Head-to-head comparison of 14 prediction models for postoperative delirium in elderly non-ICU patients: an external validation study.

OBJECTIVES: Delirium is associated with increased morbidity, mortality, prolonged hospitalisation and increased healthcare costs. The number of clinical prediction models (CPM) to predict postoperative delirium has increased exponentially. Our goal is to perform a head-to-head comparison of CPMs predicting postoperative delirium in non-intensive care unit (non-ICU) elderly patients to identify the best performing models. SETTING: Single-site university hospital. DESIGN: Secondary analysis of prospective cohort study. PARTICIPANTS AND INCLUSION: CPMs published within the timeframe of 1 January 1990 to 1 May 2020 were checked for eligibility (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). For the time period of 1 January 1990 to 1 January 2017, included CPMs were identified in systematic reviews based on prespecified inclusion and exclusion criteria. An extended literature search for original studies was performed independently by two authors, including CPMs published between 1 January 2017 and 1 May 2020. External validation was performed using a surgical cohort consisting of 292 elderly non-ICU patients. PRIMARY OUTCOME MEASURES: Discrimination, calibration and clinical usefulness. RESULTS: 14 CPMs were eligible for analysis out of 366 full texts reviewed. External validation was previously published for 8/14 (57%) CPMs. C-indices ranged from 0.52 to 0.74, intercepts from -0.02 to 0.34, slopes from -0.74 to 1.96 and scaled Brier from -1.29 to 0.088. Based on predefined criteria, the two best performing models were those of Dai et al (c-index: 0.739; (95% CI: 0.664 to 0.813); intercept: -0.018; slope: 1.96; scaled Brier: 0.049) and Litaker et al (c-index: 0.706 (95% CI: 0.590 to 0.823); intercept: -0.015; slope: 0.995; scaled Brier: 0.088). For the remaining CPMs, model discrimination was considered poor with corresponding c-indices <0.70. CONCLUSION: Our head-to-head analysis identified 2 out of 14 CPMs as best-performing models with a fair discrimination and acceptable calibration. Based on our findings, these models might assist physicians in postoperative delirium risk estimation and patient selection for preventive measures.

Plasma 5-HIAA activity indicative of serotonergic disturbances in cognitively impaired, elderly patients experiencing postoperative delirium.

OBJECTIVES: Delirium frequently arises in older demented and non-demented patients in postoperative, clinical settings. To date, the underlying pathophysiological mechanisms remain poorly understood. Monoamine neurotransmitter alterations have been linked to delirium and cognitive impairment. Our aim was to investigate if this holds true in cognitively normal and impaired patients experiencing delirium following hip surgery. METHODS: Monoamines and metabolites were measured in plasma samples of 181 individuals by means of reversed-phase ultra-high-performance liquid chromatography with electrochemical detection. Delirium and delirium severity were scored with the Confusion Assessment Method and Delirium Rating Scale-Revised-1998. Cognitive function was assessed using the Informant Questionnaire on Cognitive Decline and the Mini-Mental State Examination, multimorbidity with the Charlson Comorbidity Index. RESULTS: Plasma 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT), was significantly higher in delirious and non-delirious cognitively impaired subjects as compared to control individuals without delirium and cognitive impairment (p < 0.001 and p = 0.007), which remained highly significant after excluding patients taking psychotropic medication (p < 0.0001 and p = 0.003). No significant differences were found for cognitively normal delirious patients, although serotonergic levels were numerically higher compared to control counterparts. CONCLUSIONS: Our findings indicate a general serotonergic disturbance in delirious and non-delirious postoperative patients suffering from cognitive impairment. We observed a similar, but less pronounced difference in delirious patients, which suggests serotonergic disturbances may be further aggravated by the co-occurrence of delirium and cognitive impairment.

Geriatric Syndromes and Incident Chronic Health Conditions Among 9094 Older Community-Dwellers: Findings from the Lifelines Cohort Study.

