Management of Septic Shock

1. Management of Septic Shock

2. Epidemiology of Sepsis • 751K cases annually in the United States and rising • Most common cause of death in non-coronary ICU • 30% Mortality when shock present • Severe sepsis $22K/pt, $16 billion/year

3. DefinitionsThe ACCP/SCCM consensus conference committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992. • SIRS • Widespread inflammatory response • Two or more of the following • Temp>38 C<36 C • Heart Rate >90 bpm • Tachypnea RR>20 or hyperventilation PaCO2 <32 mmHg • WBC >12,000<4000 or presence of >10% immature neutrophils. • Sepsis: SIRS + definitive source of infection • Severe Sepsis: Sepsis + organ dysfunction, hypoperfusion, or hypotension

4. DefinitionsThe ACCP/SCCM consensus conference committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992. • Septic Shock: • Sepsis + hypotension despite fluids • Perfusion abnormalities • Lactic acidosis • Oliguria • Acute AMS • Multiple Organ System Failure: Abnormal function of two or more organs such that homeostasis cannot be achieved without intervention.

5. Brief Pathophysiology • Proinflammatory response to infection • Mediators • TNF Alpha, IL-1, IL-6 • Complement system (C5 alpha) • Bacterial factors • Endotoxin, bacterial cell wall products, bacterial toxins • Immunosuppressive

6. Time-course of inflammatory response during sepsis(modified from Management of Severe Sepsis and Septic Shock. Curr Opin Crit Care 2004;10:354-363)

7. (Modified from The Pathophysiology and Treatment of Sepsis. N Engl J Med 2003;348:138-150)

8. Cellular dysfunction • Cellular hypoxia • Reduced surface area for diffusion • Reduction in RBC deformability • Impaired utilization of oxygen by mitochondria • Circulatory system dysregulation • Vasodilation (nitric oxide) • Vascular permeability

9. Acute Organ Dysfunction • Neuro: altered mental status • Respiratory: Mechanical ventilation? (PF ratio <250, PEEP >7.5) • CV: Pressors? SBP<90 or MAP<70 despite fluids • Renal: UO <0.5ml/cc/kg/hr, 50% increase in Cr, acute dialysis • Heme: Platelets <100,000 or PT/PTT elevated • Metabolic: pH <7.3, high lactate • Hepatic: LFTs >2x normal • GI: Bacterial overgrowth and translocation

10. Management of Sepsis • Resuscitate: ABCs • Restore tissue perfusion • Identify and eradicate source of infection • Assure adequate tissue oxygenation • Activated Protein C • Steroids • Glucose Control • Nutrition

11. Resuscitation • Airway: AMS, unable to protect airway • Breathing: Respiratory failure • Circulation: Restoration of blood pressure to levels which perfuse core organs. • Sphygmomanometer unreliable • Arterial catheter • CVP • Mixed Venous O2 sat

12. Causes of poor tissue perfusion Leaky vessels Decreased vascular tone Myocardial depression Interventions Volume infusion Intravenous fluids PRBCs Vasopressors Inotropes Restoration of tissue perfusion

13. Intravenous FluidsPractice parameters for hemodynamic support of sepsis in adult patient in sepsis. Task Force of the ACCCM/SCCM. Critical Care Medicine 1999 • Administered in well-defined, rapidly infused boluses • Continued until blood pressure, tissue perfusion, and oxygen delivery acceptable or presence of pulmonary edema • Colloid vs. Crystalloid: No evidence to recommend one over the other.

14. Vasopressors • Second-line agents • Hypotensive despite fluid resuscitation, Cardiogenic pulmonary edema, or elevated wedge pressure (>18) • Vascoconstrictors • Phenylephrine, Norepinephrine, Dopamine, Epinephrine, Vasopressin

15. Vasopressors • Catecholamines may modulate immune system • Epinephrine may decrease splanchnic perfusion and pH • Dopa and norepi have similar effects on renal function • Dopamine may result in greater splanchnic acidosis vs norepinephrine • Observational studies suggest Norepinephrine as first line agent for fluid refractory hypotension Martin et al Chest 1993;103(6):1826-31

16. Vasopressors • Vasopressin • Limited data, studies suggest may be useful in vasodilatory shock • Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997. • VP levels low in septic shock • 10 patients in septic shock and already receiving catecholamines with improvement of hypotension and decreased need for catecholamines • Hemodynamic and metabolic effects of low-dose VP infusions in vasodilatory septic shock. Critical Care Medicine 2001 • VP given to 16 septic patients with refractory hypotension. • VP infusion improved MAP and SVR • Current recs are to consider with refractory hypotension despite adequate fluid resuscitation and high-dose conventional vasopressors.(infusion rates of 0.01-0.04 units per min)

