Impaired glucose utilization in the brain of patients with delirium following hip fracture.

Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and ß-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, ß-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.

Delirium is frequently underdiagnosed among older hospitalised patients despite available information in hospital medical records.

BACKGROUND: In-hospital delirium is associated with adverse outcomes and is underdiagnosed, limiting research and clinical follow-up. OBJECTIVE: To compare the incidence of in-hospital delirium determined by chart-based review of electronic medical records (D-CBR) with delirium discharge diagnoses (D-DD). Furthermore, to identify differences in symptoms, treatments and delirium triggers between D-CBR and D-DD. METHOD: The community-based cohort included 2,115 participants in the Hordaland Health Study born between 1925 and 1927. Between 2018 and 2022, we retrospectively reviewed hospital electronic medical records from baseline (1997-99) until death prior to 2023. D-DD and D-CBR were validated using The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for delirium. RESULTS: Of the 2,115 participants, 638 had in-hospital delirium. The incidence rate (IR) of D-CBR was 29.8 [95% confidence interval 28, 32] per 1,000 person-years, whereas the IR by D-DD was 3.4 [2.8, 4.2]. The IR ratio was 9.14 (P < 0.001). Patients who received pharmacological treatment for delirium (n = 121, odds ratio (OR) 3.4, [2.1, 5.4], P < 0.001), who were affected by acute memory impairment (n = 149, OR 2.8, [1.8, 4.5], P < 0.001), or change in perception (n = 137, OR 2.9, [1.8, 4.6] P < 0.001) had higher odds for D-DD. In contrast, post-operative cases (OR 0.2, [0.1, 0.4], P < 0.001) had lower odds for D-DD. CONCLUSION: Underdiagnosis of in-hospital delirium was a major issue in our study, especially in less severe delirium cases. Our findings emphasise the need for integrating systematic delirium diagnostics and documentation into hospital admission and discharge routines.

Delirium in patients with hip fracture is associated with increased heart rate variability.

BACKGROUND: Heart rate variability (HRV) is a method to assess the autonomic nervous system and reflects possibly central brain states. HRV has previously not been examined in patients with hip fracture and delirium. AIMS: To explore HRV parameters in hip fracture patients with and without delirium. METHODS: Patients admitted to Oslo University Hospital with hip fracture and sinus rhythm in electrocardiogram (ECG) were included. Delirium was diagnosed using the confusion assessment method. HRV was assessed preoperatively after a relaxing period of five minutes, by measuring an ECG signal over 5 min. Parameters in time domain (the standard deviation of the QRS distances-SDNN) and frequency domain (total power (TP), low frequency (LF), high frequency (HF) and LF/HF ratio) were calculated. RESULTS: Seventy-five patients were included in the study, and 21 of them had subsyndromal delirium and were excluded from the analysis. Fifty-four patients with a mean age of 83.5 years (SD 8.6, 78% females) were included. Twenty-six patients (48%) had preoperative delirium, 11 (20%) developed delirium postoperatively, whereas 17 (31%) never developed delirium. SDNN, TP and HF values were significantly higher in patients with delirium compared to patients without delirium, and LF and LF/HF were lower. Patients developing postoperative delirium had decreased LF and increased HF before symptom onset. DISCUSSION: Increased SDNN, TP and HF and decreased LF values might reflect an abnormal stress response in delirium. CONCLUSION: HRV measurements in patients with hip fractures provide additional information beyond heart rate and might be used to identify relevant pathophysiological factors in delirium.

The Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID: a randomised placebo-controlled trial.

OBJECTIVES: The aim of this double-blinded randomised placebo-controlled trial was to investigate the efficacy of clonidine for delirium in medical inpatients greater than 65 years. METHODS: Acutely admitted medical patients greater than 65 years with delirium or subsyndromal delirium were eligible for inclusion. Included patients were given a loading dose of either placebo or clonidine; 75 µg every third hour up to a maximum of four doses to reach steady state and further 75 µg twice daily until delirium free for 2 days, discharge or a maximum of 7 days of treatment. The primary endpoint was the trajectory of the Memorial Delirium Assessment Scale (MDAS) for the 7 days of treatment. Presence of delirium according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria and severity measured by MDAS were assessed daily until discharge or a maximum of 7 days after end of treatment. RESULTS: Because of slower enrolment than anticipated, the study was halted early. Ten patients in each group were studied. The low recruitment rate was mainly due to the presence of multiple patient exclusion criteria for patient safety. There was no significant difference between the treatment group in the primary endpoint comparing the trajectory of MDAS for the 7 days of treatment using mixed linear models with log transformation, (P = .60). The treatment group did not have increased adverse effects. CONCLUSIONS: No effect of clonidine for delirium was found, although the study was under powered. Further studies in less frail populations are now required.

