologica Scandinavica (2015) © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Worldwide 15% of all births occur by Caesarean section (2007). In developed countries, the proportion of Caesarean births is 21.1%.1 In Denmark, the number of Caesarean section accounted for 12.4% of all births in 1991 while the percentage had risen to 21% in 2011.2 After giving birth, the contact with the newborn baby and the necessity of breastfeeding cannot be emphasised enough.3,4 Breastfeeding helps to contract the uterus and accelerates the uterine involution in the post-partum period and promotes parent–child bonding.5 To ensure successful breastfeeding, early mobilisation and short length of stay in the hospital, and effective and sufficient pain control are essential.6 A large number of women that have given birth by Caesarean section have experienced post-operative pain,7 which is why any medication administered to these patients should be effective and with as few as possible side effects in both mother and child, and not restricting the mother’s care of her newborn baby. The treatment of post-operative pain after Caesarean section has mostly involved the use of opioid in combination with other analgesics (multimodal pain relief). Opioid analgesics can cause a number of well-known side effects. It would therefore be desirable to have a set up where the consumption of opioids postoperatively is reduced to a minimum. High-volume wound infiltration analgesia with local anaesthetic is a well-known, simple, safe and relatively inexpensive technique for post-operative analgesia in many procedures. Side effects are few, and there seems to be no effect on wound healing or infection rate.8 The technique is based on a systematic infiltration of local anaesthetic to all tissues during the surgery. Wound infiltration has been studied in Caesarean section, but differences in techniques, concentrations and volume of local anaesthetics, mode of administration and adjuvants may have contributed to the conflicting findings in the literature on the analgesic efficacy of wound infiltration.9–17 We hypothesised that systematic wound infiltration with local anaesthetic during surgery would reduce post-operative pain and opioid consumption after Caesarean section. So far no other study has compared the volume vs.
dose concentration relationship using systematic infiltration with local anaesthetic and described the technique in detail in patients undergoing elective Caesarean section. The aim of the present randomised, placebo-controlled and double-blind study was to assess the effect of systematic local infiltration analgesia on postoperative pain using either 0.5% ropivacaine, 50 ml, 0.2% ropivacaine, 125 ml, or isotonic saline, 50 ml. Material and methods The Regional Ethics Committee (De Videnskabsetiske Komiteer i Region Hovedstaden’, Kongens Vænge 2, DK-3400 Hillerød, Denmark) approved the study (14.04.2009, Reg.no. H-C2009-019). It was also approved by the Danish Data Protection Agency, and it was registered at http://www.clinicaltrials.gov (Reg.no. NCT00 891540). Oral and written informed consent was obtained from all patients, and the study was carried out in accordance with the principles of the Helsinki Declarations. The CONSORT recommendations for reporting randomised, controlled, clinical trials were followed.18 We included patients scheduled for elective Caesarean section. Exclusion criteria were alcohol and drug abuse, daily treatment with opioids or glucocorticoids, allergy to ropivacaine or opioids, under the age of 18, breastfeeding, psychiatric disease and non-Danish language. The trial was performed as a single-centre, prospective, randomised, double blind and placebocontrolled study. Ninety included patients were randomly assigned to three groups of 30. Patients received infiltration with 50 ml ropivacaine 0.5% (Naropin®, AstraZeneca, Copenhagen, Denmark) (group ropi 0.5%) or 125 ml ropivacaine 0.2% (Naropin) (group ropi 0.2%) or 50 ml 0.9% saline (group placebo). The ropivacaine dose of 250 mg was chosen based on experience from previous studies in gynaecology and hip and knee arthroplasty.19–21 A random allocation sequence concealed in 90 consecutively numbered, opaque, sealed envelopes determining active treatment or placebo was computer generated by a project nurse not otherwise involved in the trial. The envelopes were opened on the morning of surgery, and a Acta Anaesthesiologica Scandinavica (2015)
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© 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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senior anaesthetist not otherwise involved with data collection prepared the trial drug. Trial participants care providers and data collectors were all blinded to the allocation throughout the study. Surgery was performed under lumbar spinal anaesthesia with 10 mg hyperbaric bupivacaine (0.5%) and sufentanil 2.5 μg. Intra-operative fluid therapy was standardised and consisted of 0.9% saline 10–15 ml/kg/h in accordance with the regimen of the department. Cefuroxime 1.5 g was administered i.v. for infectious prophylaxis. The Caesarean section was performed using a skin incision 2–3 cm above the symphysis. The subcutaneous layer was opened digitally after a small incision in the midline down to the fascia. The fascia was opened 1–2 cm in the midline followed by opening to each side by scissors and digitally. The peritoneum was digitally opened 2–3 cm under the umbilical plane. The uterus was opened by Péan forceps in the midline 2–3 cm above the bladder peritoneum followed by a horizontal opening by digital caudal-cranial traction with 2 + 2 fingers. Suturing was performed by one layer of continuous Vicryl® (Johnson & Johnson, Diegem, Belgium) closing the uterus and one layer of continuous Vicryl suturing the fascia. Intradermal Vicryl was used closing the skin. Before closing the skin, local infiltration was performed in accordance with randomisation. In group ropi 0.5% and group placebo, the Pfannenstiel incision were infiltrated systematically in the deep and superficial muscle layer (m. rectus abdominis) with 15 ml with inserts of 1–2 cm apart on each side – a total of 30 ml. Before closing the wound, another 10 ml was infiltrated systematically into the subcutis with inserts of 1–2 cm apart perpendicular to the incision on each side (20 ml) – a total of 50 ml. For the group ropi 0.2, the Pfannenstiel incision was infiltrated systematically in the deep and superficial muscle layer (m. rectus abdominis) with 42.5 ml with inserts of 1–2 cm apart on each side. Before closing the wound, another 20 ml was infiltrated systematically into the subcutis with inserts of 1–2 cm apart perpendicular to the incision on each side, using a total of 125 ml. Rescue analgesics consisted of sufentanil 0.15 μg/kg i.v. in the post-anaesthesia care unit until Visual Analogue Scale (VAS) ≤ 3. The patients received oral ibuprofen 600 mg and
