Published online Jun 19, 2026. doi: 10.5498/wjp.v16.i6.116925
Revised: January 26, 2026
Accepted: March 2, 2026
Published online: June 19, 2026
Processing time: 142 Days and 1.2 Hours
Postoperative delirium (POD) is characterized as a major complication for the geriatric population, and is associated with worsening of the individual and an increase in healthcare costs. The association between POD and the presence of preoperative depression and cognitive status remains unknown.
To analyze whether preoperative cognitive status and depression would associate with POD and to what extent in the aged population with hip fractures.
A cohort study of patients aged ≥ 65 with hip fractures who underwent surgical intervention at this institution from October 2022 to October 2025 was performed. The 15-item Geriatric Depression Scale was used for assessing depression, and The Mini-Mental State Examination for cognitive status as well. POD was diagnosed using the Confusion Assessment Method within the first 7 postoperative days. Multivariate logistic regression analysis was performed to identify the independent risk factors for POD.
Of 150 patients, 46 (30.7%) developed POD. Patients with preoperative depression (15-item Geriatric Depression Scale ≥ 5) had a significantly higher incidence of POD than non-depressed patients (45.8% vs 22.1%, P = 0.003). Similarly, patients with cognitive impairment (Mini-Mental State Examination score < 24) had a higher incidence of POD than those with normal cognition (52.0% vs 18.5%, P < 0.001). Multivariable analysis revealed that preoperative depression [odds ratio (OR) = 2.84, 95%CI: 1.26-6.41, P = 0.012], cognitive impairment (OR = 3.92, 95%CI: 1.71-8.98, P = 0.001), age ≥ 80 years (OR = 2.47, 95%CI: 1.09-5.59, P = 0.030), and American Society of Anesthesiologists classification ≥ III (OR = 2.63, 95%CI: 1.18-5.87, P = 0.018) were independent predictors of POD.
Preoperative depression and cognitive impairment are independent risk factors for POD in elderly patients with hip fractures. Preoperative screening for these factors can guide preventive interventions in high-risk patients.
Core Tip: Cognitive dysfunction and preoperative depression were recognized as independent variables and were evaluated for the incidence of postoperative delirium in hip fracture surgery patients in the geriatric population. We have shown a considerable increase in the incidence of postoperative delirium with the combination of dementia and depression in this population via established techniques including the 15-item Geriatric Depression Scale, the Mini-Mental State Examination, and the Confusion Assessment Method. Higher American Society of Anesthesiologists scores and older age only increase the incidence. The incorporation of these screening mechanisms in the preoperative settings is expected to help construction of specific preoperative plans for patients at higher risk.
- Citation: Zhong JL, Cai Y, Li SH, Zhao W, Su XT, Jin CH. Association of preoperative depression and cognitive status with postoperative delirium in elderly patients with hip fracture. World J Psychiatry 2026; 16(6): 116925
- URL: https://www.wjgnet.com/2220-3206/full/v16/i6/116925.htm
- DOI: https://dx.doi.org/10.5498/wjp.v16.i6.116925
Among the concerns in the older population is the increasing projected number of hip fractures at 1.5 million annually due to the lack of care of global hip fractures[1]. Generally, the hip fractures involve individuals aged 65 and over. Most of the cases involve surgery not only to resolve the fracture, but also to address post-operative complications[2]. Advanced surgical and per-operative care are not likely to improve the outcome as hip fractures tend to be associated with which are great mortality and morbidity in the elderly, with 50% surgical cases reporting complications in elderly patients[3].
Postoperative delirium (POD) is a common complication in hip fracture patients, reporting the rates of 13.5% to 61.3% for the aged patients[4,5]. It is a disturbance in the level of consciousness characterized by disturbances in attention, cognition and level of perception which also demonstrates fluctuations in the level of consciousness throughout the day[6]. It also has a lot of complications associated with it such as extended hospital stays, a greater degree of decline in their functional level, an increased chance of being moved to a nursing home, and a significant rise in the cost of care from all sources, as well as increased mortality[7,8]. Beyond the direct impacts of decreased cognitive function and increased mortality, it is associated with an increased risk of future cognitive decline and dementia[9].
The development of POD has a broad of factors and it is not completely understood, but it is thought to be due to a combination of a number of previous factors and especially due to the combination of surgical procedures, anesthesia and medications and also changes in metabolism[10]. For effective care management of the elderly, it is important to identify elevated risk POD patients in order to lower their care burden by utilizing less impact intervention[11].
Depression, particularly in its more severe form, is common in older adult populations suffering from hip fractures, ranging from 9% to 47%[12]. Preoperative depression is considered one of the risk factors for the development of POD due to a shared and combined underlying neurobiological mechanisms, including neurotransmitter dysregulation, neuroinflammation, and stress response alterations[13]. However, the existing literature on this issue highlights a paradox about the role of preoperative depression and its association with POD in patients undergoing surgical treatment for hip fractures, with most studies reporting conflicting results[14]. Even among studies reporting a positive correlation between risk of POD and presence of preoperative depressive symptoms, most studies lack the necessary methodological rigor to rule out the effect of cognitive function and other confounding factors. Given the effect of assessing the severity of depression, depression assessment protocols and disparate patient populations, along with the complexity of the cascade of depression and cognitive impairment in elderly surgical patients, it is evident that the role of preoperative depression on POD, with the consideration of cognitive state, is of great interest for further studies.
Cognitive impairment stands out as one of the leading risk factors of POD in surgical patients[15]. Elderly patients sustaining hip fractures have a broad spectrum of cognitive impairment on the continuum between mild cognitive impairment and dementia. Preoperative cognitive impairment may signify high risk for POD and low cognitive reserve. Despite the clinical importance of POD in patients with hip fractures, few studies have systematically examined the relationships among preoperative depression, cognitive status, and POD in this vulnerable population. Furthermore, most existing studies are limited by small sample sizes, heterogeneous patient populations, and a lack of standardized assessment tools. Therefore, we conducted this retrospective cohort study to investigate the association of preoperative depression and cognitive status with the incidence of POD in elderly patients undergoing hip fracture surgery and identify additional independent risk factors for POD. We hypothesized that both preoperative depression and cognitive impairment are independently associated with an increased risk of POD.
