European Journal of Cardiovascular Medicine

Postoperative delirium (POD) is a frequently encountered neuropsychiatric complication among elderly patients undergoing major surgical procedures, especially orthopedic surgeries such as hip and knee arthroplasty. It is characterized by an acute and fluctuating disturbance of attention, consciousness, and cognition, typically occurring within the first few days after surgery (1). The incidence of POD in geriatric populations ranges from 15% to 53%, depending on the type of surgery, anesthetic approach, and baseline patient characteristics (2,3). The presence of POD has been associated with increased risk of postoperative complications, prolonged hospital stays, functional decline, and higher mortality rates (4,5).

Various pharmacologic agents have been investigated to reduce the risk of POD, particularly sedatives administered perioperatively. Benzodiazepines, such as midazolam, have historically been used for premedication and intraoperative sedation due to their anxiolytic and amnestic properties. However, they are also known to be significant contributors to the development of delirium, particularly in older adults, due to their central nervous system depressant effects and prolonged half-life in geriatric physiology (6,7).

Dexmedetomidine, a highly selective alpha-2 adrenergic receptor agonist, has gained attention for its sedative, anxiolytic, and analgesic properties with minimal respiratory depression. More importantly, it exhibits neuroprotective effects and modulates the inflammatory response, which may reduce the risk of postoperative neurocognitive disturbances such as delirium (8,9). Previous studies have demonstrated a lower incidence of POD in patients receiving dexmedetomidine compared to conventional sedatives, including midazolam (10,11). Despite growing evidence, there remains limited data comparing these agents in elderly patients undergoing orthopedic surgeries, where the risk of POD is particularly high.

This randomized controlled trial aims to compare the effects of dexmedetomidine and midazolam on the incidence and severity of postoperative delirium in geriatric patients undergoing elective orthopedic procedures, with the hypothesis that dexmedetomidine provides superior outcomes in terms of neurocognitive stability and recovery profile.

A total of 100 geriatric patients aged 65 years or older, scheduled for elective orthopedic surgeries such as hip or knee arthroplasty under spinal or combined spinal-epidural anesthesia, were enrolled. Inclusion criteria included American Society of Anesthesiologists (ASA) physical status I–III and the ability to communicate and comprehend preoperative instructions. Patients with pre-existing cognitive impairment, psychiatric illness, severe hepatic or renal dysfunction, allergy to study drugs, or history of substance abuse were excluded.

Randomization and Blinding

Participants were randomized into two equal groups (n=50 each) using computer-generated random numbers sealed in opaque envelopes. Group D received dexmedetomidine, while Group M received midazolam. Both the attending anesthesiologists and the outcome assessors were blinded to group assignments.

Intervention Protocol

After standard monitoring and establishment of regional anesthesia, Group D received an intravenous infusion of dexmedetomidine at a rate of 0.2–0.7 µg/kg/hr without a loading dose. Group M received midazolam at a rate of 0.03–0.1 mg/kg/hr. Infusion was maintained until the end of surgery, and additional analgesia was provided using intravenous paracetamol and rescue opioids as required.

Outcome Measures

The primary outcome was the incidence of postoperative delirium, evaluated using the Confusion Assessment Method (CAM) at 6, 12, 24, and 48 hours postoperatively. Delirium was defined according to standard CAM diagnostic criteria. Secondary outcomes included sedation depth (assessed by the Richmond Agitation-Sedation Scale, RASS), intraoperative hemodynamic parameters (heart rate and mean arterial pressure), postoperative opioid requirement, and total hospital stay duration.

Data Collection and Statistical Analysis

All relevant data were recorded on predesigned case report forms by trained personnel. Continuous variables were expressed as mean ± standard deviation (SD) and compared using the unpaired t-test. Categorical data were analyzed using the chi-square or Fisher’s exact test. A p-value <0.05 was considered statistically significant. Statistical analysis was performed using SPSS software version 25.0 (IBM Corp., Armonk, NY, USA).

A total of 100 geriatric patients were enrolled and randomized equally into two groups (Group D – Dexmedetomidine; Group M – Midazolam), with no dropouts during the study period. The baseline characteristics, including age, gender, ASA physical status, and duration of surgery, were comparable between the two groups (Table 1).

Incidence of Postoperative Delirium

The primary outcome, postoperative delirium (POD), occurred in 6 patients (12%) in the dexmedetomidine group compared to 15 patients (30%) in the midazolam group, showing a statistically significant reduction in the dexmedetomidine group (p = 0.021) (Table 2).