slow-release acetaminophen 2 g twice daily. In case of VAS > 5, the patients were offered oral ketobemidone 5–10 mg. Assessment of the primary outcome: pain from the operated area at rest, from supine to sitting position and during walking was done using a 100 mm visual analogue scale (VAS; 0, no pain, and 100, worst pain imaginable). Pain was evaluated immediately after surgery and at 3, 6, 8, 12 and 24 h after operation. Nausea was assessed as was vomiting by number of episodes (since last recording) at 3, 6, 8, 12 and 24 h after surgery. Cumulated consumption of ketobemidone (mg) and total amount of sufentanil (μg) administered in the PACU was registered. Time spent in the PACU and time to the first attempt to mobilisation was registered. For determination of the group sample size, we used analysis of variance with repeated measures with the following assumptions: (1) a significance level of 0.05; (2) a power of 0.90; (3) a standard deviation of each treatment group of 30; (4) a clinically meaningful difference of 30; and (5) a Bonferroni’s adjustment for four multiple comparisons.22 An R package* was used for the calculation. For a three-arm study, a sample size for each group was estimated to be about 28 ∼ 30 patients. Demographic data are presented as medians and interquartile range, and rescue opioid consumption was assessed using the Mann–Whitney U-test. We used a longitudinal linear mixed model (LMM) strategy because of the advantages over other analysis strategies as LMMs take into account the between-individual variation, and LMMs allow a specification of the correlation between the repeated measurements for the same individual. Such a strategy has recently been recommended for longitudinal data in anaesthesiology.23 With a compound symmetry structure corresponding to uniform correlation and including time as a categorical variable, the patients were treated as random effects, so the analysis could be adjusted to the pain level of each single patient. The LMM analysis was only done with the data at rest as these had the least number of missing values. The repeated measurements *Zhang E, Qian Wu V, Chow S-C, Zhang HG. TrialSize: R functions in Chapter 3, 4, 6, 7, 9, 10, 11, 12, 14, 15. R package version 1.3; 2013. http://CRAN.R-project.org/package=TrialSize [Accessed 3 March 2014].
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were analysed with the statistical software R† and the package nlme [Jose Pinheiro, Douglas Bates, Saikat DebRoy, Deepayan Sarkar and the R Development Core Team (2013). nlme: Linear and Nonlinear Mixed Effects Models. R package version 3.1–109]. Exact P values were reported. Results In all, 195 women were assessed for eligibility for the trial and 90 were enrolled from July 2009 to March 2010. Three women were excluded because of protocol violations (Fig. 1). Patient characteristics are presented in Table 1. In Fig. 2, the pain data are presented for the three observation states (rest, shift from supine to sitting and walking), and similar trends are seen. The LMM analysis for the rest data showed
a significant time trend for all three groups (P < 0.01). No overall group effects were observed (P > 0.19). Compared with placebo, only borderline time-treatment effects were noted for ropi 0.2% after 12 h (P = 0.056) and for ropi 0.5% (P = 0.073). Finally, the paired comparisons did not reveal any significant differences between the groups. However, the time until maximum pain score was significantly prolonged in the ropi 0.5% group compared with the placebo group (P = 0.0493), whereas no significant difference was found between the ropi 0.2% group and the placebo group. The difference between ropi 0.2% and ropi 0.5% was in favour of ropi 0.5%, although the result was not significant at the chosen significance level (P = 0.0597). In the PACU, sufentanil 35 μg was administered to only one patient in total (placebo group). The cumulative median (interquartile range)
Assessed for eligibility (n = 195)
Excluded (n = 105) Not meeting inclusion criteria (n = 95) Declined to participate (n = 10)
Randomised (n = 90)
Ropivacaine 0.5 % Allocated to intervention (n = 30) Received allocated intervention (n = 29)
Ropivacaine 0.2 % Allocated to intervention (n = 30) Received allocated intervention (n = 30)
Did not receive allocated intervention (Other medication than standard administered in PACU) (n = 1)
Placebo Allocated to intervention (n = 30) Received allocated intervention (n = 28) Did not receive allocated intervention (Surgical procedure modified in 1 paent and psychological reason in 1 paent (n = 2)
Lost to follow up (n = 0)
Lost to follow up (n = 0)
Lost to follow up (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Analysed (n = 29)
Analysed (n = 30)
Analysed (n = 28)
Fig. 1. Diagram of the flow through the study of patients undergoing elective Caesarean section.
†R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2013. URL http://www.R-project.org/ [Accessed 3 March 2014]. Acta Anaesthesiologica Scandinavica (2015)
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Table 1 Demographic data of the patients in the three groups studied. Data presented as median and interquartile range. Variable
Placebo (n = 28)
S ropi 0.2% (n = 30)
Ropi 0.5% (n = 29)
Age (year) Height (cm) Weight (kg) ASA I/II
33 (35.75–35.25) 167 (162.8–170.2) 76 (67.75–87.0) 21/7
32 (30.0–34.0) 169.5 (164.0–173.0) 79.5 (74.25–83.75) 25/5
31 (27.0–34.0) 169 (165.0–173.0) 79 (77.0–89.0) 28/1
ASA, American Society of Anesthesiologists Physical Status Scale.
A
B
C
Fig. 2. (A) □ = Placebo, = ropivacaine 0.2%, = ropivacaine 0.5%. VAS reported at rest. Medians are reported together with interquartile range 25–75%. No significant effects between treatment groups and time were observed. (B) □ = Placebo, = ropivacaine 0.2%, = ropivacaine 0.5%. VAS reported while changing from sitting to supine position. Medians are reported together with interquartile range 25–75%. No significant effects between treatment groups and time were observed. (C) □ = Placebo, = ropivacaine 0.2%, = ropivacaine 0.5%. VAS reported on walking. Medians are reported together with interquartile range 25–75%. No significant effects between treatment groups and time were observed.
