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1. gram negative sepsis dr shabeel pn www.hi-dentfinishingschool.blogspot.com

3. The Increasing Importance of the Intensive Care Unit 356 358 360 362 364 366 368 370 372 374 1988 1989 1990 1991 1992 1993 1994 1995 Mean no of hospital beds 36 38 40 42 44 46 48 50 Mean no of ICU beds Clin Infect Dis 1997;24:211-215 Seminars in Respiratory and critical care med 2003,24(1):3-22, Though ICUs account for only 8% of hospital beds, 45% of infections in a hospital originate in an ICU

4. Distribution of major sites of infection in medical ICU’s 5% 5% 6% 30% 30% 16% 3% 3% CVS GI LRI PN UTI BSI SST EENT Ref. : Seminars in Respiratory and critical care med 24(1):3-22,2003

6. Eight most common pathogens associated with nosocomial infection in an ICU, NNIS January 1989 - July 1998 Clinics in Chest Medicine 1999; Vol 20: No: 2,JAC 2003; 51, Suppl S2, 115-117 13.7 12.6 1.6 16.8 10.7 11.4 S. aureus 3.5 3.5 6.1 6.5 2.9 4.7 Klebsiella Pneumoniae 4.3 4.8 15.3 4.0 4.9 6.6 Candida Albicans 4.0 8.1 18.2 4.4 2.9 7.0 E. coli 6.8 8.8 5.7 10.7 4.2 7.3 Citrobacter spp. 5.9 14.5 13.8 1.9 10.3 8.1 Enterococci spp. 8.7 9.2 10.6 16.1 3.0 9.9 P. aeruginosa 15.4 13.5 3.1 2.5 39.3 14.3 Coagulase negative staphylococci Others n=52,066 SSI n=22,043 UTI n=47,502 PNEU n=64,056 BSI n=50,091 All sites n=235,758

13. Sepsis the systemic response to infection Pathophysiology : a continuum A disorder due to uncontrolled inflammation or due to failure of the immune system? Clinical presentation of sepsis A disorder due to uncontrolled inflammation ? Or due to failure of the immune system? LIR Local infection SIRS SEPSIS SIRS altered organ perfusion SEVERE SEPSIS Lung failure Cardio vascular failure ARDS SEPTIC SHOCK Renal failure Liver failure CNS failure Heme failure MOFS D E A T H D E A T H bacteria fungi, viruses parasites focus When microorganisms invade, multiply in a sterile site Site of infection TUMOR NODES METASTASES D E A T H Death Characteristics of the particular pathogen GENETIC POLYMORPHISMS

14. Mortality Increases in Septic Shock Patients Mortality Incidence Balk, R.A. Crit Care Clin 2000;337:52 Approximately 200,000 patients including 70,000 Medicare patients have septic shock annually Septic Shock 53-63% 20-53% Severe Sepsis 300,000 7-17% Sepsis 400,000

15. Dear SIRS I don’t like you...

16. Definitions Cont.

22. THE EARLIEST , THE BETTER

23. Candida endophtalmitis Urinary tract infection Candiduria with leukocyturia >10 5 mL Pancreas pancreatitis liver Candida in the blood Peritoneal infection Candida in peritoneal cavity +drainage cultures HIGH RISK PATIENT >3 risk factors and symptoms 2 or more Candida positive foci spleen Tipical Ct scan findings Prophylaxis therapy Signs and symptoms of infection and organ dysfunction Certain infection Suspected infection Definite therapy Early pre-emptive/empiric therapy Cultures of Pleural fluid Pericardial fluid, BAL, Tracheal aspirate >10 4 BAL >10 3 PBS abnormal chest radiograph

24. “ MORE IS MISSED BY NOT LOOKING THAN BY NOT KNOWING” Anonymous Patient examination in the Intensive Care Unit