OBJECTIVES: To determine the association between geriatric syndromes and any specific incident chronic health conditions among older community-dwellers. DESIGN: Population-based cohort study over a median follow-up period of 43 months. SETTING AND PARTICIPANTS: Participants from the Lifelines Cohort Study aged 60 years and older without presence of the studied chronic health conditions at baseline (n = 9094). METHODS: Baseline assessment took place between November 2006 and December 2013 and included information on socioeconomic (age, sex, level of education and income), social contact, and health-related factors [eg, self-rated health, body mass index, chronic health conditions, and health behavior (alcohol consumption and smoking)]. Participants also reported the presence of geriatric syndromes (ie, included falls, incontinence, vision impairment, hearing impairment, depressive symptoms, and frailty at baseline). Three follow-up questionnaires were used to examine the incidence of any and specific chronic health conditions (ie, pulmonary and cardiovascular diseases, diabetes, cancer, and neurological diseases). Cox regression was used to analyze the longitudinal associations between geriatric syndromes and incident chronic health conditions. RESULTS: Older community-dwelling individuals with at least one geriatric syndrome (44.7%, n = 4038) had an increased risk of developing any new chronic health condition [hazard ratio (HR) 1.35; 95% confidence interval (CI) 1.21-1.51]. The association was attenuated but remained significant after adjustment for socioeconomic factors, social contact, health status, and health behavior (HR 1.27; 95% CI 1.12-1.43). Analyses for specific chronic health conditions showed that compared with older community-dwellers without geriatric syndromes, those with geriatric syndromes had an increased risk to develop a cardiovascular health condition (HR 1.42; 95% CI 1.13-1.79) or diabetes (HR 1.53; 95% CI 1.11-2.11). They had no increased risk to develop pulmonary conditions, cancer, or neurological conditions. CONCLUSION AND IMPLICATIONS: The presence of geriatric syndromes is associated with incident chronic health conditions, specifically cardiovascular conditions and diabetes. Increased awareness is needed among older people with geriatric syndromes and their physicians. Comprehensive assessments of geriatric syndromes may help to prevent or at least delay the development of chronic health conditions.

Screening instruments for cognitive impairment in older patients in the Emergency Department: a systematic review and meta-analysis.

BACKGROUND: cognitive impairment is highly prevalent among older patients attending the Emergency Department (ED) and is associated with adverse outcomes. METHODS: we conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of cognitive screening instruments to rule out cognitive impairment in older patients in the ED. A comprehensive literature search was performed in MEDLINE, EMBASE, CINAHL and CENTRAL. A risk of bias assessment using QUADAS-2 was performed. RESULTS: 23 articles, examining 18 different index tests were included. Only seven index tests could be included in the meta-analysis. For ruling out cognitive impairment irrespective of aetiology, Ottawa 3 Day Year (O3DY) (pooled sensitivity 0.90; (95% CI) 0.71-0.97) had the highest sensitivity. Fourteen articles focused on screening for cognitive impairment specifically caused by delirium. For ruling out delirium, the 4 A's Test (4AT) showed highest sensitivity (pooled sensitivity 0.87, 95% confidence interval (95% CI) 0.74-0.94). CONCLUSIONS: high clinical and methodological heterogeneity was found between included studies. Therefore, it is a challenge to recommend one diagnostic test for use as a screening instrument for cognitive impairment in the ED. The 4AT and O3DY seem most promising for ruling out cognitive impairment in older patients attending the ED.The review protocol was registered in PROSPERO (CRD42018082509).

Uptake and effectiveness of a tailor-made online lifestyle programme targeting modifiable risk factors for dementia among middle-aged descendants of people with recently diagnosed dementia: study protocol of a cluster randomised controlled trial (Demin study).

