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In the name of GOD Sepsis and related Syndromes Dr.M.Farahbakhsh 1 Important steps in microbial pathogenesis Encounter Attachment to host cells Local or general spread in the body (invasion) Cell and tissue damage Evasion of host defenses Shedding from the body 2 Non-immunologic host defenses 3 Endogenous infections 4 Note: Asymptomatic contaminations and normal endogenous flora waits for a SUITABLE situation for invasion. e.g: Staphylococcus aureus in skin that invades soft tissues after an abrasion. 5 Exogenous infections 6 Exogenous infections Exogenous infections occur after a direct contamination from microbial populations in the environment: ▪ in air, soil and water, ▪ in live animals, ▪ in other people with infections, and ▪ in healthy people who are carriers. 7 in air, soil, food and water Clostridium tetani and Bacillus anthracis Staphylococcus aureus, Clostridium perfringens and Clostridium botulinum, may be present in our food 8 in live animals the so-called zoonoses — include brucellosis, rabies 9 in other people with infections human-to-human transmission include the common cold, AIDS, Tuberculosis and … 10 in healthy people who are carriers people recovering from typhoid fever may retain Salmonella typhi in the gallbladder 11 GENERAL SIGNS, SYMPTOMS AND CONSEQUENCES OF THE HOST RESPONSE TO INFECTION 12 The classic peripheral signs and symptoms of inflammation (rubor, calor, dolor, tumor and functio laesa — redness, heat, pain, swelling and loss of function) commonly go hand in hand with general systemic signs and symptoms such as fever, chills, myalgias, headache and anorexia 13 Infection, Toxins, Inflammatory mediators, Immune reactions Fever Heat saving Heat production Monocytes, Macrophages, Endothelial cells, … Heat saving Heat production Pyrogenic cytochines IL-1, IL-6, TNF PGE2 from Hypothalamus Endothelium C AMP Temperature set point 14 انسان سه دشمن دارد: تب ،قحطی و جنگ؛ از این سه مهم ترین و آزارنده ترین“ تب ” است. ویلیام اسلر Definition H D E E L Bacteremia Septicemia Sepsis Sever sepsis Septic shock A T T H H 19 Definition Bacteremia is defined as growth of bacteria in blood cultures. Almost always Asymptomatic! 20 Definition H D E E L Bacteremia Septicemia Sepsis Sever sepsis Septic shock A T T H H 21 Definition Septicemia is presence of microbes or their toxins in blood. Fever! 22 Definition H D E E L Bacteremia Septicemia Sepsis Sever sepsis Septic shock A T T H H 23 Definition (1) (2) (3) (4) Sepsis is defined by presence of at least two of four signs of the systemic inflammatory response syndrome (SIRS); with infectious etiology: fever (>38° C) or hypothermia (<36° C); tachycardia (>90 beats per minute); tachypnea (>24 breaths per minute), hypocapnia (partial pressure of carbon dioxide <32 mm Hg), or the need for mechanical ventilatory assistance; and leukocytosis (>12,000 cells/mm3), leukopenia (<4000 cells/mm3), or a left shift (>10% immature band cells) in the white cell differential and suspected or proven infection. 24 Definition SIRS may be seen in non-infectious conditions. 25 Definition H D E E L Bacteremia Septicemia Sepsis Sever sepsis Septic shock A T T H H 26 Definition Severe sepsis is sepsis in addition to dysfunction of `(e.g. hypoxemia, oliguria, lactic acidosis, thrombocytopenia, decreased consciousness). 27 Definition H D E E L Bacteremia Septicemia Sepsis Sever sepsis Septic shock A T T H H 28 Definition Septic shock is defined as severe sepsis in addition to hypotension (systolic blood pressure <90 mm Hg or a decrease of >40 mm Hg from baseline) despite adequate fluid resuscitation. 29 Definition H D E E L Bacteremia Septicemia Sepsis Sever sepsis Septic shock A T T H H 30 Definition At the bedside, the clinician identifies shock by linking the clinical impression, synthesized from the patient's history of present illness, age, underlying health status, and general appearance, to quantitative data, including vital signs, blood chemistry, urine output, and direct measurements of oxygenation. 32 Definition In the laboratory, the scientist defines the metabolic effect of shock quantitatively, by examining the mechanisms by which shock alters mitochondrial energy transfer, evokes the production of toxic chemicals, and reduces their removal. 33 Epidemiology Approximately 750,000 cases of severe sepsis or septic shock occur every year in the United States. Contributing factor in more than >200,000 deaths/year Sepsis causes as many deaths as acute myocardial infarction, and septic shock and its complications are the most common causes of death in noncoronary intensive care units. 34 Epidemiology The frequency of septic shock is increasing ! Why? 35 Epidemiology Septic shock may be caused by gram-positive or gram-negative bacteria(70%), fungi, and, very rarely, protozoa or rickettsiae. gram-positive bacteria, especially methicillinresistant Staphylococcus aureus, vancomycinresistant enterococci, penicillin-resistant Streptococcus pneumoniae, and resistant gramnegative bacilli. 36 Epidemiology The common sites of infection causing septic shock are: pneumonia, peritonitis, pyelonephritis, abscess (especially intra-abdominal), primary bacteremia, cholangitis, cellulitis, necrotizing fasciitis, and meningitis. 