27. Cytokines Kinetics

33. ANTIBIOTICS IN SEPSIS 2 Monotherapy with carbapenem antibiotics = β-lactam and an aminoglycoside (Netspan) Extended spectrum carboxypenicillins or ureidopenicillins combined with beta lactamase inhibitors (Tazact) have been shown to be effective for the treatment of suspected infections in febrile , neutropenic cancer patients and in patients with peritonitis or nosocomial pneumonia. Monotherapy with aztreonam appears to be as effective as combination of a beta lactam and an aminoglycoside (Netspan) for the treatment of patients with documented Gram negative sepsis

34. TREATMENT OPTIONS FOR INFECTIONS DUE TO EXTENDED –SPECTRUM β-LACTAMASE (ESBL) PRODUCING ORGANISMS ? Cefepime (in very high dose) MEROPENEM Post-neurosurgical meningitis Quinolone CARBAPENEM Intra-abdominal infection Quinolone CARBAPENEM (imipenem or meropenem) Bacteremia Quinolone CARBAPENEM / betalactam-beta-lactamase inhibitor combination (TAZACT ) Ventilator-associated pneumonia Amoxycillin/clavulanate QUINOLONE Urinary tract infection SECOND CHOICE FIRST CHOICE

35. Possible empiric antibiotic choice in severe sepsis Nosocomial severe sepsis and septic shock without a clear site of infection: Beta lactam + vancomycin + aminoglycoside or quinolone Ureidopenicillin + aminoglycoside or Ceftazidime monotherapy Neutropenic Ureidopenicillin + aminoglycoside Biliary tract Cefotaxime + metronidazole or Ureidopenicillin + aminoglycoside or Carbapenem (monotherapy), quinolone Intra-abdominal Benzyl-penicillin + nafcillin (flucloxacillin) Cefotaxime + nafcillin or Cefotaxime + vancomycin Skin and soft tissue Community acquired Hospital acquired Quinolone Amoxicillin + clavulanic acid (co-amoxiclav) Ceftazidime alone or Ureidopenicillin + aminoglycoside Urinary trait Community acquired Hospital acquired Cefotaxime + erythromicin Cefotaxime/ceftazidime alone or Ureidopenicillin + aminoglycoside Carbapenem , quinolone Pneumonia Community acquired Hospital acquired VAP antibiotic Suspected site of infection

38. Biofilm , Antimicrobial Resistance and Infections Stimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes The ability of catecholamine inotropic drugs to stimulate bacterial proliferation and biofilm formation may be an aetiological factor in the development of intravascular catheter colonisation and catheter related infection. The removal of iron from trasferrin for subsequent use by S. epidermidis is a possible mechanism by which catecholamine inotropes stimulate bacterial growth as biofilms Lancet 2003; 361:130-135 Singh PK, Parsek MR, Greenberg EP, Welsh MJ A component of innate immunity prevents bacterial biofilm development . Nature 2002; 417:552-5 Drenkard E, Ausubel FM Psedomonas biofilm formation and antibiotic resistance are linked to phenotypic variation. Nature 2002; 416:740-3 Planktonic growth Pili Flagella Antibiotic susceptibility QS QS QS QS Quorum Sensors (homoserine lactones) Transcriptional activators LasR RhIR Proteases Hemolysins ExotoxinA Pyocyanin Superoxide dismutase Catalase ANTIBIOTIC RESISTANCE

39. Mortality with and without appropriate antibiotics Pierre Yves Bochem Intensive Care Med (2001) 27

40. Hospital mortality and rates of inadequate antimicrobial treatment according to the most common pathogens associated with bloodstrem infections. OSSA= oxacillin sensitive S aureus; CNS= coagulase negative staphylococci; VRE= vancomycin resistant enterococci Chest 2000; 118:146-155

42. Immunocompromised Host + Infection septicaemia Inadequate antibiotic therapy (e.g. penicillin binding protein (PBP)-2 and 3 specific) PBP3 PBP2 Induction of filamentous bacterial forms Conversion of bacilli to round, spheroidal cells High bacterial mass High endotoxin release SEPTIC SHOCK Other factors Aztreonam Piperacillin Mezlocillin and at lower concentration Cefuroxime Ceftazidime Cefotaxime Imipenem Meropenem Mecillinam Cefepime Intermediate endotoxin release Low endotoxin release Tobramycin,Amikacin Gentamicin,Polymyxins Teicoplanim,Vancomycin Ciprofloxacin,Moxifloxacin

