Sepsis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2] ; Aditya Ganti M.B.B.S. [3]

Synonyms and keywords: sepsis syndrome; septic shock; septicemia


The immunological response that causes sepsis is a systemic inflammatory response causing widespread activation of inflammation and coagulation pathways. This may progress to dysfunction of the circulatory system and, even under optimal treatment, may result in the multiple organ dysfunction syndrome and eventually death. A subclass of distributive shock, with shock referring specifically to decreased tissue perfusion resulting in end-organ dysfunction. Cytokines TNFα, IL-1β, interferon γ, IL-6 released in a large scale inflammatory response results in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. Hypotension reduces tissue perfusion pressure and thus tissue hypoxia ensues. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction will occur. [1][2][3][4][5]


Immune system activation

Immune response

The endothelium and coagulation system

  • The vascular endothelium plays a major role in the host's defense to an invading organism, but also in the development of sepsis.
  • Activated endothelium not only allows the adhesion and migration of stimulated immune cells but becomes porous to large molecules such as proteins, resulting in the tissue edema.
  • Alterations in the coagulation systems include an increase in procoagulant factors, such as plasminogen activator inhibitor type I and tissue factor, and reduced circulating levels of natural anticoagulants, including antithrombin III and activated protein C (APC), which also carry anti-inflammatory and modulatory roles.

Inflammation and organ dysfunction

  • Through vasodilatation (causing reduced systemic vascular resistance) and increased capillary permeability (causing extravasation of plasma), sepsis results in relative and absolute reductions in circulating volume.
  • A number of factors combine to produce multiple organ dysfunctions.
  • Relative and absolute hypovolemia are compounded by reduced left ventricular contractility to produce hypotension.
  • Initially, through an increased heart rate, cardiac output increases to compensate and maintain perfusion pressures, but as this compensatory mechanism becomes exhausted, hypoperfusion and shock may result.
  • Impaired tissue oxygen delivery is exacerbated by pericapillary edema.
  • It makes oxygen to diffuse a greater distance to reach target cells.
  • There is a reduction of capillary diameter due to mural edema and the procoagulant state results in capillary microthrombus formation.

Additional contributing factors

  • Decreased blood flow through capillary beds, resulting from a combination of shunting of blood through collateral channels and an increase in blood viscosity secondary to loss of red cell flexibility.
  • As a result, organs become hypoxic, even with increased blood flow.
  • These abnormalities result in lactic acidosis, cellular dysfunction, and multiorgan failure.
  • Cellular energy levels fall as metabolic activity begins to exceed production.
  • However, cell death appears to be uncommon in sepsis, implying that cells shut down as part of the systemic response.
  • This could explain why relatively few histologic changes are found at autopsy, and the eventual rapid resolution of severe symptoms, such as complete anuria and hypotension, once the systemic inflammation resolves.


There are no genetic conditions associated with sepsis.


  1. Minasyan H (2017). "Sepsis and septic shock: Pathogenesis and treatment perspectives". J Crit Care. 40: 229–242. doi:10.1016/j.jcrc.2017.04.015. PMID 28448952.
  2. 2.0 2.1 Pop-Began V, Păunescu V, Grigorean V, Pop-Began D, Popescu C (2014). "Molecular mechanisms in the pathogenesis of sepsis". J Med Life. 7 Spec No. 2: 38–41. PMC 4391358. PMID 25870671.
  3. 3.0 3.1 Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG (2011). "The pathogenesis of sepsis". Annu Rev Pathol. 6: 19–48. doi:10.1146/annurev-pathol-011110-130327. PMC 3684427. PMID 20887193.
  4. 4.0 4.1 Cunneen J, Cartwright M (2004). "The puzzle of sepsis: fitting the pieces of the inflammatory response with treatment". AACN Clin Issues. 15 (1): 18–44. PMID 14767363.
  5. 5.0 5.1 Chaudhry H, Zhou J, Zhong Y, Ali MM, McGuire F, Nagarkatti PS, Nagarkatti M (2013). "Role of cytokines as a double-edged sword in sepsis". In Vivo. 27 (6): 669–84. PMC 4378830. PMID 24292568.

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