2.1

Study population

This prospective comparative randomized double-blinded controlled study was conducted on sixty patients aged 21 – 60 years, ASA II and ASA III with body mass index (BMI) ≥35 kg/m ² undergoing elective laparoscopic sleeve gastrectomy. The study was carried out in Zagazig University Hospitals from July 2020 to March 2022 after obtaining patients’ informed written consent and approval from the Institutional Review Board (6252/19–7-2020) and registration in Clinical Trials.gov (ID: NCT04525274). The study was carried out according to the regulations and guidelines of Helsinki and in adherence to CONSORT guidelines ( http://www.consort-statement.org ).

Patients with uncontrolled diabetes mellitus, severe hypertension, cardiac, hepatic, renal, psychological and mental disorders, chronic use of opioid or sedative agents or a known history of allergy to study drugs were excluded from this study. Patient refusal was considered an exclusion criterion

Withdrawal criteria included patient refusal to complete the study or the need for postoperative mechanical ventilation.

2.2

Study design

Preoperative evaluation and medical optimization of all patients were carried out according to local protocols. Patients were instructed on how to express pain using the visual analog scale (VAS); by marking on a horizontal line where “no pain at all” represented as 0 at one end; and ”worst pain imaginable” represented as 10 at the other end. Fasting for a minimum of 8 h before the operation was confirmed. Prophylaxis against Deep venous thrombosis (DVT) was achieved by Enoxaparin 0.5 mg/kg of lean body weight (LBW) given 12 h before the intervention along with the application of elastic stockings (removed intraoperatively).

Upon arrival in the operating room, an intravenous line was secured with an 18 G cannula. Standard monitoring was applied (automated noninvasive blood pressure monitoring “NIBP”, pulse oximetry and 5 leads electrocardiography “ECG”), and baseline data recorded. A sequential pneumatic compressions device applied to the patient’s calves after removal of the elastic stockings.

The anesthesia protocol was standardized for all patients. Pre-oxygenation with 100 % O ₂ (4 l/min for 5 min) was carried out while the patient was in a ramped position. General anesthesia induced with intravenous fentanyl (1 ug/kg) of lean body weight (LBW), propofol (2 mg/kg) of LBW followed by rocuronium (1 mg/kg) of ideal body weight (IBW) to facilitate tracheal intubation, after confirming tracheal tube position and ensuring the ability to ventilate the patient. Isoflurane (1–1.5 MAC) was used for maintenance of anesthesia through oxygen 60 % and muscle relaxation was maintained using rocuronium supplement 0.2 mg/kg of IBW guided by train of four monitoring. The patients were mechanically ventilated with tidal volume (6–8 ml/kg) of IBW, respiratory rate adjusted to keep patients normocapnic; EtCO ₂ level (34–36 mmHg).

During laparoscopy, intra-abdominal pressure was maintained at 15–18 mmHg according to BMI and the patient placed in the reverse Trendelenburg position.

After completion of the surgical procedure and adequate hemostasis, the patient was shifted to the Trendelenburg position, and randomized according to a computer-generated table into one of three study groups:

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  Control group (Group C) ( n = 20): patients received 40 ml bupivacaine 0.25 % + 5 ml normal saline with a total volume of 45 ml installed intraperitoneally.

  
  
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  Ketamine group (Group K) ( n = 20): patients received 40 ml bupivacaine 0.25 % + 0.5 mg/kg ketamine diluted in 5 ml normal saline with a total volume of 45 ml installed intraperitoneally.

  
  
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  Dexmedetomidine group (Group D) ( n = 20): patients received 40 ml bupivacaine 0.25 % + 1 µg/kg dexmedetomidine diluted in 5 ml normal saline with a total volume of 45 ml installed intraperitoneally.

