Joost Witlox

Delirium in Elderly Patients and the Risk of Postdischarge Mortality, Institutionalization, and Dementia: A Meta-analysis

CONTEXT Delirium is a common and serious complication in elderly patients. Evidence suggests that delirium is associated with long-term poor outcome but delirium often occurs in individuals with more severe underlying disease. OBJECTIVE To assess the association between delirium in elderly patients and long-term poor outcome, defined as mortality, institutionalization, or dementia, while controlling for important confounders. DATA SOURCES A systematic search of studies published between January 1981 and April 2010 was conducted using the databases of MEDLINE, EMBASE, PsycINFO, and CINAHL. STUDY SELECTION Observational studies of elderly patients with delirium as a study variable and data on mortality, institutionalization, or dementia after a minimum follow-up of 3 months, and published in the English or Dutch language. Titles, abstracts, and articles were reviewed independently by 2 of the authors. Of 2939 references in the original search, 51 relevant articles were identified. DATA EXTRACTION Information on study design, characteristics of the study population, and outcome were extracted. Quality of studies was assessed based on elements of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cohort studies. DATA SYNTHESIS The primary analyses included only high-quality studies with statistical control for age, sex, comorbid illness or illness severity, and baseline dementia. Pooled-effect estimates were calculated with random-effects models. The primary analysis with adjusted hazard ratios (HRs) showed that delirium is associated with an increased risk of death compared with controls after an average follow-up of 22.7 months (7 studies; 271/714 patients [38.0%] with delirium, 616/2243 controls [27.5%]; HR, 1.95 [95% confidence interval {CI}, 1.51-2.52]; I(2), 44.0%). Moreover, patients who had experienced delirium were also at increased risk of institutionalization (7 studies; average follow-up, 14.6 months; 176/527 patients [33.4%] with delirium and 219/2052 controls [10.7%]; odds ratio [OR], 2.41 [95% CI, 1.77-3.29]; I(2), 0%) and dementia (2 studies; average follow-up, 4.1 years; 35/56 patients [62.5%] with delirium and 15/185 controls [8.1%]; OR, 12.52 [95% CI, 1.86-84.21]; I(2), 52.4%). The sensitivity, trim-and-fill, and secondary analyses with unadjusted high-quality risk estimates stratified according to the study characteristics confirmed the robustness of these results. CONCLUSION This meta-analysis provides evidence that delirium in elderly patients is associated with poor outcome independent of important confounders, such as age, sex, comorbid illness or illness severity, and baseline dementia.

Preoperative cerebrospinal fluid cytokine levels and the risk of postoperative delirium in elderly hip fracture patients

BackgroundAging and neurodegenerative disease predispose to delirium and are both associated with increased activity of the innate immune system resulting in an imbalance between pro- and anti-inflammatory mediators in the brain. We examined whether hip fracture patients who develop postoperative delirium have altered levels of inflammatory mediators in cerebrospinal fluid (CSF) prior to surgery.MethodsPatients were 75 years and older and admitted for surgical repair of an acute hip fracture. CSF samples were collected preoperatively. In an exploratory study, we measured 42 cytokines and chemokines by multiplex analysis. We compared CSF levels between patients with and without postoperative delirium and examined the association between CSF cytokine levels and delirium severity. Delirium was diagnosed with the Confusion Assessment Method; severity of delirium was measured with the Delirium Rating Scale Revised-98. Mann–Whitney U tests or Student t-tests were used for between-group comparisons and the Spearman correlation coefficient was used for correlation analyses.ResultsSixty-one patients were included, of whom 23 patients (37.7%) developed postsurgical delirium. Concentrations of Fms-like tyrosine kinase-3 (P=0.021), Interleukin-1 receptor antagonist (P=0.032) and Interleukin-6 (P=0.005) were significantly lower in patients who developed delirium postoperatively.ConclusionsOur findings fit the hypothesis that delirium after surgery results from a dysfunctional neuroinflammatory response: stressing the role of reduced levels of anti-inflammatory mediators in this process.Trial registrationThe Effect of Taurine on Morbidity and Mortality in the Elderly Hip Fracture Patient.Registration number: NCT00497978. Local ethical protocol number: NL16222.094.07.

Cerebrospinal Fluid β-Amyloid and Tau Are Not Associated with Risk of Delirium: A Prospective Cohort Study in Older Adults with Hip Fracture

OBJECTIVES: To examine the association between cerebrospinal fluid (CSF) β‐amyloid (Aβ1–42), tau, and hyperphosphorylated tau (Ptau) and risk of delirium in older adults with hip fracture.

