Melatonin to prevent delirium in patients with advanced cancer: a double blind, parallel, randomized, controlled, feasibility trial.

BACKGROUND: Delirium is highly problematic in palliative care (PC). Preliminary data indicate a potential role for melatonin to prevent delirium, but no randomized controlled trials (RCTs) are reported in PC. METHODS: Patients aged ≥18 years, with advanced cancer, admitted to an inpatient Palliative Care Unit (PCU), having a Palliative Performance Scale rating ≥ 30%, and for whom consent was obtained, were included in the study. Patients with delirium on admission were excluded. The main study objectives were to assess the feasibility issues of conducting a double-blind RCT of exogenous melatonin to prevent delirium in PC: recruitment, retention, procedural acceptability, appropriateness of outcome measures, and preliminary efficacy and safety data. Study participants were randomized in a double-blind, parallel designed study to receive daily melatonin 3 mg or placebo orally at 21:00 over 28 days or less if incident delirium, death, discharge or withdrawal occurred earlier. Delirium was diagnosed using the Confusion Assessment Method. Efficacy endpoints in the melatonin and placebo groups were compared using time-to-event analysis: days from study entry to onset of incident delirium. RESULTS: Over 16 months, 60/616 (9.7%; 95% CI: 7.5-12.4%) screened subjects were enrolled. The respective melatonin (n = 30) vs placebo (n = 30) outcomes were: incident delirium in 11/30 (36.7%; 95%CI: 19.9-56.1%) vs 10/30 (33%; 95% CI: 17.3-52.8%); early discharge (6 vs 5); withdrawal (6 vs 3); death (0 vs 1); and 7 (23%) vs 11 (37%) reached the 28-day end point. The 25th percentile time-to-event were 9 and 18 days (log rank, χ2 = 0.62, p = 0.43) in melatonin and placebo groups, respectively. No serious trial medication-related adverse effects occurred and the core study procedures were acceptable. Compared to those who remained delirium-free during their study participation, those who developed delirium (n = 21) had poorer functional (p = 0.036) and cognitive performance (p = 0.013), and in particular, poorer attentional capacity (p = 0.003) at study entry. CONCLUSIONS: A larger double-blind RCT is feasible, but both subject accrual and withdrawal rates signal a need for multisite collaboration. The apparent trend for shorter time to incident delirium in the melatonin group bodes for careful monitoring in a larger trial. TRIAL REGISTRATION: Registered on July 21st 2014 with ClinicalTrials.gov : NCT02200172 .

Poor functional recovery after delirium is associated with other geriatric syndromes and additional illnesses.

BACKGROUND: Delirious individuals are at increased risk for functional decline, institutionalization and death. Delirium is also associated with other geriatric syndromes, behavioral care issues, and new illnesses. The objectives of this study were to determine how often certain geriatric syndromes, care issues, and additional diagnoses occur in delirious individuals, and to see whether they correlate with worse functional recovery. METHODS: Consecutive delirious older medical in-patients (n = 343) were followed for the occurrence of geriatric syndromes (falls, pressure ulcers, poor oral intake, and aspiration), care issues (refusing treatments or care, need for sitters, security services, physical restraints, and new neuroleptic medications) and additional diagnoses occurring after the third day of admission. Poor functional recovery was defined by any one of death, permanent institutionalization or increased dependence for activities of daily living (ADLs) at discharge or three months after discharge from hospital, elicited through chart review or a follow-up telephone interview. RESULTS: Poor functional recovery was seen in 237 (69%) delirious patients. Geriatric syndromes and additional illnesses were common and associated with poor functional recovery (falls in 21%, adjusted OR 2.27; possible aspiration in 26%, adjusted OR 3.06; poor oral intake in 49%, adjusted OR = 2.31; additional illnesses in 38%, adjusted OR 3.54). Care issues were also common (range 9%-54%) but not associated with poor recovery. CONCLUSIONS: Geriatric syndromes, behavioral care issues and additional illnesses are common in delirium. Future studies should assess whether monitoring for and intervening against geriatric syndromes and additional illnesses may improve functional outcomes after delirium.

