Anaesthesiology's quest for optimal perioperative care is driving anaesthesiologists to continually refine general anaesthetic techniques to both protect patients and create favourable operating and post-operative recovery environments. While general anaesthetics are the bedrock upon which much of modern surgery is based, they present multiple challenges including haemodynamic instability, the body's response to surgical trauma, insufficient intraoperative pain relief, and prolonged post-anaesthesia recovery. The development of anaesthetic techniques has evolved toward a multimodal approach, employing combinations of various agents to produce synergistic effects while limiting the negative impact of each agent.

Dexmedetomidine, ketamine, and fentanyl are among the most commonly utilised adjuvants within the realm of general anaesthesia. Since FDA approval of dexmedetomidine in 1999, it has expanded broadly into perioperative management through its stimulation of alpha-2 adrenergic receptors, producing sedation without respiratory depression, anxiolysis, analgesia, and sympathetic inhibition.¹ Ketamine, a non-competitive NMDA receptor antagonist, produces a unique form of dissociative anaesthesia characterised by profound analgesia, amnesia, and catalepsy while preserving airway protective reflexes and maintaining respiratory drive. When combined with dexmedetomidine, the complementary pharmacological profiles—sympatholysis and NMDA antagonism—may together yield haemodynamic and analgesic benefits superior to opioid-based adjuvant combinations.[2]

Fentanyl, a potent synthetic µ-opioid agonist approximately 50–100 times more potent than morphine, has been integral to balanced anaesthesia for over three decades. Its rapid onset, reliable analgesia, and well-characterised dosing paradigm make it a mainstay adjuvant; however, opioid-related adverse effects including respiratory depression, nausea, and prolonged sedation remain clinical concerns, particularly in the context of ERAS protocols. The combination of non-opioid agents such as dexmedetomidine and ketamine represents a potentially opioid-sparing strategy with a favourable perioperative profile.

Despite growing interest, direct comparative evidence evaluating dexmedetomidine-ketamine (DK) versus dexmedetomidine-fentanyl (DF) as intraoperative adjuvants in general anaesthesia during major abdominal surgery remains limited. The present prospective randomised controlled trial was therefore designed to compare these two adjuvant combinations across haemodynamic parameters, recovery characteristics, anaesthetic requirements, analgesic efficacy, and adverse event profiles, providing high-quality evidence to guide clinical practice.

Aims and Objectives

Research Question

Whether addition of ketamine or fentanyl to dexmedetomidine provides better quality of anaesthesia.

Hypothesis

Dexmedetomidine with ketamine provides better quality of anaesthesia compared to dexmedetomidine with fentanyl.

Null Hypothesis

Dexmedetomidine with ketamine does not provide better quality of anaesthesia compared to dexmedetomidine with fentanyl.

Primary Objectives

• To compare haemodynamic parameters (heart rate and blood pressure) during the intraoperative period between the two groups
• To compare recovery characteristics including emergence and agitation in the post-anaesthetic care unit between the two groups

Secondary Objectives

• To compare anaesthetic requirements during the intraoperative period between the two groups
• To compare the incidence of adverse effects in the perioperative period between the two groups
• To compare analgesic requirements during the first 24 hours after surgery between the two groups.

Review of Literature

General Anaesthesia: Principles and Adjuvants

General anaesthesia is a reversible, drug-induced state characterised by amnesia, analgesia, immobility, and attenuation of autonomic responses to noxious stimulation. The concept of Balanced Anaesthesia, first described by Lundy in the 1920s, aims to achieve effective anaesthesia using several drugs at lower doses, reducing undesirable side effects of any single agent.[3]  Adjuvant drugs—including opioids, alpha-2 agonists, and NMDA receptor antagonists—have become central to multimodal anaesthetic strategies, allowing reduction in primary anaesthetic doses while improving intraoperative haemodynamic stability, enhancing analgesia, and facilitating faster recovery.

