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Biomarkers of Delirium Duration and Delirium Severity in the ICU

Khan, Babar A. MD, MS1–4; Perkins, Anthony J. MS1; Prasad, Nagendra K. BVSc, Phd, MBA1; Shekhar, Anantha MD1; Campbell, Noll L. PharmD, MS1–6; Gao, Sujuan PhD1; Wang, Sophia MD1; Khan, Sikandar H. DO, MS1; Marcantonio, Edward R. MD, SM7,8; Twigg, Homer L. III MD1; Boustani, Malaz A. MD, MPH1–5

doi: 10.1097/CCM.0000000000004139
Clinical Investigation: PDF Only
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Objectives: Both delirium duration and delirium severity are associated with adverse patient outcomes. Serum biomarkers associated with delirium duration and delirium severity in ICU patients have not been reliably identified. We conducted our study to identify peripheral biomarkers representing systemic inflammation, impaired neuroprotection, and astrocyte activation associated with delirium duration, delirium severity, and in-hospital mortality.

Design: Observational study.

Setting: Three Indianapolis hospitals.

Patients: Three-hundred twenty-one critically ill delirious patients.

Interventions: None.

Measurements and Main Results: We analyzed the associations between biomarkers collected at delirium onset and delirium-/coma-free days assessed through Richmond Agitation-Sedation Scale/Confusion Assessment Method for the ICU, delirium severity assessed through Confusion Assessment Method for the ICU-7, and in-hospital mortality. After adjusting for age, gender, Acute Physiology and Chronic Health Evaluation II score, Charlson comorbidity score, sepsis diagnosis and study intervention group, interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100β levels in quartile 4 were negatively associated with delirium-/coma-free days by 1 week and 30 days post enrollment. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium-/coma-free days at both time points. Interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100β levels in quartile 4 were also associated with delirium severity by 1 week. At hospital discharge, interleukin-6, -8, and -10 retained the association but tumor necrosis factor-α, C-reactive protein, and S-100β lost their associations with delirium severity. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium severity at both time points. Interleukin-8 and S-100β levels in quartile 4 were also associated with higher in-hospital mortality. Interleukin-6 and -10, tumor necrosis factor-α, and insulin-like growth factor-1 were not found to be associated with in-hospital mortality.

Conclusions: Biomarkers of systemic inflammation and those for astrocyte and glial activation were associated with longer delirium duration, higher delirium severity, and in-hospital mortality. Utility of these biomarkers early in delirium onset to identify patients at a higher risk of severe and prolonged delirium, and delirium related complications during hospitalization needs to be explored in future studies.

1Indiana University School of Medicine, Indianapolis, IN.

2Indiana University Center for Aging Research, Indianapolis, IN.

3Regenstrief Institute, Inc., Indianapolis, IN.

4Indiana University Center for Health Innovation and Implementation Science, Indiana Clinical and Translational Sciences Institute, Indianapolis, IN.

5Sandra Eskenazi Center for Brain Care Innovation at Eskenazi Health, Indianapolis, IN.

6Department of Pharmacy Practice, Purdue University College of Pharmacy, West Lafayette, IN.

7Division of General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

8Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Dr. Khan’s institution received funding from the National Institutes of Health (NIH)/National Institute on Aging (NIA) (K23AG043476). Dr. Perkins’ institution received funding from the NIH and the Centers for Medicare and Medicaid Services. Dr. Prasad disclosed that he is currently employed at Eli Lilly, which has no direct or indirect role or influence on the research findings presented here. Dr. Shekhar received research grants from the NIH, Department of Defense, Eli Lilly, Johnson & Johnson, and Astra Zeneca for unrelated research. Dr. Gao’s institution received funding from the NIH. Dr. Wang received funding from American Psychiatric Publishing (royalties). Dr. Marcantonio’s effort was supported by grants R01AG044518 and K24AG035075 from the NIA. Dr. Boustani received funding from NIA (R01AG034205) and disclosed that he has ownership equity in two for profit companies, Preferred Population Health Management and RestUp; the products and services of the two companies are not related to the research activities of the published papers. Drs. Khan, Perkins, Shekhar, Gao, Wang, Marcantonio, and Boustani received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest.

This work was performed at Indiana University School of Medicine, Indianapolis, IN.

For information regarding this article, E-mail: bakhan@iu.edu

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