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SEPTICEMIA, SEPSIS, SEPTIC SHOCK Definition An expert consensus conference of the American College of Chest Physicians and the Society of Critical Care coined the phrase systemic inflammatory response syndrome (SIRS) to describe a clinical syndrome believed to be the result of an overly activated inflammatory response. This new definition recognized the important role that endogenous mediators of systemic inflammation play in sepsis, which was no longer regarded as being caused by microbial pathogenicity factors alone . Septicemia is a dramatic clinical syndrome, which Fever, chills, tachycardia, tachypnea and altered mentation are common acute manifestations of septicemia. result from acute invasion of the bloodstream by certain microorganism or their toxic products. Bacteremia: is the presence of vivid bacteria in bloodstream confirmed by the blood culture with the isolation of a pathogen. Systemic inflammatory response syndrome (SIRS): contains two or more of the following conditions: fever, over the 38oC or hypothermia less than 36oC; tachypneea more than 20 breaths/min; tachycardia more than 90 beats/min.; leucocytosis more than 12000/mmc; leucopenia less than 4000/mmc or more than 10 percents immature forms. Sepsis means: SIRS plus a documented infection Severe sepsis Septic shock Multiple organ dysfunction syndrome (MODS) Respiratory: PaO2<80 mmHg, PaCO2>50mmHg, respiratory rate<5/min, or >50/min; Renal system: increased serum creatinine, oliguria (<480ml/24h); Cardiovascular system: hypotension, heart rate<55/min, ph<7.25; Hepatic system: serum bilirubin>60mg/l, TP<15%; Gastrointestinal system: bleedings, pancreatitis, ileus, perforation; CNS: Glasgow coma score <6; Hematologic system: platelet count<20000/mmc, leucocytes<1000/mmc, hematocrit<20%. Etiology Multiple components of the microbial structure may initiate the systemic inflammatory response. Gram positive: Streptococcus pneumoniae Staphylococcus aureus/epidermidis Streptococcus pyogenes Clostridium Gram negative: Neisseria meningitidis Gram negative bacilli: E. coli, Salmonella, Klebsiella, Pseudomonas, Yersinia pestis, Vibrio vulnificans, Aeromonas species Rickettsia rickettsii Capnocytophaga canimorsus Erlichia species Bartonella species Dengue viruses Viruses - causes of the hantavirus pulmonary syndrome Plasmodium falciparum Babesia microti Anaerobes: peptococcus, microaerofili streptococci, Actimomyces israelii. Epidemiology Predisposing factors include: diabetes mellitus, cirrhosis, alcoholism, leukemia, lymphoma or disseminated carcinoma, cytotoxic chemotherapy and immunosuppresive drugs which cause neutropenia, total parenteral nutrition, a variety of surgical procedures and infections arising from the urinary, biliary or gastrointestinal tracts. Pathogenesis and pathology Most of the bacteria causing gram-negative sepsis are normal commensals in the gastrointestinal tract. From there they may spread to contiguous structures (as in peritonitis after appendiceal perforation), or they may migrate from the perineum into the urethra or bladder. Gram-negative bacteremia follows infection in a primary forms, usually the: genitourinary tract, biliary tree, gastrointestinal tract or lungs and less commonly, the skin, bones and joints. Metastatic abscess formation may complicate bacteremia. The involved target organs are: lungs: pulmonary-edema, hemorrhage and hyaline membrane formation, abscesses, bronchopneumonia kidney: tubular or cortical necrosis, myocardium: patchy necrosis, superficial ulceration or even