Nocturnal dexmedetomidine infusion versus placebo for prevention of postoperative delirium in elderly patients undergoing hip-fracture surgery: a protocol for a multicentre, randomized, double-blind trial - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. 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Learn more: PMC Disclaimer | PMC Copyright Notice Trials . 2026 Mar 9;27:303. doi: 10.1186/s13063-026-09601-x Search in PMC Search in PubMed View in NLM Catalog Add to search Nocturnal dexmedetomidine infusion versus placebo for prevention of postoperative delirium in elderly patients undergoing hip-fracture surgery: a protocol for a multicentre, randomized, double-blind trial Jin-chao Song Jin-chao Song 1 Department of Anesthesiology, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China Find articles by Jin-chao Song 1, # , Guo-pan Zhang Guo-pan Zhang 2 Department of Anesthesiology, QuanZhou Orthopedic-Traumatological Hospital, QuanZhou, China Find articles by Guo-pan Zhang 2, # , Tong Ding Tong Ding 1 Department of Anesthesiology, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China Find articles by Tong Ding 1, # , Jun Lu Jun Lu 3 Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China Find articles by Jun Lu 3 , Yi-yu He Yi-yu He 1 Department of Anesthesiology, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China Find articles by Yi-yu He 1, ✉ , Xiaoyan Meng Xiaoyan Meng 4 Department of Critical Care Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438 China Find articles by Xiaoyan Meng 4, ✉ Author information Article notes Copyright and License information 1 Department of Anesthesiology, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China 2 Department of Anesthesiology, QuanZhou Orthopedic-Traumatological Hospital, QuanZhou, China 3 Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China 4 Department of Critical Care Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438 China ✉ Corresponding author. # Contributed equally. Received 2024 Oct 17; Accepted 2026 Feb 24; Collection date 2026. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13085266 PMID: 41796315 Abstract Background Postoperative delirium (POD) is common after hip-fracture surgery in older adults and is associated with prolonged hospitalization, increased mortality, and long-term cognitive decline. Previous literature has indicated that dexmedetomidine may reduce delirium when given intra-operatively; however, the benefit of a single nocturnal infusion before surgery has not been evaluated. We hypothesize that pre-operative night-time dexmedetomidine improves sleep quality and attenuates neuro-inflammation, thereby decreasing POD incidence. Methods This multicentre, randomized, double-blind, placebo-controlled trial will enroll 560 patients aged 65–90 years undergoing hip-fracture surgery. Participants will be randomly assigned (1:1) to receive an overnight infusion of dexmedetomidine 0.2 µg/kg·h or matching saline from 20:00 to 06:00 a.m. before surgery. The primary endpoint is the incidence of POD during the first 72 h, assessed every 6 h with the 3-Minute Diagnostic Confusion Assessment Method and the relative risk (95% CI) will be calculated using the chi-square test. Secondary outcomes include delirium severity and duration, pain scores, sleep quality, cognitive function at 30 and 180 days, and plasma biomarkers. Discussion This protocol evaluates whether the night-before infusion of dexmedetomidine prevents POD in older adults undergoing hip-fracture surgery. If effective, the intervention could easily be implemented in routine peri-operative care. Trial registration Chinese Clinical Trial Registry ChiCTR2400087107. Registered on 19 July 2024. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-026-09601-x. Keywords: Dexmedetomidine, Postoperative delirium, Hip-fracture surgery, Perioperative management Introduction Postoperative delirium (POD) is a neuropsychiatric disorder that occurs frequently in elderly patients after operation under anesthesia, and is characterized by impaired consciousness, inattention, and disorganized thinking [ 1 ]. POD typically develops within 24–72 h post-operatively and is associated with prolonged hospital stay, higher healthcare costs and long-term cognitive decline [ 2 ]. Moreover, in oncological populations, each additional day of POD reduces the 1-year survival