Septic shock and pathogenesis

Septic shock
  • Definition – Septic shock is defined as hypotension asoociated with severe sepsis and cannot be corrected by infusing fluids
  • Causes for Septic shock
    • Overwhelming microbial infections (bacteria and fungi) 
    • Gram positive septicemia
    • Gram negative bacteria
    • Fungal sepsis
    • Rarely protozoa or Rickettsiae
PATHOGENESIS
Major factors contributing to the pathophysiology include
  • Inflammatory mediators
  • Endothelial activation and injury
  • Induction of procoagulant state
  • Metabolic abnormalities
  • Organ dysfunction
  • Immune suppression
Inflammatory mediators
  • Microbial cell wall constituents (LPS) engage receptors on neutrophils, mononuclear inflammatory cells and endothelial cells leading to cellular activation
  • Activated cells produce inflammatory mediators like TNF, IL-1, IFN-γ, IL-12, IL-18, HMGB 1 (High mobility group box 1 protein), prostaglandins and PAF. These mediators activate endothelial cells which express adhesion molecules
  • They activate complement and coagulation cascade
  • Complement cascade is activated by microbial components – results in production of anaphylotoxins (C3a, C5a), chemotactic fragments (C5a) and opsonins (C3b). All these contribute to proinflammatory state
  • Microbial components activate coagulation directly through factor XII and indirectly through altered endothelial function
  • Accompanying widespread activation of thrombin may further augment inflammation by triggering protease-activated receptors on inflammatory cells
Endothelial activation and injury
  • Endothelial cell activation and inflammatory mediators produce 3 major sequelae
  1. Thrombosis
  2. Increased vascular permeability
  3. Vasodilation
Induction of procoagulant state
  • Pro inflammatory cytokine affects on endothelial cells
    • Increase in tissue factor production
    • Increased plasminogen activating inhibitors which prevent fibrinolysis
    • Diminshed endothelial anticoagulant factors such as thrombomodulin and protein C

  • All these factors leads to formation of thrombi leading to Disseminated intravascular coagulation (DIC) which causes ischemic damage in various organs. 
  • Later patient develops hemorrhage and bleeding due to the deficiency of platelets and coagulation factors
Metabolic abnormalities
  • Septic patients exhibit insulin resistance and hyperglycemia
  • Pro inflammatory cytokines suppress insulin release while simultaneously promoting insulin resistance in the liver and other tissues by impairing surface expression of GLUT-4 a glucose transporter
  • Cytokines such as TNF and IL-1, stress induced hormones (glucagon, growth hormone and glycocorticoids) and catecholamines drive gluconeogenesis
  • Hyperglycemia leads decreased neutrophil function – which suppresses bactericidal activity and increased expression of adhesion molecules on endothelial cells
  • In sepsis – initially acute surge in glucocorticoid production followed by adrenal insufficiency
  • Adrenal insufficiency – due to depression in sympathetic capacity of intact gland or due to adrenal necrosis because of DIC (Waterhouse Friderichsen syndrome)
  • Hypoxia leads to metabolic acidosis and electrolyte imbalance due to sodium pump failure

Immune suppression
  • Hyper inflammatory state initiated by sepsis can activate counter regulatory immunosuppressive mechanisms
  • Shift from pro inflammatory to anti-inflammatory cytokine production (IL-10, IL-1 receptor antagonists etc)
  • Lymphocyte apoptosis and induction of cellular ageing
Organ dysfunction
  • Systemic hypotension, interstitial edema and small vessel thrombosis leads to decreased delivery of oxygen and nutrients to the tissues which produces alterations in cellular metabolism
  • High levels of cytokines and secondary mediators diminish myocardial contractility, cardiac output, endothelial injury and increased vascular permeability
  • These factors lead to multiple organ failure
Severity and outcome of septic shock depends upon
  • Extent and virulence of the infection
  • The immune status of the host
  • The presence of other co-morbid conditions
  • Levels of mediator production

 

References :

  1. Robbins and Cotrans: Pathologic basis of diseases.8th edition