Prognosis of delirium in hospitalized elderly: worse than we thought.

BACKGROUND: Despite treatment of the associated condition, delirious persons do not always recover for unknown reasons. We sought to determine early prognostic indicators of poor recovery following an episode of delirium in older medical in-patients. METHODS: Between October 2009 and July 2011, consecutively admitted older (≥70 years old) medical in-patients at the London Health Sciences Centre (Ontario) were screened for delirium. Delirious patients were followed. The primary outcome was poor recovery, in delirious patients, defined by death, long-term institutionalization, or functional decline (decreased activities of daily living), at discharge or 3 months after discharge, elicited from the medical chart or post-discharge caregiver telephone interviews. RESULTS: One thousand two hundred thirty-five in-patients (mean age 82.6 years, 42% men) were screened, delirium occurred in 355 (29%). Follow-up data was known on 342 (96%), and 237 (69%) had poor recovery: 55 died (54 in hospital and one after discharge), 136 were permanently institutionalized (86 directly from hospital and 50 after discharge), and 46 had functional decline (at a median of 103 days after discharge). Poor recovery was associated in the derivation sample with advanced age, lower baseline function, hypoxia, higher delirium severity scores, and acute renal failure; this was predictive of poor recovery in the validation sample (receiver operating characteristic area 0.68, 95% confidence interval: 0.57-0.79); however, even individuals with "low" risk had high (50%) poor recovery rates. INTERPRETATION: Poor recovery after delirium is common and associated with certain characteristics. However, even "lower risk" delirious individuals do poorly. More research is needed to understand prognostic factors in delirium.

Prevalence of dementia among people experiencing homelessness in Ontario, Canada: a population-based comparative analysis.

BACKGROUND: Cognitive decline in people experiencing homelessness is an increasingly recognised issue. We compared the prevalence of dementia among people experiencing homelessness to housed individuals in the general population and those living in low-income neighbourhoods. METHODS: We conducted a population-based, cross-sectional, comparative analysis using linked health-care administrative data from Ontario, Canada. We included individuals aged 45 years or older on Jan 1, 2019, who visited hospital-based ambulatory care (eg, emergency department), were hospitalised, or visited a community health centre in 2019; and identified people experiencing homelessness if they had one or more health-care records with an indication of homelessness or unstable housing. Prevalence of dementia was ascertained as of Dec 31, 2019, using a validated case definition for Alzheimer's disease and related dementia that was modified to include diagnoses made at a community health centre. Poisson models were used to generate estimates of prevalence. Estimates were compared with Ontarians that accessed any of the same health-care services over the same time, overall (general population group), and among those who were in the lowest quintile of area-based neighbourhood income (low-income group). FINDINGS: 12 863 people experiencing homelessness, 475 544 people in the low-income comparator group, and 2 273 068 people in the general population comparator group were included in the study. Dementia prevalence was 68·7 per 1000 population among people experiencing homelessness, 62·6 per 1000 population in the low-income group, and 51·0 per 1000 population in the general population group. Descriptively, prevalence ratios between people experiencing homelessness and the comparator groups were highest within the ages of 55-64 years and 65-74 years in both sexes, ranging from 2·98 to 5·00. After adjusting for age, sex, geographical location of residence (urban vs rural), and health conditions associated with dementia, the prevalence ratio of dementia among people experiencing homelessness was 1·71 (95% CI 1·60-1·82) compared with the low-income group and 1·90 (1·79-2·03) compared with the general population group. INTERPRETATION: People experiencing homelessness experience a high burden of dementia compared with housed populations in Ontario. Findings suggest that people experiencing homelessness might experience dementia at younger ages and could benefit from the development of proactive screening and housing interventions. FUNDING: The Public Health Agency of Canada.

Chemical and physical restraint use during acute care hospitalization of older adults: A retrospective cohort study and time series analysis.

