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1.  Markers of cerebral damage during delirium in elderly patients with hip fracture 
BMC Neurology  2009;9:21.
Background
S100B protein and Neuron Specific Enolase (NSE) can increase due to brain cell damage and/or increased permeability of the blood-brain-barrier. Elevation of these proteins has been shown after various neurological diseases with cognitive dysfunction. Delirium is characterized by temporal cognitive deficits and is an important risk factor for dementia. The aim of this study was to compare the level of S100B and NSE of patients before, during and after delirium with patients without delirium and investigate the possible associations with different subtypes of delirium.
Methods
The study population were patients aged 65 years or more acutely admitted after hip fracture. Delirium was diagnosed by the Confusion Assessment Method and the subtype by Delirium Symptom interview. In maximal four serum samples per patient S100B and NSE levels were determined by electrochemiluminescence immunoassay.
Results
Of 120 included patients with mean age 83.9 years, 62 experienced delirium. Delirious patients had more frequently pre-existing cognitive impairment (67% vs. 18%, p < 0.001). Comparing the first samples during delirium to samples of non-delirious patients, a difference was observed in S100B (median 0.16 versus 0.10 μg/L, p = < 0.001), but not in NSE (median 11.7 versus 11.7 ng/L, p = 0.97). Delirious state (before, during, after) (p < 0.001), day of blood withdrawal (p < 0.001), pre- or postoperative status (p = 0.001) and type of fracture (p = 0.036) were all associated with S100B level. The highest S100B levels were found 'during' delirium. S100B levels 'before' and 'after' delirium were still higher than those from 'non-delirious' patients. No significant difference in S100B (p = 0.43) or NSE levels (p = 0.41) was seen between the hyperactive, hypoactive and mixed subtype of delirium.
Conclusion
Delirium was associated with increased level of S100B which could indicate cerebral damage either due to delirium or leading to delirium. The possible association between higher levels of S100B during delirium and the higher risk of developing dementia after delirium is an interesting field for future research. More studies are needed to elucidate the role of S100B proteins in the pathophysiological pathway leading to delirium and to investigate its possibility as biomarker for delirium.
doi:10.1186/1471-2377-9-21
PMCID: PMC2695414  PMID: 19473521
2.  Predicting Delirium Duration in Elderly Hip-Surgery Patients: Does Early Symptom Profile Matter? 
Background. Features that may allow early identification of patients at risk of prolonged delirium, and therefore of poorer outcomes, are not well understood. The aim of this study was to determine if preoperative delirium risk factors and delirium symptoms (at onset and clinical symptomatology during the course of delirium) are associated with delirium duration. Methods. This study was conducted in prospectively identified cases of incident delirium. We compared patients experiencing delirium of short duration (1 or 2 days) with patients who had more prolonged delirium (≥3 days) with regard to DRS-R-98 (Delirium Rating Scale Revised-98) symptoms on the first delirious day. Delirium symptom profile was evaluated daily during the delirium course. Results. In a homogenous population of 51 elderly hip-surgery patients, we found that the severity of individual delirium symptoms on the first day of delirium was not associated with duration of delirium. Preexisting cognitive decline was associated with prolonged delirium. Longitudinal analysis using the generalised estimating equations method (GEE) identified that more severe impairment of long-term memory across the whole delirium episode was associated with longer duration of delirium. Conclusion. Preexisting cognitive decline rather than severity of individual delirium symptoms at onset is strongly associated with delirium duration.
doi:10.1155/2013/962321
PMCID: PMC3600209  PMID: 23533395
3.  The Epidemiology of Delirium: Challenges and Opportunities for Population Studies 
Delirium is a serious and common acute neuropsychiatric syndrome that is associated with short- and long-term adverse health outcomes. However, relatively little delirium research has been conducted in unselected populations. Epidemiologic research in such populations has the potential to resolve several questions of clinical significance in delirium. Part 1 of this article explores the importance of population selection, case-ascertainment, attrition, and confounding. Part 2 examines a specific question in delirium epidemiology: What is the relationship between delirium and trajectories of cognitive decline? This section assesses previous work through two systematic reviews and proposes a design for investigating delirium in the context of longitudinal cohort studies. Such a design requires robust links between community and hospital settings. Practical considerations for case-ascertainment in the hospital, as well as the necessary quality control of these programs, are outlined. We argue that attention to these factors is important if delirium research is to benefit fully from a population perspective.
doi:10.1016/j.jagp.2013.04.007
PMCID: PMC3837358  PMID: 23907068
Delirium; dementia; epidemiology; systematic review
4.  Detection of delirium by nurses among long-term care residents with dementia 
BMC Nursing  2008;7:4.
Background
Delirium is a prevalent problem in long-term care (LTC) facilities where advanced age and cognitive impairment represent two important risk factors for this condition. Delirium is associated with numerous negative outcomes including increased morbidity and mortality. Despite its clinical importance, delirium often goes unrecognized by nurses. Although rates of nurse-detected delirium have been studied among hospitalized older patients, this issue has been largely neglected among demented older residents in LTC settings. The goals of this study were to determine detection rates of delirium and delirium symptoms by nurses among elderly residents with dementia and to identify factors associated with undetected cases of delirium.
