1. R. Phillip Dellinger, MD Professor of Medicine Robert Wood Johnson Medical School/UMDNJ Director Critical Care Medicine Cooper University Hospital Camden, New Jersey Septic Shock: Current Management and New Therapeutic Frontiers

2. Personal Financial Disclosures None relevant to presentation today

3. Background - Basic Definitions Sepsis = known or suspected infection plus systemic manifestations of infection (SIRS and others) Severe Sepsis = Sepsis + either –Acute organ dysfunction thought to be due to sepsis –Acute tissue hypoperfusion thought to be due to sepsis Hypotension Elevated lactate Oliguria (Altered mental status)

4. Background - Basic Definitions Severe Sepsis Organ Dysfunctions –Acute lung injury –Acute kidney injury –Coagulopathy Thrombocytopenia Increased INR –Liver Dysfunction –(Cardiovascular) Septic Shock –Vasopressors +/- organ dysfunction

5. Surviving Sepsis Campaign (SSC) guidelines for management of severe sepsis and septic shock Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM and the SSC Management Guidelines Committee Crit Care Med 2004;32:858-873 Intensive Care Med 2004;30:536-555

6. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Crit Care Med 2008; 36:296-327 Intensive Care Med 2008;30:536-555

7. Sponsoring Organizations 2008 Guidelines American Association of Critical Care Nurses American College of Chest Physicians American College of Emergency Physicians Canadian Critical Care Society European Respiratory Society European Society of Clinical Microbiology and Infectious Diseases European Society of Intensive Care Medicine Indian Society of Critical Care Medicine International Sepsis Forum Japanese Society of Intensive Care Medicine Japanese Association of Acute Medicine Society of Hospital Medicine Society of Critical Care Medicine Surgical Infection Society World Federation of Critical Care Nurses World Federation of Societies of Intensive and Critical Care Medicine

8. SSC Update 2010/2011

9. Current Surviving Sepsis Campaign Guideline Sponsors (2010/11 Update) American Association of Critical-Care Nurses American College of Chest Physicians American College of Emergency Physicians Australian and New Zealand Intensive Care Society Asia Pacific Association of Critical Care Medicine American Thoracic Society Brazilian Society of Critical Care(AIMB) Canadian Critical Care Society European Respiratory Society European Society of Clinical Microbiology and Infectious Diseases European Society of Intensive Care Medicine European Society of Pediatric and Neonatal Intensive Care German Sepsis Society Infectious Diseases Society of America Indian Society of Critical Care Medicine Japanese Association for Acute Medicine Japanese Society of Intensive Care Medicine Latin American Sepsis Institute Pan Arab Critical Care Medicine Society Pediatric Acute Lung Injury and Sepsis Investigators Society Academic Emergency Medicine Society of Critical Care Medicine Society of Hospital Medicine Surgical Infection Society World Federation of Critical Care Nurses World Federation of Societies of Intensive and Critical Care Medicine

10. Evidence Based Medicine Grading System

13. Grades of Recommendation, Assessment, Development and Evaluation (GRADE)

14. Grading Quality of Evidence A- high quality –Randomized controlled trial (RCT) B- intermediate –Downgraded RCT or upgraded observational C- low –Observational or cohort D- very low –Case series or expert opinion Upgrade capability

15. Grading Strength of Recommendation 1- strong recommendation – Do it –We recommend 2- weak recommendation – Probably do it –We suggest Determinants of strength –Quality of evidence –Relative importance of outcomes –Risks and costs –Absolute magnitude and precision of effect

16. Kumar A, et al. Crit Care Med 2006; 34:1589-1596

17. Antibiotic Therapy  We recommend beginning intravenous antibiotics within first hour of recognition of severe sepsis 1B

18. Broad antibiotic coverage initially Narrow coverage after return of cultures Source control as soon as possible and within 6 hours

21. Initial Resuscitation

22. Resuscitation of Sepsis Induced Tissue Hypoperfusion Recommend MAP 65 mm Hg Recommend urine output.5 ml/kg/hr Grade 1C

23. Fluid Therapy Recommend fluid resuscitation may consist of natural or artificial colloids or crystalloids. Grade 1B

24. The SAFE Study Investigators, N Engl J Med 2004;350:2247 Probability of Survival

25. The SAFE Study Investigators, N Engl J Med 2004;350:2247 Relative Risk of Death from Any Cause among All the Patients and among the Patients in the Six Predefined Subgroups of Survival

26. Sepsis Induced Hypotension Fluid challenge –Minimum of 20 ml/kg crystalloid or colloid equivalent

27. Sepsis Induced Tissue Hypoperfusion  Requirement for Vasopressors after initial fluid challenge  Lactate ≥ 4 mg/dL

28. Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular management of septic shock. Crit Care Med 2003;31:946-955.

29. Which two adrenergic agents are most appropriate to maintain acceptable blood pressure in a patient with septic shock? A.Dopamine or epinephrine B.Epinephrine or vasopressin C.Vasopressin or norepinephrine D.Norepinephrine or dopamine

30. Which two adrenergic agents are most appropriate to maintain acceptable blood pressure in a patient with septic shock? A.Dopamine or epinephrine B.Epinephrine or vasopressin C.Vasopressin or norepinephrine D.Norepinephrine or dopamine

31. During Septic Shock 10 Days Post Shock Diastole Systole Diastole Systole Images used with permission from Joseph E. Parrillo, MD

32. Effects of Dopamine, Norepinephrine, and Epinephrine on the Splanchnic Circulation in Septic Shock Figure 2, page 1665, reproduced with permission from De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best? Crit Care Med 2003; 31:1659-1667