BACKGROUND: Chemical and physical restraints are associated with harm in older adults, but our understanding of their use during acute care hospitalizations is limited. OBJECTIVES: To (1) describe restraint use during acute care hospitalizations of older adults at the onset of the COVID-19 pandemic compared to pre-pandemic levels and (2) describe between-hospital variability in restraint use. DESIGN: Retrospective cohort study with a time series analysis. PARTICIPANTS: Acute care hospital inpatients, aged 65 years or older, who were discharged from one of four Alberta hospitals or six Ontario hospitals in Canada, between November 1, 2019, and June 30, 2020. MAIN MEASURES: We used autoregressive linear models with restricted cubic splines to compare proportions of chemical restraint (that is, psychotropic medications, namely antipsychotics, benzodiazepines, and trazodone) and physical restraint (e.g., mittens) use immediately after the onset of the COVID-19 pandemic with pre-pandemic levels. We describe between-hospital variability in restraint use using intraclass correlation coefficients (ICC) and median odds ratios (OR). KEY RESULTS: We included 71,004 hospitalizations. Adjusted for the prevalence of dementia and psychotic disorders, chemical restraint use increased in Ontario hospitals from a pre-pandemic average of 27.1% to 30.8% (p<0.001) before returning to pre-pandemic levels within eight weeks. Physical restraint orders in Ontario increased from 5.9% to 8.3% (p = 0.012) and remained elevated at eight weeks. No significant changes in restraint use were observed in Alberta. There was moderate between-hospital variability in chemical restraint use (ICC 0.041 and median OR 1.43). Variability in physical restraint use was higher (ICC 0.11 and median OR 1.83). CONCLUSIONS: The COVID-19 pandemic impacted in-hospital use of chemical and physical restraints among older adults in Ontario but not Alberta. Substantial differences in chemical and physical restraint use by region and hospital suggests there are opportunities to improve best practices in geriatric care. Future research must support implementation of evidence-informed interventions that standardize appropriate restraint use.

Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial.

BACKGROUND: Disturbance in the metabolism of tryptophan and tryptophan-derived compounds (e.g., melatonin) may have a role in the pathogenesis of delirium. OBJECTIVE: To evaluate the efficacy of low dose exogenous melatonin in decreasing delirium. DESIGN: A randomized, double-blinded, placebo-controlled study. SETTING: An Internal Medicine service in a tertiary care centre in London, Ontario, Canada. PARTICIPANTS: 145 individuals aged 65 years or over admitted through the emergency department to a medical unit in a tertiary care hospital. INTERVENTION: Patients were randomized to receive either 0.5 mg of melatonin or placebo every night for 14 days or until discharge. MEASUREMENTS: The primary outcome was the occurrence of delirium as determined by Confusion Assessment Method (CAM) criteria. RESULTS: Of a total of 145 individuals (mean age (standard deviation): 84.5 (6.1) years) 72 were randomly assigned to the melatonin group and 73 to the placebo group. Melatonin was associated with a lower risk of delirium (12.0% vs. 31.0%, p = 0.014), with an odds ratio (OR), adjusted for dementia and co-morbidities of 0.19 (95% confidence intervals (CI): 0.06-0.62). Results were not different when patients with prevalent delirium were excluded. LIMITATION: An intention to treat analysis was not possible due to loss to follow-up. CONCLUSION: Exogenous low dose melatonin administered nightly to elderly patients admitted to acute care may represent a potential protective agent against delirium.

A Non-Pharmacologic Approach to Manage Behaviours in Confused Medically Ill Older Adults in Acute Care.

