This prospective, randomized, double-blinded, three-armed, controlled trial was registered at clinicaltrial.gov (NCT04576975) in 6/10/2020 and reported according to the CONSORT guidelines. The study was approved by the Research Ethics Committee (REC) at the Faculty of Medicine, Ain Shams University (FMASU M D 108 /2020) on 14/6/2020. All procedures were conducted in accordance with the Helsinki Declaration, 2013.
The required sample size was calculated using G*power software version 3.1.0. The study required a minimum of 22 patients in each group to detect an effect size of 0.4 for mean morphine consumption in the three groups, with a power and type I error of 0.8 and 0.05, respectively. The number was increased to 30 patients in each group to compensate for the potential dropout, failure rate, and skewness.
After ethical approval, patients who were scheduled for elective laparoscopic sleeve gastrectomy were interviewed by one of our team members. We enrolled patients aged between 21 and 45 years of either sex, with a body mass index (BMI) > 35 kg/m2, and an American Society of Anesthesiologists physical status class of II or III. Patients with a history of hypersensitivity to dexmedetomidine and/or ketamine, history of substance abuse (benzodiazepines) or chronic opioid use, psychiatric or seizure disorder, uncontrolled hypertension (HTN) (systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg) or heart block, and uncontrolled diabetes mellitus (DM) (HbA1c ≥ 8.5%) were excluded from the study. Informed consent was obtained from patients who met the criteria for enrollment. Blinding of patients and random assignment to a group were achieved by allotting serial numbers to patients using a computer program (Microsoft Excel 365). All syringes were prepared by the pharmacy, coded, and labeled. The infusion was performed using an infusion pump (CareFusion Alaris CC MKIII®, Alaris Medical Systems, Hampshire, UK) for all groups. All infusion rates were determined by an independent pharmacist who was not associated with the study. Investigators were blinded to group assignments and drug coding.
All patients were assessed preoperatively, and age, sex, BMI, and type of surgery were noted. All basic investigations were performed according to our hospital protocol (e.g., fasting blood glucose level, HbA1c, thyroid profile, complete blood count, kidney function tests, liver function tests, chest radiographs, and electrocardiogram) were reviewed before the day of operation. When patients entered the pre-anesthesia unit, they were premedicated with intravenous (IV) midazolam (20 µcg/kg, total body weight [TBW]) and IV atropine (0.015 mg/kg, lean body weight [LBW]). Patients were randomly divided into three groups:
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Group 1 (Ketamine group): This group received a bolus dose of 0.3 mg/kg ketamine (Ketamine HCL; Sterop, Brussels, Belgium) according to the ideal body weight (IBW), diluted with 0.9% normal saline (NS), administered over a 10-min period via a 20-mL syringe infused before induction. Then, ketamine infusion (500 mg vial diluted in a 50-cc infusion syringe, concentration 10 mg/mL) was started at the rate of 0.3 mg/kg/h until 10 min prior to the end of the surgery.
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Group 2 (Dexmedetomidine group): This group received a bolus dose of 0.5 µcg/kg dexmedetomidine (Precedex®; Hospira, Birmingham, AL, USA) according to the IBW, diluted with 0.9% NS, administered over a 10-min period, via a 20-mL syringe infused before induction. Then, dexmedetomidine infusion (200 µcg vials diluted in a 50-cc infusion syringe, concentration 4 µcg/mL) was started at a rate of 0.5 µcg/kg/h until 10 min prior to the end of the surgery.
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Group 3 (Control group): This group received a bolus dose of 0.9% NS over a 10-min period via a 20-mL syringe infused before induction. Then, 0.9% NS (50 mL in a 50-cc syringe) was infused.
General anesthesia was induced with intravenous lidocaine 0.5 mg/kg (IBW), propofol 1.5 mg/kg (LBW), fentanyl 1 µg/kg (TBW), and rocuronium 1.1 mg/kg (IBW) to facilitate rapid sequence endotracheal intubation. No cases of failed intubation were observed in our study. Rocuronium was given every 30 minutes and its effect was monitored using Neuromuscular Testing keeping the Train-of-Four between 0 and 1. General anesthesia was maintained with sevoflurane in an oxygen and air mixture guided by a Bispectral Index Score between 40 and 60. Patients were mechanically ventilated with the maintenance of normocapnia (end-tidal CO2 35–40 mmHg). Intra-operative vital data were recorded every 5 min.