Pharmacology of Dexmedetomidine

Dexmedetomidine (Figure 1) is the dextrorotatory S-enantiomer of medetomidine, chemically designated (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. It is a highly selective α₂-adrenoceptor agonist, 8–10 times more selective than clonidine, producing sedation via the locus ceruleus and analgesia via spinal cord α₂A receptors. Its key clinical advantages include sympatholysis, anaesthetic-sparing effects, and the absence of clinically significant respiratory depression.[4]

Figure 1: Chemical structure of dexmedetomidine hydrochloride

Figure 2: Physiology of various α₂-adrenergic receptor subtypes

Dexmedetomidine exhibits linear pharmacokinetics with a rapid distribution half-life of approximately 6 minutes, elimination half-life of 2 hours, and extensive protein binding (94%). It undergoes hepatic biotransformation via direct N-glucuronidation and CYP2A6-mediated hydroxylation, with metabolites excreted primarily in the urine.¹⁹ Its biphasic haemodynamic profile—initial transient hypertension via peripheral α₂B receptors followed by sustained hypotension and bradycardia via central α₂A receptors—is clinically important during intraoperative use.[5]

Pharmacology of Ketamine

Ketamine (Figures 3–4) is a nonbarbiturate dissociative anaesthetic, a non-competitive NMDA and glutamate receptor antagonist that uniquely preserves airway reflexes and respiratory drive while producing profound analgesia. Its sympathomimetic cardiovascular effects—mediated through inhibition of catecholamine reuptake and sympathetic nervous system stimulation—distinguish it from most other anaesthetics and make it particularly valuable in haemodynamically unstable patients.[6]

Figure 3: Structural formula of ketamine

Figure 4: Three-dimensional representation of ketamine

Ketamine is rapidly absorbed with high IM bioavailability (93%), metabolised via CYP3A4, and has an elimination half-life of 2–4 hours. At sub-anaesthetic doses it provides multimodal analgesia by preventing central sensitisation and wind-up phenomenon, justifying its growing role in opioid-sparing anaesthetic regimens.[7]

Pharmacology of Fentanyl

Figure 5: Chemical structure of fentanyl

Fentanyl is a potent synthetic µ-opioid agonist, 50–100 times more potent than morphine, rapidly crossing the blood-brain barrier due to its high lipid solubility. It is FDA approved for use as an anaesthetic adjuvant, providing rapid and reliable analgesia and blunting the cardiovascular response to laryngoscopy and surgical stimulation. Fentanyl is hepatically metabolised via CYP3A4 with an elimination half-life of 3–7 hours, with 75% urinary excretion.[8] Opioid-related adverse effects—including respiratory depression, PONV, and prolonged sedation—represent its principal clinical limitations in the perioperative context.[9]

Review of Related Articles

Junior et al. (2025)[10] conducted a systematic review and single-arm meta-analysis of 20 RCTs (n = 874) evaluating the ketamine-dexmedetomidine (KD) combination and demonstrated sustained VAS scores below 2 for 2–12 hours, mean recovery time of approximately 15 minutes, and mean PACU stay of approximately 40 minutes. Haemodynamic stability was maintained with mean MAP of 86.7 ± 8.1 mmHg and mean HR of 80 bpm. Bradycardia (9%) and hypotension (10%) occurred at modest frequencies, and PONV was reported in 17% overall.

Lodhi et al. (2023)[2] compared DK versus DF intraoperative infusions and found greater heart rate and blood pressure reduction with fentanyl, a greater tendency to hypotension in the fentanyl group, and significantly lesser PACU stay, muscle relaxant dose, and VAS scores in the ketamine group—directly informing the design of the present study.

Shirisha et al. (2024)[11] compared propofol-ketamine, propofol-fentanyl, and propofol-dexmedetomidine combinations and found significant HR and MAP reductions with propofol-dexmedetomidine versus propofol-ketamine. Propofol-ketamine provided superior and more prolonged postoperative analgesia compared to fentanyl-containing combinations.

Chun et al. (2016)[12] compared DK versus dexmedetomidine-midazolam-fentanyl (DMF) in monitored anaesthesia care and found comparable recovery times, onset times, and cardiorespiratory variables, though the DMF group demonstrated better sedation quality and satisfaction scores.

Mogahd et al. (2017)[13]  demonstrated significantly shorter weaning and extubation times and dramatically reduced fentanyl consumption (41.94 vs 152.8 μg; p < 0.0001) in the ketamine-dexmedetomidine group versus ketamine-propofol combination in post-CABG patients.