INTRODUCTION: Descendants of patients with dementia have a higher risk to develop dementia. This study aims to investigate the uptake and effectiveness of an online tailor-made lifestyle programme for dementia risk reduction (DRR) among middle-aged descendants of people with recently diagnosed late-onset dementia. METHODS AND ANALYSIS: Demin is a cluster randomised controlled trial, aiming to include 21 memory clinics of which 13 will be randomly allocated to the passive (poster and flyer in a waiting room) and 8 to the active recruitment strategy (additional personal invitation by members of the team of the memory clinic). We aim to recruit 378 participants (40-60 years) with a parent who is recently diagnosed with Alzheimer's disease or vascular dementia at one of the participating memory clinics. All participants receive a dementia risk assessment (online questionnaire, physical examination and blood sample) and subsequently an online tailor-made lifestyle advice regarding protective (Mediterranean diet, low/moderate alcohol consumption and high cognitive activity) and risk factors (physical inactivity, smoking, loneliness, cardiovascular diseases (CVD), hypertension, high cholesterol, diabetes, obesity, renal dysfunction and depression) for dementia. The primary outcome is the difference in uptake between the two recruitment strategies. Secondary outcomes are change(s) in (1) the Lifestyle for Brain Health score, (2) individual health behaviours, (3) health beliefs and attitudes towards DRR and (4) compliance to the tailor-made lifestyle advice. Outcomes will be measured at 3, 6, 9 and 12 months after baseline. The effectiveness of this online tailor-made lifestyle programme will be evaluated by comparing Demin participants to a matched control group (lifelines cohort). ETHICS AND DISSEMINATION: This study has been approved by the Dutch Ministry of Health, Welfare and Sport according to the Population Screening Act. All participants have to give online informed consent using SMS-tan (transaction authentication number delivered via text message). Findings will be disseminated through peer-reviewed journals and (inter)national conferences. TRIAL REGISTRATION NUMBER: NTR7434.

Delirium, functional decline and quality of life after transcatheter aortic valve implantation: An explorative study.

AIM: Transcatheter aortic valve implantation (TAVI) has become an important treatment option for older patients with severe aortic stenosis. However, not all patients benefit from this procedure in terms of functional outcome and quality of life. This complicates patient selection and shared decision-making. Postoperative delirium might negatively affect patient outcomes after TAVI. We therefore studied the potential relationship between postoperative delirium and functional outcome, and how this impacts quality of life after TAVI. METHODS: This was a prospective cohort study of 91 consecutive patients undergoing TAVI between 2015 and 2017 at an academic medical center. All patients underwent a Comprehensive Geriatric Assessment before TAVI. Delirium symptoms were assessed daily during hospitalization. Follow up was carried out between 6 and 12 months postprocedure. The primary outcome was functional decline or death at follow up. Secondarily, we measured quality of life at follow up. RESULTS: The incidence of postoperative delirium was 15.4%. In total, 38.5% of patients experienced functional decline, and 11.0% died during a median follow-up period of 7 months. Delirium resulted in a fourfold increased odds of the combined outcome of functional decline or death. Quality of life was lower in patients that experienced this outcome. CONCLUSION: In a cohort of TAVI patients, functional decline or death was a frequent outcome in the first year postprocedure. Postoperative delirium increased the odds for this outcome substantially. This suggests that delirium risk should be an important factor to consider in shared decision-making for TAVI patients. Geriatr Gerontol Int 2020; 20: 1202-1207.

Trajectories of self-rated health in an older general population and their determinants: the Lifelines Cohort Study.

