The Patho genesis of Sepsis

1. The Pathogenesis of Sepsis Sait Karakurt, MD Marmara UniversityMedicalSchool PulmonaryandCriticalCareMedicine

2. The Pathogenesis of Sepsis • CytokineHypothesis • MicrocirculatoryHypothesis • Gut Hypothesis

3. CytokineHypothesis • malignantintravascularinflammation • uncontrolled, unregulated, and self-sustaining. • theblood-borne spread • septic response are exaggerations of the normal inflammatory response. • elevatedlevels of circulatingTNFa

4. Biologiceffects of proinflammatorycytokines

5. Determinants of outcome in sepsis Uptodate 2009

6. Potentialoutcomes of mediatorrelease in sepsis Uptodate 2009

7. The Pathogenesis of Sepsis • blocktheinflammatorycascade • corticosteroids, • antiendotoxin • antibodies, • tumornecrosisfactor (TNF) antagonists, • interleukin-1–receptorantagonists

8. The Pathogenesis of Sepsis • Initially, sepsis may be characterizedby increases in inflammatory mediators; butas sepsis persists, there is a shift toward an antiinflammatoryimmunosuppressivestate.

9. Potential Mechanisms of Immune Suppression in PatientswithSepsis. Shift from an inflammatory (Th1) to an antiinflammatory(Th2) response Anergy Apoptosis-induced loss of CD4 T cells, B cells, and dendriticcells Loss of macrophage expression of major-histocompatibilitycomplexclass II and costimulatory molecules Immunosuppressiveeffect of apoptoticcells NEngl JMed 2003, 348;138-150.

10. Immune Suppression in PatientswithSepsis. TRAUMA SEPSİS TRAUMA SEPSİS NEngl JMed 2003, 348;138-150.

11. increaseddegradation of protein C and protein S theconversion of protein C toactivated protein C is impairedduringsepsis as a result of thedown-regulation of thrombomodulinandtheendothelialcell protein C receptorbyproinflammatorycytokines. increaseduse of activated protein C Reducedlevels of protein C severe sepsisandsepticshock.

12. 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.: Efficacyandsafety of recombinanthumanactivatedprotein C for severe sepsis. N Engl J Med2001, 344:699-709 Fijnvandraat K, Derkx B, Peters M, et al. Coagulationactivationandtissuenecrosis in meningococcalsepticshock: severelyreduced protein C levelspredict a highmortality. ThrombHaemost1995;73:15–20.

13. Activated Protein C • Replacementtherapywith protein C concentrate has beenshowntopreventcoagulopathyandimprovesurvival in animalmodels of Gram negativesepsis, and in humanswith severe meningococcaemiawheredysfunction of the protein C activationpathway is deemedcriticaltothedevelopment of disseminatedintravascularcoagulationandpurpurafulminans Taylor FB, Chank A, Esmon CT, et al. Protein C preventsthecoagulopathicandlethaleffects of E coliinfusion in thebaboon. J ClinInvest1987;79:918–25. Ettingshausen CE, Veldmann A, Beeg T, et al. Replacementtherapywith protein C concentrate in infantsandadolescentswithmeningococcalsepsisandpurpurafulminans. Semin ThrombHemost1999;25:537–41.

14. MicrocirculatoryHypothesis • Themicrothrombi, microvascularconstriction, and free radicals are valuable in limiting the spread ofinfection.

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

16. Diffusecomplementactivation (left) andcomplement in thelung (right) N Engl J Med 2003; 348:167

17. Clinicalsequelae of theproinflammatoryandantiinflammatoryresponsestosepsis Bone, RC, CritCareMed 1996; 24:1125

18. Decreasedoxygenextraction in sepsis Uptodate 2009

19. Gut Hypothesis • translocation of bacteria or endotoxin, • disruptedintestinalbarrier • Bacteria or endotoxin activates whiteblood cells and induces production of cytokines. Each can alterthe behavior of both endothelial cells and the coagulationsystem, leading to microvascular aggregation and productionof free radicals, which can, in turn, create a self-sustaining cyclethatculminatesinMODS

20. The Pathogenesis of Sepsis NEngl JMed 2003, 348;138-150.

21. 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 .

23. SEPSİS-mortalite N Eng J Med 2002;347:966-967

24. ‘‘Two-Hit’’ Hypothesis • an initial period of hypotension “primes”the trauma patient for SIRS/MODS (i.e., the initial insultactivates other processes that amplify the effects of the initialevent, howevermild). • a single insult is followed by a second, moresevere insult have shown that the first “hit” is actuallyprotective.

26. Protein C is a vitamin K dependentglycoproteinsynthesisedbytheliver Protein C circulates in theblood as an inactivezymogen. Inthe presence of thrombin, protein C bindstotworeceptors on theendothelialsurface, thrombomodulinandtheendothelial protein C receptor, andbecomesconvertedintoactivated protein C. Protein S is an essentialcofactorforactivated protein C

27. Plasma kortizol düzeyleri