Delirium in Old Age : Pathophysiological and Pharmacological Aspects

Delirium, an acute neuropsychiatric syndrome, affects approximately 1 out of 3 older patients admitted to the hospital and is associated with poor outcomes, including increased rates of postdischarge institutionalization, cognitive decline and mortality. Approximately 20 to 25% of the patients who experience delirium dies within 6 to 12 months. Despite the high prevalence and clinical impact, very little is known about the underlying pathogenesis. In this thesis, we have investigated potential novel biomarkers of delirium and the role of pharmacological agents in the development of delirium. The findings may contribute to a better understanding of the pathophysiology and may help to improve the prediction, detection and treatment of this syndrome

Increased neutrophil-lymphocyte ratio in delirium

Aim: Delirium is a common and severe complication among older hospitalized patients. The pathophysiology is poorly understood, but it has been suggested that inflammation and oxidative stress may play a role. The aim of this pilot study was to investigate levels of the neutrophil-lymphocyte ratio (NLR) - a marker of systemic inflammation and oxidative stress - in patients with and without delirium. Methods: This pilot study was performed within a retrospective chart review study that included acutely ill patients, 65 years and older, who were admitted to the ward of geriatrics of the Erasmus University Medical Center. All patients in whom the differential white blood cell (WBC) counts as well as the C-reactive protein (CRP) level were determined within 24 h after admission were included in the present study. Differences in NLR between patients with and without delirium were investigated using univariate analysis of variance, with adjustments for age, sex, comorbidities, CRP level, and total WBC count. Results: Eighty-six patients were included. Thirteen patients were diagnosed with delirium. In adjusted models, higher mean NLR values were found in patients with, than in those without, delirium (9.10 vs 5.18, P=0.003). Conclusion: In this pilot study, we found increased NLR levels in patients with delirium. This finding might suggest that an inadequate response of the immune system and oxidative stress may play a role in the pathogenesis of delirium. Further studies are needed to confirm the association between NLR and delirium

Antipsychotics and Lorazepam During Delirium: Are We Harming Older Patients? A Real-Life Data Study

Background: Delirium affects approximately one out of three older hospitalized patients and is associated with poor clinical outcomes. Approaches used to manage delirium consist of non-pharmacological and pharmacological interventions. Antipsychotics and lorazepam are commonly used to treat symptoms of delirium, but conflicting data exist on the effect of these drugs on the outcomes of delirium. Objective: The aim of this study was to investigate whether the use of antipsychotics, with or without lorazepam, increases the risk of prolonged hospital stay, post-discharge institutionalization, and in-hospital mortality in older patients with delirium. Methods: In this retrospective chart review study, we included acutely ill patients aged ≥ 65 years who were admitted to a geriatric ward and diagnosed with delirium. Patients were stratified into three groups based on whether or not they received antipsychotics and lorazepam to manage delirium: (0) no antipsychotics; (1) antipsychotics only; and (2) antipsychotics plus lorazepam. Length of hospital stay (LOS) and frequencies of post-discharge institutionalization and in-hospital mortality were compared. Results: In total, 212 patients with delirium were included (mean age 81.9 ± 5.6 years); 40 did not receive antipsychotics (18.9%), 123 received antipsychotics only (58.0%) and 49 received antipsychotics and lorazepam (23.1%). There was a trend to a longer LOS in patients who received both antipsychotics and lorazepam (median LOS group 0 = 8.0 days, group 1 = 10.0 days, and group 2 = 12.0 days). Furthermore, trends to a higher incidence of post-discharge institutionalization and in-hospital mortality were observed in patients who received both treatments (institutionalization group 0 = 45.0%, group 1 = 59.3%, group 2 = 81.6%; and in-hospital mortality group 0 = 7.5%, group 1 = 10.6%, group 2 = 16.3%). Conclusion: The use of antipsychotics, with or without lorazepam, during delirium is associated with increased risks of poor outcomes. These findings suggest that clinicians should be cautious about routine prescribing of these drugs to older patients with delirium. Further investigation is needed to clarify this association

Anticholinergic Drug Burden and Delirium: A Systematic Review

Objectives: To investigate the association between anticholinergic drug burden (ADB), measured with anticholinergic drug scales, and delirium and delirium severity. Design: Systematic review. Setting and Participants: All available studies. Methods: A systematic literature search was performed in Medline, Embase, PsycINFO, Web of Science, CINAHL, Cochrane library, and Google Scholar. Studies evaluating the association between ADB (measured as a total score) and delirium or delirium severity, published in English, were eligible for inclusion. Results: Sixteen studies, including 148,756 persons, were included. Fifteen studies investigated delirium. ADB was measured with the Anticholinergic Risk Scale (ARS, n = 5), the Anticholinergic Cognitive Burden Scale (ACB, n = 6), the list of Chew (n = 1), the Anticholinergic Drug Scale (ADS, n = 5), a modified version of the ARS (n = 1), and a modified version of the ACB (n = 1). A high ADB, measured with the ARS, was associated with delirium (5/5). Also with the modified version of the ARS and ACB, an association was found between a high ADB and delirium during 3-month (1/1) and 1-year follow-up (1/1), respectively. When ADB was assessed with other scales, the results were inconclusive, with only 1 positive association for the ACB (1/6) and ADS (1/5) each. The possible association between ADB and delirium severity has also been investigated (ADS n = 2, Summers Drug Risk Number n = 1). One study found an association between a high ADB, measured with the ADS, and an increase in severity of delirium. Conclusions and Implications: ADB assessed with the ARS is consistently associated with delirium. The association found between the modified versions of the ARS and ACB and delirium needs confirmation. When ADB was assessed with other scales, the findings were inconclusive. The current findings suggest that the ARS might be a useful tool to identify patients at increased risk for delirium

