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Relationships between markers of neurologic and endothelial injury during critical illness and long-term cognitive impairment and disability

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Abstract

Purpose

Neurologic and endothelial injury biomarkers are associated with prolonged delirium during critical illness and may reflect injury pathways that lead to poor long-term outcomes. We hypothesized that blood–brain barrier (BBB), neuronal, and endothelial injury biomarkers measured during critical illness are associated with cognitive impairment and disability after discharge.

Methods

We enrolled adults with respiratory failure and/or shock and measured plasma concentrations of BBB (S100B), neuronal (UCHL1, BDNF), and endothelial (E-selectin, PAI-1) injury markers within 72 h of ICU admission. At 3 and 12 months post-discharge, we assessed participants’ global cognition, executive function, and activities of daily living (ADL). We used multivariable regression to determine whether biomarkers were associated with outcomes after adjusting for relevant demographic and acute illness covariates.

Results

Our study included 419 survivors of critical illness with median age 59 years and APACHE II score 25. Higher S100B was associated with worse global cognition at 3 and 12 months (P = 0.008; P = 0.01). UCHL1 was nonlinearly associated with global cognition at 3 months (P = 0.02). Higher E-selectin was associated with worse global cognition (P = 0.006 at 3 months; P = 0.06 at 12 months). BDNF and PAI-1 were not associated with global cognition. No biomarkers were associated with executive function. Higher S100B (P = 0.05) and E-selectin (P = 0.02) were associated with increased disability in ADLs at 3 months.

Conclusions

S100B, a marker of BBB and/or astrocyte injury, and E-selectin, an adhesion molecule and marker of endothelial injury, are associated with long-term cognitive impairment after critical illness, findings that may reflect mechanisms of critical illness brain injury.

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Acknowledgements

We acknowledge our research coordinators Leanne Boehm, PhD, RN, ACNS-BC; Brenda Truman Pun, RN, MSN; Joyce Okahashi, RN; and Cayce Strength, RSN, BSN who performed project management, data acquisition, and data management. We acknowledge our neuropsychology staff Amy Kiehl, MA, LPC-MHSP who performed neuropsychological outcome testing.

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Authors and Affiliations

  1. Department of Anesthesiology, Division of Anesthesiology Critical Care Medicine and Center for Health Services Research, Vanderbilt University Medical Center, Nashville, USA

    Christopher G. Hughes

  2. Section of Surgical Sciences, Departments of Surgery, Neurosurgery and Hearing and Speech Sciences, Division of Trauma and Surgical Critical Care, Vanderbilt Brain Institute, Center for Health Services Research, Vanderbilt University Medical Center, Nashville, USA

    Mayur B. Patel

  3. Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, USA

    Nathan E. Brummel & J. Brennan McNeil

  4. Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, USA

    Jennifer L. Thompson & Rameela Chandrasekhar

  5. Departments of Anesthesiology and Surgery, Division of Anesthesiology Critical Care Medicine, Vanderbilt University Medical Center, Nashville, USA

    Pratik P. Pandharipande

  6. Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine and Center for Health Services Research, Vanderbilt University Medical Center, Nashville, USA

    James C. Jackson & E. Wesley Ely

  7. Departments of Medicine and Pathology, Microbiology and Immunology, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, USA

    Lorraine B. Ware

  8. Department of Critical Care Medicine and Clinical Research, Investigation and Systems Modeling of Acute Illnesses Center, University of Pittsburgh, Pittsburgh, USA

    Timothy D. Girard

  9. Nashville Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, USA

    Christopher G. Hughes, Mayur B. Patel & Pratik P. Pandharipande

  10. Research Service, Nashville Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, USA

    James C. Jackson

  11. Geriatric Research, Education and Clinical Center Service, Nashville Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, USA

    E. Wesley Ely

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  1. Christopher G. Hughes
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  2. Mayur B. Patel
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  3. Nathan E. Brummel
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  4. Jennifer L. Thompson
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  5. J. Brennan McNeil
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  6. Pratik P. Pandharipande
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  7. James C. Jackson
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  10. E. Wesley Ely
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  11. Timothy D. Girard
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Corresponding author

Correspondence to Christopher G. Hughes.

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Funding

This project was supported by CTSA award TR000445 from the National Center for Advancing Translational Sciences and by the National Institutes on Aging (AG027472 and AG045085). In addition, Dr. Hughes received support from American Geriatrics Society Jahnigen Career Development Award and the National Institutes of Health (HL111111, AG045085, GM120484), Dr. Patel received support from the National Institutes of Health (HL111111, GM120484) and the Vanderbilt Faculty Research Scholars Program, Dr. Brummel received support from the National Institutes of Health TR00046 and AG040549 and by the Vanderbilt Clinical and Translational Scholars Program, Dr. Pandharipande received support from the National Institutes of Health (AG027472, HL111111, GM120484), Dr. Ely received support from the VA Clinical Science Research and Development Service and the National Institutes of Health (AG027472, AG035117, HL111111, GM120484), Dr. Ware received support from the National Institutes of Health (HL103836 and HL112656), and Dr. Girard received support from the National Institutes of Health (AG034257, AG035117, HL135144). Drs. Ely and Girard also received support from the Veterans Affairs Tennessee Valley Geriatric Research, Education and Clinical Center. We used REDCap, a secure online database, supported in part by the National Institutes of Health TR000445.

Conflicts of interest

Drs. Hughes, Jackson, and Ely received research Grant from Dr. Franz Kohler Chemie GmbH. Dr. Pandharipande and Ely received a research grant from Hospira Inc.

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Hughes, C.G., Patel, M.B., Brummel, N.E. et al. Relationships between markers of neurologic and endothelial injury during critical illness and long-term cognitive impairment and disability. Intensive Care Med 44, 345–355 (2018). https://doi.org/10.1007/s00134-018-5120-1

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