Postoperative Delirium After Dexmedetomidine versus Propofol Sedation in Older Adults Undergoing Hip Fracture Surgery with Spinal Anesthesia: A Randomized Controlled Trial

Abstract

Purpose

Postoperative delirium is a prevalent complication in elderly surgical patients and is associated with adverse outcomes, including prolonged hospitalization and long-term cognitive impairment. Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, has pharmacological properties that suggest it may reduce the incidence of postoperative delirium. This randomized controlled trial aimed to compare the incidence of postoperative delirium in elderly patients undergoing hip fracture repair under spinal anesthesia with propofol versus dexmedetomidine sedation.

Patients and Methods

This multicenter, randomized, double-blind, parallel-group trial enrolled patients from 12 centers between September 2017 and July 2020. A total of 834 patients scheduled for hip fracture surgery were randomly assigned to receive either dexmedetomidine or propofol for intraoperative sedation. The primary outcome was the incidence of postoperative delirium within 72 hours postoperatively. Secondary outcomes included postoperative pain scores and other complications.

Results

The incidence of postoperative delirium was significantly lower in the dexmedetomidine group compared to the propofol group (4.0% vs 7.8%; P = 0.021). Additionally, the dexmedetomidine group exhibited a lower incidence of postoperative headache than the propofol group (3.4% vs 1.7%; P = 0.04).

Conclusion

Dexmedetomidine sedation reduces the incidence of postoperative delirium in elderly patients undergoing hip fracture surgery under spinal anesthesia combined with iliac fascia block, compared to propofol sedation.

Trial Registration

ClinicalTrials.gov, NCT03346226. Principal investigator: Zhanggang Xue. Registered on 14 September 2017.

Introduction

Postoperative delirium (POD) is an acute cognitive dysfunction commonly observed in elderly surgical patients, characterized by disturbances in consciousness, attention deficits, and cognitive changes.1 The reported incidence of POD varies widely depending on surgical procedures and assessment tools, with particularly high rates documented in orthopedic populations.2,3 POD is associated with prolonged hospitalization, increased morbidity and mortality, and long-term cognitive impairment, underscoring the need for effective preventive strategies.4,5

Various strategies have been explored for POD prevention. Multicomponent non‑pharmacological interventions—including early mobilization, reorientation, and sleep hygiene—have been shown to reduce delirium in older surgical patients.6 Pharmacologically, several agents have been investigated. A recent network meta‑analysis of 158 trials identified dexmedetomidine, corticosteroids, melatonin receptor agonists, parecoxib, olanzapine, and intranasal insulin as the most effective interventions.7 Among these, dexmedetomidine has emerged as a particularly attractive candidate due to its unique sedative profile and opioid‑sparing effects.8

Dexmedetomidine, a highly selective α₂-adrenergic receptor agonist, offers several perioperative advantages over traditional sedatives. Unlike propofol, which acts on Gamma-Aminobutyric Acid (GABA) receptors, dexmedetomidine exerts sedative effects without direct GABAergic interference, potentially resulting in a more favorable cognitive profile.4 Additionally, dexmedetomidine induces sedation resembling natural sleep, which may mitigate postoperative sleep deprivation and circadian rhythm disruption—both recognized risk factors for delirium.9,10

Several studies have directly compared dexmedetomidine and propofol sedation in the context of postoperative delirium prevention. In a randomized trial of elderly patients undergoing hip fracture surgery under spinal anesthesia, Li et al reported that intraoperative sedation with dexmedetomidine significantly reduced POD incidence compared with propofol (11.9% vs. 23.6%; RR = 0.51, P = 0.024).11 A more recent randomized controlled trial by Ekkapat et al, focusing on nocturnal sedation in the intensive care unit following hip fracture surgery, also found a lower delirium incidence with low-dose dexmedetomidine compared to propofol (8.3% vs 22.2%), although the difference did not reach statistical significance.12 In cardiac surgery populations, dexmedetomidine has also been shown to reduce delirium compared with propofol.13 Conversely, one study reported that dexmedetomidine did not reduce POD within three days post-surgery, though it lowered emergence delirium during the recovery period.14 These discrepant findings may be attributed to differences in anesthesia techniques, dexmedetomidine dosing regimens, and timing of administration.