OBJECTIVES: Poor self-rated health (SRH) is a strong predictor of premature mortality in older adults. Trajectories of poor SRH are associated with multimorbidity and unhealthy behaviours. Whether trajectories of SRH are associated with deviating physiological markers is unclear. This study identified trajectories of SRH and investigated the associations of trajectory membership with chronic diseases, health risk behaviours and physiological markers in community-dwelling older adults. STUDY DESIGN AND SETTING: Prospective general population cohort. PARTICIPANTS: Trajectories of SRH over 5 years were identified using data of 11 600 participants aged 65 years and older of the Lifelines Cohort Study. OUTCOME MEASURES: Trajectories of SRH were the main outcome. Covariates included demographics (age, gender, education), chronic diseases, health-risk behaviour (physical activity, smoking, drinking) and physiological markers (body mass index, cardiovascular function, lung function, glucose metabolism, haematological condition, endocrine function, renal function, liver function and cognitive function). RESULTS: Four stable trajectories were identified, including excellent (n=607, 6%), good (n=2111, 19%), moderate (n=7677, 65%) and poor SRH (n=1205, 10%). Being women (OR: 1.4; 95% CI: 1.0 to 1.9), low education (OR: 2.1; 95% CI: 1.5 to 3.0), one (OR: 10.4; 95% CI: 7.4 to 14.7) or multiple chronic diseases (OR: 37.8; 95% CI: 22.4 to 71.8), smoking (OR: 1.8; 95% CI: 1.0 to 3.2), physical inactivity (OR: 3.1; 95% CI: 1.8 to 5.2), alcohol abstinence (OR: 2.2; 95% CI: 1.4 to 3.2) and deviating physiological markers (OR: 1.5; 95% CI: 1.1 to 2.0) increase the odds for a higher probability of poor SRH trajectory membership compared with excellent SRH trajectory membership. CONCLUSION: SRH of community-dwelling older adults is stable over time with the majority (65%) having moderate SRH. Older adults with higher probabilities of poor SRH often have unfavourable health status.

Plasma melatonin levels in hip fracture patients with and without delirium: A confirmation study.

BACKGROUND: Melatonin plays a major role in maintaining circadian rhythm. Changes in melatonin metabolism might lead to circadian rhythm disturbances which are often observed in delirious patients. AIM: To assess if high morning plasma melatonin concentrations were associated with delirium. METHODS: Consecutive hip fracture patients aged ≥65 years were included. Delirium was assessed daily with the Confusion Assessment METHOD: Blood samples were collected at 11.00am on weekdays during first week of hospitalization. Melatonin was analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: We analyzed 389 samples of 144 participants [mean age 84.0, 70 experienced delirium]. A Generalized Estimating Equations (GEE) model with outcome melatonin level in highest tertile ( >3.36 pg/ml) and covariates delirium group (i.e. never, before, during, post delirium), cognitive impairment, age, sex and anesthesia type, was constructed. Highest melatonin levels were associated with postoperative samples (Odds Ratio(OR) 2.11 compared to preoperative samples; 95% Confidence Interval(CI) 1.17-3.82, p=0.01) and higher age (OR 1.05 per year; CI 1.01-1.11, p=0.03), but not with delirium group(p=0.35). CONCLUSION: Undergoing surgery and aging in general may induce changes in melatonin metabolism. Future research should focus on daily multiple melatonin measurements to determine whether melatonin supplementation might be beneficial for delirium treatment or prevention.

Survival Patterns in Elderly Head and Neck Squamous Cell Carcinoma Patients Treated With Definitive Radiation Therapy.

PURPOSE: We sought to assess the effect of age on overall survival (OS), cancer-specific survival (CSS), and non-cancer-related death (NCRD) in elderly (aged ≥70 years) head and neck squamous cell carcinoma (HNSCC) patients treated with definitive radiation therapy. The results were compared with those of younger patients, and the most important prognostic factors for survival endpoints were determined. Treatments may be better justified based on identification of the main differences in survival between young and elderly patients. METHODS AND MATERIALS: Data were analyzed from all consecutive HNSCC patients treated with definitive radiation therapy (66-70 Gy) in our department between April 2007 and December 2014. A total of 674 patients, including 168 elderly patients (24.9%), were included in the study. Multivariate association models were constructed to assess the effect of age on survival endpoints. Multivariate analysis was performed to identify potential prognostic factors for survival in elderly patients. RESULTS: A total of 674 consecutive patients, including 168 elderly patients, were analyzed. The 5-year OS and NCRD rates were significantly worse for elderly patients than for young patients: 45.5% versus 58.2% (P=.007) and 39.0% versus 20.7% (P<.001), respectively. In the multivariate association analysis on the relationship between age and OS, lymph node involvement and worse World Health Organization (WHO) performance status were identified as significant confounders. Multivariate association analysis between age and NCRD identified Union for International Cancer Control stage as a significant confounder. After correction for confounders, the effect of age on OS and NCRD increased. Worse WHO performance status, lymph node involvement, and specific tumor site were independent prognostic factors for OS and CSS in the elderly patient group. Of the elderly patients, 80 (47%) died during follow-up; 45% of these deaths were ascribed to the index tumor. For elderly patients, radiation therapy combined with systemic forms of treatment was significantly associated with adverse NCRD rate (hazard ratio, 8.02; 95% confidence interval, 2.36-27.2; P=.001) after we performed a multivariate association analysis. CONCLUSIONS: Elderly HNSCC patients have worse survival outcomes than young HNSCC patients. Age is an independent prognostic factor for OS, mainly due to an increase in non-cancer-related mortality and comorbid diseases. The differences in CSS between young and elderly patients are negligible.

