The Treatment of Sepsis: Early Goal Directed Therapy and Beyond

1. The Treatment of Sepsis:Early Goal Directed Therapyand Beyond Anthony J. Hericks, D.O. South Dakota ACP Scientific Meeting September 13th, 2013

2. A clinician, armed with the sepsis bundles, attacks the three heads of severe sepsis: hypotension, hypoperfusion and organ dysfunction. Crit Care Med 2004; 320(Suppl):S595-S597

3. 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 Emirates Intensive 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 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 for 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 German Sepsis Society Surviving Sepsis CampaignSponsoring Organizations

4. Surviving Sepsis Campaign (SSC) Guidelines for Management of Severe Sepsis and Septic Shock • Dellinger RP, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. CritCare Med2004, 32:858-873. • Dellinger RP, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008Crit Care Med 2008, 36:296-327. • Levy MM, et al. Surviving Sepsis Campaign: Results of an international guidelines performance improvement program targeting severe sepsis. Crit Care Med2010, 38:367-374. • Dellinger RP, et al. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med 2013, 41(2):580-637. • Angus DC, et al. Severe Sepsis and Septic Shock. NEJM 2013; 369(9): 840-851

5. Surviving Sepsis Campaign Conclusions • Strong agreement among a large cohort of international experts • Many level 1 recommendations • Significant number of recommendations with relatively weak recommendations • Evidence-based recommendations are the foundation of improved outcomes Dellinger RP, CCM 2013

6. Grading of Recommendations(Grading of Recommendations Assessment, Develop and Evaluation – GRADE)

8. A 82 year old white female present to the emergency department with complaints of dysuria, frequency and urgency. Her temperature is 100.4 F, HR 92, RR 21 and BP 122/86. What should she be classified as? • Systemic Inflammatory Response Syndrome • Sepsis • Severe Sepsis • Septic Shock • Multi-Organ Dysfunction/Failure Syndrome

9. A 82 year old white female present to the emergency department with complaints of dysuria, frequency and urgency. Her temperature is 100.4 F, HR 92, RR 21 and BP 122/86. What should she be classified as? • Systemic Inflammatory Response Syndrome • Sepsis • Severe Sepsis • Septic Shock • Multi-Organ Dysfunction/Failure Syndrome

10. Identification of Sepsis: Definitions • Systemic Inflammatory Response (SIRS) • Sepsis • Severe Sepsis • Septic Shock • Multi-Organ Failure Syndrome (MOFS) • Death

11. SIRS • Heart Rate > 90 • Respiratory Rate > 20 • WBC > 12K or < 4K • Temp > 38 C (100.4 F) or < 36 C (96.8 F) • Any two of the above • Very nonspecific

12. Sepsis • SIRS + signs of a suspected or known infection • WBC’s in normally sterile fluid • Infiltrate on chest x-ray • Bacteria in normally sterile fluid

13. Diagnostic Criteria for Sepsis

14. Severe Sepsis • Sepsis + sepsis-induced tissue hypoperfusion or organ dysfunction

15. Sepsis Induced Hypotension • SBP < 90 mmHg OR • MAP < 70 mmHg OR • SBP > 40 mmHg < 2 SD below the nml for age

16. Septic Shock • Severe Sepsis or sepsis-induced hypoperfusion persistent despite: • Adequate/initial fluid challenge/resuscitation • Lactate > 4 mmol • Addition of pressors • Sepsis-induced hypoperfusion = infection-induced hypotension, elevated lactate or oliguria

17. MOFS • Altered organ function, involving two or more organs, in an acutely ill patient requiring medical intervention to achieve homeostasis

18. Death • The permanent the cessation of all vital functions in an individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem • Severe Sepsis/Septic Shock mortality = ~30-46%

19. Consideration for Limitation of Support • “We recommend that the goals of care and prognosis be discussed with patients and families and these be incorporated into the patients treatment along with end-of-life care planning and utilizing palliative care principles.” • Re-address goals as earlier as feasible, but no later than 72 hours of admit Grade 1B Grade 2C