Despite the growing body of evidence supporting dexmedetomidine’s potential neuroprotective effects, randomized controlled trials specifically investigating the impact of intraoperative dexmedetomidine sedation on POD in elderly patients undergoing hip fracture surgery under spinal anesthesia remain limited. Furthermore, few studies have systematically evaluated secondary outcomes such as postoperative headache and other complications in this specific population. Therefore, this multicenter, randomized controlled trial aimed to compare the incidence of POD within 72 hours postoperatively between elderly patients receiving dexmedetomidine versus propofol sedation during hip fracture repair under spinal anesthesia combined with iliac fascia block.

Materials and Methods

Study Design and Oversight

This multicenter, randomized, double-blind, parallel-group controlled trial was conducted in elderly patients undergoing hip fracture surgery under spinal anesthesia. The study protocol was registered with ClinicalTrials.gov (NCT03346226; principal investigator: Zhanggang Xue; date of registration: September 14, 2017) prior to patient enrollment. The trial was carried out at 12 university-affiliated hospitals across China: Zhongshan Hospital, Fudan University (Shanghai); Beijing Jishuitan Hospital (Beijing); Changzheng Hospital, Second Military Medical University (Shanghai); Qianfoshan Hospital of Shandong Province (Jinan); Shanghai Sixth People’s Hospital (Shanghai); Second Hospital of Shanxi Medical University (Taiyuan); Fujian Provincial Hospital (Fuzhou); First Affiliated Hospital of Anhui Medical University (Hefei); Second Affiliated Hospital of Inner Mongolia Medical University (Hohhot); First Affiliated Hospital of Bengbu Medical University (Bengbu); Tianjin Medical University General Hospital (Tianjin); and Henan Provincial People’s Hospital (Zhengzhou). The study protocol was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (approval number: B2017-155R), and all participating centers obtained approval from their respective institutional review boards. The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines.

Study Population

Elderly patients scheduled for hip fracture surgery under spinal anesthesia were eligible for enrollment. All participants provided written informed consent prior to study entry.

Inclusion Criteria

1. Provision of written informed consent;

2. Scheduled for hip fracture repair surgery under spinal anesthesia;

3. American Society of Anesthesiologists (ASA) physical status classification I–III;

4. Age ≥65 years and ≤90 years.

Exclusion Criteria

1. History of psychiatric disorders requiring long-term use of psychotropic medications (eg, dementia, schizophrenia), or history of alcohol abuse;

2. More than eight errors on the preoperative Short Portable Mental Status Questionnaire (SPMSQ), indicating severe cognitive impairment;

3. Positive Confusion Assessment Method (CAM) assessment at baseline;

4. Cerebrovascular accident within three months prior to surgery, including cerebral stroke or transient ischemic attack;

5. Systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg at preoperative evaluation, or heart rate <50 beats per minute;

6. History of heart failure with left ventricular ejection fraction <30% on echocardiography; second-degree type 2 or third-degree atrioventricular block; or active cardiac disease (eg, acute myocardial infarction, unstable angina pectoris);

7. Severe hepatic or renal dysfunction:

   • 1)
     Hepatic dysfunction: any of the following >2 times the upper limit of normal: alanine aminotransferase, conjugated bilirubin, aspartate aminotransferase, alkaline phosphatase, or total bilirubin;
   • 2)
     Renal dysfunction: serum creatinine >443 μmol/L or creatinine clearance <30 mL/min;

8. Diabetes mellitus with severe complications (eg, diabetic ketoacidosis, hyperosmolar coma, severe infections, macrovascular disease, diabetic nephropathy);

