Intranasal Dexmedetomidine the Night Before Surgery Halves Postoperative Delirium in Older Arthroplasty Patients
核心洞察
A randomized, double-blind, placebo-controlled trial found intranasal dexmedetomidine (100 μg) given the night before surgery reduced postoperative delirium (搜索) (POD) incidence from 20.7% to 10.3% (RR=0.50, P=0.030) in older adults undergoing total hip or knee arthroplasty.
The intervention significantly improved perioperative sleep quality, including total, deep, and REM sleep time, with effects persisting into the first postoperative night.
Exploratory mediation analysis suggested prolonged preoperative sleep duration accounted for 64.0% of the treatment effect on POD reduction, though the confidence interval was wide.
Intranasal dexmedetomidine administered the night before surgery reduced the incidence of postoperative delirium (搜索) (POD) by roughly half in older adults undergoing total hip or knee arthroplasty, according to a randomized, double-blind, placebo-controlled trial conducted at the Affiliated Hospital of Xuzhou Medical University. In the intention-to-treat analysis, the dexmedetomidine group had a POD incidence of 10.3% (12/116) compared with 20.7% (24/116) in the placebo group (relative risk [RR] = 0.50; 95% confidence interval [CI] = 0.26–0.95; P=0.030).
The study, approved by the Medical Ethics Committee (approval number: XYFY2024-KL448-01) on September 23, 2024, and prospectively registered at the Chinese Clinical Trial Registry (ChiCTR2500095414) on January 7, 2025, enrolled patients from January 10 to June 10, 2025. The trial complied with the Declaration of Helsinki and was reported according to CONSORT guidelines.
Study Design and Population
The trial enrolled patients 60 years or older with American Society of Anesthesiologists (ASA) status 1 to 3 undergoing total hip or knee arthroplasty under general anesthesia. Exclusion criteria included preoperative cognitive dysfunction (Mini-Mental State Examination score <15), a history of schizophrenia, epilepsy, Parkinsonism, myasthenia gravis, severe sinus bradycardia (<50 beats per minute), and severe pre-existing sleep disorders or routine use of hypnotic medications, among others.
Eligible patients were randomized 1:1 to intranasal dexmedetomidine or normal saline using permuted block randomization (block size 4). All outcome assessors, patients, anesthesiologists, nurses, surgeons, and statisticians were blinded to group assignment.
Intervention and Dosing
Drug intervention was performed by a trained researcher at 21:00 on the night before surgery. Each patient received a fixed cumulative dose of 100 μg of dexmedetomidine hydrochloride nasal spray (Shanghai Hengrui Pharmaceutical Company Ltd. (搜索)), delivered as 2 sprays per nostril (25 μg per spray), with a second spray administered to each nostril after 30 seconds. The placebo group received an equal volume of normal saline under identical conditions.
Following administration, patients were continuously monitored for 2 hours for adverse events including hypotension, bradycardia, and hypoxemia.
Primary Outcome
The primary outcome was the incidence of POD within the first three postoperative days, assessed using the Confusion Assessment Method (CAM) twice daily by two fixed researchers who had completed systematic training. All enrolled patients presented no preoperative delirium.
Consistent results were obtained from the per-protocol analysis (10.4% [12/115] vs 21.1% [24/114]; RR = 0.49; 95% CI = 0.26–0.94; P=0.027). Kaplan-Meier curves showed a difference in cumulative POD incidence between groups (hazard ratio [HR] = 0.48; 95% CI = 0.26–0.95; P=0.031).
Sleep Quality Improvements
On the night before surgery, patients in the dexmedetomidine group demonstrated significantly better subjective sleep quality, as evidenced by higher Richards-Campbell Sleep Questionnaire scores (mean difference [MD] = 15; 95% CI = 10–20; P<0.001).
Objective sleep monitoring using the Fitbit Charge 2 demonstrated similar results. Patients in the dexmedetomidine group exhibited increases in total sleep time (405.4 vs 374.7 min; MD = 31.2; 95% CI = 19.8–41.6; P<0.001), deep sleep time (108.0 vs 98.3 min; MD = 10.2; 95% CI = 2.1–18.2; P=0.011), light sleep time (220.9 vs 207.6 min; MD = 13.3; 95% CI = 5.7–20.8; P<0.001), and rapid eye movement (REM) sleep time (76.1 vs 65.8 min; MD=11.2; 95% CI=0.4–14.1; P<0.001).
The sleep-enhancing effects continued on the first postoperative night, with increases in total sleep time (273.4 vs 245.3 min; MD = 28.1; 95% CI = 17.2–38.9; P<0.001), deep sleep time, light sleep time, and REM sleep time. However, no significant differences in sleep parameters were observed on postoperative nights 2 and 3.
Pain, Anxiety, and Recovery
Patients in the dexmedetomidine group reported significantly lower Numeric Rating Scale pain scores at rest and with movement before anesthesia induction and on postoperative day 1, with no differences on postoperative days 2 and 3. Before anesthesia induction, the dexmedetomidine group also reported lower Self-Rating Anxiety Scale scores (MD = −2; 95% CI = −5–0; P=0.045).
There was no difference in the incidence of postoperative nausea and vomiting between groups (10.3% vs 11.2%; RR = 0.93; 95% CI = 0.44–1.93; P = 0.832). Quality of Recovery-15 scale scores were comparable between groups.
Mediation Analysis
In an exploratory causal mediation analysis, dexmedetomidine reduced the incidence of POD (total effect = −0.112, 95% CI [−0.172, −0.049], P = 0.008) through prolonged sleep duration (Average Causal Mediation Effect [ACME] = −0.072, 95% CI [−0.125, −0.016], P = 0.016). Sleep duration was associated with a proportion mediated of 64.0% of the total treatment effect, although the confidence interval was wide (95% CI: 11.2% to 110.8%, P=0.017).
Safety and Sensitivity Analyses
Adverse events, including hypotension, hypertension, bradycardia, tachycardia, and hypoxemia, did not differ between groups before or during surgery. Neither group experienced any incidence of nasal mucosal damage after intranasal administration.
Post-hoc subgroup analyses showed dexmedetomidine significantly reduced POD incidence among patients older than 69 years, with Pittsburgh Sleep Quality Index scores >12, Mini-Mental State Examination scores >22, and those classified as frail. After adjusting for potential confounders including age, sex, ASA, MMSE, PSQI, intraoperative hypotension, and anesthesia duration, dexmedetomidine still demonstrated a reduced risk of POD (OR, 0.28, 95% CI: 0.10–0.76, P = 0.012).
Limitations
The authors acknowledged several limitations. The study was single-center with a modest number of delirium events, limiting generalizability and statistical power to detect rare adverse events. Both mediation and subgroup analyses were post-hoc exploratory, and the mediation estimate had a wide confidence interval extending above 100%, precluding establishment of a causal pathway. Sleep was monitored with a consumer wearable rather than polysomnography, introducing measurement imprecision in sleep staging. Finally, a fixed 100-μg dose was used for all patients without weight adjustment, which may not account for individual pharmacokinetic variability.
The authors concluded that larger multicenter trials are warranted to validate these findings.