The study drugs were prepared in sterile syringes by the anesthesiologist responsible for medication who was not involved in subsequent patient care. After completing the gastrectomy and before abdominal deflation, uniform intraperitoneal instillation of the study drugs was achieved by the surgeon (who was blind to the installed drug) under camera supervision. The patient was maintained in the Trendelenburg position for 5–10 min after drug instillation. The patient, surgeon and the investigator responsible for data collection were blinded to the patient’s group allocation.

The abdomen was deflated by passive exsufflation using gentle abdominal pressure. During this maneuver, the trocar valve was kept fully open to allow the CO ₂ gas to escape. Then the trocar was removed and the abdominal incisions closed.

On emergence, isoflurane was turned off and muscle relaxant was reversed using sugammadex 2mg/kg of IBW then the patients were extubated after gentle suctioning of the oropharynx. All patients received acetaminophen 1 g (to be repeated / 6 h) for postoperative analgesia with maximum daily dose 75 mg/kg per 24 h, before shifting to post-anesthesia care unit (PACU). When the modified Aldrete score ≥ 9 was achieved the patient was transferred to the surgical ward.

Standard monitoring was maintained during PACU stay. Hemodynamics was assessed every 15 min for the first hour after instillation of study drugs, then every 30 min for the second hour and then hourly after that for 6 h then every 6 h later on till the end of the 1st postoperative 24 h. The level of sedation was assessed using the modified Ramsay Sedation Score 2 h after extubation.

For the first postoperative patient request for analgesia (VAS ≥ 4), intravenous nalbuphine 5 mg increments up to 20 mg per dose were administered with maximum daily dose 160 mg.

Instillation of study drugs was considered time 0 (T ₀ ) in data collection.

2.3

Collected data

The following data were collected for all patients:

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  Patients’ characteristics: Age, sex, BMI, ASA physical status.

  
  
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  Operative duration.

  
  
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  Time of the first request for analgesia (time elapsed from intraperitoneal instillation of the study drug to the first rescue analgesia needed) as the primary outcome.

  
  
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  Assessment of abdominal pain using VAS for pain at 1, 2, 4, 6, 12 and 24 h after instillation of study drugs and total rescue analgesic (nalbuphine) requirement in the first postoperative 24 h as secondary outcomes.

  
  
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  The incidence of postoperative complications including excessive sedation (modified Ramsay sedation score ≥ 5), hypotension (systolic arterial pressure [SAP] < 90 mmHg) which was managed by fluids and intravenous ephedrine increments as appropriate, bradycardia (HR < 60 beats/min.) was managed by 1–3 mg atropine and/or ephedrine 5 mg increments if associated with hypotension. Shoulder pain managed with rescue analgesia, nausea and vomiting (PONV) which were managed by ondansetron 4 mg intravenously.

  
  
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  Patient satisfaction using a 3-grade scale (1 for unsatisfied, 2 for neutral, and 3 for satisfied) which was assessed on hospital discharge.

2.4

Sample size calculation

Assuming that the difference in the average time to the 1st postoperative rescue analgesia is 2.78 h between patients who received intraperitoneal bupivacaine instillation and those who received intraperitoneal bupivacaine/ dexmedetomidine instillation and the standard deviation for them is 4.13 and 3.95 respectively after laparoscopic cholecystectomy , so the sample size was calculated to be 60 patients (20 patients in each group). The sample size was calculated using MedCalc statistical software with a power of 80 % and a CI of 95.

2.5

Statistical analysis

All data were statistically analyzed using SPSS version 19. Continuous quantitative variables were expressed as the mean ± SD & median (range), and categorical qualitative variables were expressed as absolute frequencies (number) & relative frequencies (percentage).

One-way ANOVA (F test) was used to compare the studied groups of normally distributed data. The Kruskal-Wallis test was used to compare the studied groups of non-normally distributed data. Mann-Whitney test was used to compare between each two groups of non-normally distributed data separately. Categorical data were compared using the Chi-square test and Fisher exact test. All tests were two-sided and a P-value < 0.05 was considered statistically significant.