Pathophysiology of sepsis

INTRODUCTION

The normal host response to infection is a complex process that localizes and controls bacterial invasion, while initiating the repair of injured tissue. It involves the activation of circulating and fixed phagocytic cells, as well as the generation of proinflammatory and antiinflammatory mediators. Sepsis results when the response to infection becomes generalized and involves normal tissues remote from the site of injury or infection.

The pathophysiology of sepsis and mechanisms of multiple organ system dysfunction are reviewed here. The definition and management of sepsis are discussed separately. (See "Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis" and "Evaluation and management of severe sepsis and septic shock in adults".)

NORMAL RESPONSE TO INFECTION

The host response to an infection is initiated when innate immune cells, particularly macrophages, recognize and bind to microbial components. This may occur by several pathways:

Pattern recognition receptors (PRRs) on the surface of host immune cells may recognize and bind to the pathogen-associated molecular patterns (PAMPs) of microorganisms [1]. There are three families of PRRs: toll-like receptors (TLRs), nucleotide-oligomerization domain (NOD) leucine-rich repeat proteins, and retinoic-acid-inducible gene I (RIG-I)-like helicases. Examples include the peptidoglycan of Gram-positive bacteria binding to TLR-2 on host immune cells, as well as the lipopolysaccharide of Gram-negative bacteria binding to TLR-4 and/or lipopolysaccharide-binding protein (CD14 complex) on host immune cells.

The triggering receptor expressed on myeloid cell (TREM-1) and the myeloid DAP12-associating lectin (MDL-1) receptors on host immune cells may recognize and bind to microbial components [2].

                   