Differences in potential biomarkers of delirium between acutely ill medical and elective cardiac surgery patients

Background/aims: The pathophysiology of delirium is poorly understood. Increasing evidence suggests that different pathways might be involved in the pathophysiology depending on the population studied. The aim of the present study was to investigate potential differences in mean plasma levels of neopterin, amino acids, amino acid ratios and homovanillic acid between two groups of patients with delirium. Methods: Data from acutely ill medical patients aged 65 years and older, and patients aged 70 years and older undergoing elective cardiac surgery, were used. Differences in biomarker levels between the groups were investigated using univariate ANOVA with adjustments for age, sex, comorbidities, C-reactive protein (CRP) and the estimated glomerular filtration rate (eGFR), where appropriate. Linear regression analysis was used to identify potential determinants of the investigated biochemical markers. Results: Eighty patients with delirium were included (23 acutely ill medical patients and 57 elective cardiac surgery patients). After adjustment, higher mean neopterin levels (93.1 vs 47.3 nmol/L, P=0.001) and higher phenylalanine/tyrosine ratios (1.39 vs 1.15, P=0.032) were found in acutely ill medical patients when compared to elective cardiac surgery patients. CRP levels were positively correlated with neopterin levels in acutely ill medical patients, exp

Delirium: A Frequent Manifestation in COVID-19 Older Patients

The authors report a high prevalence of delirium in COVID-19 old patients admitted in an academic hospital. During the recent COVID-19 period, delirium was present in 38% of old patients admitted with delirium at the COVID ward of the Erasmus MC University Medical Center of Rotterdam. We do not know in which patients COVID-19 can cause delirium; however, considering the high prevalence of delirium in COVID-19 old patients and the potential serious consequences, attention is needed in order to reduce disability and mortality in this vulnerable category of patients

Disturbed Serotonergic Neurotransmission and Oxidative Stress in Elderly Patients with Delirium

Background: Oxidative stress and disturbances in serotonergic and dopaminergic neurotransmission may play a role in the pathophysiology of delirium. Aims: In this study, we investigated levels of amino acids, amino acid ratios and levels of homovanillic acid (HVA) as indicators for oxidative stress and disturbances in neurotransmission. Methods: Plasma levels of amino acids, amino acid ratios and HVA were determined in acutely ill patients aged ≥65 years admitted to the wards of Internal Medicine and Geriatrics of the Erasmus University Medical Center and the ward of Geriatrics of the Havenziekenhuis, Rotterdam, The Netherlands. Differences in the biochemical parameters between patients with and without delirium were investigated by analysis of variance in models adjusted for age, gender and comorbidities. Results: Of the 86 patients included, 23 had delirium. In adjusted models, higher mean phenylalanine/tyrosine ratios (1.34 vs. 1.14, p = 0.028), lower mean tryptophan/large neutral amino acids ratios (4.90 vs. 6.12, p = 0.021) and lower mean arginine levels (34.8 vs. 45.2 µmol/l, p = 0.022) were found in patients with delirium when compared to those without. No differences were found in HVA levels between patients with and without delirium. Conclusion: The findings of this study suggest disturbed serotonergic neurotransmission and an increased status of oxidative stress in patients with delirium

Using the Multidimensional Prognostic Index to Predict Clinical Outcomes of Hospitalized Older Persons: A Prospective, Multicenter, International Study

Background: Multidimensional Prognostic Index (MPI) is useful as a prognostic tool in hospitalized older patients, but our knowledge is derived from retrospective studies. We therefore aimed to evaluate in a multicenter, longitudinal, cohort study whether the MPI at hospital admission is useful to identify groups with different mortality risk and whether MPI at discharge may predict institutionalization, rehospitalization, and use of home care services during 12 months. Methods: This longitudinal study, carried out between February 2015 and August 2017, included nine public hospitals in Europe and Australia. A standardized comprehensive geriatric assessment including information on functional, nutritional, cognitive status, risk of pressure sores, comorbidities, medications, and cohabitation status was used to calculate the MPI and to categorize participants in low, moderate, and severe risk of mortality. Data regarding mortality, institutionalization, rehospitalization, and use of home care services were recorded through administrative information. Results: Altogether, 1,140 hospitalized patients (mean age 84.1 years, women = 60.8%) were included. In the multivariable analysis, compared to patients with low risk group at admission, patients in moderate (odds ratio [OR] = 3.32; 95% CI: 1.79-6.17; p <.001) and severe risk (OR = 10.72, 95% CI: 5.70-20.18, p <.0001) groups were at higher risk of overall mortality. Among the 984 older patients with follow-up data available, those in the severe-risk group experienced a higher risk of overall mortality, institutionalization, rehospitalization, and access to home care services. Conclusions: In this cohort of hospitalized older adults, higher MPI values are associated with higher mortality and other negative outcomes. Multidimensional assessment of older people admitted to hospital may facilitate appropriate clinical and postdischarge management