The stress response to anesthesia and surgery is a complex neuroendocrine, metabolic, and hemodynamic phenomenon triggered by tissue injury, anxiety, and nociceptive stimuli. It manifests as increased sympathetic activity, elevated plasma catecholamines, cortisol, and inflammatory mediators, ultimately leading to tachycardia, hypertension, hyperglycemia, and altered immune responses. While this response is a physiological mechanism aimed at maintaining homeostasis, its exaggeration-particularly in vulnerable populations-can lead to perioperative complications such as myocardial ischemia, arrhythmias, and delayed recovery. Therefore, attenuation of this stress response has long been a central objective of modern anesthetic practice. Premedication forms an essential component of the anesthetic plan, designed to allay anxiety, provide sedation, facilitate smooth induction, and blunt the autonomic and endocrine response to surgical stress. Benzodiazepines, opioids, and α2-adrenergic agonists have been traditionally employed to achieve these goals. Among these, Midazolam, a short-acting benzodiazepine, has enjoyed wide popularity due to its anxiolytic, amnestic, and sedative properties with a favorable safety profile. However, its limited sympatholytic effect and potential for respiratory depression have enc aged exploration of alternative premedicants.[1][2] Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, has emerged as an effective agent providing sedation, anxiolysis, analgesia, and sympatholysis without significant respiratory depression. It acts by stimulating presynaptic α2-receptors in the locus coeruleus, reducing norepinephrine release, and thereby suppressing sympathetic outflow. The result is stable hemodynamics, reduced anesthetic and opioid requirements, and enhanced perioperative cardiovascular control. Dexmedetomidine also reduces circulating catecholamines and cortisol levels, reflecting attenuation of the stress response at both central and peripheral levels.[3] Surgical stress begins before induction, as preoperative anxiety itself triggers increased sympathetic tone and cortisol release. Thus, effective premedication is crucial not only for patient comfort but also for minimizing the adverse effects of this neuroendocrine surge. Midazolam, while effective for anxiolysis, does not sufficiently blunt sympathetic and hormonal responses during laryngoscopy and intubation-moments that produce maximal hemodynamic fluctuation. Dexmedetomidine, by contrast, provides cooperative sedation with cardiovascular stability and has been shown to reduce the pressor response to intubation, incision, and extubation. Its sedative profile mimics natural sleep, and its analgesic-sparing effect further reduces perioperative stress.[4] Aim To compare the efficacy of Dexmedetomidine and Midazolam as premedication agents in attenuating the perioperative stress response. Objectives 1. To compare the effects of Dexmedetomidine and Midazolam on hemodynamic parameters (heart rate, blood pressure) during induction and intubation. 2. To evaluate and compare the changes in serum cortisol levels following premedication with Dexmedetomidine and Midazolam. 3. To assess and compare the sedation levels, anxiolysis, and recovery profile between the two groups.