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2014. | This topic last updated: Jun 27, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Cinel I, Dellinger RP. Advances in pathogenesis and management of sepsis. Curr Opin Infect Dis 2007; 20:345.
  2. Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 2001; 410:1103.
  3. Movat HZ, Cybulsky MI, Colditz IG, et al. Acute inflammation in gram-negative infection: endotoxin, interleukin 1, tumor necrosis factor, and neutrophils. Fed Proc 1987; 46:97.
  4. van der Poll T, Lowry SF. Tumor necrosis factor in sepsis: mediator of multiple organ failure or essential part of host defense? Shock 1995; 3:1.
  5. Pruitt JH, Copeland EM 3rd, Moldawer LL. Interleukin-1 and interleukin-1 antagonism in sepsis, systemic inflammatory response syndrome, and septic shock. Shock 1995; 3:235.
  6. Barriere SL, Lowry SF. An overview of mortality risk prediction in sepsis. Crit Care Med 1995; 23:376.
  7. Szabo G, Kodys K, Miller-Graziano CL. Elevated monocyte interleukin-6 (IL-6) production in immunosuppressed trauma patients. I. Role of Fc gamma RI cross-linking stimulation. J Clin Immunol 1991; 11:326.
  8. Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 1996; 125:680.
  9. Pinsky MR, Matuschak GM. Multiple systems organ failure: failure of host defense homeostasis. Crit Care Clin 1989; 5:199.
  10. Pugin J. Recognition of bacteria and bacterial products by host immune cells in sepsis. In: Yearbook of Intensive Care and Emergency Medicine, Vincent JL (Ed), Springer-Verlag, Berlin 1996. p.11.
  11. Suffredini AF, Fromm RE, Parker MM, et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989; 321:280.
  12. Tapper H, Herwald H. Modulation of hemostatic mechanisms in bacterial infectious diseases. Blood 2000; 96:2329.
  13. Pinsky MR, Vincent JL, Deviere J, et al. Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest 1993; 103:565.
  14. Tracey, KJ, Beutler, B, Lowry, SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234:470.
  15. Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985; 229:869.
  16. Lamping N, Dettmer R, Schröder NW, et al. LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. J Clin Invest 1998; 101:2065.
  17. Walport MJ. Complement. First of two parts. N Engl J Med 2001; 344:1058.
  18. Walport MJ. Complement. Second of two parts. N Engl J Med 2001; 344:1140.
  19. Huber-Lang MS, Riedeman NC, Sarma JV, et al. Protection of innate immunity by C5aR antagonist in septic mice. FASEB J 2002; 16:1567.
  20. Riedemann NC, Guo RF, Neff TA, et al. Increased C5a receptor expression in sepsis. J Clin Invest 2002; 110:101.
  21. Furebring M, Håkansson LD, Venge P, et al. Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis. Crit Care 2002; 6:363.
  22. Huber-Lang MS, Younkin EM, Sarma JV, et al. Complement-induced impairment of innate immunity during sepsis. J Immunol 2002; 169:3223.
  23. Liu D, Lu F, Qin G, et al. C1 inhibitor-mediated protection from sepsis. J Immunol 2007; 179:3966.
  24. Liu D, Cai S, Gu X, et al. C1 inhibitor prevents endotoxin shock via a direct interaction with lipopolysaccharide. J Immunol 2003; 171:2594.
  25. Guerrero R, Velasco F, Rodriguez M, et al. Endotoxin-induced pulmonary dysfunction is prevented by C1-esterase inhibitor. J Clin Invest 1993; 91:2754.
  26. Schmidt W, Stenzel K, Gebhard MM, et al. C1-esterase inhibitor and its effects on endotoxin-induced leukocyte adherence and plasma extravasation in postcapillary venules. Surgery 1999; 125:280.
  27. Jansen PM, Eisele B, de Jong IW, et al. Effect of C1 inhibitor on inflammatory and physiologic response patterns in primates suffering from lethal septic shock. J Immunol 1998; 160:475.
  28. Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med 2007; 4:444.
  29. McGown CC, Brown NJ, Hellewell PG, Brookes ZL. ROCK induced inflammation of the microcirculation during endotoxemia mediated by nitric oxide synthase. Microvasc Res 2011; 81:281.
  30. Piagnerelli M, Boudjeltia KZ, Vanhaeverbeek M, Vincent JL. Red blood cell rheology in sepsis. Intensive Care Med 2003; 29:1052.
  31. Piagnerelli M, Boudjeltia KZ, Brohee D, et al. Modifications of red blood cell shape and glycoproteins membrane content in septic patients. Adv Exp Med Biol 2003; 510:109.
  32. Kirschenbaum LA, Aziz M, Astiz ME, et al. Influence of rheologic changes and platelet-neutrophil interactions on cell filtration in sepsis. Am J Respir Crit Care Med 2000; 161:1602.
  33. Harrois A, Huet O, Duranteau J. Alterations of mitochondrial function in sepsis and critical illness. Curr Opin Anaesthesiol 2009; 22:143.
  34. Crouser ED, Julian MW, Blaho DV, Pfeiffer DR. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med 2002; 30:276.
  35. VanderMeer TJ, Wang H, Fink MP. Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock. Crit Care Med 1995; 23:1217.
  36. Rosser DM, Stidwill RP, Jacobson D, Singer M. Cardiorespiratory and tissue oxygen dose response to rat endotoxemia. Am J Physiol 1996; 271:H891.
  37. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360:219.
  38. Haden DW, Suliman HB, Carraway MS, et al. Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis. Am J Respir Crit Care Med 2007; 176:768.