This single-center retrospective cohort study was conducted at the Department of Orthopaedics, Tianjin Binhai New Area TEDA Hospital, located in the Binhai New Area of Tianjin, a rapidly developing economic zone in northern China. This is a tertiary teaching hospital with approximately 1500 beds and a specialized geriatric orthopedic unit, primarily serving an urban and suburban population including a significant proportion of elderly residents from nearby industrial com
We performed a retrospective chart review of patients aged 65 years and older who underwent surgical intervention for a hip fracture at our facility within the date from October 1, 2022 to October 31, 2025. Hip fractures were classified as losses of continuity of the femoral neck and fractures involving the trochanteric and subtrochanteric regions as diagnosed based on plain radiology or computed tomography.
Inclusion criteria: (1) Age ≥ 65 years; (2) A hip fracture diagnosis that required surgical intervention; (3) A surgical procedure performed within 7 days of hospital admission; (4) Preoperative assessment data for depression and cognitive status; and (5) POD assessment conducted within 7 days of the surgical procedure.
Exclusion criteria: (1) Pathological fractures from malignancy or metabolic bone disease; (2) Polytrauma; (3) A diagnosis of dementia or other psychiatric diseases that warranted the use of antipsychotic medications; (4) A preoperative assessment that was incomplete due to intense aphasia or other language deficits; (5) Documented substance use or alcohol use disorder; (6) Preoperative delirium or deteriorated mental state on admission; (7) Absence of medical record data; and (8) Death occurred within 48 hours postoperatively. During this period, 198 older patients with hip fractures were surgically treated at our facility. Of 150 patients remained after fulfilling the stated criteria. The selection of patients is elaborated within the framework of the study flow chart.
Two research assistants used a structured methodology to extract data on demographics, surgical history, and elements combining operation data from electronic medical records. Any inadequacies were discussed and clarified with the senior investigator.
Demographic characteristics: (1) Age; (2) Sex; (3) Body mass index; (4) Education level; (5) Living situation; and (6) History of smoking and alcohol consumption.
Preoperative clinical data: (1) Type of fracture (femoral neck, intertrochanteric, or subtrochanteric); (2) Mechanism of injury; (3) Time from injury to surgery; (4) Comorbidities including hypertension, diabetes mellitus, coronary artery disease, chronic obstructive pulmonary disease, chronic kidney disease, and cerebrovascular disease; (5) Number of comorbidities; (6) American Society of Anesthesiologists (ASA) physical status classification; (7) Preoperative laboratory values including hemoglobin, albumin, creatinine, and electrolytes; (8) Preoperative medications; and (9) Functional status using the Activities of Daily Living scale.
Perioperative data: (1) Type of anesthesia (general or regional); (2) Surgical procedure (hemiarthroplasty, total hip arthroplasty, or internal fixation); (3) Duration of surgery; (4) Intraoperative blood loss; (5) Blood transfusion requirements; and (6) Postoperative pain scores.
Postoperative outcomes: (1) Length of hospital stay; (2) In-hospital complications; and (3) Discharge destination.
The Chinese version of the 15-item Geriatric Depression Scale (GDS-15) was used to assess the reliability of data on preoperative depression on an elderly population in China. GDS-15 questions focus on the psychological aspect of a patient’s condition and offer a more ample framework to assess geriatric depression, separating the questions from the patient's physical condition. The scale consists of 15 questions with binary answers. According to the literature, a score of 0-4 indicates no depression, 5-8 indicates mild depression, 9-11 indicates moderate depression, and a score ranging between 12-15 represents severe depression. The threshold for defining preoperative geriatric depression for most studies using the GDS-15 scale is a score 5 or greater. The GDS-15 was done by the patient’s primary care nurse in the ward the patient was admitted to, within 24 hours of patient admission to the hospital, in a quiet environment before any sedation and without providing any harmful convalescent medication.
The Mini-Mental State Examination (MMSE) is the standard for assessing the cognitive state of an individual and is one of the oldest and most widely used tools for the evaluation of cognitive deficits in a wide range of clinical and research settings. A group of trained psychologists and geriatric nurses used the local language of the MMSE and the local MMSE version within the 24 hours of a patient’s admission for the preoperative state. This examination of cognitive state involves the evaluation of the following six aspects of cognition: (1) Orientation; (2) Registration; (3) Attention and calculation; (4) Recall; (5) Verbal expression and comprehension; and (6) Visual and Spatial construction (i.e., drawing). In these six areas, the total score a participant can receive on the local version of the MMSE ranges from 0 to 30. In this report and following the identified cognitive impairment guidelines of MMSE, it is observed that if a participant has 6 years or more of formal schooling, cognitive impairment is said to be present if that participant’s score is < 24; if a participant is in formal schooling for 1-6 years, the score is < 20; and for an illiterate participant, the MMSE score is < 17. The analysis of patients’ preoperative cognitive state involved the following two groups of patients: (1) Patients diagnosed with cognitive impairment; and (2) Patients with cognitive impairment who completed the MMSE. To ensure the patients’ comfort from pain, or from any active medical crisis, the MMSE had to be completed preoperatively. To ensure that each patient’s reaction to this examination is as unbiased as possible, the same group of personnel that performed the MMSE was not involved in the evaluation of the patients with POD.
POD was assessed daily from postoperative day 1 through day 7 or until hospital discharge using the Confusion Assessment Method (CAM), which is the most widely validated and used instrument for delirium diagnosis. CAM has high sensitivity (94%-100%) and specificity (90%-95%) for detecting delirium when administered by trained clinicians. CAM requires the presence of acute onset and fluctuating course, inattention, and either disorganized thinking or altered level of consciousness. Delirium assessments were performed twice daily (in the morning between 8:00 AM and 10:00 AM and in the evening between 6:00 AM and 8:00 PM) by trained geriatric nurses who were blinded to the patients’ preoperative depression and cognitive status scores. The nurses conducting the CAM assessments had received formal training in delirium assessment and had at least 2 years of experience in geriatric care. Each assessment included direct observation of the patient, brief cognitive testing, and a review of nursing notes from the preceding shift regarding behavioral changes or confusion. If delirium was suspected, a geriatric psychiatrist was consulted to confirm the diagnosis. POD was considered present if the patient met the CAM criteria in at least one assessment during the 7-day postoperative period. Delirium severity was classified using the Memorial Delirium Assessment Scale in patients who developed POD. Additionally, the subtypes of delirium (hyperactive, hypoactive, or mixed) and the duration of delirium episodes were documented.
