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

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

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.

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

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

Epidemiology of Sepsis Increasing comorbidities

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)

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

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

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

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

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

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

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)

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

Lancet 2005; 365: 63–78

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)

Definitions Diagnostic criteria for sepsis, severe sepsis

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

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

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

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)

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

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.

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.

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.

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.

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

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

Summary

References 1. Dellinger et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med 2013; 41:580-637. 2. Rivers et al. Early Goal Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med 2001;345:1368-77. 3. Martin et al. The Epidemiology of Sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-54. 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):739-746.