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
Original

Abstract

Purpose

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

Methods

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.

Results

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.

Conclusions

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.

Keywords

Delirium Inflammation Blood coagulation Critical illness Mechanical ventilation 

Notes

Acknowledgments

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)

References

  1. 1.
    Engel GL, Romano J (1959) Delirium, a syndrome of cerebral insufficiency. J Chronic Dis 9:260–277PubMedCrossRefGoogle Scholar
  2. 2.
    Girard TD, Pandharipande PP, Ely EW (2008) Delirium in the intensive care unit. Crit Care 12(Suppl 3):S3PubMedCrossRefGoogle Scholar
  3. 3.
    Dubois MJ, Bergeron N, Dumont M, Dial S, Skrobik Y (2001) Delirium in an intensive care unit: a study of risk factors. Intensive Care Med 27:1297–1304PubMedCrossRefGoogle Scholar
  4. 4.
    Shehabi Y, Riker RR, Bokesch PM, Wisemandle W, Shintani A, Ely EW (2010) Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med 38:2311–2318PubMedCrossRefGoogle Scholar
  5. 5.
    Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, Truman B, Dittus R, Bernard R, Inouye SK (2001) The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med 27:1892–1900PubMedCrossRefGoogle Scholar
  6. 6.
    Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS (2004) Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 291:1753–1762PubMedCrossRefGoogle Scholar
  7. 7.
    Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y (2007) Incidence, risk factors and consequences of ICU delirium. Intensive Care Med 33:66–73PubMedCrossRefGoogle Scholar
  8. 8.
    Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH (2009) Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med 180:1092–1097PubMedCrossRefGoogle Scholar
  9. 9.
    Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, Shintani AK, Gordon SM, Canonico AE, Dittus RS, Bernard GR, Ely EW (2010) Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med 38:1513–1520PubMedCrossRefGoogle Scholar
  10. 10.
    Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, Stiles RA, Truman B, Bernard GR, Dittus RS, Ely EW (2004) Costs associated with delirium in mechanically ventilated patients. Crit Care Med 32:955–962PubMedCrossRefGoogle Scholar
  11. 11.
    van Eijk MM, van Marum RJ, Klijn IA, de Wit N, Kesecioglu J, Slooter AJ (2009) Comparison of delirium assessment tools in a mixed intensive care unit. Crit Care Med 37:1881–1885PubMedCrossRefGoogle Scholar
  12. 12.
    Luetz A, Heymann A, Radtke FM, Chenitir C, Neuhaus U, Nachtigall I, von Dossow V, Marz S, Eggers V, Heinz A, Wernecke KD, Spies CD (2010) Different assessment tools for intensive care unit delirium: which score to use? Crit Care Med 38:409–418PubMedCrossRefGoogle Scholar
  13. 13.
    de Rooij SE, van Munster BC, Korevaar JC, Levi M (2007) Cytokines and acute phase response in delirium. J Psychosom Res 62:521–525PubMedCrossRefGoogle Scholar
  14. 14.
    Macdonald A, Adamis D, Treloar A, Martin F (2007) C-reactive protein levels predict the incidence of delirium and recovery from it. Age Ageing 36:222–225PubMedCrossRefGoogle Scholar
  15. 15.
    Beloosesky Y, Hendel D, Weiss A, Hershkovitz A, Grinblat J, Pirotsky A, Barak V (2007) Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. J Gerontol A Biol Sci Med Sci 62:420–426PubMedCrossRefGoogle Scholar
  16. 16.
    Marshall JC (2001) Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 29:S99–S106PubMedCrossRefGoogle Scholar
  17. 17.
    Schrier RW, Wang W (2004) Acute renal failure and sepsis. N Engl J Med 351:159–169PubMedCrossRefGoogle Scholar
  18. 18.
    Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342:1334–1349PubMedCrossRefGoogle Scholar
  19. 19.
    Papadopoulos MC, Lamb FJ, Moss RF, Davies DC, Tighe D, Bennett ED (1999) Faecal peritonitis causes oedema and neuronal injury in pig cerebral cortex. Clin Sci (Lond) 96:461–466CrossRefGoogle Scholar
  20. 20.
    Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C (2008) Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res 65:229–238PubMedCrossRefGoogle Scholar
  21. 21.
    Cerejeira J, Firmino H, Vaz-Serra A, Mukaetova-Ladinska EB (2010) The neuroinflammatory hypothesis of delirium. Acta Neuropathol 119:737–754PubMedCrossRefGoogle Scholar
