Severe acute pain occurs in more than 10% of patients within the first 36 h after caesarean section1 and significantly impacts women's satisfaction.2 Reluctance to administer opioids to breastfeeding women sometimes leads to insufficient administration of postoperative analgesia.3 However, inadequate pain management can lead to delayed breastfeeding and ambulation, or impairment of respiration with potential complications such as thrombosis, ileus, atelectasis or pneumonia. Furthermore, the severity of acute pain at 2-week postpartum is an independent risk factor for persistent pain at 3 months and postpartum depression (2.5-fold and three-fold risk increase, respectively, in the case of severe acute postoperative pain).1,4–7
Today, a widely used technique for the management of postcaesarean section pain is the addition of 100 to 200 μg of intrathecal morphine (ITM) to the spinal anaesthetic as part of a multimodal analgesia strategy.8,9 However, the gain in analgesic efficacy is accompanied by adverse effects.10 The most frequent adverse effect is postoperative nausea and vomiting (PONV), which also has the greatest negative impact on maternal satisfaction.11–15
The transversus abdominis plane (TAP) block is an established alternative technique to reduce pain after caesarean section, with a potential reduction of adverse effects compared with ITM.16–19 Multiple studies and a recent meta-analysis confirm that a TAP block significantly reduces postcaesarean section pain as well as morphine consumption, with better maternal satisfaction when compared with control.16,20,21 However, the TAP block has been shown to be less efficacious than ITM, particularly during the 10 to 24 first postoperative hours.16,22–24 The TAP block is thus limited by its short duration of action.23
Clonidine is a selective partial α2-agonist widely used as an adjuvant in peripheral blocks or neuraxial anaesthesia to extend the duration of sensory block.25–28 A recent study demonstrated that the addition of clonidine 1 μg kg−1 to a TAP block significantly increases the duration of postcaesarean section analgesia (17.8 ± 3.7 vs. 7.3 ± 1.15 h) and decreases analgesic requirement (diclofenac), without adverse effects such as hypotension or bradycardia.29 Therefore, clonidine may be considered as a potentially useful adjunct to the TAP block, prolonging its action and thus further reducing unwanted adverse effects of opioid analgesia, such as PONV.
The primary aim of the current study was to test the hypothesis that TAP block using ropivacaine and clonidine after caesarean section leads to a reduced incidence of nausea and/or vomiting compared with spinal morphine. As secondary aims, the study compared other adverse effects (pruritus, respiratory depression, hypotension, bradycardia, sedation), analgesic efficacy and the quality of postoperative recovery when using a TAP block vs. ITM. A follow-up at 3 and 6 months was performed to obtain data on persistent postoperative pain.
The single-centre 1 : 1-randomised quadruple-blinded controlled trial (registered at clinicalTrials.gov as NCT 01931215) included patients who underwent elective caesarean section. The study was approved by the Ethics Committee of the Geneva Hospital (protocol CER 12-112, date of approval: 31 May 2012, Chairman: Dr Klara Posfay Barbe). The trial was blinded for patients and clinical investigators, but also for investigators reporting data and the statistician. Moreover, the code of each group was revealed only after the statistical analysis.
We included patients who underwent elective caesarean section at the Geneva University Hospitals from 2013 to 2017. Inclusion criteria were age 18 years or above, ability to read and understand the information sheet and to sign and date the consent form, and being scheduled for elective caesarean section planned with spinal anaesthesia.
Exclusion criteria were American Society of Anesthesiologists’ (ASA) physical status more than 2, complicated pregnancy (preeclampsia, abnormal placenta), contraindication to spinal anaesthesia (clotting disorders, septicaemia, local infection, spinal malformation, elevated intracranial pressure) or TAP block (skin infection, abdominal wall muscle defect), BMI more than 40 kg m−2, weight less than 50 kg, height less than 150 cm or more than 175 cm, allergy/contraindication to any medication used in the study or previous median abdominal incision.
The primary outcome chosen was the cumulative combined incidence of nausea and/or vomiting at 24 h postoperatively. This outcome was assessed using entries of the electronic patient record and verified by questioning patients directly.
