1. (hopefully) Surviving Sepsis Goals: Understand sepsis Review the reasoning behind the current sespsis treatment guidelines Look at some new targets in sepsis treatment

2. First some definitions Systemic Inflammatory Response Syndrome (SIRS) A constellation of signs and symptoms including: 1. Tachycardia (>90 bpm) 2. Tachypnea (risk stratification begins at >24 breaths/min) or hypocapnia (<32mm Hg CO2) or mechanical ventilation assistance 3. Change in temperature (>38oC or <36oC) 4. Change in WBCs (>12,000 cells/mL or <4,000 cells/mL or Left Shift= >10% immature band cells) Causes: Pancreatitis, Burns, Infection, Trauma, Blood Loss

3. Sepsis = proven or suspected bacteremia/fungemia + 2 SIRS criteria Severe Sepsis = Sepsis + organ system dysfunction distant from site of infection(thrombocytopenia, oliguria, ARDS, AMS etc.) Septic Shock = Sepsis + hypotension despite fluid resuscitation resulting in tissue hypoxia

4. What happens in sepsis Globlal tissue hypoxia is the key element leading to organ failure and death Inflammation/Cytokines Inadequate Oxygenation of Tissue Organ Failure/Death The goal in treatment is to achieve a balance between oxygen demand and delivery

5. Sepsis Epidemiology Sepsis incidence is rising: Approximately 2% of hospitalized patients and 75% of ICU patients will have severe sepsis/septic shock. The mortality of severe sepsis/septic shock is decreasing: Estimates range from 20-50% mortality. Sepsis occurs in the emergency room, ICU, medical wards and is increasingly being managed outside the ICU.

6. Finding out what works in Sepsis treatment Requires Measuring Oxygenation Mixed Venous Oxygen Saturation (SVO2) Measured with a pulmonary artery catheter. Normal values= ~75% (40 mm Hg) Central Venous Oxygen Saturation (SCVO2) Measured with a catheter inserted into the jugular or subclavian vein, catheter often ends up in right atrium. Cheaper, safer. SvO2/ScvO2 are surrogates for Cardiac Index (CO/body surface area.) and Oxygen Utilization Lactate, pH and base deficit: measurement of the amount of anaerobic glycolysis (and the organs that buffer pH changes)

7. ER Presentation: SIRS + hypotension or lactate > 4 mmol/L Before ICU admission patient receives: EARLY GOAL-DIRECTED THERAPY IN THE TREATMENT OF SEVERE SEPSIS AND SEPTIC SHOCK 6 hours of Early Goal Directed Therapy Standard of Care

8. What is early goal directed therapy? EGDT is an algorithm for optimizing fluid resuscitation by responding to 4 parameters, i.e. making sure you’re pumping enough oxygenated blood so tissues receive adequate oxygenation Ventilation: via intubation and mechanical ventilation Mean Arterial Pressure: the perfusion pressure seen by organs of the body Central Venous Pressure: measures fluid returning to heart and thus preload Mixed Central Venous Oxygenation (SCVO2): central venous oxygenation, approximates CO.

9. Why Early Goal Directed Therapy? Previous studies using pulmonary artery catheterization, immunotherapy or hemodynamic optimization all showed negligible changes in mortality How is EGDT different? It’s early. All previous studies had been initiated 72 hours or later after admission. EGDT is initiated as soon as sepsis is recognized: the golden hours of entering the emergency room

10. Beginning steps in the algorithm 1. Recognize Sepsis and obtain at least 2 blood cultures 2. Start IV broad spectrum anti-biotics within the first hour.

11. The algorithm Supplemental O2+ intubation & mechanical ventilation Central Venous & Arterial Catherization Sedation, paralysis (if intubated) or both CVP<8mm Hg Crystal/Colloid Infusion 500mL/30min Do you have enough fluid? CVP 8-12mm Hg Vasoactive Agents – NE or Dopamine for vasoconstriction MAP <65 (or >90) Are your organs being perfused? MAP >65 (and <90) RBCs until Hematocrit >30% ScvO2<70% Are you using the oxygen being delivered? <70% Goals Achieved (hospital admission) >70% Inotropes

12. Mortality Results for All Patients Standard Therapy: 59% EGDT Therapy: 39% P= 0.009

13. New findings in sepsis “Experimental resultsclearly indicate that microcirculatory dysfunction lies at the centre of sepsis pathogenesis” When ‘EARLY GOAL-DIRECTED THERAPY IN THE TREATMENT OF SEVERE SEPSIS AND SEPTIC SHOCK’ in-hospital deaths were stratified by cause: Cardiovascular collapseMultiorgan Failure Standard Therapy: 21% Standard Therapy: 21.8% EGDT: 10.3% EGDT: 16.2% P=0.02 p=0.27 EGDT did not significantly impact MOF death rate Lehr HA, Bittinger F, Kirkpatrick CJ: Microcirculatory dysfunction in sepsis: a pathogenetic basis for therapy?

14. Microcirculation …and dilate other arterioles to reduce shear stress and prevent one area stealing all the blood Is integrated: When one portion dilates in response to local hypoxia signals via endothelial cells are sent upstream…

15. Microcirculation is a little more than hemodynamics Experimental evidence shows that at the same level of hypotension perfusion abnormalities are significantly less in hypovolemic shock than in septic shock Possible mechanism: bacterial toxins inhibits endothelial cell communication producing shunting when only those arterioles that can communicate dilate efficiently

16. Is microcirculation malfunction causing organ failure? 31 bed ICU: Microcirculation (orthogonal polarization spectral imaging device) was the only discriminant between those who survived vs. those who died from multiple organ failure after shock had resolved. Hemodynamic parameters were similar for both groups. Persistent Microcirculatory Alterations Are Associated With Organ Failure and Death in Patients With Septic Shock . Crit Care Med. 2004

17. Guideline Updates Recombinant Activated Protein C (anticoagulant and anti-inflammatory) is now on the sepsis guidelines for those with a high risk of death, as are steroids for those who don’t respond to vasopressor A weak recommendation due to lack of clear evidence

18. Future therapies Inducible Nitric Oxide Synthase knockout mice do not have the microperfusion abnormalities in response to sepsis. iNOS inhibitors may prevent the vasodilation and microcirculatory shunting causing hypoxia Microcirculation Monitoring: experimented with in cardiac surgeries with orthogonal polarization spectral imaging (OPS) to observe whole organ perfusion.