Source of Data: The study was conducted among patients scheduled for elective surgical procedures under general anesthesia at the Department of Anesthesiology, at GMC and SSH, Nagpur. Study Design: A prospective, randomized, double-blind, comparative study. Study Location: Department of Anesthesiology, at GMC and SSH, Nagpur. Study Duration: The study was conducted over a period of 12 months. Sample Size: A total of 200 patients were enrolled and randomly divided into two equal groups: • Group D (n = 100): Received Dexmedetomidine as premedication. • Group M (n = 100): Received Midazolam as premedication. Inclusion Criteria: 1. Adult patients aged 18–60 years. 2. ASA physical status I and II. 3. Patients scheduled for elective surgical procedures under general anesthesia. 4. Patients providing written informed consent. Exclusion Criteria: 1. Patients with cardiovascular, hepatic, or renal dysfunction. 2. Patients with bradyarrhythmias or conduction abnormalities. 3. Patients on β-blockers, α2-agonists, or psychotropic drugs. 4. Pregnant and lactating women. 5. Known hypersensitivity to study drugs. 6. Refusal to participate in the study. Procedure and Methodology: After obtaining institutional ethics committee approval, patients were randomly allocated into two groups using computer-generated randomization. Both the anesthesiologist administering the drug and the observer recording parameters were blinded to the group allocation. Baseline parameters-heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), oxygen saturation (SpO₂), and electrocardiogram (ECG)-were recorded preoperatively. • Group D received intravenous Dexmedetomidine 1 μg/kg diluted in 20 ml normal saline, infused over 10 minutes, 15 minutes before induction. • Group M received intravenous Midazolam 0.05 mg/kg diluted in 20 ml normal saline, infused over 10 minutes, 15 minutes before induction. Following premedication, sedation level was assessed using the Ramsay Sedation Scale. Hemodynamic parameters (HR, SBP, DBP, MAP) were recorded at baseline, after premedication, during induction, 1 minute after intubation, 5 minutes after intubation, and every 10 minutes thereafter. Induction of anesthesia was achieved using propofol (2 mg/kg) and succinylcholine (1.5 mg/kg) to facilitate intubation. Maintenance was done using oxygen, nitrous oxide, and isoflurane with vecuronium for muscle relaxation. Intraoperative hemodynamics were monitored continuously. Any hypotension (MAP < 60 mmHg) was managed with fluids or mephentermine; bradycardia (HR < 50 bpm) was treated with atropine 0.6 mg IV. Venous blood samples were drawn at baseline (pre-premedication), 15 minutes after premedication, and 60 minutes after induction to measure serum cortisol levels using standard chemiluminescent immunoassay techniques. Blood glucose and oxygen saturation were also recorded. At the end of surgery, reversal was achieved with neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg). Recovery characteristics were assessed using the Modified Aldrete Recovery Score. Side effects such as nausea, vomiting, bradycardia, hypotension, and respiratory depression were noted. Sample Processing: Serum cortisol levels were analyzed in the hospital’s central biochemistry laboratory. Samples were centrifuged at 3000 rpm for 10 minutes, serum separated, and stored at -20°C until analysis. All assays were performed in duplicate to ensure reliability. Data Collection: Data were recorded in a predesigned proforma including demographic profile, baseline vitals, drug dosage, intraoperative hemodynamics, cortisol levels, sedation and recovery scores, and adverse events. Statistical Methods: Data were entered into Microsoft Excel and analyzed using SPSS software version 26. Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables as frequency and percentage. • Student’s t-test was used for intergroup comparison of quantitative variables (e.g., heart rate, cortisol). • Repeated-measures ANOVA was used for intra-group comparison over time. • Chi-square or Fisher’s exact test was used for categorical data. A p-value < 0.05 was considered statistically significant, and < 0.01 highly significant.

