What is the pathophysiology of septic shock?

Pathophysiology of Septic Shock

Septic shock is characterized by a dysregulated host response to infection that triggers profound circulatory, cellular, and metabolic abnormalities, resulting in vasodilation, endothelial dysfunction, coagulopathy, and multiple organ failure. 1

Initial Immune Response Phase

• The pathophysiological cascade begins when pathogen-associated molecular patterns (PAMPs) from microorganisms are recognized by pattern-recognition receptors, triggering inflammatory signaling pathways 1
• This recognition activates inflammatory pathways that converge toward interferon regulatory factor (IRF) signaling and nuclear factor-κB (NF-κB), leading to production of pro-inflammatory cytokines 1
• Damage-associated molecular patterns (DAMPs) released from injured tissues further amplify this inflammatory cascade 1
• The initial inflammatory reaction is mediated by the release of cytokines, including tumor necrosis factor-alpha, interleukins, and prostaglandins, from neutrophils and macrophages 2

Endothelial Dysfunction and Coagulopathy

• Sepsis converts the endothelium from its natural anticoagulant state to a procoagulant state 1
• Disrupted endothelium leads to loss of fluid, recruitment of inflammatory cells, and activation of the coagulation cascade 1
• The coagulation system is activated primarily through upregulation of tissue factor (TF), leading to excessive fibrin deposition and reduced plasmin activity 1
• This creates a vicious cycle where inflammation induces coagulopathies and endothelial injury, which further promotes inflammation 1
• Activation of the coagulation system leads to consumption of endogenous anticoagulants (e.g., protein C and antithrombin), contributing to microvascular coagulation 2

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 1
• 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 3
• The systemic vasodilation and subsequent tissue hypoperfusion are key components of septic shock pathophysiology 4

Cellular and Metabolic Abnormalities

• Altered cellular metabolism leads to lactate accumulation, which is why lactate levels are part of the diagnostic criteria for septic shock 1, 3
• Cellular dysfunction occurs across multiple organ systems, contributing to the development of multiple organ failure 1
• Septic shock is clinically identified by persistent hypotension requiring vasopressors to maintain mean arterial pressure ≥65 mmHg and elevated serum lactate >2 mmol/L despite adequate volume resuscitation 3

Immunosuppressive Phase

• After the initial inflammatory response, sepsis often leads to an immunocompromised state 1
• This phase is characterized by mobilization of immunosuppressive cells, skewing of monocyte differentiation, and production of anti-inflammatory cytokines 1
• Both inflammatory and anti-inflammatory mediators play important roles in sepsis, and an excess of either can result in poor patient outcomes 2

Clinical Trajectory and Outcomes

• The clinical trajectory of sepsis reflects concurrent inflammatory and immunosuppressive responses 1
• Some patients experience a pronounced early inflammatory response leading to multiple organ failure and death 1
• Others survive the early inflammatory response but develop chronic critical illness characterized by persistent inflammation, immunosuppression, and catabolism syndrome (PICS) 1

Common Pitfalls in Understanding Septic Shock Pathophysiology

• Failing to recognize that patients receiving vasopressors may still have perfusion abnormalities despite normal blood pressure 1, 3
• Overlooking the importance of measuring lactate levels, which reflect cellular metabolic dysfunction 3
• Confusing septic shock with other forms of distributive shock, which may lead to inappropriate management 3
• Not appreciating the complex interplay between inflammation and coagulation that drives the pathophysiology 2