rate by approximately 10% [ 3 ]. As the aging surgical population grows, POD poses an increasingly major challenge to peri-operative care. The pathophysiological mechanism of POD remains unveiled, while investigations into its risk factors and prevention strategies have attracted extensive research interest. The incidence of POD varies according to the population, procedure, and pre-operative state. Generally, age is recognized to be an independent risk factor, while a more complicated interaction of multifactorial risks, such as pain, anxiety, and sleep deprivation, is also reported. Various techniques and medications have been applied to reduce POD risks, yet no reliable prevention method has been proven [ 2 , 4 ]. Dexmedetomidine is a highly selective α−2 adrenergic receptor agonist that provides sedation, analgesia, and anxiety relief effect [ 5 ]. Accumulating evidence suggests that it also reduces neuro-inflammation by inhibiting central sympathetic output, making it a promising candidate for POD prevention [ 6 ]. Large randomized trials have yielded conflicting results: while some demonstrate reduced delirium, a meta-analysis of continuous intra- and post-operative dexmedetomidine in cardiac surgery found no benefit [ 7 ]. Other meta-analyses included low-quality studies and used heterogeneous doses and durations [ 8 , 9 ]. Notably, most previous randomized trials of peri-operative dexmedetomidine have evaluated intra- or post-operative administration, while systematic reviews indicate that preexisting factors, including baseline frailty, sleep deprivation, anxiety, and elevated inflammation, are the strongest predictors of POD [ 10 ]. Early intervention is therefore logical. As discussed, dexmedetomidine preserves physiological sleep and attenuates systemic inflammation. We hypothesize that pre-operative administration may confer neuroprotection in older patients awaiting surgery; however, few randomized trials have tested this hypothesis. The present study investigates whether a single night-before infusion of dexmedetomidine reduces POD in elderly patients undergoing hip-fracture surgery. Sleep quality and anxiety levels will also be recorded, as these factors may mediate any observed benefit. Methods Study setting and design The study is designed as a multicentre, randomized, double-blind, placebo-controlled trial. The protocol is in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement [ 11 ]. This trial is registered at Chinese Clinical Trial Registry with ID number ChiCTR2400087107. Ethics approval was granted by the IRB-AF37-V1.0 board. The Department of Anesthesiology, Shidong Hospital, University of Shanghai for Science and Technology, serves as the sponsor and is responsible for data collection, management, analysis, and manuscript submission. Trial conduct is monitored by the local clinical research centre of the same university. We will recruit 560 participants from four Chinese sites: Shidong Hospital (220 cases), Eastern Hepatobiliary Surgery Hospital (140 cases), Quanzhou Orthopedic-Traumatological Hospital (120 cases), and Shanghai Fourth People’s Hospital (80 cases). If a site reaches its quota early, the coordinating centre will reallocate remaining randomization to preserve balance. The participant flow is outlined in Fig. 1 and the study schedule in Table 1 . Fig. 1. Open in a new tab Flowchart of study design Table 1. Schedule of enrollment, interventions, and assessments (SPIRIT protocol) Open in a new tab Note: t 1 = the night before surgery; t 2 = the morning before surgery; t 3 = during anesthesia Participant recruitment Inclusion criteria: (1) scheduled for hip-fracture surgery (proximal femoral nail anti-rotation, cannulated screw fixation, hemiarthroplasty or total hip replacement); (2) aged 65–90 years; (3) ASA Physical Status I–III (to avoid ICU-sedation confounding); (4) will undergo general anesthesia; (5) be able to provide written informed consent. Exclusion criteria: (1) any mental illness or nervous-system disease (stroke, TIA, visual/auditory impairment, etc.) within 3 months; (2) dementia or Mini-Mental State Examination (MMSE) score ≤ 23 [ 12 ]; (3) illiteracy or inability to complete telephone follow-up; (4) communication difficulties precluding cognitive testing; (5) Child–Pugh C liver disease or renal-replacement therapy; (6) BMI > 35 kg/m or obstructive sleep