Systemic inflammation and delirium during critical illness

Abstract

Purpose: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness.

Methods: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). We collected blood samples on study days 1, 3, and 5, measuring levels of C-reactive protein (CRP), interferon gamma (IFN-γ), interleukin (IL)-1 beta (IL-1β), IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), and protein C using validated protocols. We used multinomial logistic regression to analyze associations between biomarkers and the odds of delirium or coma versus normal mental status the following day, adjusting for age, sepsis, Sequential Organ Failure Assessment (SOFA), study day, corticosteroids, and sedatives.

Results: Among 991 participants with a median age (interquartile range, IQR) of 62 [53-72] years and enrollment SOFA of 9 [7-11], higher concentrations of IL-6 (odds ratio [OR] [95% CI]: 1.8 [1.4-2.3]), IL-8 (1.3 [1.1-1.5]), IL-10 (1.5 [1.2-1.8]), TNF-α (1.2 [1.0-1.4]), and TNFR1 (1.3 [1.1-1.6]) and lower concentrations of protein C (0.7 [0.6-0.8])) were associated with delirium the following day. Higher concentrations of CRP (1.4 [1.1-1.7]), IFN-γ (1.3 [1.1-1.5]), IL-6 (2.3 [1.8-3.0]), IL-8 (1.8 [1.4-2.3]), and IL-10 (1.5 [1.2-2.0]) and lower concentrations of protein C (0.6 [0.5-0.8]) were associated with coma the following day. IL-1β, IL-12, and MMP-9 were not associated with mental status.

Conclusion: Markers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness.

Keywords: Coma; Critical illness; Delirium; Inflammation.

Figure 1:. Natural log concentration of each marker stratified by mental status on study days 1, 3, and 5.

These box plots display the natural log concentration of each marker on study days 1, 3, and 5 according to mental status on the day following marker measurement (i.e., days 2, 4, and 6) with blue representing normal mental status, red representing delirium, and gray representing coma. The bold horizontal line represents the median. The top and bottom of the boxes represent the 75^th and 25^th percentiles, respectively.

Figure 2:. Associations between markers of inflammation and mental status

These figures display the natural log concentration of each biomarker level (x-axis) versus the adjusted probabilities of mental status on the following day (y-axis). For each figure, the 3 panels from left to right, display the association between marker concentration and normal mental status (blue), delirium (red), or coma (gray), respectively. Solid lines indicate associations. Shading indicates 95% confidence intervals. Higher concentrations IL-6 (panel A), IL-8 (panel B), and IL-10 (panel C) were associated with a lower adjusted probability of normal mental status the following day and higher probabilities of delirium or coma (see Table 2). In contrast, higher concentrations of protein C (panel D) were associated with a higher adjusted probability of normal mental status on the following day and lower probabilities of delirium or coma (see Table 2).

Figure 3:. Associations between markers of inflammation and delirium/coma-free days

These figures display the natural log concentration of each marker level (x-axis) versus the adjusted probabilities of more delirium/coma-free days during the next week (y-axis). The association with IL-6 is indicated in panel A, with IL-8 in panel B, with IL-10 in panel C, and with protein C in panel D. Solid lines indicate associations. Shading indicates 95% confidence intervals. The adjusted probability of more delirium/coma-free days decreased as the concentrations of IL-6 (Figure 2A), IL-8 (Figure 2B) and IL-10 (Figure 2C) increased (see Table 3 for effect size). As the concentration of Protein C increased (Figure 2D), however, the probability of more delirium/coma-free days increased (see Table 3 for effect size).