1. Priyank Desai, MD Ryan Griffin, RN

2. HOW COMMON? DEFINITION PATHOGENESIS CLINICAL FEATURES MANAGEMENT CORE Measures!!

3. A SIGNIFICANT HEALTHCARE CHALLENGE  Major cause of morbidity and mortality worldwide *  Leading cause of death in noncoronary ICU (US) *  11 th leading cause of death overall (US) †§  More than 750,000 cases of severe sepsis in US annually ‡  More than 500 patients die of severe sepsis daily ‡ * Sands KE et al. JAMA. 1997;278:234-40 ; Based on data for septicemia. * Sands KE et al. JAMA. 1997;278:234-40 ; † Based on data for septicemia. § Murphy SL. National Vital Statistics Reports. ‡ Angus DC et al. Crit Care Med. 2001

4. SEVERE SEPSIS: A GROWING HEALTHCARE CHALLENGE *Angus DC. Crit Care Med. 2001 2001 >750,000 cases of severe sepsis/year in the US * Future 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000 200120252050 Year 100,000 200,000 300,000 400,000 500,000 600,000 Severe Sepsis Cases US Population Sepsis Cases Total US Population/1,000

5. SEPSIS IS A VERY COMMON CAUSE OF INPATIENT DEATHS Hospital Deaths in Patients with Sepsis from Two Independent Cohorts Liu et al JAMA May 18, 2014 All Sepsis 52% All Sepsis 45% National Sample data shows that coding doesn’t catch all sepsis cases, UNC rates are likely higher than reported.

6. SEVERE SEPSIS: COMPARISON WITH OTHER MAJOR DISEASE † National Center for Health Statistics, 2001. § American Cancer Society, 2001. *American Heart Association. 2000. ‡ Angus DC et al. Crit Care Med. 2001 AIDS*Colon Breast Cancer § CHF † Severe Sepsis ‡ Cases/100,000 Incidence of Severe Sepsis Mortality of Severe Sepsis AIDS* Severe Sepsis ‡ AMI † Breast Cancer §

7. UNC HEALTH SYSTEMS TOTAL SEPSIS DEATHS 2014 947 NASH SEPSIS DEATHS 2014 147

8.  Infection: Inflammatory response to microorganisms, or Invasion of normally sterile tissue  Systemic Inflammatory Response Syndrome (SIRS) Systemic response to variety of process  Sepsis: Infection + ≥ 2 SIRS Criteria  Severe Sepsis Sepsis + Organ dysfunction  Septic Shock Severe Sepsis Hypotension despite of fluid resuscitation  Multiple Organ Dysfunction Syndrome (MODS) Altered organ function in an acutely ill patient Homeostasis cannot be maintained without intervention ACCP / SCCM CONSENSUS DEFINITIONS INFECTION MUST BE PRESENT

9. SIRS/SEPSIS CRITERIA HR > 90 Temp >100.4 Resp Rate >20 Sys B/P <90 Lactate >2

10. ACUTE ORGAN DYSFUNCTION AS MARKERS OF SEPSIS AND SEVERE SEPSIS Balk RA. Crit Care Clin 2000;16:337-52. TachycardiaHypotension Altered CVP Altered PAOP OliguriaAnuria  Creatinine  Platelets  PT/APTT  Protein C  D-dimer Jaundice  Enzymes  Albumin Altered Consciousness ConfusionPsychosis Tachypnea PaO 2 <70 mm Hg SaO 2 <90% PaO 2 /FiO 2  300

12. PATHOGENESIS

13. SEVERE SEPSIS: A COMPLEX AND UNPREDICTABLE CLINICAL SYNDROME Systemic Inflammation Coagulation Activation Impaired Fibrinolysis SEVERE SEPSIS

14. CLINICAL EFFECTS

15. HOW TO DIAGNOSE SEPSIS?

16. DEATH Multi- Organ Dysfunction Syndrome Septic Shock Severe Sepsis SepsisSIRS Infection no simple defining symptoms, signs, lab values or imaging findings