Methods
In this prospective study (N = 156), nurse ratings of delirium were compared to researcher ratings of delirium. This procedure was repeated for 6 delirium symptoms. Sensitivity, specificity, positive and negative predictive values were computed. Logistic regressions were conducted to identify factors associated with delirium that is undetected by nurses.
Results
Despite a high prevalence of delirium in this cohort (71.5%), nurses were able to detect the delirium in only a minority of cases (13%). Of the 134 residents not identified by nurses as having delirium, only 29.9% of them were correctly classified. Detection rates for the 6 delirium symptoms varied between 39.1% and 58.1%, indicating an overall under-recognition of symptoms of delirium. Only the age of the residents (≥ 85 yrs) was associated with undetected delirium (OR: 4.1; 90% CI: [1.5–11.0]).
Conclusion
Detection of delirium is a major issue for nurses that clearly needs to be addressed. Strategies to improve recognition of delirium could result in a reduction of adverse outcomes for this very vulnerable population.
doi:10.1186/1472-6955-7-4
PMCID: PMC2277396  PMID: 18302791
5.  Delirium episode as a sign of undetected dementia among community dwelling elderly subjects: a 2 year follow up study 
Cognitive decline is commonly stated as one of the main risk factors for delirium. The aim was to assess the importance of a delirium episode as a symptom of an underlying dementia among community dwelling healthy elderly people in a prospective 2 year follow up study. The study patients consisted of 51 people living at home and older than 65 years of age, without severe underlying disorders including diagnosed dementia, admitted consecutively as emergency cases to hospital because of an acute delirious state and followed up for 2 years. The diagnosis of delirium and dementia were based on the DSM-III-R criteria. The community dwelling patients were evaluated and tested annually by a clinical investigator, a geriatric study nurse, and a neuropsychologist. The medical records of the institutionalised patients were also evaluated. Dementia was diagnosed immediately after the assurance that delirium symptoms had subsided in 14 out of 51 subjects (27%) and the additional 14 subjects were diagnosed as being demented during the 2 year follow up, 28 out of 51 patients (55%) altogether. Alzheimer's disease or mixed dementia was diagnosed in 14 out of 51 patients (27%), vascular dementia in 10 (20%), and dementia with Lewy bodies in two (4%). One case of alcoholic dementia and one case of a non-alcoholic hepatic encephalopathia were also found. A delirium episode is often the first sign of dementia requiring attention from medical and social professionals.


doi:10.1136/jnnp.69.4.519
PMCID: PMC1737142  PMID: 10990515
6.  Delirium in Australian Hospitals: A Prospective Study 
Objectives. Australian data regarding delirium in older hospitalized patients are limited. Hence, this study aimed to determine the prevalence and incidence of delirium among older patients admitted to Australian hospitals and assess associated outcomes. Method. A prospective observational study (n = 493) of patients aged ≥70 years admitted to four Australian hospitals was undertaken. Trained research nurses completed comprehensive geriatric assessments using standardized instruments including the Confusion Assessment Method to assess for delirium. Nurses also visited the wards daily to assess for incident delirium and other adverse outcomes. Diagnoses of dementia and delirium were established through case reviews by independent physicians. Results. Overall, 9.7% of patients had delirium at admission and a further 7.6% developed delirium during the hospital stay. Dementia was the most important predictor of delirium at (OR = 3.18, 95% CI: 1.65–6.14) and during the admission (OR = 4.82; 95% CI: 2.19–10.62). Delirium at and during the admission predicted increased in-hospital mortality (OR = 5.19, 95% CI: 1.27–21.24; OR = 31.07, 95% CI: 9.30–103.78). Conclusion. These Australian data confirm that delirium is a common and serious condition among older hospital patients. Hospital clinicians should maintain a high index of suspicion for delirium in older patients.
doi:10.1155/2013/284780
PMCID: PMC3787633  PMID: 24151504
7.  Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study 
Background
Delirium in older hospital inpatients appears to be associated with various adverse outcomes. The limitations of previous research on this association have included small sample sizes, short follow-up periods and lack of consideration of important confounders or modifiers, such as severity of illness, comorbidity and dementia. The objective of this study was to determine the prognostic significance of delirium, with or without dementia, for cognitive and functional status during the 12 months after hospital admission, independent of premorbid function, comorbidity, severity of illness and other potentially confounding variables.
Methods
Patients 65 years of age and older who were admitted from the emergency department to the medical services were screened for delirium during their first week in hospital. Two cohorts were enrolled: patients with prevalent or incident delirium and patients without delirium, but similar in age and cognitive impairment. The patients were followed up at 2, 6 and 12 months after hospital admission. Analyses were conducted for 4 patient groups: 56 with delirium, 53 with dementia, 164 with both conditions and 42 with neither. Baseline measures included delirium (Confusion Assessment Method), dementia (Informant Questionnaire on Cognitive Decline in the Elderly), physical function (Barthel Index [BI] and premorbid instrumental activities of daily living, IADL), the Mini-Mental State Examination (MMSE), comorbidity, and physiologic and clinical severity of illness. Outcome variables measured at follow-up were the MMSE, Barthel Index, IADL and admission to a long-term care facility.
