Willem A. van Gool

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.

Inflammatory mechanisms in Alzheimer's disease

Alzheimers disease is aetiologically heterogeneous, but the pathogenesis is often considered to be initiated by the deposition of amyloid fibrils, followed by neuritic tau pathology and neuronal death. A variety of inflammatory proteins has been identified in the brains of patients with Alzheimers disease post mortem. In this article, Piet Eikelenboom and colleagues review evidence to suggest that the inflammatory processes are intimately involved in several crucial events in the pathological cascade. This suggests possibilities for the treatment of Alzheimers disease with anti-inflammatory drugs.

Systemic infection and delirium: when cytokines and acetylcholine collide

Systemic infection and drugs with anticholinergic effects are well-recognised and prevalent risk factors for delirium in elderly people. Experimental findings and neuropathological observations suggest that activation of microglia is pivotal for mediation of the behavioural effects of systemic infections. The microglial response is usually regulated tightly, but defensive features could turn neurotoxic once microglial cells escape from cholinergic inhibition. A self-propelling neuroinflammatory reaction might follow, and this cascade could account for the strong association between delirium and long-term cognitive impairment and even dementia. Here, we propose a hypothetical model, suggesting that poor outcome after delirium can be averted in vulnerable elderly people by use of readily available drugs. Agents that either restore cholinergic control of microglia or directly inhibit neuroinflammation warrant testing in clinical trials.

Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients : a multicentre, double-blind, placebo-controlled randomised trial

BACKGROUND Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. METHODS Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301. FINDINGS Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7-14·2) than in the placebo group (3·0 days, IQR 1·0-9·3; p=0·06). INTERPRETATION Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. FUNDING ZonMw, the Netherlands Brain Foundation, and Novartis.

Effect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study

BACKGROUND Results of epidemiological studies, neuropathological observations, and in-vitro experiments all suggest that inflammatory mechanisms contribute to the destructive lesions in Alzheimers disease. We aimed to establish the effect of the anti-inflammatory drug hydroxychloroquine on the progression of dementia. METHODS We did a double-blind, parallel-group, multicentre trial in which we randomly assigned 168 patients with early Alzheimers disease to hydroxychloroquine (200 or 400 mg dependent on bodyweight), or placebo for 18 months. Outcome measures were related to activities of daily living, cognitive function, and behavioural abnormalities. Analysis was by intention to treat. RESULTS At 18 months, mean scores for the interview for deterioration in daily life in dementia in patients on hydroxychloroquine (22.6 [SD 11.4]) did not differ from those for patients on placebo (21.3 [10.5]). Also, mean scores on the cognitive subscale of the Alzheimers disease assessment scale were closely similar in hydroxychloroquine (26.4 [14.9]) and placebo (25.7 [14.3]) treated patients, as were behavioural changes, measured by the revised memory and behavioural problems checklist (36.3 [12.0] and 34.2 [12.4], respectively). Explorative analyses did not suggest any specific subgroup that benefited from hydroxychloroquine. The frequency and nature of serious adverse events and side-effects were much the same in both groups. 155 (92%) patients completed all assessments over the entire study. INTERPRETATION Anti-inflammatory treatment with hydroxychloroquine for 18 months does not slow the rate of decline in minimal or mild Alzheimers disease.

Risk factors and prediction of postoperative delirium in elderly hip-surgery patients : Implementation and validation of a medical risk factor model

OBJECTIVES: To evaluate risk factors for postoperative delirium in a cohort of elderly hip‐surgery patients and to validate a medical risk stratification model.

Systemic inflammation and microglial activation: systematic review of animal experiments

BackgroundAnimal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated delirium. We systematically reviewed animal experiments related to the effects of systemic inflammation on the microglial and inflammatory response in the brain.MethodsWe searched PubMed between January 1, 1950 and December 1, 2013 and Embase between January 1, 1988 and December 1, 2013 for animal studies on the influence of peripheral inflammatory stimuli on microglia and the brain. Identified studies were systematically scored on methodological quality. Two investigators extracted independently data on animal species, gender, age, and genetic background; number of animals; infectious stimulus; microglial cells; and other inflammatory parameters in the brain, including methods, time points after inoculation, and brain regions.ResultsFifty-one studies were identified of which the majority was performed in mice (n = 30) or in rats (n = 19). Lipopolysaccharide (LPS) (dose ranging between 0.33 and 200 mg/kg) was used as a peripheral infectious stimulus in 39 studies (76 %), and live or heat-killed pathogens were used in 12 studies (24 %). Information about animal characteristics such as species, strain, sex, age, and weight were defined in 41 studies (80 %), and complete methods of the disease model were described in 35 studies (68 %). Studies were also heterogeneous with respect to methods used to assess microglial activation; markers used mostly were the ionized calcium binding adaptor molecule-1 (Iba-1), cluster of differentiation 68 (CD68), and CD11b. After LPS challenge microglial activation was seen 6 h after challenge and remained present for at least 3 days. Live Escherichia coli resulted in microglial activation after 2 days, and heat-killed bacteria after 2 weeks. Concomitant with microglial response, inflammatory parameters in the brain were reviewed in 23 of 51 studies (45 %). Microglial activation was associated with an increase in Toll-like receptor (TLR-2 and TLR-4), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) messenger ribonucleic acid (mRNA) expression or protein levels.InterpretationAnimal experiments robustly showed that peripheral inflammatory stimuli cause microglial activation. We observed distinct differences in microglial activation between systemic stimulation with (supranatural doses) LPS and live or heat-killed bacteria.