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administration of ketobemidone at 24 h postoperatively in the ropi 0.5% group was 10 mg (5–20) vs. 20 mg (10–20) in the placebo group (P = 0.020). The same was found between the ropi 0.2% group, 15 mg (10–20) and the ropi 0.5% group (P = 0.044). However, there was no significant difference between the placebo group and the ropi 0.2% group (P = 0.936). The median (interquartile range) time spent in the PACU was 90 min (80–100) in the ropi 0.5% group vs. 97.5 min (76.25–130) in the ropi 0.2% group vs. 92.5 min (80–116.2) in the placebo group (ns). There were no differences among the three groups in time to first mobilisation; the median (interquartile range) time to first mobilisation was 3 h (3–6) in the ropi 0.5% group vs. 3.75 h (3–6) in the ropi 0.2% group vs. 4.25 h (3–6) in the placebo group. There was no difference in the number of women with nausea (P > 0.05) or vomiting (P > 0.05) between groups. No apparent complications related to ropivacaine during hospitalisation were observed. Discussion In the immediate post-operative period following Caesarean section, one major challenge is to avoid excessive pain and Postoperative Nausea and Vomiting (PONV) because both will compromise the mother–child bonding. Treatment of moderate-to-severe pain in the early postoperative period has mostly involved the use of opioids. However, non-opioid analgesics are more frequently used in a multimodal regime because of their ability to reduce post-operative dynamic pain and their opioid-sparing effect.24 Because surgical pain originates from the surgical wound, a rational approach to perioperative pain treatment has been directed towards the use of local anaesthetic infiltration at the site of surgery, as this technique is effective, with minimal side effects, inexpensive and without need for expertise.25 A major disadvantage is the limitation of the duration of action of the local anaesthetic used. For bupivacaine and ropivacaine, this tends to be only 4–8 h.12,13 The present randomised, double-blind, placebo-controlled study, with detailed information on the infiltration technique, did not demonstrate any significant effect on post-operative pain
intensity using wound infiltration with either 0.5% or 0.2% ropivacaine, 250 mg, compared with placebo. No other studies have evaluated the potential difference between a high concentration – low volume local anaesthesia infiltration vs. low concentration – high volume regime. Our findings are in accordance with most other studies comparing local anaesthetic wound infiltration with placebo, although these studies all used low volumes and concentrations.9,11,12,17 In a study comparing a single injection of bupivacaine with adrenaline, 40 ml to a placebo injection of saline, the bupivacaine group had a small but significantly lower pain intensity score in the first 6 h post-operatively, but pain was only evaluated at rest.17 In our study, we found that the time until maximum pain score was significantly prolonged in the ropi 0.5% group, meaning that dose concentration seemed more important than volume with regard to efficacy and duration of the local anaesthetic. This finding is confirmed by the fact that women in the 0.5% ropivacaine group had significantly lower 24 h opioid consumption than the placebo and 0.2% ropivacaine groups even when added to spinal anaesthesia. So far, the evidence regarding the advantages of a single dose of wound infiltration with local anaesthetics in Caesarean section has been limited. In a review by Bamigboye et al., women who had Caesarean section under spinal or general anaesthesia and a single-shot wound infiltration with local anaesthetic had decreased morphine consumption at 24 h compared with placebo.6 Also Nguyen et al. found a reduction of 30% in the overall consumption of analgesics when infiltrating the wound with 0.75% ropivacaine, 30 ml, compared with placebo.12 Finally, Niklasson et al. in 260 women found that a single injection of bupivacaine with adrenaline decreased the need for morphine for the first 12 h.17 Application site for the anaesthetic infiltration may be of limited importance because a recent study comparing subcutaneous, intramuscular or a combination of the two sites showed significantly lower consumption of analgesics and lower VAS scores independent of anatomical location of local anaesthetic.10 Theoretically, one way to overcome the short duration of single-shot wound infiltration is by giving a continuous infusion of the local anaesthetic through an intra-operative placed catheter, using a special designed pump. This Acta Anaesthesiologica Scandinavica (2015)
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technique has been used in post-Caesarean pain management, but with conflicting results. Kainu et al. compared continuous wound infusion with ropivacaine and was unable to demonstrate a reduction in opioid consumption and pain scores compared with saline control.16 The same results were found by Zohar et al.26 On the other hand, Givens et al. found a significant reduction in morphine consumption with a local infusion of bupivacaine with a Patient Controlled Analgesia (PCA) catheter in the wound for 48 h postoperatively compared with a control group receiving saline.27 The literature does not provide conclusive information on specific dose and timing of local anaesthetic infiltration, but a dose of more than 100 mg of long-acting local anaesthetic should be used for abdominal/gynaecology surgery.28 Moreover, risk of local anaesthetic toxicity using wound infiltration is probably by large overestimated.29 Nevertheless, a recent study using bilateral Transversus Abdominis Plane (TAP) block for Caesarean section indicated surprisingly high plasma concentration when using ropivacaine 2.5 mg/kg, although only a minority of patients reported mild symptoms of neurotoxicity.30 We did not find any differences between the groups regarding time spent in the PACU and time to first mobilisation; neither did we observe any complications related to ropivacaine during hospitalisation. Interpretation of these data is a limitation of our study because it was not powered to evaluate these secondary data. The strength of this trial is primarily the detailed assessment of pain, and a standardised surgical, anaesthetic and multimodal analgesic regime. Protocol violations were rare, and the use of only three data collectors may have minimised the risk of performance bias. Our study with detailed description of the infiltration technique demonstrated a significant effect on post-operative opioid consumption, but not on post-operative pain intensity. One explanation for the lack of reduced post-operative pain intensity could be the addition of sufentanil to the spinal anaesthesia that might ensure effective analgesia without the need for an alternative technique such as wound in filtration. On the other hand, we were able to prolong the time until maximum pain score significantly in the ropivacaine 0.5% group.
