Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients

Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen, 6500HB, The Netherlands.
Critical care (London, England) (Impact Factor: 4.48). 12/2011; 15(6):R297. DOI: 10.1186/cc10598
Source: PubMed


Delirium occurs frequently in critically ill patients and is associated with disease severity and infection. Although several pathways for delirium have been described, biomarkers associated with delirium in intensive care unit (ICU) patients is not well studied. We examined plasma biomarkers in delirious and nondelirious patients and the role of these biomarkers on long-term cognitive function.
In an exploratory observational study, we included 100 ICU patients with or without delirium and with ("inflamed") and without ("noninflamed") infection/systemic inflammatory response syndrome (SIRS). Delirium was diagnosed by using the confusion-assessment method-ICU (CAM-ICU). Within 24 hours after the onset of delirium, blood was obtained for biomarker analysis. No differences in patient characteristics were found between delirious and nondelirious patients. To determine associations between biomarkers and delirium, univariate and multivariate logistic regression analyses were performed. Eighteen months after ICU discharge, a cognitive-failure questionnaire was distributed to the ICU survivors.
In total, 50 delirious and 50 nondelirious patients were included. We found that IL-8, MCP-1, procalcitonin (PCT), cortisol, and S100-β were significantly associated with delirium in inflamed patients (n = 46). In the noninflamed group of patients (n = 54), IL-8, IL-1ra, IL-10 ratio Aβ1-42/40, and ratio AβN-42/40 were significantly associated with delirium. In multivariate regression analysis, IL-8 was independently associated (odds ratio, 9.0; 95% confidence interval (CI), 1.8 to 44.0) with delirium in inflamed patients and IL-10 (OR 2.6; 95% CI 1.1 to 5.9), and Aβ1-42/40 (OR, 0.03; 95% CI, 0.002 to 0.50) with delirium in noninflamed patients. Furthermore, levels of several amyloid-β forms, but not human Tau or S100-β, were significantly correlated with self-reported cognitive impairment 18 months after ICU discharge, whereas inflammatory markers were not correlated to impaired long-term cognitive function.
In inflamed patients, the proinflammatory cytokine IL-8 was associated with delirium, whereas in noninflamed patients, antiinflammatory cytokine IL-10 and Aβ1-42/40 were associated with delirium. This suggests that the underlying mechanism governing the development of delirium in inflamed patients differs from that in noninflamed patients. Finally, elevated levels of amyloid-β correlated with long-term subjective cognitive-impairment delirium may represent the first sign of a (subclinical) dementia process. Future studies must confirm these results.The study was registered in the Clinical Trial Register (NCT00604773).