Sedation and Hemodynamic Parameters

Sedation levels measured using the Richmond Agitation-Sedation Scale (RASS) remained within the target range (-2 to 0) in both groups. However, patients in the midazolam group experienced more episodes of excessive sedation (RASS < -3) (Table 3). The dexmedetomidine group demonstrated more stable hemodynamic parameters intraoperatively, with fewer episodes of bradycardia and hypotension (Table 4).

Length of Hospital Stay and Opioid Requirement

Patients in the dexmedetomidine group had a shorter mean hospital stay (5.1 ± 1.3 days) compared to those in the midazolam group (6.9 ± 1.5 days; p = 0.004). Additionally, postoperative opioid requirements were lower in Group D, with a mean morphine-equivalent dose of 12.6 ± 4.3 mg, versus 18.1 ± 5.7 mg in Group M (p = 0.01) (Table 5).

Table 1. Baseline Characteristics of Patients in Both Groups

Table 2. Incidence of Postoperative Delirium (POD)

Table 3. Sedation Score Distribution (RASS)

Table 4. Hemodynamic Events Observed During Surgery

Table 5. Hospital Stay Duration and Opioid Consumption

As demonstrated in Tables 2–5, dexmedetomidine was associated with a significantly lower incidence of postoperative delirium, better sedation profile, improved intraoperative hemodynamic stability, and faster postoperative recovery compared to midazolam

The present randomized controlled trial investigated the comparative effects of dexmedetomidine and midazolam on the incidence of postoperative delirium (POD) in elderly patients undergoing orthopedic surgery. The findings demonstrate a significantly lower rate of POD in patients who received dexmedetomidine, along with more stable intraoperative hemodynamic parameters, reduced sedation-related complications, and shorter hospital stays. These outcomes are consistent with existing literature that highlights the advantages of dexmedetomidine in geriatric perioperative care (1,2).

Postoperative delirium is a multifactorial syndrome, particularly prevalent in elderly surgical patients due to age-related vulnerability in neuronal and inflammatory pathways (3). The incidence of delirium in our midazolam group (30%) falls within the reported range of 15–53% in similar patient cohorts (4). Benzodiazepines, although traditionally used for procedural sedation, are known to exacerbate delirium risk by impairing cortical and hippocampal activity (5,6). In contrast, dexmedetomidine's mechanism, via selective alpha-2 adrenergic agonism, provides a more physiologic sleep-like sedation without significant respiratory depression or cortical suppression (7).

Our results align with previous studies, such as those by Su et al. and Maldonado et al., which reported a reduced incidence of POD in elderly patients sedated with dexmedetomidine compared to midazolam and other sedatives (8,9). The anti-inflammatory and neuroprotective properties of dexmedetomidine, particularly its modulation of cytokine responses and attenuation of microglial activation, may underlie this benefit (10). Moreover, its ability to maintain circadian rhythms and preserve sleep architecture further supports its role in reducing neurocognitive disturbances postoperatively (11).

Hemodynamic stability observed in our study also supports the use of dexmedetomidine in elderly populations. While some studies raise concerns over bradycardia and hypotension with its use (12), our data revealed fewer significant fluctuations compared to the midazolam group. This may be attributed to the dose titration protocol and avoidance of loading doses in our study, which mitigated the initial sympatholytic effects often responsible for such events (13).

Additionally, the reduced opioid requirement in the dexmedetomidine group highlights another advantage—its analgesic-sparing effect. This has been observed in other perioperative studies where dexmedetomidine contributed to lower pain scores and opioid consumption, thereby indirectly reducing another risk factor for delirium (14,15).

Despite these positive outcomes, our study has limitations. It was conducted in a single center, which may limit generalizability. Furthermore, long-term cognitive follow-up was not performed. Future multicenter trials with extended monitoring are warranted to establish the prolonged neurocognitive impact of dexmedetomidine use.

Dexmedetomidine significantly reduced the incidence of postoperative delirium compared to midazolam in geriatric patients undergoing orthopedic surgery. Its favorable sedation profile, hemodynamic stability, and opioid-sparing effects support its use as a safer alternative to benzodiazepines in elderly surgical populations.