All patients received standardized perioperative care according to the institutional protocols for elderly patients with hip fractures. Preoperative management included comprehensive geriatric assessment, optimization of medical comorbidities, pain management with multimodal analgesia, maintenance of hydration and nutrition, and early mobilization, when feasible. The patients received either general or regional anesthesia (spinal or epidural) based on the anesthesiologist’s assessment and patient factors. Surgical procedures included hemiarthroplasty, total hip arthroplasty, or internal fixation with a dynamic hip screw or intramedullary nailing depending on the fracture type, patient age, functional status, and surgeon’s preference. Postoperative care included continued multimodal analgesia with a preference for non-opioid medications when possible, prevention of common postoperative complications through early mobilization, deep vein thrombosis prophylaxis, urinary catheter removal within 24-48 hours when feasible, maintenance of sleep-wake cycles with non-pharmacological interventions, regular reorientation, involvement of family members, and minimization of unnecessary medical interventions. Benzodiazepines and anticholinergic medications were avoided unless necessary. Low-dose antipsychotics were used under psychiatric guidance when the pharmacological management of delirium was required.
Statistical analyses were performed using SPSS (version 26.0; IBM Corp., Armonk, NY, United States) and R version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were tested for normality using the Shapiro-Wilk test and visual inspection of Q-Q plots. Normally distributed continuous variables were expressed as mean ± SD and compared between groups using independent t-tests, whereas non-normally distributed variables were expressed as median with interquartile range (IQR) and compared using the Mann-Whitney U test. Categorical variables were expressed as frequencies and percentages and compared using the χ2 test or Fisher’s exact test when the expected cell frequencies were less than 5.
The primary outcome was POD incidence. Univariate logistic regression analysis was initially performed to identify potential risk factors associated with POD, with variables showing p-values < 0.10. considered for inclusion in the multivariate models. Multivariate logistic regression analysis with backward stepwise selection was conducted to identify the independent predictors of POD. Variables with clinical relevance or established associations with POD in previous studies were also considered for inclusion, regardless of univariate significance. The final multivariate model included age, sex, ASA classification, preoperative depression status, preoperative cognitive status, type of anesthesia, and surgical duration. The results were reported as odds ratio (OR) with 95%CI. The discrimination ability of the final model was assessed using the area under the curve, and model calibration was evaluated using the Hosmer-Lemeshow goodness-of-fit test.
Subgroup analyses were performed to explore potential effect modifications by examining the association between preoperative depression and POD stratified by cognitive status (normal vs impaired) and vice versa. Interaction terms were included in the logistic regression models to test for statistical interactions. Additionally, sensitivity analyses were conducted using different cut-off values for depression (GDS-15 ≥ 8) and cognitive impairment (MMSE < 20).
All statistical tests were two-sided, and a P value < 0.05 was considered statistically significant. No adjustment for multiple comparisons was made given the exploratory nature of some analyses. Missing data were minimal (< 5% for any variable) and handled using a complete case analysis. Power calculation indicated that with 150 patients and an expected POD incidence of 30%, the study had 80% power to detect an OR of 2.5 or greater for the association between preoperative depression and POD at a significance level of 0.05.
A total of 150 elderly patients with hip fracture were enrolled in the study. The mean age of the study population was 78.4 ± 7.8 years (65-96 years). Demographic and clinical characteristics of the patients are presented in Table 1. The study population was predominantly female (68.0%, n = 102). Intertrochanteric fractures were the most common type of fracture (57.3%, n = 86), followed by neck of femur fractures (38.0%, n = 57), and subtrochanteric fractures (4.7%, n = 7). Most patients fractured the neck of femur due to a simple fall (89.3%, n = 134). The median time to the hip surgery was 3 days (IQR: 2-5 days). Nearly half of the patients (48.0%, n = 72) were classified by the ASA to have an ASA score classification of III or greater, suggesting significant comorbidity.
Patients were also assessed for depression using a GDS to determine whether the patient had depression (0-4: Normal, 5-8: Mild, 9- 11: Moderate, 12 and above: Severe). Pre-operatively, 38.7% (n = 58) of patients were reported to be depressed (GDS-15 ≥ 5). Mild depression was reported in 28.7% (n = 43), moderate in 8.0% (n = 12), and severe depression in (n = 3). Cognitive impairment, MMSE score 24, were reported in 33.3% (n = 50) of patients. Of the 150 patients, 58.0% (n = 87) underwent internal fixation as part of the surgical management, 30.7% (n = 46) underwent hemiarthroplasty, and 11.3% (n = 17) underwent total hip arthroplasty. General anesthesia was utilized in 56.0% (n = 84) and regional anesthesia was utilized in 44.0% (n = 66) of the cases.
POD was observed in 46 (30.7%) patients during a 7-day risk window. The IQR of the time to onset of POD was 2 days (IQR: 1-3 days). The largest fraction of cases developed POD in the first 3 days. The type and frequency of delirium were as follows: 43.5% (n = 20) hypoactive delirium, 26.1% (n = 12) hyperactive delirium, and 30.4% (n = 14) mixed type delirium. The duration of delirium ranged between 2-5 days. The average Memorial Delirium Assessment Scale score was 18.6 ± 5.4, which denotes a moderate severity classification.
