Participants were recruited from a single-center gynecologic department at the Edith Wolfson Medical center, Holon, Israel, from September 1st, 2017 until November 30th, 2019. Inclusion criteria included women in general good health (defined as American Society of Anesthesiologists grade 1–2) who underwent elective vaginal hysterectomy indicated by pelvic organ prolapse (POP). Exclusion criteria included chronic pain requiring use of analgesics, allergy to Bupivacaine hydrochloride, additional concurrent abdominal/ laparoscopic procedures, active pelvic infection, or malignancy. Post-assignment exclusion was executed in cases of conversion to laparotomy/ laparoscopy.
This study was approved by the Wolfson medical center review board (approval number 0156-17-WOMC, dated 17/08/2017) and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov (NCT03268525, Principal investigator: Ohad Gluck, Date of registration: 31/08/2017). This manuscript adheres to the applicable CONSORT guidelines .
This is a double-blinded study, with parallel assignments, to one of two groups:
The medication group- Bupivacaine hydrochloride 0.5%, and the placebo group- Sodium Chloride (NaCl) 0.9%.
At the day of surgery, women were randomly assigned to one of the study groups. In order to ensure allocation concealment the random allocation sequence was kept with the lead author (OG), which was not a part of the recruiting, operating, or pain assessment team.
An assigned nurse (IW) prepared syringes prior to each surgery, outside of the operation room, according to the randomization list, and unlabeled syringes were provided to the surgeons upon commencing surgery. The content of each syringe was written in the concealed list only. Women, surgeons, anesthesiologists, and pain assessment researchers were all blinded to participants’ allocations.
The syringes contained 10 ml of Bupivacaine hydrochloride 0.5% or NaCl 0.9% as placebo. A total of 8 ml of solution was injected before incision, to the sub-mucosa layer of the exo-cervix, 2 cm above the external OS, in a circumferential manner. In addition, 1 ml of the solution was injected in each resection line (sacro-uterine and cardinal ligaments), adding up to a total of 10 ml. In case of performing additional anterior/ posterior colporrhaphy, an extra 5 ml of solution were injected to the cutting line at the anterior/ posterior vaginal wall, respectively, prior to incision (additional 5 ml for anterior or posterior repair and 10 ml if both were performed). Based on previous studies [12, 13], a total amount of 10–20 ml of Bupivacaine hydrochloride 0.5% or NaCl 0.9%, was injected prior to surgery. No vasoconstrictors were injected. After injection, a 5 minutes pause was conducted, prior to cutting, for reaching maximal effect of anesthesia.
All surgeries were performed under general anesthesia. All patients received standardized anesthetic induction and maintenance. Patients were premedicated with 2mg intravenous (IV) midazolam. General anesthesia was induced with 2mg/kg IV Propofol, 2 mg/kg IV Fentanyl citrate, and 0.6 mg/kg IV Rocuronium Bromide. General anesthesia was maintained with an infusion of 50–150 mg/kg/minute IV Propofol, combined with inhaled Sevoflurane and oxygen. Under general anesthesia with endotracheal intubation, the patient was positioned properly and draped. Prior to surgery, second generation Cephalosporins was routinely administered, as part of our departmental protocols, and Clexane (Enoxaparin) was administered when indicated.
All procedures were performed by one of two senior surgeons (authors A.C and S.G). Vaginal hysterectomy was conducted with concomitant McCall Culdoplasty, for addressing apical support, in order to prevent recurrence of POP . Additional procedures (colporrhaphy and/or mid-urethral sling), if conducted, were performed after the hysterectomy was completed.
Pain medication in the recovery room, was provided by the attending nurses upon demand, according to the following regime:
First-line: 1g IV Paracetamol, up to 4 times per day upon demand
Second-line: 1g oral Dipyrone (not available in the USA), up to 4 times per day upon demand
Third-line: Opioid- based medication, either 2–3 mg IV Morphine (As Kalceks, Riga, Latvia) or 20-30mg IV Meperidine.
Upon transfer from the recovery room to our department, a uniform, standardized, postoperative pain-relief regime was applied for all patients (upon demand), consisting of:
First-line: IV Paracetamol 1g, up to 4 times per day
Second-line: Oral Dipyrone 1g, up to 4 times per day
Third-line: Intramuscular Diclofenac Sodium 75mg, up to 3 times per day
Fourth-line: 100 mg IV Tramadol Hydrochloride (Dexcel, Or-Yehuda, Israel), up to 3 times per day upon demand, usually along with 10mg IV Metoclopramide (Rafa, Jerusalem, Israel).
A urine catheter and vaginal dressing were left at the end of the surgery, and were removed at postoperative day 1. Patients were discharged 2–3 days postoperatively, and returned for a routine follow-up visit 2–3 weeks after surgery.
Postoperative pain level at rest was evaluated at 3, 8, and 24 hours after surgery, and postoperative pain level during ambulation was evaluated at 8 and 24 hours after surgery. A member of the surgical team who was not involved in the index surgical case administered the pain level assessment.
Since the visual analog scale (VAS) has been used in prior studies for evaluating similar outcomes , a 100-mm VAS was used to grade the level of pain. For assessing pain at rest, patients were asked to grade their level of pain from 0 (no pain) to 10 (worst pain ever experienced) at the abdomen and at the vagina while lying in bed. For assessing pain during ambulation, patients were asked to stand up, walk a few steps, and sit in a chair. Then, they were asked to grade their pain, using the same scale, during ambulation. In addition, patients were also asked whether they have nausea or vomiting, and were evaluated for analgesics requirements.
The primary outcome was the level of abdominal pain during ambulation (according to VAS score) 8 hours after surgery. Based on previous studies, it was estimated that the intervention would cause a 25% reduction in the primary outcome, as compared to placebo [10, 13]. In order to attain a power of 80% and a significance level of 0.05, the required total sample size was calculated to be 27 women for each group. We included 30 women in each group, in order to make up for any potential loss of follow up. The randomization was performed in blocks of 30, using an on-line randomization program (http://www.randomization.com).
Secondary outcomes were levels of pain (abdomen and/or vagina) at other points in time, at rest and/or during ambulation, as well as the demand for postoperative analgesics.
All statistical analyses were conducted using the R Statistical Software, version 3.5.2 (Foundation for Statistical Computing, Vienna, Austria).
We used Analysis of Variance (ANOVA) for continuous variables and the Chi-square or Fisher exact tests for categorical variables.