Sepsis, Severe Sepsis, and Septic Shock

1. Sepsis, Severe Sepsis, and Septic Shock Anna Piekarska MD, PhD

2. Epidemiology • severe sepsis, defined as documented infection and acute organ dysfunction, occurred in 300 cases per 100,000 population • Incidence was higher in men than in women and in nonwhite persons than in white persons.

3. Epidemiology • median age for patientswith a sepsis-relatedhospitaldischargediagnosisisapproximately60 years • low-birth-weightnewborns - 500 cases/100,000 population per year

4. Epidemiology • 80% of the cases of severe sepsis in adults occurred in individuals who were already hospitalized for another reason • In 30% to 50% of the cases, a definite microbial etiology was not found

5. Pathogenesis- normal host immune response to infection

6. Normal Systemic Responses to Infection and Injury • Leukocytosis • Mobilizes neutrophils into the circulation • Tachycardia • Increases cardiac output, blood flow to injured tissue • Fever • Raises core temperature; • Peripheral vasoconstriction shunts blood flow to injured tissue. • Occurs much more often when infection is the trigger for systemic responses

7. Acute-Phase Responses • Anti-infective • Anti-inflammatory • Procoagulant • Metabolic • Thermoregulatory

8. Normal Systemic Responses to Infection and Injury: Presumed Contributions to Host Defense • Anti-infective: • Increases synthesis of complement factors, microbe pattern-recognition molecules (mannose-binding lectin, LBP, CRP, CD14, others)  • Sequesters iron (lactoferrin) and zinc (metallothionein)

9. Normal Systemic Responses to Infection and Injury: Presumed Contributions to Host Defense • Anti-inflammatory • Releases anti-inflammatory neuroendocrine hormones: cortisol, ACTH, epinephrine , α-MSH • Increases synthesis of proteins that help prevent inflammation within the systemic compartment • Cytokine antagonists (IL-1Ra, sTNF-Rs) • Anti-inflammatory mediators (e.g., IL-4, IL-6, IL-6R, IL-10, IL-13, TGF-β) • Protease inhibitors (e.g., α1-antiprotease) • Antioxidants (haptoglobin)

10. Normal Systemic Responses to Infection and Injury: Presumed Contributions to Host Defense • Procoagulant: • Wallsoffinfection, preventssystemicspread • Increasessynthesisorrelease of fibrinogen, PAI-1, C4b • Decreasessynthesis of protein C, anti-thrombin III

11. Normal Systemic Responses to Infection and Injury: Presumed Contributions to Host Defense • Metabolic: • Preserves euglycemia, mobilizes fatty acids, amino acids • Epinephrine , cortisol, glucagon, cytokines

12. Normal Systemic Responses to Infection and Injury: Presumed Contributions to Host Defense • Thermoregulatory; • Inhibits microbial growth • Fever

13. Pathologic Host Responses to Infection • Sepsis • Severe Sepsis • Septic Shock

14. Bacteremia • Cultivatable bacteria in the blood stream • May be transient and inconsequential; inconsistent correlation with severe sepsis

15. Sepsis • The systemic response to infection • If associated with proven or clinically suspected infection, SIRS is called "sepsis" in the American consensus scheme

16. Systemic inflammatory response syndrome (SIRS) • The systemic response to a wide range of stresses. • Currently used criteria include two or more of the following: • Temperature >38°C or <36°C • Heart rate >90 beats/min • Respiratory rate >20 breaths/min, or Paco2 <32 mm Hg • WBC >12,000 cells/mm3 or <4000 cells/mm3, or >10% immature (band) forms

17. Severe sepsis • Sepsis associated with dysfunction of organ(s) distant from the site of infection, hypoperfusion, or hypotension. The term sepsis syndrome had a similar definition • Hypotension: • A systolic blood pressure of <90 mm Hg, • Or: MAP <70 mm Hg, • or a reduction of >40 mm Hg from baseline

18. Pathogenesis of Severe Sepsis • Microcirculatory Dysfunction. • Activation or Injury of the Vascular Endothelium. • Cytokines and Other Mediators. • Complement Activation. • Coagulopathy. • Immunosuppression.