Table 1 presents a comparison of the demographic, clinical, and perioperative characteristics of patients who developed POD and those who did not. Patients who developed POD were significantly older (mean age 81.2 ± 7.4 years vs 77.1 ± 7.7 years, P = 0.003) and more likely to have ASA classification ≥ III (65.2% vs 40.4%, P = 0.006), had lower preoperative hemoglobin levels (mean 103.2 ± 18.6 g/L vs 110.5 ± 16.2 g/L, P = 0.021), and had lower preoperative albumin levels (mean 34.2 ± 4.8 g/L vs 36.8 ± 4.2 g/L, P = 0.002) compared to those without POD.
Notably, the prevalence of preoperative depression was significantly higher in patients who developed POD than in those who did not develop POD (54.3% vs 31.7%, P = 0.012). Similarly, the prevalence of preoperative cognitive impairment was markedly higher in the POD group (54.3% vs 23.1%, P < 0.001). As shown in Table 2, patients with preoperative depression had a significantly higher incidence of POD than those without depression (45.8% vs 22.1%, P = 0.003), and patients with cognitive impairment had a substantially higher incidence of POD than those with normal cognition (52.0% vs 18.5%, P < 0.001).
| Variable | n | POD | No POD | P value |
| Preoperative depression (GDS-15) | ||||
| No depression (GDS-15 < 5) | 92 | 20 (21.7) | 72 (78.3) | 0.003 |
| Depression (GDS-15 ≥ 5) | 58 | 26 (44.8) | 32 (55.2) | |
| Preoperative Cognitive Status (MMSE) | ||||
| Normal cognition (MMSE ≥ 24) | 100 | 19 (19.0) | 81 (81.0) | < 0.001 |
| Cognitive impairment (MMSE < 24) | 50 | 27 (54.0) | 23 (46.0) | |
| Combined categories | ||||
| Neither depression nor cognitive impairment | 64 | 9 (14.1) | 55 (85.9) | < 0.001 |
| Depression only (no cognitive impairment) | 36 | 13 (36.1) | 23 (63.9) | |
| Cognitive impairment only (no depression) | 28 | 11 (39.3) | 17 (60.7) | |
| Both depression and cognitive impairment | 22 | 13 (59.1) | 9 (40.9) |
Regarding surgical factors, there were no significant differences between the groups in terms of the type of fracture, surgical procedure, or type of anesthesia. However, patients who developed POD had longer surgical duration (mean 128.6 ± 38.4 minutes vs 112.3 ± 32.6 minutes, P = 0.008) and were more likely to receive intraoperative blood transfusion (45.7% vs 28.8%, P = 0.048).
Univariable logistic regression analysis identified multiple potential risk factors for POD (Table 3), including age ≥ 80 years (OR = 2.68, 95%CI: 1.32-5.44, P = 0.006), ASA classification ≥ III (OR = 2.77, 95%CI: 1.38-5.58, P = 0.004), preoperative depression (OR = 2.64, 95%CI: 1.28-5.44, P = 0.008), preoperative cognitive impairment (OR = 4.67, 95%CI: 2.25-9.70, P < 0.001), preoperative hemoglobin < 100 g/L (OR = 2.18, 95%CI: 1.06-4.49, P = 0.035), preoperative albumin
| Variable | Odds ratio | 95%CI | P value |
| Age ≥ 80 years | 2.68 | 1.32-5.44 | 0.006 |
| Female sex | 0.84 | 0.40-1.76 | 0.635 |
| Body mass index < 18.5 kg/m2 | 1.86 | 0.74-4.67 | 0.189 |
| Education < 6 years | 1.34 | 0.66-2.72 | 0.414 |
| Living alone | 1.32 | 0.59-2.95 | 0.509 |
| American Society of Anesthesiologists classification ≥ III | 2.77 | 1.38-5.58 | 0.004 |
| Preoperative depression (15-item Geriatric Depression Scale ≥ 5) | 2.64 | 1.28-5.44 | 0.008 |
| Preoperative cognitive impairment (Mini-Mental State Examination < 24) | 4.67 | 2.25-9.70 | < 0.001 |
| Activities of Daily Living score (per 10-point decrease) | 1.28 | 1.04-1.58 | 0.021 |
| Number of comorbidities ≥ 3 | 1.65 | 0.82-3.31 | 0.164 |
| Hypertension | 1.31 | 0.62-2.75 | 0.477 |
| Diabetes mellitus | 1.37 | 0.65-2.90 | 0.410 |
| Coronary artery disease | 1.47 | 0.66-3.26 | 0.350 |
| Hemoglobin < 100 g/L | 2.18 | 1.06-4.49 | 0.035 |
| Albumin < 35 g/L | 2.92 | 1.44-5.93 | 0.003 |
| Intertrochanteric fracture (vs femoral neck) | 1.23 | 0.60-2.54 | 0.574 |
| Time to surgery > 3 days | 1.54 | 0.77-3.08 | 0.222 |
| General anesthesia (vs regional) | 1.17 | 0.58-2.37 | 0.659 |
| Surgical duration > 120 minutes | 2.34 | 1.16-4.71 | 0.017 |
| Intraoperative blood transfusion | 2.09 | 1.01-4.31 | 0.046 |
Multivariable logistic regression analysis (Table 4) revealed that preoperative depression (adjusted OR = 2.84, 95%CI: 1.26-6.41, P = 0.012), preoperative cognitive impairment (adjusted OR = 3.92, 95%CI: 1.71-8.98, P = 0.001), age ≥ 80 years (adjusted OR = 2.47, 95%CI: 1.09-5.59, P = 0.030), and ASA classification ≥ III (adjusted OR = 2.63, 95%CI: 1.18-5.87, P = 0.018) were independent predictors of POD after adjusting for other covariates. The final multivariable model demonstrated good discrimination with an area under the curve of 0.78 (95%CI: 0.71-0.86), and adequate calibration with a Hosmer-Lemeshow test P value of 0.42.
