Why does it matter? Sepsis

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1 Sepsis 2015 Mitchell M. Levy MD, FCCM Professor of Medicine Chief, Division of Pulmonary, Sleep, and Critical Care Warren Alpert Medical School of Brown University Providence, RI

2 Sepsis Why does it matter? 1,665,000 cases of sepsis diagnosed in US in 2009 Principal diagnosis in 2% of all admissions Single most expensive condition treated in the US. ($20.3B in 2011) The inpatient mortality rate from sepsis is 8 times higher than the overall US inpatient mortality rate

3 Pathophysiology

4 Sepsis as Cytokine Storm: Innate Immunity Sepsis presentation Fever, shock, respiratory failure Pro-inflammatory cytokines TNFα, IL-1, IL-6 All increased in sepsis Encouraging results in animal models pretreated with therapeutics that blocked proinflammatory cytokines

5 Traditional view of sepsis and its pathophysiology Virulent pathogens (pneumococci, meningococcus, Group A strep, S. aureus, Clostrida spp.) Virulent pathogens: pneumococcus, Pro-inflammatory markers-cytokines, S. aureus, Group chemokines A strep, C Clostridia, meningococci C, ROS RNS kinins, procoagulants Proinflammatory mediatorscytokines, chemokines, Early onset septic shock, MODS procoagulants, kinins, ROI, RNI, C Young, previously healthy patients with rapid onset septic shock - fits our animal models (Hotchkiss and Karl N Engl J Med 2003;348:138)

6 Adaptive Immunity: Compensatory Response Antigen is presented to naive CD4 lymphocytes by receptors of major histocompatibility complex class II. Differentiation into four cell subtypes: Th2 lymphocytes IL-4, IL-6 and IL-10 and mediate antiinflammatory response N regulatory T cells (Treg) mediate anti-inflammatory responses by either cytokine secretion or direct cell cytotoxicity Th1 lymphocytes TNF, IL-2, interferon-gamma, and propagate pro-inflammatory responses Lymphocytes that secrete IL-17 and mediate chemotaxis and neutrophils priming at the site of infection

7 Immunosuppression: How do septic patients die? 70% of septic patients die > 3 days after admission End Stage septic patients: Apoptosis-induced loss of cells of innate and adaptive immune system CD4, CD8, T, B, dendritic cells Occurring when clonal expansion of lymphocytes should be dominant Severe depletion of immune effector cells is universal finding in sepsis

8 Failure of Anti-Inflammatory Trials The failure of over 30 trials of anti-inflammatory and anti-cytokine agents led to a reevaluation of the concept of sepsis as causing death by unbridled inflammation. Sepsis a new paradigm- both pro- and antiinflammatory responses occur early and simultaneously in sepsis. Some patients die of the initial hyperinflammatory (hyper-cytokinemia) but most surviving patients progresses over time to a state of profound immunosuppression. *Death due to uncontrolled primary infection or lethal secondary infections.

9 What are the Phase of Sepsis? Immuno-inflammatory response in sepsis Hotchkiss and Karl NEJM 348:

10 Sepsis Management

11 Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012 R Phillip Delllinger MD 1 ; Mitchell M. Levy MD 2, Andrew Rhodes MD BS 3 ; Djillali Annane MD 4 ; Herwig Gerlach MD PhD 5 ; Steven M. Opal MD 6 ; Jonathan E. Sevransky MD 7 ; Charles L. Sprung MD 8 ; Ivor S. Douglas MD 9 ; Roman Jaeschke MD 10 ; Tiffany M. Osborn MD MPH 11 ; Mark E. Nunnally MD 12 ; Sean R. Townsend MD 13 ; Konrad Reinhart MD 14 ; Ruth M. Kleinpell PhD RN-CS 15 ; Derek C. Angus MD MPH 16, Clifford S. Deutschman MD MS 17 ; Flavia R. Machado MD PhD 18, Gordon Dr. Rubenfeld MD 19 ; Steven A. Webb MB BS PhD 20 ; Richard J. Beale MB BS 21 ; Jean-Louis Vincent MD PhD 22 ; Rui Moreno MD PhD 23 ; and the Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup* Critical Care Med Feb;41(2): Intensive Care Med Feb;39(2):

12 Diagnosis 1. To optimize identification of causative organisms, we recommend at least two blood cultures be obtained before antimicrobial therapy is administered as long as such cultures do not cause significant delay (>45 minutes) in antimicrobial administration, with at least one drawn percutaneously and one drawn through each vascular access device, unless the device was recently (<48 hr.) inserted (Grade 1C).

13 Initial Resuscitation 1. We recommend the protocolized resuscitation of a patient with sepsis-induced shock, defined as tissue hypoperfusion (hypotension persisting after initial fluid challenge or blood lactate concentration 4 mmol/l). This protocol should be initiated as soon as hypoperfusion is recognized and should not be delayed pending ICU admission. During the first 6 hrs of resuscitation, the goals of initial resuscitation of sepsisinduced hypoperfusion should include all of the following as one part of a treatment protocol: Central venous pressure (CVP): 8 12mm Hg Mean arterial pressure (MAP) 65mm Hg Urine output 0.5mL.kg 1.hr 1 Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively (Grade 1C)

14 Current Resuscitation Approach ProCESS, ARISE, promise All failed to demonstrate benefit to protocolized resuscitation using CVP and ScvO 2. No harm demonstrated with EGDT Patient population and clinical very different from the Rivers trial

