Pathophysiology of Acute Illness and Injury

  • Sergio ArlatiEmail author


The pathophysiology of acute illness and injury recognizes three main effectors: infection, trauma, and ischemia-reperfusion injury. Each of them can act by itself or in combination with the other two in developing a systemic inflammatory reaction syndrome (SIRS) that is a generalized reaction to the morbid event. The time course of SIRS is variable and influenced by the number and severity of subsequent insults (e.g., reparative surgery, acquired hospital infections). It occurs simultaneously with a complex of counter-regulatory mechanisms (compensatory anti-inflammatory response syndrome, CARS) that limit the aggressive effects of SIRS. In adjunct, a progressive dysfunction of the acquired (lymphocytes) immune system develops with increased risk for immunoparalysis and associated infectious complications. Both humoral and cellular effectors participate to the development of SIRS and CARS. The most important humoral mediators are pro-inflammatory (IL-1β, IL-6, IL-8, IL-12) and anti-inflammatory (IL-4, IL-10) cytokines and chemokines, complement, leukotrienes, and PAF. Effector cells include neutrophils, monocytes, macrophages, lymphocytes, and endothelial cells. The endothelium is a key factor for production of remote organ damage as it exerts potent chemo-attracting effects on inflammatory cells, allows for leukocyte trafficking into tissues and organs, and promotes further inflammation by cytokines release. Moreover, the loss of vasoregulatory properties and the increased permeability contribute to the development of hypotension and tissue edema. Finally, the disseminated activation of the coagulation cascade causes the widespread deposition of microthrombi with resulting maldistribution of capillary blood flow and ultimately hypoxic cellular damage. This mechanism together with increased vascular permeability and vasodilation is responsible for the development of the multiple organ dysfunction syndrome (MODS).


  1. 1.
    Bone RC. Sir Isaac Newton, sepsis, SIRS and CARS. Crit Care Med. 1996;24:1125–8.PubMedPubMedCentralGoogle Scholar
  2. 2.
    American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–74.Google Scholar
  3. 3.
    Lord JM, Midwinter MJ, Chen Y, Belli A, Brohi K, Kovacs EJ, Koenderman L, Kubes P, Lilford RJ. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014;384:1455–65.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Osuchowski MF, Craciun F, Weixelbaumer KM, Duffy ER, Remick DG. Sepsis chronically in MARS: systemic cytokine responses are always mixed regardless of the outcome, magnitude, or phase of sepsis. J Immunol. 2012;189(9):4648–56.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–50.PubMedGoogle Scholar
  6. 6.
    Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock. 2001;16:83–96.PubMedGoogle Scholar
  7. 7.
    Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and new therapeutic approach. Lancet Infect Dis. 2013;13:260–8.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Riche FC, Cholley BP, Panis YH, Laisne MJ, Briard CG, Grauler AM, Gueris JL, Valleur PD. Inflammatory cytokine response in patients with septic shock secondary to generalized peritonitis. Crit Care Med. 2000;28:433–7.PubMedGoogle Scholar
  9. 9.
    Brunialti MK, Martins PS, de Carvalho B, Machado FR, Barbosa LM, Salomao R. TLR2, TLR4, CD14, CD11B, and CD11C expressions on monocytes surface and cytokine production in patients with sepsis, severe sepsis and septic shock. Shock. 2006;25:351–7.PubMedGoogle Scholar
  10. 10.
    Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, Kurosawa S, Stepien D, Valentine C, Remick DG. Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding. Physiol Rev. 2013;93:1247–88.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Osuchowski MF, Welch K, Yang H, Siddiqui J, Remick D. Sepsis: always in MARS. Shock. 2006;25:5.Google Scholar
  12. 12.
    Heidecke CD, Hensler T, Weighardt H, Zantl N, Wagner H, Siewert JR, Holzmann B. Selective defects on T lymphocytes function in patients with lethal intraabdominal infection. Am J Surg. 1999;178:288–92.PubMedGoogle Scholar
  13. 13.
    Ploder M, Pelinka L, Schmuckenschlager C, Wessner B, Ankersmit HJ, Fuerst W, Redl H, Roth E, Spittler A. Lipopolysaccharide-induced tumor necrosis factor alpha production and not monocyte human leukocyte antigen-DR expression is correlated with survival in septic trauma patients. Shock. 2006;25:129–34.PubMedGoogle Scholar
  14. 14.
    Cavaillon JM, Adib-Conquy M, Cloez-Tayarani I, Fitting C. Immunodepression in sepsis and SIRS assessed by ex-vivo cytokine production is not a generalized phenomenon: a review. J Endotoxin Res. 2001;7:85–93.PubMedGoogle Scholar
  15. 15.
    Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5.PubMedGoogle Scholar
  16. 16.
    Pugin J. How tissue injury alarms the immune system and causes a systemic inflammatory response. Ann Intensive Care. 2012;2:22.Google Scholar
  17. 17.
    Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPSs cause inflammatory response to injury. Nature. 2010;464:104–7.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Chen G, Li J, Ochani M, Rendon-Mitchell B, Qiang X, Susarla S, Ulloa L, Yang H, Fan S, Goyert SM, Wang P, Tracey KJ, Sama AE, Wang H. Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms. J Leukoc Biol. 2004;76:994–1001.PubMedGoogle Scholar
  19. 19.
    Zedler S, Faist E. The impact of endogenous triggers on trauma-associated inflammation. Curr Opin Crit Care. 2006;12:595–601.PubMedGoogle Scholar
  20. 20.
    Manson J, Thiemermann C, Brohi K. Trauma alarmins as activators of damage-induced inflammation. Br J Surg. 2012;99(Suppl 1):12–20.PubMedGoogle Scholar
  21. 21.
    Burk AM, Martin M, Flierl MA, Rittirsch D, Helm M, Lampl L, Bruckner U, Stahl GL, Blom AM, Perl M, Gebhard F, Huber-Lang MS. Early complementopathy after multiple injuries in humans. Shock. 2012;37(4):348–54.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Neher MD, Weckbach S, Flierl MA, Huber-Lang MS, Stahel PF. Molecular mechanisms of inflammatory and tissue injury after major trauma-is complement the “bad guy”? J Biomed Sci. 2011;18(1):90.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Huber-Lang MS, Kotvun A, Ignatius A. The role of complement in trauma and fracture healing. Semin Immunol. 2013;25:73–8.PubMedGoogle Scholar
  24. 24.
    Harris HE, Raucci A. Alarmin(s) news about danger: workshop on innate danger signals and HMGB1. EMBO Rep. 2006;7:774–8.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Wang H, Vishunabhakat JM, Bloom O, Zhang M, Ombrellino M, Sama A, tracey KJ. Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes. Surgery. 1999;126:389–92.PubMedGoogle Scholar
  26. 26.
    Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191–5.PubMedGoogle Scholar
  27. 27.
    Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli A. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 2002;3:995–1001.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H, Tracey KJ. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 2000;192:565–70.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Rouhianen A, Kuja-Panula J, Wilkman E, Pakkanen J, Stenfors J, Touminen RK, Leptanlo M, Carpén O, Parkkinen J, Rauvala H. Regulation of monocyte migration by amphoterin (HMGB1). Blood. 2004;104:1174–82.Google Scholar
  30. 30.
