The Pathogenesis of Sepsis

Sait Karakurt, MDMarmara University Medical School

Pulmonary and Critical Care Medicine

The Pathogenesis of Sepsis

• Cytokine Hypothesis

• Microcirculatory Hypothesis

• Gut Hypothesis

Cytokine Hypothesis

• malignant intravascular inflammation– uncontrolled, unregulated, and self-sustaining.– the blood-borne spread– septic response are exaggerations of the normal

inflammatory response.– elevated levels of circulating TNFa

Biologic effects of proinflammatory cytokines

FeverHypotensionAcute phase protein responseInduction of IL-6 and IL-8Coagulation activationFibrinolytic activationLeukocytosisNeutrophil degranulation and augmented antigen expression (TNF)Increased endothelial permeability (TNF)Stress hormone responseEnhanced gluconeogenesis (TNF)

Enhanced lipolysis (TNF)

Determinants of outcome in sepsis

Uptodate 2009

Potential outcomes of mediator release in sepsis

Uptodate 2009

The Pathogenesis of Sepsis

• block the inflammatory cascade – corticosteroids,– antiendotoxin– antibodies,– tumor necrosis factor (TNF) antagonists,– interleukin-1–receptor antagonists

• Initially, sepsis may be characterized by increases in inflammatory mediators; but as sepsis persists, there is a shift toward an antiinflammatory immunosuppressive state.

The Pathogenesis of Sepsis

Potential Mechanisms of Immune Suppression in Patients with Sepsis.

Shift from an inflammatory (Th1) to an antiinflammatory(Th2) response

Anergy

Apoptosis-induced loss of CD4 T cells, B cells, and dendritic cells

Loss of macrophage expression of major-histocompatibilitycomplex class II and costimulatory molecules

Immunosuppressive effect of apoptotic cells

N Engl J Med 2003, 348;138-150.

TRAUMA SEPSİS TRAUMA SEPSİS

Immune Suppression in Patients with Sepsis.

N Engl J Med 2003, 348;138-150.

Reduced levels of protein C severe sepsis and septic shock.

• increased degradation of protein C and protein S

• the conversion of protein C to activated protein C is impaired during sepsis as a result of the down-regulation of thrombomodulin and the endothelial cell protein C receptor by proinflammatory cytokines.

• increased use of activated protein C

Activated Protein C

• Almost 88% of patients with sepsis have low levels of PC (< 80% of normal), and 40% have levels of PC that are severely reduced (< 40% of normal).

• Reduced levels of protein C have been correlated with increased morbidity and mortality in patients with severe sepsis and septic shock.

Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF,Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al.: Efficacy and safety of recombinant human activatedprotein C for severe sepsis. N Engl J Med 2001, 344:699-709

Fijnvandraat K, Derkx B, Peters M, et al. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995;73:15–20.

Activated Protein C• Replacement therapy with protein C concentrate has been

shown to prevent coagulopathy and improve survival in animal models of Gram negative sepsis, and in humans with severe meningococcaemia where dysfunction of the protein C activation pathway is deemed critical to the development of disseminated intravascular coagulation and purpura fulminans

Taylor FB, Chank A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of E coli infusion in the baboon. J Clin Invest 1987;79:918–25.

Ettingshausen CE, Veldmann A, Beeg T, et al. Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans. Semin Thromb Hemost 1999;25:537–41.

Microcirculatory Hypothesis

• The microthrombi, microvascular constriction, and free radicals are valuable in limiting the spread of infection.

Bernard G et al. N Engl J Med 2001;344:699-709

Microcirculatory Hypothesis

Diffuse complement activation (left) and complement in the lung (right)

N Engl J Med 2003; 348:167

Clinical sequelae of the proinflammatory and antiinflammatory responses to sepsis

Bone, RC, Crit Care Med 1996; 24:1125

Decreased oxygen extraction in sepsis

Uptodate 2009

Gut Hypothesis

• translocation of bacteria or endotoxin, • disrupted intestinal barrier• Bacteria or endotoxin activates white blood cells

and induces production of cytokines. Each can alter the behavior of both endothelial cells and the coagulation system, leading to microvascular aggregation and production of free radicals, which can, in turn, create a self-sustaining cycle that culminates inMODS

The Pathogenesis of Sepsis

N Engl J Med 2003, 348;138-150.

Sepsis• The significant consequences of a systemic proinflammatory reaction include

endothelial damage, microvascular dysfunction, and impaired tissue oxygenation and organ injury.

• The significant consequences of an excessive antiinflammatory response include anergy and immunosuppression.

• In addition, pro- and anti-inflammatory processes may interfere with each other, creating a state of destructive immunologic dissonance.

• Sepsis may therefore be described as an autodestructive process that permits the extension of a normal pathophysiologic response to infection to involve otherwise normal tissue. This can result in the multiple organ dysfunction syndrome .

SEPSİS-mortalite

N Eng J Med 2002;347:966-967

‘‘Two-Hit’’ Hypothesis

• an initial period of hypotension “primes” the trauma patient for SIRS/MODS (i.e., the initial insult activates other processes that amplify the effects of the initial event, however mild).

• a single insult is followed by a second, more severe insult have shown that the first “hit” is actually protective.

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• Protein C is a vitamin K dependent glycoprotein synthesised by the liver

• Protein C circulates in the blood as an inactive zymogen.

• In the presence of thrombin, protein C binds to two receptors on the endothelial surface, thrombomodulin and the endothelial protein C receptor, and becomes converted into activated protein C.

• Protein S is an essential cofactor for activated protein C

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