Abstract
BackgroundNeuroinflammation is thought to play an important role in the pathogenesis of ICU-acquired delirium, but the association between inflammatory and brain-specific proteins and ICU delirium is poor. We investigated whether or not serial determinations of markers may improve this association.MethodsCritically ill patients with a high risk of ICU delirium and with an ICU length of stay of at least 6 days were included in the study. Blood was drawn on days 1, 2, 4 and 6 after ICU admission and analyzed for different markers of inflammation and several brain proteins. Differences in courses over time prior to and following the onset of delirium and absolute differences over time were analyzed in patients with and without delirium using repeated measurement analysis of variance. In addition, a cross-sectional analysis of levels of these markers before the first onset of delirium was performed.ResultsFifty patients were included in this study. In the longitudinal analysis, there were no differences in the levels of any of the markers immediately prior to and following the onset of delirium, but overall, median levels of adiponectin (9019 (IQR 5776–15,442) vs. 6148 (IQR 4447–8742) ng/ml, p = 0.05) were significantly higher in patients with delirium compared to patients without delirium. In the cross-sectional analysis, median levels of the brain protein Tau (90 (IQR 46–224) vs. 31 (IQR 31–52) pg/ml, p = 0.009) and the ratio Tau/amyloid β1–42 (1.42 ((IQR 0.9–2.57) vs. 0.68 (IQR 0.54–0.96), p = 0.003) were significantly higher in patients with hypoactive delirium compared to patients without. Levels of neopterin (111 (IQR 37–111) vs. 29 (IQR 16–64) mmol/l, p = 0.004) and IL-10 (28 (IQR 12–39) vs. 9 (IQR 4–12) pg/ml, p = 0.001) were significantly higher in patients with hypoactive delirium compared to patients with mixed-type delirium.ConclusionsWhile there are differences in markers (adiponectin and several brain proteins) between patients with and without delirium, the development of delirium is not preceded by a change in the biomarker profile of inflammatory markers or brain proteins. Patients with hypoactive delirium account for the observed differences in biomarkers.Trial registrationClinicalTrials.gov, NCT 01274819. Registered on 12 January 2011.
Highlights
Neuroinflammation is thought to play an important role in the pathogenesis of ICU-acquired delirium, but the association between inflammatory and brain-specific proteins and ICU delirium is poor
We found no differences between patients with and without delirium in the levels of brain-specific proteins; when evaluating the clinical subtypes of delirium we found that levels of Tau protein and the ratio of Tau/Amyloid β1–42 (Aβ1–42) were significantly higher in the hypoactive delirium group compared to the non-delirium group
We found levels of neopterin and IL-10 before the onset of delirium to be significantly higher in patients with hypoactive delirium compared to patients with mixed-type delirium
Summary
Neuroinflammation is thought to play an important role in the pathogenesis of ICU-acquired delirium, but the association between inflammatory and brain-specific proteins and ICU delirium is poor. The inflammatory response as a trigger for brain damage and its clinical substrate, delirium, has been a subject of investigation. This neuro-inflammatory hypothesis assumes a systemic inflammatory response, which stimulates release of cytokines in the brain by microglial cells. Associations between levels of pro-inflammatory markers and the presence of delirium have been found in ICU and nonICU patients [7,8,9,10]. Serum levels of other biomarkers involved in the inflammatory response, such as neopterin and monocyte chemoattractant protein-1 (MCP-1) are found in higher concentrations in patients with delirium [11, 12]. Markers of brain damage have been associated with delirium [9, 13, 14]
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