apnea; (7) chronic psychotropic medication or alcohol abuse; (8) significant cardiac conduction disorders (sinus bradycardia < 60 beats/min, sick-sinus syndrome, second-degree AV block, WPW syndrome) or major cardiovascular events; (9) have a known allergy to dexmedetomidine. Each condition was excluded because it causes baseline cognitive fluctuation, contraindicates dexmedetomidine, or mandates post-operative ICU care that would confound delirium assessment [ 2 ]. Participants’ consent and ethics issue This study is approved by the Ethics Committee of Shidong hospital, University of Shanghai for Science and Technology. All patients scheduled for hip surgery will be screened 1 day before the operation for eligibility at the pre-operative evaluation clinic. A study team coordinator will explain this trial to interested potential participants in detail and provide them with an informed consent form (institutional consent form as Supplementary File 1). Written informed consent must be signed by the participant personally; should a participant lose capacity after enrollment, he or she will be withdrawn and no further data collected. Blinding and randomization An independent statistician (not otherwise involved in the trial) created the computer-generated randomization list (1:1; block sizes 4 and 6) stratified by centre, age ≥ 80 years and surgical type (arthroplasty vs internal fixation). Only the central pharmacy holds the list and prepares sequentially numbered, opaque, sealed 50 mL syringes identical in appearance. After eligibility confirmation and consent, the site investigator logs into the secure web-based randomization module (Research Randomizer) which immediately allocates the next number and prints a time-stamped label; the corresponding syringe is then dispensed to the ward. Anesthesiologists, patients, outcome assessors and the statistician remain blinded until the syringe is opened at the bedside, ensuring full allocation concealment. Study drugs’ administration Patients will be visited by a designated anesthesiologist one day before surgery. After screening for inclusion criteria and obtaining informed consent, patients were then allocated into the study group. Peripheral venous access will be opened in the ward, and therapeutic drugs of each group will be perfused via intravenous electronic micropump. For patients in group A, dexmedetomidine (0.2 µg/kg h) was continuously infused from 20:00 of the night before operation to 6:00 a.m. of the next morning of the surgical day, while patients in group B accepted saline infusion with the same speed. Dexmedetomidine (200 µg, 2 mL) is diluted to 50 mL (4 µg/mL) with 48 mL normal saline. All drugs are identical in appearance, packaged in identical 50 mL syringes labeled with “study medications”. Intervention and monitoring After randomization and study-drug commencement, overnight polysomnography will record heart rate, ECG, non-invasive blood pressure, respiratory rate and SpO₂. An alarm will trigger if HR < 50 beats/min for ≥ 1 min, mean arterial pressure < 60 mmHg, or SpO₂ < 90%; the infusion will be stopped immediately, and the team will re-evaluate the risk and, if necessary, provide emergency treatment. Note that the analysis will follow the intention-to-treat principle; such patients remain in the dataset unless they meet an exclusion criterion. Except for the study infusion, all participants will receive identical anesthetic care (Supplementary file 2). On the day of surgery, antibiotic prophylaxis will be given according to local protocol. Anesthesia will be induced with midazolam 0.05 mg/kg, propofol 1–2 mg/kg, and sufentanil 0.2–0.4 µg/kg; rocuronium 0.6 mg/kg will facilitate tracheal intubation. Anesthesia will be maintained with sevoflurane and sufentanil, targeting BIS 40–60 and end-tidal CO₂ 35–45 mmHg; additional rocuronium will be given as required. HR, NIBP, SpO₂, etCO₂, and BIS will be recorded continuously. Post-operatively, a patient-controlled intravenous analgesia pump (sufentanil plus flurbiprofen axetil) will be started. If pain scores are ≥ 5 on the numerical rating scale, intravenous parecoxib 40 mg will be administered. Data collection Demographics, medical history, ASA class, BMI, education, fracture type, and comorbidities will be extracted from the electronic medical record. Before study-drug administration we will record