9. Severe active infection;

10. Preoperative arterial partial pressure of oxygen (PaO₂) <60 mmHg or pulse oximetry (SpO₂) <92%;

11. Participation in another interventional clinical trial within 30 days prior to enrollment;

12. Inability to communicate verbally or to complete cognitive assessments;

13. Prosthetic fracture, revision surgery, or hip fracture complicated by severe trauma at other sites;

14. Known allergy to the study drugs or contraindication to spinal anesthesia.

Withdrawal Criteria

1. Conversion to general anesthesia due to failure of spinal anesthesia as determined by the attending anesthesiologist;

2. Incomplete monitoring records or case report forms precluding evaluation of efficacy or safety;

3. Postoperative admission to the ICU;

4. Voluntary withdrawal from the study without available postoperative delirium data.

Study Design and Interventions

Patients were screened according to the eligibility criteria, and those who met the criteria provided written informed consent prior to randomization. Eligible patients were randomly assigned to either the dexmedetomidine group or the propofol group.

Upon arrival in the operating room, all patients underwent placement of intravenous access, received supplemental oxygen via a standard face mask at a flow rate of 2 L/min, and were monitored for electrocardiogram (ECG), heart rate (HR), SpO₂, end-tidal carbon dioxide (P_ETCO₂), BIS, and invasive arterial blood pressure.

Invasive arterial blood pressure was monitored continuously throughout the procedure to enable precise recording of intraoperative hemodynamic events, which constituted a secondary outcome of this study. This approach was chosen to ensure accurate and real‑time blood pressure measurements for the detection and management of hypotension and hypertension.

Regional Anesthesia and Preoperative Analgesia

To alleviate positioning-related pain, an ultrasound-guided fascia iliaca block was performed 30 minutes prior to positioning using 20 mL of 0.375% ropivacaine. Spinal anesthesia was then administered via the L2–3 interspace using 10–15 mg of isobaric ropivacaine, with the target sensory level maintained below T10. Surgery commenced after confirmation of adequate anesthesia.

Intraoperative Sedation Protocols

Patients assigned to the dexmedetomidine group received a loading dose of 0.5 μg/kg administered over 15 minutes, initiated 10 minutes before surgical incision. Following the loading dose, a maintenance infusion was started at 0.5 μg/kg/h. For patients assigned to the propofol group, propofol was administered with an initial infusion rate of 2–10 mg/kg/h, started when the operation began.

In both groups, the infusion rate was titrated to maintain a BIS value between 70 and 80 until 30 minutes before the end of surgery. The Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score (detailed criteria provided in Supplemental Table 1) was assessed every 15 minutes, with a target of maintaining a score of 4. In cases of discrepancy between BIS and MOAA/S, the MOAA/S score was prioritized.

Intraoperative Hemodynamic Management

Preoperative administration of scopolamine, penehyclidine hydrochloride, or phenobarbital was prohibited. Intraoperative hypertension was defined as systolic blood pressure (SBP) exceeding 20% above baseline or >160 mmHg, and was managed with a single bolus of nicardipine 0.4 mg, which could be repeated after 5 minutes as needed. Intraoperative hypotension was defined as SBP <20% below baseline or <90 mmHg. Hypotension was treated with vasopressors according to heart rate: if HR <50 beats per minute (bpm), ephedrine 6 mg was administered; if HR ≥50 bpm, phenylephrine 0.1 mg was administered.

Intraoperative bradycardia was defined as HR <60 bpm or a decrease of ≥30% from baseline persisting for ≥2 minutes, when the investigator determined that pharmacological intervention was indicated. Bradycardia was treated sequentially with atropine followed by isoproterenol as needed. Intraoperative tachycardia was defined as HR >100 bpm or an increase of ≥30% from baseline persisting for ≥2 minutes. When tachycardia occurred, the anesthesia provider first verified that the patient was adequately sedated and that the depth of anesthesia was appropriate; if tachycardia persisted, a single bolus of esmolol 20 mg was administered, which could be repeated after 5 minutes as needed.