BACKGROUND: Non-pharmacological interventions are recommended to manage challenging behaviours among cognitively impaired older adults, however few studies have enrolled patients in acute care. This study aimed to determine the feasibility of implementing non-pharmacological interventions to manage behaviours in hospitalized older adults. METHOD: A self-identity approach was used to identify potentially engaging activities for 13 older medically ill adults admitted to acute hospital; these activities were trialed for a two-week period. Data were collected on frequency of intervention administration and assistance required, as well as frequency of behaviours and neuroleptic use in the seven days prior to and following the trial of activities. RESULTS: Per participant, 5-11 interventions were prescribed. Most frequently interventions were tried two or more times (46%); 9% were not tried at all. Staff or family assistance was not required for 27% of activities. The mean number of documented behaviours across participants was 4.8 ± 2.3 in the pre-intervention period and 2.1 ± 1.9 in the post-intervention period. Overall the interventions were feasible and did not result in increasing neuroleptic use. CONCLUSION: Non-pharmacologic interventions may be feasible to implement in acute care. More research in this area is justified.

Factors associated with prolonged delirium: a systematic review.

BACKGROUND: Delirium frequently accompanies acute illness. With treatment of the illness, some individuals recover from delirium while for others the symptoms persist. It is not understood why some individuals improve but others do not. The purpose of this paper is to review systematically what is known about the factors associated with the persistence of delirium. METHODS: A medical literature search was conducted using several bibliographic databases, supplemented by manual searches of the references. English or French studies were included if they compared two groups of delirious individuals in delirium duration or persistence up to six months after the onset of delirium, diagnosed prospectively with the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria (or a scale derived and validated against the DSM). Information was collected on the association between possible non-therapeutic prognostic variables and delirium persistence. RESULTS: Twenty-one observational studies were included, in various settings (e.g. mixed medical-surgical, medical or geriatric, surgical, psychiatric, cancer or palliative care units). Variables assessed included patient characteristics (e.g. age, dementia, medical comorbidity, functional status), delirium characteristics (e.g. presence of hypoactive symptoms, delirium severity) and illness characteristics (e.g. severity of illness, and underlying acute illness). Overall, studies suggested that delirium is often persistent at discharge or beyond. Persistence was associated with dementia, increasing numbers of medical conditions, increasing severity of delirium, hypoactive symptoms and hypoxic illnesses. CONCLUSIONS: Preliminary findings suggest that some factors may identify those at risk for persistent delirium; however, more research is needed.

Efficacy of Ondansetron in the Prevention or Treatment of Post-operative Delirium-a Systematic Review.

BACKGROUND: Post-operative delirium (POD) is associated with higher rates of functional decline and death. Ondansetron is a serotonin antagonist which could represent a therapeutic or preventive option in POD. METHODS: A systematic review of MEDLINE, EMBASE, CENTRAL, and PsychINFO was performed. Three randomized controlled trials (RCTs) met inclusion criteria (intervention of ondansetron compared to a control group). RESULTS: Two RCTs examined ondansetron for the treatment of POD in patients after cardiac or post-trauma surgery in the ICU. Studies assessed either a one-time dose or doses for 3 days of ondansetron or haloperidol IV. They suggested similar reductions in average delirium scores and rates in both interventions, although one study suggested ondansetron to be associated with higher rates of rescue haloperidol use. One RCT examined prophylactic ondansetron versus placebo IV, for five days postoperatively, to prevent POD in orthopedic patients. There were significantly fewer delirious patients in the ondansetron group. In general, studies had major methodological limitations and were very heterogenous in study tools, interventions used, and populations studied. CONCLUSIONS: Ondansetron may be an effective agent for the prevention or treatment of POD, but studies are few and of poor quality, thus making the conclusions tenuous. Further large RCTs are needed.

Rationale and design for the detection and neurological impact of cerebrovascular events in non-cardiac surgery patients cohort evaluation (NeuroVISION) study: a prospective international cohort study.