baseline MMSE and plasma concentrations of BDNF, IL-6 and TNF-α. After drug administration, parameters of HR, NIBP, SpO2 as well as sleep quality will be recorded via a PSG device and Pittsburgh sleep quality index (PSQI) [ 13 ], with the incidence of hypotension and bradycardia episodes calculated. Intra-operative measurements (on arrival, induction, skin incision, closure, extubation and 30 min post-extubation) include HR, BP, SpO₂ and BIS; the incidence of hypotension, bradycardia, hypertension, tachycardia and desaturation will be noted together with consumption of dexmedetomidine, propofol, opioids, norepinephrine and atropine. Plasma biomarkers will be sampled before induction and at the end of surgery. Surgical details (type, duration, blood loss) will be taken from the anesthesia record. Post-operatively, delirium will be assessed at least every 6 h for 72 h (3D-CAM); pain scores will be recorded at 4 h, day 1 and day 2. All adverse events, analgesic consumption and cognitive function will be assessed at 1 day, 1 month, and 6 months post-operatively. An independent data-management team, supervised by the local Clinical Research Center, will enter and store all data. Concomitant medications that may influence delirium (benzodiazepines, anticholinergics, antipsychotics, gabapentin, melatonin, dexamethasone, regional blocks) will be captured daily from the day before surgery until post-operative day 5 and analyzed as time-varying covariates. Outcomes The primary outcome is the incidence of POD within the first 72 h. Secondary outcomes comprise: POD subtype, severity and duration (assessed daily up to post-operative day 5); pain and anxiety severity at 3 h, day 1 and day 2; sleep quality from the pre-operative night to post-operative day 3; cognitive function at 30 and 60 days; plasma inflammatory biomarkers (BDNF, IL-6, TNF-α and others) before and after surgery; and the incidence of adverse events plus anesthetic and analgesic consumption. Measurement of outcomes POD Delirium will be assessed by 6 trained nurses who are blinded to the study group, from 4 h after surgery till the third post-operative day, with an interval of 6 h. A validated 3-Minute Diagnostic Confusion Assessment Method (3D-CAM Chinese version) [ 14 ] will be applied for assessment; all assessors will have undergone training on the scale in advance. The 3D-CAM which contains four diagnostic features, a patient who displays both features 1 and 2, with either feature 3 or 4, will be diagnosed with delirium. The severity of POD will be rated as mild, moderate, and severe, using the CAM-Severity Short-Form Scale (CAM-S) [ 15 ]. The subtype of POD will be classified into hyperactive, hypoactive, and mixed according to the RASS score. Pain and sleep quality measurement Post-operative pain will be evaluated using the 11-point numerical rating scale (NRS, 0–10) and analyzed as a continuous outcome. Post-operative sleep quality will also be evaluated using the PSQI (0 = best-quality sleep, 10 = worst-quality sleep). Cognitive function Post-operative cognitive function will be assessed using the MMSE and the Chinese version of the Telephone Interview for Cognitive Status-40 (TICS-40) [ 16 ]. The TICS-40 scale used in this study consists of nine items with a maximum score of 40 points, including the following variables and corresponding points: address, current date, counting backward, word-list recalling, subtractions, object naming, repetition, the presidents and prime minister’s names, and delayed recall of the word list. A score below 21 will be defined as mild cognitive impairment. Besides, concurrent validity will be examined by administering the Montreal Cognitive Assessment (MoCA) to the first 50 participants (telephone version (T-MoCA) will be used if in-person assessment is not feasible) [ 17 ] and correlating its scores with TICS-40. Inflammatory biomarkers Venous blood (approximately 6 mL) will be sampled one day before surgery, before anesthesia, and 3 days after surgery. Blood samples will be contained in EDTA tubes at 4 °C, centrifuged for 20 min at 2000 × g for plasma and then stored at −80 °C. Biomarkers of ACh, BDNF and TNF-α levels via ELISA assay by an independent specialist. Adverse events The potential adverse events that may be associated with the use of study medications are