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Open Access 01-12-2015 | Review

Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome

Authors: Philip Toner, Danny Francis McAuley, Murali Shyamsundar

Published in: Critical Care | Issue 1/2015

Abstract

Sepsis is a common condition that is associated with significant morbidity, mortality and health-care cost. Pulmonary and non-pulmonary sepsis are common causes of the acute respiratory distress syndrome (ARDS). The mortality from ARDS remains high despite protective lung ventilation, and currently there are no specific pharmacotherapies to treat sepsis or ARDS. Sepsis and ARDS are characterised by activation of the inflammatory cascade. Although there is much focus on the study of the dysregulated inflammation and its suppression, the associated activation of the haemostatic system has been largely ignored until recently. There has been extensive interest in the role that platelet activation can have in the inflammatory response through induction, aggregation and activation of leucocytes and other platelets. Aspirin can modulate multiple pathogenic mechanisms implicated in the development of multiple organ dysfunction in sepsis and ARDS. This review will discuss the role of the platelet, the mechanisms of action of aspirin in sepsis and ARDS, and aspirin as a potential therapy in treating sepsis and ARDS.

Whittaker SA, Fuchs BD, Gaieski DF, Christie JD, Goyal MG, Meyer NJ, et al. Epidemiology and outcomes in patients with severe sepsis admitted to the hospital wards. J Crit Care. 2014;30:78–84.PubMedCrossRef

Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–10.PubMedCrossRef

Matthay MA, Ware LB, Zimmerman GA. Review series: The acute respiratory distress syndrome. J Clin Invest. 2012;122:2731–40.PubMedPubMedCentralCrossRef

Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353:1685–93.PubMedCrossRef

McAuley DF, Laffey JG, O’Kane CM, Perkins GD, Mullan B, Trinder J, et al. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014;371:1695–703.PubMedCrossRef

Cheung AM, Tansey CM, Tomlinson G, Diaz-Granados N, Matte A, Barr A, et al. Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2006;174:538–44.PubMedCrossRef

Patel GP, Gurka DP, Balk RA. New treatment strategies for severe sepsis and septic shock. Curr Opin Crit Care. 2003;9:390–6.PubMedCrossRef

Martin-loeches I, Levy MM, Artigas A. Management of severe sepsis: advances, challenges, and current status. Drug Des Devel Ther. 2015;9:2079–88.PubMedPubMedCentralCrossRef

Póvoa P, Salluh JIF, Martinez ML, Guillamat-Prats R, Gallup D, Al-Khalidi HR, et al. Clinical impact of stress dose steroids in patients with septic shock: insights from the PROWESS-Shock trial. Crit Care. 2015;19:1–10.CrossRef

10.

Network ARDS. Ventilation with lower tidal volumes as compared with traditional tidal volumes for ALI and ARDS. N Engl J Med. 2000;342:1301–8.CrossRef

11.

Papazian L, Forel JM, Gacouin A, Penot-Rogan C, Gilles Perrin Loundou A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107.PubMedCrossRef

12.

The National Heart, Lung and Blood Institute ARDS CTN. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564–75.CrossRef

13.

The National Heart, Lung and Blood Institute ARDS CTN. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354:1671–84.CrossRef

14.

Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Taylor B, Thompson T, et al. The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med. 2012;185:1307–15.PubMedPubMedCentralCrossRef

15.

Duggal A, Ganapathy A, Ratnapalan M, Adhikari NKJ. Pharmacological treatments for acute respiratory distress syndrome: systematic review. Minerva Anestesiol. 2015;81:567–88.PubMed

16.

Boyle AJ, Mac Sweeney R, McAuley DF. Pharmacological treatments in ARDS: a state-of-the-art update. BMC Med. 2013;11:166.PubMedPubMedCentralCrossRef

17.

Zarbock A, Polanowska-Grabowska RK, Ley K. Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev. 2007;21:99–111.PubMedCrossRef

18.

Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem. 2004;279:44250–7.PubMedCrossRef

19.

Shi G, Morrell CN. Platelets as initiators and mediators of inflammation at the vessel wall. Thromb Res. 2011;127:387–90.PubMedCrossRef

20.

Bozza FA, Shah AM, Weyrich AS, Zimmerman GA. Amicus or adversary platelets in lung biology, acute injury, and inflammation. Am J Respir Cell Mol Biol. 2009;40:123–34.PubMedCrossRef

21.

Fiusa MM, Carvalho-Filho MA, Annichino-Bizzacchi JM, De Paula EV. Causes and consequences of coagulation activation in sepsis: an evolutionary medicine perspective. BMC Med. 2015;13:105.PubMedPubMedCentralCrossRef

22.

Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med. 2010;38(2 Suppl):S35–42.PubMedCrossRef

23.

Levi M, Van der Poll T. Inflammation and coagulation. Crit Care Med. 2010;38(2 Suppl):S26–34.PubMedCrossRef

24.

Snow RL, Davies P, Pontoppidan H, Zapol WM, Reid L. Pulmonary vascular remodeling in adult respiratory distress syndrome. Am Rev Respir Dis. 1982;126:887–92.PubMed

25.

Nuckton TJ, Alonso JA, Kallet RH, Daniel BM, Pittet JF, Eisner MD, et al. Pulmonary dead-space fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med. 2002;346:1281–6.PubMedCrossRef

26.

Yaguchi A, Lobo FLM, Vincent JL, Pradier O. Platelet function in sepsis. J Thromb Haemost. 2004;2:2096–102.PubMedCrossRef

27.

Gros A, Ollivier V, Ho-Tin-Noe B. Platelets in inflammation: regulation of leukocyte activities and vascular repair. Front Immunol. 2015;5:1–8.CrossRef

28.

Smith TL, Weyrich AS. Platelets as central mediators of systemic inflammatory responses. Thromb Res. 2011;127:391–4.PubMedCrossRef

29.

McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe. 2012;12:324–33.PubMedCrossRef

30.

Zawrotniak M, Rapala-kozik M. Neutrophil extracellular traps (NETs)—formation and implications. Acta Biochim Pol. 2013;60:277–84.PubMedCrossRef

31.

Fuchs T, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107:15880–5.PubMedPubMedCentralCrossRef

32.

Asaduzzaman M, Lavasani S, Rahman M, Rahman M, Zhang S, Braun OO, et al. Platelets support pulmonary recruitment of neutrophils in abdominal sepsis. Crit Care Med. 2009;37:1389–96.PubMedCrossRef

33.

Hidalgo A, Chang J, Jang JE, Peired A, Chiang EY, Frenette PS. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thrombo-inflammatiry injury. Nat Med. 2009;15:384–91.PubMedPubMedCentralCrossRef

34.

Goff CD, Corbin RS, Theiss SD, Frierson HF, Cephas GA, Tribble CG, et al. Postinjury thromboxane receptor blockade ameliorates acute lung injury. Ann Thorac Surg. 1997;64:826–9.PubMedCrossRef

35.

Grommes J, Alard JE, Drechsler M, Wantha S, Morgelin M, Kuebler WM, et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med. 2012;185:628–36.PubMedPubMedCentralCrossRef

36.

Wuescher LM, Takashima A, Worth RG. A novel conditional platelet depletion mouse model reveals the importance of platelets in protection against Staphylococcus aureus bacteremia. J Thromb Haemost. 2015;13:303–13.PubMedCrossRef

37.

De Stoppelaar SF, Veer C, Claushuis TM, Albersen BJ, Roelofs JJTH, Van Der Poll T. Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice. Blood. 2014;124:3781–91.PubMedPubMedCentralCrossRef

38.

Eisen DP. Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti-inflammatory drugs on sepsis. Intensive Care Med. 2012;38:1249–57.PubMedCrossRef

39.

Gawaz M, Dickfeld T, Bogner C, Fateh-Moghadam S, Neumann FJ. Platelet function in septic multiple organ dysfunction syndrome. Intensive Care Med. 1997;23:379–85.PubMedCrossRef

40.

Idell S, Maunder R, Fein AM, Switalska HI, Tuszynski GP, McLarty J, et al. Platelet-specific alpha-granule proteins and thrombospondin in bronchoalveolar lavage in the adult respiratory distress syndrome. Chest. 1989;96:1125–32.PubMedCrossRef

41.

Ortiz-Muñoz G, Mallavia B, Bins A, Headley M, Krummel MF, Looney MR. Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood. 2014;23:2625–34.CrossRef

42.

Mandal RV, Mark EJ, Kradin RL. Megakaryocytes and platelet homeostasis in diffuse alveolar damage. Exp Mol Pathol. 2007;83:327–31.PubMedCrossRef

43.

Floyd CN, Ferro A. Mechanisms of aspirin resistance. Pharmacol Ther. 2014;141:69–78.PubMedCrossRef

44.

Weber C, Erl W, Pietsch A, Weber PC. Aspirin inhibits nuclear factor B mobilization and monocyte adhesion in stimulated human endothelial cells. Circulation. 1995;91:1914–7.PubMedCrossRef

45.