20. Incidence of Severe Sepsis • Estimated to be: • 2% of all patients admitted to the hospital • 10% of all patients in the ICU • < 750,000 cases per year and rising • Mortality rate of 20-30% NEJM 369(9): 840-851

21. Pathophysiology of Sepsis

22. Based on Dr. Rivers article re: Early Goal Directed Therapy, what is the ultimate goal in the first 6 hours? • CVP of 8-12 unventilated/12-15 ventilated • MAP >65 • Cardiac Output > 8 LPM • Hemoglobin > 10 gm/dL • ScvO2 > 70%

23. Based on Dr. Rivers article re: Early Goal Directed Therapy, what is the ultimate goal in the first 6 hours? • CVP of 8-12 unventilated/12-15 ventilated • MAP >65 • Cardiac Output > 8 LPM • Hemoglobin > 10 gm/dL • ScvO2 > 70%

24. Initial Resuscitation:Goals of Early Goal Directed Therapy • CVP 8-12 cmH2O • 12-15 cmH2O on the ventilator • MAP > 65 mmHg • May need to be higher in patients with HTN • UOP > 0.5 mL/Kg /hour • ScvO2> 70% • SvO2> 65% • Goal: Normalize lactate • Goal in the first 6 hours after diagnosis • 16-17% decrease in mortality Grade 1C Grade 2C Rivers E. N Engl J Med 2001; 345:1368-77

25. Central Venous Pressure • Crystalloid or Colloid? • Volume? • Goal?

26. SAFE Study Crystalloid (NS) = Colloid (4% Albumin) Less volume, more PRBC’s, higher CVP and Albumin No difference in mortality (p = 0.87) Trend for increased risk of death in Trauma (0.06) Trend for decreased risk of death in Severe Sepsis (0.09) Crystalloid or Colloid Grade 1B Finfer S. N Engl J Med 2004; 350:2247–2256

27. SSC Recommendations • Crystalloids • Albumin • If substantial fluid is required Grade 1B Grade 2C

28. Hydroxyethyl Starch (HES) • Increased risk of acute kidney injury and death in sepsis • Variable findings depending on studies • Schortgen G. Lancet 2001; 357:911-916. • Sakr Y. Br J Anaesth 2007; 98:216-224. • Brunkhorst FM. NEngl J Med 2008; 358: 125-139. • Perner A. N Engl J Med 2012; 367:124-134. • Risk and no benefit, HES should not be used!!! Grade 1B

29. Fluid Volume • 30 mL/Kg crystalloid • A portion may be an albumin equivalent • More rapid administration or larger amounts may be needed • Continue fluid administration as long as there appears to be hemodynamic improvement Grade 1C Grade UG

30. Volume Responsiveness Grade 1C • CVP > 8 cmH2O • > 12 cmH2O on the vent • Swan-Ganz Catheter • PCWP • Cardiac output • Non-invasive Monitors • PiCCO Catheter • FloTrac • Pulse Pressure Variation • IVC via Echo • MAP and Heart Rate Grade 1D

31. CVP • Spontaneous Breathing > 8 cmH2O • Ventilatory Breathing > 12 cmH2O • Primarily based on expert opinion • Dellinger RP. Crit Care Med 2004; 32:858–873 • Rivers E. N Engl J Med 2001; 345:1368–1377 • Practice parameters for hemodynamic support of sepsis in adult patients with sepsis. Crit Care Med 1999; 27:639–660

32. Pulmonary Capillary Wedge Pressure • PCWP < 12 mmHg predicts a fluid bolus with increase cardiac output with a PPV of only 54% • However the “Gold Standard” for “volume responsiveness” may be a increase in cardiac output of > 15% after a fluid challenge Osman D. Crit Care Med 2007; 35:64–68