43. SCREEN * Hemocultures *Colonization index *Signs and symptoms of sepsis SICK NOT SICK NOT SICK SICK + - SEPTIC OK Removal of catheters To treat? =To treat Removal of catheters Antifungal therapy Know the fungal species and antibiogram (MIC) Fluconazole or Ambisome or Caspofungin or both Prophylaxis with high dose fluconazole SEPTIC Surveillance: Hemocultures plus Colonization index >2 sites or clinical or sterile site positive. Sepsis in spite of antibiotics Treat like candida NOT SEPTIC bacterical sepsis plus 2 sites probably treatment PROPHYLAXIS In high risk patient *oral nasogastric Nystatin Fluconazole *Yoghurt Positive Fungal hemocultures Negative Fungal hemocultures Assess clinical scenario

45. Supplemental oxygen +/- Endotracheal intubation and Mechanical ventilation Central venous and Arterial catheterization Sedation,paralysis (if intubated) Or both CVP MAP ScvO2 Goals achieved ICU admission crystalloid colloid 8-12 mmHg Vasoactive agents >65 and<90mmHg <65mmHg >90mmHg Transfusion of red cells Until hematocrit>30% >70% <70% Inotropic agents <70% >70% NO YES Rivers E et al “ EGDT in the treatment of severe sepsis and septic shock” N Engl J Med 2001, 345:1368-1377

46. Clinical diagnosis of ALI If 150 > PaO2/FiO2 >100 If PaO2/FiO2 < 100 Colloids and diuresis Colloids and CVVH Colloids and CVVH

48. Administration of low dose dopamine by continuous intravenous infusion (2 μg/Kg/min/) to critically ill patients at risk of renal failure does not confer clinically significant protection from renal dysfunction Low dose dopamine in patients with early renal dysfunction: A placebo controlled randomized trial (ANZICS clinical trials group) Lancet 2000; 356:2139-43 low dose of dopamine is thought to be harmless. That is not true. DOPAMINE: * suppress respiratory drive * increase cardiac output * increase myocardial VO2 * trigger myocardial ischaemia, arrhytmias * induce hypokalaemia, hypophosphataemia * predispose to gut ischaemia * disrupt metabolic, immunological homoeostasis (action on T cells function) There is no justification for using “renal dose” dopamine in the critically ill

49. Normal nonstressed function of the hypothalamic- pituitary-adrenal axis Normal function of the hypothalamic-pituitary- adrenal axis during illness Corticosteroid insufficiency during acute illness Binding of cortisol to corticosteroid binding globulin Increased cortisol and decreased corticosteroid binding globulin Decreased cortisol and Decreased corticosteroid Binding globulin Normal action in tissue Increased action in tissue Decreased action in tissue Hypothalamus Reduced feedback Pitutary Adrenal CTRH + ACTH + - - Stress cytokines CTRH++ ACTH++ + Cytokines,local corticosteroid activation + - CTRH+ ACTH+ Cytokines Glucocorticoid resistance - Central nervous system disease, corticosteroids Pituitary apoplexy, corticosteroids Cytokines, anesthetics antiinfective agents corticosteroids hemorrage, infection - - - - - A B C Activity of the Hypothalamic-Pitutary-Adrenal Axis under Normal Conditions (A), during an Appropriate Response to Stress (B) and during an Inappropriate Response to Critical Illness ( C )

50. Potential effetcs of corticosteroids during septic shock Activation of IKB-  Inhibition of NFk-  Correction of a relative adrenocortical deficiency Reversal of adrenergic receptor desensitization deficiency Inhibition of inducible iNOS Hemodynamic improvement Decrease in the dosage of catecholamines Decreased trascription for proinflammatory cytokines, Cox-2, ICAM-1, VCAM-1. Increased transcription for IL-1-RA