Taubert D, Berkels R, Grosser N, Schröder H, Gründemann D, Schömig E. Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action. Br J Pharmacol. 2004;143:159–65.PubMedPubMedCentralCrossRef

46.

El Kebir D, József L, Pan W, Wang L, Petasis NA, Serhan CN, et al. 15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury. Am J Respir Crit Care Med. 2009;180:311–9.PubMedPubMedCentralCrossRef

47.

Eliopoulos AG, Dumitru CD, Wang C, Cho J, Tsichlis PN. Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. EMBO J. 2002;21:4831–40.PubMedCrossRef

48.

Bishop-Bailey D, Pepper JR, Larkin SW, Mitchell JA. Differential induction of cyclooxygenase-2 in human arterial and venous smooth muscle: role of endogenous prostanoids. Arterioscler Thromb Vasc Biol. 1998;18:1655–61.PubMedCrossRef

49.

Morris T, Stables M, Hobbs A, de Souza P, Coiville-Nash P, Watner P, et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol. 2009;183:2089–96.PubMedCrossRef

50.

Yoo C, Lee S, Lee C, Kim TW, Han SK, Shim YS. Effect of acetylsalicylic acid on endogenous IkB kinase activity in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2001;280:L3–9.PubMedCrossRef

51.

Brune K, Graft P. Non-steroid anti-inflammatory drugs: influence of extra-cellular pH on biodistribution and pharmacological effects. Biochem Pharmacol. 1978;27:525–30.PubMedCrossRef

52.

Cyrus T, Sung S, Zhao L, Funk CD, Tang S, Praticò D. Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation. 2002;106:1282–7.PubMedCrossRef

53.

Trzeciak S, Cinel IC, Dellinger P, Shapiro NI, Arnold RC, Parrillo JE, et al. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med. 2008;15:399–413.PubMedPubMedCentralCrossRef

54.

Fukunaga K, Kohli P, Bonnans C, Fredenburgh LE, Levy BD. Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J Immunol. 2005;174:5033–9.PubMedCrossRef

55.

Smith WL, De Witt DL. Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs. Semin Nephrol. 1995;15:179–94.PubMed

56.

József L, Zouki C, Petasis N, Serhan CN, Filep JG. Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-kappa B and AP-1 activation, and IL-8 gene expression in human leukocytes. Proc Natl Acad Sci U S A. 2002;99:13266–71.PubMedPubMedCentralCrossRef

57.

Hussain M, Javeed A, Ashraf M, Zhao Y, Mukhtar MM, Rehman MU. Aspirin and immune system. Int Immunopharmacol. 2012;12:10–20.PubMedCrossRef

58.

Godson C, Mitchell S, Harvey K, Petasis NA, Hogg N, Brady HR. Lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J Immunol. 2000;164:1663–7.PubMedCrossRef

59.

Matut T, Ell AD. Neutrophil apoptosis in the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;156:1969–77.CrossRef

60.

Fang X, Abbott J, Cheng L, Colby JK, Lee JW, Levy BD, et al. Human mesenchymal stem (stromal) cells promote the resolution of acute lung injury in part through lipoxin A 4. J Immunol. 2015;195:875–81.PubMedCrossRef

61.

Halushka PV, Wise WC, Cook JA. Studies on the beneficial effects of aspirin in endotoxic shock. Relationship to inhibition of arachidonic acid metabolism. Am J Med. 1983;74:91–6.PubMedCrossRef

62.

Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest. 2006;116:3211–9.PubMedPubMedCentralCrossRef

63.

Looney MR, Nguyen JX, Hu Y, Van Ziffle JA, Lowell CA, Matthay MA. Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury. J Clin Invest. 2009;119:3450–61.PubMedPubMedCentral

64.

Tsai MJ, Ou SM, Shih CJ, Chao PW, Wang LF, Shih YN, et al. Association of prior antiplatelet agents with mortality in sepsis patients: a nationwide population-based cohort study. Intensive Care Med. 2015;41:806–13.PubMedCrossRef

65.

Mazzeffi M, Kassa W, Gammie J, Tanaka K, Roman P, Zhan M, et al. Preoperative aspirin use and lung injury after aortic valve replacement surgery. Anesth Analg. 2015;121:271–7.PubMedCrossRef

66.

Lösche W, Boettel J, Kabisch B, Winning J, Claus RA, Bauer M. Do aspirin and other antiplatelet drugs reduce the mortality in critically ill patients? Thrombosis. 2012;2012:720254.PubMedCrossRef

67.