Delirium motor subtypes in elderly hip fracture patients: Risk factors, outcomes and longitudinal stability

OBJECTIVE Delirium is often accompanied by changes in motor activity but the longitudinal expression of these features and etiological and prognostic significance of clinical subtypes defined by motor activity is unclear. METHODS This is a prospective cohort study of elderly patients undergoing hip fracture surgery. Baseline characteristics were assessed preoperatively. During hospital admission presence of delirium was assessed daily according to CAM criteria. This study compared baseline characteristics and outcomes according to a longitudinal pattern of motor subtype expression (predominantly hyperactive, predominantly hypoactive, predominantly mixed, no motor subtype and variable). Motor subtype categorization was performed with the DRS-R98. We also investigated the longitudinal stability of motor subtypes across the delirium episode. RESULTS 62 patients had experienced in-hospital delirium postoperatively. The full course of the delirium episode could be defined for 42/62 (67.7%) patients. Of the patients with multiple days of delirium only 4/30 (13.3%) patients had a consistent motor subtype profile throughout the delirium episode, while 26/30 (86.7%) patients had a variable course. Of the patients with multiple days of delirium, 5/30 (16.7%) were predominantly hypoactive in profile, 7/30 (23.3%) predominantly hyperactive, 6/30 (20%) predominantly mixed, 1/30 (3.3%) had no motor subtype and 11/30 (36.7%) had a variable profile. Baseline characteristics and outcomes did not differ between the groups. CONCLUSION The majority of elderly hip fracture patients in this homogenous sample experienced variable expression of motor subtype over the course of their delirium episodes. The subtype categorization according to dominant motor subtype across the delirium episode identified groups with similar characteristics and outcomes.

Validation and psychometric properties of the Delirium Motor Subtype Scale in elderly hip fracture patients (Dutch version)

The Delirium Motor Subtype Scale (DMSS) was developed to capture all the previous different approaches to delirium motor subtyping into one new instrument and emphasize disturbances of motor activity rather than associated psychomotoric symptoms. We investigated reliability and validity of the DMSS Dutch version. Elderly patients who had undergone hip fracture surgery received the DMSS and the Delirium Rating Scale Revised-98 (DRS-R-98). A diagnosis of delirium was defined according to the Confusion Assessment Method (CAM). Among 146 patients, 46 (32%) patients were diagnosed with delirium (mean age 86.3 years; SD 5.2). The internal consistency of the DMSS was acceptable (Cronbachs alpha=0.72). If an item was removed at random the internal consistency of the scale remained the same. Similarly the concurrent validity of DMSS was good (Cohens kappa=0.73) while for each motor subtype the Cohens kappa ranged from 0.58 to 0.85. The sensitivity and specificity of DMSS to detect each subtype ranged from 0.56 to 1 and from 0.88 to 0.98, respectively. This study suggests that the Dutch version of the DMSS is a reliable and valid instrument. The DMSS has scientific validity that could allow for greater precision in further research on motor subtypes.

The neuropsychological sequelae of delirium in elderly patients with hip fracture three months after hospital discharge

BACKGROUND Delirium is a risk factor for long-term cognitive impairment and dementia. Yet, the nature of these cognitive deficits is unknown as is the extent to which the persistence of delirium symptoms and presence of depression at follow-up may account for the association between delirium and cognitive impairment at follow-up. We hypothesized that inattention, as an important sign of persistent delirium and/or depression, is an important feature of the cognitive profile three months after hospital discharge of patients who experienced in-hospital delirium. METHODS This was a prospective cohort study. Fifty-three patients aged 75 years and older were admitted for surgical repair of acute hip fracture. Before the surgery, baseline characteristics, depressive symptomatology, and global cognitive performance were documented. The presence of delirium was assessed daily during hospital admission and three months after hospital discharge when patients underwent neuropsychological assessment. RESULTS Of 27 patients with in-hospital delirium, 5 were still delirious after three months. Patients with in-hospital delirium (but free of delirium at follow-up) showed poorer performance than patients without in-hospital delirium on tests of global cognition and episodic memory, even after adjustment for age, gender, and baseline cognitive impairment. In contrast, no differences were found on tests of attention. Patients with in-hospital delirium showed an increase of depressive symptoms after three months. However, delirium remained associated with poor performance on a range of neuropsychological tests among patients with few or no signs of depression at follow-up. CONCLUSION Elderly hip fracture patients with in-hospital delirium experience impairments in global cognition and episodic memory three months after hospital discharge. Our results suggest that inattention, as a cardinal sign of persistent delirium or depressive symptomatology at follow-up, cannot fully account for the poor cognitive outcome associated with delirium.

