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

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.

Epidemiology median age for patients with a sepsis-related hospital discharge diagnosis is approximately 60 years low-birth-weight newborns - 500 cases/100,000 population per year

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

Pathogenesis- normal host immune response to infection                                                                                                                             Pathogenesis- normal host immune response to infection

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

Acute-Phase Responses Anti-infective Anti-inflammatory Procoagulant Metabolic Thermoregulatory

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)

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)

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

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

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

Pathologic Host Responses to Infection Sepsis Severe Sepsis Septic Shock

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

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

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

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

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

Sepsis – what’s the point? Patologic activation of immunology system Immunosupression and anergy

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

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

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

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

Microbial Triggers for Severe Sepsis

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

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

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.

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

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

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 )

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

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

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

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)

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

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

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

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

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)

                     DIC

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

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

Prognosis Mortality: 30% and 50%