Table 1: Primary efficacy outcomes (attenuation of peri-operative stress response) Variable Dexmedetomidine (n=100) n(%) or Mean ± SD Midazolam (n=100) n(%) or Mean ± SD Test of significance Effect size & 95% CI p-value ≥20% rise in HR within 1 min of intubation 19 (19.0%) 41 (41.0%) χ²(1)=10.84 RD -22.0% (-34.9% to -9.1%) 0.0010 ≥20% rise in MAP within 1 min of intubation 16 (16.0%) 39 (39.0%) χ²(1)=12.89 RD -23.0% (-35.7% to -10.2%) 0.00033 Rescue fentanyl for pressor response 14 (14.0%) 33 (33.0%) χ²(1)=10.02 RD -19.0% (-31.5% to -6.5%) 0.0016 Propofol induction dose (mg/kg) 1.76 ± 0.22 2.02 ± 0.25 t(198)=8.18 MD -0.26 (-0.32 to -0.20) <0.0001 Intra-op opioid (μg fentanyl) 57 ± 18 78 ± 21 t(198)=7.64 MD -21 (-26 to -15) <0.0001 Intra-op hypotension (MAP<60) 11 (11.0%) 8 (8.0%) χ²(1)=0.57 RD +3.0% (-5.5% to +11.5%) 0.45 Bradycardia (HR<50) 9 (9.0%) 5 (5.0%) χ²(1)=1.36 RD +4.0% (-3.8% to +11.8%) 0.24 Time to extubation (min) 8.3 ± 2.1 7.1 ± 1.9 t(198)=4.13 MD +1.2 (0.63 to 1.77) <0.0001 PONV within 2 h 13 (13.0%) 21 (21.0%) χ²(1)=2.27 RD -8.0% (-18.0% to +2.0%) 0.13 Patient-reported comfort (0–10) 8.4 ± 1.1 7.6 ± 1.3 t(198)=4.71 MD +0.8 (0.46 to 1.14) <0.0001 Table 1 presents the comparative efficacy outcomes between Dexmedetomidine and Midazolam in attenuating the perioperative stress response. A significantly lower proportion of patients in the Dexmedetomidine group exhibited a ≥20% rise in heart rate (19.0%) and mean arterial pressure (16.0%) within one minute of intubation compared to those receiving Midazolam (41.0% and 39.0%, respectively; p=0.0010 and p=0.00033). The need for rescue fentanyl to control pressor responses was also markedly reduced in the Dexmedetomidine group (14.0%) versus the Midazolam group (33.0%; p=0.0016). The mean propofol induction dose was significantly lower with Dexmedetomidine (1.76 ± 0.22 mg/kg) compared to Midazolam (2.02 ± 0.25 mg/kg; p<0.0001), demonstrating a notable anesthetic-sparing effect. Intraoperative fentanyl requirement was similarly reduced (57 ± 18 μg vs 78 ± 21 μg; p<0.0001). Both groups showed comparable rates of intraoperative hypotension and bradycardia (p>0.05), indicating acceptable hemodynamic safety. However, the Dexmedetomidine group had a slightly longer extubation time (8.3 ± 2.1 vs 7.1 ± 1.9 minutes; p<0.0001), likely due to its deeper sedative action. Postoperative nausea and vomiting were less frequent in the Dexmedetomidine group, though not statistically significant. Overall, patient comfort scores were significantly higher with Dexmedetomidine (8.4 ± 1.1 vs 7.6 ± 1.3; p<0.0001), suggesting superior subjective experience and smoother perioperative c se. Table 2: Hemodynamic profile during induction and intubation Variable Dexmedetomidine (n=100) Mean ± SD Midazolam (n=100) Mean ± SD Test of significance 95% CI for MD (Dex-Mid) p-value HR baseline (bpm) 78.9 ± 8.7 79.6 ± 9.1 t(198)=0.57 -2.8 to 1.5 0.57 HR after premed (bpm) 71.2 ± 8.1 76.8 ± 8.5 t(198)=4.77 -7.8 to -3.4 <0.0001 HR 1 min post-intubation (bpm) 82.7 ± 9.6 96.4 ± 11.2 t(198)=9.19 -16.6 to -10.8 <0.0001 HR 5 min post-intubation (bpm) 76.5 ± 8.9 86.1 ± 9.8 t(198)=7.27 -12.2 to -6.8 <0.0001 MAP baseline (mmHg) 92.4 ± 7.8 93.1 ± 8.0 t(198)=0.63 -2.7 to 1.3 0.53 MAP after premed (mmHg) 86.8 ± 7.5 90.9 ± 7.9 t(198)=3.59 -6.3 to -1.9 0.00044 MAP 1 min post-intubation (mmHg) 96.1 ± 8.2 106.7 ± 9.1 t(198)=8.50 -12.9 to -7.9 <0.0001 MAP 5 min post-intubation (mmHg) 90.3 ± 7.7 97.2 ± 8.4 t(198)=6.31 -9.1 to -4.8 <0.0001 Table 2 highlights the hemodynamic trends during induction and intubation. Baseline heart rate and mean arterial pressure (MAP) were comparable between groups (p>0.05). Following premedication, patients receiving Dexmedetomidine exhibited a significant reduction in heart rate (71.2 ± 8.1 bpm) compared to Midazolam (76.8 ± 8.5 bpm; p<0.0001), reflecting enhanced sympatholysis. The