  22. 22.
    van Gool WA, van de Beek D, Eikelenboom P (2010) Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 375:773–775PubMedCrossRefGoogle Scholar
  23. 23.
    Esmon CT (2001) Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med 29:S48–S52PubMedCrossRefGoogle Scholar
  24. 24.
    Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, Taichman DB, Dunn JG, Pohlman AS, Kinniry PA, Jackson JC, Canonico AE, Light RW, Shintani AK, Thompson JL, Gordon SM, Hall JB, Dittus RS, Bernard GR, Ely EW (2008) Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 371:126–134PubMedCrossRefGoogle Scholar
  25. 25.
    Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, Bernard GR, Ely EW (2006) Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 104:21–26PubMedCrossRefGoogle Scholar
  26. 26.
    Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 31:1250–1256PubMedCrossRefGoogle Scholar
  27. 27.
    Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829PubMedCrossRefGoogle Scholar
  28. 28.
    Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, Truman B, Speroff T, Gautam S, Margolin R, Hart RP, Dittus R (2001) Delirium in mechanically ventilated patients: validity and reliability of the Confusion Assessment Method for the intensive care unit (CAM-ICU). JAMA 286:2703–2710PubMedCrossRefGoogle Scholar
  29. 29.
    Ely EW, Margolin R, Francis J, May L, Truman B, Dittus R, Speroff T, Gautam S, Bernard GR, Inouye SK (2001) Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the intensive care unit (CAM-ICU). Crit Care Med 29:1370–1379PubMedCrossRefGoogle Scholar
  30. 30.
    Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA, Tesoro EP, Elswick RK (2002) The Richmond Agitation–Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 166:1338–1344PubMedCrossRefGoogle Scholar
  31. 31.
    Ely EW, Truman B, Shintani A, Thomason JW, Wheeler AP, Gordon S, Francis J, Speroff T, Gautam S, Margolin R, Sessler CN, Dittus RS, Bernard GR (2003) Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation–Sedation Scale (RASS). JAMA 289:2983–2991PubMedCrossRefGoogle Scholar
  32. 32.
    Harrell FE Jr (2001) Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis. Springer, New YorkGoogle Scholar
  33. 33.
    Ihaka R, Gentlemen R (1996) R: a language for data analysis and graphics. J Comput Graph Stat 5:299–314Google Scholar
  34. 34.
    Parsons PE, Matthay MA, Ware LB, Eisner MD (2005) Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol 288:L426–L431PubMedCrossRefGoogle Scholar
  35. 35.
    De Freitas I, Fernandez-Somoza M, Essenfeld-Sekler E, Cardier JE (2004) Serum levels of the apoptosis-associated molecules, tumor necrosis factor-alpha/tumor necrosis factor type-I receptor and Fas/FasL, in sepsis. Chest 125:2238–2246PubMedCrossRefGoogle Scholar
  36. 36.
    van Munster BC, Bisschop PH, Zwinderman AH, Korevaar JC, Endert E, Wiersinga WJ, van Oosten HE, Goslings JC, de Rooij SE (2010) Cortisol, interleukins and S100B in delirium in the elderly. Brain Cogn 74:18–23PubMedCrossRefGoogle Scholar
  37. 37.
    Tsuruta R, Girard TD, Ely EW, Fujimoto K, Ono T, Tanaka R, Oda Y, Kasaoka S, Maekawa T (2008) Associations between markers of inflammation and cholinergic blockade and delirium in intensive care unit patients: a pilot study. Bull Yamaguchi Med School 55:35–42Google Scholar
  38. 38.
    Pfister D, Siegemund M, Dell-Kuster S, Smielewski P, Ruegg S, Strebel SP, Marsch SC, Pargger H, Steiner LA (2008) Cerebral perfusion in sepsis-associated delirium. Crit Care 12:R63PubMedCrossRefGoogle Scholar
  39. 39.
    Plaschke K, Fichtenkamm P, Schramm C, Hauth S, Martin E, Verch M, Karck M, Kopitz J (2010) Early postoperative delirium after open-heart cardiac surgery is associated with decreased bispectral EEG and increased cortisol and interleukin-6. Intensive Care Med 36:2081–2089PubMedCrossRefGoogle Scholar
  40. 40.
    McGrane S, Girard TD, Thompson JL, Shintani AK, Woodworth A, Ely EW, Pandharipande PP (2011) Procalcitonin and C-reactive protein levels at admission as predictors of duration of acute brain dysfunction in critically ill patients. Crit Care 15:R78PubMedCrossRefGoogle Scholar
  41. 41.
    van den Boogaard M, Kox M, Quinn KL, van Achterberg T, van der Hoeven JG, Schoonhoven L, Pickkers P (2011) Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients. Crit Care 15:R297PubMedCrossRefGoogle Scholar