51. Nonresolving acute respiratory distress syndrome Initiate pharmacologic glucocorticoid therapy Critical illness (especially if features of corticosteroids insufficiecy are present Randomly, timed measurement of cortisol level <15 μg/dl 15-34 μg/dl >34 μg/dl Increase in response to corticotropin test <9 μg/dl > 9 μg/dl Hypoadrenalism likely Functional hypoadrenalism unlikely Consider physiologic Corticosteroid replacement Corticosteroid therapy Unlikely to be helpful Investigation of adrenal corticosteroid function in critically ill patients on the basis of cortisol levels and response to the corticotropin stimulation test. It must be borne in mind that no cutoff value will be entirely reliable THE SCHEME HAS BEEN EVALUATED FOR PATIENTS WITH SEPTIC SHOCK Annane et al. JAMA 2000 283:1038-1045 Annane et al JAMA 2002 288:862-871

52. Mild illness or condition (nonfebrile cough or cold Dental extraction with Local anesthetic) Moderate illness or condition(fever, minor trauma,minor surgery) Severe illness or condition (major surgery, trauma, critical illness Septic shock (cathecolamine dependency, poor response to ACTH) Increase dose to 15mg of prednisolone/day or equivalent Increase dose to 50mg of Hydrocortisone IM or IV every 6 hr 50 mg of Hydrocortisone IV Every 6 hr with or without 50 μg of Fludrocortisone/ day Return to normal dose 24 hr after resolution Taper dose to normal by decreasing by 50% per day Treat for 7 days No change Suggested corticosteroid replacement doses during intercurrent and acute illness in patients with proven or suspected adrenal insufficiency, including those receiving corticosteroid therapy

54. Glycolysis Proteinolysis Lipolysis Lactate pyruvate Gluconeogenesis Glycolysis Glycerol Amino acids Glucose Lactate Glycogen Glucose Pyruvate Alanine Glucose Pyruvate Alanine Lactate Alanine COUNTER REGULATORY HORMONES CYTOKINES STRESS glycogen LIVER

55. INFECTION symptoms Specific care Supportive care SEPSIS SEVERE SEPSIS SEPTIC SHOCK MODS BP Oxygenation BP Oxygenation Oliguria Fever Tachycardia Tachypnea Empiric antibiotic therapy Source control *Fluids *oxygen therapy * vasopressors *mechanical *EGDT *pressure support * inotropes ventilation ventilation * moderate *low TV *NIV corticosteroids *recruitment * vasopressin manovreus *prone position *CVVH etc Drotecogin α (activated) Cultures, source control , antibiotics, intensive insulin therapy ? High risk patient APACHE II > 25

56. Conceptual models of multiple organ dysfunction syndrome Metabolic,endocrine dysfunction Hyperglicemia,relative adrenal insufficiency, hypothyroidism Strict control of glycemia, coticosteroids in stress doses in septic shock Selective digestive tract decontamination, enteral feeding, immunenutrition, reconditioning of the gut flora Increased infection with gut organisms (translocation?) endotoxemia, Kupffer cell activation, spill over Gut liver axis Caspase inhibition Anti-oxidants Increased epithelial and lymphoid apoptosis (gut and spleen), decreased neutrophil apoptosis Dysregulated apoptosis Augmentation of anticoagulant mechanisms (APC-Prowess trial !, AT-Kybersept trial ? TFPI ?) Increased procoagulant activity, decreased anticoagulant activity, increased von Willebrand factor, soluble thrombomodulin; increased capillary permeability Microvascular coagulopathy and endothelial activation Augmentation of DO 2 (early optimization of DO 2 and SvO 2 ) Increased lactate Tissue hypoxia G-CSF, interferon gamma Nosocomial infection, increased anti-inflammatory cytokine levels (IL-10), decreased HLA-DR expression Immune paralysis Neutralization of specific cytokines (IL-1, TNF, PAF) or of activational pathways (afelimomab when IL-6 ) Cytokinemia (particularly IL-6,IL-8,TNF), leukocytosis, increased capillary permeability: edema Systemic inflammation (SIRS) Aggressive (?!) use of antibiotics and source control measure Persistent infection, nosocomial ICU acquired infection, endotoxemia Uncontrolled infection, occult poorly controlled infections (pneumonia, peritonitis) Therapeutic Implications Manifestations of MODS Pathologic process