Results
After adjustment for covariates, the mean differences in MMSE scores at follow-up between patients with and without delirium were –4.99 (95% confidence interval [CI] –7.17 to –2.81) for patients with dementia and –3.36 (95% CI –6.15 to –0.58) for those without dementia. At 12 months, the adjusted mean differences in the BI were –16.45 (95% CI –27.42 to –5.50) and –13.89 (95% CI –28.39 to 0.61) for patients with and without dementia respectively. Patients with both delirium and dementia were more likely to be admitted to long-term care than those with neither condition (adjusted odds ratio 3.18, 95% CI 1.19 to 8.49). Dementia but not delirium predicted worse IADL scores at follow-up. Unadjusted analyses yielded similar results.
Interpretation
For older patients with and without dementia, delirium is an independent predictor of sustained poor cognitive and functional status during the year after a medical admission to hospital.
PMCID: PMC81415  PMID: 11563209
8.  Delirium in Early-Stage Alzheimer’s Disease 
Delirium is a disorder of acute onset with fluctuating symptoms and is characterized by inattention, disorganized thinking, and altered levels of consciousness. The risk for delirium is greatest in individuals with dementia, and the incidence of both is increasing worldwide because of the aging of our population. Although several clinical trials have tested interventions for delirium prevention in individuals without dementia, little is known about the mechanisms for the prevention of delirium in early-stage Alzheimer’s disease (AD). The purpose of this article is to explore ways of preventing delirium and slowing the rate of cognitive decline in early-stage AD by enhancing cognitive reserve. An agenda for future research on interventions to prevent delirium in individuals with early-stage AD is also presented.
PMCID: PMC2814421  PMID: 19326827
9.  Measures of Executive Function and Depression Identify Patients at Risk for Postoperative Delirium 
Anesthesiology  2009;110(4):788-795.
Background
Postoperative delirium is associated with increased morbidity and mortality. Pre-existing cognitive impairment and depression have been frequently cited as important risk factors for this complication. This prospective cohort study was designed to determine if individuals who perform poorly on preoperative cognitive tests and/or exhibited depressive symptoms would be at high risk for the development of postoperative delirium.
Methods
One hundred nondemented patients, 50 years and older, scheduled for major, elective noncardiac surgery completed a preoperative test battery that included measures of global cognition, executive function and symptoms of depression. Known preoperative risk factors for delirium were collected and examined with the results of the preoperative test battery to determine the independent predictors of delirium.
Results
The overall incidence of delirium was 16% and was associated with increased hospital length of stay (p<0.05) and an increased incidence of postoperative complications (p<0.01). Delirious subjects did not differ from their non-delirious cohorts with regard to their preoperative global cognitive function, preexisting medical comorbidities, age, anesthetic management or history of alcohol use. Preoperative executive scores (p<0.001) and depression (p<0.001), as measured by the Trail Making B test and Geriatric Depression Scale Short Form, respectively, were found to be independent predictors of postoperative delirium.
Conclusions
Low preoperative executive scores and depressive symptoms independently predict postoperative delirium in older individuals. A rapid, simple test combination including tests of executive function and depression could improve physicians’ ability to recognize patients who might benefit from a perioperative intervention strategy to prevent postoperative delirium.
PMCID: PMC2953946  PMID: 19326494
10.  PREVALENCE AND RISK FACTORS FOR DEVELOPMENT OF DELIRIUM IN SURGICAL AND TRAUMA ICU PATIENTS 
The Journal of trauma  2008;65(1):34-41.
Background
Delirium or acute brain dysfunction is extremely prevalent in medical intensive care unit (ICU) patients, but limited data exist regarding its prevalence and risk factors among surgical (SICU) and trauma ICU (TICU) patients. The purpose of this study was to determine the prevalence and risk factors for delirium in surgical and trauma ICU patients.
Methods
SICU and TICU patients requiring mechanical ventilation (MV) >24 hours were prospectively evaluated for delirium using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method for the ICU (CAM-ICU). Those with baseline dementia, intracranial injury, or ischemic/hemorrhagic strokes that would confound the evaluation of delirium were excluded. Markov models were used to determine predictors for daily transition to delirium.
Results
One-hundred patients (46 SICU and 54 TICU) were enrolled. Prevalence of delirium was 73% in the SICU and 67% in the TICU. Multivariable analyses identified midazolam [OR 2.75 (CI 1.43–5.26, p = 0.002)] exposure as the strongest independent risk factor for transitioning to delirium. Opiate exposure showed an inconsistent message such that fentanyl was a risk factor for delirium in the SICU (p = 0.007) but not in the TICU (p = 0.936), while morphine exposure was associated with a lower risk of delirium (SICU, p = 0.069; TICU p = 0.024).
