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Systemic inflammation and delirium during critical illness

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


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.


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.


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

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Data availability

Data and supporting documents from this study are available for academic research purposes upon request from the Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA (


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This study was supported by the National Institutes of Health K76AG054864, K23AG034257, R01AG027472, R01AG035117) and VA MERIT. In addition, WE received support from the Veterans Affairs Tennessee Valley GRECC.

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Authors and Affiliations



All authors contributed to study conception and design as well as acquisition, analysis, or interpretation of data. JLT, OMO, and RC conducted statistical analyses. All authors interpreted the results. NEB and TDG drafted the manuscript, and all authors critically revised the manuscript and approved the final version.

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Correspondence to Timothy D. Girard.

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Conflicts of interest

CGH is a consultant for Sedana Medical and has received research grant from Kohler Chemie GMBH. PP has received a research grant from Hospira. WE has received research grants and/or honoraria from Hospira, Orion, Pfizer, Abbott, and Kohler Chemie GMBH. The remaining authors declare no competing interests.

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Brummel, N.E., Hughes, C.G., McNeil, J.B. et al. Systemic inflammation and delirium during critical illness. Intensive Care Med 50, 687–696 (2024).

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