This study was approved by the Human Research Ethics Committee of Institutional Review Board of Guangzhou Women and Children’s Medical Center (IRB2017062201). The trial was registered before patient enrollment at chictr.org.cn (ChiCTR-IOR-17011956, Principal investigator: Ying-Jun She, Date of registration: 2017.07.12). In the pre-op room, all eligible obstetric patients were informed about the study, and written informed patient consent was obtained for study participation.
The study was operated in four anesthesiology departments from August 2017 to December 2018. 1000 ASA physical status I or II obstetric patients scheduled for elective cesarean delivery at 8 am to noon were recruited into the study. Exclusion criteria included age younger than 18 years or older than 45 years, BMI < 18 or > 35, pregnancy-related hypertensive disease, cardiovascular, cerebrovascular or renal disease, bleeding disorders, infection at the site of injections, gestational age < 36 weeks, drug abusers, allergic to NSAIDs, known abnormal fetal development, and other conditions that were considered unsuitable for this study by the attending anesthesiologists.
Using a computer-generated table, obstetric patients were randomly allocated into two groups (Epidural analgesia only group (group E); epidural analgesia plus intravenous flurbiprofen axetil group (group EF).) To ensure proper blinding, in each center there was one anesthetist responsible for the random allocation, performing the combined spinal-epidural anesthesia (CSEA), and managing the anesthesia procedure, the other anesthetist blinded to the group assignment was responsible for postoperative follow-up during surgery and analyzing the outcomes. All patients were unaware of group allocation.
All obstetric patients underwent preoperative fasting for 8 hours and water deprivation for 4 hours. After entering the operating room, standard monitors such as non-invasive blood pressure measurement, pulse oximetry, and electrocardiography were attached, the baseline was recorded. A 20-G IV catheter was placed in a peripheral vein in the obstetric patient’s forearm, and a loading infusion of lactated Ringer’s solution 10ml/kg was commenced. In all patients, the skin was infiltrated with 1% Lidocaine, and CSEA was performed at the midline L3-4 interspace in the left lateral positions, 2.5ml 0.5% Ropivacaine was injected into the subarachnoid space in 10 seconds. After placing an epidural catheter, the patient was positioned at a 15°left lateral tilt. Oxygen was administered through a face mask at a flow rate of 2 L/min during the operation. The level of sensory block was evaluated by cold sensation and the level of motor block was recorded according to the modified Bromage scale (3 = Cannot move foot or knee, 2 = Can move foot only, 1 = Can flex the knee, move a foot, but cannot raise a leg, 0 = no motor block). We adjusted the block level between T4 and T6 with an epidural supplement of 0.5% Ropivacaine. 0.25mg Palonosetron was given intravenously after delivery. At the end of the surgery, 0.1% Ropivacaine plus 2mg morphine in 8ml sterile saline was injected via an epidural catheter, then the catheter was connected with a PCEA pump. The PCEA pump was contained 200ml 0.1% Ropivacaine, the bolus was 3ml, the lockout interval was 15 minutes, the infusion speed was 3ml/h. The patient in group EF was given 50mg flurbiprofen axetil intravenously after delivery, and then 50mg flurbiprofen axetil was administrated twice a day (7:00 and 19:00) intravenously until the third day after cesarean section. Group E was given saline as a placebo instead. Intravenous oxytocin was administrated during the surgery and from 7:30 to 8:00 the next morning.
We followed up patients 2 hours, 6 hours, 12 hours, 24 hours, and 48 hours after a cesarean section. The primary outcome was considered to be the VAS scale of the incision pain and uterine contraction pain. The secondary outcomes were the PCEA drug consumption and the quality of recovery. Side effects like dizziness, hypotension, palpitation, respiratory depression, pruritus, fever, postoperative nausea, and vomiting (PONV) were recorded. Adjuvant drugs, accumulated PCEA counts were recorded. Patients were asked to rank their satisfaction, according to the following scale: 1 = unsatisfactory; 2 = neutral; 3 = satisfactory; and 4 = very satisfactory.
Sample size calculation was based on an initial pilot study where the standard deviation (SD) within each group was 3.1 cm VAS points 24 hours after a cesarean section. To achieve 90% power at α = 0.05 level to detect a difference of 1 cm on the VAS between treatment and control groups, we needed a total of 774 patients (387 in each group). We recruited 1000 (500 in each group) patients to account for 15% of potential missing data or loss-to-follow up.
Statistical analyses were performed in SPSS (IBM SPSS Statistics, Version 22, USA). The data were reported as mean (SD) and count (percentage) as appropriate and were analyzed using T-test or one-way ANOVA test. Qualitative variables were analyzed using chi-squared test. P < 0.05 were considered statistically significant.