Study Design Prospective randomised controlled study, registered with the Clinical Trials Registry-India (CTRI) and conducted after obtaining Institutional Ethics Committee (IEC) clearance at R. L. Jalappa Hospital and Research Centre, Tamaka, Kolar. The study was conducted over an 18-month period from May 2024 to December 2025. Participants Fifty-four adult patients aged 18–60 years, of ASA physical status I or II, undergoing elective major abdominal surgery under general anaesthesia, were enrolled. Patients were excluded if they had cardiac arrhythmias or heart block, were on chronic beta-blockers or calcium channel blockers, long-term analgesics or sedatives, or had chronic respiratory, renal, hepatic, or psychiatric disease. Patients with a family history of prolonged neuromuscular blockade or from the Vyshya community were also excluded. Sample Size Sample size was calculated using the two-group means comparison formula: n = 2 × (zα + zβ)² × σ² / d², where zα = 1.96 (5% significance), zβ = 0.84 (80% power), σ = 0.725 mg (standard deviation from Lodhi et al., 2023), and d = 0.55 (minimum clinically important difference). This yielded a minimum of 27 patients per group, totalling 54 patients. Randomisation and Blinding Patients were randomised into two equal groups using a computer-generated random sequence concealed by the closed envelope technique. Group DK received intravenous dexmedetomidine 0.5 μg/kg/hr combined with ketamine 0.5 mg/kg/hr. Group DF received intravenous dexmedetomidine 0.5 μg/kg/hr combined with fentanyl 0.5 μg/kg/hr. Study drug infusions were prepared by an anaesthesiologist not involved in data collection or patient monitoring, ensuring blinding. Anaesthetic Technique On arrival in the operating theatre, a peripheral IV line was secured and baseline parameters recorded. Standard monitors (ECG, non-invasive blood pressure, pulse oximetry, capnography) were attached. After 3 minutes of pre-oxygenation with 100% oxygen, premedication was administered as intravenous glycopyrrolate 0.2 μg/kg, fentanyl 2 μg/kg, and midazolam 30 μg/kg. Anaesthesia was induced with propofol titrated to loss of verbal commands and muscle relaxation achieved with succinylcholine 2 mg/kg, followed by endotracheal intubation with an appropriately-sized cuffed tube. Maintenance was with 50:50 oxygen/nitrous oxide, intermittent vecuronium, and the allocated study drug infusion. The study drug infusion was discontinued 10 minutes before skin closure. Mechanical ventilation maintained tidal volume by ideal body weight; EtCO₂ was maintained between 30–35 mmHg. Outcome Measures Heart rate, MAP, SpO₂, and EtCO₂ were recorded at baseline, induction, 10 minutes post-induction, and then every 15 minutes throughout surgery and at extubation. VAS pain scores (0–10) were assessed at end of surgery and at 2, 4, and 6 hours postoperatively. Rescue analgesia (IV tramadol) was administered for VAS ≥44 at rest. Muscle relaxant dose, extubation time, Ramsay Sedation Score, PACU stay, and adverse events including bradycardia (HR <60 bpm), hypotension (MAP <65 mmHg or >20% decrease), hypertension, emergence delirium, and PONV were recorded. Statistical Analysis Quantitative variables were expressed as mean ± SD (normally distributed data) or median with interquartile range (non-normal). Qualitative variables were expressed as frequency and percentage. Between-group comparisons used the independent samples t-test (continuous variables) and chi-square or Fisher's exact test (categorical variables) as appropriate. A p-value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS software.

Demographic and Baseline Characteristics

A total of 54 patients were enrolled and randomised into Group DK (n = 27) and Group DF (n = 27). Both groups were well-matched across all baseline demographic and clinical variables with no statistically significant intergroup differences (Tables 1–5).

Table 1: Age Distribution

Chi-square test. p > 0.05, not statistically significant.

Table 2: Gender Distribution

Table 3: BMI Distribution

Table 4: ASA Physical Status

Table 5: Surgery Duration

Intraoperative Haemodynamic Parameters

Heart Rate

Baseline heart rates were comparable between groups (p = 0.179). A statistically significant progressive divergence emerged from 65 minutes, with Group DK consistently demonstrating higher heart rates through extubation and the postoperative period (Table 6).