    Roumen RM, Redl H, Schlag G. Inflammatory mediators in relation to the development of multiple organ failure in patients after severe blunt trauma. Crit Care Med. 1995;23:474–80.PubMedGoogle Scholar
  31. 31.
    Rose S, Marzi L. Pathophysiology of polytrauma. Zentralbl Chir. 1996;121(11):896–913.PubMedGoogle Scholar
  32. 32.
    Mollnes TE, Fosse E. The complement system in trauma-related and ischemic tissue damage: a brief review. Shock. 1994;2:301–10.PubMedGoogle Scholar
  33. 33.
    Biffl WL, Moore EE, Moore FA, Carl VS, Kim FJ, Franciose RJ. Interleukin-6 potentiates neutrophil priming with platelet-activating factor. Arch Surg. 1994;129:1131–6.PubMedGoogle Scholar
  34. 34.
    Friese RS, Rehring TF, Wollmering M, Moore EE, Ketch LL, Banerjee A, Harken AH. Trauma primes cells. Shock. 1994;1:388–94.PubMedGoogle Scholar
  35. 35.
    Hietbrink F, Koenderman L, Rijkers G, Leenen L. Trauma: the role of the innate immune system. World J Emerg Surg. 2006;1:15.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Partrick DA, Moore FA, Moore EE, Barnett CC Jr, Silliman CC. Neutrophil priming and activation in the pathogenesis of postinjury multiple organ failure. New Horiz. 1996;4:196–210.Google Scholar
  37. 37.
    Alcaide P, Auerbach S, Luscinskas FW. Neutrophil recruitment under shear flow: it’s all about endothelial rings and gaps. Microcirculation. 2009;16:43–57.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Giannoudis PV, Hildebrand F, Pape HC. Inflammatory serum markers in patients with multiple trauma. Can they predict outcome. J Bone Joint Surg Br. 2004;86(3):313–23.PubMedGoogle Scholar
  39. 39.
    Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury. 2007;38:1336–45.PubMedGoogle Scholar
  40. 40.
    Zhu J, Yamane H, Paul WE. Differentiation of effector C4 T cell populations. Annu Rev Immunol. 2010;28:445–89.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Botha AJ, Moore FA, Moore EE. Postinjury neutrophil priming and activation: an early vulnerable window. Surgery. 1995;118:358–65.PubMedGoogle Scholar
  42. 42.
    DeLong WG Jr, Born CT. Cytokines in patients with polytrauma. Clin Orthop Relat Res. 2004;422:57–65.Google Scholar
  43. 43.
    Grell M, Becke FM, Wajant H, Mannel DN, Scheurich P. TNF receptor type 2 mediates thymocyte proliferation independently of TNF receptor type 1. Eur J Immunol. 1998;28:257–63.PubMedGoogle Scholar
  44. 44.
    Carpentier I, Coonaert B, Beyaert R. Function and regulation of tumor necrosis factor type 2. Curr Med Chem. 2004;11:2205–12.PubMedGoogle Scholar
  45. 45.
    Dinarello CA. Interleukin-1 beta. Crit Care Med. 2005;33:S460–2.PubMedGoogle Scholar
  46. 46.
    Shalaby MR, Waage A, Espevik T. Cytokine regulation of interleukin 6 production by human endothelial cells. Cell Immunol. 1989;121:372–82.PubMedGoogle Scholar
  47. 47.
    Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest. 2000;117:1162–72.PubMedGoogle Scholar
  48. 48.
    Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW. Interleukin-6 (IL-6) as an anti-inflammatory cytokine. Induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood. 1994;83:113–8.PubMedGoogle Scholar
  49. 49.
    Lin E, Calvano SE, Lowry SF. Inflammatory cytokines and cell response in surgery. Surgery. 2000;127:117–26.PubMedGoogle Scholar
  50. 50.
    Xing Z, Gauldie J. Cox G IL6 is an anti-inflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest. 1998;101:311–20.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Jekarl DW, Lee SY, Park YJ, Kim Y, Park JH, Wee JH, Choi SP. Procalcitonin as a diagnostic marker and IL-6 as a prognostic marker for sepsis. Diagn Microbiol Infect Dis. 2013;75(4):342–7.PubMedGoogle Scholar
  52. 52.
    Takahashi W, Nakada TA, Yazaki M, Oda S. Interleukin-6 levels act as a diagnostic marker for infection and a prognostic marker in patients with organ dysfunction in the intensive care unit. Shock. 2016;46(3):254–60.PubMedGoogle Scholar
  53. 53.
    Inagaki T, Hoshino M, Hayakawa T, Ohara H, Yamada T, Yamada H, Lida M, Nakazawa T, Ogasawara T, Uchida A, Hasegawa C, Miyaji M, Takeuchi T. Interleukin 6 is a useful marker for early prediction of the severity of acute pancreatitis. Pancreas. 1997;14(1):1–8.PubMedGoogle Scholar
  54. 54.
    Keane MP, Strieter RM. Chemokine signaling in inflammation. Crit Care Med. 2000;28:N13–26.PubMedGoogle Scholar
  55. 55.
    Fosse E, Pillgram-Larsen J, Svennevig JL, Nordby C, Skulberg A, Mollnes TE, Abdelnoor M. Complement activation in injured patients occurs immediately and is dependent on the severity of the trauma. Injury. 1998;29(7):509–14.PubMedGoogle Scholar
  56. 56.
    Stahel PF, Morganti-Kossman MC, Kossmann T. The role of the complement system in traumatic brain injury. Brain Res Rev. 1998;27:243–56.PubMedGoogle Scholar
  57. 57.
    Buzdon MM, Napolitano LM, Shi HJ, Ceresoli DM, Rauniya R, Bass BL. Femur fracture induces site-specific changes in T-cells immunity. J Surg Res. 1999;82(2):201–8.PubMedGoogle Scholar
  58. 58.
    Weiser MR, William JP, Moore FD Jr, Kobzik L, Ma M, Hechtman HB, Carroll MC. Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J Exp Med. 1996;183(5):2343–8.PubMedGoogle Scholar
  59. 59.
    Zhang M, Alicot EM, Chiu I, Li J, Verna N, Vorup-Jensen T, Kessler B, Shimaoka M, Chan R, Friend D, Mahmood U, Weissleder R, Moore RD, Carrol MC. J Exp Med. 2006;203(1):141–52.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Bouvet Zouali M. Silent antibodies. Arch Inst Pasteur Tunis. 2005;83:3–8.Google Scholar
  61. 61.
    Carrol MC, Holers VM. Innate autoimmunity. Adv Immunol. 2005;86:137–57.Google Scholar
  62. 62.
    Fleming SD. Natural antibodies, autoantibodies and complement activation in tissue injury. Autoimmunity. 2006;39:379–86.PubMedGoogle Scholar
  63. 63.
    Stahel PF, Smith WR, Moore EE. Role of biological modifiers regulating the immune response after trauma. Injury. 2007;38:1409–22.PubMedGoogle Scholar
  64. 64.
    Schmidt OI, Infanger M, Heyde CE, Ertel W, Stahel PF. The role of neuroinflammation in traumatic brain injury. Eur J Trauma. 2004;30:135–49.Google Scholar
  65. 65.
    Sugimoto K, Hirata M, Majima M, Katori M, Ohwada T. Evidence for a role of kallikrein-kinin system in patients with shock after blunt trauma. Am J Physiol. 1998;274:1556–60.Google Scholar
  66. 66.