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Available from: Mark Van den Boogaard
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    • "Indeed, van den Boogaard and colleagues demonstrated that differences in inflammatory biomarkers did exist between inflamed (presenting with infection or systemic inflammatory response syndrome) and non-inflamed patients with delirium [9]. IL-8 was associated with delirium in inflamed patients, whereas IL-10 was associated with delirium in non-inflamed patients [9]. In contrast, sepsis did not modify the relationship between procalcitonin or C-reactive protein and brain dysfunction; thus, patients with higher biomarker levels had fewer delirium/coma-free days irrespective of whether they had sepsis or not [8]. "
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    ABSTRACT: Introduction Delirium is a common occurrence in critically ill patients and is associated with an increase in morbidity and mortality. Septic patients with delirium may differ from a general critically ill population. The aim of this investigation was to study the relationship between systemic inflammation and the development of delirium in septic and non-septic critically ill patients. Methods We performed a prospective cohort study in a 20-bed mixed intensive care unit (ICU) including 78 (delirium = 31; non-delirium = 47) consecutive patients admitted for more than 24 hours. At enrollment, patients were allocated to septic or non-septic groups according to internationally agreed criteria. Delirium was diagnosed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) during the first 72 hours of ICU admission. Blood samples were collected within 12 hours of enrollment for determination of tumor necrosis factor (TNF)-α, soluble TNF Receptor (STNFR)-1 and -2, interleukin (IL)-1β, IL-6, IL-10 and adiponectin. Results Out of all analyzed biomarkers, only STNFR1 (P = 0.003), STNFR2 (P = 0.005), adiponectin (P = 0.005) and IL-1β (P < 0.001) levels were higher in delirium patients. Adjusting for sepsis and sedation, these biomarkers were also independently associated with delirium occurrence. However, none of them were significant influenced by sepsis. Conclusions STNFR1, STNFR2, adiponectin and IL-1β were associated with delirium. Sepsis did not modify the relationship between the biomarkers and delirium occurrence.
    Full-text · Article · May 2014 · Critical care (London, England)
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    • "Pathophysiologically, delirium is thought to be associated with inflammatory response. Proinflammatory cytokines such as interleukin 1, tumor necrosis factor α, and interleukin 8 have been associated with the development of delirium in both ICU and non-ICU patients [8] [9]. However, most of these cytokines are not routinely measured in clinical settings, and some are only for research purpose. "
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    ABSTRACT: Delirium is thought to be associated with systemic inflammatory response. However, its association with the most widely used inflammatory biomarker C-reactive protein (CRP) has not been well established. We aimed to examine whether CRP on intensive care unit (ICU) entry was associated with subsequent development of delirium. This prospective observational study was conducted in a mixed 24-bed ICU in a tertiary teaching hospital. All patients admitted to the ICU from February 2011 to June 2012 were screened for eligibility. Demographic data and clinical characteristics of included patients were recorded. Patients were screened for the presence of delirium by using the tool Confusion Assessment Method for the ICU (CAM-ICU). C-reactive protein was obtained on ICU entry and 24 hours thereafter. Eligible patients were followed up for 28 days or until death. Univariate and multivariate analyses were performed to evaluate independent risk factors for delirium. Clinical outcome included the length of stay (LOS) in the ICU, 28-day mortality, and duration of mechanical ventilation. Two-tailed P < .05 was considered statistically significant. A total of 223 patients were included during study period. In univariate analysis, patients with delirium showed significantly higher CRP values than those without (120.5 vs 57.5 mg/L; P = .0001). By adjusting for confounding variables (including age, sex, Acute Physiology and Chronic Health Evaluation II, intubation, living alone, physical restraint, alcohol drinking, smoking, type of medical condition, and hospital LOS before ICU admission) in logistic regression model, CRP remained an independent predictor of delirium (odds ratio, 1.07; 95% confidence interval, 1.01-1.15). As compared with nondelirious patients, those with delirium showed longer LOS in ICU (13 vs 5 days; P < .001) and duration of mechanical ventilation (6 vs 1 days; P < .001). An increase in CRP greater than 8.1 mg/L within 24 hours was associated with 4-fold increase in the risk of delirium (odds ratio: 4.47, 95% confidence interval, 1.28-15.60). C-reactive protein measured on ICU entry and its changes within 24 hours are risk indicators of delirium. Further studies exploring the treatment of delirium according to CRP levels are warranted.
    Full-text · Article · Oct 2013 · Journal of critical care
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    • "A recent study performed in critically ill patients suggested that high baseline inflammatory biomarkers of systemic inflammation at admission, such as C-reactive protein and procalcitonin, predicted prolonged periods of acute brain dysfunction, irrespective of whether patients had sepsis or not [55]. In another study performed in 50 patients with systemic inflammatory response syndrome (SIRS), IL-8 was independently associated with delirium [56]. These findings suggest that sustained systemic inflammation may contribute to prolong or aggravate brain dysfunction. "
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    ABSTRACT: Sepsis often is characterized by an acute brain dysfunction, which is associated with increased morbidity and mortality. Its pathophysiology is highly complex, resulting from both inflammatory and noninflammatory processes, which may induce significant alterations in vulnerable areas of the brain. Important mechanisms include excessive microglial activation, impaired cerebral perfusion, blood--brain-barrier dysfunction, and altered neurotransmission. Systemic insults, such as prolonged inflammation, severe hypoxemia, and persistent hyperglycemia also may contribute to aggravate sepsis-induced brain dysfunction or injury. The diagnosis brain dysfunction in sepsis relies essentially on neurological examination and neurological tests, such as EEG and neuroimaging. A brain MRI should be considered in case of persistent brain dysfunction after control of sepsis and exclusion of major confounding factors. Recent MRI studies suggest that septic shock can be associated with acute cerebrovascular lesions and white matter abnormalities. Currently, the management of brain dysfunction mainly consists of control of sepsis and prevention of all aggravating factors, including metabolic disturbances, drug overdoses, anticholinergic medications, withdrawal syndromes, and Wernicke's encephalopathy. Modulation of microglial activation, prevention of blood--brain-barrier alterations, and use of antioxidants represent relevant therapeutic targets that may impact significantly on neurologic outcomes. In the future, investigations in patients with sepsis should be undertaken to reduce the duration of brain dysfunction and to study the impact of this reduction on important health outcomes, including functional and cognitive status in survivors.
    Full-text · Article · May 2013 · Annals of Intensive Care
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