  39. Marshall JC, Watson RW. Apoptosis in the resolution of systemic inflammation. In: Yearbook of Intensive Care and Emergency Medicine, Vincent JL (Ed), Springer-Verlag, Berlin 1997. p.100.
  40. Coopersmith CM, Stromberg PE, Dunne WM, et al. Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis. JAMA 2002; 287:1716.
  41. Takasu O, Gaut JP, Watanabe E, et al. Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med 2013; 187:509.
  42. Schefold JC, Hasper D, Reinke P, et al. Consider delayed immunosuppression into the concept of sepsis. Crit Care Med 2008; 36:3118.
  43. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348:138.
  44. Adib-Conquy M, Cavaillon JM. Compensatory anti-inflammatory response syndrome. Thromb Haemost 2009; 101:36.
  45. Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011; 306:2594.
  46. Parrat JR, Stoclet JC. Vascular smooth muscle function under conditions of sepsis and ARDS. In: Role of Nitric Oxide in Sepsis and ARDS, Fink MP, Payen D (Eds), Springer-Verlag, Berlin 1995. p.44.
  47. Vincent JL, Zhang H, Szabo C, Preiser JC. Effects of nitric oxide in septic shock. Am J Respir Crit Care Med 2000; 161:1781.
  48. Sharshar T, Gray F, Lorin de la Grandmaison G, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 2003; 362:1799.
  49. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122.
  50. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997; 25:1279.
  51. Tsuneyoshi I, Yamada H, Kakihana Y, et al. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med 2001; 29:487.
  52. Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999; 47:699.
  53. Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 2002; 96:576.
  54. Price S, Anning PB, Mitchell JA, Evans TW. Myocardial dysfunction in sepsis: mechanisms and therapeutic implications. Eur Heart J 1999; 20:715.
  55. Hoffmann JN, Werdan K, Hartl WH, et al. Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock 1999; 12:174.
  56. Fink MP. Systemic and splanchnic hemodynamic derangements in the sepsis syndrome. In: Splanchnic ischemia and Multiple Organ Failure, Martson A, Bulkey GB, Giddian-Green RG, Haglund U (Eds), CV Mosby, St. Louis 1989. p.101.
  57. Astiz ME, DeGent GE, Lin RY, Rackow EC. Microvascular function and rheologic changes in hyperdynamic sepsis. Crit Care Med 1995; 23:265.
  58. Neviere R, Mathieu D, Chagnon JL, et al. Skeletal muscle microvascular blood flow and oxygen transport in patients with severe sepsis. Am J Respir Crit Care Med 1996; 153:191.
  59. Temmesfeld-Wollbrück B, Szalay A, Mayer K, et al. Abnormalities of gastric mucosal oxygenation in septic shock: partial responsiveness to dopexamine. Am J Respir Crit Care Med 1998; 157:1586.
  60. De Backer D, Creteur J, Preiser JC, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002; 166:98.
  61. Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003; 101:3765.
  62. De Backer D, Donadello K, Favory R. Link between coagulation abnormalities and microcirculatory dysfunction in critically ill patients. Curr Opin Anaesthesiol 2009; 22:150.
  63. Luce JM. Pathogenesis and management of septic shock. Chest 1987; 91:883.
  64. Ghosh S, Latimer RD, Gray BM, et al. Endotoxin-induced organ injury. Crit Care Med 1993; 21:S19.
  65. Hassoun HT, Kone BC, Mercer DW, et al. Post-injury multiple organ failure: the role of the gut. Shock 2001; 15:1.
  66. Upperman JS, Deitch EA, Guo W, et al. Post-hemorrhagic shock mesenteric lymph is cytotoxic to endothelial cells and activates neutrophils. Shock 1998; 10:407.
  67. Doig CJ, Sutherland LR, Sandham JD, et al. Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patients. Am J Respir Crit Care Med 1998; 158:444.
  68. Hakim RM, Wingard RL, Parker RA. Effect of the dialysis membrane in the treatment of patients with acute renal failure. N Engl J Med 1994; 331:1338.
  69. Joannes-Boyau O, Honoré PM, Perez P, et al. High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial. Intensive Care Med 2013; 39:1535.
  70. Borthwick EM, Hill CJ, Rabindranath KS, et al. High-volume haemofiltration for sepsis. Cochrane Database Syst Rev 2013; 1:CD008075.
  71. Iacobone E, Bailly-Salin J, Polito A, et al. Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med 2009; 37:S331.
  72. Rosengarten B, Hecht M, Auch D, et al. Microcirculatory dysfunction in the brain precedes changes in evoked potentials in endotoxin-induced sepsis syndrome in rats. Cerebrovasc Dis 2007; 23:140.
  73. Gaykema RP, Dijkstra I, Tilders FJ. Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion. Endocrinology 1995; 136:4717.
  74. Fleshner M, Goehler LE, Schwartz BA, et al. Thermogenic and corticosterone responses to intravenous cytokines (IL-1beta and TNF-alpha) are attenuated by subdiaphragmatic vagotomy. J Neuroimmunol 1998; 86:134.
  75. Romanovsky AA, Simons CT, Székely M, Kulchitsky VA. The vagus nerve in the thermoregulatory response to systemic inflammation. Am J Physiol 1997; 273:R407.
  76. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405:458.
  77. Wang H, Liao H, Ochani M, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 2004; 10:1216.