    Van Gils JM, Zwaginga JJ, Hordijk PL. Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J Leukoc Biol. 2009;85:195–204.PubMedGoogle Scholar
  67. 67.
    Jenne CN, Urrutia R, Kubes P. Platelets: bridging hemostasis, inflammation and immunity. Int J Lab Hematol. 2013;35:254–61.PubMedGoogle Scholar
  68. 68.
    Abraham E. Coagulation abnormalities in acute lung injury and sepsis. Am J Respir Cell Mol Biol. 2000;22:401–4.PubMedGoogle Scholar
  69. 69.
    Fan J, Kapus A, Li YH, Rizoli S, Marshall JC, Rotstein OD. Priming for enhanced alveolar fibrin deposition after hemorrhagic shock: role for tumor necrosis factor. Am J Respir Cell Mol Biol. 2000;22(4):412–21.PubMedGoogle Scholar
  70. 70.
    Levi M, de Jonge E, Van der Poll T. New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology. Ann Med. 2004;36:41–9.PubMedGoogle Scholar
  71. 71.
    Gando S, Kameue T, Matsuda N, Sawamura A, Hayakawa M, Kato H. Systemic inflammation and disseminated intravascular coagulation in early stage of ALI and ARDS: role of neutrophil and endothelial activation. Inflammation. 2004;28(4):237–44.PubMedGoogle Scholar
  72. 72.
    Lo EH, Wang X, Cuzner ML. Extracellular proteolysis in brain injury and inflammation: role for plasminogen activators and matrix metalloproteinases. J Neurosci Res. 2002;69:1–9.PubMedGoogle Scholar
  73. 73.
    Whicher JT, Westacott CI. The acute phase response. In: Whicher JT, Evans SW, editors. Biochemistry of inflammation. London: Kluwer Academic; 1992. p. 243–71.Google Scholar
  74. 74.
    Du Clos TW. Function of C-reactive protein. Ann Med. 2000;32:274–8.PubMedGoogle Scholar
  75. 75.
    Zweigner J, Gramm HJ, Singer OC, Wegscheider K, Schumann RR. High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes. Blood. 2001;98(13):3800–8.PubMedGoogle Scholar
  76. 76.
    Fujishima S, Aikawa N. Neutrophil-mediated tissue injury and its modulation. Intensive Care Med. 1995;21:277–85.PubMedGoogle Scholar
  77. 77.
    Laroux FS, Pavlick KP, Hines IN, Kawachi S, Harada H, Bharwani S, Hoffman JM, Grisham MB. Role of nitric oxide in inflammation. Acta Physiol Scand. 2001;173(1):113–8.PubMedGoogle Scholar
  78. 78.
    Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1 and Th2 and more. Immunol Today. 1996;17:138–46.PubMedGoogle Scholar
  79. 79.
    Blanchette J, Jaramillo M, Olivier M. Signalling events involved in interferon-gamma-inducible macrophage nitric oxide generation. Immunology. 2003;108(4):513–22.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Kelso A. Th1 and Th2 subsets: paradigms lost? Immunol Today. 1995;16:374–9.PubMedGoogle Scholar
  81. 81.
    Monneret G, Debard AL, Venet F, Bohe J, Hequet O, Bienvenu J, Lepape A. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis induced immunoparalysis. Crit Care Med. 2006;34:2561–6.Google Scholar
  82. 82.
    Venet F, Pachot A, Debard AL, Bienvenu J, Lepape A, Powell WS, Monneret G. Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol. 2006;177(9):6540–7.PubMedGoogle Scholar
  83. 83.
    Romani L. Immunity to fungal infections. Nat Rev Immunol. 2011;11:275–88.PubMedGoogle Scholar
  84. 84.
    Blaschitz C, Raffatellu M. Th17 cytokines and the gut mucosal barrier. J Clin Immunol. 2010;30(2):196–203.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Van de Veerdonk FL, Mouktaroudi M, Ramakers BP, Pistiki A, Pickkers P, van der Meer JWM, Netea MG, Giammarellos-Bourboulis EJG. Deficient candida-specific T-helper 17 response during sepsis. J Infect Dis. 2012;206:1798–802.PubMedGoogle Scholar
  86. 86.
    Pachot A, Monneret G, Voirin N, Leissner P, Venet F, Bohé J, Payen D, Bienvenu J, Mougin B, Lepape A. Longitudinal study of cytokine and immune transcription factor mRNA expression in septic shock. Clin Immunol. 2005;114(1):61–9.PubMedGoogle Scholar
  87. 87.
    Tschoeke SK, Ertel W. Immunoparalysis after multiple trauma. Injury. 2007;38:1346–57.PubMedGoogle Scholar
  88. 88.
    Rossato M, Curtale G, Tamassia N, Castellucci M, Mori L, Gasperini S, Mariotti B, De Luca MC, Mirolo M, Cassatella MA, Locati M, Bazzoni F. IL-10-induced micro-RNA-187 negatively regulates TNF-alpha, IL-6 and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci U S A. 2012;109:E3101–10.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Monneret G, Lepape A, Voirin N, Bohé G, Venet F, Debard AL, Thizy H, Bienvenu J, Gueyffier F, Vanhems P. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med. 2006;32:1175–83.PubMedGoogle Scholar
  90. 90.
    Schouten M, Wiersinga WJ, Levi M, van der Poll T. Inflammation endothelium and coagulation in sepsis. J Leukoc Biol. 2008;83(3):536–45.PubMedGoogle Scholar
  91. 91.
    Bajaj MS, Tricomi SM. Plasma levels of the three endothelial-specific proteins von Willebrand factor, tissue factor pathway inhibitor, and thrombomodulin do not predict the development of acute respiratory distress syndrome. Intensive Care Med. 1999;25:1259–66.PubMedGoogle Scholar
  92. 92.
    Kayal S, Jais JP, Aguini N, Chaudiere J, Labrousse J. Elevated circulating E-selectin, intercellular adhesion molecule 1, and von Willebrand factor in patients with severe infection. Am J Respir Crit Care Med. 1998;157:776–84.PubMedGoogle Scholar
  93. 93.
    Leclerc J, Pu Q, Corseaux D, Haddad E, Decoene C, Bordet R, Six I, Jude B, Vallet B. A single endotoxin injection in the rabbit causes prolonged blood vessel dysfunction and a procoagulant state. Crit Care Med. 2000;28:3672–8.PubMedGoogle Scholar
  94. 94.
    Wiel E, Vallet B. Vascular endothelial cell dysfunction in septic shock. Crit Care Med. 2001;29(Suppl):S36–41.PubMedGoogle Scholar
  95. 95.
    Bombeli T, Mueller M, Haeberli A. Anticoagulant properties of the vascular endothelium. Thromb Haemost. 1997;77:408–23.PubMedGoogle Scholar
  96. 96.
    Rapaport S, Rao L. Initiation and regulation of tissue factor-dependent blood coagulation. Arterioscler Thromb. 1992;12:1111–21.PubMedGoogle Scholar
  97. 97.
    Ott I, Miyagi Y, Miyazaki K, Heeb MJ, Mueller BM, Rao LV, Ruf W. Reversible regulation of tissue factor-induced coagulation by glycosyl phosphatidylinositol-anchored tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol. 2000;20(3):874–82.PubMedGoogle Scholar
  98. 98.
