Methods
Participants were recruited from the Gynecologic Department at the Edith
Wolfson Medical Center, Holon, Israel, from December
1st, 2016 until July 31st, 2019.
Inclusion criteria included patients with good general health (defined
as American Society of Anesthesiologists grade 1–2), who were
undergoing a laparoscopic surgery for benign indications. Exclusion
criteria included patients who suffered from chronic pelvic pain
(non-menstrual pain of 6 or more months, that alters daily function or
necessitates medical or surgical treatment), pregnancy, allergy to
Bupivacaine hydrochloride, emergency surgeries, execution of additional
vaginal procedures, and surgeries performed for the following
indications: active pelvic infection, ectopic pregnancy, or malignancy.
In order to eliminate possible confounders that might increase the level
of postoperative pain independently, post-assignment exclusion was
executed in cases of conversion to laparotomy and intraoperative
diagnosis of malignancy (confirmed by frozen section pathology).
This study was approved by the Wolfson medical center review board
(approval number 0198-16-WOMC, dated 03/11/2016), and written informed
consent was obtained from all subjects participating in the trial. The
trial was registered prior to patient enrollment at clinicaltrials.gov
(NCT02976571, Principal investigator Ohad Gluck, date of trial
registration 11/23/2016). This manuscript adheres to the applicable
CONSORT guidelines 15.
This is a double-blinded study, with parallel assignments, to one of the
four following groups:
Group 1- SC Bupivacaine
hydrochloride (AstraZeneca, Sodertalje, Sweden) 0.5% and IP Bupivacaine
hydrochloride 0.5%.
Group 2- SC Bupivacaine hydrochloride 0.5% and IP Sodium Chloride 0.9%
(NaCl).
Group 3- SC NaCl 0.9% and IP Bupivacaine hydrochloride 0.5%.
Group 4- SC NaCl 0.9% and IP NaCl 0.9%.
After providing written informed consent, patients were randomly
assigned to one of the study groups.
The
randomization was performed in blocks of 40, using an on-line
randomization program (http://www.randomization.com). 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. Patients, surgeons, anesthesiologists, and pain assessment
researchers were all blinded to patients’ allocations.
Syringes were prepared according to the following instructions:
The first syringe, for SC injection, contained 9 ml of Bupivacaine
hydrochloride 0.5% or NaCl 0.9%, as placebo. Three ml of this solution
were injected subcutaneously (exclusively beneath the skin) at each
trocar site, prior to skin incision.
The second syringe, for IP instillation, contained 10 ml of Bupivacaine
hydrochloride 0.5% or 10 ml of NaCl 0.9%, as placebo, with an
additional 40 ml of NaCl 0.9% (50ml total volume). This solution was
instilled intra-abdominally prior to abdominal closure by irrigating the
diaphragm and the pelvis (15 ml under each diaphragm, and 20 ml in the
pelvis). All surgeons administered the solutions at the same locations
and in the same manner.
In order to study the short-term and long-term effects of intervention,
postoperative pain at rest was evaluated at 3, 8, and 24 hours after
surgery. According to our
protocol, patient ambulation starts 8 hours following surgery;
therefore, postoperative pain with change of position was evaluated at 8
and 24 hours after surgery.
Prior studies have utilized the
visual analog scale (VAS) for
evaluating similar outcomes 12,16,17. Therefore, we
used a 10-cm VAS to scale the level of pain. For assessing pain at rest,
prone patients were asked to grade the level of pain in the abdomen and
at the tip of the shoulder on a scale of 0 (defined as no pain) to 10
(defined as the worst pain ever experienced). For assessing pain with
change of position , patients were asked to grade their pain using the
same scale, while shifting from
lying in bed to sitting in a
chair. A member of the surgical team who was not involved in the index
surgical case administered the VAS scale.
We conducted a preoperative fasting of 6 hours for solids and liquids,
and formulated a standardized protocol for preoperative management,
anesthesia and analgesia.
All patients received general anesthetic induction and maintenance.
Patients were premedicated with 2mg intravenous (IV) Midazolam (Rafa,
Jerusalem, Israel). General anesthesia was induced with 2mg/kg IV
Propofol (Fresenius Kabi, Graz, Austria), 2 mg/kg IV Meperidine
(Panpharma, Luitre, France), and 0.6 mg/kg IV Rocuronium Bromide
(Unipharm, Melsungen, Germany). General anesthesia was maintained with
an infusion of 50–150 mg/kg/minute IV Propofol, combined with inhaled
Sevoflurane (LGM pharma, USA) and
oxygen. Under general anesthesia with endotracheal intubation, the
patient was positioned properly and draped. Antibiotics and
thrombophylaxis were given when indicated.
In the recovery ward, pain medication was provided by the attending
nurses upon demand, and consisted of either 2-3 mg IV Morphine (As
Kalceks, Riga, Latvia), 20-30mg IV Meperidine , 1g IV Dipyrone (Teva,
Petah-Tikva, Israel), or 1g IV Paracetamol (B. Braun, Melsungen,
Germany), or a combination of both.
Upon transfer to the postoperative ward, a uniform, standardized,
postoperative pain-relief regime was applied for all patients,
consisting of:
- 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: 75mg Intramuscular Diclofenac Sodium (Teva, Petah-Tikva,
Israel) 75mg, up to 3 times per day upon demand
- 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).
All procedures were performed by one of three senior surgeons in our
department. Three trocars were placed in all laparoscopies - umbilical
(5-mm), another 5-mm trocar, positioned at the left lower abdomen, and
an additional 10-mm trocar placed in the supra-pubic area. Both SC and
IP solution administration was performed in the same manner by all
surgeons, as described above. At the end of each surgery, the fascia was
closed using absorbable suture (Vicryl 1, Ethicon), and the skin was
closed using skin glue (Dermabond, Johnson and Johnson).
All but 8 patients were discharged on postoperative day 1, according to
our departmental protocol. The latter requested later discharge and
therefore discharged on postoperative day 2-3. The patients were
instructed to use non-opioid, over-the-counter analgesics (oral
paracetamol 1000mg, Ibuprofen 200mg, or Dipyrone 1000mg) at home, and
refer to unit when these interventions were not helpful- no patient
referred for this reason. All patients returned for a routine follow-up
visit 2-3 weeks after surgery.