The study was conducted at Almashfa Medical Center in Alkhobar Saudi Arabia between March and August 2020 (ClinicalTrials.gov: NCT04285255; registered Study Chair: Mohamed Ibrahim; registration date: February 2020). Approval was provided by the Almashfa ethics committee (Chairperson Dr. Mohamed Ramadan) on January 20, 2020, under the number 1/1-2020. The trial was registered before patient enrollment. A hundred and eight patients provided written informed consent to enter the trial before undergoing laparoscopic sleeve gastrectomy. This manuscript adheres to the applicable Equator guidelines.
2.1 Study Design
A single-blinded randomized control trial was designed using the sealed envelope method and computer-generated random numbers were kept with a pharmacist. The original random allocation sequence was locked and a copy was used instead. A non-participant nurse anaesthetist prepared syringes with the study medications (propofol, ketamine, dexmedetomidine, lidocaine, and bupivacaine for oblique subcostal transversus abdominis plane (OSTAP) block and placed them into opaque envelopes according to the allocation orders (fig.1).
The patient, surgical team, operating theatre staff, PACU, and surgical ward nurses were blinded to both groups. The anesthesiologist or principal investigator was the only individual aware of patient allocation and administered anaesthesia to all study patients. Sealed envelopes were labelled as multimodal analgesia (MMA) or Opioid free anaesthesia (OFA) and envelopes were only opened upon patient entry into the operating theatre.
Eligible patients included adult patients between the age of 18 and 65; Body mass index between 40 and 60; American Society of Anesthesia (ASA) class II or III; planned for elective laparoscopic
sleeve gastrectomy through trocars positioned at or above the umbilicus (T10 dermatome). Exclusion criteria included preoperative chronic use of opioid or NSAID; allergy to bupivacaine; local skin infection at the injection site of OSTAP (oblique subcostal transverse abdominis plane block); liver or renal insufficiency; psychiatric, or neurological disease; prior open abdominal surgery above T10 dermatome; patients converted to open surgery; and patients expected to be subjected to more tissue trauma.
A team of a single anesthesiologist and surgeon standardized the preoperative workup, patient preparation; and arranged appropriate referrals to medical services for comorbidity optimization. Patients received preoperative teaching on how to mark a point on a 100 mm numerical rating scale (NRS) with 0 = no pain, to 100mm = the worst imaginable pain at the specified time. All operations were performed using a standardized technique. An investigator blinded to both study groups was trained to interview patients and fill the quality of recovery 40 questionnaires (QoR-40) at six and 24 hours postoperatively.
2.2 Enhanced recovery and anaesthesia protocol:
A dedicated bariatric coordinator provided preoperative teaching to patients and caregivers about the QoR-40 questionnaire and total plan of care: Preoperative oral fluids were encouraged and patients were instructed to take 100 mg carbohydrate loading at midnight, and another 50 mg two hours before surgery. Patients were premedicated with intravenous (IV) midazolam 25 µg.kg-1 in the preoperative holding area. Normothermia was maintained, and sequential pneumatic compression was applied before the start of surgery.
Following maximal pre-oxygenation (end-tidal oxygen > 90% ), general anaesthesia was induced using IV propofol 2 mg. kg-1 and fentanyl 1 µg. kg-1 in patients in the MMA group while patients in the OFA group were premedicated with IV dexmedetomidine 0.1 µg.kg-1 in 100 ml normal saline over 10 minutes then induced with propofol (2 mg. kg-1) -ketamine (0.5 mg. kg-1) mixture and maintained on dexmedetomidine 0.5µg. kg-1.h-1 , ketamine 0.5 mg.kg-1.h-1, and lidocaine 1 mg. kg-1.h-1 each prepared in 50 ml normal saline to run at a rate of 50 ml.h-1. Cisatracurium (0.15 mg.kg-1) was used in both groups for muscle relaxation. Dosage was based on the ideal body weight using the Devine formula [16].
All Patients underwent endotracheal intubation and placement of a 36 French gastric calibration tube under video laryngoscopic guidance. Ultrasound-guided bilateral oblique subcostal transverse abdominis plane (OSTAP) block was performed in all patients using 40 ml of 0.25% bupivacaine hydrochloride (Marcaine, Astra Zeneca UK) following intubation. Anaesthesia was maintained using Sevoflurane to 1.5-2.0 minimum alveolar concentration in air/oxygen with fractional inspired oxygen of 0.6, and a bispectral index (BIS) range between 40 and 60 in all patients. Standard ASA monitoring of patients included ECG, heart rate, pulse oximetry, non-invasive blood pressure, end tidal Co2 (Etco2) and core temperature monitoring.
The Ventilator was set to maintain normocapnia of 35-45 mmHg and Spo2 between 94-100%. All patients received parecoxib 40 mg IV after induction, and 1 gm of paracetamol IV around 15 minutes before extubation. Furthermore, patients received dual intravenous antiemetic therapy with 8 mg of ondansetron, and 8 mg of dexamethasone.