17. HOW TO MANAGE SEPSIS? SURVIVING SEPSIS GUIDELINES

18.  Hemodynamic Support  Antibiotics  Source Control  Mechanical Ventilation  Renal Replacement Therapy  Nutrition  Supportive measures SEVERE SEPSIS THERAPY: SURVIVING SEPSIS GUIDELINES

19. EARLY GOAL DIRECTED THERAPY Blood Cultures Lactic Acid Broad Spectrum Antibiotic Crystalloid Fluids of 30cc/kg.

20. 15.9% absolute reduction in 28- day mortality rate

21. HEMODYNAMIC SUPPORT Refractory Hypotension or blood lactate ≥ 4 Goals during the first 6hrs of resuscitation: o CVP 8–12 o MAP ≥ 65 o Urine output ≥ 0.5 mL/kg/hr o ScvO2 > 70% or SvO2 > 65% o Normalize lactate in patients with elevated lactate levels

22. ProCESS TRIAL 1341 patients with septic shock Protocol based therapies EGDT VS Protocol based standard therapy VS Usual Care EGDT Targets: ScvO2, CVP, MAP, UOP (with Central access) Usual Care (no protocol to direct fluid management) NO difference in 60- day Mortality PROTOCOL-DIRECTED THERAPY ARISE TRIAL 1600 patients with septic shock Protocol based therapies vs Usual Care NO difference in 60- day Mortality ProMISe TRIAL 1260 patients with septic shock Protocol based therapies vs Usual Care NO difference in 60- day Mortality “ Lack of benefit may also be attributed to overall better outcomes in these studies, perhaps due to early administration of antibiotics (70 to 100 percent before randomization) in all groups, and to improved clinical performance by highly trained clinicians in academic centers during an era that follows an aggressive sepsis education and management campaign”

23. WHICH FLUID? Crystalloids as the initial fluid of choice Albumin when patients require substantial amounts of crystalloids Initial fluid challenge to achieve 30cc/kg NEJM 2004;350(22):2247

24. Norepinephrine first choice Goal: MAP > 65mm Hg Epinephrine can be added as a second vasopressor Vasopressin 0.03-0.04 units/min can be added to NE to raise MAP OR decrease NE dose Dopamine only in selective patients Phenylephrine only if NE cause serious arrhythmias Arterial catheters should be placed in patients on vasopressors WHICH VASOPRESSOR?

25. WHY NOT DOPAMINE AS A FIRST PRESSOR?

26.  Hemodynamic Support  Antibiotics  Source Control  Mechanical Ventilation  Renal Replacement Therapy  Nutrition  Supportive measures SEVERE SEPSIS THERAPY: SURVIVING SEPSIS GUIDELINES

27. ANTIBIOTICS Administration of effective empirical intravenous antimicrobials or antifungal within the first hour of recognition of sepsis as the goal of therapy at the same time of drawing cultures Empiric combination therapy should not be administered for more than 3–5 days. Reassessed daily for potential de-escalation De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin Duration of therapy typically 7–10 days; longer courses may be appropriate in patients who have a slow clinical response

28. THE DURATION OF HYPOTENSION PRIOR TO INITIATION OF EFFECTIVE ANTIMICROBIAL THERAPY IS THE CRITICAL DETERMINANT OF SURVIVAL IN SEPTIC SHOCK Over the first 6 hrs after the onset of recurrent or persistent hypotension, each hour of delay in initiation of effective antimicrobial therapy was associated with mean decrease in survival of 7.6%

29. TIME TO 1 ST ANTIBIOTIC DOSE IS THE MOST IMPORTANT PREDICTOR OF SURVIVAL IN SEPTIC SHOCK! Kumar et al. Critical Care Medicine 2006 34:1589

30. THE DURATION OF HYPOTENSION PRIOR TO INITIATION OF EFFECTIVE ANTIMICROBIAL THERAPY IS THE CRITICAL DETERMINANT OF SURVIVAL IN SEPTIC SHOCK Mortality increased with increasing delays in initiation of effective antimicrobial Rx. An increased risk of death is already present by the second hour after hypotension onset (compared with the first hour after hypotension).