17. Eradicate infectious source • Empiric broad spectrum antibiotics • ASAP after blood cultures collected • Modify as culture results dictate • Remove infectious source • Remove catheter, Drain abscess/fluid collections, Divert gut, etc

18. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. NEJM. Nov 8, 2001 • Study design: Prospective, randomized study in urban emergency department enrolling 263 patients • Inclusion Criteria: Adults severe sepsis, septic shock, or sepsis syndrome. SIRS. SBP<90 (after fluid bolus) or lactate>4. • Exclusion Criteria: Age<18, pregnancy, acute CVA, ACS, pulmonary edema, status asthmaticus, arrhythmia, GIB, seizure, drug OD, burns, trauma, immediate surgery, uncured cancer, immunosupressed, DNR. • Treatment: In ER 500 ml crystalloid given q 30 min to achieve CVP 8-12 mmHg. Pressors given to achieve MAP >65. If MAP >90 vasodilators given until <90. If ScvO2<70, transfused to Hct of 30. +/-Dobutamine. • Results: Improved in-hospital mortality (30.5% vs. 46.5%). Higher mean ScvO2, lower lactate, lower base deficit and a higher pH. Lower APACHE scores.

19. Assuring adequate tissue oxygenation • Goal: Maintain oxygen delivery (DO2) at levels that match tissue O2 needs (VO2) • Supratherapeutic oxygenation not consistently shown to be effective • Detection of tissue hypoxia--Lactate • May be difficult to interpret • Treatment of tissue hypoxia • Maximize arterial oxygen content • Keep SaO2 >97% • Augment cardiac output • Support hematocrit

20. Activated protein C • Known inflammatory and procoagulant host responses to infection. • TNF-alpha, IL-1, IL-6, thrombin • Diffuse endovascular injury, multiorgan dysfunction and death. • Activated Protein C • anticoagulant, modulates the inflammatory response • reduced levels of protein C found in majority of patients with sepsis and are associated with increased risk of death.

21. Efficacy and Safety of Recombinant HumanActivated Protein C for Severe Sepsis. NEJM 2001. • Randomized, double-blind, placebo-controlled, multicenter trial enrolling 1,690 patients with severe sepsis. • 96 hour infusion of recombinant APC or placebo beginning within 24 hours of presentation. • 28 day mortality significantly lower in the APC group • 24.7 vs. 30.8% • Trend towards increased bleeding (3.5 vs/ 2.0% p=0.06)

22. Activated Protein C Guidelines

23. Glucocorticoids • Ten prospective, randomized, controlled trials of pharmacologic doses of glucocorticoids in sepsis/septic shock • Steroid controversy in sepsis and septic shock: A meta-analysis. Critical Care Medicine 1995 • Glucocorticoids offer no benefit • Positive findings reported in 1/10 trials

24. Revisiting Steroids… • Adrenal Insufficiency • 25-40% of ICU patients with septic shock • Mortality is more than double that of patients with normal adrenal responsiveness • Hypotension refractory to vasopressors • hyponatremia, hyperkalemia, weakness, and hyperpigmentation not specific enough in ICU setting

25. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA Aug 21, 2002 • Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 French ICUs. • 300 adults with severe sepsis who underwent corticotropin test were randomly assigned to receive hydrocortisone and fludrocortisone or placebo for 7 days. • Main outcome measure: 28 day survival in patients with abnormal corticotropin test. • Results: Corticosteroids vs. Placebo • Deaths: 53% vs 63%(Hazards ratio 0.67, 95% CI 0.47-0.95, p=0.02) • Withdraw of pressors: 57% vs 40% (Hazards ratio 1.91, 95% CI 1.29-2.84, p=0.001) • No difference in adverse outcomes. • Conclusion: 7 day treatment with steroids beneficial in patients with sepsis and adrenal insufficiency.

26. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA Aug 21, 2002

27. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA Aug 21, 2002

28. Glucose Control • Recs are to keep serum glucose levels < 150

29. Nutrition • Start early • Route: preferably enteral • Nutritional support improves wound healing and decreases susceptibility to infection. • Nutritional support results in higher lymphocyte counts and higher serum albumin (surrogate markers of immune competency)

30. Summary • Ensure tissue perfusion: resuscitate early with liberal IVF, pressors and inotropes. • Ensure tissue oxygenation: oxygen content, oxygen saturation, cardiac output • Identify and eradicate infection • APC in patients with severe sepsis • Consider corticosteroids • Glucose Control

31. Septic Shock Algorithm Example(modified from Septic Shock. Lancet 2005;365:63-78.)