bradycardia, hypotension, tachycardia, hypertension, arrhythmia, nystagmus, hypersalivation, euphoria, emergence agitation, hallucinations, and nightmares. Serious adverse events such as death or serious postoperative complications are also recorded. Details of adverse events and medical rescue are described in Table 2 . Table 2. Definitions and rescue treatments for adverse events Adverse events Description Treatment Hypotension Mild (SBP 80–89 mm Hg) Moderate (SBP 70–79 mm Hg; > 2 min) Severe (SBP < 69 mm Hg; > 1 min) None or norepinephrine 2 µg Stop infusion, norepinephrine 4–8 µg and followed with continuous infusion when necessary Stop infusion, suspension of the study and call for intensive intervention Hypertension Mild (SBP > 140 mmHg; DBP > 90 mmHg) Moderate (SBP > 160 mmHg; DBP > 100 mmHg) Severe (SBP > 180 mmHg; DBP > 120 mmHg) None or urapidil 12.5 mg Urapidil 12.5–25 mg and stop infusion Stop infusion, suspension of the study and call for intensive intervention Bradycardia Mild (HR 55–60 bpm) Moderate (HR 45–54 bpm; > 2 min) Severe (HR < 45 bpm; > 2 min) None or atropine 0.5 mg Atropine 1–2 mg Stop infusion, suspension of the study and call for intensive intervention Tachycardia Mild (HR 90–100 bpm) Moderate (HR 100–120 bpm; > 2 min) Severe HR (> 120 bpm; > 3 min) None or esmolol 20 mg Esmolol 20 mg and followed with continuous infusion when necessary Stop infusion, suspension of the study and call for intensive intervention Hypoxemia Mild (SpO 2 91–95%) Moderate (SpO 2 85–90%; > 1 min) Severe (SpO2 < 85%; > 1 min) Oxygen inhalation Stop infusion, wake-up and/or nasopharyngeal airway establishment Stop infusion, suspension of the study and call for intensive intervention Emergence delirium RASS > 2 Stop infusion, suspension of the study and call for intensive intervention Allergy Mild (rash) Severe (low blood pressure or dyspnea) Stop infusion Stop infusion, suspension of the study and call for intensive intervention Others Nystagmus, hypersalivation, euphoria, emergence agitation, hallucinations and Arrhythmia - For new occurred severe arrythmia, stop infusion immediately and aware the study team Delayed recovery Recovery for more than 2 h - PONV - Antiemetic drugs (metoclopramide or 5-hydroxytryptamine antagonist) Post-surgical pain Short-term, NRS > 4 in 3 postoperative days CPSP, NRS > 4 in long-term follow-ups - Sleep deprivation/nightmares - - Open in a new tab Note: bpm beats per minute, CPSP chronic post-surgical pain, DBP diastolic blood pressure, 3D-C AM 3-Minute Diagnostic Confusion Assessment Method, HR heart rate, MAP mean arterial pressure, NA not applicable, NG nitroglycerine, PONV postoperative nausea and vomiting, RASS Richmond Agitation-Sedation Scale, SBP systolic blood pressure, SpO 2 oxyhemoglobin saturation by pulse oximetry Data and safety monitoring An independent DSMB (charter approved by the coordinating centre prior to first participant enrollment) will review unblinded safety summaries for every 50 recruited participants and at study close-out. The board consists of three voting members: a geriatrician (chair), an anesthesiologist, and a biostatistician, none of whom are involved in trial conduct or have financial conflicts. Closed meetings will be held with the unblinded statistician; recommendations (continue, modify, or stop) will be communicated in writing to the principal investigator within 48 h. The PI is responsible for forwarding serious safety concerns to the ethics committee and, if necessary, to the journal editors. Pre-specified stopping rules are also detailed in Table 2 . Sample size calculation We calculated the sample size using PASS 11. Assuming a 36% POD incidence in the placebo arm (pooled hip-fracture data) [ 18 ] and a conservative 33% relative reduction with dexmedetomidine [ 19 ], two-sided χ 2 , α = 0.05, power = 80%, and 15% attrition yielded 560 participants (280 per group). Statistical methods We will use SPSS 26.0 (IBM, Armonk, NY) and GraphPad Prism 9.0 (GraphPad Software, San Diego, CA). Continuous variables will first be tested for normality (Kolmogorov–Smirnov). Normally distributed data are presented as mean ± SD, non-normal data as median (IQR), and categorical variables as counts (%). Primary outcome (POD incidence) will be analyzed in both the intention-to-treat (ITT) and per-protocol (PP) populations; secondary outcomes will be assessed in the PP set only. Pre-specified sensitivity analyses