| Variable | Adjusted odds ratio | 95%CI | P value |
| Preoperative depression (15-item Geriatric Depression Scale ≥ 5) | 2.84 | 1.26-6.41 | 0.012 |
| Preoperative cognitive impairment (Mini-Mental State Examination < 24) | 3.92 | 1.71-8.98 | 0.001 |
| Age ≥ 80 years | 2.47 | 1.09-5.59 | 0.030 |
| American Society of Anesthesiologists classification ≥ III | 2.63 | 1.18-5.87 | 0.018 |
| Albumin < 35 g/L | 1.85 | 0.82-4.18 | 0.137 |
| Surgical duration > 120 minutes | 1.72 | 0.78-3.80 | 0.179 |
Subgroup analyses stratified by cognitive status showed that preoperative depression was associated with increased risk of POD in both cognitively normal patients (OR = 2.45, 95%CI: 1.02-5.89, P = 0.045) and cognitively impaired patients (OR = 3.18, 95%CI: 0.98-10.32, P = 0.054), with no significant interaction detected (P for interaction = 0.68). Similarly, when stratified by depression status, cognitive impairment was associated with higher POD risk in both non-depressed (OR = 3.94, 95%CI: 1.58-9.82, P = 0.003) and depressed patients (OR = 4.12, 95%CI: 1.23-13.79, P = 0.022), with no significant interaction (P for interaction = 0.89). These findings suggest that depression and cognitive impairment have both independent and additive effects on the risk of POD.
Further analysis of the combined risk categories (Table 5) revealed a dose-response relationship. Patients with both depression and cognitive impairment had the highest risk of POD (61.5%), followed by those with either depression alone (35.7%) or cognitive impairment alone (37.5%); the lowest risk was in those with neither condition (14.1%).
| Depression status | Cognitive status | n | Postoperative delirium | Adjusted odds ratio1 | 95%CI | P value |
| No | Normal | 64 | 9 (14.1) | Reference | - | - |
| Yes | Normal | 36 | 10 (27.8) | 2.45 | 0.89-6.71 | 0.082 |
| No | Impaired | 28 | 11 (39.3) | 3.94 | 1.42-10.95 | 0.008 |
| Yes | Impaired | 22 | 16 (72.7) | 12.89 | 4.01-41.49 | < 0.001 |
The patients who developed POD had significantly worse clinical outcomes than those without POD. The median length of hospital stay was longer in the POD group (15 days, IQR: 11-21 days) than in the non-POD group (10 days, IQR: 8-13 days, P < 0.001). In-hospital complications, including pneumonia (21.7% vs 6.7%, P = 0.009), urinary tract infection (17.4% vs 5.8%, P = 0.028), and pressure ulcers (13.0% vs 2.9%, P = 0.021), were more frequent in patients with POD. At discharge, patients with POD were more likely to be transferred to nursing facilities or to require extended rehabilitation (56.5% vs 26.0%, P < 0.001) than to return to their previous living situation.
This retrospective cohort study of 150 elderly patients who underwent hip fracture surgery demonstrated that preoperative depression and cognitive impairment are independent and significant risk factors for POD. It was observed that POD was nearly trifold prevalent in patients with preoperative depression compared to patients without depression. Cognitive impairment had a more pronounced relative risk compared to depression. Moreover, POD was exacerbated for patients with both impairment risk factors, where more than 70% of patients developed POD. This emphasizes the need for comprehensive risk assessments, along with pre-surgical planning, in order to implement better preparatory countermeasures.
The incidence of podium delay observed in our study was 30.7%. While this incidence lies within the broad range of previously reported cases of POD, it coincides with the range found in substantial cohort studies[16]. The differences in the reported incidence of POD in the reviewed cases seem to be the result of patient-driven characteristics, evaluation, timing and frequency of the delirium tests, and the usual practices seen in each institution. We used the CAM in our study as part of our institution’s commitment to valuing the operational imperative of testing delirium in this cohort. It was done every 12 hours by staff who were trained, which represents a thorough approach to detection. Additionally, it is possible our method captured POD cases that would ordinarily be missed using other less deliberate tests. Our study’s median duration of inactivity was 2 days, which is the same as previously cited papers. Most inactivity is recorded in the first 3 days following a post-operative procedure, which highlights the importance of close observation during this important time[17].
Our study indicates a positive relationship between preoperative pelvic organ prolapse and POD, which is in further support of the view that depression may be a risk factor which is still doubtfully of the cognitive failure after a post-operative procedure. First, depression and delirium share overlapping neurobiological substrates, including dysfunction of neurotransmitter systems such as serotonin, dopamine, and acetylcholine, as well as alterations in inflammatory pathways[18]. Depression is associated with elevated levels of pro-inflammatory cytokines and oxidative stress, which may lower the threshold for the development of delirium in response to surgical stress. Second, depression may reflect an underlying brain vulnerability or reduced cognitive reserve, making the brain more susceptible to acute insults. Third, patients with depression often have disrupted sleep architecture and circadian rhythms, which are known risk factors for delirium[19]. Finally, some antidepressant medications, particularly those with anticholinergic properties, may contribute to the risk of delirium; however, we did not find a significant association between antidepressant use and POD.
Our finding that cognitive impairment is a strong predictor of POD is consistent with extensive previous research that has established baseline cognitive function as one of the most robust risk factors for delirium[20]. Cognitive impairment may represent decreased brain reserves and diminished capacity to compensate for perioperative stressors. Patients with preexisting cognitive deficits have less functional neural capacity to maintain normal cognitive function when faced with the multiple challenges of surgery, anesthesia, pain, medications, and an unfamiliar hospital environment. Additionally, cognitive impairment and delirium may share common underlying neuropathological processes, including neuroinflammation, neurotransmitter imbalance, and neuronal dysfunction. Our study indicates a positive relationship between preoperative pelvic organ prolapse and POD, which is in further support of the view that depression may be a risk factor which is still doubtfully of the cognitive failure after a post-operative procedure.
The POD and the cognitive impairment were positively related. It indicates the brain is by no means in a rest state and thus it is a part of the continue vulnerability of the brain[21]. Furthermore, we found that both cognitive impairment and depression have independent and additive effects on POD, with no effects on the interaction level. This means these features relate through different mechanisms, and their combo substantially raises POD risk. Approximately 60% of POD cases stem from the combination of both cognitive impairment and depression, suggesting a critical area of the POD risk continuum. Perioperative staff should most actively manage this area through close observation and consideration of intervention requests. Clinically, this finding suggests the necessity of screening both depression and cognitive status, as risk for depression and cognitive impairment, each provides independent and valuable data for risk assessment[22].