OBJECTIVES: Covert stroke after non-cardiac surgery may have substantial impact on duration and quality of life. In non-surgical patients, covert stroke is more common than overt stroke and is associated with an increased risk of cognitive decline and dementia. Little is known about covert stroke after non-cardiac surgery.NeuroVISION is a multicentre, international, prospective cohort study that will characterise the association between perioperative acute covert stroke and postoperative cognitive function. SETTING AND PARTICIPANTS: We are recruiting study participants from 12 tertiary care hospitals in 10 countries on 5 continents. PARTICIPANTS: We are enrolling patients ≥65 years of age, requiring hospital admission after non-cardiac surgery, who have an anticipated length of hospital stay of at least 2 days after elective non-cardiac surgery that occurs under general or neuraxial anaesthesia. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients are recruited before elective non-cardiac surgery, and their cognitive function is measured using the Montreal Cognitive Assessment (MoCA) instrument. After surgery, a brain MRI study is performed between postoperative days 2 and 9 to determine the presence of acute brain infarction. One year after surgery, the MoCA is used to assess postoperative cognitive function. Physicians and patients are blinded to the MRI study results until after the last patient follow-up visit to reduce outcome ascertainment bias.We will undertake a multivariable logistic regression analysis in which the dependent variable is the change in cognitive function 1 year after surgery, and the independent variables are acute perioperative covert stroke as well as other clinical variables that are associated with cognitive dysfunction. CONCLUSIONS: The NeuroVISION study will characterise the epidemiology of covert stroke and its clinical consequences. This will be the largest and the most comprehensive study of perioperative stroke after non-cardiac surgery. TRIAL REGISTRATION NUMBER: NCT01980511; Pre-results.

Treatment of asymptomatic UTI in older delirious medical in-patients: A prospective cohort study.

BACKGROUND: Despite clinical practice guidelines, asymptomatic bacteriuria (ASB) in older people is frequently treated. A common reason for treating ASB is a change in mental status. OBJECTIVE: To determine how often asymptomatic UTI is treated in older medically ill delirious individuals and its association with functional recovery. METHODS: Consecutive older medical in-patients were screened for delirium, and followed in hospital. Treatment for asymptomatic UTI was defined as documented treatment for a possible urinary tract infection with antibiotics, without concurrent infectious or urinary symptoms. The primary outcome was functional recovery at discharge or 3 months post-discharge. Poor functional recovery was defined by any one of death, new permanent long-term institutionalization or decreased ability to perform activities of daily living. RESULTS: The study sample comprised 343 delirious in-patients, of which 237 (69%) had poor functional recovery. Ninety two (27%) delirious in-patients were treated for asymptomatic UTI. Treatment for asymptomatic UTI was associated with poor functional recovery compared to other delirious in-patients (RR 1.30, 95% CI: 1.14-1.48 overall). Similar results were seen when the analysis was restricted to only bacteriuric delirious individuals. Seven (7.5%) individuals treated for asymptomatic UTI developed Clostridium difficile infection compared to eight (3.2%) in the remainder of the delirious cohort (OR 2.45, 95% CI: 0.86-6.96). CONCLUSIONS: These results suggest that treatment of asymptomatic UTI in older medical in-patients with delirium is common, and of questionable benefit. Further research is needed to establish guidelines to minimize over-treatment of UTI in older delirious in-patients.

Preoperative risk assessment for delirium after noncardiac surgery: a systematic review.

Delirium is a common postoperative complication in older adults associated with adverse events including functional decline, longer lengths of stay, and risk of institutionalization. The purpose of this article is to systematically review preoperative risk factors associated with delirium following noncardiac surgery. A medical literature search was conducted using several bibliographic databases (PubMed, CINAHL, Cochrane, PsychInfo), supplemented by a manual search of the references of retrieved articles. Studies were retained for review after meeting strict inclusion criteria that included only operative patients with incident postoperative delirium diagnosed prospectively using criteria derived from the Diagnostic and Statistical Manual of Mental Disorders Third or Fourth Edition. Quantitative analyses included significance testing, homogeneity testing, and effect-size pooling. Twenty-five articles were included for review. The incidence of delirium ranged from 5.1% to 52.2%, with greater rates after hip fracture and aortic surgeries. This review found two scales, a clinical prediction rule, and a delirium risk classification system that were validated in other operative settings. Individual risk factor analysis suggested that cognitive impairment, older age, functional impairment, sensory impairment, depression, preoperative psychotropic drug use, psychopathological symptoms, institutional residence, and greater comorbidity were associated with postoperative delirium. Of the risk factors examined, evidence was most robust for an association between delirium and cognitive impairment or psychotropic drug use, with moderate effect sizes for both. Missing data and measurement differences did not allow for inferences to be made about other risk factors. Effect-size pooling supports the concept that delirium is a heterogeneous disorder with multiple risk factors. More research is needed to better identify patients at risk for postoperative delirium and to develop preventive strategies.