Postoperative Analgesia

Immediately after surgery, all patients received patient-controlled intravenous analgesia for 48 hours. The analgesic pump was prepared with 250 μg of sufentanil and 100 mg of flurbiprofen axetil diluted in 250 mL of normal saline, programmed to deliver a continuous infusion rate of 1 mL/h, with a bolus dose of 3 mL and a lockout interval of 8 minutes.

A standardized patient‑controlled intravenous analgesia (PCA) protocol was used in all patients to ensure uniformity of postoperative pain management between the two study groups. This approach minimized the potential confounding effect of varying analgesic regimens on the assessment of postoperative delirium and other secondary outcomes. We acknowledge that this level of analgesia may exceed routine clinical practice in some centers.

Primary Outcome

The primary outcome was the incidence of postoperative delirium within 72 hours after surgery. Delirium assessments were performed by trained research assistants who were blinded to group allocation. Evaluations were conducted preoperatively and twice daily (at 9:00 AM and 3:00 PM) on postoperative days 1 through 3.

During each postoperative assessment, the Richmond Agitation-Sedation Scale (RASS) was first used to evaluate the patient’s level of sedation (detailed criteria provided in Supplemental Table 2). For patients with a RASS score > −4 (ie, −3 to +4), the CAM was subsequently administered to assess for delirium (detailed criteria provided in Supplemental Table 3). Patients with a RASS score ≤ −4 were considered unable to complete the CAM assessment, consistent with the withdrawal criteria. A patient was considered to have developed postoperative delirium if they met the diagnostic criteria for delirium at any time point during the follow-up period. In patients who developed delirium, a structured clinical evaluation was performed to identify potential contributing factors, including infection (blood tests and cultures), metabolic disturbances (electrolytes, glucose, renal and liver function), hypoxemia (arterial blood gas analysis), pain (NRS score), and medication‑related causes. These data were recorded in the case report form.

Secondary Outcomes

The secondary outcomes of this study were as follows:

(1) Postoperative pain scores. Pain was assessed at rest and during activity using the Numerical Rating Scale (NRS), which ranges from 0 (no pain) to 10 (worst possible pain). Assessments were performed immediately after recovery from anesthesia and once daily at 9:00 AM on postoperative days 1 through 3.

(2) Intraoperative hemodynamic events requiring intervention. These included hypotension, hypertension, bradycardia, and tachycardia that necessitated pharmacological treatment during surgery, as defined in the intraoperative hemodynamic management section.

(3) Length of hospital stay. This was defined as the duration from the day of surgery to the date of discharge, as determined by the attending surgical team.

(4) Postoperative complications other than delirium. All adverse events occurring during the postoperative period were recorded and categorized using open reporting.

(5) 30-day mortality. Mortality within 30 days after surgery was recorded.

Randomization, Masking, and Sample Size Estimation Randomization

An independent statistician generated the randomization sequence using a computer‑based random number generator (SAS version 9.4; SAS Institute Inc., Cary, NC, USA). A permuted block design with randomly varying block sizes of 4 and 6 was used, stratified by time from injury (≤48 hours vs >48 hours). The allocation sequence was uploaded to a secure, web‑based central randomization system hosted by the Clinical Research Center of Zhongshan Hospital, Fudan University. Upon confirmation of eligibility and written informed consent—typically on the day of surgery—the enrolling investigator at each participating center logged into the system and entered the patient’s screening number and stratification variable. The system then immediately displayed the allocated treatment (dexmedetomidine or propofol). The allocation result was transmitted electronically to the anesthesia team.

Masking (Blinding)

All patients were blinded to their treatment assignment; the infusion line and syringe were shielded to maintain blinding. The anesthesia nurse or anesthesiologist prepared the investigational medication (dexmedetomidine or propofol) according to the group assignment and labeled the syringe with the patient’s randomization number. The anesthesiologist responsible for intraoperative management was not involved in postoperative follow-up assessments. The follow-up assessors, who performed postoperative cognitive function evaluations, were blinded to group allocation. The anesthesiologist did not disclose group information to the follow-up assessor and did not communicate any details regarding the patient’s medication or postoperative delirium status.