While depression and cognitive impairment were the most noted risk factors, others included advanced age and higher ASA. For many, older age and decreased mental faculties that support reason and judgment lead to greater POD risk[23]. The association between ASA classification and POD likely reflects the cumulative effect of multiple comorbidities and the reduced physiological reserve to withstand surgical stress. While we found that longer surgical duration and lower preoperative albumin levels were associated with POD in the univariate analysis, these did not remain significant in the multivariate model, possibly because of correlation with other included variables or insufficient statistical power[24].
Interestingly, we did not find significant associations between POD and several factors that have been inconsistently associated with delirium in previous studies, including the type of anesthesia, specific fracture type, and time to surgery. The lack of association with anesthesia type is consistent with recent evidence suggesting that the choice between general and regional anesthesia may be less important than previously thought when modern anesthetic techniques are used[25]. The absence of an association with time to surgery, despite some studies suggesting that delayed surgery increases delirium risk, may reflect our institutional policy of relatively prompt surgical intervention, with a median time to surgery of only three days.
Our findings have several significant clinical implications. First, routine preoperative screening for depression and cognitive impairment using validated instruments should be considered part of the standard care for elderly patients with hip fractures. The GDS-15 and MMSE are brief and easily administered tools that can be incorporated into preoperative assessment protocols without significant resource burden. Second, patients identified as high risk based on the presence of depression, cognitive impairment, or both should be targeted for intensive multicomponent delirium prevention interventions[26]. These may include non-pharmacological strategies, such as cognitive stimulation, early mobilization, sleep enhancement, optimization of vision and hearing, adequate hydration and nutrition, and minimization of psychoactive medications. Pharmacological prophylaxis remains controversial; however, it may be considered as part of an individualized care plan in very high-risk patients. Third, high-risk patients may benefit from enhanced postoperative monitoring, involvement of geriatric psychiatry or geriatric medicine specialists, and proactive family engagement in orientation and support[27].
Our study contributes to a broader discussion on the importance of integrating mental health assessments into perioperative care. Depression in elderly surgical patients is often underdiagnosed and undertreated. However, our findings suggest that depression has important implications for postoperative outcomes beyond those of traditional surgical complications. The recognition and management of depression may represent an important but underutilized opportunity to improve surgical outcomes in elderly patients. While treating depression in the immediate preoperative period is often not feasible, identifying depressed patients allows closer monitoring and may inform decisions regarding perioperative management and discharge planning[28].
While we have suggested an array of relationships that combine depression, cognitive impairment, and the development of POD, we support that line of reasoning and believe the networks are tied with POD, which would suggest depression and cognitive impairment are linked to POD through common mechanisms. Insufficient inhibition of oxidative stress, disruption of neural networks, and neuroinflammation are some of the many mechanisms that may unite these factors. For example, decreased immunity for the biophysical networks of the body combined with decreased inhibition of POD risk factors may actively contribute to decreasing POD risk. Other suggested areas for coping mechanisms consist of inflammation control in the nervous system and POD coping mechanisms[29]. It is believed that further research is required to support mental health coping mechanisms rather than phytotherapy coping mechanisms to try and help reverse POD risk.
Our study has several limitations. First, its retrospective design limits our ability to establish causality and may introduce selection bias and unmeasured confounding factors. Information bias may also exist because retrospective data collection relies on the accuracy and completeness of medical records, which may vary among healthcare providers. Prospective studies with more comprehensive assessments of the potential confounders should provide stronger evidence. Second, our study was conducted at a single institution in the Binhai New Area of Tianjin, which may limit its generalizability to other healthcare settings with different patient populations, resources, or clinical practices. The patient population in our study primarily comprised urban and suburban elderly residents, and the findings may not be directly applicable to rural populations or regions with different healthcare infrastructures. Third, although we used validated instruments to assess depression, cognitive status, and delirium, the timing of the assessments in the acute postoperative period may have been influenced by pain, medications, or medical complications. Additionally, the GDS-15 and MMSE assessments were conducted within 24 hours of admission, during which patients may have been experiencing acute stress responses that could affect their psychological and cognitive performance. However, assessments were performed by trained personnel using standardized protocols to minimize such effects. Fourth, we did not obtain detailed information on the severity, duration, or treatment history of preoperative depression, which may have influenced the risk of delirium. Similarly, we did not distinguish between different types of cognitive impairment or assess specific cognitive domains. The presence of subclinical or undiagnosed dementia might have confounded our results. Fifth, our sample size, although adequate for primary analyses, may have limited the power to detect interactions or associations with less common risk factors[30]. Finally, we did not assess long-term outcomes, such as persistent cognitive decline, functional recovery, or mortality, which would provide important information about the clinical significance of POD in this population.
Future studies should focus on the following key topics. Prospective studies with larger sample sizes and multicenter designs would provide more robust evidence of the relationship between preoperative depression, cognitive status, and POD. Further research is needed to determine whether preoperative screening and treatment of depression can reduce the incidence of POD. Further studies should investigate the optimal timing, content, and delivery of delirium-prevention interventions for patients with preoperative depression and cognitive impairment. In addition, research on the biological mechanisms linking depression, cognitive impairment, and delirium may help identify new therapeutic targets. Long-term follow-up studies are needed to understand the impact of POD on the cognitive trajectory, functional recovery, and quality of life in patients with hip fractures. Finally, cost-effectiveness analyses of screening and prevention strategies can inform clinical practice and policy decisions.