Distinct Cognitive Trajectories in the First Year After Hip Fracture.

OBJECTIVES: Change in cognitive functioning is often observed after hip fracture. Different patterns, with both improvement and decline, are expected, depending on premorbid cognitive functioning and events that occur during hospitalization. These patterns are unknown and important for older hip fracture patients with different levels of premorbid cognitive functioning. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: We conducted a secondary analysis of a multi-center randomized controlled trial. 302 consecutive patients aged 65-102 years old, admitted for hip fracture surgery, were enrolled. The Mini Mental State Examination (MMSE) was obtained at hospital admission, at discharge, and at 3 and 12 months after discharge. Cognitive trajectories were identified with Group Based Trajectory Modelling, using the repeated MMSE measurements as outcome variable. To illustrate the specific characteristics of this relative novel methodological approach, it was contrasted with results obtained from linear mixed effects modeling. RESULTS: 146 (48.3%) patients had premorbid cognitive impairment and 85 patients (28.1%) experienced delirium during admission. Three distinct cognitive trajectories were identified and labeled based on different MMSE course over time: improvement (57.9%), stable (28.1%), and rapid decline (13.9%), with an annual MMSE change of 1.7, 0.8, and -3.5 points respectively. With mixed effects modeling an overall annual increase of 0.7 MMSE points was estimated for the group as a whole. CONCLUSION: Three distinct cognitive trajectories were identified in a population of older hip fracture patients. These trajectory groups can be used as a starting point to inform patients and caregivers on the possible prognosis after hip fracture. Group based trajectory modelling is a useful technique when the purpose is to describe patterns of change within a population and a variety of trajectories are expected to exist.

Pathophysiological and behavioral effects of systemic inflammation in aged and diseased rodents with relevance to delirium: A systematic review.

Delirium is a frequent outcome for aged and demented patients that suffer a systemic inflammatory insult. Animal models that reconstruct these etiological processes have potential to provide a better understanding of the pathophysiology of delirium. Therefore, we systematically reviewed animal studies in which systemic inflammation was superimposed on aged or diseased animal models. In total, 77 studies were identified. Aged animals were challenged with a bacterial endotoxin in 29 studies, 25 studies superimposed surgery on aged animals, and in 6 studies a bacterial infection, Escherichia coli (E. coli), was used. Diseased animals were challenged with a bacterial endotoxin in 15 studies, two studies examined effects of the cytokine IL-1ß, and one study used polyinosinic:polycytidilic acid (poly I:C). This systematic review analyzed the impact of systemic inflammation on the production of inflammatory and neurotoxic mediators in peripheral blood, cerebrospinal fluid (CSF), and on the central nervous system (CNS). Moreover, concomitant behavioral and cognitive symptoms were also evaluated. Finally, outcomes of behavioral and cognitive tests from animal studies were compared to features and symptoms present in delirious patients.

Unraveling the Relationship Between Delirium, Brain Damage, and Subsequent Cognitive Decline in a Cohort of Individuals Undergoing Surgery for Hip Fracture.