  42. 42.
    Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440:1054–1059PubMedCrossRefGoogle Scholar
  43. 43.
    Esmon CT (2006) Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost 32(Suppl 1):49–60PubMedCrossRefGoogle Scholar
  44. 44.
    Gorbacheva L, Pinelis V, Ishiwata S, Strukova S, Reiser G (2010) Activated protein C prevents glutamate- and thrombin-induced activation of nuclear factor-kappaB in cultured hippocampal neurons. Neuroscience 165:1138–1146PubMedCrossRefGoogle Scholar
  45. 45.
    Guo H, Liu D, Gelbard H, Cheng T, Insalaco R, Fernandez JA, Griffin JH, Zlokovic BV (2004) Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 41:563–572PubMedCrossRefGoogle Scholar
  46. 46.
    Spapen H, Nguyen DN, Troubleyn J, Huyghens L, Schiettecatte J (2010) Drotrecogin alfa (activated) may attenuate severe sepsis-associated encephalopathy in clinical septic shock. Crit Care 14:R54PubMedCrossRefGoogle Scholar
  47. 47.
    Michaluk P, Kaczmarek L (2007) Matrix metalloproteinase-9 in glutamate-dependent adult brain function and dysfunction. Cell Death Differ 14:1255–1258PubMedCrossRefGoogle Scholar
  48. 48.
    Nagy V, Bozdagi O, Matynia A, Balcerzyk M, Okulski P, Dzwonek J, Costa RM, Silva AJ, Kaczmarek L, Huntley GW (2006) Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 26:1923–1934PubMedCrossRefGoogle Scholar
  49. 49.
    Meighan SE, Meighan PC, Choudhury P, Davis CJ, Olson ML, Zornes PA, Wright JW, Harding JW (2006) Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J Neurochem 96:1227–1241PubMedCrossRefGoogle Scholar
  50. 50.
    Lorenzl S, Albers DS, Relkin N, Ngyuen T, Hilgenberg SL, Chirichigno J, Cudkowicz ME, Beal MF (2003) Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer’s disease. Neurochem Int 43:191–196PubMedCrossRefGoogle Scholar
  51. 51.
    Laskowitz DT, Kasner SE, Saver J, Remmel KS, Jauch EC (2009) Clinical usefulness of a biomarker-based diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study. Stroke 40:77–85PubMedCrossRefGoogle Scholar
  52. 52.
    Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J (2008) Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med 34:1384–1392PubMedCrossRefGoogle Scholar
  53. 53.
    Izidoro-Toledo TC, Guimaraes DA, Belo VA, Gerlach RF, Tanus-Santos JE (2011) Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells. Naunyn Schmiedebergs Arch Pharmacolo 383:547–554CrossRefGoogle Scholar
  54. 54.
    Morandi A, Hughes CG, Girard TD, McAuley DF, Ely EW, Pandharipande PP (2011) Statins and brain dysfunction: a hypothesis to reduce the burden of cognitive impairment in patients who are critically ill. Chest 140:580–585PubMedCrossRefGoogle Scholar
  55. 55.
    Morandi A, Pandharipande PP, Shintani AK, Hughes CG, Vasilevskis EE, Thompson JL, Han JH, Jackson JC, Bernard GR, Laskowitz DT, Ely EW, Girard TD (2012) Statin use and the daily risk of delirium in a prospective cohort of critically ill patients. Am J Respir Crit Care Med 185:A3646Google Scholar
  56. 56.
    van den Boogaard M, Ramakers BP, van Alfen N, van der Werf SP, Fick WF, Hoedemaekers CW, Verbeek MM, Schoonhoven L, van der Hoeven JG, Pickkers P (2010) Endotoxemia-induced inflammation and the effect on the human brain. Crit Care 14:R81PubMedCrossRefGoogle Scholar
  57. 57.
    van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, De Rooij SE (2008) Time-course of cytokines during delirium in elderly patients with hip fractures. J Am Geriatr Soc 56:1704–1709PubMedCrossRefGoogle Scholar
  58. 58.
    Marcantonio ER, Rudolph JL, Culley D, Crosby G, Alsop D, Inouye SK (2006) Serum biomarkers for delirium. J Gerontol A Biol Sci Med Sci 61:1281–1286PubMedCrossRefGoogle Scholar
  59. 59.
    Chou FP, Chu SC, Cheng MC, Yang SF, Cheung WN, Chiou HL, Hsieh YS (2002) Effect of hemodialysis on the plasma level of type IV collagenases and their inhibitors. Clin Biochem 35:383–388PubMedCrossRefGoogle Scholar
  60. 60.
    Perneger TV (1998) What’s wrong with Bonferroni adjustments. BMJ 316:1236–1238PubMedCrossRefGoogle Scholar
  61. 61.
    Zampieri FG, Park M, Machado FS, Azevedo LC (2011) Sepsis-associated encephalopathy: not just delirium. Clinics (Sao Paulo) 66:1825–1831CrossRefGoogle Scholar

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

Personalised recommendations