Delirium in hip fracture patients: consequences, prevention strategies and pathophysiological mechanisms

Background A hip fracture is a dramatic event with serious consequences. Many patients do not survive the first year after the fracture, and those who survive will often experience loss of function and increased need of assistance. Patients suffering a hip fracture are often elderly and frail, and many suffer from several medical conditions in addition to the fracture. The patients often use several medications, have malnutrition and poor social support. Dementia is very common. All these conditions are often seen among patients treated by geriatricians, and it has therefore been argued that a hip fracture is a geriatric, rather than an orthopedic disease. In many countries geriatricians have been involved in the care of such patients. A structured collaboration between orthopedic surgeons and geriatricians is labeled an orthogeriatric service. There exists a wide range of models of orthogeriatric care, and despite a lot of research, it is still not concluded which orthogeriatric model is most effective. Due to demographic changes, an increase in the number of hip fractures can be expected in the future. With limited resources it is therefore interesting to know which orthogeriatric model is best. Delirium, an acute change in cognition and alertness, is a common complication in hip fracture patients and is associated with poor outcome, including a dramatically increased risk of dementia. There is little knowledge concerning what happens in the brain during delirium, and no effective drug treatment exists. Delirium can in many cases be prevented through optimizing the quality of medical care. Multidisciplinary geriatric intervention has been shown to be particularly effective in preventing delirium in hip fracture patients. When this study first was planned, the main objective was to evaluate the orthogeriatric service in use at Oslo University Hospital - Ullevaal from June 2008 to January 2012. We hypothesised that the intervention could be effective in reducing delirium and thus prevent long term cognitive decline. During the work, some further aims have emerged, including studying the long-term consequences of delirium and its pathophysiology. Methods From September 2009 to January 2012, 329 patients acutely admitted with a hip fracture were included in this study. All patients were included in the Emergency Room (ER) at Oslo University Hospital, Ullevaal. In the ER, the patients were randomized to stay in either the acute geriatric ward or the orthopedic ward. The patients were sent directly from the ER to the allocated ward, and had their whole hospital stay in the same ward, except for surgery and a few hours in the post operative care unit. While the patients were admitted in the hospital they were closely monitored for complications, especially delirium. The care givers were interviewed for pre-fracture cognitive function and function in activities of daily living (ADL). Since the hip fracture patients often are elderly and frail, we believed that they could benefit of the expertise and routines established in the acute geriatric ward. We hypothesised that this intervention could be effective in reducing delirium and thus prevent long term cognitive decline. To explore this hypothesis, the patients were assessed with cognitive tests four and twelve months after surgery. In addition to evaluate the effect of the orthogeriatric model, we could use these data to explore the effect delirium had on cognition in the long run. In relation to the surgery, cerebrospinal fluid (CSF) and blood samples were collected. These samples have been analyzed in order to explore possible pathogenic mechanisms in delirium. In these analyses we have also included samples collected from hip fracture patients in Edinburgh, and elderly patients undergoing other elective surgery in Oslo. Results We found no evidence that cognitive function four months after surgery was improved in patients treated pre- and postoperatively in an acute geriatric ward, compared to usual care in an orthopaedic ward. The intervention had, however, a positive effect on mobility in patients not admitted from nursing homes. Delirium was an important predictor of accelerated cognitive decline in patients that had dementia before the fracture. Anticholinergic activity was not higher in CSF or serum in patients with delirium compared to those that did not have delirium. In those patients that developed delirium, and did not have dementia before the fracture, AA was associated with delirium severity. Neopterin (a marker of inflammation) was higher in CSF and serum in patients with delirium. This supports a theory of inflammation being important in the pathogenesis of delirium. Conclusion The orthogeriatic model tested in this study was not effective in reducing delirium or long term cognitive decline. There was, however, a trend that the intervention had a positive effect on mobility in patients not admitted from nursing homes. Delirium is very common among hip fracture patients, and in our study 50 % of the patients were affected. We found that delirium was associated with acceleration of cognitive decline in patients that had dementia before the fracture. Analyses of CSF and blood taken from the hip fracture patients in our study have given important new knowledge regarding the pathophysiology in delirium. Yet, much more research is needed to increase our understanding of this common, dramatic and serious condition