Sample Size Estimation

The sample size calculation was based on a previous study reporting the incidence of postoperative abnormal behavior following sedation with dexmedetomidine and propofol as 2.3% and 6.5%, respectively.15 Using PASS 15.0 software, we estimated that a total of 371 patients per group would be required to detect this difference with 80% power and a two-sided significance level of 0.05. Accounting for a 10% dropout rate, a total of 826 patients were enrolled. We acknowledge that this calculation was based on “abnormal behavior” rather than delirium assessed by a validated tool (CAM), which represents a limitation. At the time of study design, this was the most relevant available evidence for our population.

Statistical Analysis

All statistical analyses were performed using Statistical Analysis System (version 9.4; Statistical Analysis System Institute, USA). The primary outcome, postoperative delirium rate, was analyzed using the chi-square test in both the intention-to-treat and per-protocol populations.

Quantitative data were described as means ± standard deviations, medians, and minimum and maximum values. One-way analysis of variance was used for comparison between groups. Qualitative data were expressed as frequencies and percentages, and the chi-square test was used for comparison between groups.

The chi-square test or Fisher’s exact probability method was used to compare the adverse events between the two groups; adverse events and adverse reactions were expressed as frequencies and percentages. There were no controls for multiplicity of secondary outcomes and adverse events.

A two-sided P value <0.05 was considered statistically significant for all analyses.

Results

Study Population

As of July 30, 2020, a total of 850 patients were enrolled. Of these, 16 were excluded before enrollment: four due to dementia, six due to cognitive impairment, and six who declined to participate (ie, refused to provide written informed consent). The remaining 834 patients were randomly assigned to either the propofol group (n = 412) or the dexmedetomidine group (n = 422). No patients were withdrawn after randomization; therefore, the per-protocol population was identical to the intention-to-treat population. A flowchart of patient enrollment and randomization is presented in Figure 1.

Figure 1.

The specific flow diagram of patient selection.

Baseline Characteristics

Baseline demographic and clinical characteristics of the two groups are summarized in Table 1. The groups were well balanced at baseline. The mean age of the study population was approximately 78 years, and the majority of patients were female. Vital signs in both groups were within normal ranges.

Table 1.

Patients Demographic and Clinical Characteristics at Baseline

		Propofol Group n= 412	Dexmedetomidine Group n = 422
Gender	Male	125 (30.3%)	125 (29.6%)
Age (year)	Mean (SD)	78 (7)	78 (7)
Weight (kg)	Mean (SD)	59.3 (14.2)	59.6 (12.3)
Height (cm)	Mean (SD)	161.8 (8.1)	161.6 (8.8)
Education status	High school unfinished	297 (72.1%)	322 (76.3%)
	High school graduated	59 (14.3%)	52 (12.3%)
	University unfinished	5 (1.2%)	3 (0.7%)
	University graduated	46 (11.2%)	35 (8.3%)
	Post-graduated	1 (0.2%)	1 (0.2%)
	Other	4 (1.0%)	9 (2.1%)
ASA grade	I	23 (5.6%)	24 (5.7%)
	II	196 (47.6%)	194 (46.0%)
	III	193 (46.8%)	204 (48.3%)
Anesthesia History		116 (28.2%)	106 (25.1%)
Allergy History		29 (7.0%)	29 (6.9%)
Surgery History		140 (34.0%)	129 (30.6%)
Application of combined drugs		190 (46.1%)	184 (43.6%)
Smoking History		29 (7.0%)	31 (7.35)
Baseline vital signs
Systolic blood pressure (mmhg)	Mean (sd)	145 (19)	145 (20)
Diastolic blood pressure (mmhg)	Mean (sd)	74 (12)	75 (12)
HR (beats/min)	Mean (sd)	78 (12)	79 (12)
SpO2 (%)	Mean (sd)	96 (3)	96 (6)

Abbreviations: ASA, American Society of Anesthesiologists; HR, heart rate; SpO₂, oxygen saturation measured by pulse oximetry.