OBJECTIVES: To assess the association between serum S100B levels (a marker of brain damage), delirium, and subsequent cognitive decline. DESIGN: Substudy of a multicenter randomized controlled trial. SETTING: Surgical, orthopedic, and trauma surgery wards of two teaching hospitals. PARTICIPANTS: Individuals aged 65 and older (range 65-102) admitted for hip fracture surgery (N = 385). MEASUREMENTS: During hospitalization, presence of delirium was assessed daily. S100B was assayed in repeated serum samples. Twelve months after discharge, cognitive decline and mortality were evaluated. Cognitive decline was defined as an increase in Informant Questionnaire on Cognitive Decline Short Form score of 1 standard deviation or more or a decrease in Mini Mental State Examination score of 3 points or more between admission and 12 months after discharge. RESULTS: Premorbid cognitive impairment was present in 226 (58.7%) participants, and 127 (33.0%) experienced perioperative delirium. Multivariable analysis showed that older age and presence of infection, but not of delirium, were associated with higher S100B levels. Levels were also higher after surgery than before. Of participants with perioperative delirium, 58.6% experienced cognitive decline or death, and only age was a risk factor; 36.5% of participants without perioperative delirium experienced cognitive decline or death in the following year, and higher S100B, premorbid cognitive impairment, and older age were risk factors. CONCLUSION: In a cohort of older adults with hip fracture, no association was found between serum S100B levels and occurrence of delirium. S100B was associated with cognitive decline or death in the first year after hip fracture only in participants without perioperative delirium. S100B seems to be of limited value as a biomarker of brain damage associated with delirium.

Variability of Delirium Motor Subtype Scale-Defined Delirium Motor Subtypes in Elderly Adults with Hip Fracture: A Longitudinal Study.

OBJECTIVES: To examine changes in motor subtype profile in individuals with delirium. DESIGN: Observational, longitudinal study; substudy of a multicenter, randomized controlled trial. SETTING: Departments of surgery and orthopedics, Academic Medical Center and Tergooi Hospital, the Netherlands. PARTICIPANTS: Elderly adults acutely admitted for hip fracture surgery who developed delirium according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for 2 days or longer (n = 76, aged 86.4 ± 6.1, 68.4% female). MEASUREMENTS: Delirium Motor Subtype Scale (DMSS), Delirium Rating Scale R98 (DRS-R98), comorbidity, and function. RESULTS: Median delirium duration was 3 days (interquartile range 2.0 days). At first assessment, the hyperactive motor subtype was most common (44.7%), followed by hypoactive motor subtype (28.9%), mixed motor subtype (19.7%), and no motor subtype (6.6%). Participants with no motor subtype had lower DRS-R98 scores than those with the other subtypes (P < .001). The DMSS-defined motor subtype of 47 (61.8%) participants changed over time. Katz Index of Activities of Daily Living, Charlson Comorbidity Index, cognitive impairment, age, sex, and delirium duration or severity were not associated with change in motor subtype. CONCLUSION: Motor subtype profile was variable in the majority of participants, although changes that occurred were often related to changes from or to no motor subtype, suggesting evolving or resolving delirium. Changes appeared not be associated with demographic or clinical characteristics, suggesting that evidence from cross-sectional studies of motor subtypes could be applied to many individuals with delirium. Further longitudinal studies should be performed to clarify the stability of motor subtypes in different clinical populations.

Preoperative CSF Melatonin Concentrations and the Occurrence of Delirium in Older Hip Fracture Patients: A Preliminary Study.

BACKGROUND: Delirium is characterized by disturbances in circadian rhythm. Melatonin regulates our circadian rhythm. Our aim was to compare preoperative cerebrospinal fluid (CSF) melatonin levels in patients with and without postoperative delirium. METHODS: Prospective cohort study with hip fracture patients ≥ 65 years who were acutely admitted to the hospital for surgical treatment and received spinal anaesthesia. CSF was collected after cannulation, before administering anaesthetics. Melatonin was measured by radioimmunoassay (RIA). Data on delirium was obtained from medical and nursing records. Nurses screened every shift for delirium using the Delirium Observation Screening Scale (DOSS). If the DOSS was ≥3, a psychiatrist was consulted to diagnose possible delirium using the DSM-IV criteria. At admission, demographic data, medical history, and information on functional and cognitive status was obtained. RESULTS: Seventy-six patients met the inclusion criteria. Sixty patients were included in the analysis. Main reasons for exclusion were technical difficulties, insufficient CSF or exogenous melatonin use. Thirteen patients (21.7%) experienced delirium during hospitalisation. Baseline characteristics did not differ between patients with and without postoperative delirium. In patients with and without postoperative delirium melatonin levels were 12.88 pg/ml (SD 6.3) and 11.72 pg/ml (SD 4.5) respectively, p-value 0.47. No differences between patients with and without delirium were found in mean melatonin levels in analyses stratified for cognitive impairment or age. CONCLUSION: Preoperative CSF melatonin levels did not differ between patients with and without postoperative delirium. This suggests that, if disturbances in melatonin secretion occur, these might occur after surgery due to postoperative inflammation.