Conclusions
Approximately 7 out of 10 SICU and TICU patients experience delirium. In keeping with other recent data on benzodiazepines, exposure to midazolam is an independent and potentially modifiable risk factor for the transitioning to delirium.
doi:10.1097/TA.0b013e31814b2c4d
PMCID: PMC3773485  PMID: 18580517
trauma; surgery; cognitive impairment; delirium; mechanical ventilation; critical care; sedatives and analgesic
11.  Obstructive sleep apnea and incidence of postoperative delirium after elective knee replacement in the nondemented elderly 
Anesthesiology  2012;116(4):788-796.
Background
Postoperative delirium, a common complication in the elderly, can occur following any type of surgery and is associated with increased morbidity and mortality; it may also be associated with subsequent cognitive problems. Effective therapy for postoperative delirium remains elusive because the causative factors of delirium are likely multiple and varied.
Methods
Patients ≥ 65 years old undergoing elective knee arthroplasty were prospectively evaluated for postoperative Diagnostic and Statistical Manual of Mental Disorders-IV delirium. Exclusion criteria included dementia, mini-mental state exam score<24, delirium, clinically significant CNS/neurological disorder, current alcoholism, or any serious psychiatric disorder. Delirium was assessed on postoperative days 2 and 3 using standardized scales. Patients’ pre-existing medical conditions were obtained from medical charts. The occurrence of obstructive sleep apnea (OSA) was confirmed by contacting patients to check their polysomnography records. Data were analyzed using Pearson Chi-Square or Wilcoxon Rank Sum tests and multiple logistic regressions adjusted for effects of covariates.
Results
Of 106 enrolled patients, 27 (25%) developed postoperative delirium. Of the 15 patients with obstructive sleep apnea, 8 (53%) experienced postoperative delirium, compared to 19 (20%) of the patients without obstructive sleep apnea (p=0.0123, OR: 4.3). Obstructive sleep apnea was the only statistically significant predictor of postoperative delirium in multivariate analyses.
Conclusions
This is the first prospective study employing validated measures of delirium to identify an association between pre-existing obstructive sleep apnea and postoperative delirium.
doi:10.1097/ALN.0b013e31824b94fc
PMCID: PMC3321273  PMID: 22337162
12.  Association between leptin and delirium in elderly inpatients 
Leptin is a hormone with significant effects on the brain, both at the cellular level and cognitive level. This study aimed to establish the association between leptin levels and delirium in a Colombian elderly population. 115 patients older than 60 years were included. Leptin was measured by enzyme-linked immunosorbent assay after overnight fasting and Mini-Mental State Examination and Confusion Assessment Method (CAM) tests were employed. Delirium was diagnosed using CAM in 23.48% of patients, being most frequent in men. There were no significant differences in hematology and renal test values between patients with delirium and those without delirium, but cerebrovascular diagnoses were more frequent in patients with delirium. No correlation with any specific medication was found, but patients with delirium had a higher number of comorbidities and medications. Leptin levels were significantly lower in patients with delirium and correlated negatively with the number of diagnoses and medications, but not with age, gender, body mass index, or hematology and renal test results. Leptin levels may have a role in the pathophysiological process of delirium and low leptin could be a useful clinical biomarker to establish risk in elderly patients given the association with delirium.
doi:10.2147/NDT.S44573
PMCID: PMC3663476  PMID: 23717044
delirium; elderly; hospitalization; leptin
13.  Derivation and Validation of a Preoperative Prediction Rule for Delirium after Cardiac Surgery 
Circulation  2008;119(2):229-236.
Background
Delirium is a common outcome after cardiac surgery. Delirium prediction rules identify patients at risk for delirium who may benefit from targeted prevention strategies, early identification and treatment of underlying causes. The purpose of this prospective study was to develop a prediction rule for delirium in a cardiac surgery cohort and validate it in an independent cohort.
Methods and Results
Prospectively, cardiac surgery patients ≥60 years were enrolled in a derivation sample (n=122) and then a validation sample (n=109). Beginning on the second postoperative day, patients underwent a standardized daily delirium assessment and delirium was diagnosed according to the Confusion Assessment Method. Delirium occurred in 63 (52%) of the derivation cohort patients. Multivariable analysis identified four variables independently associated with delirium: prior stroke or transient ischemic attack (TIA), Mini Mental State Examination (MMSE) score, abnormal serum albumin, and the Geriatric Depression Scale (GDS). Points were assigned to each variable: MMSE ≤23 received 2 points; MMSE 24-27, GDS >4, prior stroke/TIA, and abnormal albumin received 1 point each. In the derivation sample, the cumulative incidence of delirium for point levels of 0, 1, 2, and ≥3 was 19%, 47%, 63%, and 86%, respectively (C-statistic 0.74). The corresponding incidence of delirium in the validation sample was 18%, 43%, 60%, and 87%, respectively (C-statistic 0.75).
