What is the pathophysiology of septic shock?

Pathophysiology of Septic Shock

Septic shock results from a dysregulated host response to infection that causes profound circulatory, cellular, and metabolic abnormalities characterized by vasodilation, increased vascular permeability, and microcirculatory dysfunction leading to tissue hypoperfusion and organ failure. 1, 2

Initial Immune Response Phase

• Sepsis is initiated when pathogen-associated molecular patterns (PAMPs) from microorganisms are recognized by pattern-recognition receptors including Toll-like receptors (TLRs), triggering inflammatory signaling pathways 3
• This recognition activates inflammatory signaling pathways that converge toward interferon regulatory factor (IRF) signaling and nuclear factor-κB (NF-κB), leading to production of pro-inflammatory cytokines 3
• Early activation of inflammatory genes such as TNF, IL-1, and those encoding endothelial cell-surface molecules drives the initial inflammatory response 3
• Damage-associated molecular patterns (DAMPs) released from injured tissues further amplify this inflammatory cascade 3

Endothelial Dysfunction and Coagulopathy

• Sepsis produces profound changes that convert the endothelium from its natural anticoagulant state to a procoagulant state 3
• Disrupted endothelium leads to:
  • Loss of fluid through disengaged tight junctions, contributing to edema 3
  • Recruitment, attachment, and extravasation of inflammatory cells 3
  • Activation of the coagulation cascade, which potentiates inflammation 3
• The coagulation system is activated primarily through upregulation of tissue factor (TF), leading to excessive fibrin deposition and reduced plasmin activity 3
• This creates a vicious cycle where inflammation induces and exacerbates coagulopathies and endothelial injury 3
• Microvascular thrombosis results in tissue hypoperfusion and contributes to organ dysfunction 4

Hemodynamic Alterations

• Profound circulatory dysfunction characterized by vasodilation is a hallmark of septic shock 1
• Increased vascular permeability leads to fluid leakage into tissues, contributing to hypovolemia 2
• Microcirculatory dysfunction results in tissue hypoperfusion despite potentially normal macrocirculatory parameters 1
• These changes manifest clinically as hypotension requiring vasopressors to maintain mean arterial pressure ≥65 mmHg 2

Cellular and Metabolic Abnormalities

• Altered cellular metabolism leads to lactate accumulation, which is why lactate levels >2 mmol/L are part of the diagnostic criteria for septic shock 1, 2
• Cellular dysfunction occurs across multiple organ systems, contributing to the development of multiple organ failure 3
• Mitochondrial dysfunction impairs oxygen utilization at the cellular level, contributing to tissue hypoxia despite adequate oxygen delivery 5

Immunosuppressive Phase

• After the initial inflammatory response, sepsis often leads to an immunocompromised state 3
• This phase is characterized by:
  • Mobilization of immunosuppressive immature polymorphonuclear leukocytes (PMNs) and myeloid-derived suppressor cells (MDSCs) from bone marrow 3
  • Skewing of monocyte differentiation toward M2 macrophages that decrease inflammation 3
  • Production of anti-inflammatory cytokines like IL-10 and transforming growth factor-β (TGFβ) 3
  • Reduced expression of MHC class II molecules on antigen-presenting cells 3
  • Upregulation of negative co-stimulatory molecules like PD1 and PDL1 3
  • Apoptosis of follicular dendritic cells, B cells, and T cells 3

Clinical Trajectory and Outcomes

• The clinical trajectory of sepsis has evolved to reflect concurrent inflammatory and immunosuppressive responses 3
• Some patients experience a pronounced early inflammatory response leading to multiple organ failure and death 3
• Others survive the early inflammatory response but develop chronic critical illness characterized by persistent inflammation, immunosuppression, and catabolism syndrome (PICS) 3
• This can lead to reactivation of latent viral infections, nosocomial infections, and long-term functional and cognitive declines 3

Common Pitfalls in Understanding Septic Shock Pathophysiology

• Failing to recognize that patients receiving vasopressors may still have perfusion abnormalities despite normal blood pressure 2
• Not appreciating the biphasic nature of sepsis with initial hyperinflammation followed by immunosuppression 6
• Overlooking the importance of measuring lactate levels, which reflect cellular metabolic dysfunction 1
• Confusing septic shock with other forms of distributive shock, which may lead to inappropriate management 1