Physiological melatonin levels in healthy older people: A systematic review.

OBJECTIVE: Melatonin plays a major role in maintaining circadian rhythm. Previous studies showed that its secretion pattern and levels could be disturbed in persons with dementia, psychiatric disorders, sleep disorders or with cancer. Also ageing is a factor that could alter melatonin levels, although previous research provides contradicting results. As melatonin supplementation is increasingly applied in older persons as sleep medication, it is important to know if melatonin levels decrease in healthy ageing and/or secretion patterns change. The objective of this study is to determine physiological levels and secretion patterns of melatonin in healthy older people. METHODS: We performed a systematic review and searched PubMed and Embase for studies published between January 1st 1980 and October 5th 2015 that measured melatonin in healthy persons aged ≥65years. RESULTS: Nineteen studies were retrieved. The number of participants ranged from 5 to 60 per study. Melatonin was mostly measured by radioimmunoassay (RIA) and the number of measurements per 24hours varied from 1 to 96. Sixteen studies showed a secretion pattern with a clear peak concentration, mostly at 0200h or 0300h. Maximum concentrations varied greatly from 11.2 to 91.3pgml(-1). Maximum melatonin level in studies with participants mean aged 65-70years was 49.3pgml(-1) and in studies with participants mean aged ≥75years 27.8pgml(-1), p-value <0.001. CONCLUSION: Total melatonin production in 24hours seems not to change in healthy ageing, but the maximal nocturnal peak concentration of melatonin might decline. It is important to take this into account when prescribing melatonin supplementation to older people.

The Effects of Blood Transfusion on Delirium Incidence.

BACKGROUND: Both anemia and blood transfusion could be precipitating factors for delirium; hence in postoperative patients with anemia at high risk for delirium, it is controversial whether transfusion is the best option. The aim of this study is to investigate the association of anemia and delirium and the role of blood transfusion within the multicomponent prevention strategy of delirium. METHODS: We conducted a substudy of a multicenter randomized controlled trial. Four hundred fifteen patients aged 65 to 102 years old admitted for hip fracture surgery were enrolled. Delirium was assessed daily using criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Data on hemoglobin values and transfusion were collected from the electronic medical records. RESULTS: One hundred fifteen (32.5%) patients experienced delirium during hospitalization, 238 (57.5%) had a hemoglobin level ≤ 6.0 mmol/L (9.7 g/dL) at any time during hospitalization, and 140 (33.7%) received a blood transfusion. Anemia (a hemoglobin level ≤ 6.0 mmol/L [9.7 g/dL]) was associated with delirium (odds ratio, 1.81; 95% confidence interval, 1.15-2.86). Blood transfusion was a protective factor for delirium in patients with the lowest measured hemoglobin level ≤ 6.0 mmol/L (9.7 g/dL) (odds ratio, 0.26; 95% confidence interval, 0.10-0.70). CONCLUSION: Low hemoglobin level is associated with delirium, and receiving a blood transfusion is associated with a lower delirium incidence. It would be interesting to investigate the effect of blood transfusion as part of the multicomponent treatment of delirium in patients with anemia.

Psychometric evaluation of the DMSS-4 in a cohort of elderly post-operative hip fracture patients with delirium.

