Causative agents vary significantly, depending on several factors including the region, hospital size, season, and type of unit (neonatal, transplantation, oncology, or haemodialysis; if acquired in hospital).[10][11][12][13][14][15][16][17][18][19]

The Extended Prevalence of Infection in Intensive Care (EPIC II) study provides the best recent evidence on the infectious causes of sepsis in an intensive care setting.[20] The prospective study gathered extensive data from more than 14,000 adult patients in 1265 intensive care units from 75 countries on a single day in May 2007. Of the 7087 patients classified as ‘infected’, the sites of infection were the:

  • Lungs: 64%

  • Abdomen: 20%

  • Bloodstream: 15%

  • Renal or genitourinary tract: 14%.

Of the 70% of infected patients with positive microbiology:

  • 47% of isolates were gram-positive (Staphylococcus aureus alone accounted for 20%)

  • 62% were gram-negative (20% Pseudomonas species and 16% Escherichia coli)

  • 19% were fungal.

Other studies tend to broadly concur on the relative frequencies of sources of infection. In people over 65, the most common site is the genitourinary tract.[21][22] A definite source of infection cannot be found in 20% to 30% of people with sepsis.[9]


Sepsis is a syndrome comprising an immune system-mediated collection of physiological responses to an infectious agent. Clinical signs such as fever, tachycardia, and hypotension are common but the clinical course depends on the type and resistance profile of infectious organism, the site and size of the infecting insult, and the genetically determined or acquired properties of the host's immune system.

Immune-system activation:

  • Pathogen entry and survival is facilitated by tissue contamination (surgery or infection), foreign body insertion (catheters), and immune status (immunosuppression).[23]

  • The innate immune system is activated by bacterial cell wall products, such as lipopolysaccharide, binding to host receptors, including Toll-like receptors (TLRs).[24][25] These are widely found on leukocytes and macrophages, and some types are found on endothelial cells.[26] At least 10 TLRs have been described in humans. These have specificity for different bacterial, fungal, or viral surface markers or products. Genetic polymorphisms are associated with a predisposition to shock with gram-negative organisms.[27]

  • Activation of the innate immune system results in a complex series of cellular and humoural responses, each with amplification steps:[28]

    • Pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukins 1 and 6 are released, which in turn activate immune cells.

    • Reactive oxygen species, nitric oxide (NO), proteases, and pore-forming molecules are released, which bring about bacterial killing. NO is responsible for vasodilatation and increased capillary permeability, and has been implicated in sepsis-induced mitochondrial dysfunction.[29]

    • The complement system is activated, and mediates activation of leukocytes, attracting them to the site of infection where they can directly attack the organism (phagocytes, cytotoxic T lymphocytes), identify it for attack by others (antigen presenting cells, B lymphocytes), ‘remember’ it in case of future infection (memory cells, B lymphocytes), and cause the increased production and chemotaxis of more T helper cells.[30]

The endothelium and coagulation system:

  • The vascular endothelium plays a major role in the host’s defence 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 tissue oedema.

  • Alterations in the coagulation systems include an increase in pro-coagulant 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, which also carry anti-inflammatory and modulatory roles.[31][32]

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 hypovolaemia are compounded by reduced left ventricular contractility, leading to 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 oedema. This means that oxygen has to diffuse a greater distance to reach target cells. There is a reduction of capillary diameter due to mural oedema and the pro-coagulant state results in capillary microthrombus formation.

  • Additional contributing factors include disordered 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.[33] As a result, organs may become hypoxic, even though gross blood flow to an organ may increase. These abnormalities may lead to lactic acidosis, cellular dysfunction, and multi-organ failure.[34]

  • 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 histological changes are found at autopsy, and the eventual rapid resolution of severe symptoms, such as anuria and hypotension, once the systemic inflammation resolves.[35]


Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) (2016)[1]

  • Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection.

  • Septic shock is a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Septic shock can be defined clinically as a patient diagnosed with sepsis, with persistent hypotension requiring vasopressors to maintain a mean arterial pressure ≥65 mmHg, and a lactate level >2 mmol/L (>18 mg/dL), despite adequate fluid resuscitation.

  • Owing to revisions to the definition of sepsis, the term 'severe sepsis' (as previously defined in the 1991/2001 international consensus definitions) should no longer be used.

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