Secondary outcomes related to other adverse effects included cumulative incidence at 6 and 24 h of pruritus, treated nausea and vomiting, sedation (defined as an Observer Assessment of Alertness and Sedation score lower than 4),30 arterial hypotension (defined as a SBP of less than 100 mmHg for more than 5 min during the first 6 h, or as one episode of blood pressure (BP) of less than 100 mmHg from 6 to 24 h), bradycardia [defined as heart rate (HR) of less than 50 min−1 for more than 5 min during the first 6 h, or as one episode of HR of less than 50 min−1 from 6 to 24 h], and respiratory depression (defined as a respiratory frequency of less than 8 min−1 for more than 5 min during the first 6 h, or as one episode of respiratory frequency of less than 8 min−1 from 6 to 24 h). These outcomes were assessed using the electronic patient record.
Outcomes related to analgesic efficacy included cumulative morphine consumption at 6 and 24 h [obtained from patient-controlled-analgesia (PCA) pump], time until first PCA request and pain scores at 6, 24 and 48 h postoperatively [using a verbal numerical rating scale (NRS) from 0 to 10] at rest and on movement (i.e. during coughing, sitting or standing up). Maternal satisfaction with analgesia at 6 h postoperatively was assessed on a 0 to 10 NRS and quality of postoperative recovery was assessed at 24 and 48 h using the QOR-40 questionnaire.31 Patients were interviewed by telephone at 3 and 6 months to assess analgesic medication need, and persistent postoperative pain at the surgical site, using a 0 to 10 NRS to rate pain at rest and on movement.
Participants were screened for eligibility during the pre-operative anaesthetic consultation, which was scheduled about 1 to 6 weeks before surgery, depending on caesarean section indication. During the consultation, the study was explained and the information material was handed out.
Written informed consent was obtained the day before surgery during the last pre-operative consultation, and the randomisation was performed on arrival at the operating theatre.
Patients were allocated randomly in blocks of 10 patients (1 : 1 ratio) according to a computer-generated randomisation list, provided by the hospital pharmacy, to one of two groups: ITM group and TAP group. The randomisation list was kept at the hospital pharmacy, secret to all investigators, including the study statistician, until the end of statistical analysis. The hospital pharmacy prepared, in batches of 100, identically appearing study drug kits for both groups, containing either 100 μg of preservative-free morphine (ITM group) or 0.9% sodium chloride (TAP group) for intrathecal injection and either 2 × 20 ml ropivacaine 0.375% with 75 μg clonidine for the TAP block (TAP group) or 0.9% sodium chloride (ITM group).
Upon arrival in the operating theatre, the patient was monitored with noninvasive arterial BP, ECG and peripheral pulse oximetry. A peripheral venous line was inserted.
The anaesthetist in charge performed spinal anaesthesia using a 25-gauge pencil point needle in the sitting position at the L3 to L4 or L4 to L5 interspace. After skin disinfection with 2% alcoholic chlorhexidine solution and skin anaesthesia with 2 ml of lignocaïne 2%, all patients received spinal anaesthesia using 2.85 ml of the following solution: 2 ml hyperbaric bupivacaïne 0.5% (10 mg), 0.5 ml fentanyl 0.005% (25 μg), 0.1 ml adrenaline 1% (100 μg), and 0.25 ml of the solution for intrathecal injection of the study drug (containing either 100 μg morphine or 0.9% sodium chloride).
Following spinal injection, the patient was placed in the supine position with 15 to 20° left uterine displacement, and 1000 ml of a crystalloid solution was infused over 15 min. In parallel, a phenylephrine infusion was started at 3000 μg h−1 and adjusted to keep SBP within 20% of the baseline value. Supplemental oxygen was delivered through a nasal cannula at 2 l min−1 if needed.
Surgery began as soon as a T4 to T6 sensory blockade to cold sensation (and T8 to pinprick) was established.
At the end of surgery, a bilateral TAP block was performed by one of the five designated anaesthesiologists experienced with this procedure. For the TAP block, a sterile technique under ultrasound guidance was used with the following material: SonoSite S-Nerve ultrasound with a 13 to 6 MHz linear array, 6 cm scan depth transducer (HFL38x) and an 80 or 100 mm 22-gauge Stimuplex D and needle (Braun, Kronberg, Germany). Using an in-plane posterior technique, 20 ml of the solution provided in the study drug kit (containing either ropivacaine and clonidine or placebo) were injected on each side, with confirmation of correct location by visualisation of hydrodissection of the muscle plane.
Following surgery, the patient was monitored for 6 h in the obstetric intermediate care unit, allowing for continuous registration of heart and respiratory rate, and noninvasive BP every 15 min (frequency adapted in case of abnormal values).