In conclusion, the present study did not demonstrate any significant effect on post-operative pain intensity when using systematic wound infiltration with high concentration – low volume ropivacaine compared with low concentration – high volume ropivacaine. Compared with placebo, a statistic significant but clinical limited analgesic and opioid sparing effect was demonstrated, most pronounced in the high concentration – low volume group. Acknowledgement None. References 1. Betrán AP, Merialdi M, Lauer JA, Bing-Shun W, Thomas J, Van Look P, Wagner M. Rates of caesarean section: analysis of global, regional and national estimates. Paediatr Perinat Epidemiol 2007; 21: 98–113. 2. Tal og analyse: Fødselsstastikken 2011, Sundhedsstyrelsen 2012; 11. Available at: http://www.sst.dk/ (accessed 26 January 2014). 3. Labbok MH. Effects of breastfeeding on the mother. Pediatr Clin North Am 2001; 48: 143–58. 4. Doulougeri K, Panagopoulou E, Montgomery A. The impact of maternal stress on initiation and establishment of breastfeeding. J Neonatal Nurs 2013; 19: 162–7. 5. Uvnäs-Moberg K, Eriksson M. Breastfeeding: physiological, endocrine and behavioural adaptations caused by oxytocin and local neurogenic activity in the nipple and mammary gland. Acta Paediatr 1996; 85: 525–30. 6. Bamigboye AA, Hofmeyr GJ. Local anaesthetic wound infiltration and abdominal nerves block during caesarean section for postoperative pain relief. Cochrane Database Syst Rev 2009; (3): CD006954. 7. Karlström A, Engström-Olofsson R, Norberg KG, Sjöling M, Hildingsson I. Postoperative pain after cesarean birth affects breastfeeding and infant care. J Obstet Gynecol Neonatal Nurs 2007; 36: 430–40. 8. Scott NB. Wound infiltration for surgery. Anaesthesia 2010; 65: 67–75. 9. Demiraran Y, Albayrak M, Yorulmaz IS, Ozdemir I. Tramadol and levobupivacaine wound infiltration at cesarean delivery for postoperative analgesia. J Anesth 2013; 27: 175–9. 10. Navali N, Fouladi RF, Nikpour MA. A comparison of post-incisional subcutaneous, intramuscular, and
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subcutaneous plus intramuscular infiltrations of lidocaine in postcaesarean section pain control. S Afr J Obstet Gynaecol 2013; 19: 8–12. Bamigboye AA, Justus HG. Ropivacain abdominal wound infiltration and peritonel spraying at cesarean delivery for preemptive analgesia. Int J Gynaecol Obstet 2008; 102: 160–4. Nguyen NK, Landais A, Barbaryan A, M’Barek MA, Benbaghdad Y, McGee K, Lanba P. Analgesic efficacy of Pfannenstiel incision infiltration with ropivacaine 7.5 mg/ml for caesarean section. Anesthesiol Res Pract 2010; 2010: Article ID 542375, doi:10.1155/2010/542375. Momani O. Controlled trial of wound infiltration with bupivacaine for postoperative pain relief after caesarean section. Bahrain Med Bull 2001; 23: 83–5. Bamigboye AA, Hofmeyr J, Labeodan M. Caesarean section wound infiltration with ropivacaine versus placebo: survey of chronic pelvic pain after 4 years’ follow-up. S Afr J Obstet Gynaecol 2013; 19: 75–6. Navali N, Fouladi RF, Abbassi A. Pre-incisional, post-incisional and combined pre- and post-incisional local wound infiltrations with lidocaine in elective caesarean section delivery: a randomized clinical trial. J Obstet Gynaecol 2013; 33: 54–9. Kainu JP, Sarvela J, Halonen P, Puro H, Toivonen HJ, Halmesmäki E, Korttila KT. Continuous wound infusion with ropivacaine fails to provide adequate analgesia after caesarean section. Int J Obstet Anesth 2012; 21: 119–24. Niklasson B, Börjesson A, Carmnes UB, Segerdahl M, Öhman SG, Blanck A. Intraoperative injection of bupivacaine-adrenaline close to the fascia reduces morphine requirements after cesarean section: a randomized controlled trial. Acta Obstet Gynecol Scand 2012; 91: 1433–9. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. J Am Med Assoc 2001; 285: 1987–91. Kristensen BB, Rasmussen YH, Agerlin M, Topp MW, Weincke MO, Kehlet H. Local infiltration analgesia in urogenital prolapse surgery: a prospective randomized, double-blind,
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placebo-controlled study. Acta Obstet Gynecol Scand 2011; 90: 1121–5. Hristovska AM, Kristensen BB, Rasmussen MA, Rasmussen YH, Elving LB, Nielsen CV, Kehlet H. Effect of systematic local infiltration analgesia on postoperative pain in vaginal hysterectomy: a randomized, placebo-controlled trial. Acta Obstet Gynecol Scand 2014; 93: 233–8. Andersen LØ, Kehlet H. Analgesic efficacy of local infiltration analgesia in hip and knee arthroplasty: a systematic review. Br J Anaesth 2014; 113: 360–74. Chow SC, Shao J, Wang H. Sample size calculations in clinical research, 2nd edn. New York: Chapman & Hall, 2008. Ma Y, Mazumdar M, Memtsoudis SG. Beyond repeated-measures analysis of variance. Advanced statistical methods for the analysis of longitudinal data in anesthesia research. Reg Anesth Pain Med 2012; 37: 99–10510. Kehlet H, Dahl JB. The value of ‘multimodal’ or ‘balanced analgesia’ in postoperative pain treatment. Anesth Analg 1993; 77: 1048–56. Kehlet H, Kristensen BB. Local anesthetics in the surgical wound – is the pendulum swinging towards increased use? Reg Anesth Pain Med 2009; 34: 389–90. Zohar E, Shapiro A, Eidinov A, Fishman A, Fredman B. Postcesarean analgesia: the efficacy of bupivacaine wound instillation with and without supplemental diclofenac. J Clin Anesth 2006; 18: 415–21. Givens VA, Lipscomb GH, Meyer NL. A randomized trial of postoperative wound irrigation with local anesthetic for pain after cesarean delivery. Am J Obstet Gynecol 2002; 186: 1188–91. Bisgaard T. Analgesic treatment after laparoscopic cholecystectomy: a critical assessment of the evidence. Anesthesiology 2006; 104: 835–46. Dahl JB, Møiniche S. Relief of postoperative pain by local anaesthetic infiltration. Efficacy for major abdominal and orthopedic surgery. Pain 2009; 143: 7–11. Griffiths JD, Le NV, Grant S, Bjorksten A, Hebbard P, Royse C. Symptomatic local anaesthetic toxicity and plasma ropivacaine concentrations after transversus abdominis plane block for caesarean section. Br J Anaesth 2013; 110: 996–1000.