    Monroe DM, Key NS. The tissue factor-factor VIIa complex: procoagulant activity, regulation, and multitasking. J Thromb Haemost. 2007;5:1097–105.PubMedGoogle Scholar
  99. 99.
    Esmon CT. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med. 2001;29:S48–51.PubMedGoogle Scholar
  100. 100.
    Binder BR, Christ G, Gruber F, Grubic N, Hufnagl P, Krebs M, Mihaly J, Prager GW. Plasminogen activator inhibitor 1: physiological and pathophysiological roles. News Physiol Sci. 2002;17(2):56–61.PubMedGoogle Scholar
  101. 101.
    Regoeczi E, Brain MC. Organ distribution of fibrin in disseminated intravascular coagulation. Br J Haematol. 1969;17:73–81.PubMedGoogle Scholar
  102. 102.
    Carr C, Bild GS, Chang AC. Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock. Circ Shock. 1994;44:126–37.PubMedGoogle Scholar
  103. 103.
    Camerota AJ, Creasey AA, Patla V, Larkin VA, Fink MP. Delayed treatment with recombinant human tissue factor pathway inhibitor improves survival in rabbit gram-negative peritonitis. J Infect Dis. 1998;177:668–76.PubMedGoogle Scholar
  104. 104.
    Springer T. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol. 1995;57:827–72.Google Scholar
  105. 105.
    Varani J, Ward P. Mechanisms of endothelial cell injury in acute inflammation. Shock. 1994;2:311–9.PubMedGoogle Scholar
  106. 106.
    Doerschuk CM. Leukocyte trafficking in alveoli and airway passage. Respir Res. 2000;1:136–40.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Levi M, van der Poll T. Endothelial injury in sepsis. Intensive Care Med. 2013;39:1839–42.PubMedGoogle Scholar
  108. 108.
    Riewald M, Ruf W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc Natl Acad Sci U S A. 2001;98:7742–7.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002;296:1880–2.PubMedGoogle Scholar
  110. 110.
    Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibucki K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996;273:245–8.PubMedGoogle Scholar
  111. 111.
    Bhagat K, Moss R, Collier J, Vallance P. Endothelial “stunning” following a brief exposure to endotoxin: a mechanism to link infection and infarction? Cardiovasc Res. 1996;32:822–9.PubMedGoogle Scholar
  112. 112.
    Sandow SL, Hill CE. Incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in endothelium-derived hyperpolarizing factor-mediated response. Circ Res. 2000;86:341–6.PubMedGoogle Scholar
  113. 113.
    Emerson GG, Segal SS. Endothelial cell pathway for conduction of hyperpolarization and vasodilation along hamster feed artery. Circ Res. 2000;86:94–100.PubMedGoogle Scholar
  114. 114.
    Segal SS. Microvascular recruitment in hamster striated muscle: role for conducted vasodilation. Am J Physiol. 1991;261:H180–9.Google Scholar
  115. 115.
    Pinsky MR. Regional blood flow distribution. In: Pinsky MR, Dhainaut JF, Artigas A, editors. The splanchnic circulation: no longer a silent partner. Berlin: Springer; 1995. p. 1–13.Google Scholar
  116. 116.
    Nelson DP, Samsel RW, Wood LDH, Schumacker PT. Pathological supply dependence of systemic and intestinal O2 uptake and endotoxemia. J Appl Physiol. 1988;64:2410–9.PubMedGoogle Scholar
  117. 117.
    Lam C, Tyml K, Martin C, Sibbald W. Microvascular perfusion is impaired in a rat model of normotensive sepsis. J Clin Invest. 1994;94(5):2077–83.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Humer MF, Phang PT, Friesen BP, Allard MF, Goddard CM, Walley KR. Heterogeneity of gut capillary transit times and impaired gut oxygen extraction in endotoxemic pigs. J Appl Physiol. 1996;81:895–904.PubMedGoogle Scholar
  119. 119.
    Elis CG, Bateman RM, sharpe MD, Sibbald WJ, Gill R. Effect of a maldistribution of microvascular blood flow on capillary O2 extraction in sepsis. Am J Physiol Heart Circ Physiol. 2002;282:H156–64.Google Scholar
  120. 120.
    Eigenbrod T, Park JH, Harder J, Iwakura Y, Nunez G. Cutting edge: critical role of mesothelial cells in necrosis-induced inflammation through the recognition of IL-1 alpha released from dying cells. J Immunol. 2008;181:8194–8.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117:3720–32.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Koppelman B, Neefjes JJ, de Vries JE, de Waal Malefyt R. Interleukin-10 down regulates MHC class II alphabeta peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity. 1997;7:861–71.PubMedGoogle Scholar
  123. 123.
    Giannoudis PV, Smith RM, Perry SL, Windsor AJ, Dickson RA, Bellamy MC. Immediate IL-10 expression following major orthopaedic trauma. Relationship to anti-inflammatory response and subsequent development of sepsis. Intensive Care Med. 2000;26:1076–81.PubMedGoogle Scholar
  124. 124.
    Galbraith N, Walker S, Galandiuk S, Gardner S, Polk HC Jr. The significance and challenges of monocyte impairment: for the patient and the surgeon. Surg Infect. 2016;17:303–12.Google Scholar
  125. 125.
    Hotchkiss RS, Tinsley KW, Swanson PE, Grayson MH, Osborne D, Wagner TH, Cobb JP, Coppersmith C, Karl IE. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol. 2002;168:2493–500.PubMedGoogle Scholar
  126. 126.
    Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A. Leukocyte apoptosis and its significance in sepsis and septic shock. J Leukoc Biol. 2005;78:325–37.PubMedGoogle Scholar
  127. 127.
    Delogu G, Moretti S, Antonucci A. Apoptosis and surgical trauma: dysregulated expression of death and survival factors on peripheral lymphocytes. Arch Surg. 2000;135:1141–7.PubMedGoogle Scholar
  128. 128.
    Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–19.PubMedGoogle Scholar
  129. 129.
    Zimmermann KC, Green DR. How cells die: apoptosis pathways. J Allergy Clin Immunol. 2001;108:S99–S103.PubMedGoogle Scholar
  130. 130.
    Pop C, Salvesen GS. Human caspases: activation, specificity, and regulation. J Biol Chem. 2009;284:21777–81.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Pinheiro da Silva F, Nizet V. Cell death during sepsis: integration of disintegration in the inflammatory response to overwhelming infection. Apoptosis. 2009;14:509–21.PubMedGoogle Scholar
  132. 132.
    Melino G. The sirens’ song. Nature. 2001;412:23.PubMedGoogle Scholar
  133. 133.
    Jimenez MF, Watson RW, Parodo J, Evans D, Foster D, Steinberg M, Rotstein OD, Marshall JC. Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome. Arch Surg. 1997;132:1263–70.PubMedGoogle Scholar
  134. 134.
    Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matischak GM, Buchman TG, Karl IE. Apoptotic cell death in patients with sepsis, shock and multiple organ dysfunction. Crit Care Med. 1999;27:1230–51.PubMedGoogle Scholar
  135. 135.
    Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo J. Prolonged lymphopenia, lymphoid depletion and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol. 2005;174:3765–72.PubMedGoogle Scholar
  136. 136.