hemorrhage necrosis gastrointestinal tract, superficial ulceration or even hemorrhage necrosis capillaries in many tissues: leukocyte-platelet or fibrin thrombus formation brain /meninges: abscesses, meningitis Pathophysiology Table 1: Virulence factors of Staphylococcus aureus and their proposed pathogenic mechanism VIRULENCE FACTORS OF STAPHYLOCOCCUS AUREUS AND THEIR PROPOSED PATHOGENIC MECHANISM ` Twart host defenses Microcapsule Protein A Coagulase Fatty acid-metabolizing enzyme Leukocidin and/or gama-toxin Invade tissueProteases NucleasesLipases Hyaluronate lyase StaphylokinaseElicit sepsis syndrome Toxic shock syndrome toxin Enterotoxins Cytolytic toxins (alpha, beta, gama and delta)Induce specific toxinosis Toxic shock syndrome toxin EnterotoxinExfoliative toxin Attach to endothelial cells and basement membrane Binding proteins for fibrinogen, fibronectin, laminin, collagen, vitronectin and Clinical manifestations Clinical manifestations are related to the following elements: I.Portal of entry Skin: erysipelas, staphylococcal skin infection, trauma, burns; Respiratory tract infections Gastrointestinal tract lesions: stomatitis, gingivitis, teeth extraction, enterocolitis; Genito-urinary tract infections II.Lymphangitis and primary sites of infection III.Positive blood cultures: hematogenous dissemination is manifested with fever, chills, headache; IV.Metastatic foci of infection: Cardiovascular system: infective endocarditis, myocarditis, pericarditis Central nervous system: brain abscess, epidural abscess, purulent meningitis (confusion, obtundation, coma); Respiratory system: bronchopneumonia, pleural effusion (acute respiratory distress syndrome, tachypnea, hypocapnea); Gastrointestinal: liver and spleen abscess, impaired gastrointestinal motility, sterss related mucosal disease, hyperbilirubinemia, elevation of liver enzymes. Renal system: renal abscess, nephritis Bone and joint involvement: osteitis, osteomyelitis, spondylodiscitis, arthritis Cutaneous manifestations: cellulitis, flegmons, diffuse erythroderma (caused by gram-positive organisms and by the action of pyrogenic or erythrogenic toxins); colorful skin lesions such as ecthyma gangrenosum (associated with P. aeruginosa septicemia), colorful vezicular or bullous lesions, cellulitis, petechial lesions (may appear in gram negative septicemia) Toxic shock syndrome Clinical manifestations 1. Hemodynamic changes: 2. Dermatologic findings: 3. Severe myalgias, muscle tenderness, weakness 4. Diarrhea, nausea, vomiting] 5. Encephalopathy 6. Respiratory distress syndrome 7. Acute renal failure 8. Hepatic necrosis 9. Disseminated intravascular coagulation. Table 4: Streptococcal Toxic Shock Syndrome Streptococcal Toxic Shock Syndrome – definition An acute, febrile illness that begins with a mild viral-like prodrome or minor soft-tissue infection and may progress to shock, multiorgan failure and death Symptoms Early symptoms are vague: Viral-like prodrome Severe pain and erythema of an extremity Mental confusion Signs Hypotension, systolic Fever > 38 degree Soft-tissue swelling Tenderness Respiratory failure, rales, cyanosis, tachypneea Laboratory features Hematologic: Marked left shift Decline in hematocrit Thrombocytopenia Renal azotemia (2,5 x normal on admission) and hematuria Hypocalcemia Hypoalbuminemia Creatine phosphokinase elevation Pulmonary abnormalities: -Pulmonary infiltrate on chest x-ray -Hypoxia Table 5. Laboratory investigations in sepsis Complete blood count Blood chemistry Urinalysis Chest radiography Erythrocyte sedimentation rate Blood cultures (3 or