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Effect of high-volume systematic local infiltration analgesia in Caesarean section: a randomised, placebo-controlled trial K. R. Larsen1, B. B. Kristensen1, M. A. Rasmussen1, Y. H. Rasmussen1, T. Weber2, B. Kristensen3 and H. Kehlet4 1
Department of Anaesthesiology, Hvidovre University Hospital, Hvidovre, Denmark Department of Gynaecology and Obstetrics, Hvidovre University Hospital, Hvidovre, Denmark 3 Department of Clinical Physiology, Hillerød Hospital, Hilleroed, Denmark 4 Section of Surgical Pathophysiology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark 2
Correspondence B. B. Kristensen, Department of Ambulatory Surgery 141, Hvidovre University Hospital, Kettegård Allé 30, DK-2650 Hvidovre, Denmark E-mail: [email protected] Conflicts of interest Katrine Rose Larsen: no conflict of interest. Billy B. Kristensen: has received an independent research grant from AstraZeneca to study local infiltration analgesia. AstraZeneca had no influence on study protocol. Marianne A. Rasmussen: no conflict of interest. Yvonne H. Rasmussen: no conflict of interest. Tom Weber: no conflict of interest. Bent Kristensen: no conflict of interest. Henrik Kehlet: has received an independent research grant from AstraZeneca to study local infiltration analgesia. AstraZeneca had no influence on study protocol. Funding None. Submitted 31 January 2015; accepted 5 February 2015; submission 3 May 2014. Citation Larsen KR, Kristensen BB, Rasmussen MA, Rasmussen YH, Weber T, Kristensen B, Kehlet H. Effect of high-volume systematic local infiltration analgesia in Caesarean section: a randomised, placebo-controlled trial. Acta Anaesthesiologica Scandinavica 2015
Background: Pain after Caesarean section is often treated with opioids with a risk of side effects. Wound infiltration with local anaesthetics is effective and has few side effects, but volume vs. dose concentration has not been examined. Methods: Ninety patients scheduled for elective Caesarean section included in a randomised, double-blinded, placebo-controlled trial receiving infiltration with 50 ml ropivacaine 0.5% or 125 ml ropivacaine 0.2% or 50 ml 0.9% saline (placebo) during surgery. Surgery was performed under lumbar spinal anaesthesia. Primary endpoint was post-operative pain. Secondary endpoints were rescue analgesic, post-operative nausea and vomiting, time spent in the postanesthesia care unit (PACU) and time to first mobilisation. Results: No difference in pain response between groups, but time until maximum pain score was prolonged in the ropivacaine 0.5% group compared with the placebo group (P = 0.0493). The administration of ketobemidone at 24 h post-operatively in the ropivacaine 0.5% group was reduced compared with the placebo group (P = 0.020), and between the ropivacaine 0.2% group and the ropivacaine 0.5% group (P = 0.044). No significant differences between groups were found concerning time spent in the PACU, to first mobilisation or in number of women with nausea/vomiting (P ≥ 0.05). No complications related to ropivacaine were observed. Conclusions: Systematic infiltration with a high concentration, low volume compared with low concentration, high volume showed no significant effect on post-operative pain intensity. However, a statistically significant, but clinically limited opioid sparing effect was demonstrated compared with placebo in the high concentration, low volume group.
doi: 10.1111/aas.12509
Editorial comment: what this article tells us This study assessed the analgesic effect of wound infiltration with 50 ml ropivacaine 0.5% (high concentration – low volume), 125 ml ropivacaine 0.2% (low concentration – high volume) vs. placebo in patients undergoing Caesarean section. No significant effect of ropivacaine on post-operative pain was found. A limited opioid sparing effect was demonstrated in the high concentration, low volume ropivacaine group. Acta Anaesthesiologica Scandinavica (2015) © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Worldwide 15% of all births occur by Caesarean section (2007). In developed countries, the proportion of Caesarean births is 21.1%.1 In Denmark, the number of Caesarean section accounted for 12.4% of all births in 1991 while the percentage had risen to 21% in 2011.2 After giving birth, the contact with the newborn baby and the necessity of breastfeeding cannot be emphasised enough.3,4 Breastfeeding helps to contract the uterus and accelerates the uterine involution in the post-partum period and promotes parent–child bonding.5 To ensure successful breastfeeding, early mobilisation and short length of stay in the hospital, and effective and sufficient pain control are essential.6 A large number of women that have given birth by Caesarean section have experienced post-operative pain,7 which is why any medication administered to these patients should be effective and with as few as possible side effects in both mother and child, and not restricting the mother’s care of her newborn baby. The treatment of post-operative pain after Caesarean section has mostly involved the use of opioid in combination with other analgesics (multimodal pain relief). Opioid analgesics can cause a number of well-known side effects. It would therefore be desirable to have a set up where the consumption of opioids postoperatively is reduced to a minimum. High-volume wound infiltration analgesia with local anaesthetic is a well-known, simple, safe and relatively inexpensive technique for post-operative analgesia in many procedures. Side effects are few, and there seems to be no effect on wound healing or infection rate.8 The technique is based on a systematic infiltration of local anaesthetic to all tissues during the surgery. Wound infiltration has been studied in Caesarean section, but differences in techniques, concentrations and volume of local anaesthetics, mode of administration and adjuvants may have contributed to the conflicting findings in the literature on the analgesic efficacy of wound infiltration.9–17 We hypothesised that systematic wound infiltration with local anaesthetic during surgery would reduce post-operative pain and opioid consumption after Caesarean section. So far no other study has compared the volume vs.