Conclusion
Delirium occurs frequently after cardiac surgery. Using four preoperative characteristics, clinicians can determine cardiac surgery patients' risk for delirium. Patients at higher delirium risk could be candidates for close postoperative monitoring and interventions to prevent delirium.
doi:10.1161/CIRCULATIONAHA.108.795260
PMCID: PMC2735244  PMID: 19118253
Delirium; Cardiac surgery; aged; cognition; prediction rule; depression
14.  Complications in Post-Acute Care are Associated with Persistent Delirium 
Background
Delirium is highly prevalent and persistent in post-acute care (PAC). However, few risk factors have been identified for delirium persistence.
Objectives
To investigate whether complications in PAC are associated with delirium persistence 30 days after PAC admission.
Design
Observational cohort study
Setting
8 Boston-area PAC facilities
Participants
350 patients with delirium at PAC admission
Measurements
We interviewed participants at PAC admission and 30 days later. Delirium presence was determined using the Confusion Assessment Method. We performed medical record reviews to ascertain new cardiac, non-cardiac, and geriatric syndrome complications in PAC. We also determined complication status 30 days after admission or at PAC discharge, whichever came first.
Results
The participants (mean age 83.6 years, 66% women) experienced the following incidence of PAC complications: cardiac complications 7%, non-cardiac complications 21%, geriatric syndrome complications 39%. Delirium persisted in 56% of participants one month after PAC admission. Neither cardiac nor non-cardiac complications were associated with delirium persistence. Delirium persistence at one month was significantly greater in patients with more geriatric syndrome complications (no complication 51%, one complication 61%, ≥2 complications 100%, adjusted p=0.048). There was also a trend toward greater delirium persistence in patients with unresolved geriatric syndrome complications (no complication 51%, resolved complication 61%, unresolved complication 68%, adjusted p=0.1).
Conclusion
Geriatric syndrome complications are common in patients admitted to post-acute care with delirium, and are associated with the persistence of delirium one month later. Proactively addressing risk factors for geriatric syndromes may improve outcomes of vulnerable patients in post-acute care.
doi:10.1111/j.1532-5415.2012.03958.x
PMCID: PMC3374879  PMID: 22646692
delirium; complications; geriatric syndromes; post-acute care
15.  Insulin-Like Growth Factor I and the Pathogenesis of Delirium: A Review of Current Evidence 
Journal of Aging Research  2011;2011:951403.
Delirium is a frequent complication in medically ill elderly patients that is associated with serious adverse outcomes including increased mortality. Delirium risk is linked to older age, dementia, and illness that involves activation of inflammatory responses. IGF-I is increasingly postulated as a key link between environmental influences on body metabolism with a range of neuronal activities and has been described as the master regulator of the connection between brain and bodily well-being. The relationships between IGF-I and ageing, cognitive impairment and inflammatory illness further support a possible role in delirium pathogenesis. Five studies of IGF-I in delirium were identified by a systematic review. These conflicting findings, with three of the five studies indicating an association between IGF-1 and delirium occurrence, may relate to the considerable methodological differences in these studies. The relevance of IGF-I and related factors to delirium pathogenesis can be clarified by future studies which account for these issues and other confounding factors. Such work can inform therapeutic trials of IGF-I and/or growth hormone administration.
doi:10.4061/2011/951403
PMCID: PMC3134253  PMID: 21766035
16.  Serum anticholinergic activity and cerebral cholinergic dysfunction: An EEG study in frail elderly with and without delirium 
BMC Neuroscience  2008;9:86.
Background
Delirium increases morbidity, mortality and healthcare costs especially in the elderly. Serum anticholinergic activity (SAA) is a suggested biomarker for anticholinergic burden and delirium risk, but the association with cerebral cholinergic function remains unclear. To clarify this relationship, we prospectively assessed the correlation of SAA with quantitative electroencephalography (qEEG) power, delirium occurrence, functional and cognitive measures in a cross-sectional sample of acutely hospitalized elderly (> 80 y) with high dementia and delirium prevalence.
Methods
61 consecutively admitted patients over 80 years underwent an extensive clinical and neuropsychological evaluation. SAA was determined by using radio receptor assay as developed by Tune, and standard as well as quantitative EEGs were obtained.
Results
15 patients had dementia with additional delirium (DD) according to expert consensus using DSM-IV criteria, 31 suffered from dementia without delirium (D), 15 were cognitively unimpaired (CU). SAA was clearly detectable in all patients but one (mean 10.9 ± 7.1 pmol/ml), but was not associated with expert-panel approved delirium diagnosis or cognitive functions. Delirium-associated EEG abnormalities included occipital slowing, peak power and alpha decrease, delta and theta power increase and slow wave ratio increase during active delirious states. EEG measures correlated significantly with cognitive performance and delirium severity, but not with SAA levels.
Conclusion
In elderly with acute disease, EEG parameters reliable indicate delirium, but SAA does not seem to reflect cerebral cholinergic function as measured by EEG and is not related to delirium diagnosis.
doi:10.1186/1471-2202-9-86
PMCID: PMC2564970  PMID: 18793418
17.  Persistent Delirium Predicts Increased Mortality 
OBJECTIVES
To examine the association between persistent delirium and one-year mortality in newly admitted delirious post-acute care (PAC) facility patients, who were followed regardless of residence.