Plasma neurofilament light chain protein as a predictor of days in delirium and deep sedation, mortality and length of stay in critically ill patients

BACKGROUND: Delirium predicts poor outcomes, however identifying patients with the worst outcomes is challenging. Plasma neurofilament light protein (NfL) is a sensitive indicator of neuronal damage. We undertook an exploratory observational study to determine the association between plasma NfL and delirium in the critically ill. METHODS: MoDUS was a randomised placebo-controlled delirium trial of simvastatin done in an UK adult general ICU. We measured NfL levels in plasma samples using a Single molecule array (Simoa) platform. We explored associations between patient's plasma NfL levels and number of delirium days, and clinical outcomes. The control group for baseline NfL were preoperative patients undergoing major surgery. FINDINGS: The majority of critically ill patients already had a high NfL level on admission. Patients with higher plasma NfL levels at days one and three spent more days in delirium or deep sedation. Patients with zero or one day in delirium or deep sedation had day one mean concentrations of 37.8 pg/ml (SD 32.6) compared with 96.5 pg/ml (SD 106.1)) for patients with two days or more, p-value 0.002 linear mixed effects model. Survivors discharged before 14 days had lower mean plasma NfL concentrations compared to those with longer hospital stays and/or who died within six months. The area under ROC curve for predicting death within six months using day one NfL was 0.81 (0.7,0.9). INTERPRETATION: Measurement of plasma NfL within three days of admission may be useful to identify those patients with worse clinical outcomes, and as an enrichment strategy for future delirium interventional trials in the critically ill. FUNDING: Alzheimer's Society UK, UK Dementia Research Institute

A comparison of the revised Delirium Rating Scale (DRS–R98) and the Memorial Delirium Assessment Scale (MDAS) in a palliative care cohort with DSM–IV delirium

Objective: Assessment of delirium is performed with a variety of instruments, making comparisons between studies difficult. A conversion rule between commonly used instruments would aid such comparisons. The present study aimed to compare the revised Delirium Rating Scale (DRS–R98) and Memorial Delirium Assessment Scale (MDAS) in a palliative care population and derive conversion rules between the two scales. Method: Both instruments were employed to assess 77 consecutive patients with DSM–IV delirium, and the measures were repeated at three-day intervals. Conversion rules were derived from the data at initial assessment and tested on subsequent data. Results: There was substantial overall agreement between the two scales [concordance correlation coefficient (CCC) = 0.70 (CI95 = 0.60–0.78)] and between most common items (weighted κ ranging from 0.63 to 0.86). Although the two scales overlap considerably, there were some subtle differences with only modest agreement between the attention (weighted κ = 0.42) and thought process (weighted κ = 0.61) items. The conversion rule from total MDAS score to DRS–R98 severity scores demonstrated an almost perfect level of agreement (r = 0.86, CCC = 0.86; CI95 = 0.79–0.91), similar to the conversion rule from DRS–R98 to MDAS. Significance of results: Overall, the derived conversion rules demonstrated promising accuracy in this palliative care population, but further testing in other populations is certainly needed

Delirium, neurofilament light chain, and progressive cognitive impairment: analysis of a prospective Norwegian population-based cohort