Routine use of the confusion assessment method for the intensive care unit : a multicenter study

RATIONALE Delirium is often unrecognized in ICU patients and associated with poor outcome. Screening for ICU delirium is recommended by several medical organizations to improve early diagnosis and treatment. The Confusion Assessment Method for the ICU (CAM-ICU) has high sensitivity and specificity for delirium when administered by research nurses. However, test characteristics of the CAM-ICU as performed in routine practice are unclear. OBJECTIVES To investigate the diagnostic value of the CAM-ICU in daily practice. METHODS Teams of three delirium experts including psychiatrists, geriatricians, and neurologists visited 10 ICUs twice. Based on cognitive examination, inspection of medical files, and Diagnostic and Statistic Manual of Mental Disorders, 4th edition, Text Revision criteria for delirium, the expert teams classified patients as awake and not delirious, delirious, or comatose. This served as a gold standard to which the CAM-ICU as performed by the bedside ICU-nurses was compared. Assessors were unaware of each others conclusions. MEASUREMENTS AND MAIN RESULTS Fifteen delirium experts assessed 282 patients of whom 101 (36%) were comatose and excluded. In the remaining 181 (64%) patients, the CAM-ICU had a sensitivity of 47% (95% confidence interval [CI], 35%-58%); specificity of 98% (95% CI, 93%-100%); positive predictive value of 95% (95% CI, 80%-99%); and negative predictive value of 72% (95% CI, 64%-79%). The positive likelihood ratio was 24.7 (95% CI, 6.1-100) and the negative likelihood ratio was 0.5 (95% CI, 0.4-0.8). CONCLUSIONS Specificity of the CAM-ICU as performed in routine practice seems to be high but sensitivity is low. This hampers early detection of delirium by the CAM-ICU.

Microglia activation in sepsis: a case-control study

Backgroundinfection induces an acute phase response that is accompanied by non-specific symptoms collectively named sickness behavior. Recent observations suggest that microglial cells play a role in mediating behavioral changes in systemic infections. In animal models for sepsis it has been shown that after inducing lipopolysaccharide, LPS, microglia in the brain were activated. The aim of this study was to investigate whether activation of microglia can be detected in patients who died of sepsis.Methodsin a case-control study brain tissue of 13 patients who died with sepsis was compared with that of 17 controls. Activated microglia were identified by expression of MHC-class II antigens and CD68. Microglia activation was analyzed by a semiquantitative score combining both the number of the immunoreactive cells and their morphology.Resultsin patients who died with sepsis there was a significant increase in activated microglia in the grey matter when stained with CD68 compared to controls. This effect was independent of the effect of age.Conclusionthis study shows for the first time in human brain tissue an association between a systemic infection and activation of microglia in the brain. Activated microglia during sepsis could play a role in behavioral changes associated with systemic infection.

Prevention of dementia by intensive vascular care (PreDIVA): a cluster-randomized trial in progress.

Background and PurposeCardiovascular risk factors are associated with an increased risk of dementia. Treatment of hypertension and hypercholesterolemia is associated with a decrease in incident dementia. Whether interventions aimed at cardiovascular risk factors in late life also reduce dementia risk is unknown. Here, we report the outline of a pragmatic study that will attempt to answer this question and we describe the prevalence of cardiovascular risk factors in the target population. MethodsWe designed a large cluster-randomized trial with a 6-year follow-up in 3700 elderly subjects (70 to 78 y) to assess whether nurse-led intensive vascular care in primary care decreases the incidence of dementia and reduces disability. Secondary outcome parameters are mortality, incidence of vascular events, and cognitive functioning. Intensive vascular care comprises treatment of hypertension, hypercholesterolemia, diabetes and reducing overweight, smoking cessation, and stimulating physical exercise. ResultsBaseline data of 1004 subjects show that 87% of the subjects have 1 or more cardiovascular risk factors and 44% have even 2 or more risk factors amenable to treatment. Seventy-nine percent of the subjects receiving antihypertensive medication still have a systolic pressure of >140 mm Hg. ConclusionsIn this older age group, the very high percentage of elderly subjects with cardiovascular risk factors illustrates the large window of opportunity for therapies directed to lower the cardiovascular risk and potentially also the risk for dementia.