33. Non-invasive Monitoring

34. PPV PPV PPV CVP PCWP

35. Echocardiography

36. Does volume overload contribute to morbidity and mortality? • True • False

37. Does volume overload contribute to morbidity and mortality? • True • False

38. Avoid Volume Overload • Tolerated as long as volume responsive • Fluid challenges usually required for the initial 24-48 hours • Finfer S. N Engl J Med 2004; 350:2247–2256 • Decrease the rate when no longer volume responsive Grade 1D

39. Volume Overload, Cont’d • Independent predictor of mortality • Boyd JH. Crit Care Med 2011; 39(2):259-265 • Vincent JL. CritCare Med 2006; 34:344–353 • Uchino S. CritCare Med2006; 10:R174 • Prolonged mechanical ventilation • Upadya A. Intensive Care Med 2005; 31:1643–1647 • ARDS • Humphrey H. Chest 1990; 97:1176–1180 • Simmons RS. Am Rev RespirDis 1987; 135:924–929 • Mitchell JP. Am Rev RespirDis 1992; 145:990–998 • Wiedemann HP. N Engl J Med 2006; 354:2564–2575 • Sepsis • Alsous F. Chest 2000; 117:1749–1754 • Rivers E. N Engl J Med 2001; 345:1368–1377 • Abdominal compartment syndrome • Malbrain ML. Crit Care Med 2005; 33:315–322 • McNelis J. Arch Surg 2002;137:133–136 • Cerebral edema and herniation • Uchino S. Crit Care 2006; 10:R174

40. MAP Grade 1C

41. What is the pressor of choice for a patient in septic shock? • Dopamine • Norepinephrine (Levophed) • Vasopressin • Phenylephrine (Neosynephrine) • All the above

42. What is the pressor of choice for a patient in septic shock? • Dopamine • Norepinephrine (Levophed) • Vasopressin • Phenylephrine (Neosynephrine) • All the above

43. Vasopressors • Norepinephrine • Dopamine • Vasopressin • Epinephrine • Phenylephrine

44. Norepinephrinevs Dopamine • No significant difference in mortality (p = 0.10) • Trend for less death in the ICU (p = 0.07) • No difference at hospital discharge or 1 yr • Increased rate of adverse events with Dopamine • Arrhythmias (p = < 0.001) • Atrial Fibrillation • Ventricular Tachycardia • Ventricular Fibrillation • Skin Ischemia (trend; p = 0.09) DeBacker D. N Engl J Med 2010; 362:779-789

45. Norepinephrinevs Dopamine,Cont’d • Norepinephrine should be the first line vasopressor • Dopamine is an alternative to Norepinephrine • Only in highly selected patients with low risk of: • Tachyarrhythmias • Absolute or relative bradycardia Grade 1B Grade 2C

46. Vasopressin • Adding Vasopressin to Norepinephrine showed no mortality benefit compared to Norepinephrine alone (p = 0.26) • Did lower Norepinephrine requirements • May have other potential physiologic benefits • Should not be used as a single agent Russel JA. N Engl J Med 2008; 358:877-887 Grade UG

47. Epinephrine • First line in pts poorly responsive to Norepinephrine and Dopamine • No evidence of worse outcomes • Increased risk of: • Tachycardia • Elevated lactate • Decreased splanchniccirculation • Add to or instead of Norepinephrine Grade 2B

48. Phenylephrine • Not recommended!!! • Except: • Norepinephrine induced arrhythmias • Cardiac output is high • Persistently low BP • Salvage therapy • Decreases cardiac output Grade 1C

49. Hemodynamic Equations • DaO2 = CO x Hgb x SaO2 • Oxygen delivery • VO2 = CO x Hgb x (SaO2 - SvO2) • Oxygen consumption • O2 ER= VO2/DaO2 • Oxygen extraction ratio • ~ 0.2 to 0.3 • VO2 > DaO2 OR DaO2 < VO2 = Dysoxia • Dysoxia = lactic acidosis = organ failure = death

50. Venous Oxygen Saturation • Physiology Adapted from: http://ht.edwards.com/resourcegallery/products/swanganz/pdfs/svo2edbook.pdf