DESIGN
Observational cohort study.
SETTING
Eight greater-Boston skilled nursing facilities specializing in PAC.
PARTICIPANTS
Four hundred and twelve PAC patients with delirium at the time of admission after an acute hospitalization.
MEASUREMENTS
Assessments were done at baseline and four follow-up times: 2-week, 4-week, 12-week and 26-week. “Confusion Assessment Method”-defined delirium was assessed, as were factors used as covariates in analyses including: age, gender, comorbidity, functional status and dementia. The outcome was one-year mortality determined by the National Death Index and corroborated by medical record, and proxy telephone interview.
RESULTS
Nearly one-third remained delirious at 6 months. The cumulative one-year mortality was 39%. Independent of age, gender, comorbidity, functional status and dementia, subjects with persistent delirium were 2.9 (95% confidence interval, 1.9, 4.4) times more likely to die during the one-year follow-up compared to subjects who resolved their delirium. This association remained strong and significant in groups with and without dementia. Additionally, when delirium resolved, the risk of death diminished thereafter.
CONCLUSION
Among patients who were delirious at the time of PAC admission and followed regardless of residence, persistent delirium was a significant independent predictor of one-year mortality.
doi:10.1111/j.1532-5415.2008.02092.x
PMCID: PMC2744464  PMID: 19170790
delirium; mortality; survival; post-acute care
18.  Prevalence and detection of delirium in elderly emergency department patients 
Background
Delirium is a complex medical disorder associated with high morbidity and mortality among elderly patients. The goals of our study were to determine the prevalence of delirium in emergency department (ED) patients aged 65 years and over and to determine the sensitivity and specificity of a conventional clinical assessment by an ED physician for the detection of delirium in the same population.
Methods
All elderly patients presenting to the ED in a primary acute care, university-affiliated hospital who were triaged to the observation room on a stretcher because of the severity of their illness were screened for delirium by a research psychiatrist using the Mini-Mental State Examination and the Confusion Assessment Method. The diagnosis of "delirium" or an equivalent term by the ED physician was determined by 2 methods: completion of a mental status checklist by the ED physician and chart review. The prevalence of delirium and the sensitivity and specificity of the ED physician's clinical assessment were calculated with their 95% confidence intervals. The demographic and clinical characteristics of patients with detected delirium and those with undetected delirium were compared.
Results
A sample of 447 patients was screened. The prevalence of delirium was 9.6% (95% confidence interval 6.9%-12.4%). The sensitivity of the detection of delirium by the ED physician was 35.3% and the specificity, 98.5%. Most patients with delirium had neurologic or pulmonary diseases, and most patients with detected delirium had neurologic diseases.
Interpretation
Despite the relatively high prevalence of delirium in elderly ED patients, the sensitivity of a conventional clinical assessment for this condition is low. There is a need to improve the detection of delirium by ED physician
PMCID: PMC80546  PMID: 11068569
19.  Probable risk factors for postoperative delirium in patients undergoing spinal surgery 
European Spine Journal  2008;17(11):1531-1537.
Postoperative delirium and its risk factors had been widely reported in several kinds of surgeries; however, there is only one known article relative to postoperative delirium in spinal surgery. We retrospectively examined the incidence of postoperative delirium and the probable risk factors in patients undergoing spinal surgery in our hospital, with the same aged non-delirium patients as controls, over a 6-month period. Studies about postoperative delirium were reviewed and referenced for variable factors collecting in our study. T tests, χ2 test and logistic regression analysis were performed to evaluate the various factors related to postoperative delirium. A total of 18 patients (3.3%), all of them were aged 54 years or older, had postoperative delirium after surgery. Patients without postoperative delirium aged 54 years or older served as the control group. The percentage of patients older than 65 years (P = 0.003), with comorbid diseases such as diabetes mellitus (P = 0.042) or central nervous system disorders (P = 0.013), with a surgical history (P = 0.028) in delirium group was larger than the control group. The absolute number of medications being taken before the operation in the delirium patients was also more than the control group (P = 0.000). The percentage of patients transfused with 800 mL or more blood was also larger (P = 0.024) in delirium group was larger than the control group. Logistic regression analysis showed that central nervous system disorder (OR 6.480), surgical history (OR 3.499), age older than 65 years (OR 3.390), diabetes mellitus (OR 2.981), transfused 800 mL or more blood (OR 2.537), and hemoglobin less than 100 g/L (OR 0.281) were significantly related to the occurrence postoperative delirium. Our findings suggest that postoperative delirium in spinal surgery can also occurred in younger patients and with an acceptable incidence in total. The risk for postoperative delirium is multifactorial. More prospective research is necessary in order to evaluate these and other risk factors in greater detail.
doi:10.1007/s00586-008-0771-1
PMCID: PMC2583180  PMID: 18795347
Postoperative delirium; Spinal surgery; Delirium observation screening (DOS) scale; Logistic regression analysis
20.  Brain Autopsy Findings in ICU Patients Previously Suffering from Delirium: A Pilot Study 
Journal of critical care  2010;25(3):538.e7-538.12.
