Peri-operative use of ketamine infusion versus dexmedetomidine infusion for analgesia in obese patients undergoing bariatric surgery: A double-blinded three-armed randomized controlled trial

Abstract

Background: The development of different techniques in bariatric surgeries has required the development of novel anesthetic techniques to reduce the incidence of complications and improve post-operative patient outcomes. Ketamine and dexmedetomidine have been used for their peri-operative analgesic profiles in different studies.

Methods: Ninety patients were studied and randomized equally into three groups. The Ketamine group received a bolus dose (0.3 mg/kg) of ketamine over 10 min followed by an infusion (0.3 mg/kg/h). The Dexmedetomidine group received a bolus dose (0.5 mcg/kg) of dexmedetomidine over 10 min followed by an infusion (0.5 mcg/kg/h). The control group received normal saline infusion. The total morphine dose was the primary outcome ,and intra-operative fentanyl requirements, time to extubation, post-operative nausea and vomiting (PONV), Numerical Rating Scale (NRS) scores, and Modified Observer’s Agitation/Sedation Scale (MOASS) scores were secondary outcomes of the study.

Results: The Dexmedetomidine group showed decreased intra-operative fentanyl requirements (160.000 ± 42.345 µcg), less time to extubation (3.700 ± 0.925 min), and better scores on MOASS than the other groups. Post-operative NRS scores and the morphine requirement in the Ketamine group (1.867 ± 2.921 mg) were lower than in the other groups. The Dexmedetomidine group showed the lowest scores for PONV.

Conclusions: The Dexmedetomidine group showed lower total fentanyl doses, a significantly shorter time to extubation, better MOASS scores, and lower PONV. The Ketamine group showed significantly lower NRS scores and morphine doses than the other two groups. Dexmedetomidine was effective on the reduction of intraoperative fentanyl requirement with early extubation, and ketamine was effective on the reduction of postoperative pain.

Trial Registration: this trail has been registered on clinicaltrials.gov registry (NCT04576975)  since 06/10/2020

Background

The various surgical interventions used for treating obesity are collectively known as bariatric surgeries. The use of bariatric surgeries has shown a universal increase for patients with medically complicated obesity who have difficulty losing weight by other methods [1].

The evolution of anesthesia techniques has allowed surgeons to provide better outcomes and safer surgical procedures for patients [2]. However, despite the advantages of anesthesia, it can have detrimental effects on the recovery of obese patients who have a high prevalence of respiratory conditions and sleep disorders [3]. The regular peri-operative use of opiates in the management of bariatric surgeries has resulted in many side effects, such as sedation, post-operative nausea and vomiting (PONV), respiratory depression, and depressed gastrointestinal motility [4]. Moreover, these side effects increase the risk of developing cardiac and respiratory complications [5].

Due to the increased sensitivity and risk of complications with the use of these drugs, their judicious use is necessary. Meanwhile, a reduction in their use may result in post-operative pain that has detrimental effects on post-operative recovery [6]. Therefore, we need to minimize opioid use and administer other drugs that, apart from having analgesic effects, also have opioid-sparing effects [7].

Ketamine is an N-methyl-D-aspartate-dependent antagonist that has analgesic and anti-hyperalgesic properties when used at low doses [8]. It can prevent the development of opioid tolerance. This benefit is evidenced by the fact that it can reduce post-operative pain and minimize the use of opioids, thereby decreasing opioid-related post-operative morbidity [9].

Dexmedetomidine is a highly selective α₂ adrenoceptor agonist used as an adjuvant to analgesia in the peri-operative period [10]. It has been shown to improve hemodynamic stability and reduce the stress induced by intubation due to its central sympatholytic action [11]. Reports also suggest that dexmedetomidine decreases opioid and anesthetic requirements, which provides additional benefits for obese patients [12].

Our study aimed to compare the analgesic effect of peri-operative use of ketamine and dexmedetomidine in patients undergoing bariatric surgeries. We hypothesized that their use could decrease the post-operative analgesic requirements, and this was the primary outcome of the study. The secondary outcomes included intra-operative analgesic requirements, post-operative sedation scores, and nausea and vomiting scores.