pressor and tachycardic responses to intubation were markedly attenuated in the Dexmedetomidine group-mean heart rate at one minute post-intubation was 82.7 ± 9.6 bpm versus 96.4 ± 11.2 bpm in the Midazolam group (p<0.0001). Similarly, MAP increased minimally after intubation in the Dexmedetomidine group (96.1 ± 8.2 mmHg) compared to the Midazolam group (106.7 ± 9.1 mmHg; p<0.0001). At five minutes post-intubation, hemodynamic parameters remained significantly lower and stable in the Dexmedetomidine group, confirming its superior efficacy in blunting sympathetic surges induced by laryngoscopy and intubation. Table 3: Serum cortisol comparison Variable Dexmedetomidine (n=100) Mean ± SD Midazolam (n=100) Mean ± SD Test of significance 95% CI for MD (Dex-Mid) p-value Baseline cortisol (μg/dL) 12.7 ± 3.6 12.9 ± 3.5 t(198)=0.39 -1.1 to 0.7 0.70 60 min after induction (μg/dL) 16.4 ± 4.1 21.8 ± 4.6 t(198)=8.03 -6.7 to -4.1 <0.0001 Δ Cortisol (post - baseline) (μg/dL) 3.7 ± 2.3 8.9 ± 3.0 t(198)=14.29 -5.9 to -4.5 <0.0001 % rise from baseline 30.1 ± 14.8% 70.2 ± 18.3% t(198)=16.03 -45.3% to -35.0% <0.0001 Table 3 compares the serum cortisol responses between the two study groups. Baseline cortisol levels were comparable (12.7 ± 3.6 vs 12.9 ± 3.5 μg/dL; p=0.70). However, 60 minutes after induction, the Midazolam group demonstrated a marked rise in serum cortisol (21.8 ± 4.6 μg/dL) compared to the Dexmedetomidine group (16.4 ± 4.1 μg/dL; p<0.0001). The mean rise (Δ cortisol) from baseline was significantly smaller in the Dexmedetomidine group (3.7 ± 2.3 μg/dL) versus the Midazolam group (8.9 ± 3.0 μg/dL; p<0.0001), corresponding to a 30.1% increase in cortisol versus 70.2% in the Midazolam group (p<0.0001). This biochemical evidence clearly indicates that Dexmedetomidine effectively suppresses the hypothalamic-pituitary-adrenal stress response to surgical stimulation, corroborating its potent central sympatholytic and hormonal-modulatory effects. Table 4: Sedation, anxiolysis, and recovery profile Variable Dexmedetomidine (n=100) n(%) or Mean ± SD Midazolam (n=100) n(%) or Mean ± SD Test of significance Effect size & 95% CI p-value Ramsay Sedation Scale at transfer (1–6) 3.2 ± 0.6 2.6 ± 0.7 t(198)=6.68 MD +0.6 (0.42 to 0.78) <0.0001 Adequate anxiolysis (APAIS-A ≤10) 84 (84.0%) 67 (67.0%) χ²(1)=7.33 RD +17.0% (+4.6% to +29.4%) 0.0068 Time to Aldrete ≥9 (min) 12.9 ± 3.4 12.2 ± 3.1 t(198)=1.63 MD +0.7 (-0.12 to 1.52) 0.105 Time to first analgesic (min) 54 ± 15 38 ± 14 t(198)=7.18 MD +16 (12 to 20) <0.0001 Emergence agitation 6 (6.0%) 14 (14.0%) χ²(1)=3.64 RD -8.0% (-16.7% to +0.7%) 0.056 Desaturation (SpO₂<94%) in PACU 3 (3.0%) 7 (7.0%) χ²(1)=1.67 RD -4.0% (-10.0% to +2.0%) 0.20 Patient satisfaction (0–10) 8.6 ± 1.0 7.8 ± 1.2 t(198)=5.39 MD +0.8 (0.50 to 1.10) <0.0001 Table 4 focuses on sedation, anxiolysis, and recovery parameters. Dexmedetomidine produced deeper sedation as reflected by higher Ramsay Sedation Scale scores (3.2 ± 0.6 vs 2.6 ± 0.7; p<0.0001). Adequate anxiolysis (APAIS-A ≤10) was achieved in 84% of Dexmedetomidine-pretreated patients compared to 67% in the Midazolam group (p=0.0068). Although the mean time to achieve an Aldrete score ≥9 did not differ significantly between groups (p=0.105), the Dexmedetomidine group experienced a substantially longer pain-free interval before the first analgesic request (54 ± 15 vs 38 ± 14 minutes; p<0.0001), reflecting its analgesic-sparing benefits. Incidence of emergence agitation was lower in the Dexmedetomidine group (6.0% vs 14.0%; p=0.056), suggesting smoother recovery, though this difference approached but did not reach statistical significance. Desaturation events in the post-anesthesia care unit were infrequent and comparable between groups. Importantly, overall patient satisfaction was significantly higher in the Dexmedetomidine group (8.6 ± 1.0 vs 7.8 ± 1.2; p<0.0001), confirming superior perioperative comfort and subjective well-being.