Autonomic cardiovascular control in older patients with acute infection and delirium: a pilot study of orthostatic stress responses.

BACKGROUND: Alterations in autonomic nervous system (ANS) activity might be involved in the pathophysiology of delirium. The aim was to explore autonomic cardiovascular control in older patients with and without delirium. METHODS: Fourteen patients (five with delirium) acutely admitted to the geriatric ward with an infection were enrolled in the study. Patients with atrial fibrillation, a pacemaker, or on treatment with beta-blockers, calcium channel blockers or acetylcholinesterase inhibitors were not eligible. Continuous, non-invasive hemodynamic variables were measured during supine rest (5 min) and head-up tilt (HUT) to 15 degrees (10 min). Heart rate (HR), blood pressure (BP) and stroke volume (SV) were recorded beat-to-beat. Cardiac output (CO), total peripheral resistance (TPR), end-diastolic volume (EDV) and heart rate variability (HRV) values were calculated. RESULTS: Median age was 86 years. HR, BP, SV, CO, TPR and EDV were similar across the two groups at rest, but there was a trend towards a greater increase in systolic BP and HR during HUT in the delirium group. At rest, all HRV indices were higher in the delirium group, but the differences were not statistically significant. During HUT, the delirium group had higher power spectral density (PSD) (representing total variability) (p = 0.06) and a lower low frequency (LF)/high frequency (HF)-ratio (an index of sympathovagal balance) than the control group (p = 0.06). Also, delirious patients had a significantly greater reduction in standard deviation of RR-intervals (SDNN) (representing total variability) from baseline than controls (p = 0.01) during HUT. CONCLUSIONS: This explorative pilot study on autonomic cardiovascular control in delirium suggests that there may be differences in HRV that should be further investigated in larger samples.

Delirium and cognitive impairment among older patients in Norwegian emergency departments. / Delirium og kognitiv svikt blant eldre i norske akuttmottak.

BACKGROUND: Delirium is common and underdiagnosed among patients in hospitals, and is associated with complications, increased mortality, onset of dementia and need for nursing home care. Cognitive impairment from other causes is also common among hospitalised elderly people and is a key risk factor for delirium. Since no relevant prevalence studies have been undertaken in Norwegian hospitals, we investigated the prevalence of delirium among elderly patients in Norwegian emergency departments on World Delirium Awareness Day, 14 March 2018. MATERIAL AND METHOD: We included patients ≥ 75 years who arrived in ten Norwegian emergency departments between 08:00 and 22:00 on that day. We identified delirium and cognitive impairment using the '4AT' screening tool and registered the patients' age and gender and the hospital and department to which they were admitted (internal medicine, surgery, orthopaedics, 'other'). RESULTS: Of 118 included patients, 20 (17 per cent) showed signs of delirium and 36 (30 per cent) showed signs of other forms of cognitive impairment. All hospitals and all categories of departments received patients with signs of delirium and cognitive impairment. INTERPRETATION: Delirium and other forms of cognitive impairment are both common among elderly patients in Norwegian emergency departments. Our results indicate that all hospital departments who treat elderly patients frequently observe these issues. All departments should therefore have routines to identify and deal with patients who suffer from delirium and cognitive impairment.

The protocol of the Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID: a randomised placebo-controlled trial.

BACKGROUND: Delirium affects 15% of hospitalised patients and is linked with poor outcomes, yet few pharmacological treatment options exist. One hypothesis is that delirium may in part result from exaggerated and/or prolonged stress responses. Dexmedetomidine, a parenterally-administered alpha2-adrenergic receptor agonist which attenuates sympathetic nervous system activity, shows promise as treatment in ICU delirium. Clonidine exhibits similar pharmacodynamic properties and can be administered orally. We therefore wish to explore possible effects of clonidine upon the duration and severity of delirium in general medical inpatients. METHODS/DESIGN: The Oslo Study of Clonidine in Elderly Patients with Delirium (LUCID) is a randomised, placebo-controlled, double-blinded, parallel group study with 4-month prospective follow-up. We will recruit 100 older medical inpatients with delirium or subsyndromal delirium in the acute geriatric ward. Participants will be randomised to oral clonidine or placebo until delirium free for 2 days (Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria), or after a maximum of 7 days treatment. Assessment of haemodynamics (blood pressure, heart rate and electrocardiogram) and delirium will be performed daily until discharge or a maximum of 7 days after end of treatment. The primary endpoint is the trajectory of delirium over time (measured by Memorial Delirium Assessment Scale). Secondary endpoints include the duration of delirium, use of rescue medication for delirium, pharmacokinetics and pharmacodynamics of clonidine, cognitive function after 4 months, length of hospital stay and need for institutionalisation. DISCUSSION: LUCID will explore the efficacy and safety of clonidine for delirium in older medical inpatients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01956604. EudraCT Number: 2013-000815-26.