Table 6: Heart Rate (bpm) at Each Time Point

Values are Mean ± SD. Independent samples t-test. *p < 0.05, statistically significant. DK = Dexmedetomidine + Ketamine; DF = Dexmedetomidine + Fentanyl.

Mean Arterial Pressure

MAP was comparable from baseline through 125 minutes. Significant differences emerged from 140 minutes onward, with Group DK maintaining higher values through extubation and the 2-hour postoperative period (Table 7).

Table 7: Mean Arterial Pressure (mmHg) at Each Time Point

Values are Mean ± SD. Independent samples t-test. *p < 0.05, statistically significant.

Oxygenation and Ventilation

SpO₂ remained within normal limits in both groups throughout with no statistically significant intergroup differences (Table 8). EtCO₂ was comparable at all time points; a borderline significant difference at 25 minutes (p = 0.049) was not clinically relevant (Table 9).

Table 8: Peripheral Oxygen Saturation (SpO2 %) at Each Time Point

Table 9: End-Tidal CO2 (EtCO2 mmHg) at Each Time Point

Values are Mean ± SD. *Borderline; not clinically significant. All values within acceptable capnographic limits.

Postoperative Pain — VAS Scores

VAS scores at the end of surgery and at 2 hours were comparable between groups. Significant divergence emerged at 4 and 6 hours postoperatively, demonstrating superior sustained analgesia in Group DK (Table 10).

Table 10: VAS Pain Scores (0–10) at Each Assessment Time

VAS: 0 = no pain, 10 = worst imaginable pain. *p < 0.05, statistically significant.

Muscle Relaxant Dose, Extubation Time, Sedation and PACU Stay

Table 11: Muscle Relaxant Dose

Table 12: Extubation Time Category

Table 14: PACU Stay Duration

Chi-square test. *p < 0.05, statistically significant. Group DF had significantly longer PACU stay.

Table 13: Ramsay Sedation Score (RSS) at PACU

Adverse Events

Table 15: Incidence of Adverse Events

Fisher's Exact Test. p > 0.05 for all adverse events, not statistically significant.

The present prospective randomised controlled study directly compared dexmedetomidine combined with ketamine (Group DK) versus dexmedetomidine combined with fentanyl (Group DF) as intraoperative adjuvants during general anaesthesia, evaluating haemodynamic parameters, recovery characteristics, anaesthetic requirements, analgesic efficacy, and adverse event profiles. Both groups were well-matched at baseline (p > 0.05 for all demographic variables), ensuring that observed intergroup differences are attributable to the pharmacological agents employed.

Haemodynamic Parameters

Heart Rate

In the present study, baseline heart rates were comparable (DK: 77.19 ± 8.23 bpm; DF: 74.41 ± 6.65 bpm; p = 0.179). A significant and progressive divergence emerged from 65 minutes intraoperatively, with Group DK maintaining higher heart rates at extubation (69.30 ± 6.80 vs 62.11 ± 4.56 bpm; p < 0.001) and at 2 hours postoperatively (p < 0.001). This reflects ketamine’s sympathomimetic cardiovascular properties—catecholamine reuptake inhibition maintaining sympathetic tone—in contrast to fentanyl’s vagotonic tendency producing progressive heart rate reduction when combined with dexmedetomidine’s central sympatholysis.[14] Lodhi et al.[2]  corroborate this finding, reporting greater heart rate reduction in the fentanyl group. Shirisha et al.[11] similarly noted significant HR decrease with propofol-dexmedetomidine versus propofol-ketamine. Junior et al.[10]  confirmed haemodynamic stability of the KD combination with a mean HR of 80 bpm across 20 RCTs.

Mean Arterial Pressure

MAP was comparable between groups from baseline through 125 minutes. Significant differences favouring Group DK emerged from 140 minutes onward, persisting at extubation (79.56 ± 5.42 vs 74.59 ± 6.70 mmHg; p = 0.004) and at 2 hours postoperatively (82.93 ± 7.99 vs 77.19 ± 9.26 mmHg; p = 0.018). The haemodynamic advantage of ketamine in sustaining MAP, particularly during prolonged surgery, is attributed to its sympathomimetic mechanism counterbalancing the hypotensive effects of dexmedetomidine.[13] Lodhi et al.[2] corroborate this, noting a tendency toward hypotension in the fentanyl group. Junior et al.[10] reported an overall MAP of 86.7 mmHg with the KD combination. SpO₂ and EtCO₂ remained comparable throughout, confirming the respiratory safety of both combinations.