Materials And Methods

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:

• 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.

• 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.

• 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.

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.

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.

Results

A total of 100 patients were assessed for eligibility between April 2021 and November 2021. Ninety patients were enrolled in the study, and there were 30 patients in each group. Four patients were excluded as they refused to participate, three patients because of a history of psychiatric problems, and three because of uncontrolled medical conditions (two cases of uncontrolled DM and one case of uncontrolled HTN) (Fig. 1).

A comparison between the three groups concerning personal data did not show statistically significant differences in terms of sex, medical conditions, or BMI (Table 3). Males represented 43.3% of the studied population. DM was a major disease in all groups with a prevalence of 47.78%. HTN was next most common at 34.44% and hypothyroidism occurred in 12.22%. When compared with the other groups, the mean age of patients was the highest in the Ketamine group (36.967 ± 4.247 years).. However, the BMI of patients in the Dexmedetomidine group (42.900 ± 4.452 kg/m2) was found to be the highest.

Concerning the surgery duration, there were no statistically significant differences between the three groups (Table 4). The mean surgery duration was higher in the control group (88.167 ± 16.582 min) than that in the other two groups.

The Ketamine group showed higher MAP readings most of the time (Fig. 2). There was no statistical difference in MAP readings between the Dexmedetomidine and control groups. On the other hand, the HRs recorded in the Dexmedetomidine group were significantly lower than in the other two groups (Fig. 3).

The total fentanyl doses were significantly lower in the Dexmedetomidine group than in the two other groups (Table 5). The mean dose administered in the Ketamine group was lower than in the control group (160.000 ± 42.345 µcg vs. 186.667 ± 55.605 µcg), but the difference was not statistically significant. Time to extubation was significantly shorter in the Dexmedetomidine group than in the other two groups (Table 5).

With regard to the MOASS score, the Dexmedetomidine group showed better scores (around 5) on the MOASS than the other two groups, especially in the first 10 min (statistically significant at 0 and 10 min) (Table 6) (Figs. 4–6). The values of patients at 30 and 60 min after observation in all three groups equally returned to normal.

NRS scores were significantly lower in the ketamine group than in the two other groups (Table 7) (Figs. 7–9). This was reflected in the total morphine consumption, with the ketamine group showing a mean dose of 1.867 ± 2.921 mg, which was significantly lower than that observed in the two other groups (Table 8) (Fig. 10).

Our study showed that PONV scores were lower in the Dexmedetomidine group than in the Ketamine and control groups (Table 9) (Figs. 11–13). This result was statistically significant at 12 h post-operatively. There were no statistically significant differences at any other points in time.

Discussion

Around half a million procedures are performed globally as treatments for obesity each year. Most of these procedures are performed under laparoscopy [14]. High levels of post-operative pain remain common following these procedures [15].

With multiple system changes and a co-morbidity burden, patients with morbid obesity (MO) are prone to experiencing significant morbidity and adverse effects when it comes to managing their pain [16]. They require a more comprehensive approach to pain management [16]. Current literature supports the use of systemic analgesics and highlights the need for further research in the pharmacological, regional, and non-pharmacological management of acute pain in patients with MO [17].

A study conducted by Garg et al. demonstrated that both ketamine and dexmedetomidine in small infusions provide good and safe analgesia, decrease morphine requirements, and increase the pain-free period during the post-operative period in patients undergoing spine surgeries [18].

There was no clinical or statistical difference between patients in the three groups in our study in terms of demographic data. The most common diseases among the studied population were DM and HTN, which are correlated with obesity as part of the metabolic syndrome. Hypothyroidism was the next most common disease that may contribute to the development of obesity.