This retrospective cohort study demonstrated that preoperative depression and cognitive impairment are independent and significant risk factors for POD in elderly patients undergoing hip fracture surgery, with patients with both conditions at particularly high risk. These findings support the implementation of routine preoperative screening for depression and cognitive status as part of comprehensive geriatric assessment and highlight the need for targeted delirium prevention strategies in high-risk patients. Addressing the mental health and cognitive status of elderly surgical patients represents an important opportunity to improve perioperative outcomes and the quality of care.
| 1. | Ebeling PR. Hip Fractures and Aging: A Global Problem Requiring Coordinated Global Solutions. J Bone Miner Res. 2023;38:1062-1063. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 17] [Reference Citation Analysis (0)] |
| 2. | Sing CW, Lin TC, Bartholomew S, Bell JS, Bennett C, Beyene K, Bosco-Levy P, Bradbury BD, Chan AHY, Chandran M, Cooper C, de Ridder M, Doyon CY, Droz-Perroteau C, Ganesan G, Hartikainen S, Ilomaki J, Jeong HE, Kiel DP, Kubota K, Lai EC, Lange JL, Lewiecki EM, Lin J, Liu J, Maskell J, de Abreu MM, O'Kelly J, Ooba N, Pedersen AB, Prats-Uribe A, Prieto-Alhambra D, Qin SX, Shin JY, Sørensen HT, Tan KB, Thomas T, Tolppanen AM, Verhamme KMC, Wang GH, Watcharathanakij S, Wood SJ, Cheung CL, Wong ICK. Global Epidemiology of Hip Fractures: Secular Trends in Incidence Rate, Post-Fracture Treatment, and All-Cause Mortality. J Bone Miner Res. 2023;38:1064-1075. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 21] [Cited by in RCA: 378] [Article Influence: 126.0] [Reference Citation Analysis (1)] |
| 3. | Rapp K, Becker C, Todd C, Rothenbacher D, Schulz C, König HH, Liener U, Hartwig E, Büchele G. The Association Between Orthogeriatric Co-Management and Mortality Following Hip Fracture. Dtsch Arztebl Int. 2020;117:53-59. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 13] [Cited by in RCA: 68] [Article Influence: 11.3] [Reference Citation Analysis (0)] |
| 4. | Yang Y, Zhao X, Dong T, Yang Z, Zhang Q, Zhang Y. Risk factors for postoperative delirium following hip fracture repair in elderly patients: a systematic review and meta-analysis. Aging Clin Exp Res. 2017;29:115-126. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 202] [Cited by in RCA: 175] [Article Influence: 19.4] [Reference Citation Analysis (0)] |
| 5. | Hua Y, Yuan Y, Wang X, Liu L, Zhu J, Li D, Tu P. Risk prediction models for postoperative delirium in elderly patients with hip fracture: a systematic review. Front Med (Lausanne). 2023;10:1226473. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 8] [Reference Citation Analysis (0)] |
| 6. | Oh ST, Park JY. Postoperative delirium. Korean J Anesthesiol. 2019;72:4-12. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 131] [Cited by in RCA: 111] [Article Influence: 15.9] [Reference Citation Analysis (0)] |
| 7. | Foley KA, Djaiani G. Update of the European Society of Anaesthesiology and Intensive Care Medicine evidence-based and consensus-based guideline on postoperative delirium in adult patients. Eur J Anaesthesiol. 2025;42:86-87. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 6] [Cited by in RCA: 10] [Article Influence: 10.0] [Reference Citation Analysis (0)] |
| 8. | Bugiani O. Why is delirium more frequent in the elderly? Neurol Sci. 2021;42:3491-3503. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 1] [Cited by in RCA: 37] [Article Influence: 7.4] [Reference Citation Analysis (0)] |
| 9. | Huang H, Li H, Zhang X, Shi G, Xu M, Ru X, Chen Y, Patel MB, Ely EW, Lin S, Zhang G, Zhou J. Association of postoperative delirium with cognitive outcomes: A meta-analysis. J Clin Anesth. 2021;75:110496. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 5] [Cited by in RCA: 76] [Article Influence: 15.2] [Reference Citation Analysis (0)] |
| 10. | Maldonado JR. Neuropathogenesis of delirium: review of current etiologic theories and common pathways. Am J Geriatr Psychiatry. 2013;21:1190-1222. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 628] [Cited by in RCA: 495] [Article Influence: 38.1] [Reference Citation Analysis (0)] |
| 11. | Cechinel C, Lenardt MH, Rodrigues JAM, Binotto MA, Aristides MM, Kraus R. Frailty and delirium in hospitalized older adults: A systematic review with meta-analysis. Rev Lat Am Enfermagem. 2022;30:e3687. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 16] [Reference Citation Analysis (0)] |
| 12. | Barcelos-Ferreira R, Nakano EY, Steffens DC, Bottino CM. Quality of life and physical activity associated to lower prevalence of depression in community-dwelling elderly subjects from Sao Paulo. J Affect Disord. 2013;150:616-622. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 34] [Cited by in RCA: 38] [Article Influence: 2.9] [Reference Citation Analysis (0)] |
| 13. | Wilson JE, Mart MF, Cunningham C, Shehabi Y, Girard TD, MacLullich AMJ, Slooter AJC, Ely EW. Delirium. Nat Rev Dis Primers. 2020;6:90. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 985] [Cited by in RCA: 803] [Article Influence: 133.8] [Reference Citation Analysis (0)] |
| 14. | Elie M, Cole MG, Primeau FJ, Bellavance F. Delirium risk factors in elderly hospitalized patients. J Gen Intern Med. 1998;13:204-212. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 354] [Cited by in RCA: 314] [Article Influence: 11.2] [Reference Citation Analysis (0)] |
| 15. | Watt J, Tricco AC, Talbot-Hamon C, Pham B, Rios P, Grudniewicz A, Wong C, Sinclair D, Straus SE. Identifying Older Adults at Risk of Delirium Following Elective Surgery: A Systematic Review and Meta-Analysis. J Gen Intern Med. 2018;33:500-509. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 78] [Cited by in RCA: 108] [Article Influence: 13.5] [Reference Citation Analysis (3)] |