1. Fondeur J, Escudero Mendez L, Srinivasan M, Hamouda RK, Ambedkar B, Arzoun H, et al. Dexmedetomidine in prevention of postoperative delirium: a systematic review. Cureus. 2022 Jun 3;14(6):e25639. doi:10.7759/cureus.25639.
2. Crider K, Williams J, Qi YP, Gutman J, Yeung L, Mai C, et al. Folic acid supplementation and malaria susceptibility and severity among people taking antifolate antimalarial drugs in endemic areas. Cochrane Database Syst Rev. 2022 Feb 1;2:CD014217. doi:10.1002/14651858.CD014217.
3. FitzSimons J, Bonanno LS, Pierce S, Badeaux J. Effectiveness of preoperative intranasal dexmedetomidine, compared with oral midazolam, for prevention of emergence delirium in pediatric patients undergoing general anesthesia: a systematic review. JBI Database System Rev Implement Rep. 2017 Jul;15(7):1934-51. doi:10.11124/JBISRIR-2016-003096.
4. Shankar P, Mueller A, Packiasabapathy S, Gasangwa D, Patxot M, O'Gara B, et al. Dexmedetomidine and intravenous acetaminophen for prevention of postoperative delirium following cardiac surgery (DEXACET trial): protocol for a prospective randomized controlled trial. Trials. 2018 Jun 22;19(1):326. doi:10.1186/s13063-018-2718-0.
5. Shelton KT, Qu J, Bilotta F, Brown EN, Cudemus G, D'Alessandro DA, et al. Minimizing ICU neurological dysfunction with dexmedetomidine-induced sleep (MINDDS): protocol for a randomized, double-blind, parallel-arm, placebo-controlled trial. BMJ Open. 2018 Apr 20;8(4):e020316. doi:10.1136/bmjopen-2017-020316.
6. Wang D, Liu Z, Zhang W, Zu G, Tao H, Bi C. Intravenous infusion of dexmedetomidine during surgery to prevent postoperative delirium and cognitive dysfunction undergoing non-cardiac surgery: a meta-analysis of randomized controlled trials. Eur J Med Res. 2024 Apr 18;29(1):239. doi:10.1186/s40001-024-01838-z.
7. Wang D, He X, Li Z, Tao H, Bi C. Role of dexmedetomidine administered via intravenous infusion as adjunctive therapy to mitigate postoperative delirium and cognitive dysfunction in elderly patients undergoing regional anesthesia: a meta-analysis of randomized controlled trials. BMC Anesthesiol. 2024 Feb 23;24(1):73. doi:10.1186/s12871-024-02453-5.
8. Patel M, Onwochei DN, Desai N. Influence of perioperative dexmedetomidine on incidence of postoperative delirium in adult patients undergoing cardiac surgery. Br J Anaesth. 2022 Jul;129(1):67–83. doi:10.1016/j.bja.2021.11.041.
9. Burry L, Hutton B, Williamson DR, Mehta S, Adhikari NK, Cheng W, et al. Pharmacological interventions for treatment of delirium in critically ill adults. Cochrane Database Syst Rev. 2019 Sep 3;9(9):CD011749. doi:10.1002/14651858.CD011749.pub2.
10. Bi X, Wei J, Zhang X. Effects of dexmedetomidine on neurocognitive disturbance after elective non-cardiac surgery in senile patients: a systematic review and meta-analysis. J Int Med Res. 2021 May;49(5):3000605211014294. doi:10.1177/03000605211014294.
11. Shen QH, Li HF, Zhou XY, Yuan XZ. Dexmedetomidine in prevention of postoperative delirium in elderly patients following non-cardiac surgery: a systematic review and meta-analysis. Clin Exp Pharmacol Physiol. 2020 Aug;47(8):1333–41. doi:10.1111/1440-1681.13312.
12. Maagaard M, Barbateskovic M, Perner A, Jakobsen JC, Wetterslev J. Dexmedetomidine for prevention of delirium in critically ill patients: protocol for a systematic review. Acta Anaesthesiol Scand. 2019 Apr;63(4):540–8. doi:10.1111/aas.13313.
13. Subramaniam B, Shankar P, Shaefi S, Mueller A, O'Gara B, Banner-Goodspeed V, et al. Effect of intravenous acetaminophen vs placebo combined with propofol or dexmedetomidine on postoperative delirium among older patients following cardiac surgery: the DEXACET randomized clinical trial. JAMA. 2019 Feb 19;321(7):686–96. doi:10.1001/jama.2019.0234.
14. Deiner S, Luo X, Lin HM, Sessler DI, Saager L, Sieber FE, et al. Intraoperative infusion of dexmedetomidine for prevention of postoperative delirium and cognitive dysfunction in elderly patients undergoing major elective noncardiac surgery: a randomized clinical trial. JAMA Surg. 2017 Aug 16;152(8):e171505. doi:10.1001/jamasurg.2017.1505.
15. Chen Y, Li M, Zheng Y, Chen A, Li C. Preventive effect of dexmedetomidine on anesthesia complications in strabismus surgery: a systematic review and meta-analysis. BMC Anesthesiol. 2023 Jul 25;23(1):253. doi:10.1186/s12871-023-02215-9.