Primary Outcome

The primary outcome results are presented in Table 2. Within 72 hours postoperatively, the incidence of delirium, as assessed by the CAM, was significantly lower in the dexmedetomidine group (17/422, 4.0%) compared to the propofol group (32/412, 7.8%; P = 0.021).

Table 2.

Comparison of Postoperative Delirium at Different Time Points

		Propofol Group n=412	Dexmedetomidine Group n=422	P value
Delirium		32(7.8%)	17(4.0%)	0.021
Post-operative day −1	9AM	24(5.8%)	14(3.3)	0.106
	3PM	22(5.3%)	16(3.8%)	0.177
Post-operative day −2	9AM	6(1.5%)	7(1.7%)	0.447
	3PM	6(1.5%)	6(1.4%)	0.582
Post-operative day −3	9AM	4(1.0%)	2(0.5%)	0.556
	3PM	1(0.2%)	1(0.2%)	0.677

Secondary Outcomes

As shown in Table 3, the incidence of postoperative headache was significantly lower in the dexmedetomidine group (7/422, 1.7%) than in the propofol group (14/412, 3.4%; P = 0.04). No significant differences were observed between the two groups in the incidence of other postoperative complications (P > 0.05).

Table 3.

Comparison of Postoperative Complications Except Delirium

	Propofol Group n = 412	Dexmedetomidine Group n = 422	P value
Headache	14 (3.4%)	7 (1.7%)	0.040
Uroschesis	8 (1.9%)	4 (0.9%)	0.051
Bradycardia	5 (1.2%)	4 (0.9%)	0.123
Hypotension	6 (1.5%)	4 (0.9%)	0.110

The frequency of sedation-related adverse events requiring pharmacological intervention did not differ significantly between the two groups (P > 0.05) (Table 4).

Table 4.

Comparison of Adverse Reactions

		Propofol Group n = 412	Dexmedetomidine Group n = 422	P value
		Median [IQR]	Median [IQR]
Numbers of sedation related adverse reactions	Hypertension	0 [0, 1]	0 [0, 1]	0.615
	Hypotension	1 [1, 2]	1 [1, 2]	0.262
	Bradycardia	1 [1, 1]	1[1, 2]	0.593
	Tachycardia	0 [0, 1]	0 [0, 0]	0.187
Numbers of intra-operative adverse reactions which need treatment	Hypertension	0 [0, 1]	0 [0, 1]	0.850
	Hypotension	1 [1, 2]	1 [1, 2]	0.123
	Bradycardia	1 [0, 1]	1 [1, 1]	0.358
	Tachycardia	0 [0, 0]	0 [0, 0]	0.442

Abbreviation: SpO₂, oxygen saturation measured by pulse oximetry.

Pain scores, assessed both at rest and during activity, showed no statistically significant differences between the two groups at any time point (preoperative, immediately postoperatively, and on postoperative days 1–3; P > 0.05 for all comparisons) (Supplemental Table 4).

The mean surgical duration was 85 minutes in the propofol group and 67 minutes in the dexmedetomidine group. The mean length of hospital stay was 9 days in the propofol group and 12 days in the dexmedetomidine group. The wide standard deviations reflect substantial inter‑center and inter‑case variability, attributable to differences in surgical technique, case complexity, and the teaching hospital setting. Neither of these differences reached statistical significance (P > 0.05) (Table 5).

Table 5.

Comparison of Surgical Duration, Hospital Stay and Survival Status

	Propofol Group n = 412	Dexmedetomidine Group n = 422	P value
	Mean (SD)	Mean (SD)
Hospital Stay (day)	9 (41)	12 (51)	0.378
Surgical Duration (min)	85 (243)	67 (95)	0.149
Postoperative mortality rate (%)	1 (0.3%)	2 (0.6%)	0.620

As of July 30, 2020, one death occurred in the propofol group (0.3%) and two deaths occurred in the dexmedetomidine group (0.6%). This difference in postoperative mortality was not statistically significant (P > 0.05) (Table 5).