include age (≥ 80 vs < 80 years), education (≥ 7 vs < 7 years), surgery type (nailing/screws vs arthroplasty), baseline MMSE (28–30 vs 24–27), and analgesia protocol (general vs combined). Between-group comparisons of continuous variables will use one-way ANOVA or Kruskal–Wallis tests as appropriate. Repeated-measures ANOVA will evaluate NRS pain scores, biomarker concentrations, and cognitive function over time. Categorical outcomes will be compared with the χ 2 test, and relative risk with 95% CI will be reported. Two-sided P < 0.05 indicates statistical significance. Missing longitudinal data will be handled with random-forest imputations; values that are missing because of the patient’s inability to cooperate will be coded as positive for delirium at that time point, to maintain a conservative approach. Discussion The prevalence of POD in the elderly represents an area in need of neural protection in the peri-operative period. The effective method for prevention and treatment of POD remains to be inconclusive, as it often involves a multifaceted intervention, including anesthetic administration, analgesic agents, and technology [ 1 ]. Among them, dexmedetomidine infusion alone or combined with other drugs shows a promising further in protecting patients’ cognitive function and improving recovery from surgery [ 20 ]. Yet enormous research has been proceeded, as several essential questions for dexmedetomidine in POD remain to be solved. One is that neither the pathophysiology of POD nor the mechanism of dexmedetomidine have been well interpreted, as the drug may act as sedative, analgesic, neuroprotectant, anxiolytic, and potentiator within the anesthesia regime, which obscures its real mechanism in preventing POD. Besides, the adverse effects of dexmedetomidine in the elderly with various pre-existing comorbidities can be amplified and unpredictable. Moreover, an optimal timing, dose, and combination strategy to maximize the therapeutic agent’s benefits while minimizing the adverse effects, especially in specified populations, need to be verified. Dexmedetomidine continuous infusion during anesthesia and surgery period has long been accepted by anesthesiologists for its potential analgesia and neuroprotective value. However, one professional guideline, the 2020 American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) Joint Consensus Statement [ 21 ], pointed out that there was insufficient evidence to recommend intraoperative dexmedetomidine infusion for POD prevention. It has reviewed six recent RCT trials with mixed results. Yet the guideline recommended that the medication still has benefits in select patient populations. Actually, a more recent randomized double-blind controlled trial studying 150 elderly patients undergoing hip replacement reported promising results for dexmedetomidine in POD prophylaxis. The trial also compared different loading dosages and found out that a higher-loading dose regime (0.75 µg/kg for 15 min followed by 0.5 µg/kg·h continuous infusion) was associated with the lowest POD rate and highest cognition scoring [ 22 ]. Unlike the intra-operative prophylaxis of POD, the benefits of dexmedetomidine infusions in ICU patients receiving mechanical ventilation appear to be more consolidated. One large sample trial reported that dexmedetomidine resulted in a 60% decrease in the POD incidence in ICU patients who underwent non-cardiac surgery [ 19 ]. A meta-analysis compared dexmedetomidine to other 3 other sedatives in ICU patients and proved that the significant benefits of it in ICU stay, duration of ventilation and POD [ 23 ]. Besides, the 2020 ASER and POQI Joint Consensus Statement also strongly recommended that dexmedetomidine be used for sedation of postoperative mechanical ventilation in ICU. Although the mechanism remains unrevealed, it seems that applying dexmedetomidine for longer-term sedation may play its strength in neuroprotection. Yet one critical but less discussed question regarding dexmedetomidine administration is its timing. Few studies have focused on the value of premedicating with dexmedetomidine on the night before surgery. A major concern is that dexmedetomidine may cause significant adverse events, as almost all clinical trials have reported cases of hypotension and bradycardia after administration. Nevertheless, the potential benefits of night-before