Cognitive Impairment in Hospitalized Seniors.

Cognitive disorders are highly prevalent in hospitalized seniors, and can be due to delirium, dementia, as well as other disorders. Hospitalization can have adverse cognitive effects, and cognitive dysfunction adversely affects hospital outcomes. In this article, the literature is reviewed on how hospitalization affects cognitive function and how cognitive impairment affects hospital outcomes. Possible interventions in cognitively impaired hospitalized seniors are reviewed.

Cytochrome P450 2D6 phenotyping in an elderly population with dementia and response to galantamine in dementia: a pilot study.

BACKGROUND: The cytochrome P450 (CYP) 2D6 enzyme is involved in the metabolism of many drugs used by the elderly population. Variations in its activity can lead to altered drug response. However, few studies on the activity of this enzyme system have enrolled the elderly population. OBJECTIVE: The goal of this pilot study was to assess the feasibility of in vivo phenotyping of CYP2D6 in an elderly population with dementia and to determine if part of the variability in response to treatment with galantamine is attributable to CYP2D6 phenotype. METHODS: Patients with dementia attending geriatric clinics and receiving galantamine treatment for at least 6 months were enrolled in this case-control study. CYP2D6 phenotype was determined by analysis of the urinary concentrations of the probe drug dextromethorphan and its primary metabolite dextrorphan after ingestion of 30 mg of dextromethorphan. Patients were classified as robust responders to galantamine if their cognitive testing, as measured by using scores on the Mini-Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive subscale, had not changed or had improved after 6 months of treatment. RESULTS: Forty-three patients (23 men, 20 women; mean age, 78.4 years; 98% white) underwent phenotyping. The mean number of concomitantly prescribed medications was 5.7, and 16 patients (37%) were receiving other CYP2D6 substrate or inhibitor drugs. The distribution of CYP2D6 phenotype was similar to that seen in other white populations. There was no correlation between the phenotypic metabolic ratio and age, the number of routinely taken medications, whether patients were receiving other prescribed substrate or inhibitor drugs of CYP2D6 (P = 0.63), or whether they were a robust responder (P = 0.47). CONCLUSIONS: Urinary assays of CYP2D6 phenotype are technically feasible in older individuals with dementia who are taking multiple medications, and may be a useful clinical tool in this population. However, the study was unable to make inferences about an association between CYP2D6 phenotype and galantamine responsiveness.

Frailty is associated with postoperative complications in older adults with medical problems.

We sought to test whether frailty may be predictive of operative risk in older adults with medical problems. One hundred and twenty-five patients at least 70 years of age had a previously developed frailty screen, the Edmonton Frail Scale (EFS), administered at a pre-surgical clinic, prior to elective non-cardiac surgery. A blinded chart audit assessed for postoperative medical complications, length of stay and inability to be discharged home. The mean age of patients was 77 (range 70-92) and most (82%) underwent orthopedic procedures. Increasing frailty was associated with postoperative complications (p=0.02), increased length of hospitalization (p=0.004) and inability to be discharged home (p=0.01), independent of age. EFS scores of 3 or less were associated with a lower risk of having a complication (age-adjusted OR 0.27, 95% CI 0.09-0.80, likelihood ratio of 0.33) and a higher chance (80%) of being discharged home (p<0.02). EFS scores exceeding 7 were associated with increased complications (OR 5.02, 95% CI 1.55-16.25, likelihood ratio of 3.9) and a lower chance of being discharged home (40%, p<0.02). This study suggests that a frailty screen can refine risk estimates of postoperative complications in older adults undergoing elective non-cardiac surgery.