dose concentration relationship using systematic infiltration with local anaesthetic and described the technique in detail in patients undergoing elective Caesarean section. The aim of the present randomised, placebo-controlled and double-blind study was to assess the effect of systematic local infiltration analgesia on postoperative pain using either 0.5% ropivacaine, 50 ml, 0.2% ropivacaine, 125 ml, or isotonic saline, 50 ml. Material and methods The Regional Ethics Committee (De Videnskabsetiske Komiteer i Region Hovedstaden’, Kongens Vænge 2, DK-3400 Hillerød, Denmark) approved the study (14.04.2009, Reg.no. H-C2009-019). It was also approved by the Danish Data Protection Agency, and it was registered at http://www.clinicaltrials.gov (Reg.no. NCT00 891540). Oral and written informed consent was obtained from all patients, and the study was carried out in accordance with the principles of the Helsinki Declarations. The CONSORT recommendations for reporting randomised, controlled, clinical trials were followed.18 We included patients scheduled for elective Caesarean section. Exclusion criteria were alcohol and drug abuse, daily treatment with opioids or glucocorticoids, allergy to ropivacaine or opioids, under the age of 18, breastfeeding, psychiatric disease and non-Danish language. The trial was performed as a single-centre, prospective, randomised, double blind and placebocontrolled study. Ninety included patients were randomly assigned to three groups of 30. Patients received infiltration with 50 ml ropivacaine 0.5% (Naropin®, AstraZeneca, Copenhagen, Denmark) (group ropi 0.5%) or 125 ml ropivacaine 0.2% (Naropin) (group ropi 0.2%) or 50 ml 0.9% saline (group placebo). The ropivacaine dose of 250 mg was chosen based on experience from previous studies in gynaecology and hip and knee arthroplasty.19–21 A random allocation sequence concealed in 90 consecutively numbered, opaque, sealed envelopes determining active treatment or placebo was computer generated by a project nurse not otherwise involved in the trial. The envelopes were opened on the morning of surgery, and a Acta Anaesthesiologica Scandinavica (2015)
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senior anaesthetist not otherwise involved with data collection prepared the trial drug. Trial participants care providers and data collectors were all blinded to the allocation throughout the study. Surgery was performed under lumbar spinal anaesthesia with 10 mg hyperbaric bupivacaine (0.5%) and sufentanil 2.5 μg. Intra-operative fluid therapy was standardised and consisted of 0.9% saline 10–15 ml/kg/h in accordance with the regimen of the department. Cefuroxime 1.5 g was administered i.v. for infectious prophylaxis. The Caesarean section was performed using a skin incision 2–3 cm above the symphysis. The subcutaneous layer was opened digitally after a small incision in the midline down to the fascia. The fascia was opened 1–2 cm in the midline followed by opening to each side by scissors and digitally. The peritoneum was digitally opened 2–3 cm under the umbilical plane. The uterus was opened by Péan forceps in the midline 2–3 cm above the bladder peritoneum followed by a horizontal opening by digital caudal-cranial traction with 2 + 2 fingers. Suturing was performed by one layer of continuous Vicryl® (Johnson & Johnson, Diegem, Belgium) closing the uterus and one layer of continuous Vicryl suturing the fascia. Intradermal Vicryl was used closing the skin. Before closing the skin, local infiltration was performed in accordance with randomisation. In group ropi 0.5% and group placebo, the Pfannenstiel incision were infiltrated systematically in the deep and superficial muscle layer (m. rectus abdominis) with 15 ml with inserts of 1–2 cm apart on each side – a total of 30 ml. Before closing the wound, another 10 ml was infiltrated systematically into the subcutis with inserts of 1–2 cm apart perpendicular to the incision on each side (20 ml) – a total of 50 ml. For the group ropi 0.2, the Pfannenstiel incision was infiltrated systematically in the deep and superficial muscle layer (m. rectus abdominis) with 42.5 ml with inserts of 1–2 cm apart on each side. Before closing the wound, another 20 ml was infiltrated systematically into the subcutis with inserts of 1–2 cm apart perpendicular to the incision on each side, using a total of 125 ml. Rescue analgesics consisted of sufentanil 0.15 μg/kg i.v. in the post-anaesthesia care unit until Visual Analogue Scale (VAS) ≤ 3. The patients received oral ibuprofen 600 mg and
slow-release acetaminophen 2 g twice daily. In case of VAS > 5, the patients were offered oral ketobemidone 5–10 mg. Assessment of the primary outcome: pain from the operated area at rest, from supine to sitting position and during walking was done using a 100 mm visual analogue scale (VAS; 0, no pain, and 100, worst pain imaginable). Pain was evaluated immediately after surgery and at 3, 6, 8, 12 and 24 h after operation. Nausea was assessed as was vomiting by number of episodes (since last recording) at 3, 6, 8, 12 and 24 h after surgery. Cumulated consumption of ketobemidone (mg) and total amount of sufentanil (μg) administered in the PACU was registered. Time spent in the PACU and time to the first attempt to mobilisation was registered. For determination of the group sample size, we used analysis of variance with repeated measures with the following assumptions: (1) a significance level of 0.05; (2) a power of 0.90; (3) a standard deviation of each treatment group of 30; (4) a clinically meaningful difference of 30; and (5) a Bonferroni’s adjustment for four multiple comparisons.22 An R package* was used for the calculation. For a three-arm study, a sample size for each group was estimated to be about 28 ∼ 30 patients. Demographic data are presented as medians and interquartile range, and rescue opioid consumption was assessed using the Mann–Whitney U-test. We used a longitudinal linear mixed model (LMM) strategy because of the advantages over other analysis strategies as LMMs take into account the between-individual variation, and LMMs allow a specification of the correlation between the repeated measurements for the same individual. Such a strategy has recently been recommended for longitudinal data in anaesthesiology.23 With a compound symmetry structure corresponding to uniform correlation and including time as a categorical variable, the patients were treated as random effects, so the analysis could be adjusted to the pain level of each single patient. The LMM analysis was only done with the data at rest as these had the least number of missing values. The repeated measurements *Zhang E, Qian Wu V, Chow S-C, Zhang HG. TrialSize: R functions in Chapter 3, 4, 6, 7, 9, 10, 11, 12, 14, 15. R package version 1.3; 2013. http://CRAN.R-project.org/package=TrialSize [Accessed 3 March 2014].