The markedly lower proportions of ≥20% rises in HR and MAP within 1 minute of intubation with DEX (Table 1) mirror classic attenuation data: Saad BB et al.(2020)[5] showed IV DEX significantly suppressed the tachycardic/pressor surges to laryngoscopy and intubation versus control, attributing this to potent central α2-mediated sympatholysis. In cohort, fewer patients required rescue fentanyl and total intra-operative opioid consumption was lower with DEX-an opioid-sparing effect echoed by RCTs and meta-evidence reporting reduced anesthetic/analgesic requirements and smoother hemodynamics when DEX is used as premedication or adjuvant. Ali ST et al.(2020)[6] The hemodynamic time-c se in Table 2-lower HR/MAP after premedication and persistently blunted responses at 1 and 5 minutes post-intubation-aligns with multiple delivery routes studied for DEX. Intranasal and nebulized DEX have each demonstrated attenuation of the laryngoscopy response without excess bradycardia or hypotension, supporting a class effect across routes. While MDZ can provide some reduction in intubation-related fluctuations, head-to-head comparisons generally show DEX achieves greater stability-consistent with between-group mean differences. Roy N et al.(2022)[7] Biochemically, Table 3 shows a substantially smaller rise in serum cortisol with DEX. This dovetails with controlled studies demonstrating that DEX dampens HPA-axis activation and peri-operative stress hormones (including cortisol), sometimes alongside reductions in pro-inflammatory cytokines. A registered trial rationale also highlights DEX’s sympatholytic effect lowering intra-operative cortisol, consistent with Δ-cortisol and %-rise findings. Medhat MM et al.(2022)[8] For patient-centered outcomes (Table 4), higher Ramsay scores and a greater proportion achieving adequate anxiolysis with DEX align with work showing deeper, cooperative sedation and superior preoperative calm compared with MDZ, with comparable or fewer cardiorespiratory effects in adults and children. longer time to first analgesic request fits DEX’s analgesic-sparing profile noted across airway and non-airway procedures. Patient satisfaction was higher with DEX in series-again concordant with comparative sedation literature where DEX yields calmer induction and smoother recovery. Notably, small, nonsignificant differences in hypotension/desaturation are consistent with modern trials/meta-analyses reporting low rates of clinically important brady-hypotensive events when dosing is conservative and infused over time. Chandra K et al.(2020)[9] Two nuances deserve mention. First, DEX group had a modestly longer extubation time, a trade-off commonly described with deeper peri-operative sedation from α2-agonists; nonetheless, readiness for discharge (Aldrete ≥9) was similar, mirroring several trials. Second, contexts such as awake fiberoptic intubation show both drugs can be effective, yet DEX typically provides better patient tolerance and hemodynamic stability-supporting its versatility beyond standard GA induction. Rathod S et al.(2024)[10]

The present study demonstrated that dexmedetomidine is significantly more effective than midazolam as a premedication agent in attenuating the perioperative stress response. Dexmedetomidine premedication produced superior hemodynamic stability during induction and intubation, as evidenced by lower heart rate and mean arterial pressure variations, along with a marked reduction in anesthetic and opioid requirements. It also resulted in significantly lower postoperative serum cortisol levels, confirming effective suppression of the neuroendocrine stress response. In addition, dexmedetomidine provided better sedation and anxiolysis without respiratory depression and was associated with higher patient comfort and satisfaction scores. Although extubation was slightly delayed, recovery profiles remained clinically acceptable. Overall, dexmedetomidine proved to be a safe, well-tolerated, and superior alternative to midazolam for achieving optimal preoperative sedation, anxiolysis, and attenuation of surgical stress responses.