Background: Previous population-based, longitudinal studies have shown that delirium is associated with an increased risk of dementia and cognitive decline. However, the underlying biological mechanisms are largely unknown. We aimed to assess the effects of delirium on both cognitive trajectories and any neuronal injury, measured via neurofilament light chain (NfL). // Methods: In this analysis of a prospective, 2-year follow-up, cohort study of participants aged 65 years or older living in Sandefjord municipality, Norway, we included cohort participants who were receiving domiciliary care services at least once per week between May 12, 2015, and July 8, 2016. Individuals with a life expectancy of less than 1 week, with Lewy body dementia, with psychiatric illness (except dementia), or for whom substance misuse was the principal indication for domiciliary services were excluded. Participants had a comprehensive assessment at 6-month intervals for 2 years, which included the Montreal Cognitive Assessment (MoCA) and a blood sample for NfL to measure neuronal injury. All information on clinical diagnoses and medications were cross-referenced with medical records. During any acute change in mental status or hospitalisation (ie, admission to hospital), participants were assessed once per day for delirium with Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria. We also measured NfL from blood samples taken from participants who were acutely hospitalised. // Findings: Between May 12, 2015, and July 8, 2016, 210 participants were eligible for inclusion and assessed at baseline (138 [66%] of whom were female and 72 [34%] of whom were male), 203 completed cognitive assessment, and 141 were followed up for 2 years. 160 (76%) of 210 had moderate or severe frailty and 112 (53%) were living with dementia. During the 2-year follow-up, 89 (42%) of 210 participants were diagnosed with one or more episodes of delirium. Incident delirium was independently associated with a decrease in MoCA score at the next 6-month follow-up, even after adjustment for age, sex, education, previous MoCA score, and frailty (adjusted mean difference –1·5, 95% CI –2·9 to –0·1). We found an interaction between previous MoCA score and delirium (β –0·254, 95% CI –0·441 to –0·066, p=0·010), with the largest decline being observed in people with better baseline cognition. Participants with delirium and good previous cognitive function and participants with a high peak concentration of NfL during any hospitalisation had increased NfL at the next 6-month follow-up. Mediation analyses showed independent pathways from previous MoCA score to follow-up MoCA score with contributions from incident delirium (–1·7, 95% CI –2·8 to –0·6) and from previous NfL to follow-up MoCA score with contributions from acute NfL concentrations (–1·8, –2·5 to –1·1). Delirium was directly linked with a predicted value of 1·2 pg/mL (95% CI 1·02 to 1·40, p=0·029) increase in NfL. // Interpretation: In people aged 65 years or older, an episode of delirium was associated with a decline in MoCA score. Greater neuronal injury during acute illness and delirium, measured by NfL, was associated with greater cognitive decline. For clinicians, our finding of delirium associated with both signs of acute neuronal injury, measured via NfL, and cognitive decline is important regarding the risk of long-term cognitive deterioration and to acknowledge that delirium is harmful for the brain

Cerebrospinal fluid catecholamines in Alzheimer's disease patients with and without biological disease

Noradrenergic and dopaminergic neurons are involved in cognitive functions, relate to behavioral and psychological symptoms in dementia and are affected in Alzheimer's disease (AD). Amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N) hallmarks the AD neuropathology. Today, the AT(N) pathophysiology can be assessed through biomarkers. Previous studies report cerebrospinal fluid (CSF) catecholamine concentrations in AD patients without biomarker refinement. We explored if CSF catecholamines relate to AD clinical presentation or neuropathology as reflected by CSF biomarkers. CSF catecholamines were analyzed in AD patients at the mild cognitive impairment (MCI; n = 54) or dementia stage (n = 240) and in cognitively unimpaired (n = 113). CSF biomarkers determined AT status and indicated synaptic damage (neurogranin). The AD patients (n = 294) had higher CSF noradrenaline and adrenaline concentrations, but lower dopamine concentrations compared to the cognitively unimpaired (n = 113). AD patients in the MCI and dementia stage of the disease had similar CSF catecholamine concentrations. In the CSF neurogranin positively associated with noradrenaline and adrenaline but not with dopamine. Adjusted regression analyses including AT status, CSF neurogranin, age, gender, and APOEε4 status verified the findings. In restricted analyses comparing A+T+ patients to A-T- cognitively unimpaired, the findings for CSF adrenaline remained significant (p < 0.001) but not for CSF noradrenaline (p = 0.07) and CSF dopamine (p = 0.33). There were no differences between A+T+ and A-T- cognitively unimpaired. Thus, we find alterations in CSF catecholamines in symptomatic AD and the CSF adrenergic transmitters to increase simultaneously with synaptic damage as indexed by CSF neurogranin

Plasma neurofilament light chain protein as a predictor of days in delirium and deep sedation, mortality and length of stay in critically ill patients