    Hotchkiss RS, Schmieg RE Jr, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Karl IE, Buchman TG. Rapid onset of intestinal epithelial and lymphocyte apoptotic cell death in patient with trauma and shock. Crit Care Med. 2000;28:3207–17.PubMedGoogle Scholar
  137. 137.
    Fink MP, Evans TW. Mechanisms of organ dysfunction in critical illness: report from a round table conference held in Brussels. Intensive Care Med. 2002;28:369–75.PubMedGoogle Scholar
  138. 138.
    Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med. 2007;35:2408–16.PubMedGoogle Scholar
  139. 139.
    Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–74.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Meakins JL, Pietsch JB, Bubenick O, Kelly R, Rode H, Gordon J, MacLean LD. Delayed hypersensitivity: indicator of acquired failure of host defenses in sepsis and trauma. Ann Surg. 1977;186:241–50.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Luyt CE, Combes A, Deback C, Aubriot-Lorton MH, Nieszkkowska A, Trouillet JL, Capron F, Agut H, Gilbert C, Chastre J. Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care Med. 2007;175(9):935–42.PubMedGoogle Scholar
  142. 142.
    Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, Gibran NS, Huang ML, Santo Hayes TK, Corey L, Boeckh M. Cytomegalovirus reactivation in critically immunocompetent patients. JAMA. 2008;300:413–22.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Otto GP, Sossdorf M, Claus RA, Rodel J, Menge K, Reinhardt K, Bauer M, Riedemann NC. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Crit Care. 2011;15(4):R183.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Kollef KE, Schramm GE, Wills AR, Reichley RM, Micek ST, Kollef MH. Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria. Chest. 2008;134:281–7.PubMedGoogle Scholar
  145. 145.
    Cavaillon M, Adib-Conquy M. Bench to bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit Care. 2006;10:233. Scholar
  146. 146.
    Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30:475–87.Google Scholar
  147. 147.
    Zhang X, Morrison DC. Lipopolysaccharide structure-function relationship in activation versus reprogramming of mouse peritoneal macrophages. J Leukoc Biol. 1993;54:444–50.PubMedGoogle Scholar
  148. 148.
    Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD II, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306:2594–605.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Morre M, Beq S. Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival. Target Oncol. 2012;7:55–68.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Levy Y, Sereti I, Tambussi G, Routy JP, Leliévre JD, Delfraissy JF, Molina JM, Fischl M, Goujard C, Rodriguez B, Rouzioux C, Avettand-Fenoel V, Croughs T, Beq S, Morre M, Poulin JF, Sekaly RP, Thiebaut R, Lederman MM. Effects of recombinant human interleukin-7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: result of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis. 2012;55:291–300.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Hotchkiss RS, Swanson PE, Knudson CM, Chang KC, Cobb JP, Osborne DF, Zollner KM, Buchman TG, Korsemeyer SJ, Karl IE. Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol. 1999;162:4148–56.PubMedGoogle Scholar
  152. 152.
    Venet F, Foray AP, Villars-Mechin A, Malcus C, Poitevin-Later F, Lepape A, Monneret G. IL-7 restores lymphocyte function in septic patients. J Immunol. 2012;189:5073–81.PubMedGoogle Scholar
  153. 153.
    Usinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, McDonough JS, Tschoep J, Ferguson TA, McDunn JE, Morre M, Hildeman DA, Caldwell CC, Hotchkiss RS. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010;184:3768–79.Google Scholar
  154. 154.
    Cheadle WG, Pemberton RM, Robinson D, Livingstone DH, Rodriguez JL, Polk HC Jr. Lymphocyte subset responses to trauma and sepsis. J Trauma. 1993;35:844–9.PubMedGoogle Scholar
  155. 155.
    Gouel-Cheron A, Venet F, Allaouchiche B, Monneret G. CD4+ T-lymphocyte alterations in trauma patients. Crit Care. 2012;16:432.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Le Tulzo Y, Pangault C, Gacouin A, Guilloux V, Tribut O, Amiot L, Tattevin P, Thomas R, Fauchet R, Drenou B. Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock. 2002;18:487–94.PubMedGoogle Scholar
  157. 157.
    Venet F, Davin F, Guignant C, Larue A, Cazalis MA, Darbon R, Allombert C, Mougin B, Malcus C, Poitevin-Later F, Lepape A. Early assessment of leukocyte alterations at diagnosis of septic shock. Shock. 2010;34(4):358–63.PubMedGoogle Scholar
  158. 158.
    Monneret G, Venet F, Kullberg BJ, Netea MG. ICU-acquired immunosuppression and the risk for secondary fungal infections. Med Mycol. 2011;49(Suppl 1):S17–23.PubMedGoogle Scholar
  159. 159.
    Venet F, Chung CS, Monneret G, Huang X, Horner B, Garber M, Ayala A. Regulatory T cell populations in sepsis and trauma. J Leukoc Biol. 2008;83(3):523–35.PubMedGoogle Scholar
  160. 160.
    Leng FY, Liu JL, Liu ZJ, Qu HP. Increased proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells during the early-stage sepsis in ICU patients. J Microbiol Immunol Infect. 2013;46(5):338–44.PubMedGoogle Scholar
  161. 161.
    Delano MJ, Scumpia PO, Weinstein JS, Coco, Nagaraj S, Kelly-Scumpia KM, O’Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, Ramphal R, Gabrilovich DJ, Reeves W, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL. J Exp Med. 2007;204(6):1463–74.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Drifte G, Dunn-Siegrist I, Tissieres P, Pugin J. Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome. Crit Care Med. 2013;41:820–32.PubMedGoogle Scholar
  163. 163.
    Alves-Filho JC, Spiller F, Cunha FQ. Neutrophil paralysis in sepsis. Shock. 2010;34(Suppl 1):15–21.PubMedGoogle Scholar
  164. 164.
    Kovach MA, Standiford TJ. The function of neutrophils in sepsis. Curr Opin Infect Dis. 2012;25:321–7.PubMedGoogle Scholar
  165. 165.
    Cummings CJ, Martin TR, Frevert CW, Quan JM, Wong VA, Mongovin SM, Hagen TR, Steinberg KP, Goodman RB. Expression and function of the chemokine receptor CXCR1 and CXCR2 in sepsis. J Immunol. 1999;162(4):2341–6.PubMedGoogle Scholar
  166. 166.
    Kasten KR, Muenzer JT, Caldwell CC. Neutrophils are significant producers of IL-10 during sepsis. Biochem Biophys Res Commun. 2010;393:28–31.PubMedPubMedCentralGoogle Scholar
  167. 167.
    Pillay J, Kamp VM, van Hoffen E, Visser T, Tak T, Lammers JW, Ulfman LH, Leenen LP, Pickkers P, Koenderman L. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest. 2012;122:327–36.PubMedGoogle Scholar
  168. 168.
    Makarenkova VP, Bansal V, Matta BM, Perez LA, Ochoa JB. CD11+/Gr-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol. 2006;176(4):2085–94.PubMedGoogle Scholar
  169. 169.
