Pathogenesis of Septic shock

Septic shock is most commonly caused by the endotoxin producing gram negative bacteriae.

How is the endotoxins so cunning ?! Endotoxins are heat stable lipopolysaccharides (LPS). They are integral part of the cell wall of gram negative bacteria. They are not secreted but are released after the cell wall lysis (after bacteria is killed). So, we cannot make toxoids for these endotoxins.

(Toxoids are made only from exotoxins. When exotoxins are treated with formaldehyde, they become nontoxic but still have their antigenic property to induce antibodies.)

LPS :

·       L (lipo) – consists of toxic fatty acid core that is common for all gram-negative bacteria – known as lipid A.

·       PS (polysaccharide) – a complex coat specific for each species.

Pathogenesis :

When LPS (endotoxins) are released in the blood, it binds with the LPS-binding protein and this complex bind with the special CD14 receptor on monocytes, macrophages and neutrophils and activates them.

ü At low doses of LPS, this activation of mononuclear cells intents to enhance the ability to eliminate the invading bacteria.

Mononuclear phagocytes after activation produces TNF, which in turn induces IL1 synthesis.

TNF and IL1 act on endothelial cells and produce cytokines (IL6, IL8) and induce adhesion molecules ( causing neutrophil adherence to pulmonary capillaries). LPS also directly activates cytokines cascade and complement pathway.

ü At higher doses of LPS i.e. moderate or severe infections , the cytokine induced secondary effectors become significant . They are  NITRIC OXIDE, PAF- platelet activating factor, prostacyclin, thromboxane A2,B2 etc.

This results in :

Ø Systemic vasodilation- causing hypotension

Ø Diminished myocardial contractility

Ø Widespread endothelial damage causing capillary permeability. This may cause diffuse alveolar capillary damage leading to ARDS.

Ø Activation of intrinsic and extrinsic coagulation system – leads to DIC.