Sepsis Overview

1. Sepsis Overview December 5, 2006

2. Sepsis Continuum of clinical pathophysiology and severity Process rather than an event Mild dysfunction to frank organ failure Changes in the function of every organ system mediated by the host immune system.

3. Sepsis Systemic Inflammatory Response Syndrome-ACCP/SCCM Consensus Temperature >38�C or <36� Heart rate >90 bpm Respiratory Rate>20 or PaCO2<32mmHg WBC>12,000/�l or <4,000/�l

4. Sepsis Sepsis: 2 or more- Tachycardia >90bpm Rectal temp>38�C or <36�C Tachypnea(>20bpm) With 1 or more Alteration in mental status Hypoxemia (PaO2<72mmHG at FiO20.21) Elevated plasma lactate Oligouria

5. Sepsis Severe Sepsis Tachycardia >90bpm Rectal temp>38�C or <36�C Tachypnea(>20bpm) or PaCO2<32mmHg Hypotension despite fluid resuscitation Presence of perfusion abnormalities: lactic acidosis, oligouria, alteration in mental status

6. Sepsis Mediators of Sepsis Lipospolysaccharide (gram-negative bacteria) Lipoteichoic acid (gram-positive bacteria Peptidoglycan Cytokines IL-1 � mediates systemic effects of infection IL-6 � effects liver function TNF-a- potentiates the activation of neutrophils and macrophages IL-8 � regulates neutrophil function, mediates lung injury in sepsis

7. Sepsis Mediators of Sepsis Complement Nitric Oxide Lipid Mediators: Chemotaxis, Cell activation, Vascular Permeability Phospholipase A2 PAF Eicosanoids

8. Sepsis Mediators of Sepsis Adhesion Molecules Selectins Leukocyte Antigens

9. Sepsis Circulatory Manifestations Vasodilation Tachycardia Increased Cardiac Output Depressed Myocardial Function Increased Delivery Decreased Extraction

10. Sepsis Circulatory Manifestations Downregulation of catecholamine receptors Increased local vasodilating substances Nitric oxide Prostacyclin Decreased Oxygen Low pH Increased anaerobic metabolism Shunting

11. Sepsis Pulmonary Dysfunction Endothelial Injury Interstitial Edema Alveolar Edema Neutrophil entrapment Injury Type I pneumocyte Hyperplasia Type II pneumocyte Continued Neutrophil, monocyte, leukocyte and platelet aggregation

12. Sepsis Other Organ Dysfunction GI Ileus Malabsorption Overgrowth of bacteria, Translocation Liver Renal CNS

13. Sepsis Organisms Lower Respiratory Tract Infections (25%) Urinary Tract Infections (25%) Gastrointestinal Infections (25%) Soft Tissue Infections (15%) Reproductive Organs (5%)

14. Sepsis Risk Factors Extremes of Age (<10 and >70 years) Pre-existing Organ Dysfunction Immunosuppression Major Surgery, Trauma, Burns Indwelling Devices Prolonged Hospitalization Malnutrition Prior Antibiotic Treatment

15. Sepsis Principles for Management of Sepsis Early Recognition Early and Adequate Antibiotic Therapy Source Control Early Hemodynamic Resuscitation and continued support Drotrecogin Alpha (Apache II>25) Tight Glycemic Control Ventilatory Support

16. Sepsis Drotrecogin-alpha/Recombinant Human Activated Protein C Reduced levels of anti-inflammatory mediators Activated Protein C Inhibits thrombosis Decreases inflammation Promotes fibrinolysis Side Effect: Bleeding PROWESS study group Lower mortality rate (24.7 vs. 30.8%)

17. Sepsis Steroids??? Older trials used high doses Recent trials suggest low dose, with taper and tight glycemic control may improve outcome Vasopressor-dependent shock Cosyntropin Stim Test-Relative Adrenal Insufficiency (<9mcg/dL)

18. Sepsis Experimental Therapies Dopexamine- beta 2 adrenergic and dopaminergic effects, NO alpha adrenergic activity Vasopressin- reduces inducible NO synthase, upregulates endogenous catecholamine receptors Phosphodiesterase Inhibitors-ionotropic agents with vasodilating actions Nitric Oxide Inhibitors- N-monomethyl-l-arginine

19. ARDS Frequent Complication in Sepsis(40%) Adult Respiratory Distress Syndrome Oxygenation abnormality: PaO2/FiO2 ratio less than 200 Bilateral opacities on CXR PAOP <18mm Hg or no evidence of L atrial hypertension

20. ARDS Frequent Complication in Sepsis(40%) Adult Respiratory Distress Syndrome Oxygenation abnormality: PaO2/FiO2 ratio less than 200 Bilateral opacities on CXR PAOP <18mm Hg or no evidence of L atrial hypertension Frequency of ARDS in sepsis 18-38% 16% patients die w/irreversible respiratory failure

21. ARDS Pathophysiology Injury to Alveolocapillary unit Exudative Phase Endothelial injury, immune cell infiltration, pneumocyte and endothelial injury and necrosis Proliferative Phase Organization of exudate, myofibroblast proliferation Conversion of exudate to fibrous tissue Fibrotic Phase Remodeling of fibrosis, microcystic honeycomb formation and traction bronchiectasis

22. ARDS Management Lung-Protective Strategy-Reduction of Barotrauma TV 5ml/kg Longer inspiratory time Peak Inspiratory Pressure<35-40cmH2O Permissive Hypercapnea PEEP

23. Acute Renal Failure Increases Mortality in ICU 30% Physiology Glomerular Filtration dependent on perfusion pressure (MAP 60-80mmHg) Less than 60mmHG Decreased flow Arterial dilation in pre-glomerular arterioles (prostaglandins) Constriction of post-glomerular arterioles (angiotensin II)

24. Acute Renal Failure As Renal Perfusion Falls Increased reabsorption in proximal tubules 90% water is reabsorbed (normal is 60%) Decreased fluid to the distal tubules Loss of potassium elimination Tubular cells dependent on aerobic respiration Ascending loop is most sensitive to ischemia

25. Acute Renal Failure Dose all drugs appropriately Correction of Metabolic Acidosis Isotonic Bicarbonate Cannot Correct Ongoing Hypoperfusion Renal Replacement Therapy Absolute indication Acidosis Hyperkalemia Uremia (relative)

26. Sepsis Principles for Management of Sepsis Early Recognition Early and Adequate Antibiotic Therapy Source Control Early Hemodynamic Resuscitation and continued support Drotrecogin Alpha (Apache II>25) Tight Glycemic Control Ventilatory Support