15 Comparison of 4 Trials N Mortality power calc BP Lactate Fluids BEFORE Enrolment Median time to randomize Rivers (Mar Mar 2000) % Not reported cc/kg 59 min 50 ProCESS (Mar May 2013) 1341 Initial: 30-46% Adjusted after 1st IA 55% 59% Unknown At least: 20cc/kg or 1000 cc min ARISE (Oct April 2014) % hosp 38% 90 day 70% 46% 2500 cc 35 cc/kg 165 min ProMISe Feb July % 90- day 55% 65% 2000cc 150 min

16 Comparison of 4 Trials: Results Volume EGDT vs. pbs vs. Control Vasopressors RBCs dobutamine Rivers 4981± ±2438 P< % 30.3% 64.1% 18.5% P< % 0.8% P<0.001 ProCESS P < % 52.2% 44.1% P = % 8.3% 7.5% P= % 1.1% 0.9% P <0.001) ARISE 1964± ±1401 P < % 57.8% 13.6% 7.0% 15.4% 2.6% ProMISe 2000 ( )1784 ( ) /

17 Conclusions EGDT 4 trials Different populations, different time periods Most recent trials: pts less ill 18% mortality?? No longer evidence to mandate central lines for all pts with severe sepsis and septic shock

18 IF: So.Where are we? Timely antibiotics 30cc/kg fluids in first few hours Then: TLC for CVP and ScvO 2 monitoring probably not necessary Unless pt is hypotensive and then need central line for pressors No adverse events with EGDT Harm not demonstrated

19 Antibiotic therapy 1. We recommend that intravenous antimicrobial therapy be started as early as possible and within the first hour of recognition of septic shock (1B) and severe sepsis without septic shock (grade1c).

20 Hospital Mortality by Time to Antibiotics

21 Time to Antibiotics: Wards vs. ED

22 Fluid therapy 1. We recommend crystalloids be used as the initial fluid of choice in the resuscitation of severe sepsis and septic shock (grade 1B). 1. Normal Saline vs. LR vs. balanced salt solution 2. We recommend against the use of hydroxy ethyl starches for fluid resuscitation of severe sepsis and septic shock (grade 1B). 3. We suggest the use of albumin in the fluid resuscitation of severe sepsis and septic shock when patients require repeated boluses of crystalloids (grade 2C).

23 Vasopressors 1. We recommend that vasopressor therapy initially target a mean arterial pressure (MAP) of 65 mm Hg (grade 1C). 2. We recommend norepinephrine as the first choice vasopressor (Grade 1 B). 3. We recommend epinephrine (added or substituted) when an additional agent is needed to maintain adequate blood pressure (Grade 2B). 4. We suggest vasopressin 0.03 units/minute can be added to and subsequently potentially substituted for norepinephrine (Grade 2A).

24 Corticosteroids in Septic Shock

25 CORTICUS Trial % mortality (33.5%) 77 (31.0%) 0 steroids (n=251) Sprung CL, et al. NEJM Jan 10;358(2): placebo (n=248) P = 0.567

26 Steroids: CORTICUS vs French Trial Severity of illness was greater in CORTICUS Placebo: 91/149 (61%) vs 77/248 (31%) In shock longer in CORTICUS Up to 72 hrs. vs no longer than 8 hrs Not as unstable from blood pressure standpoint in CORTICUS Normal blood pressure on vasopressors vs hypotensive on vasopressors During CORTICUS steroids were now recognized as potentially useful during enrollment Sprung et al. N Engl J Med 358:111, January 10, 2008

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28 Corticosteroids 1. We suggest not using intravenous corticosteroids in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy is able to restore hemodynamic stability. In case this is not achievable we recommend a daily dose of 200 mg intravenous hydrocortisone given by continuous intravenous infusion (Grade 2C).

29 Adjunctive Therapies for Septic Shock

30 Recent Failed Clinical Trials in Sepsis TNFα Activated Protein C TLR4 inhibitor Talectoferrin Tissue Factor Pathway Inhibitor Statins Vitamin D

31 Ongoing trials: What s Coming? Thrombomodulin Extracorporeal blood detoxification Hemadsorption Fluid therapy SPLIT trial (balanced salt solution) Improved clinical trial design and conduct Adaptive design Response driven Focused populations

32 The Surviving Sepsis Campaign A Performance Improvement Initiative in Sepsis Using Sepsis Bundles to Improve Care

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34 SSC Mortality: Participation effect Levy MM et al; CCM 2015;43:3-12

35 SSC Duration Effect: Mortality Change over time The adjusted odds of hospital mortality is decreasing 1% per site quarter (p = 0.005) The longer a site participated, the greater the associated mortality reduction Levy MM et al; CCM 2015;43:3-12

36 Association between compliance and Mortality: Dose Effect

37 High vs. Low Compliance Levy MM et al; CCM 2015;43:3-12

38 Conclusions: Managing Severe Sepsis and Shock Early identification Use lactate to risk assess Aggressive source control Blood cultures Rapid administration of appropriate antibiotics Early, aggressive resuscitation Utilize some monitoring technique as target Try to do more good than harm.

39 Conclusions: Complex, redundant mechanisms of inflammation and immune suppression Likely balance between hyperimmune response and prolonged immune suppression Early identification of sepsis is key to therapy Rapid administration of appropriate antibiotics Early, aggressive resuscitation All trials for immunotherapy have failed There are no new agents for sepsis Increased compliance with performance metrics is associated with improved survival

40 Thank You