    Souza-Fonseca-Guimaraes F, Parlato M, Phillipart F, Misset B, Cavaillon JM, Adib-Conquy M. Captain study group. Toll-like receptors expression and interferon-gamma production by NK cells in human sepsis. Crit Care. 2012;16:R206.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Andreu-Ballester JC, Tormo-Calandin C, Garcia-Ballestreros C, Perez-Griera J, Amigò V, Almela-Quilis A, Ruiz del Castillo J, Penarroja-Otero C, Ballester. Association of ϒδ Tcells with disease severity and mortality in septic patients. Clin Vaccine Immunol. 2013;20(5):738–46.PubMedPubMedCentralGoogle Scholar
  171. 171.
    Singer PM, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet. 2004;364:545–8.PubMedGoogle Scholar
  172. 172.
    Mizock BA. The multiple organ dysfunction syndrome. Dis Mon. 2009;55:476–526.PubMedGoogle Scholar
  173. 173.
    Moore FA, Moore EE. Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am. 1995;75:257–77.PubMedGoogle Scholar
  174. 174.
    MacFie J. Current status of bacterial translocation as a cause of surgical sepsis. Br Med Bull. 2004;71:1–11.PubMedGoogle Scholar
  175. 175.
    Umegaki T, Ikai H, Imanaka Y. The impact of acute organ dysfunction on patients’ mortality with severe sepsis. J Anaesthesiol Clin Pharmacol. 2011;27:180–4.PubMedPubMedCentralGoogle Scholar
  176. 176.
    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.Google Scholar
  177. 177.
    Danai PA, Moss M, Mannino DM, Martin GS. The epidemiology of sepsis in patients with malignancy. Chest. 2006;129(6):1432–40.PubMedGoogle Scholar
  178. 178.
    Esper AM, Moss M, Lewis CA, Nisbet R, Mannino DM, Martin GS. The role of infections and comorbidity. Factors that influence disparities in sepsis. Crit Care Med. 2006;34(10):2576–82.PubMedPubMedCentralGoogle Scholar
  179. 179.
    Angus DC. The lingering consequences of sepsis: the hidden public health disaster? JAMA. 2010;304:1833–4.PubMedGoogle Scholar
  180. 180.
    Chavan SS, Huerta PT, Robbiati S, Valdes-Ferrer SI, Ochani M, Dancho M, Frankfurt M, Volpe BT, Tracey KJ, Diamond B. HMGB1 mediates cognitive impairment in sepsis survivors. Mol Med. 2012;18:930–7.PubMedPubMedCentralGoogle Scholar
  181. 181.
    Rothwell NJ, Hopkins SJ. Cytokines and the nervous system II: actions and mechanisms of action. Trends Neurosci. 1995;18:130–6.PubMedGoogle Scholar
  182. 182.
    Terrando N, Eriksson LI, Ryu JK, Yang T, Monaco C, Felmann M, Jonssson Fagerlund M, Charo IF, Akassoglou K, Maze M. Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol. 2011;70:986–95.PubMedPubMedCentralGoogle Scholar
  183. 183.
    Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D, Chretien F, Sharshar T. Understanding brain dysfunction in sepsis. Ann Intensive Care. 2013;3:1–11.Google Scholar
  184. 184.
    Lamar CD, Hurley RA, Taber KH. Sepsis-associated encephalopathy: review of neuropsychiatric manifestations and cognitive outcome. J Neuropsychiatry Clin Neurosci. 2011;23:237–41.PubMedGoogle Scholar
  185. 185.
    Sharshar T, Annane D, de la Grandmaison GL, Brouland GP, Hopkinson NS, Francoise G. The neuropathology of septic shock. Brain Pathol. 2004;14:21–33.PubMedGoogle Scholar
  186. 186.
    Sprung CL, Peduzzi PN, Shatney CH, Schein RM, Wilson ME, Sheagren JN, Hinshaw LB. Impact of encephalopathy on mortality in the sepsis syndrome. The veterans Administration Systemic Sepsis Cooperative Study Groups. Crit Care Med. 1990;18(8):801–6.PubMedGoogle Scholar
  187. 187.
    ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307(23):2526–33.Google Scholar
  188. 188.
    Pelosi P, Caironi P, Gattinoni L. Pulmonary and extrapulmonary forms of acute respiratory distress syndrome. Semin Respir Crit Care Med. 2001;22:259–68.PubMedGoogle Scholar
  189. 189.
    Blank M, Napolitano LM. Epidemiology of ARDS and ALI. Crit Care Clin. 2011;27:439–58.PubMedGoogle Scholar
  190. 190.
    Woolf N. Chapter 33: Pulmonary edema (including respiratory distress syndrome). In: Pathology: basic and systemic. London: WB Saunders Ed; 1998. p. 446–51.Google Scholar
  191. 191.
    Muller NL, Frase RS, Colman NC, Paré PD. Chapter 14: Pulmonary edema. In: Radiologic diagnosis of diseases of the chest. London: WB Saunders Ed; 2001. p. 432–51.Google Scholar
  192. 192.
    Agarwal R, Srinivas R, Nath A. Is the mortality higher in the pulmonary vs the extrapulmonary ARDS? A meta-analysis. Chest. 2008;133:1463–73.PubMedGoogle Scholar
  193. 193.
    The Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–8.Google Scholar
  194. 194.
    Rohde JM, Odden AJ, Bonham C, Kuhn L, Malani P, Flanders S, Iwashyna TJ, Chen LM. The epidemiology of acute organ system dysfunction from severe sepsis outside the intensive care unit. J Hosp Med. 2013;8:243–7.PubMedPubMedCentralGoogle Scholar
  195. 195.
    Ogura H, Gando S, Saitoh D, Takeyama N, Kushimoto S, Fujishima S, Mayumi T, Araki T, Ikeda H, Kotani J, Miki Y, Shiraishi S, Suzuki K, Suzuki Y, Takuma K, Tsuruta R, Yamaguchi Y, Yamashita N, Aikawa N. Epidemiology of severe sepsis in Japanese intensive care units: a prospective multicenter study. J Infect Chemother. 2014;20(3):157–62.PubMedGoogle Scholar
  196. 196.
    Guidet B, Aegerter P, Gauzit R, Meshaka P, Dreyfuss D, CUB-Réa Study Group. Incidence and impact of organ dysfunctions associated with sepsis. Chest. 2005;127:942–51.PubMedGoogle Scholar
  197. 197.
    Kumar A, Haery C, Parrillo JE. Myocardial dysfunction in septic shock: part 1. Clinical manifestation of cardiovascular dysfunction. J Cardiothorac Vasc Anesth. 2001;15(3):364–76.PubMedGoogle Scholar
  198. 198.
    Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med. 1984;100(4):483–90.PubMedGoogle Scholar
  199. 199.
    Hassoun SM, Marechal X, Montaigne D, Bouazza Y, Decoster B, Lancel S, Neviere R. Prevention of endotoxin-induced sarcoplasmic reticulum calcium leak improves mitochondrial and myocardial dysfunction. Crit Care Med. 2008;36:2590–6.PubMedGoogle Scholar
  200. 200.
    Kao YH, Chen YC, Cheng CC, Lee TI, Chen YJ, Chen SA. Tumor necrosis factor-alpha decreases sarcoplasmic reticulum Ca2+-ATPase expressions via the promoter methylation in cardiomyocytes. Crit Care Med. 2009;38(1):217–22.Google Scholar
  201. 201.
    Stein B, Frank P, Schmitz W, Scholz H, Thoenes M. Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J Mol Cell Cardiol. 1996;28(8):1631–9.PubMedGoogle Scholar
  202. 202.