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were analysed with the statistical software R† and the package nlme [Jose Pinheiro, Douglas Bates, Saikat DebRoy, Deepayan Sarkar and the R Development Core Team (2013). nlme: Linear and Nonlinear Mixed Effects Models. R package version 3.1–109]. Exact P values were reported. Results In all, 195 women were assessed for eligibility for the trial and 90 were enrolled from July 2009 to March 2010. Three women were excluded because of protocol violations (Fig. 1). Patient characteristics are presented in Table 1. In Fig. 2, the pain data are presented for the three observation states (rest, shift from supine to sitting and walking), and similar trends are seen. The LMM analysis for the rest data showed
a significant time trend for all three groups (P < 0.01). No overall group effects were observed (P > 0.19). Compared with placebo, only borderline time-treatment effects were noted for ropi 0.2% after 12 h (P = 0.056) and for ropi 0.5% (P = 0.073). Finally, the paired comparisons did not reveal any significant differences between the groups. However, the time until maximum pain score was significantly prolonged in the ropi 0.5% group compared with the placebo group (P = 0.0493), whereas no significant difference was found between the ropi 0.2% group and the placebo group. The difference between ropi 0.2% and ropi 0.5% was in favour of ropi 0.5%, although the result was not significant at the chosen significance level (P = 0.0597). In the PACU, sufentanil 35 μg was administered to only one patient in total (placebo group). The cumulative median (interquartile range)
Assessed for eligibility (n = 195)
Excluded (n = 105) Not meeting inclusion criteria (n = 95) Declined to participate (n = 10)
Randomised (n = 90)
Ropivacaine 0.5 % Allocated to intervention (n = 30) Received allocated intervention (n = 29)
Ropivacaine 0.2 % Allocated to intervention (n = 30) Received allocated intervention (n = 30)
Did not receive allocated intervention (Other medication than standard administered in PACU) (n = 1)
Placebo Allocated to intervention (n = 30) Received allocated intervention (n = 28) Did not receive allocated intervention (Surgical procedure modified in 1 paent and psychological reason in 1 paent (n = 2)
Lost to follow up (n = 0)
Lost to follow up (n = 0)
Lost to follow up (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Discontinued intervention (n = 0)
Analysed (n = 29)
Analysed (n = 30)
Analysed (n = 28)
Fig. 1. Diagram of the flow through the study of patients undergoing elective Caesarean section.
†R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2013. URL http://www.R-project.org/ [Accessed 3 March 2014]. Acta Anaesthesiologica Scandinavica (2015)
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Table 1 Demographic data of the patients in the three groups studied. Data presented as median and interquartile range. Variable
Placebo (n = 28)
S ropi 0.2% (n = 30)
Ropi 0.5% (n = 29)
Age (year) Height (cm) Weight (kg) ASA I/II
33 (35.75–35.25) 167 (162.8–170.2) 76 (67.75–87.0) 21/7
32 (30.0–34.0) 169.5 (164.0–173.0) 79.5 (74.25–83.75) 25/5
31 (27.0–34.0) 169 (165.0–173.0) 79 (77.0–89.0) 28/1
ASA, American Society of Anesthesiologists Physical Status Scale.
A
B
C
Fig. 2. (A) □ = Placebo, = ropivacaine 0.2%, = ropivacaine 0.5%. VAS reported at rest. Medians are reported together with interquartile range 25–75%. No significant effects between treatment groups and time were observed. (B) □ = Placebo, = ropivacaine 0.2%, = ropivacaine 0.5%. VAS reported while changing from sitting to supine position. Medians are reported together with interquartile range 25–75%. No significant effects between treatment groups and time were observed. (C) □ = Placebo, = ropivacaine 0.2%, = ropivacaine 0.5%. VAS reported on walking. Medians are reported together with interquartile range 25–75%. No significant effects between treatment groups and time were observed.
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administration of ketobemidone at 24 h postoperatively in the ropi 0.5% group was 10 mg (5–20) vs. 20 mg (10–20) in the placebo group (P = 0.020). The same was found between the ropi 0.2% group, 15 mg (10–20) and the ropi 0.5% group (P = 0.044). However, there was no significant difference between the placebo group and the ropi 0.2% group (P = 0.936). The median (interquartile range) time spent in the PACU was 90 min (80–100) in the ropi 0.5% group vs. 97.5 min (76.25–130) in the ropi 0.2% group vs. 92.5 min (80–116.2) in the placebo group (ns). There were no differences among the three groups in time to first mobilisation; the median (interquartile range) time to first mobilisation was 3 h (3–6) in the ropi 0.5% group vs. 3.75 h (3–6) in the ropi 0.2% group vs. 4.25 h (3–6) in the placebo group. There was no difference in the number of women with nausea (P > 0.05) or vomiting (P > 0.05) between groups. No apparent complications related to ropivacaine during hospitalisation were observed. Discussion In the immediate post-operative period following Caesarean section, one major challenge is to avoid excessive pain and Postoperative Nausea and Vomiting (PONV) because both will compromise the mother–child bonding. Treatment of moderate-to-severe pain in the early postoperative period has mostly involved the use of opioids. However, non-opioid analgesics are more frequently used in a multimodal regime because of their ability to reduce post-operative dynamic pain and their opioid-sparing effect.24 Because surgical pain originates from the surgical wound, a rational approach to perioperative pain treatment has been directed towards the use of local anaesthetic infiltration at the site of surgery, as this technique is effective, with minimal side effects, inexpensive and without need for expertise.25 A major disadvantage is the limitation of the duration of action of the local anaesthetic used. For bupivacaine and ropivacaine, this tends to be only 4–8 h.12,13 The present randomised, double-blind, placebo-controlled study, with detailed information on the infiltration technique, did not demonstrate any significant effect on post-operative pain
