nach oben

Erschienen in:

01.12.2012 | Original

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

verfasst von: 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

Erschienen in: Intensive Care Medicine | Ausgabe 12/2012

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

Engel GL, Romano J (1959) Delirium, a syndrome of cerebral insufficiency. J Chronic Dis 9:260–277PubMedCrossRef

Girard TD, Pandharipande PP, Ely EW (2008) Delirium in the intensive care unit. Crit Care 12(Suppl 3):S3PubMedCrossRef

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 27:1297–1304PubMedCrossRef

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 38:2311–2318PubMedCrossRef

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 27:1892–1900PubMedCrossRef

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 291:1753–1762PubMedCrossRef

Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y (2007) Incidence, risk factors and consequences of ICU delirium. Intensive Care Med 33:66–73PubMedCrossRef

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 180:1092–1097PubMedCrossRef

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 38:1513–1520PubMedCrossRef

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 32:955–962PubMedCrossRef

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 37:1881–1885PubMedCrossRef

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 38:409–418PubMedCrossRef

13.

de Rooij SE, van Munster BC, Korevaar JC, Levi M (2007) Cytokines and acute phase response in delirium. J Psychosom Res 62:521–525PubMedCrossRef

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 36:222–225PubMedCrossRef

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 62:420–426PubMedCrossRef

16.

Marshall JC (2001) Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 29:S99–S106PubMedCrossRef

17.

Schrier RW, Wang W (2004) Acute renal failure and sepsis. N Engl J Med 351:159–169PubMedCrossRef

18.

Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342:1334–1349PubMedCrossRef

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) 96:461–466CrossRef

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 65:229–238PubMedCrossRef

21.

Cerejeira J, Firmino H, Vaz-Serra A, Mukaetova-Ladinska EB (2010) The neuroinflammatory hypothesis of delirium. Acta Neuropathol 119:737–754PubMedCrossRef

22.

van Gool WA, van de Beek D, Eikelenboom P (2010) Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 375:773–775PubMedCrossRef

23.

Esmon CT (2001) Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med 29:S48–S52PubMedCrossRef

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 371:126–134PubMedCrossRef

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 104:21–26PubMedCrossRef

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 31:1250–1256PubMedCrossRef

27.

Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829PubMedCrossRef

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 286:2703–2710PubMedCrossRef

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 29:1370–1379PubMedCrossRef

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 166:1338–1344PubMedCrossRef

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 289:2983–2991PubMedCrossRef

32.

Harrell FE Jr (2001) Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis. Springer, New York

33.

Ihaka R, Gentlemen R (1996) R: a language for data analysis and graphics. J Comput Graph Stat 5:299–314

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–L431PubMedCrossRef

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 125:2238–2246PubMedCrossRef

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 74:18–23PubMedCrossRef

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 55:35–42

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:R63PubMedCrossRef

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 36:2081–2089PubMedCrossRef

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:R78PubMedCrossRef

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:R297PubMedCrossRef

42.

Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440:1054–1059PubMedCrossRef

43.

Esmon CT (2006) Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost 32(Suppl 1):49–60PubMedCrossRef

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 165:1138–1146PubMedCrossRef

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 41:563–572PubMedCrossRef

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:R54PubMedCrossRef

47.

Michaluk P, Kaczmarek L (2007) Matrix metalloproteinase-9 in glutamate-dependent adult brain function and dysfunction. Cell Death Differ 14:1255–1258PubMedCrossRef

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 26:1923–1934PubMedCrossRef

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 96:1227–1241PubMedCrossRef

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 43:191–196PubMedCrossRef

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 40:77–85PubMedCrossRef

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 34:1384–1392PubMedCrossRef

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 383:547–554CrossRef

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 140:580–585PubMedCrossRef

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:A3646

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:R81PubMedCrossRef

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 56:1704–1709PubMedCrossRef

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 61:1281–1286PubMedCrossRef

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 35:383–388PubMedCrossRef

60.

Perneger TV (1998) What’s wrong with Bonferroni adjustments. BMJ 316:1236–1238PubMedCrossRef

61.

Zampieri FG, Park M, Machado FS, Azevedo LC (2011) Sepsis-associated encephalopathy: not just delirium. Clinics (Sao Paulo) 66:1825–1831CrossRef

Titel: Associations of markers of inflammation and coagulation with delirium during critical illness
verfasst von: 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
Publikationsdatum: 01.12.2012
Verlag: Springer-Verlag
Erschienen in: Intensive Care Medicine / Ausgabe 12/2012
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-012-2678-x

Update AINS

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

hier abonnieren

Springer Medizin

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