For postoperative analgesia, paracetamol 1 g and ketorolac 30 mg were given intravenously 1 h after the end of the caesarean section. Thereafter, paracetamol 1 g was given every 6 h orally and ibuprofen 600 mg orally every 8 h. In parallel, a morphine PCA device was connected to the patient's intravenous line (PCA concentration and settings: morphine 1 mg ml−1 + droperidol 0.025 mg ml−1, bolus dose 1 mg, lock-out interval 5 min). The patient was instructed to use the pump when pain occurred. In addition, nurses in the intermediate care unit were allowed to titrate intravenous morphine if analgesia was insufficient.
Following transfer from the intermediate care unit, patients stayed 4 to 5 days in the maternity general ward. At 24 h after the caesarean section, the PCA pump was disconnected and on-demand oral morphine (20 mg every 4 h) was prescribed in addition to paracetamol and ibuprofen.
Patients were visited 6, 24 and 48 h after the caesarean section to collect data concerning PONV and other adverse effects, pain score and satisfaction. For PONV assessment, nausea, vomiting and treatment for PONV were reported separately. Patients were allowed to eat when the spinal block regressed below L1.
A period of 3 and 6 months after the caesarean section, an investigator telephoned the patient to obtain information on persistent postoperative pain: patients were asked to rate pain at rest and on movement and specifically pain around the caesarean section scar with a 0 to 10 NRS, and whether they had needed analgesic medication during the previous week.
The sample size was determined to reach a statistical power of 90% with an α of 0.05 bilaterally. In the absence of data in the literature for the combined outcome used as the primary endpoint in this study, we based our sample size calculation on published data for the separate outcomes ‘vomiting’ and ‘nausea’.13,23 Using these data, we estimated a 30% incidence of patients presenting with the combined endpoint (nausea and/or vomiting) in the ITM group (lower end of the range reported in the literature) and 10% in the TAP group. We considered this risk reduction of 20% as clinically relevant. Sample size was thus calculated as 82 patients per group. Due to potential drop-outs, we attempted to include a total of 2 × 90 = 180 patients.
Quantitative variables were described by the number of missing data, mean, SD, median, interquartile range (IQR) and extreme values (minimum and maximum). Qualitative variables were described by the frequency and the percentage of each response choice.
Analysis was on an intention-to-treat basis, with a secondary per protocol analysis. The data analyses were performed in a blinded manner. Only after termination of the analysis were the treatment groups unblinded.
The primary outcome was the total number of patients presenting with nausea and/or vomiting (composite endpoint) at 24 h. The proportions of patients with adverse effects (nausea, vomiting, pruritus) were described and compared by a χ2 test. The 95% confidence intervals (CIs) were assessed by the exact method of Clopper–Pearson.
Qualitative outcome measures were also compared by means of a χ2 test. The distribution of quantitative variables was tested for normality. Student t test was used (with correction for multiple testing) for normally distributed variables; in cases of clearly non-Gaussian distribution in which no transformation is possible, a Wilcoxon test was used. The significance level was 0.05 for all inferential analyses.
R version 3.3.1 (The R Foundation for Statistical Computing, Vienna, Austria) and StatXact Version 11.1.0 (Cytel Inc., Cambridge, Massachusetts, USA) were used for statistical analysis.
A total of 182 participants were included in the study from October 2013 to February 2017, with completion of the 6-month telephone follow-up (due to block randomisation, we included more patients than finally necessary to assure the minimum of 82 patients in each group). Figure 1 shows the flow diagram of participants. All demographic and surgical data were comparable in both groups. The main epidemiological data are shown in Table 1. Other descriptive data are shown in Supplementary Table 1S, http://links.lww.com/EJA/A203. All patients had an ASA physical status of 2 (a pregnant woman without any comorbidity is considered as ASA 2 and not ASA 1).
Ninety-three patients were allocated to the TAP group and 89 to the ITM group. One patient was excluded after allocation because she had an exclusion criterion not noticed before (previous median abdominal incision). The groups are not of exactly the same size due to a break of block randomisation when the first batch of study drugs passed the expiry date. The primary outcome ‘nausea and/or vomiting at 24 h’ was available in 92 and 88 patients in the TAP group and the ITM group, respectively.