31. MORTALITY INCREASES BY 7.6% EVERY HOUR THAT TREATMENT IS DELAYED

32.  Hemodynamic Support  Antibiotics  Source Control  Mechanical Ventilation  Renal Replacement Therapy  Nutrition  Supportive measures SEVERE SEPSIS THERAPY: SURVIVING SEPSIS GUIDELINES

33. SOURCE CONTROL Source Control should be performed within 12 hours of presentation

34.  Hemodynamic Support  Antibiotics  Source Control  Mechanical Ventilation  Renal Replacement Therapy  Nutrition  Supportive measures SEVERE SEPSIS THERAPY: SURVIVING SEPSIS GUIDELINES

35. MECHANICAL VENTILATION Low tidal volume strategies 6cc/kg predicted body weight PLT < 30 Recruitment maneuvers for refractory hypoxemia VAP bundles HOB > 30 degree Weaning protocols including spontaneous breathing trials once hemodynamically stable

36.  Hemodynamic Support  Antibiotics  Source Control  Mechanical Ventilation  Renal Replacement Therapy  Nutrition  Supportive measures SEVERE SEPSIS THERAPY: SURVIVING SEPSIS GUIDELINES

37.  Corticosteroids Only if shock is irreversible with fluid resuscitation and vasopressors Hydrocortisone 200mg/day No ACTH stim test required Tapered once off of pressors  Glucose Control Goal 110 – 180 mg/dL Insulin drip if 2 consecutive glucose level > 180  DVT Prophylaxis LMWH or Heparin Cr clearance < 30 o Dalteparin Combined with SCDs  GI Prophylaxis H2 blocker or PPI only if bleeding risk factors presents SUPPORTIVE MEASURES

38.  Measure lactate level  Obtain blood cultures prior to administration of antibiotics  Administer broad spectrum antibiotics  Hypotension/Lactate ≥ 4  30cc/kg crystalloid KEY POINTS / GOALS COMPLETE WITHIN 3 HOURS

39. SEPSIS AT NASH BUNDLE APPROACH Care elements selected From evidence based guidelines Implemented together, provides improved outcomes compared to individual elements alone

40. CARE ELEMENTS TO BE MEASURED @ NASH Lactate completed within 1 hour Blood cultures x 2 prior to antibiotics (do not hold antibiotics if unable to obtain) Antibiotics started within 1 hour Fluid Resuscitation of 30ml/kg in the first hour with a diagnosis of Septic shock (SBP 4) or 2 liters bolus if diagnosis of sepsis

41. ADULT SEPSIS TREATMENT BUNDLE GOALS Blood Culture x 2 Lactate Level Initiate first dose of Antibiotic in 1 hour IV Fluid resuscitation to goal of 30ml/kg in first hour

42. SYSTEM LEVEL METRICS DescriptionU/MFrequencySourceBaselineGoal Bundle Compliance %MonthlyTBD0%100% Sepsis LOS# DaysMonthlyTBD10.79.6 (10% reduction) Sepsis Deaths #MonthlyTBD12066 (16% Reduction) Sepsis Mortality %MonthlyTBD13.7%Watch Metric

43. NASH VS UNC SYSTEM Hospital Total # Sepsis Deaths CY 14 Avg sepsis deaths / month = baseline (Column B/12) Total # sepsis pt's CY 14 Overall Sepsis Mortality = baseline (column B / column D) AVG Sepsis LOS (total # pt days / # pt's) # Total Patients (all dx) CY 14 # Total Deaths (all dx) CY 14 Overall Mortality = baseline (column H / column G) Caldwell Memorial Hospital201.716112.4%10.13880651.7% Chatham Hospital 0.0 #DIV/0! High Point Regional Hospital 0.0 #DIV/0! Johnston Medical Center 0.0 #DIV/0! Pardee Memorial Hospital363.06056.0%5.57180891.2% Nash Health Care System14712.382217.9%8.5126573462.7% Rex Healthcare19316.1151112.8%7.8307955861.9% UNCMC36630.5244715.0%15.53400028302.1% TOTAL

44. TAKE AWAY POINTS Fluid Delivery of 30ml/kg in first hour (In order to achieve this bolus given with pressure bag) Begin Broad Spectrum Antibiotic within first hour Obtain Lactate Level Obtain blood cultures x 2

46. Thank you