1. Agarwal S, Agarwal N. Intranasal midazolam and dexmedetomidine as premedication on haemodynamic stability: A comparative study. European Journal of Molecular and Clinical Medicine. 2022 Jan 15;9(2):160-7. 2. Wang S, Xing H, Xu X. Comparison of midazolam and dexmedetomidine combined with thoracic paravertebral block in hemodynamics, inflammation and stress response, and cognitive function in elderly lung cancer patients. International Immunopharmacology. 2025 Feb 6;147:113961. 3. Gupta P, Kumari S, Chauhan R, Bhatia PS. To compare effects of pre-treatment with two doses of dexmedetomidine on etomidate induced myoclonus and attenuation of stress response at intubation. Panacea J Med Sci. 2022 Aug 30;12:436-1. 4. Oriby ME, Elrashidy A, Khafagy AG, Rezkalla PP. Dexmedetomidine vs. fentanyl-midazolam combination to mitigate the stress response in microlaryngoscopy: a randomized double-blind clinical trial. Anesthesiology and Pain Medicine. 2023 May 8;13(3):e135276. 5. Saad BB, Tharwat AI, Ghobrial HN, Elfawal SM. Intranasal dexmedetomidine versus intranasal midazolam as pre-anesthetic medication in pediatric age group undergoing adenotonsillectomy. Ain-Shams journal of anesthesiology. 2020 Sep 15;12(1). 6. Ali ST, Asthana V, Gupta D, Singh SK. A comparative evaluation of oral clonidine, dexmedetomidine, and melatonin as premedicants in pediatric patients undergoing subumbilical surgeries. Romanian journal of anaesthesia and intensive care. 2020 Aug 10;27(1):35. 7. Roy N, Gupta N, Gupta A. Comparison of Premedication with Midazolam and Dexmedetomidine on Sedation and Anxiety in Controlled Hypertensive Patients Undergoing Elective Surgery under General Anaesthesia. Archives of Anesthesia and Critical Care. 2022 Jul 31. 8. Medhat MM, Abd Elnaby SM. Comparison of nebulized fentanyl, midazolam, and dexmedetomidine as a sedative premedication in outpatient pediatric dental surgeries: a randomized double-blind study. Research and Opinion in Anesthesia & Intensive Care. 2022 Jan 1;9(1):19-28. 9. Chandra K, Mukherjee D. Comparative study of Melatonin and Pregabalin for attenuation of hemodynamic stress response to laryngoscopy and endotracheal intubation in Laparoscopic Cholecystectomy. IOSR J Dent Med Sci. 2020;19(10):4-12. 10. Rathod S, Haque M, Patra S, Biswas C. Comparative study between dexmedetomidine and midazolam as pre-medication for the prevention of etomidate-induced myoclonus and attenuation of stress response at endotracheal intubation in laparoscopic cholecystectomies. Asian Journal of Medical Sciences. 2024 Jul 1;15(7):27-32.