What is the pathophysiology of the septic stress response?

Pathophysiology of the Septic Stress Response

The septic stress response is a dysregulated host reaction to infection characterized by concurrent hyperinflammation and immunosuppression, driven by inflammatory cytokines and stress hormones that trigger profound metabolic, circulatory, and cellular dysfunction across multiple organ systems. 1

Initial Inflammatory Cascade

The stress response begins when pathogen-associated molecular patterns (PAMPs) from microorganisms bind to pattern-recognition receptors, activating nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) signaling pathways. 1 This triggers massive release of pro-inflammatory cytokines including interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-8 from neutrophils, macrophages, and injured cells. 2, 3 Damage-associated molecular patterns (DAMPs) released from injured tissues further amplify this inflammatory cascade. 1

Metabolic Derangements

Catabolic State and Lipolysis

Inflammatory cytokines (IL-1β, TNF-α) combined with stress hormones (cortisol, catecholamines, glucagon) directly induce profound catabolism to meet increased energy and biomass demands for the immune response. 2 These mediators upregulate hormone-sensitive lipase, triggering massive adipocyte lipolysis. 2

• Plasma free fatty acids (FFAs) and triglycerides increase up to four-fold in septic patients. 2
• Simultaneously, inflammation downregulates fatty acid oxidation enzymes and ketone production, preventing utilization of these mobilized lipids. 2
• Toxic accumulation of FFAs causes severe organ damage and interferes with mitochondrial function, potentiating energy deprivation. 2, 1

Hyperglycemia and Insulin Resistance

Sepsis produces severe dysregulation of glucose metabolism through multiple mechanisms. 2 Counter-regulatory hormones and cytokines induce profound insulin resistance while stimulating hepatic gluconeogenesis. 4

• Hyperglycemia redirects glucose to immune cells, promoting aerobic glycolysis. 2
• Excessive glycolytic metabolism paradoxically amplifies pro-inflammatory cytokine release, myocardial apoptosis, and multi-organ dysfunction. 2, 4
• Hyperglycemia activates NF-κB, generating oxidative stress that increases vascular permeability and impairs mitochondrial function. 4

Protein Catabolism

The cytokine-driven systemic inflammatory response syndrome causes catabolism of glycogen, fat, and protein with release of substrates into circulation. 2 Substrates are diverted from maintaining peripheral muscle mass to healing and immune response tasks. 2 The consequence is loss of muscle tissue, creating both short and long-term burdens for functional recovery. 2

Circulatory and Endothelial Dysfunction

Hemodynamic Alterations

Septic shock involves profound vasodilation, increased vascular permeability with fluid leakage into tissues, and microcirculatory dysfunction leading to tissue hypoperfusion despite potentially normal macrocirculatory parameters. 4, 1

Endothelial Injury and Coagulopathy

Sepsis converts the endothelium from its natural anticoagulant state to a procoagulant state. 1 The disrupted endothelium recruits inflammatory cells and activates the coagulation cascade primarily through upregulation of tissue factor, leading to excessive fibrin deposition and reduced plasmin activity. 1, 5

• Degradation of the endothelial glycocalyx increases vascular permeability, allowing plasma fluid and proteins to leak into interstitial space, exacerbating tissue edema. 1
• This creates a vicious cycle where inflammation induces and exacerbates coagulopathies and endothelial injury. 1
• Consumption of endogenous anticoagulants (protein C, antithrombin) contributes to microvascular thrombosis and organ dysfunction. 5

Cellular and Mitochondrial Dysfunction

Altered cellular metabolism leads to lactate accumulation, reflecting cellular energy failure across multiple organ systems. 4, 1 Severe lactic acidosis impairs cellular enzyme activity, reduces myocardial contractility, and diminishes vascular responsiveness to catecholamines. 1

• Accumulated FFAs disrupt mitochondrial respiration, contributing to cellular energy failure and multi-organ failure. 2, 4
• Oxidative stress causes lipid peroxidation of cellular membranes, further damaging membrane integrity. 1
• Prolonged shock beyond critical time thresholds leads to irreversible cellular injury where restoration of perfusion cannot prevent cell death. 1

Immunosuppressive Phase

Immune Cell Dysfunction

After the initial inflammatory response, sepsis transitions to an immunocompromised state. 2, 1

• Extensive apoptosis of lymphocytes, B cells, and dendritic cells causes profound loss of immune effector cells. 2
• Persistent lymphopenia after sepsis diagnosis predicts increased mortality. 2
• Surviving neutrophils exhibit impaired phagocytic capacity and abnormal calcium signaling despite normal appearance. 2, 1
• Monocytes display decreased HLA-DR expression, indicating immune paralysis and compromised antigen presentation. 2, 1

Immunosuppressive Cell Populations

Mobilization of immunosuppressive immature polymorphonuclear leukocytes and myeloid-derived suppressor cells (MDSCs) occurs from bone marrow. 2, 1 Monocyte differentiation skews toward M2 macrophages that produce anti-inflammatory cytokines (IL-10, TGF-β). 2 Professional antigen-presenting cells reduce expression of HLA-DR. 2 T cells upregulate negative co-stimulatory molecules (PD-1, PD-L1), driving expansion of regulatory T cells and anergic T cells. 2

Neuroendocrine Alterations

The immune system signals pathogen presence to the brain through the vagus nerve, endothelial activation, cytokines, and circumventricular organs. 6 This produces a "pan-endocrine illness" with inappropriately low vasopressin levels, sick euthyroid syndrome, reduced adrenal responsiveness to ACTH, and hyperleptinemia. 6

Clinical Trajectory

The current model reflects concurrent inflammatory and immunosuppressive responses occurring simultaneously rather than sequentially. 2, 1 Some patients experience pronounced early inflammatory response leading to multiple organ failure and death. 2 Others survive the early phase but develop chronic critical illness characterized by persistent inflammation, immunosuppression, and catabolism syndrome (PICS), with reactivation of latent viral infections and nosocomial infections. 2, 1

Common Pitfalls

• Failing to recognize that the majority of patients with protracted sepsis develop infections with opportunistic-type pathogens, strongly supporting progression to an immunosuppressive disorder. 2
• Overlooking that patients receiving vasopressors may still have perfusion abnormalities despite normal blood pressure. 4, 1
• Not measuring lactate levels, which reflect cellular metabolic dysfunction and are essential for diagnosis. 4, 1
• Misunderstanding that both excessive inflammatory and excessive anti-inflammatory responses result in poor outcomes. 5