There was no statistical difference in the surgery duration between the studied groups. Intra-operative MAP comparison between the three groups showed higher trends in the Ketamine group than in the Dexmedetomidine and control groups. Conversely, the HR readings were very similar between the Ketamine and control groups. This observation suggests that the sympathomimetic action of ketamine does not preclude an analgesic effect. HR readings were significantly lower in the Dexmedetomidine group, which was predominantly due to decreased sympathetic outflow; this finding supports its analgesic effect. There were no significant drops in blood pressure or HR in any of the groups. We suggest that both drugs can maintain stable hemodynamics during surgery.

Unlike in the study by Zeeni et al., we did not find an initially high blood pressure reading in the Dexmedetomidine group. However, lower HRs were recorded in the Dexmedetomidine arm of their study. This finding may be attributed to the fact that an additional loading dose of dexmedetomidine was administered [19].

We could not identify any studies in the literature that compared the effect of ketamine infusion with placebo in terms of the effect of Ketamine infusion on vital data in patients undergoing similar surgical procedures. More studies are needed to assess the effect of ketamine on intra-operative vital data. In the current study, the intra-operative analgesic requirement was significantly lower in the Dexmedetomidine group than in the other groups. Ketamine was associated with a lower fentanyl dose requirement. We suggest that this finding may be due to the sympatholytic action of dexmedetomidine.

A study conducted by Bakhamees et al. on morbidly obese patients undergoing laparoscopic bypass surgery found a similar decrease in the intra-operative fentanyl requirement in the Dexmedetomidine group than in the control group, and this was consistent with our finding [20]. A trial comparing ketamine infusion to morphine infusion as analgesia in obese patients undergoing abdominoplasty surgery performed by Ali et al. showed higher intraoperative analgesic requirements in the form of higher fentanyl doses in comparison with controls; this was contradictory to our findings. We suggest that the main difference may be due to the different infusion dose regimens between our study and that of Ali et al. [21].

Our study showed a significantly lower time to extubation in the Dexmedetomidine group than in the two other groups. However, this difference is not of clinical significance. On the other hand, the Dexmedetomidine group showed better scores (around 5) in the post-operative sedation assessment (MOASS), and again, the difference in scores was not of clinical significance. All patients in all groups returned to normal alertness within 60 min. We did not observe any severe emergency or agitation during recovery from anesthesia.

Zeeni et al. studied the effect of dexmedetomidine on post-operative sedation scores in comparison with a group receiving morphine infusion in laparoscopic surgery and showed no significant difference in scores [19]. A study conducted by Tufanogullari et al. showed that there was no difference between three regimens of dexmedetomidine infusion with the control group in terms of the drug effects on post-operative sedation and time to extubation. These findings were also demonstrated in our study [22]. Ali et al. compared the effect between ketamine and morphine infusion for post-operative sedation. There was no difference in effect between the Ketamine group and the other groups, similar to our study [21].

The NRS scores correlated with the need for morphine as rescue analgesia in the post-operative period. NRS scores in the Ketamine group were significantly lower at most points of time than in the two other groups. Our primary outcome was the effect of ketamine and dexmedetomidine on the total morphine requirement 24 h post-surgery. We found that the Ketamine group had the lowest morphine doses with a mean of 1.867 ± 2.921 mg. The Dexmedetomidine group had a lower dose requirement than the control group, although it was not clinically significant; however, we cannot ignore the benefits of reduced post-operative morphine requirements.

In a study conducted by Mehta et al., which compared a Ketamine infusion group to a control group of patients undergoing laparoscopic bariatric surgery, assessment of oral morphine equivalent doses revealed a significant decrease in post-operative analgesic requirements in the Ketamine group when compared with those in the control group. This finding was consistent with our results [23].

Tufanogullari et al. were able to demonstrate reduced total post-operative morphine doses in patients undergoing laparoscopic bariatric surgery who received three different regimens of dexmedetomidine infusion compared with control patients. We demonstrated the same findings [22]. Moreover, our study demonstrated that dexmedetomidine infusion reduced PONV scores compared with that observed in the two other groups, suggesting that dexmedetomidine has an anti-emetic effect during the post-operative course.