    MacLean LD, Mulligan WG, McLean APH, Duff JH. Patterns of septic shock in man: a detailed study of 56 patients. Ann Surg. 1967;166:543–62.PubMedPubMedCentralGoogle Scholar
  203. 203.
    Waisbren BA. Bacteremia due to gram-negative bacilli other than the Salmonella: a clinical and therapeutic study. Arch Intern Med. 1951;88(4):467–88.Google Scholar
  204. 204.
    Parker MM, McCarthy KE, Ognibene FP. Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest. 1990;97:126–31.PubMedGoogle Scholar
  205. 205.
    Granger DN, Kvietys PR, Korthuis RJ. Microcirculation of the intestinal mucosa. In: Wood JD, editor. Handbook of physiology section 6. The gastrointestinal system vol. 1: motility and circulation. Part II. American Physiological Society; 1989. p. 1405–74.Google Scholar
  206. 206.
    Granger HJ. Autoregulation of tissue perfusion and oxygenation. In: Kamada T, Shiga T, McCuskey RS, editors. Tissue perfusion and organ function: ischemia/reperfusion injury. Amsterdam: Elsevier-Science; 1996. p. 29–45.Google Scholar
  207. 207.
    Matta BF, Stow PJ. Sepsis-induced vasoparalysis does not involve the cerebral vasculature: indirect evidence from autoregulation and carbon dioxide reactivity studies. Br J Anaesth. 1996;76:790–4.PubMedGoogle Scholar
  208. 208.
    Parker JL, Emerson TE Jr. Cerebral hemodynamics vascular reactivity and metabolism during canine endotoxin shock. Circ Shock. 1977;4:41–53.PubMedGoogle Scholar
  209. 209.
    McCormack DG. Control of vascular reactivity. New Horiz. 1995;3:248–56.PubMedGoogle Scholar
  210. 210.
    Scott JA, Machoun M, McCormack DG. Inducible nitric oxide synthase and vascular reactivity in rat thoracic aorta: effect of aminoguanidine. J Appl Physiol. 1996;80:271–7.PubMedGoogle Scholar
  211. 211.
    el-Dwairi Q, Comtois A, Guo Y, Hussain SN. Endotoxin induced skeletal muscle contractile dysfunction: contribution of nitric oxide synthases. Am J Physiol. 1998;274:C770–9.PubMedGoogle Scholar
  212. 212.
    Goddard CM, Poon BY, Khu ME, Wiggs BR, VanEden SF, Hogg JC. KR. Leukocyte activation does not mediate myocardial leukocyte retention during endotoxemia in rabbits. Am J Physiol. 1998;275:H1548–57.PubMedGoogle Scholar
  213. 213.
    Sutton ET, Norman JC, Newton CA, Hellermann GR, Richard IS. Endothelial structural integrity is maintained during endotoxic shock in an interleukin-1 type 1 receptor knockout mouse. Shock. 1997;7:105–10.PubMedGoogle Scholar
  214. 214.
    Tyml K, Yu J, McCormack DG. Capillary and arteriolar responses to local vasodilators are impaired in a rat model of sepsis. J Appl Physiol. 1998;84:837–44.PubMedGoogle Scholar
  215. 215.
    Vallet B. Vascular reactivity and tissue oxygenation. Intensive Care Med. 1998;24:3–11.PubMedGoogle Scholar
  216. 216.
    Lang CH, Bagby GJ, Ferguson JL, Spitzer JJ. Cardiac output and redistribution of organ blood flow in hypermetabolic sepsis. Am J Physiol. 1984;246:R331–7.PubMedPubMedCentralGoogle Scholar
  217. 217.
    Mann KG, Van’t Veer C, Cawthern K, Butenas S. The role of the tissue factor pathway in initiation of coagulation. Blood Coagul Fibrinolysis. 1998;9(Suppl):S3–7.PubMedGoogle Scholar
  218. 218.
    Ruf W, Edgington TS. Structural biology of tissue factor, the initiator of thrombogenesis in vivo. FASEB J. 1994;8:385–90.PubMedGoogle Scholar
  219. 219.
    Camerer E, Kolsto AB, Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation. Thromb Res. 1996;81:1–41.PubMedGoogle Scholar
  220. 220.
    Nieuwland R, Berckmans RJ, McGregor S, Boing AN, Romijn FP, Westendorp RG, Hack CE, Sturk A. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood. 2000;83:861–7.Google Scholar
  221. 221.
    Bockmeyer CL, Claus RA, Budde U. Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Hematologica. 2008;93:137–40.Google Scholar
  222. 222.
    Osterud B. Tissue factor expression by monocytes: regulation and pathophysiological roles. Blood Coagul Fibrinolysis. 1998;9(Suppl):S9–S14.PubMedGoogle Scholar
  223. 223.
    Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med. 2010;38(2 Suppl):S35–42.PubMedGoogle Scholar
  224. 224.
    Dhainault JF, Jan SB, Joyce DE, Pettila V, Basson BR, Brandt JT, Sundin D, Levi M. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost. 2004;2:1924–33.Google Scholar
  225. 225.
    Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan. Bibl Haematol. 1983;49:265–75.Google Scholar
  226. 226.
    Taylor FB, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. On behalf of the Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society of Thrombosis and Haemostasis (ISTH). Thromb Haemost. 2001;86:1327–30.PubMedGoogle Scholar
  227. 227.
    Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, Mayumi T, Murata A, Ikeda T, Ishikura H, Ueyama M, Ogura H, Kushimoto S, Saitoh D, Endo S, Shimazaki A. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med. 2006;34:625–31.PubMedGoogle Scholar
  228. 228.
    Takemitsu T, Wada H, Hatada T, Ohmori Y, Ishikura K, Takeda T, Sugiyama T, Yamada N, Maruyama K, Katayama N, Isaji S, Shimpo H, Kusunoki M, Nobori T. Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation. Thromb Haemost. 2011;105:40–4.PubMedGoogle Scholar
  229. 229.
    Aird WC. The hematologic system as a marker of organ dysfunction in sepsis. Mayo Clin Proc. 2003;78:869–81.PubMedGoogle Scholar
  230. 230.
    Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A, Mercier JC, Offenstadt G, Régnier B. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults: a multicenter prospective study in intensive care unit. French ICU group for Severe Sepsis. JAMA. 1995;274:968–74.PubMedGoogle Scholar
  231. 231.
    Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopolou-Kokkinou V, Zakynthinos S. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med. 2000;28(2):451–7.PubMedGoogle Scholar
  232. 232.
    Parmar A, Langerberg C, Wan L, May CN, Bellomo R, Bagshaw SM. Epidemiology of sepsis acute kidney injury. Curr Drug Targets. 2009;10:1169–78.PubMedGoogle Scholar
  233. 233.
    Thakar CV, Christianson A, Freyberg R, Almenoff P, Render ML. Incidence and outcomes of acute kidney injury in intensive care units: a Veterans Administration Study. Crit Care Med. 2009;37(9):2252–8.Google Scholar
  234. 234.
    Hoste EA, Kellum JA. Incidence classification and outcomes of acute kidney injury. Contrib Nephrol. 2007;156:32–8.PubMedGoogle Scholar
  235. 235.