Intraoperative hemodynamic parameters (MAP and heart rate) were recorded at 5-minute intervals. Baseline values were taken 5 minutes after induction and a 15% rise in the MAP or HR prompted the administration of a 20µg fentanyl bolus in the MMA group versus a 10 mg bolus of labetalol in the OFA group. Duration of surgery was defined as the time from the first incision to the completed wound dressing. After surgery, the reversal of neuromuscular blockade was administered to achieve a TOF of 0.9. Extubation time was defined as the time between the end of surgery and endotracheal extubation.
In the PACU, nurses blinded to the two groups administered 15 mg of pethidine if the NRS was between 4-6 (moderate pain) versus 30 mg if the NRS was greater than 7 (severe pain). The pain was assessed at 5-minute intervals until pain relief was achieved (NRS ≤3). Total pethidine dose in the PACU was recorded. The level of sedation was assessed 15 min after arrival to the PACU according to the Ramsay score [17]. Low saturation (<94%), obstructed breathing, shivering or feeling cold, and duration of PACU stay were also recorded. Patients were discharged from the PACU if they achieved a modified Aldrete score of ≥ 9 [18].
In the ward, all patients received 1 gram of IV paracetamol 6 hourly, and 40 mg IV parecoxib 12 hourly. Patients were asked about their level of pain using NRS on arrival to the ward (0h), 2h, 4h, 6h, 12h, and 24h postoperatively. A 25 mg pethidine intravenous bolus was administered if NRS ≥ 4, and the pain was reassessed at 15min intervals. Additional intravenous boluses of 10 mg of pethidine were given till the NRS score dropped below 4. Intravenous 4 mg of ondansetron and or 10 mg of metoclopramide were administered to treat nausea or vomiting.
Patients were encouraged to ambulate, start oral ice chips, and void within 2 hours from arrival to the ward. The timing of the first rescue analgesic dose or need for antiemetic therapy in the ward were recorded as well as further doses during the 24-hour stay.
Primary Outcome: A blinded investigator trained on the QoR-40 interviewed patients and completed the form at 6 and 24 hours from patient arrival to the ward. Twelve questions measured the comfort state; 9 questions measured the emotional state; 7 questions measured the psychological state; 5 questions measured the physical independence and 7 questions measured the level of pain and each question received a score of 1 to 5. The worst possible score was 40 and the best possible score was 200 [15].
Secondary outcome: Time to first independent ambulation, time to tolerate oral fluids, and time to readiness for discharge were measured according to the modified postoperative discharge scoring system (PADSS) [19]. The Blinded investigator-assessed patient readiness for discharge according to PADSS on an hourly basis and documented the time to achieve discharge eligibility in minutes. Patients were considered eligible for discharge if they achieved a total score ≥ 9 on the condition that the vital signs parameter score was not less than 2, and none of the other five parameter scores was a zero.
Numerical rating scale (NRS) in the PACU, and at 0 (arrival to the ward), 2, 4, 6, 12, and 24 hours postoperatively were recorded. Total pethidine consumption during the 24 hours was calculated as an equivalent oral morphine dose. Pethidine dose (as morphine equivalent dose) in the recovery unit (PACU) and time of first rescue analgesic dose in the ward were also recorded.
Intraoperative hemodynamic parameters, surgical time, extubation time, PACU stay, and postoperative nausea and vomiting in the PACU, and in the ward were also documented.
2.3 Statistical analysis:
Statistical analysis was done using IBM-SPSS 20 software (IBM Corp., Armonk, N.Y., USA). Prior published studies on heterogeneous patients undergoing cardiac, general, and neurosurgical procedures have suggested a 3.2% difference in the QoR-40 score to be of clinical significance which we have used in calculating our sample size [20]. Adoption of ERAS in MMA and the use of OSTAP block has already improved the quality in minimally invasive surgery and particularly in bariatric surgery above the 90 percentile in almost all patients. Most of the work nowadays must focus on improving the remaining 10% of the score. A difference of 1.5% in the score will mean a 15% improvement in the non-achieved score and would probably be statistically significant but we will only consider a statistical difference of significance if it results in change and we have chosen the time to discharge a target of ERAS, as the indicator of the relevance of any statistical difference we come to. A sample size of 43 patients in each arm had a 90% power to detect the 3.2% difference in the mean score and a 3.5% standard deviation at an alpha of 0.05 using a two-sided two-sample equal-variance t-test. Fifty-four patients were recruited in each arm assuming a 20% drop-out rate.
Data were presented as median, range, and interquartile range (IQR) or mean and SD when appropriate. The normality of distribution was assessed by Shapiro- Wilk test and Q-Q plot. Mann–Whitney–Wilcoxon test was used to analyze morphine consumption since it was not normally distributed. Normally distributed data were analyzed using an independent sample t-test. Categorical data were analyzed using the chi-square (χ2) test.