After randomisation, 12 patients were excluded from the per protocol analysis because of protocol deviation (intra-operative ondansetron administration for severe PONV in nine patients, and noncompliance with dosages of spinal anaesthesia or TAP block in three patients). Three patients were also excluded due to postoperative use of medication possibly interfering with the results (intravenous clonidine and cabergoline).
The main results, primary outcome and secondary outcomes, are presented in Tables 2 and 3 for the intention-to-treat analysis. Results of the intention-to-treat analysis with mean values are available in Supplementary Table 2S, http://links.lww.com/EJA/A203 to be used in an eventual meta-analysis, and results of the per protocol analysis are available in Supplementary Tables 3S to 5S, http://links.lww.com/EJA/A203.
At 24 h, the total number of patients presenting with nausea and/or vomiting was not significantly different between the two groups with 18.5% (17 of 92 patients) in the TAP group and 30.7% (27 of 88 patients) in the ITM group (P = 0.065). The risk difference of the combined outcome nausea/vomiting did not approach the 20% considered as clinically significant in the sample size calculation of the study. In the per protocol analysis, we found significantly less PONV in the TAP group (14/84 patients vs. 26/81 patients, P = 0.02), but the risk difference also did not reach 20%.
Significantly more patients needed treatment of PONV in the ITM group (17/88 patients, 19.3%) compared with the TAP group (8/92 patients, 8.7%). Concerning other secondary outcomes related to morphine-induced adverse effects, there was no difference in the total number of patients presenting with pruritus at 24 h (43.5% for TAP vs. 56.2% for ITM, P = 0.10), and none of the patients had respiratory depression at 6 or 24 h in either group.
Concerning secondary outcomes related to potential adverse effects of the clonidine used in the TAP block, there was significantly more hypotension during the first 24 h in the TAP group, with 50/92 patients (54.3%) vs. 26/89 patients (29.2%) in the ITM group (P = 0.0006). None of the patients presented with sedation episodes during the first 24 h, and there was no difference for bradycardia between the groups.
Regarding the efficacy of analgesia, cumulative morphine consumption at 24 h was significantly lower in the ITM group than in the TAP group (7 vs. 17.5 mg, P < 0.0001). However, time until first PCA request was not different (140 min in the TAP group vs. 147.5 min in the ITM group, P = 0.43). Pain score at rest at 6 h was also significantly lower in the ITM group (median pain score 1 [IQR 0 to 2] vs. 2.5 [2 to 4], P < 0.0001), but differences were not found between the groups for pain at rest or on movement at 24 and 48 h.
Maternal satisfaction at 6 h postoperatively was high in both groups and not significantly different.
Concerning the quality of recovery assessed using the QOR-40 questionnaire, there was no difference at 24 h, but the scores at 48 h were in favour of ITM (P = 0.03).
Secondary outcomes also included persistent pain at 3 and 6 months. Data were available for 146 patients at 3 months and for 145 patients at 6 months. At 3 months, nine of 69 patients (13%) in the ITM group and 18 of 77 patients in the TAP group (23%) reported scar pain (P = 0.12). At 6 months, fewer patients reported scar pain in the ITM group (two of 69 patients, 3%) than in the TAP group (9 of 76 patients, 12%) (P = 0.05). There was no significant difference for median pain scores at rest and on movement at 3 and 6 months, and only one patient in the TAP group still used analgesics for persistent postoperative pain at 6 months.