BACKGROUND: Delirium is a common neuropsychiatric syndrome with considerable heterogeneity in clinical profile. Rapid reliable identification of clinical subtypes can allow for more targeted research efforts. METHODS: We explored the concordance in attribution of motor subtypes between the Delirium Motor Subtyping Scale 4 (DMSS-4) and the original Delirium Motor Subtyping Scale (DMSS) (assessed cross-sectionally) and subtypes defined longitudinally using the Delirium Symptom Interview (DSI). RESULTS: We included 113 elderly patients developing DSM-IV delirium after hip-surgery [mean age 86.9 ± 6.6 years; range 65-102; 68.1% females; 25 (22.1%) had no previous history of cognitive impairment]. Concordance for the first measurement was high for both the DMSS-4 and original DMSS (k = 0.82), and overall for the DMSS-4 and DSI (k = 0.84). The DMSS-4 also demonstrated high internal consistency (McDonald's omega = 0.90). The DSI more often allocated an assessment to "no subtype" compared to the DMSS-4 and DMSS-11, which showed higher inclusion rates for motor subtypes. CONCLUSIONS: The DMSS-4 provides a rapid method of identifying motor-defined clinical subtypes of delirium and appears to be a reliable alternative to the more detailed and time-consuming original DMSS and DSI methods of subtype attribution. The DMSS-4, so far translated into three languages, can be readily applied to further studies of causation, treatment and outcome in delirium.

Multiple imputation strategies for zero-inflated cost data in economic evaluations: which method works best?

Cost and effect data often have missing data because economic evaluations are frequently added onto clinical studies where cost data are rarely the primary outcome. The objective of this article was to investigate which multiple imputation strategy is most appropriate to use for missing cost-effectiveness data in a randomized controlled trial. Three incomplete data sets were generated from a complete reference data set with 17, 35 and 50 % missing data in effects and costs. The strategies evaluated included complete case analysis (CCA), multiple imputation with predictive mean matching (MI-PMM), MI-PMM on log-transformed costs (log MI-PMM), and a two-step MI. Mean cost and effect estimates, standard errors and incremental net benefits were compared with the results of the analyses on the complete reference data set. The CCA, MI-PMM, and the two-step MI strategy diverged from the results for the reference data set when the amount of missing data increased. In contrast, the estimates of the Log MI-PMM strategy remained stable irrespective of the amount of missing data. MI provided better estimates than CCA in all scenarios. With low amounts of missing data the MI strategies appeared equivalent but we recommend using the log MI-PMM with missing data greater than 35 %.

End-of-life care during and after an acute hospitalization in older patients with cancer, end-stage organ failure, or frailty: A sub-analysis of a prospective cohort study.

BACKGROUND: Many patients show deterioration in functioning and increased care needs in the last year of life. End-of-life care needs and health care utilization might differ between groups of acutely hospitalized older patients. AIM: To investigate differences in geriatric conditions, advance care planning, and health care utilization in patients with cancer, organ failure, or frailty, who died within 1 year after acute hospitalization. DESIGN: Prospective cohort study conducted between 2002 and 2008, with 1-year follow-up. SETTING: University teaching hospital in the Netherlands. PARTICIPANTS: Aged ⩾65 years, acutely hospitalized for ⩾48 h, and died within 1 year after hospitalization. At admission, all patients received a systematic comprehensive geriatric assessment. Hospital records were searched for advance care planning information and health care utilization. Differences between patient groups were calculated. RESULTS: In total, 306 patients died within 1 year after acute admission (35%) and were included; 151 with cancer, 98 with end-stage organ failure, and 57 frail older persons. At hospital admission, 72% of the frail group had delirium and/or severe pre-existing cognitive impairment. The frail and organ failure group had many pre-existing disabilities. Three months post-discharge, 75% of the frail and organ failure group had died, 45% of these patients had an advance care plan in their hospital records. CONCLUSION: Patients with frailty and organ failure had highest rates of geriatric conditions at hospital admission and often had missing information on advance care planning in the hospital records. There is a need to better identify end-of-life needs for these groups.

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.