Intensive Care Medicine

, Volume 38, Issue 12, pp 1965–1973 | Cite as

Associations of markers of inflammation and coagulation with delirium during critical illness

  • Timothy D. Girard
  • Lorraine B. Ware
  • Gordon R. Bernard
  • Pratik P. Pandharipande
  • Jennifer L. Thompson
  • Ayumi K. Shintani
  • James C. Jackson
  • Robert S. Dittus
  • E. Wesley Ely



To assess the associations between a priori-selected markers of inflammation and coagulation and delirium during critical illness.


In this prospective cohort study, we collected blood from mechanically ventilated medical intensive care unit (ICU) patients and measured nine plasma markers of inflammation and coagulation. We assessed patients daily for delirium using the Confusion Assessment Method for the ICU and used multivariable regression to analyze the associations between plasma markers and subsequent delirium, after adjusting for age, severity of illness, and sepsis.


Among the 138 patients studied, with median age of 66 years and median Acute Physiology and Chronic Health Evaluation (APACHE) II of 27, 107 (78 %) were delirious at some point during the study. Two markers of inflammation and one of coagulation were significantly associated with delirium. After adjusting for covariates, lower plasma concentrations of matrix metalloproteinase-9 (MMP-9) and protein C were associated with increased probability of delirium (p = 0.04 and 0.01, respectively), and higher concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were associated with increased probability of delirium (p < 0.01). Concentrations of C-reactive protein (p = 0.82), myeloperoxidase (p = 0.11), neutrophil gelatinase-associated lipocalin (p = 0.70), D-dimer (p = 0.83), plasminogen activator inhibitor type 1 (p = 0.98), and Von Willebrand factor antigen (p = 0.65) were not associated with delirium.


In this study, MMP-9, protein C, and sTNFR1 were independently associated with subsequent ICU delirium. These results suggest that specific aspects of inflammation and coagulation may play a role in the evolution of delirium during critical illness and that these markers should be examined in larger studies of ICU patients.


Delirium Inflammation Blood coagulation Critical illness Mechanical ventilation 



Dr. Girard is supported by the National Institutes of Health (NIH) (AG034257) and the Veterans Affairs (VA) Tennessee Valley Geriatric Research, Education, and Clinical Center (GRECC), Dr. Ware is supported by the NIH (HL103836) and an American Heart Association Established Investigator Award, Dr. Pandharipande is supported by the VA Clinical Science Research and Development Service (VA Career Development Award), Dr. Jackson is supported by the NIH (AG031322), and Dr. Ely is supported by the NIH (AG027472 and AG035117) and the VA Tennessee Valley GRECC. Additional funding for this research project was provided by the Saint Thomas Foundation (Nashville, TN, USA), National Institutes of Health (AG001023 and HL007123), Hartford Geriatrics Health Outcomes Research Scholars Award Program, Vanderbilt Physician Scientist Development Program, and Alere Inc. These sponsors had no role in study design; data collection, analysis, and interpretation; or publication of results.

Conflicts of interest

Drs. Girard, Pandharipande, Shintani, and Ely have received honoraria from Hospira Inc. Dr. Pandharipande has received honoraria from Orion Corporation. Drs. Pandharipande and Ely have received grant support from Hospira Inc. Dr. Ely has also received grant support from Eli Lilly and Company and Masimo Corporation and is an advisor to Healthways Inc. All other authors have no disclosures.

Supplementary material

134_2012_2678_MOESM1_ESM.docx (62 kb)
Supplementary material 1 (DOCX 61 kb)
134_2012_2678_MOESM1_ESM.docx (62 kb)
Supplementary material 1 (DOCX 61 kb)
134_2012_2678_MOESM1_ESM.docx (62 kb)
Supplementary material 1 (DOCX 61 kb)


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Copyright information

© Copyright jointly held by Springer and ESICM 2012

Authors and Affiliations

  • Timothy D. Girard
    • 1
    • 2
    • 8
  • Lorraine B. Ware
    • 1
    • 4
  • Gordon R. Bernard
    • 1
  • Pratik P. Pandharipande
    • 5
    • 9
  • Jennifer L. Thompson
    • 6
  • Ayumi K. Shintani
    • 6
  • James C. Jackson
    • 1
    • 7
    • 10
  • Robert S. Dittus
    • 2
    • 3
    • 8
  • E. Wesley Ely
    • 1
    • 2
    • 8
  1. 1.Division of Allergy, Pulmonary, and Critical Care MedicineVanderbilt University School of MedicineNashvilleUSA
  2. 2.Center for Health Services ResearchVanderbilt University School of MedicineNashvilleUSA
  3. 3.Division of General Internal Medicine and Public Health, Department of MedicineVanderbilt University School of MedicineNashvilleUSA
  4. 4.Department of Pathology, Microbiology and ImmunologyVanderbilt University School of MedicineNashvilleUSA
  5. 5.Division of Critical Care, Department of AnesthesiologyVanderbilt University School of MedicineNashvilleUSA
  6. 6.Department of BiostatisticsVanderbilt University School of MedicineNashvilleUSA
  7. 7.Department of PsychiatryVanderbilt University School of MedicineNashvilleUSA
  8. 8.Geriatric Research, Education and Clinical Center Service, Department of Veterans Affairs Medical CenterTennessee Valley Healthcare SystemNashvilleUSA
  9. 9.Anesthesia Service, Department of Veterans Affairs Medical CenterTennessee Valley Healthcare SystemNashvilleUSA
  10. 10.Research Service, Department of Veterans Affairs Medical CenterTennessee Valley Healthcare SystemNashvilleUSA

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