Hussein and Mostafa were able to show that among patients undergoing bariatric surgeries, those treated with dexmedetomidine had reduced PONV as opposed to those in the control group [24]. In addition, a systematic review conducted by Brinck et al. showed that although it is not yet clear if the effect is clinically significant, peri-operative IV ketamine was generally considered to reduce PONV. Our study failed to show a decrease in PONV scores in the ketamine group contrast to those in the other groups; however, we argue that the difference in scores is of little clinical significance [25].

We did not observe any serious post-operative complications such as post-operative airway obstruction, life-threatening hypoxic events, or serious PONV.

Limitations

The major limitation of our study was that we did not include a pre-operative assessment of confounding factors that may affect the need for analgesia, such as depression or pre-existing painful conditions. A long-term assessment of the effect of these factors on post-operative pain is needed.

Conclusion

Ketamine and dexmedetomidine can provide good pain control in morbidly obese patients undergoing bariatric surgeries. Dexmedetomidine has been shown to result in better outcomes in the intra-operative period while ketamine has been shown to improve analgesia in the post-operative period. Dexmedetomidine may provide a better post-operative recovery profile in terms of sedation and PONV.

Abbreviations

BMI, body mass index

DM, diabetes mellitus

HR, heart rate

HTN, hypertension

IBW, ideal body weight

IV, intravenous

LBW, lean body weight

MAP, mean arterial pressure

MO, morbid obesity

MOASS, Modified Observer’s Agitation/Sedation Scale 

NRS, Numerical Rating Scale 

PONV, post-operative nausea and vomiting

TBW, total body weight

Declarations

Ethics approval and consent to participate 

The study was approved by the Research Ethics Committee 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. Informed consent was obtained from patients who met the criteria for enrollment.

Consent for publication 

Not applicable. 

Availability of data and materials 

The data collected during the study from deindividualized participants will be shared with researchers. Materials including the study protocol, informed consent forms, and statistical analysis plan will be made available for use after a review of the study’s methodology.

Request for access to patient data should be sent to the corresponding author. The study management committee will then review the requests and determine if the authors should be granted access to the data. To gain access to the data, researchers must first sign a data access agreement. This agreement should specify that the data will only be used for the purpose that was agreed upon.

Competing interests 

The authors declare that they have no competing interests.

Funding 

None.

Authors' contributions 

Belal Nabil Mahfouz Khalil: This author contributed to conceptualization, study design/planning, data collection, data analysis and writing manuscript.

Maha Sadek Hussein Elderh: This author contributed to study design/planning, data collection, data analysis and writing manuscript.

Mohamed Abdel Rasoul Khaja: This author contributed to study design/planning and data collection.

Ahmed Nagah El-Shaer: This author contributed to data analysis and writing manuscript.

Bahaa El-Din Ewees Hassan Ali: This author contributed to data analysis and writing manuscript.

Mohamed Osman Awad Taeimah: This author contributed to study design/planning, data collection, data analysis and writing manuscript.

Acknowledgments 

We would like to thank the patients who participated in the study.

Authors' information

• Belal Nabil Mahfouz Khalil, FCAI , MCAI , M.Sc. - Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt - ORCID ID : https://orcid.org/0000-0001-9544-2538
• Maha Sadek Hussein Elderh, M.Sc., PhD. - Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt - ORCID ID : https://orcid.org/0000-0002-9879-750X
• Mohamed Abdel Rasoul Khaja, FCARCSI - Anesthesiology and Intensive Care Department , Jahra Hospital , Jahra, Kuwait – ORCID ID: https://orcid.org/0000-0002-8320-8995
• Ahmed Nagah El-Shaer, M.Sc., PhD. - Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt 
• Bahaa El-Din Ewees Ali Hassan , M.Sc., PhD. - Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt - ORCID ID : https://orcid.org/0000-0003-1318-2803
• Mohamed Osman Awad Taeimah - Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt - ORCID ID : https://orcid.org/0000-0002-4283-8560

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