| 16. | Patel V, Champaneria R, Dretzke J, Yeung J. Effect of regional versus general anaesthesia on postoperative delirium in elderly patients undergoing surgery for hip fracture: a systematic review. BMJ Open. 2018;8:e020757. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 81] [Cited by in RCA: 89] [Article Influence: 11.1] [Reference Citation Analysis (0)] |
| 17. | Xiao MZ, Liu CX, Zhou LG, Yang Y, Wang Y. Postoperative delirium, neuroinflammation, and influencing factors of postoperative delirium: A review. Medicine (Baltimore). 2023;102:e32991. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 40] [Cited by in RCA: 75] [Article Influence: 25.0] [Reference Citation Analysis (0)] |
| 18. | Geng J, Zhang Y, Chen H, Shi H, Wu Z, Chen J, Luo F. Associations between Alzheimer's disease biomarkers and postoperative delirium or cognitive dysfunction: A meta-analysis and trial sequential analysis of prospective clinical trials. Eur J Anaesthesiol. 2024;41:234-244. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 10] [Cited by in RCA: 24] [Article Influence: 12.0] [Reference Citation Analysis (0)] |
| 19. | Leung JM, Sands LP, Newman S, Meckler G, Xie Y, Gay C, Lee K. Preoperative Sleep Disruption and Postoperative Delirium. J Clin Sleep Med. 2015;11:907-913. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 67] [Cited by in RCA: 79] [Article Influence: 7.2] [Reference Citation Analysis (0)] |
| 20. | Evered LA, Silbert BS, Scott DA, Maruff P, Ames D, Choong PF. Preexisting cognitive impairment and mild cognitive impairment in subjects presenting for total hip joint replacement. Anesthesiology. 2011;114:1297-1304. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 68] [Cited by in RCA: 70] [Article Influence: 4.7] [Reference Citation Analysis (0)] |
| 21. | Fong TG, Davis D, Growdon ME, Albuquerque A, Inouye SK. The interface between delirium and dementia in elderly adults. Lancet Neurol. 2015;14:823-832. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 317] [Cited by in RCA: 406] [Article Influence: 36.9] [Reference Citation Analysis (0)] |
| 22. | Gold C, Ray E, Christianson D, Park B, Kournoutas IA, Kahn TA, Perez EA, Berger JI, Sander K, Igram CA, Pugely A, Olinger CR, Carnahan R, Chen PF, Mueller R, Hitchon P, Howard MA, Banks M, Sanders RD, Woodroffe RW. Risk factors for delirium in elderly patients after lumbar spinal fusion. Clin Neurol Neurosurg. 2022;219:107318. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 6] [Cited by in RCA: 25] [Article Influence: 6.3] [Reference Citation Analysis (0)] |
| 23. | Shen Y, Li X, Yao J. Develop a Clinical Prediction Model for Postoperative Cognitive Dysfunction after Major Noncardiac Surgery in Elderly Patients: A Protocol for a Prospective Observational Study. Gerontology. 2022;68:538-545. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 15] [Reference Citation Analysis (0)] |
| 24. | Kazmierski J, Banys A, Latek J, Bourke J, Jaszewski R. Raised IL-2 and TNF-α concentrations are associated with postoperative delirium in patients undergoing coronary-artery bypass graft surgery. Int Psychogeriatr. 2014;26:845-855. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 64] [Cited by in RCA: 69] [Article Influence: 5.8] [Reference Citation Analysis (0)] |
| 25. | Li T, Li J, Yuan L, Wu J, Jiang C, Daniels J, Mehta RL, Wang M, Yeung J, Jackson T, Melody T, Jin S, Yao Y, Wu J, Chen J, Smith FG, Lian Q; RAGA Study Investigators. Effect of Regional vs General Anesthesia on Incidence of Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery: The RAGA Randomized Trial. JAMA. 2022;327:50-58. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 330] [Cited by in RCA: 290] [Article Influence: 72.5] [Reference Citation Analysis (0)] |
| 26. | Shen H, Liu X, Wu L, Jia J, Jin X. Effect of hospital elder life program on the incidence of delirium: A systematic review and meta-analysis of clinical trials. Geriatr Nurs. 2024;56:225-236. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 5] [Cited by in RCA: 11] [Article Influence: 5.5] [Reference Citation Analysis (0)] |
| 27. | Chen CC, Li HC, Liang JT, Lai IR, Purnomo JDT, Yang YT, Lin BR, Huang J, Yang CY, Tien YW, Chen CN, Lin MT, Huang GH, Inouye SK. Effect of a Modified Hospital Elder Life Program on Delirium and Length of Hospital Stay in Patients Undergoing Abdominal Surgery: A Cluster Randomized Clinical Trial. JAMA Surg. 2017;152:827-834. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 193] [Cited by in RCA: 167] [Article Influence: 18.6] [Reference Citation Analysis (0)] |
| 28. | Tsui A, Searle SD, Bowden H, Hoffmann K, Hornby J, Goslett A, Weston-Clarke M, Howes LH, Street R, Perera R, Taee K, Kustermann C, Chitalu P, Razavi B, Magni F, Das D, Kim S, Chaturvedi N, Sampson EL, Rockwood K, Cunningham C, Ely EW, Richardson SJ, Brayne C, Terrera GM, Tieges Z, MacLullich A, Davis D. The effect of baseline cognition and delirium on long-term cognitive impairment and mortality: a prospective population-based study. Lancet Healthy Longev. 2022;3:e232-e241. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 29] [Cited by in RCA: 55] [Article Influence: 13.8] [Reference Citation Analysis (0)] |
| 29. | Vasunilashorn SM, Ngo L, Inouye SK, Libermann TA, Jones RN, Alsop DC, Guess J, Jastrzebski S, McElhaney JE, Kuchel GA, Marcantonio ER. Cytokines and Postoperative Delirium in Older Patients Undergoing Major Elective Surgery. J Gerontol A Biol Sci Med Sci. 2015;70:1289-1295. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 87] [Cited by in RCA: 126] [Article Influence: 11.5] [Reference Citation Analysis (0)] |
| 30. | Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in Older Persons: Advances in Diagnosis and Treatment. JAMA. 2017;318:1161-1174. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 556] [Cited by in RCA: 614] [Article Influence: 68.2] [Reference Citation Analysis (0)] |