COVID-19 in an elderly woman with acute functional decline. / Covid-19 påvist hos eldre kvinne med akutt funksjonssvikt.

A woman in her late eighties was referred to Accident and Emergency because of acute functional decline with falls and increasing confusion. SARS-CoV-2 infection was confirmed 48 hours later. Many older people and residents of care homes are vulnerable to functional decline with acute illness. Healthcare professionals should be aware that such symptoms may be due to COVID-19.

Differences in metalloproteinases and their tissue inhibitors in the cerebrospinal fluid are associated with delirium.

BACKGROUND: The aetiology of delirium is not known, but pre-existing cognitive impairment is a predisposing factor. Here we explore the associations between delirium and cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), proteins with important roles in both acute injury and chronic neurodegeneration. METHODS: Using a 13-plex Discovery Assay®, we quantified CSF levels of 9 MMPs and 4 TIMPs in 280 hip fracture patients (140 with delirium), 107 cognitively unimpaired individuals, and 111 patients with Alzheimer's disease dementia. The two delirium-free control groups without acute trauma were included to unravel the effects of acute trauma (hip fracture), dementia, and delirium. RESULTS: Here we show that delirium is associated with higher levels of MMP-2, MMP-3, MMP-10, TIMP-1, and TIMP-2; a trend suggests lower levels of TIMP-4 are also associated with delirium. Most delirium patients had pre-existing dementia and low TIMP-4 is the only marker associated with delirium in adjusted analyses. MMP-2, MMP-12, and TIMP-1 levels are clearly higher in the hip fracture patients than in both control groups and several other MMP/TIMPs are impacted by acute trauma or dementia status. CONCLUSIONS: Several CSF MMP/TIMPs are significantly associated with delirium in hip fracture patients, but alterations in most of these MMP/TIMPs could likely be explained by acute trauma and/or pre-fracture dementia. Low levels of TIMP-4 appear to be directly associated with delirium, and the role of this marker in delirium pathophysiology should be further explored.

Delirium is a syndrome in which there are substantial changes in a person's ability to focus, understand, or pay attention to events. Delirium often occurs in response to sudden trauma and is more common in persons with pre-existing cognitive impairment. What happens in the brain during delirium is not well understood. To learn more, we have studied whether markers in the cerebrospinal fluid were altered in people with delirium compared to people without delirium. To understand differences specifically caused by delirium, we included two control groups without acute trauma, one with cognitively healthy participants and one with dementia patients. We found several markers altered in people with delirium, with most of the markers similarly altered in people with cognitive impairment due to dementia. One marker was directly linked to delirium and could potentially shed light on the brain processes that cause the syndrome.

[Delirium in elderly patients]. / Delirium hos eldre pasienter.

BACKGROUND: Delirium, «acute confusional state¼, is a frequent and serious complication of acute illness, particularly in the elderly. The strain on the patient, the next of kin and the health service is considerable. The purpose of the article is to provide healthcare personnel who deal with delirium with updated information about the condition. METHOD: The article is based on a literature search in PubMed combined with articles from the author's own archives and own clinical experience. RESULTS: Delirium is a serious acute medical condition that is often overlooked in the elderly. The prevalence is estimated to be between 11% and 42% for elderly patients on medical wards and close to 50% in patients with hip fractures. The prevalence is probably also high in nursing homes, but this is less well surveyed. Advanced age and dementia are the most important risk factors. Traumas, infections, stroke and metabolic disturbances are the most common triggering factors. The pathophysiology is poorly surveyed and the possibilities for drug treatment are few and are little studied. Delirium is associated with increased risk of dementia, loss of function and mortality. Short-term use of low-dosage antipsychotics is the first-line choice, but is contraindicated for patients with Parkinsonian symptoms. INTERPRETATION: Detection and treatment of triggering causes must have high priority in case of delirium. Non-drug interventions are most important to prevent and treat the condition.

Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients.

BACKGROUNDThe kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanisms underlying delirium, particularly in relation to the KP, remain elusive.METHODSWe undertook a multicenter observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and 1-year mortality.RESULTSIn delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA) (OR 2.26 [1.78, 2.87], P < 0.001) to be increased and also found increases in several other KP metabolites in serum and CSF. In addition, CSF-QA was associated with the neuronal damage marker neurofilament light chain (NfL) (ß 0.43, P < 0.001) and was a strong predictor of 1-year mortality (HR 4.35 [2.93, 6.45] for CSF-QA ≥ 100 nmol/L, P < 0.001). The associations between CSF-QA and delirium, neuronal damage, and mortality remained highly significant following adjustment for confounders and multiple comparisons.CONCLUSIONOur data identified how systemic inflammation, neurotoxicity, and delirium are strongly linked via the KP and should inform future delirium prevention and treatment clinical trials that target enzymes of the KP.FUNDINGNorwegian Health Association and South-Eastern Norway Regional Health Authorities.