Background: Delirium predicts poor outcomes, however identifying patients with the worst outcomes is challenging. Plasma neurofilament light protein (NfL) is a sensitive indicator of neuronal damage. We undertook an exploratory observational study to determine the association between plasma NfL and delirium in the critically ill. Methods: MoDUS was a randomised placebo-controlled delirium trial of simvastatin done in an UK adult general ICU. We measured NfL levels in plasma samples using a Single molecule array (Simoa) platform. We explored associations between patient's plasma NfL levels and number of delirium days, and clinical outcomes. The control group for baseline NfL were preoperative patients undergoing major surgery. Findings: The majority of critically ill patients already had a high NfL level on admission. Patients with higher plasma NfL levels at days one and three spent more days in delirium or deep sedation. Patients with zero or one day in delirium or deep sedation had day one mean concentrations of 37.8 pg/ml (SD 32.6) compared with 96.5 pg/ml (SD 106.1)) for patients with two days or more, p-value 0.002 linear mixed effects model. Survivors discharged before 14 days had lower mean plasma NfL concentrations compared to those with longer hospital stays and/or who died within six months. The area under ROC curve for predicting death within six months using day one NfL was 0.81 (0.7,0.9). Interpretation: Measurement of plasma NfL within three days of admission may be useful to identify those patients with worse clinical outcomes, and as an enrichment strategy for future delirium interventional trials in the critically ill

Biomarker profiling beyond amyloid and tau: cerebrospinal fluid markers, hippocampal atrophy, and memory change in cognitively unimpaired older adults

Brain changes occurring in aging can be indexed by biomarkers. We used cluster analysis to identify subgroups of cognitively unimpaired individuals (n ¼ 99, 64e93 years) with different profiles of the cerebrospinal fluid biomarkers beta amyloid 1e42 (Ab42), phosphorylated tau (P-tau), total tau, chitinase-3-like protein 1 (YKL-40), fatty acid binding protein 3 (FABP3), and neurofilament light (NFL). Hippocampal volume and memory were assessed across multiple follow-up examinations covering up to 6.8 years. Clustering revealed one group (39%) with more pathological concentrations of all biomarkers, which could further be divided into one group (20%) characterized by tauopathy and high FABP3 and one (19%) by brain b-amyloidosis, high NFL, and slightly higher YKL-40. The clustering approach clearly outperformed classification based on Ab42 and P-tau alone in prediction of memory decline, with the individuals with most tauopathy and FABP3 showing more memory decline, but not more hippocampal volume change. The results demonstrate that older adults can be classified based on biomarkers beyond amyloid and tau, with improved prediction of memory decline

Associations of neuroinflammatory IL-6 and IL-8 with brain atrophy, memory decline, and core AD biomarkers - in cognitively unimpaired older adults

Concentrations of pro-inflammatory cytokines -interleukin-6 (IL-6) and interleukin-8 (IL-8) - are increased with age and in Alzheimer's disease (AD). It is not clear whether concentrations of IL-6 and IL-8 in the central nervous system predict later brain and cognitive changes over time nor whether this relationship is mediated by core AD biomarkers. Here, 219 cognitively healthy older adults (62-91 years), with baseline cerebrospinal fluid (CSF) measures of IL-6 and IL-8 were followed over time - up to 9 years - with assessments that included cognitive function, structural magnetic resonance imaging, and CSF measurements of phosphorylated tau (p-tau) and amyloid-β (Aβ-42) concentrations (for a subsample). Higher baseline CSF IL-8 was associated with better memory performance over time in the context of lower levels of CSF p-tau and p-tau/Aβ-42 ratio. Higher CSF IL-6 was related to less CSF p-tau changes over time. The results are in line with the hypothesis suggesting that an up-regulation of IL-6 and IL-8 in the brain may play a neuroprotective role in cognitively healthy older adults with lower load of AD pathology

Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here, we used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1β (25 µg/kg) but not prevented in IL-1RI-/- mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1β synthesis. Using the ME7 model of chronic neurodegeneration in female mice, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 µg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.SIGNIFICANCE STATEMENT Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1β trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus "bioenergetic stress" drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium