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. Definitions The ACCP/SCCM consensus conference committee
Definitions The 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. Definitions The ACCP/SCCM consensus conference committee
Definitions The 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: )

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

8. Cellular dysfunction Cellular hypoxia Circulatory system dysregulation
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. Restoration of tissue perfusion
Causes of poor tissue perfusion
Leaky vessels
Decreased vascular tone
Myocardial depression
Interventions
Volume infusion
Intravenous fluids
PRBCs
Vasopressors
Inotropes

13. Intravenous Fluids Practice 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):

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 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 /-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 Human Activated 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 , p=0.02)
Withdraw of pressors: 57% vs 40% (Hazards ratio 1.91, 95% CI , 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
Septic Shock Algorithm Example (modified from Septic Shock. Lancet 2005;365:63-78.)