33. Norepinephrine vs. Dopamine

34. De Backer D, et al. N Engl J Med 2010, 362;9:779-789 28-day Survival

35. De Backer D, et al. N Engl J Med 2010, 362;9:779-789 Predefined subgroup analysis by type of shock

36. Phenylephrine Pure vasoconstrictor in general should be avoided –Decreases cardiac output Rare exceptions –Cardiac output measured and high and difficulty with maintaining MAP with other vasopressor agents –Profound tachycardia or severe ventricular arrhythmias with norepinephrine

37. Initial Resuscitation of Persistent Hypotension or Lactate >4 Recommend Insertion central venous catheter Recommended goals : Central venous pressure: 8–12 mm Hg Higher with altered ventricular compliance or increased intrathoracic pressure ScvO2 saturation (SVC)  70% Grade 1C

38. The Early Bird Gets the Worm

39. The Importance of Early Goal-Directed Therapy for Sepsis Induced Hypoperfusion Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al. Early goal- directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377 In-hospital mortality (all patients) 0 10 20 30 40 50 60 Standard therapy EGDT 28-day mortality 60-day mortality NNT to prevent 1 event (death) = 6-8 Mortality (%)

40. Trials of Late Hemodynamic Optimization with Control Group Mortality > 20% Kern and Shoemaker Crit Care Med 2002 After After onset of organ failure Alia et al. 1999 Yu et al. 1998 Gattinoni et al. 1995 Hayes et al. 1994 Yu et al. 1993 OVERALL RESULT Favors Optimization Favors Control 0.0-0.4 0.4

41. Role of Collaboration ICUED

42. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739-46.

43. Copyright restrictions may apply. Jones, A. E. et al. JAMA 2010;303:739-746. Hospital Mortality and Length of Stay

44. Vasopressin Continue to recommend against using high doses of vasopressin (unless salvage therapy) Vasopressin.03 units per min plus NE equivalent to norepinephrine alone –VASST trial

46. Figure 2A, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862-871 Steroid Therapy

47. CORTICUS: Results No benefit in intent to treat –Mortality –Shock reversal Earlier reversal of shock with steroids in those that had shock reversal

48. FRENCH TRIALCORTICUS Overall Severity of Illness++++++ Duration of Shock < 8 hrs< 72 hrs Degree of Hypotension++++++ Potential for Selection BiasUnlikelyYes

49. Steroids Suggest intravenous hydrocortisone be given only to adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy Grade 2C

50. Recombinant Human Activated Protein C (rhAPC) Suggest use in patients with clinical assessment of high risk of death due to sepsis induced organ dysfunction typically with APACHE II 25 or greater or multiple organ failure No absolute contraindications Weigh relative contraindications Grade 2B

51. PROWESS SHOCK

52. As to Guidelines Publications “Knowledge is Good”

55. Guidelines Are Not Enough Protocols Performance Improvement Programs

56. Severe Sepsis Resuscitation Bundle Implement the 6-hour bundle. Available at: http://ssc.sccm.org/6hr_bundles. Complete tasks within 6 hours of identifying severe sepsis. 1.Measure serum lactate. 2.Obtain blood cultures prior to antibiotic administration. 3.Administer broad-spectrum antibiotic within 3 hours of ED admission and within 1 hour of non-ED admission. 4.In the event of hypotension and/or serum lactate > 4 mmol/L: a.Deliver an initial minimum of 20 mL/kg of crystalloid or equivalent. b.Begin vasopressors for hypotension not responding to initial fluid resuscitation to maintain MAP > 65 mm Hg. 5.In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L: a.Achieve a central venous pressure (CVP) of > 8 mm Hg b.Achieve a central venous oxygen saturation (ScvO 2 ) > 70% or mixed venous oxygen saturation (ScvO 2 ) > 65%

58. SSC Interactive Database

59. Surviving Sepsis Campaign: Phase III A global, multi-center, 2-year trial –Multiple hospital networks –166 sites –15,022 patients Primary outcome –The impact of a model for changing bedside management of sepsis Secondary outcome –Mortality

61. Findings Primary outcome of SSC: behavior change –20% increase in bundle compliance over 24 months Secondary outcome - Mortality -- 7.0% ARR, 19% RRR -- 5.4% ARR after severity adjustment

62. Septic Shock Research at Cooper

63. Intrathoracic Pressure Regulation (ITPR) in Porcine Peritonitis Septic Shock

64. p<0.001 n=28

65. p<0.001 n=28

66. : ITPR application and duration

67. FE202158 Vasopressin A1 receptor agonist

68. Septic sheep – Traber et al.

69. V1a Receptor Agonist in a Rat Model of PAF- Induced Hypotension & Vascular Leak Syndrome

70. The EUPHRATES Trial Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock

71. Endotoxemia Sources of Endotoxin Endotoxin translocation from GI Tract Every human has 25-30 grams of Endotoxin in their GI tract Less than 0.001 grams of Endotoxin is enough to kill a person Endotoxin shed from local bacterial infection

72. Opal SM, et al. Infect Dis, 1999 Sepsis and Endotoxin

73. Intervention DIRECT HEMOPERFUSION WITH ADSORBENT COLUMN USING POLYMYXIN B IMMOBILIZED FIBER ANTICOAGULANT FEMORAL or IJ VEIN BLOOD TUBE P BLOOD PUMP Perfusion rate 80-120 ml/min Duration: 2 hours 73

75. EUPHAS: 10 centres, Italy, randomized, unblinded Groups were equal at baseline

76. Endotoxin Activity Assay EAA™ Spectral Diagnostics Inc. 76 The only FDA cleared test for detection of Endotoxin

77. THANK YOU