Discussion

This randomized controlled trial demonstrated that among elderly patients undergoing hip fracture surgery under spinal anesthesia, intraoperative sedation with dexmedetomidine significantly reduced the incidence of postoperative delirium within 72 hours compared with propofol (4.0% vs 7.8%; P = 0.021). This finding is consistent with previous research.11,16–18 A 2024 RCT in elderly hip fracture patients reported delirium incidences of 8.3% with low‑dose dexmedetomidine versus 22.2% with propofol.12

We acknowledge that the overall incidence of delirium observed in our study (4.0–7.8%) is substantially lower than the 20–25% typically reported in hip fracture populations. This is likely attributable to our stringent exclusion criteria, which eliminated patients with dementia, severe cognitive impairment, ASA ≥4, and significant comorbidities, thereby selecting a relatively low‑risk subgroup. Furthermore, the use of regional anesthesia and avoidance of general anesthesia may have contributed to the reduced incidence. Consequently, our findings are primarily applicable to this selected population, and caution should be exercised when generalizing to higher‑risk or unselected hip fracture patients.

A study comparing dexmedetomidine and propofol sedation in healthy elderly patients undergoing lower limb orthopedic surgery under spinal anesthesia also reported a lower incidence of delirium in the dexmedetomidine group (3.0% vs 6.6%).16 However, the delirium rates in that study were lower than those observed in our trial. This discrepancy may be explained by differences in surgical procedures: our study specifically enrolled patients undergoing hip fracture repair, a procedure associated with a higher risk of postoperative delirium compared to other orthopedic surgeries.15,19

In contrast, one clinical study investigating the effects of dexmedetomidine on emergence delirium and electroencephalography in elderly patients undergoing lower limb orthopedic surgery found that dexmedetomidine did not reduce the incidence of postoperative delirium within three days after surgery, although it did lower the incidence of emergence delirium during the recovery period.14 The discrepancy between our findings and those of that study may be attributed to differences in anesthesia techniques and dexmedetomidine dosing. In that study, general anesthesia combined with nerve block was used, and dexmedetomidine was administered at a rate of 0.3 mL/kg/h until 20 minutes before the end of surgery.

In the broader context, multicomponent non‑pharmacological interventions and other agents such as melatonin receptor agonists have also shown promise20 but dexmedetomidine remains a particularly attractive option due to its favorable sedative profile and acceptable safety profile.

Regarding secondary outcomes, we observed no significant difference in the length of hospital stay between the two groups. However, a clinical trial involving elderly patients undergoing hip replacement surgery reported that the dexmedetomidine group had earlier mobilization and shorter hospital stays compared to the propofol group.21 This difference may be explained by the anesthesia technique used in that trial, which involved combined lumbar plexus and paravertebral nerve blocks—a regional anesthesia approach that may facilitate earlier mobilization and accelerate recovery and discharge.

In terms of safety, our study found no significant differences between the two groups in the incidence of hypotension or bradycardia, nor in 30-day mortality rates. These findings are consistent with previous research.22 We acknowledge that the incidence of hypotension and bradycardia requiring intervention in our dexmedetomidine group appears lower than that reported in some published studies.23–25 This likely reflects our exclusion of high‑risk patients (ASA ≥4, severe cardiovascular disease), our use of a slow loading infusion and light sedation target (BIS 70–80), and protocol‑driven early hemodynamic intervention. Additionally, differences in event definitions (events requiring pharmacological intervention vs any deviation from baseline) may contribute to the observed variation. Our findings suggest that, in a carefully selected low‑risk population and with a conservative dosing strategy, dexmedetomidine can be used with a manageable hemodynamic safety profile. Notably, we observed a significantly lower incidence of postoperative headache in the dexmedetomidine group (1.7% vs 3.4%; P = 0.04). This may be related to the pharmacologic properties of dexmedetomidine, which can constrict cerebral blood vessels and reduce cerebral blood flow, potentially alleviating headache associated with subarachnoid block.26

We acknowledge that our finding—dexmedetomidine reducing postoperative delirium compared with propofol—is not entirely novel, as prior meta‑analyses have reported similar directions of effect. Nonetheless, we believe our study provides meaningful confirmatory value by focusing specifically on elderly hip fracture patients under spinal anesthesia, a population less extensively studied in large RCTs, and by offering detailed safety data that complement the existing literature.

