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 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 patients with a sepsis-related hospital discharge diagnosis is approximately 60 years
low-birth-weight newborns 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
                                                                                                                           
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:
Walls off infection, prevents systemic spread
Increases synthesis or release of fibrinogen, PAI-1, C4b
Decreases synthesis 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’s the point?
Patologic activation of immunology system
Immunosupression and anergy

20. Activation and stimulation of cytokines, neutrofiles, macrofages, dendritic and endothelial cells prevents systemic spread of infection
Pro-inflamatory
Cytokines
e. TNF-α
Anti-inflamatory
Cytokines
e. IL-10

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 treatment Lungs
Major community-acquired pathogens
Empirical antibiotic therapy
Streptococcus pneumoniae Haemophilus influenzae Legionella Chlamydophila pneumoniae
Moxifloxacin or gatifloxacin or azithromycin
plus either
cefotaxime or ceftazidime

29. Microbiology and treatment Lungs
Major commensal or nosocomial microorganisms
Empirical antibiotic therapy
Aerobic gram-negative bacilli
Imipenem-cilastatin
or meropenem
or cefepime

30. Microbiology and treatment Abdomen
Major community-acquired pathogens
Empirical antibiotic therapy
Aerobic gram-negative rods Anaerobes Candida species
Imipenem
or meropenem
or piperacillin-tazobactam ± aminoglycoside
(Consider amphotericin B )

31. Microbiology and treatment Abdomen
Major commensal or nosocomial microorganisms
Empirical antibiotic therapy
Aerobic gram-negative bacilli
Imipenem-cilastatin
or meropenem
or cefepime

32. Microbiology and treatment Skin/Soft Tissue
Major community-acquired pathogens
Empirical antibiotic therapy
Streptococcus pyogenes Staphylococcus aureus Polymicrobial
Vancomycin plus either imipenem
or meropenem
or piperacillin-tazobactam

33. Microbiology and treatment Skin/Soft Tissue
Major commensal or nosocomial microorganisms
Empirical antibiotic therapy
Staphylococcus aureus
(? MRSA) Aerobic gram-negative rods
Vancomycin plus cefepime

34. Microbiology and treatment Urinary Tract
Major community-acquired pathogens
Empirical antibiotic therapy
E. coli Klebsiella species Enterobacter species Proteus species Enterococci
Ciprofloxacin or levofloxacin (If gram-positive cocci, use ampicillin plus gentamicin)

35. Microbiology and treatment Urinary Tract
Major commensal or nosocomial microorganisms
Empirical antibiotic therapy
Aerobic gram-negative rods Enterococci
Vancomycin plus cefepime

36. Microbiology and treatment Meninges
Major community-acquired pathogens
Empirical antibiotic therapy
S. pneumoniae Neisseria meningitidis Listeria monocytogenes H. influenzae
Vancomycin plus either ceftriaxone
or cefepime

37. Microbiology and treatment Meninges
Major commensal or nosocomial microorganisms
Empirical antibiotic therapy
Aerobic gram-negative rods Staphylococci
Cefepime plus vancomycin

38. Dosages for intravenous administration (normal renal function)
Imipenem-cilastatin, 0.5 g q6h
Meropenem,1.0 g q8h
Piperacillin-tazobactam, g q4h or 4.5 g q6h
Vancomycin 15 mg/kg q12h (if meningitis, 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 Augmentation of host defenses
keep the blood glucose level between 100 and 140 mg/dL
Augmentation of host defenses

43. Prognosis
Mortality: 30% and 50%