premedication are clear: dexmedetomidine not only provides anxiolysis and analgesia but also promotes physiological sleep. Previous work shows that sleep deprivation is common in elderly patients awaiting surgery and is associated with elevated pro-inflammatory cytokines and subsequent cognitive impairment [ 24 ]. Further, dexmedetomidine activates endogenous sleep pathways, increasing physiologic N2/N3 stages while reducing N1 and REM sleep [ 25 ]. In a recent study, Dr. Huang [ 26 ] demonstrated that a nighttime dexmedetomidine infusion improved sleep quality and lowered plasma inflammatory markers without causing desaturation or requiring rescue interventions. We therefore infer that a single, low-dose nighttime infusion of dexmedetomidine is both safe and potentially effective for preventing postoperative delirium in elderly patients. Several limitations deserve emphasis. First, the nighttime infusion employs a single, low, fixed dose of dexmedetomidine. Although the regimen we used has previously been shown to promote sleep and to remain safe during prolonged administration, the optimal dose and duration for any clinical setting remain to be defined. Second, both short- and long-term outcomes rely partly on patient-completed questionnaires, introducing potential response bias. Third, despite a tightly defined population, peri-operative techniques cannot be identical for every participant; we will therefore collect detailed surgical and anesthetic data to enable subgroup comparisons and more cautious interpretation of the findings. Trial status The trial recruitment is going to be opened in August 2024 and will continue for 18 months or more. Protocol number and date: 1.0, 1 st August 2024. Recruitment started: 1 st August 2024. Supplementary Information 13063_2026_9601_MOESM1_ESM.docx (22.1KB, docx) Supplementary Material 1: Informed Consent Form. 13063_2026_9601_MOESM2_ESM.docx (19.4KB, docx) Supplementary Material 2: Supplementary file. 13063_2026_9601_MOESM3_ESM.docx (39.4KB, docx) Supplementary Material 3: SPIRIT checklist. Acknowledgements We appreciate Mr. Hao-ye Tan and his group for their professional work during the enrollment and follow-up. Authors’ contributions JC Song and XY Meng designed the trial; JC Song, T Ding, J Lu, and XY Meng will participate in the experiment and data conduction, YY He is arranged for blinding and randomization, an independent data-collection team is involved for enrollment, informed consent, data collection, and follow-up, JC Song analyzes the data and writes the manuscript. Funding This study was supported by the Cultivation Project of Scientific Research (2023LC002); the Shanghai Yangpu District Medical Key Discipline Construction Fund (22YPZA08); the Science and Technology Commission and Health Committee of Yangpu District, Shanghai (YPM202509). Data availability Data from the trial will be available after reasonable request from the corresponding author. Declarations Ethics approval and consent to participate The study is approved by the ethics committee of the Shidong hospital, University of Shanghai for Science and Technology (Ethics approval No. IRB-AF37-V1.0), and the local Clinical Trial Center will be responsible for trial monitoring. All patients could be enrolled only after their own approval of the informed consent before surgery. Consent for publication All authors have read the protocol and approved it for this publication. Competing interests No competing interests need to be declared. Footnotes Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Jin-chao Song, Guo-pan Zhang and Tong Ding contributed equally to this work. Contributor Information Yi-yu He, Email: [email protected]. Xiaoyan Meng, Email: [email protected]. References 1. Jin Z, Hu J, Ma D. Postoperative delirium: perioperative assessment, risk reduction, and management. 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Supplementary Materials 13063_2026_9601_MOESM1_ESM.docx (22.1KB, docx) Supplementary Material 1: Informed Consent Form. 13063_2026_9601_MOESM2_ESM.docx (19.4KB, docx) Supplementary Material 2: Supplementary file. 13063_2026_9601_MOESM3_ESM.docx (39.4KB, docx) Supplementary Material 3: SPIRIT checklist. Data Availability Statement Data from the trial will be available after reasonable request from the corresponding author. 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