Limitations

This study has several limitations. First, we assessed delirium only during the first three postoperative days, which may have underestimated the overall incidence of delirium, as some cases may occur beyond this period. Second, the optimal dose of dexmedetomidine for preventing postoperative delirium remains to be determined. In our study, we administered a loading dose of 0.5 μg/kg over 15 minutes, followed by a maintenance infusion of 0.5 μg/kg/h until the end of surgery. Whether different dosing regimens or timing of administration could yield better outcomes requires further investigation. Third, our findings are limited to the specific patient population (elderly patients undergoing hip fracture surgery under spinal anesthesia), and caution should be exercised when generalizing to other surgical populations or anesthesia techniques. Fourthly, we acknowledge that our sample size was estimated based on a study evaluating “abnormal behavior” rather than CAM‑assessed delirium. This may have resulted in an optimistic effect size estimate, as the true effect of dexmedetomidine on CAM‑assessed delirium may be smaller than that observed for abnormal behavior. Therefore, our study may have been underpowered to detect a more modest but clinically realistic effect size. Future studies with larger sample sizes and using validated delirium assessment tools are warranted to confirm our findings.

Conclusion

In this randomized controlled trial of elderly patients undergoing hip fracture surgery under spinal anesthesia combined with iliac fascia block, intraoperative sedation with dexmedetomidine significantly reduced the incidence of postoperative delirium and headache compared with propofol. No significant differences were observed between the two groups in the frequency of sedation-related adverse events during surgery, length of hospital stay, other postoperative complications, or 30-day mortality.

Funding Statement

This work was supported by Jiangsu Enhua Pharmaceutical Co., Ltd. The company covered research operational costs, including case report form printing, and article processing charges. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Access and Timing

Data and supporting documents will be available upon reasonable request to the corresponding author (Xiaoguang Zhang; email: zhang.xiaoguang@zs-hospital.sh.cn), beginning 12 months after publication and ending 36 months after publication. Requests will be considered from researchers who provide a methodologically sound proposal and sign a data access agreement.

Trial Registration Compliance

This data sharing plan aligns with the trial registration (ClinicalTrials.gov NCT03346226). Any deviations will be disclosed in future publications.

Abbreviations

POD, Postoperative delirium; ICU, Intensive Care Unit; BIS, ‘Bispectral Index; ASA, American Society of Anesthesiologists; SPMSQ, Short Portable Mental Status Questionnaire; CAM, Confusion Assessment Method; PaO₂, partial pressure of oxygen; SpO₂, pulse oximetry; ECG, electrocardiogram; HR, heart rate; PETCO₂, end-tidal carbon dioxide; MOAA/S, Modified Observer’s Assessment of Alertness/Sedation; SBP, systolic blood pressure; RASS, Richmond Agitation-Sedation Scale; NRS, Numerical Rating Scale.

Data Sharing Statement

In compliance with Dove Medical Press policy, the authors intend to share de-identified individual participant data from this study. The data to be shared include demographic information, baseline characteristics, primary and secondary outcome data, and adverse event records. Additionally, the study protocol, statistical analysis plan, and informed consent form will be made available.

Ethics Approval and Informed Consent

The study protocol was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (approval number: B2017-155R) and the institutional review boards of all participating centers. Written informed consent was obtained from every patient before enrollment. The trial was registered with ClinicalTrials.gov (NCT03346226) and conducted in accordance with the Declaration of Helsinki.

Consent for Publication

All authors have reviewed and approved the final version of this manuscript and consent to its publication in Drug Design, Development and Therapy. The authors have agreed to be accountable for all aspects of the work. This manuscript has not been published elsewhere and is not under consideration for publication by any other journal.

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.