19. Sepsis – what’sthe point? Patologicactivation of immunology system Immunosupression and anergy

20. Pro-inflamatory Cytokines e. TNF-α Anti-inflamatory Cytokines e. IL-10 Activation and stimulation of cytokines, neutrofiles, macrofages, dendritic and endothelialcells preventssystemicspread of infection

21. Severe sepsis • Brain blood flow decreasing • Oliguria or anuria • ARDS- lung injury • Cardiovascular injury • Liver injury • DIC

22. Septic shock • Sepsis with hypotension that, despite adequate fluid resuscitation, requires pressor therapy. • In addition, there are perfusion abnormalities that may include: • lactic acidosis, • oliguria, • altered mental status, • and acute lung injury

23. Pathogenesis of Septic Shock • Tachyphylaxis to catecholamines, which diminishes the sensitivity of vascular smooth muscle to catecholamines as pressors • The underproduction or ineffectiveness of glucocorticoids, which upregulate adrenergic receptors • The production of adrenomedullin, which has vasodilatory actions, increases renal blood flow, and inhibits aldosterone secretion • The release of nitric oxide from sites of inflammation and/or distant vascular endothelium • The absence of the normal baroreflex response that increases circulating vasopressin levels (and depletion of neurohypophyseal vasopressin stores) • The release of PAF • The activation of KATP channels in arteriolar smooth muscle cells by hypoxia and lactate • The generation of bradykinin, a vasodilator that also increases capillary permeability

24. Microbial Triggers for Severe Sepsis

25. Diagnosis No bedside or laboratory test provides a definitive diagnosis. • SIRS (tachycardia, tachypnea, leukocytosis or leukopenia, and fever or hypothermia, altered mental status, unexplained hyperbilirubinemia, metabolic acidosis, thrombocytopenia • The appearance of new lesions on the skin or mucosae

26. Differential Diagnosis • burns, trauma, • adrenal insufficiency, • pancreatitis, • pulmonary embolism, • dissecting or ruptured aortic aneurysm, • myocardial infarction, • occult hemorrhage, • cardiac tamponade, • drug overdose.

27. Differential Diagnosis • Fever and hypotension can also be caused by a number of noninfectious processes: • including adrenal insufficiency, • thyroid storm, • pancreatitis, • drug hypersensitivity reactions, • malignant hyperthermia, • heatstroke.

28. Microbiology and treatmentLungs

29. Microbiology and treatmentLungs

30. Microbiology and treatmentAbdomen

31. Microbiology and treatmentAbdomen

32. Microbiology and treatment Skin/Soft Tissue

33. Microbiology and treatment Skin/Soft Tissue

34. Microbiology and treatmentUrinary Tract

35. Microbiology and treatmentUrinary Tract

36. Microbiology and treatment Meninges

37. Microbiology and treatment Meninges

38. Dosages for intravenous administration (normal renal function) • Imipenem-cilastatin, 0.5 g q6h • Meropenem,1.0 g q8h • Piperacillin-tazobactam, 3.375 g q4h or 4.5 g q6h • Vancomycin 15 mg/kg q12h (if meningitis, 25 mg/kg q12h) • Cefepime 1-2 g q8h • Ciprofloxacin, 400 mg q12h, • Gatifloxacin  , 400 mg qd, Moxifloxacin 400 mg qd • Ceftriaxone, 2.0 gm q24h • Levofloxacin   500 mg qd

39. Special procedures • Surgical drainage • Intravenous fluids- 4-6 l of crystaloids • Blood transfusion • Pressor drugs- MAP above 60 mm Hg • Hydrocortisone- 50 or 100 mg every 6 to 8 h i.v. • Vasopressin • Anti-inflammatory Drugs (antiendotoxin antibodies and bactericidal permeability-increasing protein, which neutralizes endotoxin; antibodies to TNF and TNF-immunoglobulin fusion proteins that trap TNF; IL-1 receptor antagonist; and antagonists to PAF, bradykinin, phospholipase A2, NO synthase, cyclooxygenase, bradykinin, and others)

40. DIC

41. Special procedures Anticoagulants • aPC (drotrecogin alfa [Xigris]) • Indication: severe sepsis with DIC • Contrindications: • severe liver disease, • a platelet count of less than 30,000/mm3, • prothrombin time- (INR) greater than 3.0, • recent bleeding (including hemorrhagic stroke) • known bleeding diathesis, • recent surgery

42. Prevention • Prevention of hyperglycemia • keep the blood glucose level between 100 and 140 mg/dL • Augmentation of host defenses

43. Prognosis • Mortality: 30% and 50%