Recovery Characteristics

Extubation time was comparable between groups (p = 0.570), with the majority of patients in both groups extubated within 6–10 minutes. Ramsay Sedation Scores at PACU were similar (DK: 2.67 ± 0.48; DF: 2.52 ± 0.51; p = 0.277). However, PACU stay duration was significantly prolonged in Group DF (p = 0.001): 55.6% of Group DK patients were discharged within 1.2 hours compared to only 7.4% in Group DF, while 40.7% of Group DF patients required ≥1.5 hours compared to only 7.4% in Group DK. This finding corroborates Lodhi et al.,[2] who also reported shorter PACU stay with the ketamine-dexmedetomidine combination. Emergence delirium occurred in 7.4% of DK versus 14.8% of DF patients (p = 0.669); the lower rate in Group DK, though non-significant, suggests that dexmedetomidine may attenuate ketamine-induced psychomimetic emergence phenomena through its sedative properties.

Anaesthetic Requirements

Group DF required a significantly higher dose of muscle relaxant than Group DK (4.07 ± 0.87 vs 3.63 ± 0.69 mg; p = 0.043), indicating a clinically relevant muscle relaxant-sparing effect with the dexmedetomidine-ketamine combination. This finding is directly corroborated by Lodhi et al.,⁴ who reported significantly lesser muscle relaxant requirement in the ketamine group. Shirisha et al.[11] confirmed that ketamine-containing and dexmedetomidine-containing combinations were more effective in reducing overall anaesthetic requirements compared to fentanyl-containing regimens.

Postoperative Analgesia

VAS scores were comparable at the end of surgery and at 2 hours postoperatively, reflecting adequate coverage by both adjuvants in the immediate perioperative period. A clinically and statistically significant divergence emerged at 4 hours (DK: 1.67 ± 0.78 vs DF: 3.89 ± 0.85; p < 0.001) and persisted at 6 hours (DK: 1.78 ± 0.80 vs DF: 4.44 ± 1.09; p < 0.001). The sustained analgesic superiority of Group DK is attributable to ketamine’s NMDA receptor antagonism preventing central sensitisation and wind-up phenomenon, an analgesic mechanism that outlasts the intraoperative period. This is consistent with Lodhi et al.,⁴ who found significantly lower VAS scores and reduced postoperative analgesic consumption in the ketamine-dexmedetomidine group; with Shirisha et al.,[11] who found early pain onset and greater analgesic need in fentanyl-containing regimens; and with Junior et al.,[10]  who demonstrated sustained mean VAS ≤2 for up to 12 hours with the KD combination.

Adverse Events

All adverse events were infrequent in both groups with no statistically significant intergroup differences. Bradycardia was more frequent in Group DF (11.1% vs 3.7%; p = 0.236), consistent with the unopposed vagotonic effect of dexmedetomidine in the absence of ketamine’s sympathomimetic counterbalance. Hypotension was more frequent in Group DF (14.8% vs 3.7%; p = 0.351), correlating with Lodhi et al.[2] observation of a greater hypotension tendency in the fentanyl group.[2] PONV was more frequent in Group DF (11.1% vs 3.7%; p = 0.610), consistent with opioid-related nausea. The low incidence of emergence delirium in both groups confirms that dexmedetomidine effectively attenuates ketamine-induced psychomimetic effects, in keeping with known pharmacodynamic synergy of the DK combination.

