Setting and participants
This study was carried out in the general operating theatre of the University Malaya Medical Centre, Kuala Lumpur, Malaysia. Written informed consent was obtained during patient visits to the gynaecology clinic a few weeks before the date of surgery or during ward admission a day before the surgery. Patients assigned to the American Society of Anaesthesiologists (ASA) physical classification of I or II, aged between 18 years and 60 years, and scheduled to undergo a laparoscopic procedure for benign gynaecological conditions were considered eligible for participation. The definitions of ASA are as follows: ASA I, normal healthy patient; ASA II, mild systemic disease without substantial functional limitations (body mass index < 40 kg/m2, well-controlled diabetes mellitus/mild hypertension, mild lung disease). Patients with known drug allergies to substances in parecoxib, celecoxib, paracetamol, or having received analgesia 12 h before the scheduled procedure were excluded. This study was registered and approved by the Ministry of Health Research and Ethics Committee (MREC) of the National Medical Research Register (NMRR) and the Clinical Research Centre, Malaysia (NMRR-19-1532-48232) on 06/03/2019 and the Medical Research Ethics Committee of the University Malaya Medical Centre (MREC ID No: 201926-7106) on 20/03/2019. Furthermore, the International Standardised Randomised Controlled Trial Number (ISRCTN) for this study was registered with an ID of 87898051 (https://doi.org/10.1186/ISRCTN87898051), dated 26/06/2019. This trial was conducted in accordance with the Declaration of Helsinki (2000) for human studies.
Randomisation and blinding
Women were assigned to two groups in a 1:1 ratio using a random-permuted block randomisation algorithm via a web-based system (www.randomization.com) by a research assistant (RA-A) who was not involved in the recruitment process. The same research assistance kept the master list for the randomised treatment allocation sequences. Concealment was performed using serially numbered opaque, sealed envelopes containing a paper with the legend ‘INSI’ or ‘Control’. The following available randomisation number was assigned to the patient once she consented to participate. Upon arrival at the theatre, the allotted envelope was subsequently given to the operating theatre nurse, who was not involved in managing the patient. The envelope was opened at the end of the surgery, before the removal of laparoscopic trocars. Patients who withdrew from the study before surgery were replaced by the next consented patient. However, patients who withdrew from the study at the end of surgery were counted as dropouts, and no replacement was made.
For each laparoscopy, while the patient was in the supine position, a sub-umbilical incision was made, and a 10-mm trocar was inserted sub-umbilically under direct vision. Pneumoperitoneum was created by insulating 2.5 L of carbon dioxide into the peritoneal cavity. Another 5-mm trocar was inserted into the right iliac fossa, left iliac fossa, or suprapubic region. At the end of the surgery, patients allocated to both groups were placed in the Trendelenburg position (30º). Subsequently, trial protocols were carried out as follows:
The intervention group (INSI): Intraperitoneal normal saline (15 mL/kg body weight) was infused at the upper part of the abdominal cavity evenly by the surgeon through a 5-mm trocar. The trocar sleeve valves were left open during the instillation of normal saline to allow carbon dioxide to escape from the abdominal cavity. The instilled normal saline solution was left in situ.
The control group: Trocar sleeve valves were left open to allow carbon dioxide to escape from the abdominal cavity with gentle abdominal pressure.
In both groups, the trocar incision site was closed in two layers using Vicryl 3/0 or Monosyn 3/0. Patients were then placed in a neutral position, and standard protocols of anaesthesia reversal were carried out.
The patients received standard postoperative care in the ward and were discharged according to the discretion of each managing team. A standard regime of analgesia was administered to all women, in which 1 g of paracetamol and 40 mg of parecoxib were administered intravenously, or 75 mg of suppository diclofenac acid was administered at the end of the surgery. This was followed by standard regular doses of 1 g paracetamol every 6 h for 5 days. Additional rescue doses of analgesia (oral celecoxib 200 mg twice a day) were recorded.
Measurement of pain score
The primary outcome of this study was the severity of post-laparoscopic pain in the shoulder and upper abdominal areas at 24 h, 48 h, and 72 h after the surgery. It was measured using a 0-10 visual analogue score (VAS), where 0 = no pain and 10 = worst possible pain. The VAS has been adapted by the Ministry of Health Malaysia as a pain assessment tool (24) (18).
Women rated their postoperative pain using the VAS at rest and during movement, at a specific location (shoulder and upper abdomen) and time (24 h, 48 h, and 72 h postoperatively). The occurrence of nausea, vomiting, and abdominal distension was documented in accordance with our secondary outcomes. The data were recorded by another research assistant (RA-B), who was blinded to the patients' assigned group. If the patients were discharged before day 3 (72 h), the patients were contacted over the phone by the research assistant RA-B, who was blinded to the assigned group of patients to obtain their pain scores.
The sample size was calculated using the PS software version 3.0 2009. Based on a previous study (11), the mean shoulder pain (standard deviation [SD]) of VAS at 48 h post laparoscopic procedure was pain 0.7 (1.55) and 2.2 (2.42) for control and INSI groups, respectively. With a two-sided significance level of 5% and power of 80%, the minimum number needed for each group was 27. By estimating a 20% dropout rate and rounding up, we planned to recruit 68 patients (34 women in each arm).
Statistical analysis was performed using standard parametric and non-parametric statistics with JMP Pro 14.1 (SAS Institute Inc., Cary, NC, USA). Data were expressed as mean ± SD or number (%). Fisher’s exact test was used to analyse categorical variables, while the independent sample t-test or one-way ANOVA test was used to analyse continuous variables. A two-sided p-value < 0.05, was considered as the threshold for significance.