    Kellum JA, Levin N, Bouman C, Lameire N. Developing a consensus classification system for acute renal failure. Curr Opin Crit Care. 2002;8:509–14.PubMedGoogle Scholar
  236. 236.
    Bellomo R, Ronco C, Kellum JA, Metha RL, Palevsky P. Acute Dialysis Quality Initiative workgroup: acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–12.PubMedPubMedCentralGoogle Scholar
  237. 237.
    Langenberg C, Bagshaw SM, May CM, Bellomo R. The histopathology of septic acute kidney injury: a systematic review. Crit Care. 2008;12(2):R38.PubMedPubMedCentralGoogle Scholar
  238. 238.
    Messmer UK, Winkel G, Briner VA, Pfeilschifter J. Glucocorticoids potently block tumor necrosis factor-alpha and lipopolysaccharide-induced apoptotic cell death in bovine glomerular endothelial cells upstream of caspase 3 activation. Br J Pharmacol. 1999;127:1633–40.PubMedPubMedCentralGoogle Scholar
  239. 239.
    Langenberg C, Wan L, Egi M, May CN, Bellomo R. Renal blood flow distribution in experimental septic acute renal failure. Kidney Int. 2006;69:1996–2002.PubMedGoogle Scholar
  240. 240.
    Wan L, Bagshaw SM, Langenberg C, Saotome T, May C, Bellomo R. Pathophysiology of septic acute kidney injury: what do we really know? Crit Care Med. 2008;36(4 Suppl):S198–203.PubMedGoogle Scholar
  241. 241.
    Wan L, Langenberg C, Bellomo R, May CN. Angiotensin II in experimental hyperdynamic sepsis. Crit Care. 2009;13:R190.PubMedPubMedCentralGoogle Scholar
  242. 242.
    Baud L, Oudinet JP, Bens M, Noe L, Peraldi MN, Rondeau E, Etienne J, Ardaillou R. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989;35(5):1111–8.PubMedGoogle Scholar
  243. 243.
    Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C. Beginning and Ending Supportive Therapy for the kidney (BEST Kidney). Acute renal failure in critically ill patients: a multinational multicenter study. JAMA. 2005;294:813–8.PubMedPubMedCentralGoogle Scholar
  244. 244.
    Bagshaw SM, Lapinsky S, Dial S, Arabi Y, Dodek P, Wood G, Ellis P, Guzman J, Marshall J, Parrillo JE, Skrobik Y, Kumar A. Cooperative Antimicrobial Therapy of Sepstic Shock (CATSS) Database Research Group. Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy. Intensive Care Med. 2009;35:871–81.PubMedGoogle Scholar
  245. 245.
    Podoll AS, Kozar R, Holcomb JB, Finkel KW. Incidence and outcome of early acute kidney injury in critically ill trauma patients. PLoS One. 2013;8:1–5.Google Scholar
  246. 246.
    Ulkeja A. Altered gastrointestinal motility in critically ill patients: current understanding of pathophysiology, clinical impact, and diagnostic approach. Nutr Clin Pract. 2010;25:16–25.Google Scholar
  247. 247.
    Chapman MJ, Nguyen NQ, Deane AM. Gastrointestinal dysmotility: clinical consequences and management of the critically ill patient. Gastroenterol Clin North Am. 2011;40:725–39.PubMedGoogle Scholar
  248. 248.
    Hayakawa M, Asahara T, Henzan N, et al. Dramatic changes of the gut flora immediately after severe and sudden insults. Dig Dis Sci. 2011;56:2361–5.PubMedGoogle Scholar
  249. 249.
    Guarner F, Malagelada JR. Gut flora in health and disease. Lancet. 2003;361:512–9.PubMedGoogle Scholar
  250. 250.
    Farrell CP, Barr M, Mullin JM, Mullin JM, Lande L, Zitin M. Epithelial barrier leak in gastrointestinal disease and multiorgan failure. J Epithel Biol Pharmacol. 2012;5:13–8.Google Scholar
  251. 251.
    Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol. 1985;249:G549–56.PubMedGoogle Scholar
  252. 252.
    Furhmann V, Kneidinger H, Herkner H, Heinz G, Nikfardjam M, Bojic A, Schellongowski P, Angermayr B, Kitzberger R, Warszawska J, Holzinger U, Schenk P, Madi C. Hypoxic hepatitis: underlying conditions and risk factors for mortality in cirtically ill patients. Intensive Care Med. 2009;35:1397–405.Google Scholar
  253. 253.
    Henrion J, Schapira M, Luwaert R, Colin L, Delanoy A, Heller FR. Hypoxic hepatitis: clinical and hemodynamic studies in 142 consecutive cases. Medicine (Baltimore). 2003;82:392–406.Google Scholar
  254. 254.
    Henrion J. Hypoxic hepatitis. Liver Int. 2012;32(7):1039–52.Google Scholar
  255. 255.
    Gimson AE. Hepatic dysfunction during bacterial sepsis. Intensive Care Med. 1987;13:162–6.PubMedGoogle Scholar
  256. 256.
    Banks JG, Foulis AK, Ledingham IM, MacSween RN. Liver function in septic shock. J Clin Pathol. 1982;35:1249–52.PubMedPubMedCentralGoogle Scholar
  257. 257.
    Moreno R, Vincent JL, Matos R, Mendoca A, Cantraine F, Thijs L, Takala J, Sprung C, Antonelli M, Bruining H, Willats S. The use of maximum SOFA score to quantify organ dysfunction/failure in intensive care. Results of a prospective, multicenter study. Working Group on Sepsis relate Problems of the ESICM. Intensive Care Med. 1999;25:686–96.PubMedGoogle Scholar
  258. 258.
    Moseley RH. Sepsis and cholestasis. Clin Liver Dis. 2004;8:83–94.PubMedGoogle Scholar
  259. 259.
    Assimakopoulos SF, Scopa CD, Vagianos CE. Pathophysiology of increased intestinal permeability in obstructive jaundice. World J Gastroenterol. 2007;13:6458–64.PubMedPubMedCentralGoogle Scholar
  260. 260.
    Kamiya S, Nagino M, Kanazawa H, Komatsu S, Mayumi T, Takagi K, Asahara T, Nomoto K, Tanaka R, Nimura Y. The value of bile replacement during external biliary drainage: an analysis of intestinal permeability, integrity, and microflora. Ann Surg. 2004;239:510–7.PubMedPubMedCentralGoogle Scholar
  261. 261.
    Padillo FJ, Muntane J, Montero JL, Briceno J, Mino G, Solorzano G, Stiges-Serra A, Pera-Madrazo C. Effect of internal biliary drainage on plasma levels of endotoxin, cytokines, and C-reactive protein in patients with obstructive jaundice. World J Surg. 2002;26:1328–32.PubMedGoogle Scholar
  262. 262.
    Fuchs M, Sanyal AJ. Sepsis and cholestasis. Clin Liver Dis. 2008;12:151–72.PubMedGoogle Scholar
  263. 263.
    Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296–327.PubMedGoogle Scholar
  264. 264.
    McClave SA, Martindale RG, Vanek WW, McCarthy M, Roberts P, Taylor B, Ochoa JB, Napolitano L, Cresci G. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2009;33:277–316.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Anesthesia and Intensive Care 1 (1st Dept)ASST Grande Ospedale Metropolitano NiguardaMilanItaly

Personalised recommendations