37 Pathobiology Initially, septic shock activates inflammation, thereby leading to enhanced coagulation, activated platelets, increased neutrophils and mononuclear cells, and diminished fibrinolysis 39 Pathobiology After several days, a compensatory antiinflammatory response with immunosuppression may contribute to death. 40 Pathobiology Several pathways amplify one another inflammation coagulation 41 Pathobiology Widespread endothelial injury is an important feature of septic shock; an injured endothelium is more permeable, so fluid flux of protein-rich edema fluid into tissues such as the lung increases. Injured endothelial cells release nitric oxide, a potent vasodilator that is a key mediator of septic shock 42 Pathobiology Septic shock also injures epithelial cells of the lung and intestine. Intestinal epithelial injury increases intestinal permeability, and this leads to translocation of intestinal bacteria and endotoxin, which further augment the inflammatory phenotype of septic shock. 43 Pathobiology 1. Innate immune response TNF-α and interleukin-6 (IL-6) Cytokines upregulate adhesion molecules of neutrophils and endothelial cells, and neutrophil activation leads to bacterial killing Injury to endothelial cells 44 Pathobiology 2. Adaptive Immunity Adds Specificity and Amplification of the Immune Response Microorganisms stimulate specific humoral and cell-mediated adaptive immune responses that amplify innate immunity B cells release immunoglobulins that bind to microorganisms and thereby facilitate delivery of microorganisms to natural killer cells and neutrophils. 45 Pathobiology 3. Coagulation Response to Infection Septic shock activates coagulation system Fibrinogen fibrin which is bound to platelets to form microvascular thrombi. Microvascular thrombi further amplify endothelial injury by release of mediators and by tissue hypoxia because of obstruction to blood flow. 46 Pathobiology 4. Tissue hypoxia Upregulation of Erithropoitin that is protective for Brain and other tissues 47 Pathobiology 5. Late septic shock and immunosuppression Genetic: Death from infectious diseases appears to be heritable! Sepsis is a polygenic disease with an environmental insult (infection) 48 Pathobiology 6. Cardiovascular dysfunction Sinus tachycardia Decreased blood pressure Distributive shock and Functional hypovolemia Vasodilatation and Microvascular vasoconstriction Hypovolemia Decreased ventricular contractility Coronary ischemia 49 Clinical Manifestations 1.Primary source of sepsis and it’s presentations: Lung: Cough, Sputum, Fever, Chest pain,… Urinary: Disuria, Frequency, Flank pain, Tenderness … 2.Secondary manifestations: Acute Lung Injury Renal Dysfunction Gastrointestinal Tract Injury Hepatic Dysfunction Immune Dysfunction Cutaneous Manifestations Coagulopathy 50 Diagnosis Vital signs WBC ABG, lactate levels Source evaluation Lung, Urinary tract, Peritonitis Intravascular devices and I.V Skin and Soft tissues Surgical sites CNS 51 Diagnosis Appropriate cultures and Gram stains Positive blood culture in 40-70% of septic shock and 20-40% of sever sepsis cases. CXRay Abdominal sonography and CTscan Cardiac output Renal, Hepatic and Coagulation tests 52 Differential Diagnosis Acute pancreatitis Acute respiratory distress syndrome Aspiration pneumonitis Multiple trauma Recent major surgery Anaphylactic shock Spinal shock Acute adrenal insufficiency Acute hepatic failure Other causes of shock 53 Treatment 1.Respiratory therapy 2.Circulatory therapy 3.Erythrocytes and Erythropoietin 4.Drugs Antibiotics Corticosteroids Recombinant Human Activated Protein C 54 Treatment 1.Respiratory therapy O2 for all patients Mechanical ventilation (TV = 6ml/kg) Sedation with daily interruption 55 Treatment 2.Circulatory therapy Goals Increasing BP Increasing blood flow Increasing arterial oxygen saturation 57 Treatment 2.Circulatory therapy Central venous oxygen saturation > 70% CVP = 8-12 cmH2O Albumin (5 mL/kg) or Normal Saline (20 mL/kg) 58 Treatment 2.Circulatory therapy Dopamine, infused at 5-15μg/kg/min, or Norepinephrine , infused at 0.1-1μg/kg/min Packed red cells (if CV saturation <70%) to maintain Hct > 30% Dobutamine (2.5-20 μg/kg/minute) if CVP, arterial pressure, and hematocrit are optimized yet the central venous oxygen saturation remains less than 70% 59 Treatment 3.Erythrocytes and Erythropoietin Hematocrite = 30% In patients with M.I or U.A Recombinant Erithropoietine 60 Treatment 4. Drugs Antibiotics 61 Treatment 4. Drugs Antibiotics 62 Treatment 4. Drugs Antibiotics 63 Treatment 4. Drugs Antibiotics 64 Treatment 4. Drugs Antibiotics 65 Treatment 4. Drugs Antibiotics 66 Treatment 4. Drugs Antibiotics 67 Treatment 4. Drugs Antibiotics 68 Treatment 4. Drugs Antibiotics 69 Treatment 4.Drugs Corticosteroids are not recommended for all!! May be useful in patients who have serum Cortisol levels 9 μg/dL or less after a 250-μg corticotropin stimulation test Hydrocortisone 50mg IV QID + Fludrocortisone 50 μg/day P.O For 7 days 70 Treatment Recombinant Human Activated Protein C For high risk patients but not post surgery Activated protein C infusion (24 μg/kg/hour for 96 hours) decreases mortality, improves organ dysfunction, and decreases biomarkers of inflammation and coagulation in severe sepsis and septic shock 71 Prognosis 28 days mortality in septic shock is 40 – 70 % and 20-35% in sever sepsis. 72