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
Overview
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]
Pathophysiology
- Sepsis is defined as a collection of physiologic responses by the immune system in response to an infectious agent.
- Sepsis results when an infectious insult triggers a localized inflammatory reaction that resulting in systemic symptoms of fever or hypothermia, tachycardia, tachypnea, and either leukocytosis or leukopenia.
- The clinical course of sepsis depends on the type and resistance of the infectious organism, the site and size of the infecting insult, and the genetically determined or acquired properties of the host's immune system.
- The pathogenesis of sepsis can be discussed as follows [2][3][4][5]
Immune system activation
- The immune system is activated by pathogen entry which is facilitated by contamination of tissue either by surgery or infection, foreign body insertion (catheters) and in an immunocompromised state.
- Products of activation include
- Bacterial cell wall products such as lipopolysaccharide
- Binding to host receptors, including Toll-like receptors (TLRs).
- Toll-like receptors are found in leukocytes and macrophages, and endothelial cells.
- These have specificity for different bacterial, fungal, or viral products.
- TLRs are associated with a predisposition to shock with gram-negative organisms.
- Activation of the innate immune system results in a complex series of cellular and humoral responses.
Immune response
- Immune response includes the release of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukins 1 and 6 along with reactive oxygen species, nitric oxide (NO), proteases, and pore-forming molecules, which bring about activation of immune cells and bacterial killing.
- Nitrous oxide is responsible for vasodilatation and increased capillary permeability and has been implicated in sepsis-induced mitochondrial dysfunction.
- The complement system gets activated which mediates activation of leukocytes, attracting them to the site of infection (phagocytes, cytotoxic T lymphocytes),
- Complement system also helps as a mediator for antigen-presenting cells and B lymphocytes
- This response by complement system helps the B lymphocyte to produce memory cells in case of future infection and is responsible for the increased production and chemotaxis of more T helper cells.
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.
Genetics
There are no genetic conditions associated with sepsis.
References
- ↑ 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.
- ↑ 2.0 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.
- ↑ 3.0 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.
- ↑ 4.0 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.
- ↑ 5.0 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.