PURPOSE
Delirium affects 50–80% of patients in intensive care units and is associated with long-term cognitive impairment and increased risk of mortality. There are a paucity of data reporting the neuropathologic findings in ICU patients experiencing delirium. The purpose of this pilot, hypothesis-generating study was to evaluate brain autopsies in ICU patients who suffered from delirium in order to explore possible neuroanatomic correlates.
METHODS
Utilizing study databases at Vanderbilt University we retrospectively identified patients who suffered from delirium in the ICU and subsequently died and received a brain autopsy during the same hospitalization. Information was also gathered regarding exposure to sedation and analgesia during ICU stay, number of delirium days, medical conditions surrounding death, and time with hypoxia and hypotension.
RESULTS
Patients’ mean age was 55 (SD±8.4), median number of days spent with delirium was 7 (±5 IQR). In 6 of 7 (86%) patients, pathologic lesions normally attributed to hypoxia or ischemia were noted in the hippocampus, pons, and striatum. Hippocampal lesions represented the most common neuropathological site of injury, present in 5 of 7 (71%) patients.
CONCLUSIONS
Hypoxic ischemic injury in multiple locations of the brain was a common finding in this pilot autopsy study of patients who had demonstrated delirium in the ICU. In particular, study of the hippocampus seems especially warranted in patients experiencing ICU delirium. Further correlation between clinical diagnoses, risk factors for neurological injury, neuroimaging, and neuropathology will help elucidate the mechanisms underlying acute brain dysfunction in our patients and long-term cognitive implications upon survival.
doi:10.1016/j.jcrc.2010.05.004
PMCID: PMC3755870  PMID: 20580199
Delirium; Brain Autopsy; Neuropathology; Intensive Care; Hippocampus
21.  Risk factors for delirium in acutely admitted elderly patients: a prospective cohort study 
BMC Geriatrics  2005;5:6.
Background
Delirium is a neuropsychiatric syndrome frequently observed in elderly hospitalised patients and can be found in any medical condition. Due to the severe consequences, early recognition of delirium is important in order to start treatment in time. Despite the high incidence rate, the occurrence of delirium is not always identified as such. Knowledge of potential risk factors is important. The aim of the current study is to determine factors associated with the occurrence of a prevalent delirium among elderly patients acutely admitted to an internal medicine ward.
Methods
All consecutive patients of 65 years and over acutely admitted to the Department of Internal Medicine of the Academic Medical Centre, Amsterdam, a university hospital, were asked to participate. The presence of delirium was determined within 48 hrs after admission by an experienced geriatrician.
Results
In total, 126 patients were included, 29% had a prevalent delirium after acute admission. Compared to patients without delirium, patients with delirium were older, more often were cognitively and physically impaired, more often were admitted due to water and electrolyte disturbances, and were less often admitted due to malignancy or gastrointestinal bleeding. Independent risk factors for having a prevalent delirium after acute admission were premorbid cognitive impairment, functional impairment, an elevated urea nitrogen level, and the number of leucocytes.
Conclusions
In this study, the most important independent risk factors for a prevalent delirium after acute admission were cognitive and physical impairment, and a high serum urea nitrogen concentration. These observations might contribute to an earlier identification and treatment of delirium in acutely admitted elderly patients.
doi:10.1186/1471-2318-5-6
PMCID: PMC1097727  PMID: 15826320
22.  Alzheimer disease pathology and longitudinal cognitive performance in the oldest-old with no dementia 
Neurology  2012;79(9):915-921.
Objective:
It has been hypothesized that individuals without dementia with Alzheimer disease (AD) neuropathology may be in the preclinical stages of dementia and could be experiencing subtle cognitive decline. The purpose of this study was to compare longitudinal cognitive performance in oldest-old individuals without dementia with and without AD neuropathology.
Methods:
The study included 58 individuals without dementia from The 90+ Autopsy Study, a population-based study of aging and dementia in individuals aged 90 and older. Participants had neurologic and neuropsychological testing every 6 months with an average of 3 years of follow-up. We compared the trajectory of cognitive performance on the Modified Mini-Mental State Examination (3MS) and the California Verbal Learning Test II (CVLT) by level of AD neuropathology. Based on Consortium to Establish a Registry for Alzheimer's Disease plaque staging, individuals were categorized as having low (none or sparse) or high (moderate or frequent) plaques. Based on Braak and Braak staging, participants were classified as having low (stages I–III) or high (IV–VI) tangles.
Results:
No significant differences were found in 3MS or CVLT cognitive performance over time based on plaque or tangle staging. Both high and low pathology groups showed modest improvements on the 3MS and CVLT consistent with learning effects.
Conclusions:
AD neuropathology at autopsy is not associated with the trajectory of cognitive performance in the 3 years before death in oldest-old without dementia. Despite the presence of AD neuropathology at death, oldest-old without dementia display learning effects on cognitive tests. Further research is necessary to understand factors other than AD neuropathology that may affect cognition in the oldest-old.
doi:10.1212/WNL.0b013e318266fc77
PMCID: PMC3425842  PMID: 22895581
23.  Benzodiazepine and opioid use and the duration of ICU delirium in an older population 
Critical care medicine  2009;37(1):177-183.