more separate specimens) Cultures from other biologic fluids (pus, pleural effusion, joint effusion, catheter, etc) Antinuclear antibodies Rheumatoid factor Computed tomography of abdomen, pelvis, other sites Radionuclide scansVenous duplex imaging of lower limbs Echocardiography Differential diagnosis Infectious diseases Bacterial infections Rickettsial infections Viral infections:, Parasitic infections: Fungal infections: Non-infectious diseases Neoplastic diseases:; Autoimmune diseases: Hypersensitivity; Granulomatous diseases: Other: CNS hemorrhage, CNS degenerative diseases, familial Mediteranean fever, cholangitis. Treatment A. Initial therapy for the sepsis syndrome Community-acquired infections Suspected staphyloccocal etiology: oxacillin+aminoglycoside Suspected genito-urinary source: a third generation cephalosporin (3GC); a quinolone; ticarcillin/piperacillin with/without an aminoglycoside; Non-urinary tract source: 3GC or ampicillin/ticarcillin/piperacillin – beta lactamase-inhibitor (BLI) Hospital-acquired infections: Non-neutropenic patients: 3GC with/without metronidazole, cefepime, a beta lactam drug-BLI/imipenem with/without an aminoglycoside Neutropenic patients: ceftazidime + an aminoglycoside; ticarcillinclavulanat/piperacillin-tazobactam + an aminoglycoside; imipenem/meropenem + an aminoglycoside. Tabel 6.First intention treatment and alternative therapy for infective endocarditis on native valve Etiology S.aureus metiSS.aureus meti-RS.viridans, S. bovis- sensitive to Pen. G(CMI<o,1microg/ml) S.viridans, S.bovis with CMI PenG:0,1-0,5microg/ml. S viridans, S.bovis (CMI PenG>1), enterococi sensitive to ampi/Pen G, vanco, genta Enterococi (CMI Pen G >16ng/ml) Enterococi pen/ampi R, high resistance to genta, vancoR Difteroizi sensitive to genta (MIC<4/ml)Difteroizi resistent to genta (>4/ml) gram-negative cocobacili from the group HACEK* BartonellaCandida EI on valvular prothesis with negative bloodcultures First intention treatment Alternative (oxaciline 8g/d iv, every 4h)x4-6wks +gentax3-5days (Vanco 2g/d iv, every 12h)x4-6wks Pen.G 12-18milU/d, iv, cont/4hx2 wks + genta 3mg/kg/d x2wks or Pen G x4wks or Ceftriaxone 4g/d x4wks Pen G 18mil U/d x4wks+genta 3mg/kg/d x 2wks, Pen G 18milU/24h, 4-6spt+genta 46wks, or (AMP12g/zi iv cont or every 4h+genta)x4-6wks Vanco+gentax4-6wks Quinupristin/dalfopristin or linezolid 1200mg/zi iv PenG+gentax6wks Vancox6wks Ceftriaxone 2-3g iv or cefotaxime 3g ivx6wks Fluoroquinolone or RIF or macrolide Amfotericine B+/-an azol (fluconazole) Vanco+RIF+gentax6wks 1. Cefazolin 6g ivx46weeks+genta3mg/kgx 3-5d, OR 2. Vanco 46wks 3. (Ceftriaxone + genta)x2wks 4. vanco 30mg/kgc/d until la 2g/dx4wks 5. (vanco+genta) x46wks 7.Vancox6wks Ampi 12g/d+(strepto 15mg/kg-1g/d or genta)x6wks Table 7. Infective endocarditis on prosthetic valve Etiology S. epidermidis S.aureus meti-R S.aureus meti-S EI on valvular prothesis with negative bloodcultures For the other etiology First intention treatment (Vanco 2g/d iv, every 12h+RIF 900mg/d, every 8h)x6wks +genta* 240mg/d every 8 hx2wks “ “ “ (oxaciline 8g/d iv, every 4h+RIF)x6wks +gentax2wks Vanco+RIF+gentax6wks As for the native valve endocarditis. Alternative Vanco+Fluoroquinolone+RI F “ “ “ B. Adjunctive measures in the treatment of sepsis syndrome Maintenance of adequate tissue perfusion with volume replacement: normal saline solution, fresh frozen plasma, albumin, dextran, crystaloid solutions. Sympatomimetic amines: dopamine, dobutamine Corticosteroids for gram-negative rod septicemia-is controversed. Diuretics for the early oliguric phases of schock.