The present prospective randomised controlled study demonstrates that both dexmedetomidine-ketamine (Group DK) and dexmedetomidine-fentanyl (Group DF) combinations provide clinically acceptable and safe perioperative profiles. However, the two regimens differ meaningfully in several key outcomes. The dexmedetomidine-ketamine combination offered superior haemodynamic stability, maintaining significantly higher heart rate from 65 minutes intraoperatively onward and higher mean arterial pressure from 140 minutes onward through the postoperative period, thereby reducing the risk of intraoperative hypotension. It conferred a significantly lower muscle relaxant requirement, reflecting a clinically relevant anaesthetic-sparing effect, and demonstrated markedly superior postoperative analgesia at 4 and 6 hours, attributable to ketamine’s NMDA receptor antagonism preventing central sensitisation. The dexmedetomidine-ketamine combination was also associated with a significantly shorter PACU stay (p = 0.001), with 55.6% of Group DK patients discharged within 1.2 hours versus only 7.4% in Group DF. Both groups demonstrated comparable and acceptable adverse event profiles. These findings support the preferential use of dexmedetomidine-ketamine in procedures requiring prolonged intraoperative haemodynamic stability and good postoperative analgesia, while dexmedetomidine-fentanyl remains an appropriate choice where shorter procedure duration and rapid recovery of deeper sedation are prioritised. The choice of adjuvant combination should ultimately be individualised based on surgical requirements, expected postoperative pain, and institutional recovery logistics.

1. Bajwa S, Kulshrestha A. Dexmedetomidine: An adjuvant making large inroads into clinical practice. Ann Med Health Sci Res. 2013;3(4):475. doi:10.4103/2141-9248.122044

2. Lodhi M, Sulakshana S, Singh AP, Gupta BK. A comparative study of clinical effects and recovery characteristics of intraoperative dexmedetomidine infusion with ketamine versus fentanyl as adjuvants in general anaesthesia. Indian J Anaesth. 2023;67(14):S126–32. doi:10.4103/ija.ija_294_22

3. Brown EN, Lydic R, Schiff ND. General Anesthesia, Sleep, and Coma. N Engl J Med. 2010;363(27). doi:10.1056/nejmra0808281

4. Kamibayashi T, Maze M. Clinical uses of alpha2-adrenergic agonists. Anesthesiology. 2000;93(5):1345–9.

5.   Franowicz JS, Arnsten AFT. The α-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology (Berl). 1998;136(1). doi:10.1007/s002130050533

6. Buratti S, Giacheri E, Palmieri A, et al. Ketamine as advanced second-line treatment in benzodiazepine-refractory convulsive status epilepticus in children. Epilepsia. 2023. doi:10.1111/epi.17550

7. Sin B, Ternas T, Motov SM. The use of subdissociative-dose ketamine for acute pain in the emergency department. Academic Emergency Medicine. 2015;22(3). doi:10.1111/acem.12604

 8. Comer SD, Cahill CM. Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment. Neuroscience and Biobehavioral Reviews. 2019. doi:10.1016/j.neubiorev.2018.12.005

9.  Mars SG, Rosenblum D, Ciccarone D. Illicit fentanyls in the opioid street market: desired or imposed? Addiction. 2019;114(5). doi:10.1111/add.14474

10.  Junior AB, Bendazzoli PS, Ferreira Melo FW, Porto Franco RM, de Sousa Rocha EM, Matos Lima RD, et al. Efficacy and Safety of the Ketamine-Dexmedetomidine Combination in Adult Sedation and Anesthesia: A Systematic Review and Single-Arm Meta-Analysis of Randomized Controlled Trials. Cureus. 2025. doi:10.7759/cureus.97432

11. Shirisha N, Murthy TKK, Gangadhar SB. Comparative Evaluation of Propofol-Ketamine, Propofol-Fentanyl and Propofol-Dexmedetomidine in Terms of Hemodynamic Variables and Recovery Characteristics in Upper Abdominal Surgeries under General Anaesthesia. Int J Pharm Clin Res. 2024;16(8).

12. Chun EH, Han MJ, Baik HJ, et al. Dexmedetomidine-ketamine versus Dexmedetomidine-midazolam-fentanyl for monitored anesthesia care during chemoport insertion: A Prospective Randomized Study. BMC Anesthesiol. 2016;16(1). doi:10.1186/s12871-016-0211-4

13. Mogahd MM, Mahran MS, Elbaradi GF. Safety and efficacy of ketamine-dexmedetomidine versus ketamine-propofol combinations for sedation in patients after coronary artery bypass graft surgery. Ann Card Anaesth. 2017;20(2). doi:10.4103/aca.ACA_254_16

14. Mostafa M, Hasanin A, Reda B, et al. Comparing the hemodynamic effects of ketamine versus fentanyl bolus in patients with septic shock: a randomized controlled trial. J Anesth. 2024;38(6).