1. Rogers Kyle, MD Medical University of South Carolina 5/21/13
Sepsis
Rogers Kyle, MD
Medical University of South Carolina
5/21/13

2. Objectives Examine the epidemiology of sepsis in the US.
Review the definitions of SIRS, sepsis, severe sepsis, septic shock.
Understand the elements of early goal directed therapy in the non-ICU setting.
Review the Surviving Sepsis Campaign Bundles

3. Key Messages
Epidemiologic studies suggest that the incidence of sepsis is increasing as well as the co-morbidities of patients admitted to the ICU with sepsis.
The mortality from sepsis is declining, suggesting improvements in recognition and care.
Rapid recognition of sepsis is essential in its treatment.
Early goal directed therapy - including rapid fluid resuscitation, measurement of tissue perfusion, cultures and diagnostic studies, and broad spectrum antibiotic coverage - is imperative.

4. Epidemiology of Sepsis
Steady increase in frequency
NEJM 03
1970’s ~ 164,000 cases/year
Now > 1.6 million
Estimated cost > $50,000/pt
>$17 billion/year
Mortality remains 20-50%
Second leading cause of death among patients in non-coronary ICU’s.
10th leading overall

5. Epidemiology of Sepsis
Consensus definition
Combination of pathologic infection and systemic inflammatory response syndrome
Patients with acute organ dysfunction are considered to have severe sepsis
However, there remains a fair amount of contention over the use of these definitions

6. Epidemiology of Sepsis
Increasing comorbidities

8. Epidemiology of Sepsis
Increasing comorbidities
Significant disparities among races and between men and women
Men more likely to have sepsis although there are more women in the U.S.
Men are more likely to be enrolled in trials
Almost double risk for sepsis in non-white, especially black men (youngest and highest mortality)

11. Epidemiology of Sepsis
Increasing comorbidities
Significant disparities among races and between men and women
Men more likely to have sepsis although there are more women in the U.S.
Men are more likely to be enrolled in trials
Almost double risk for sepsis in non-white, especially black men (youngest and highest mortality)
Increasing incidence

13. Epidemiology of Sepsis
Increasing comorbidities
Significant disparities among races and between men and women
Men more likely to have sepsis although there are more women in the U.S.
Men are more likely to be enrolled in trials
Almost double risk for sepsis in non-white, especially black men (youngest and highest mortality)
Increasing incidence
Decreasing mortality

15. Epidemiology of Sepsis
Decline in mortality
Increased fungal infections
Increase in organ failure
Increased age
Increased severity of illness
Increased discharge to subacute facilities
All of which point to continued growth in the need for care of this population

16. Epidemiology of Sepsis
What else has increased?
Invasive procedures
Immunosuppressive drugs
Chemotherapy
Transplantation
HIV
Microbial resistance
Coding

17. Epidemiology of Sepsis
Predicted that the rate of sepsis will continue to increase at 1.5% per year due to aging of the population

18. Surviving Sepsis Campaign: 2012
Crit Care Med 2013; 41:580–637

19. Surviving Sepsis Campaign: 2012
Update from 2008
68 international experts representing 30 international organizations
Literature reviewed
Use GRADE (Grading of Recommendations Assessment, Development and Evaluation)
Quality of evidence: A-D
Strength 1 (strong) or 2 (weak)
UG (ungraded)

21. Definitions Definitions
Systemic Inflammatory Response Syndrome, sepsis, severe sepsis, septic shock from 1992 (ACCP, SCCM)

22. Lancet 2005; 365: 63–78

23. Definitions Definitions
Systemic Inflammatory Response Syndrome, sepsis, severe sepsis, septic shock from 1992 (ACCP, SCCM)
Continuum of severity from SIRS to septic shock and multiple organ dysfunction syndrome (MODS)

24. Definitions
Diagnostic criteria for sepsis, severe sepsis

27. Therapeutic Priorities
Early supportive care to correct physiologic abnormalities
Hypoxemia, hypotension
Distinguish SIRS from sepsis
Most of the guidelines are directed towards severe sepsis or septic shock
Stabilize respiration
O2 to intubation
Assess perfusion
SBP < 90, MAP < 70, drop in BP > 40
Note difference in threshold vs. definition

28. Therapeutic Priorities
May need arterial line
Tissue hypoperfusion can occur in the absence of hypotension
Cool, mottled extremities, lactate > 1 (> 4 is consistent with severe sepsis)
CVC should be inserted with severe sepsis or septic shock (not pulm art catheter)
CVP, ScvO2

29. Early Goal Directed Therapy
Early resuscitation prevents or limits multiple organ dysfunction and reduces mortality
Goals for fluid resuscitation in the first 6 hours
Protocolized, quantitative resuscitation of patients with sepsis- induced tissue hypoperfusion (defined in this document as hypotension persisting after initial fluid challenge or blood lactate concentration ≥ 4 mmol/L). Goals during the first 6 hrs of resuscitation:
a) Central venous pressure 8–12 mm Hg
b) Mean arterial pressure (MAP) ≥ 65 mm Hg
c) Urine output ≥ 0.5 mL/kg/hr
d) Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively
In patients with elevated lactate levels targeting resuscitation to normalize lactate

30. Early Goal Directed Therapy
ScvO2
Same CVP, MAP, urine output. Lower mortality in group targeting ScvO2 > 70 (31 vs. 47%) (NEJM 01)
Lactate
Lactate clearance may be a substitute for ScvO2 (JAMA 10)

31. Early Goal Directed Therapy
Restoring perfusion
Fluids – crystalloid vs. albumin (no HES)
Crystalloid…at least initially
30 ml/kg minimum early
As long as there is hemodynamic improvement (change in pulse pressure, stroke volume, HR, sys BP)
Dobutamine up to 20mcg/kg/min if adequate volume resuscitation with persistent low BP

32. Early Goal Directed Therapy
Fluid Resuscitation
Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock.
Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock.
Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids.
Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients.
Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables.

33. Early Goal Directed Therapy
Diagnosing Infection
Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobial(s). At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted.
Use of the 1,3 beta-D-glucan assay, mannan and anti-mannan antibody assays, if available and invasive candidiasis is in differential diagnosis of cause of infection.
Imaging studies performed promptly to confirm a potential source of infection.

34. Early Goal Directed Therapy
Antibiotics
Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock and severe sepsis without septic shock as the goal of therapy.
Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis.
Antimicrobial regimen should be reassessed daily for potential deescalation.
Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection .
Combination empirical therapy for neutropenic patients with severe sepsis and for patients with difficult-to-treat, multidrug resistant bacterial pathogens such as Acinetobacter and Pseudomonas. For patients with severe infections associated with respiratory failure and septic shock, combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia . A combination of beta-lactam and macrolide for patients with septic shock from bacteremic Streptococcus pneumoniae infections.
Empiric combination therapy should not be administered for more than 3–5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known.
Duration of therapy typically 7–10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia.
Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin.
Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause.

35. Early Goal Directed Therapy
Early is important - Larger meta-analysis of trials with therapy initiated more than 24 hrs after onset of sepsis did not show the same mortality benefit.

36. Vasopressor Therapy
Recommended when required to sustain life and maintain perfusion in the face of life-threatening hypotension, even when hypovolemia has not yet been resolved
MAP > 65
Norepinephrine first
Epinephrine added
Vasopressin 0.03 U/min may be substituted for epi, not to be used alone
Dopamine instead of norepi only in selected patients
Phenylephrine only if arrhythmias with norepi, high CO with low BP, salvage

37. Many additional recommendations in the Surviving Sepsis Campaign
Mostly in the ICU setting
Steroids
Hgb target
ARDS
Neuromuscular blockade
Glycemic control
DVT prophylaxis
Nutrition
Goals of care

38. Summary

39. References
1. Dellinger et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: Crit Care Med 2013; 41:
2. Rivers et al. Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med 2001;345:
3. Martin et al. The Epidemiology of Sepsis in the United States from 1979 through N Engl J Med 2003;348:
4. Annane et al. Septic Shock. Lancet 2005; 365: 63–78.
5. Jones et al. The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: A meta-analysis. Crit Care Med 2008; 36:2734–2739.
6. Jones et al. Lactate Clearance vs Central Venous Oxygen Saturation as Goals of Early Sepsis Therapy. JAMA 2010;303(8):