1. Severe Sepsis and Activated Protein C Jeff Hurley MD

2. Perspective Most common cause of death in medical and surgical ICUs (20-60%). Approximately 225,000 cases of sepsis which are fatal annually. Sepsis Syndrome represents a systemic inflammatory response to various insults. Severity is determined by alteration in normal physiological parameters, etiology, and response to treatment

3. Spectrum SIRSSevere Clinical insult manifested by 2 or more of the following: Temperature > 38°C or <36°C Tachycardia > 90 beats/minute Respiratory rate > 20 or PaCO2 < 32 mm Hg White blood count > 12,000 or 10% Bands SepsisSIRS due to an infection (known or suspected—not obligatory). Considered SEVERE if hypotension or systemic manifestations of hypoperfusion (lactic acidosis, oliguria, changes in mental status, ARDS, hypoxemia PaO2 < 72 on RA) is present. Septic Shock Sepsis induced hypotension (SBP 40 mm Hg from baseline) despite adequate fluid resuscitation that requires pressors to maintain normotension, along with perfusion abnormalities that may induce lactic acidosis, oliguria, or changes in mental status. MODSThe presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.

4. Pathophysiology Normal responses to insults result in the development of: 1.Inflammatory response 2.Thrombotic response 3.Anti-Fibrinolytic response

5. Pathophysiology Infectious process Mobilization of PMNs and Monos Creation of inflammatory cytokines triggering a casade. Noteably: IL-1, TNF, IL-6. Innappropriate regulation or ongoing stimulation of pathway (LPS, peptidoglycan, lipotoeichoic acid, super antigens) Resulting in Sepsis

7. Treatment Many therapeutic interventions have been attempted. 1.Anti-endotoxin 2.Mabs against TNF 3.Bradykinin antagonists 4.PAF antagonists 5.Prostaglandin antagonists 6.IL-ra None have shown a benefit over placebo.

8. Activated Protein C Protein C is a vitamin K dependent endogenous protein that is a regulator of the inflammatory, coagulation, and fibrinolytic pathways. Under normal conditions, the generation of Thrombin (IIa) is balanced by the combination of thrombin with thrombomodulin. This combination converts the inactive precursor to the activated from of the protein. Evidence suggests that in sepsis, then is a cytokine induced decrease in thrombomodulin. APC then degrades factors VIIIa and Va, both cofactors in the coagulation cascade. Hence, APC acts as an antithrombotic. APC, through decreased Thrombin levels, decreases the release of Plasminogen activator inhibitor-1 resulting in an increase in plasmin generation. Hence, APC acts an a pro-fibrinolytic. APC, through in vitro studies, has also shown to decrease the production of inflammatory cytokines such as IL-1, IL-6, and TNF. Hence, APC acts as an anti-inflammatory. Also shown to decrease selectin-mediated adhesion. Other avenues: Factor XII activation leads to kallikrein activation. Kallifrein then cleaves kininogen to the vasoactive peptite bradykinin which has been related to the iNOS (inducible nitric oxide system) system. Sepsis also is suspected to alter mitochondrial function.

9. Study Summary Randomized, double-blinded, placebo-controlled, multicenter trial. 1690 enrolled patients Inclusion criteria: 3 out of 4 SIRS plus 1 out of 5 of the following: 1.Hypotension unresponsive to fluids 2.Oliguria 3.ARDS criteria Pao2 to FiO2 < 250 4.Hematologic disorder platelets < 80,000 or 50% decrease in 3 days 5.Metabolic acidemia 5 with plasma lactate > 1.5 normal levels Exclusion criteria: Pregnancy, age <18, Platelets < 30,000, conditions that increased risk of bleeding, others. Randomized to APACHE II Measure: Survival at 28 days. Delivery: 96 hour infusion of APC at 24 ug/kg/hr. No dosage adjustment of age, gender, hepatic or renal dysfunction.

10. Results Study stopped early. Relative risk reduction of 19.4% with an absolute reduction of 6.1% Number needed to treat: 16.4

11. Physiology Reduction in D-Dimer, a measure of intravascular thrombus formation. Reduction in IL-6 levels.

12. Complications Bleeding was the most serious complication 3.5% in study group versus 2.0% in placebo. Occurred predominately in those predisposed to bleeding. 1 serious bleeding event for every 66 patients treated. Contraindications: Internal bleeding, recent hemorrhagic stroke, recent brain surgery or severe head trauma, trauma, epidural catheter, intracranial neoplasm or mass lesion. Predisposed: INR > 3.0, platelets < 30,000, heparin infusion, recent GI bleed, recent thrombolytic use, recent G IIb/IIIa inhibitors, recent aspirin or other antiplatelet, recent ischemic stroke, AVM or aneurysm, severe hepatic disease.

13. Legal Isssues in Sepsis Failure to recognize SIRS criteria or potential sources of infection. Failure to take unstable patients to surgery to treat infectious processes. Insufficient fluid resuscitation or failure to institute vasoactive drugs or mechanical ventilation. Incorrect sequence of pressors such as single use epinephrine that impairs splanchnic blood flow and perfusion. Excessive use of pressors to supranormal cardiac output that has shown to increase morbidity and mortality. Administration of bicarbonate therapy that worsens intracellular acidosis.

14. Summary APC (drotrecogin alfa) indicated for the reduction of mortality in Severe Sepsis who have a high risk of death. Absolute reduction in mortality of 6.1% Standard of Care?