To our knowledge, this randomised controlled trial is the first to focus on opioid-induced PONV after caesarean section as the primary outcome. There are many studies on the optimal technique of postoperative analgesia for caesarean section, mainly on ITM and more recently on TAP block, but the majority report PONV only as secondary outcome. However, an article discussing patients’ fears about side effects following caesarean section found PONV to be ranked high among patients’ concerns, just after postoperative pain.32
Although ITM is currently the most widely used technique, it is nevertheless legitimate to study alternative treatments, such as TAP block, that limit the side effects associated with morphine. On the contrary, the analgesic effect of a single-shot TAP block is limited in duration. In our study, we choose to add clonidine to a traditional ropivacaine TAP block to prolong its duration of action. This was studied in two trials using TAP block with clonidine for caesarean section analgesia, however none compared TAP block and ITM efficacy and induced side effects. One study29 compared TAP block with and without clonidine (1 μg kg−1 bilaterally) and concluded that clonidine prolonged the duration of analgesia by 10 h and decreased analgesic requirement without side effects such as bradycardia or hypotension. The other study33 used TAP block with or without clonidine (75 μg bilaterally) in addition to ITM, finding no benefit from the addition of a TAP block with clonidine on acute pain and demonstrating no preventive effect on wound hyperalgesia and persistent pain. These results are consistent with those in the literature which does not demonstrate any benefit from using both ITM and TAP block for acute pain management.16
The results of our study show that a TAP block does not confer a significant benefit in reducing PONV incidence within the 24 first postoperative hours compared with ITM. However, the per protocol analysis found significantly less PONV in the TAP group. Moreover, fewer patients needed treatment of PONV in the TAP group. Although the difference does not reach the reduction of 20% considered ‘a priori’ as clinically relevant, there seems to be a clear trend towards PONV reduction in the TAP group. These findings are therefore only partly consistent with previous meta-analyses and studies that found a significantly reduced incidence of PONV in patients who received a TAP block.16,21,24,34,35 Several reasons can explain this discrepancy. Our study found an incidence of patients presenting PONV in the first 24 h of 30.7% in the ITM group, which is relatively low compared with the 30 to 100% incidence described in the literature.12,13,23 As morphine induces dose-dependent PONV, this can be explained by the relatively low dose of ITM we used (100 μg), compared with the commonly used 200 μg.36 Furthermore, our systematic multimodal analgesia protocol using ibuprofen 600 mg every 8 h and paracetamol 1 g every 6 h may lead to postoperative morphine sparing, and thus less PONV compared with literature data. Conversely, the incidence of PONV in the TAP group (18.5%) is much higher than the 10% which we expected. A potential explanation is the significantly higher postoperative morphine consumption in the TAP group (median consumption 2.5 times higher in the TAP group), as a consequence of less effective analgesia in the postoperative period. Another possible explanation may be the greater incidence of hypotension in the TAP group, another known contributor to PONV. Unlike the two studies previously cited, in which the addition of clonidine had no impact on haemodynamic side effects, we found hypotension during the first 24 h in more than 50% of patients in the TAP group. This could be explained by the systematic absorption of clonidine from the TAP block. High plasma concentrations of ropivacaine in patients undergoing caesarean section with TAP block have been found,37 and clonidine is probably absorbed to a similar degree.
We controlled other factors known to influence nausea and vomiting, even though they mainly cause nausea and/or vomiting during caesarean delivery and not in the postoperative period. These include intra-operative hypotension, exteriorisation of the uterus during repair of the hysterotomy, and use of uterotonic agents (oxytocin and others).
Our results confirm the superiority of ITM compared with a TAP block for analgesia after caesarean section, demonstrated in many studies and a recent meta-analysis.16 However, it should be acknowledged that the CI of the primary outcome does not exclude a significative effect of a 20% PONV risk reduction, indicating that the study was not sufficiently powered to provide a definitive answer.
Our study provides the additional information that even with added clonidine, TAP block does not achieve the analgesic efficacy of ITM. Even with a longer duration of action provided by clonidine, TAP block analgesia is probably still limited to parietal pain and does not reduce visceral and uterine pain.35,38 Nevertheless, maternal satisfaction was very high in both groups.
At 6 months, fewer patients reported scar pain in the ITM group but there was no difference in analgesic use at that time. As severe acute postoperative pain is a risk factor for persistent pain,39 this could be explained by the fact that patients reported lower acute pain scores in the first 24 h postoperatively in the ITM group than in the TAP group. Indeed, inadequate acute analgesia is associated with wound hyperalgesia, central sensitisation and chronic pain development.40 ITM may thus lead to a lower risk of persistent pain after C-section (compared with other, less efficient, forms of postoperative analgesia such as a TAP block), but this hypothesis needs to be confirmed in a prospective study.
In conclusion, we found that a TAP block with clonidine as an adjunct does not significantly reduce the incidence of PONV compared with ITM, but reduces the need for treatment of PONV in the first 24 postoperative hours. Therefore, a TAP block may be an alternative to ITM when PONV is of concern in the analgesic strategy, and may be offered to women in these cases.
Acknowledgements relating to this article
Assistance with the study: the authors thank all patients and the medical staff for their participation in the study.
Financial support and sponsorship: this work was supported by departmental funding (Department of Anaesthesia, Pharmacology and Intensive Care, Geneva University Hospital, Geneva, Switzerland).
Conflicts of interest: none.
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