Objective
There is a high prevalence of delirium in older medical intensive care unit (ICU) patients and delirium is associated with adverse outcomes. We need to identify modifiable risk factors for delirium in the ICU, such as medication use. The objective of this study was to examine the impact of benzodiazepine or opioid use on the duration of ICU delirium in an older medical population.
Design
Prospective cohort study.
Setting
Fourteen-bed medical intensive care unit in an urban university teaching hospital.
Patients
304 consecutive admissions age 60 and older.
Interventions
None
Main Outcome Measurements
The main outcome measure was duration of ICU delirium, specifically the first episode of ICU delirium. Patients were assessed daily for delirium with the Confusion Assessment Method for the ICU (CAM-ICU) and a validated chart review method. Our main predictor was the receipt of benzodiazepines or opioids during ICU stay. A multivariable model was developed using Poisson rate regression.
Results
Delirium occurred in 239 of 304 patients (79%). The median duration of ICU delirium was 3 days with a range of 1-33 days. In a multivariable regression model receipt of a benzodiazepine or opioid (RR, 1.64, 95% CI, 1.27-2.10) was associated with increased delirium duration. Other variables associated with delirium duration in this analysis include preexisting dementia (RR, 1.19, 95% CI 1.07-1.33), receipt of haloperidol (RR, 1.35, 95% CI, 1.21-1.50), and severity of illness (RR, 1.01, 95% CI, 1.00-1.02).
Conclusions
The use of benzodiazepines or opioids in the ICU is associated with longer duration of a first episode of delirium. Receipt of these medications may represent modifiable risk factors for delirium. Clinicians caring for ICU patients should carefully evaluate the need for benzodiazepines, opioids and haloperidol.
doi:10.1097/CCM.0b013e318192fcf9
PMCID: PMC2700732  PMID: 19050611
delirium; critical care; risk factors; aged; benzodiazepines; opioids; haloperidol
24.  Evidence-Based Treatment of Delirium in Patients With Cancer 
Journal of Clinical Oncology  2012;30(11):1206-1214.
Delirium is the most common neuropsychiatric complication seen in patients with cancer, and it is associated with significant morbidity and mortality. Increased health care costs, prolonged hospital stays, and long-term cognitive decline are other well-recognized adverse outcomes of delirium. Improved recognition of delirium and early treatment are important in diminishing such morbidity. There has been an increasing number of studies published in the literature over the last 10 years regarding delirium treatment as well as prevention. Antipsychotics, cholinesterase inhibitors, and alpha-2 agonists are the three groups of medications that have been studied in randomized controlled trials in different patient populations. In patients with cancer, the evidence is most clearly supportive of short-term, low-dose use of antipsychotics for controlling the symptoms of delirium, with close monitoring for possible adverse effects, especially in older patients with multiple medical comorbidities. Nonpharmacologic interventions also appear to have a beneficial role in the treatment of patients with cancer who have or are at risk for delirium. This article presents evidence-based recommendations based on the results of pharmacologic and nonpharmacologic studies of the treatment and prevention of delirium.
doi:10.1200/JCO.2011.39.8784
PMCID: PMC3646320  PMID: 22412123
25.  Cognitive Decline and Dementia in the Oldest-Old 
The oldest-old are the fastest growing segment of the Western population. Over half of the oldest-old will have dementia, but the etiology is yet unknown. Age is the only risk factor consistently associated with dementia in the oldest-old. Many of the risk and protective factors for dementia in the young elderly, such as ApoE genotype, physical activity, and healthy lifestyle, are not relevant for the oldest-old. Neuropathology is abundant in the oldest-old brains, but specific pathologies of Alzheimer’s disease (AD) or vascular dementia are not necessarily correlated with cognition, as in younger persons. It has been suggested that accumulation of both AD-like and vascular pathologies, loss of synaptic proteins, and neuronal loss contribute to the cognitive decline observed in the oldest-old. Several characteristics of the oldest-old may confound the diagnosis of dementia in this age group. A gradual age-related cognitive decline, particularly in executive function and mental speed, is evident even in non-demented oldest-old. Hearing and vision losses, which are also prevalent in the oldest-old and found in some cases to precede/predict cognitive decline, may mechanically interfere in neuropsychological evaluations. Difficulties in carrying out everyday activities, observed in the majority of the oldest-old, may be the result of motor or physical dysfunction and of neurodegenerative processes. The oldest-old appear to be a select population, who escapes major illnesses or delays their onset and duration toward the end of life. Dementia in the oldest-old may be manifested when a substantial amount of pathology is accumulated, or with a composition of a variety of pathologies. Investigating the clinical and pathological features of dementia in the oldest-old is of great importance in order to develop therapeutic strategies and to provide the most elderly of our population with good quality of life.
doi:10.5041/RMMJ.10092
PMCID: PMC3678827  PMID: 23908850
Dementia; epidemiology; neurobiology; oldest-old; risk factors

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