If hypotension (defined as a mean arterial pressure [MAP] value < 20% of the baseline as shown by two consecutive readings within 5 min not responding to a 1% decrease in the inspired sevoflurane concentration) occurred, a crystalloid fluid bolus of 20 mL/kg was administered for 2 min, and then, ephedrine was administered in 6-mg increments. For bradycardia (defined as a heart rate [HR] below 60 mmHg for ≥ 1 min), atropine 0.5 mg was administered as determined by the anesthesiologist.
Intra-operative pain was defined as the development of HTN and tachycardia despite adequate anesthesia and muscle relaxation. HTN was defined as an MAP value greater than 20% of the baseline value on two consecutive readings within 5 min. Tachycardia was defined as an HR value of more than 20% of the baseline value for 5 min. A rescue dose of fentanyl increments was administered (0.5 µcg/kg TBW). The total number of fentanyl doses was calculated.
Upon awakening, the patient received sugammadex (2 mg/kg) with a repeated dose of 4 mg/kg after 5 min if needed for muscle relaxant recovery. The time taken for tracheal extubation after the discontinuation of anesthesia was noted.
All patients were monitored post-operatively in the post-anesthesia care unit and ward. They were assessed for sedation scores using the Modified Observer’s assessment of alertness/sedation scale [MOAS/S] (Table 1). The score was recorded at 0, 10, 30, and 60 min from admission to PACU.
Table 1
Modified Observer's Assessment of Alertness/Sedation scale
Responsiveness | Score |
Agitated | 6 |
Responds readily to name spoken in a normal tone (alert) | 5 |
Lethargic response to name spoken in a normal tone | 4 |
Responds only after the name is called loudly and/or repeatedly | 3 |
Responds only after mild prodding or shaking | 2 |
Does not respond to mild prodding or shaking | 1 |
Does not respond to deep stimulus | 0 |
The patients were assessed for post-operative pain using the Numerical Rating Scale (NRS) with a score of 0 representing no pain and 10 representing the worst pain ever. The patients were informed preoperatively about the use and values of the NRS. The NRS score was recorded at 0, 30, and 60 min and 2, 6, 12, and 24 h after the surgery.
All patients received IV paracetamol (1 g Perfalgan®; Bristol-Myers Squibb, Munich, Germany) every 6 h for 24 h post-operatively. A rescue dose of 4 mg morphine IV with a minimum 6-h interval was administered between doses if the NRS score was ≥ 4 if needed. The total doses of morphine were calculated.
All patients were assessed for PONV using the PONV intensity scale (Table 2). Assessments were performed at 0, 6, 12, and 24 h after recovery from general anesthesia. Ondansetron (4 mg Zofran®; GlaxoSmithKline, Rockville, ML) was administered if the patient developed an intense sensation of nausea and repeated after 30 min if required.
Table 2
Post-operative Nausea and Vomiting intensity scale
Have you vomited or had dry retching? * | No | 0 |
Once or twice | 1 |
Three or more | 50 |
Have you experienced a feeling of nausea (“an unsettled feeling in the stomach and slight urge to vomit”)? If yes, has your feeling of nausea interfered with activities of daily living, such as being able to get out of bed, being able to move about freely in bed, being able to walk normally, or eating and drinking. | No | 0 |
Sometimes | 1 |
Often or most of the times | 2 |
All the time | 25 |
How has your nausea been mostly? | Varying “comes and goes” | 1 |
Constant “nearly or almost always present” | 2 |
What was the duration of your feeling of nausea (in hours [whole or fraction])? | ____: ____ h | |
*Count distinct episodes: several vomits or retching events occurring over a short time frame, say 5 min, should be counted as one vomiting/dry-retching episode; multiple episodes require distinct periods without vomiting/dry-retching [13] |
Post-operative complications (such as airway obstruction, development of hypoxia, serious nausea, respiratory depression, and vomiting) were recorded.
Data were coded, tabulated, and analyzed using an SPSS software package (SPSS for Windows®, Version 16.0. Chicago, SPSS Inc.). The numerical variables are presented as mean (standard deviation) or median (Q3-Q1) and were compared using a one-way analysis of variance or the Kruskal-Wallis test as appropriate. Categorical variables are presented as frequency (%) and were compared using the Chi-square test. Multiple pairwise comparisons were performed, whenever indicated, using the Tukey HSD test, Mann–Whitney test, or Chi-square test, as appropriate. A difference with a p-value < 0.05 was considered statistically significant and a Bonferroni correction was applied when necessary.