Paper I
Question
Pathogenesis of septic shock
Answer
Septic shock is a form of distributive shock triggered by an overwhelming systemic response to infection, most commonly Gram-negative bacteria (endotoxin/lipopolysaccharide), though Gram-positive bacteria and fungi can also be causative.
Pathogenesis
- Pathogen-associated molecular patterns (e.g., LPS) bind pattern recognition receptors (Toll-like receptors, especially TLR4) on innate immune cells (macrophages, neutrophils, endothelial cells)
- This triggers massive systemic release of pro-inflammatory cytokines (TNF-α, IL-1, IL-6, IL-8) — the “cytokine storm”
- Vascular effects: Widespread vasodilatation (via nitric oxide induction) causes profound hypotension; increased vascular permeability causes fluid leakage into the interstitium, worsening effective circulating volume
- Coagulation activation: Endothelial injury and tissue factor exposure activate the coagulation cascade, which can progress to disseminated intravascular coagulation, further compromising microvascular perfusion
- Myocardial depression: Circulating cytokines and other mediators (myocardial depressant factors) reduce cardiac contractility
- Metabolic derangements: Initial hyperglycaemia (stress response) may be followed by hypoglycaemia in later/prolonged sepsis; lactic acidosis develops from tissue hypoperfusion
- Multi-organ dysfunction: The combination of hypotension, microvascular thrombosis, and direct cytokine-mediated cellular injury leads to progressive dysfunction of the lungs (ARDS), kidneys (acute kidney injury), liver, and CNS
Outcome
- If uncorrected, progresses through the stages of shock (non-progressive → progressive → irreversible), culminating in multi-organ failure and death