intensity using wound infiltration with either 0.5% or 0.2% ropivacaine, 250 mg, compared with placebo. No other studies have evaluated the potential difference between a high concentration – low volume local anaesthesia infiltration vs. low concentration – high volume regime. Our findings are in accordance with most other studies comparing local anaesthetic wound infiltration with placebo, although these studies all used low volumes and concentrations.9,11,12,17 In a study comparing a single injection of bupivacaine with adrenaline, 40 ml to a placebo injection of saline, the bupivacaine group had a small but significantly lower pain intensity score in the first 6 h post-operatively, but pain was only evaluated at rest.17 In our study, we found that the time until maximum pain score was significantly prolonged in the ropi 0.5% group, meaning that dose concentration seemed more important than volume with regard to efficacy and duration of the local anaesthetic. This finding is confirmed by the fact that women in the 0.5% ropivacaine group had significantly lower 24 h opioid consumption than the placebo and 0.2% ropivacaine groups even when added to spinal anaesthesia. So far, the evidence regarding the advantages of a single dose of wound infiltration with local anaesthetics in Caesarean section has been limited. In a review by Bamigboye et al., women who had Caesarean section under spinal or general anaesthesia and a single-shot wound infiltration with local anaesthetic had decreased morphine consumption at 24 h compared with placebo.6 Also Nguyen et al. found a reduction of 30% in the overall consumption of analgesics when infiltrating the wound with 0.75% ropivacaine, 30 ml, compared with placebo.12 Finally, Niklasson et al. in 260 women found that a single injection of bupivacaine with adrenaline decreased the need for morphine for the first 12 h.17 Application site for the anaesthetic infiltration may be of limited importance because a recent study comparing subcutaneous, intramuscular or a combination of the two sites showed significantly lower consumption of analgesics and lower VAS scores independent of anatomical location of local anaesthetic.10 Theoretically, one way to overcome the short duration of single-shot wound infiltration is by giving a continuous infusion of the local anaesthetic through an intra-operative placed catheter, using a special designed pump. This Acta Anaesthesiologica Scandinavica (2015)
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technique has been used in post-Caesarean pain management, but with conflicting results. Kainu et al. compared continuous wound infusion with ropivacaine and was unable to demonstrate a reduction in opioid consumption and pain scores compared with saline control.16 The same results were found by Zohar et al.26 On the other hand, Givens et al. found a significant reduction in morphine consumption with a local infusion of bupivacaine with a Patient Controlled Analgesia (PCA) catheter in the wound for 48 h postoperatively compared with a control group receiving saline.27 The literature does not provide conclusive information on specific dose and timing of local anaesthetic infiltration, but a dose of more than 100 mg of long-acting local anaesthetic should be used for abdominal/gynaecology surgery.28 Moreover, risk of local anaesthetic toxicity using wound infiltration is probably by large overestimated.29 Nevertheless, a recent study using bilateral Transversus Abdominis Plane (TAP) block for Caesarean section indicated surprisingly high plasma concentration when using ropivacaine 2.5 mg/kg, although only a minority of patients reported mild symptoms of neurotoxicity.30 We did not find any differences between the groups regarding time spent in the PACU and time to first mobilisation; neither did we observe any complications related to ropivacaine during hospitalisation. Interpretation of these data is a limitation of our study because it was not powered to evaluate these secondary data. The strength of this trial is primarily the detailed assessment of pain, and a standardised surgical, anaesthetic and multimodal analgesic regime. Protocol violations were rare, and the use of only three data collectors may have minimised the risk of performance bias. Our study with detailed description of the infiltration technique demonstrated a significant effect on post-operative opioid consumption, but not on post-operative pain intensity. One explanation for the lack of reduced post-operative pain intensity could be the addition of sufentanil to the spinal anaesthesia that might ensure effective analgesia without the need for an alternative technique such as wound in filtration. On the other hand, we were able to prolong the time until maximum pain score significantly in the ropivacaine 0.5% group.
In conclusion, the present study did not demonstrate any significant effect on post-operative pain intensity when using systematic wound infiltration with high concentration – low volume ropivacaine compared with low concentration – high volume ropivacaine. Compared with placebo, a statistic significant but clinical limited analgesic and opioid sparing effect was demonstrated, most pronounced in the high concentration – low volume group. Acknowledgement None. References 1. Betrán AP, Merialdi M, Lauer JA, Bing-Shun W, Thomas J, Van Look P, Wagner M. Rates of caesarean section: analysis of global, regional and national estimates. Paediatr Perinat Epidemiol 2007; 21: 98–113. 2. Tal og analyse: Fødselsstastikken 2011, Sundhedsstyrelsen 2012; 11. Available at: http://www.sst.dk/ (accessed 26 January 2014). 3. Labbok MH. Effects of breastfeeding on the mother. Pediatr Clin North Am 2001; 48: 143–58. 4. Doulougeri K, Panagopoulou E, Montgomery A. The impact of maternal stress on initiation and establishment of breastfeeding. J Neonatal Nurs 2013; 19: 162–7. 5. Uvnäs-Moberg K, Eriksson M. Breastfeeding: physiological, endocrine and behavioural adaptations caused by oxytocin and local neurogenic activity in the nipple and mammary gland. Acta Paediatr 1996; 85: 525–30. 6. Bamigboye AA, Hofmeyr GJ. Local anaesthetic wound infiltration and abdominal nerves block during caesarean section for postoperative pain relief. Cochrane Database Syst Rev 2009; (3): CD006954. 7. Karlström A, Engström-Olofsson R, Norberg KG, Sjöling M, Hildingsson I. Postoperative pain after cesarean birth affects breastfeeding and infant care. J Obstet Gynecol Neonatal Nurs 2007; 36: 430–40. 8. Scott NB. Wound infiltration for surgery. Anaesthesia 2010; 65: 67–75. 9. Demiraran Y, Albayrak M, Yorulmaz IS, Ozdemir I. Tramadol and levobupivacaine wound infiltration at cesarean delivery for postoperative analgesia. J Anesth 2013; 27: 175–9. 10. Navali N, Fouladi RF, Nikpour MA. A comparison of post-incisional subcutaneous, intramuscular, and
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