Music Interventions and Delirium in Adults: A Systematic Literature Review and Meta-Analysis.

Delirium is a neuropsychiatric syndrome represented by an acute disturbance in attention, awareness and cognition, highly prevalent in older, and critically ill patients, and associated with poor outcomes. This review synthesized existing evidence on the effectiveness of music interventions on delirium in adults, and music interventions (MIs), psychometric assessments and outcome measures used. We searched MEDLINE, PsychINFO, SCOPUS, Clinical Trials and CENTRAL for quantitative designs comparing any MIs to standard care or another intervention. From 1150 studies 12 met the inclusion criteria, and 6 were included in the meta-analysis. Narrative synthesis showed that most studies focused on prevention, few assessed delirium severity, with the majority of studies reporting beneficial effects. The summary relative risk for incident delirium comparing music vs. no music in postsurgical and critically ill older patients was 0.52 (95% confidential interval (CI): 0.20−1.35, I2 = 79.1%, heterogeneity <0.0001) for the random effects model and 0.47 (95% CI: 0.34−0.66) using the fixed effects model. Music listening interventions were more commonly applied than music therapy delivered by credentialed music therapists, and delirium assessments methods were heterogeneous, including both standardized tools and systematic observations. Better designed studies are needed addressing effectiveness of MIs in specific patient subgroups, exploring the correlations between intervention-types/dosages and delirium symptoms.

Association between clinical frailty, illness severity and post-discharge survival: a prospective cohort study of older medical inpatients in Norway.

PURPOSE: Study associations between frailty, illness severity and post-discharge survival in older adults admitted to medical wards with acute clinical conditions. METHODS: Prospective cohort study of 195 individuals (mean age 86; 63% females) admitted to two medical wards with acute illness, followed up for all-cause mortality for 20 months after discharge. Ward physicians screened for frailty and quantified its degree from one to eight using Clinical Frailty Scale (CFS), while clinical illness severity was estimated by New Early Warning Score 2 (NEWS2) and laboratory illness severity was calculated by a frailty index (FI-lab) using routine blood tests. RESULTS: CFS, NEWS2 and FI-lab scores were independently associated with post-discharge survival in an adjusted Cox proportional hazards model with age, ward category (acute geriatric and general medical) and comorbidity as covariates. Adjusted hazard ratios and 95% confidence intervals were 1.54 (1.24-1.91) for CFS, 1.12 (1.03-1.23) for NEWS2, and 1.02 (1.00-1.05) for FI-lab. A frailty × illness severity category interaction effect (p = 0.003), suggested that the impact of frailty on survival was greater in those experiencing higher levels of illness severity. Among patients with at least moderate frailty (CFS six to eight) and high illness severity according to both NEWS2 and FI-lab, two (13%) were alive at follow-up. CONCLUSION: Frailty screening aided prognostication of survival following discharge in older acutely ill persons admitted to medical wards. The prognostic value of frailty increased when combined with readily available illness severity markers acquired during admission.

Delirium screening with 4AT in patients aged 65 years and older admitted to the Emergency Department with suspected sepsis: a prospective cohort study.

PURPOSE: We aimed to study the use of The 4 'A's test (4AT), a rapid delirium screening tool, performed upon Emergency Department (ED) admission, and to characterize older patients admitted to the ED with and without sepsis in terms of delirium features. METHODS: In this prospective cohort study, we included patients aged ≥ 65 years, admitted to the ED with suspected sepsis. ED nurses and doctors performed delirium screening with 4AT within two hours after ED admission, and registered the time spent on the screening in each case. Sepsis and delirium during the hospital stay were diagnosed retrospectively, according to recommended diagnosis criteria. RESULTS: Out of the 196 patients included (mean age 81 years, 60% men), 100 patients fulfilled the sepsis diagnosis criteria. The mean 4AT screening time was 2.5 Minutes. In total, 114 patients (58%) had a 4AT score ≥ 1, indicating cognitive impairment, upon ED admission. Sepsis patients more often had a 4AT score ≥ 4, indicating delirium, than patients without sepsis (40% vs. 26%, p < 0.05). Out of the 100 patients with sepsis, 68 (68%) had delirium during the hospital stay, as compared to 34 out of 96 patients (35%) without sepsis (p < 0.05). CONCLUSION: Delirium screening upon ED admission, using 4AT, was feasible among patients aged ≥ 65 years admitted with suspected sepsis. Two out of three patients had at least one feature of delirium upon admission. The prevalence of delirium during the hospital stay was high, particularly in patients with sepsis. Delirium screening with 4AT in the Emergency Department.