Winning J, Neumann J, Kohl M, Claus RA, Reinhard K, Bauer M, et al. Antiplatelet drugs and outcome in mixed admissions to an intensive care unit. Crit Care Med. 2010;38:32–7.PubMedCrossRef

68.

Valerio-Rojas JC, Jaffer IJ, Kor DJ, Gajic O, Cartin-Ceba R. Outcomes of severe sepsis and septic shock patients on chronic antiplatelet treatment: a historical cohort study. Crit Care Res Pract. 2013;2013:782573.PubMedPubMedCentral

69.

Erlich JM, Talmor DS, Cartin-Ceba R, Gajic O, Kor DJ. Prehospitalization antiplatelet therapy is associated with a reduced incidence of acute lung injury: a population-based cohort study. Chest. 2011;139:289–95.PubMedCrossRef

70.

Chen W, Janz DR, Bastarache JA, May AK, O'Neal HR, Bernard GR, et al. Prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients. Crit Care Med. 2015;43:801–7.PubMedPubMedCentralCrossRef

71.

Harr JN, Moore EE, Johnson J, Chin TL, Wohlauer MV, Maier R, et al. Antiplatelet therapy is associated with decreased transfusion-associated risk of lung dysfunction, multiple organ failure, and mortality in trauma patients. Crit Care Med. 2013;41:399–404.PubMedPubMedCentralCrossRef

72.

Eisen DP, Reid D, McBryde ES. Acetyl salicylic acid usage and mortality in critically ill patients with the systemic inflammatory response syndrome and sepsis. Crit Care Med. 2012;40:1761–7.PubMedCrossRef

73.

Sossdorf M, Otto GP, Boettel J, Winning J, Lösche W. Benefit of low-dose aspirin and non-steroidal anti-inflammatory drugs in septic patients. Crit Care. 2013;17:402.PubMedPubMedCentralCrossRef

74.

Boyle AJ, Di Gangi S, Hamid UI, Mottram LJ, McNamee L, White G, et al. Aspirin therapy in patients with acute respiratory distress syndrome (ARDS) is associated with reduced intensive care unit mortality: a prospective analysis. Crit Care. 2015;19:1–8.CrossRef

75.

O’Neal HR, Koyama T, Koehler EA, Siew E, Curtis BR, Fremont RD, et al. Prehospital statin and aspirin use and the prevalence of severe sepsis and ALI/ARDS. Crit Care Med. 2011;39:1343–50.PubMedPubMedCentralCrossRef

76.

Kor DJ, Erlich J, Gong MN, Malinchoc M, Carter RE, Gajic O, et al. Association of prehospitalization aspirin therapy and acute lung injury: results of a multicenter international observational study of at-risk patients. Crit Care Med. 2011;39:2393–400.PubMedPubMedCentralCrossRef

77.

Bernard G, Wheeler A. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med. 1997;336:912–8.PubMedCrossRef

78.

Drewes RE, Weinberger SE. Thrombocytopenic disorders in critically ill patients. Am J Respir Crit Care Med. 2000;162:347–51.CrossRef

79.

Vanderschueren S, De Weerdt A, Malbrain M, Vankersschaever D, Frans E, Wilmer A, et al. Thrombocytopenia and prognosis in intensive care. Crit Care Med. 2000;28:1871–6.PubMedCrossRef

80.

Venkata C, Kashyap R, Farmer JC, Afessa B. Thrombocytopenia in adult patients with sepsis: incidence, risk factors, and its association with clinical outcome. J Intensive Care. 2013;1:9.PubMedPubMedCentralCrossRef

81.

Sarkiss MG, Yusuf SW, Warneke CL, Botz G, Lakkis N, Hirch-Ginsburg C, et al. Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes. Cancer. 2007;109:621–7.PubMedCrossRef

82.

Kor DJ, Talmor DS, Banner-Goodspeed VM, Carter RE, Hindes R, Park PK, et al. Lung Injury Prevention with Aspirin (LIPS-A): a protocol for a multicentre randomised clinical trial in medical patients at high risk of acute lung injury. BMJ Open. 2012;2. doi: 10.1136/bmjopen-2012-001606

83.

Otto GP, Sossdorf M, Boettel J, Kabisch B, Breuel H, Winning J, et al. Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock. Platelets. 2013;24:480–5.PubMedCrossRef

Title: Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome
Authors: Philip Toner
Danny Francis McAuley
Murali Shyamsundar
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Critical Care / Issue 1/2015
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/s13054-015-1091-6

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Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome

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