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.

Effect of Oral Taurine on Morbidity and Mortality in Elderly Hip Fracture Patients: A Randomized Trial

Hip fracture patients represent a large part of the elderly surgical population and face severe postoperative morbidity and excessive mortality compared to adult surgical hip fracture patients. Low antioxidant status and taurine deficiency is common in the elderly, and may negatively affect postoperative outcome. We hypothesized that taurine, an antioxidant, could improve clinical outcome in the elderly hip fracture patient. A double blind randomized, placebo controlled, clinical trial was conducted on elderly hip fracture patients. Supplementation started after admission and before surgery up to the sixth postoperative day. Markers of oxidative status were measured during hospitalization, and postoperative outcome was monitored for one year after surgery. Taurine supplementation did not improve in-hospital morbidity, medical comorbidities during the first year, or mortality during the first year. Taurine supplementation lowered postoperative oxidative stress, as shown by lower urinary 8-hydroxy-2-deoxyguanosine levels (Generalized estimating equations (GEE) analysis average difference over time; regression coefficient (Beta): −0.54; 95% CI: −1.08–−0.01; p = 0.04), blunted plasma malondialdehyde response (Beta: 1.58; 95% CI: 0.00–3.15; p = 0.05) and a trend towards lower lactate to pyruvate ratio (Beta: −1.10; 95% CI: −2.33–0.12; p = 0.08). We concluded that peri-operative taurine supplementation attenuated postoperative oxidative stress in elderly hip fracture patients, but did not improve postoperative morbidity and mortality.

Preoperative protein profiles in cerebrospinal fluid in elderly hip fracture patients at risk for delirium: A proteomics and validation study

Background A neuroinflammatory response is suggested to play an important role in delirium, a common complication in older hospitalized patients. We examined whether hip fracture patients who develop postoperative delirium have a different proteome in cerebrospinal fluid (CSF) prior to surgery. Methods Patients (≥ 75 years) were admitted for hip fracture surgery. CSF was collected during spinal anaesthesia; proteins were separated using gel electrophoresis and identified with mass spectrometry. We compared the proteome of patients with and without postoperative delirium. Findings were validated in an independent, comparable cohort using immuno-assays. Results In the derivation cohort 53 patients were included, 35.8% developed postoperative delirium. We identified differences in levels of eight CSF proteins between patients with and without subsequent delirium: complement factor C3, contactin-1, fibulin-1 and I-beta-1,3-N-acetylglucosaminyltransferase were significantly lower in patients with postoperative delirium, while neural cell adhesion molecule-2, fibrinogen, zinc-α-2-glycoprotein and haptoglobin levels were significantly higher. In the validation cohort 21.2% of 52 patients developed postoperative delirium. Immuno-assays confirmed contactin-1 results although not statistically significant. Complement factor C3 was significantly higher in patients with postoperative delirium. Conclusion Our results show the complexity of pathophysiological mechanisms involved in delirium and emphasizes the need of independent validation of findings. General significance This study highlights the challenges and inconsistent findings in studies of delirium, a serious complication in older patients. We analysed proteins in CSF, the most proximal fluid to the brain. All patients were free from delirium at the time of sampling.

Reliability of delirium rating scale (DRS) and delirium rating scale-revised-98 (DRS-R98) using variance-based multivariate modelling

Deliriums characteristic fluctuation in symptom severity complicates the assessment of test-retest reliability of scales using classical analyses, but application of modelling to longitudinal data offers a new approach. We evaluated test-retest reliability of the delirium rating scale (DRS) and delirium rating scale-revised-98 (DRS-R98), two widely used instruments with high validity and inter-rater reliability. Two existing longitudinal datasets for each scale included DSM-IV criteria for delirium diagnosis and repeated measurements using the DRS or DRS-R98. To estimate the reliability coefficients RT and RΛ for each scale we used a macros provided by Dr. Laenen at http://www.ibiostat.be/software/measurement.asp. For each dataset a linear mixed-effects model was fitted to estimate the variance-covariance parameters. A total of 531 cases with between 4 and 9 measurement points across studies including both delirious and non-delirious patients. Comorbid dementia in the datasets varied from 27% to 55%. Overall RT for the DRS were 0.71 and 0.50 and for DRS-R98 0.75 and 0.84. RΛ values for DRS were 0.99 and 0.98 and for DRS-R98 were 0.92 and 0.96. Individual RT measures for DRS-R98 and DRS across visits within studies showed more range than overall values. Our models found high overall reliability for both scales. Multiple factors impact a scales reliability values including sample size, repeated measurements, patient population, etc in addition to rater variability.