李建璋 MD, MSc NEUH ED Staff Physician

1. Early Goal Directed Therapy for Septic Shock in the Emergency Department of National Taiwan University Hospital Preliminary Experience 李建璋MD, MSc NEUH ED Staff Physician

3. The Continuum of Sepsis SIRS Sepsis Severe Sepsis Septic Shock • Systemic Inflammatory Response Syndrome • SIRS criteria • Temp < 36° or > 38° C • HR > 90 • RR > 20 or PCO2 < 32 • WBC < 4k or > 12k or bands > 10% Bone et al. Chest 1992;101:1644

4. The Continuum of Sepsis Bone et al. Chest 1992;101:1644; Balk, RA

5. The Continuum of Sepsis SIRS Sepsis Severe Sepsis Septic Shock • Sepsis plus Organ Dysfunction • Elevated Creatinine (>2) • Elevated INR (DIC) • Altered Mental Status (GCS <12) • Elevated Lactate (>4) • Hypotension that responds to fluid Bone et al. Chest 1992;101:1644

6. The Continuum of Sepsis SIRS Sepsis Severe Sepsis Septic Shock • Severe Sepsis and Hypotension • Hypotension that does NOT respond to fluid (500cc bolus) Bone et al. Chest 1992;101:1644

7. Why is this so Important? • 750,000 cases/yr of severe sepsis in US • 215,000 deaths/yr directly related to sepsis • Tenth leading cause of death in USA • Rate of sepsis cases is increasing faster than the population • 37% of severe sepsis patients come through the ED

8. Why so Important? (cont’d) Mortality of Severe Sepsis Breast Cancer§ AMI† AIDS* Severe Sepsis‡ †National Center for Health Statistics, 2001.§American Cancer Society, 2001. *American Heart Association. 2000.‡Angus DC et al. Crit Care Med. 2001

9. Estimated Statistics in NTUH ED • 2002 statistics • 1 year  994 episodes of bacteremia • Blood culture yield rate  ~13% • Estimation • 6626 blood culture drawn • Sepsis 50%  3313 Mortality (30day) 5% 165 • Severe Sepsis 20%  1325 Mortality (30day) 22% 292 • Septic Shock 5%  331 Mortality (30day) 50% 165 • 1 day  2.7 BSI  9 Sepsis  3.6 severe sepsis 0.9 septic shock  1.7 Mortality  0.85 early mortality

10. Major Advance in Sepsis Tx • In the past 20 yrs, the mortality of severe sepsis/ septic shock remains dismal (40~50%) • In the past 5 yrs, there were 4 major breakthroughs • Early goal directed therapy • Steroid for vasopressor resistant septic shock • Activated protein C in septic shock • Intensive insulin for hyperglycemic pts

11. Early Goal-Directed Therapy (EGDT)

12. EGDT • Design • Randomized, Blinded, Controlled trial • Patients • 263 adults with severe sepsis and lactate > 4 or septic shock • Intervention • 6 hours of algorithmic care which optimized • CVP 8-12 • MAP > 65 • ScvO2> 70% • Outcome • Mortality in house, 28 day, and 60 day

13. Mixed venous O2

14. ScvO2 correlates with SvO2 in shock states

15. Rivers, E. et al. N Engl J Med 2001;345:1368-1377

16. EGDT Results 28-day Mortality 60 49.2% P = 0.01* 50 40 33.3% 30 20 10 0 Standard Therapy n=133 EGDT n=130 Rivers E. N Engl J Med 2001;345:1368-77.

17. Early Interventions in Medicine • AMI – “Time is Muscle” • ACC/AHA guidelines for STEMI • Door-to-needle time for initiation of fibrinolytic therapy should be achieved within 30 minutes • Door-to-balloon (or medical contact–to-balloon) time for PCI can be kept under 90 minutes. • Stroke – “Time is Brain” • ASA • IV rtPA is stronglyrecommended within 3 hours of onset of ischemic stroke (grade A). • Trauma • Golden Hour – …the lives of severely injured people could be saved if treated by trauma specialists

18. Time Matters in the Treatment of Sepsis

19. Other Problem in Sepsis Management • Inconsistency in early diagnosis • Inadequate volume resuscitation • Late or inappropriate antibiotics • Failure to support depressed cardiac output • Failure to control hyperglycemia • Failure to treat adrenal insufficiency in refractory shock

20. Surviving Sepsis Campaign • An international effort to increase awareness and improve outcome – reduce sepsis mortality by 25% in the next five years • Experts representing 11 international organizations developed guidelines for management of severe sepsis and septic shock • Includes early goal-directed therapy in addition to other measures • Guidelines revealed at SCCM in Feb 2004 • Critical Care Medicine March 2004 32(3):858-87.

21. Key Component • Early Goal Directed Therapy • Fluid resuscitation • Use of vasopressors/inotropes • PRBC transfusions • Early targeted antibiotics and source control • Stress dose corticosteroid administration • Recombinant human activated protein C (xigris) for severe sepsis • Low tidal volume mechanical ventilation for ARDS • Tight glucose control

22. Fluid • Crystalloids and colloids are equally effective in restoring intravascular volume

23. SAFE study • In a RCT conducted in 16 ICUs in Australia and New Zealand 6997 patients were randomized to receive either saline or 4% albumin for fluid resuscitation

24. Kaplan-Meier Estimates of the Probability of Survival The SAFE Study Investigators, N Engl J Med 2004;350:2247-2256 Primary Endpoint was 28 day mortality

25. What Pressors ? dopamine vs norepinephrine • Several non-randomized studies and one small prospective randomized study for septic shock favored the use of norepinephrine

26. Norepinephrine vs Dopamine+/- Epinephrine in Septic Shock Results of a prospective observational study Claude, Critical Care Med 2000;28:2758

27. Dobutamine • Used when cardiac output is inadequate, as indicated by a reduced ScvO2 • Vasopressin • Considered in catecholamine refractory hypotension • Increased adrenergic receptor sensitivity • Increases urine output in septic patients, and increases creatinine clearance

28. VASOPRESSIN DEFICIENCY OCCURS IN SHOCK A. Normal B. After one hour of hemorrhagic shock

29. Antibiotics and Source Control 62% 28% Chest 2000;118(1):146 Chest 1992;101:1644.

30. sepsis Severe sepsis Septic shock Effect of Inappropriate Antibiotics

31. Tight Glucose Control Improved Survival

32. Results of 250 DM Bacteremic Patients in NTIUH ED

34. Adrenal Insufficiency in Septic Shock • There is significant disagreement about how to best evaluate adrenal function in critical illness • General agreement that a random cortisol of less than 25 is abnormal in this population • Some screen with random cortisol and reserve ACTH stim test for those with low levels • Use of total rather than free cortisol in those with hypoalbuminemia may overestimate the incidence of adrenal insufficiency

35. Placebo-controlled, randomized, double-blind study 19 ICUs in France 300 patients Infection + Temp >38.3 or <35.6C, HR >90, SBP <90 or on vasopressor, UO < 0.5 mL/kg/hr or PaO2/FiO2 < 280, Lactate > 2 mmol/L, mech ventilation Treatment – Low doses compared to previous trials Hydrocortisone 50 mg IV q 6 yrs Fludrocortisone 50 mcg NGT qd 7-day course Laboratory – Cosyntropin stimulation test Relative adrenal insufficiency Nonresponders = cortisol response < 9 mcg/dL Primary end point – 28-day survival in nonresponders Steroids for Relative Adrenal Insufficiency

36. Survival

37. Sepsis Bundle in NTUH ED Since Jan 2006, We start EGDT in Selected Patients with Septic Shock

38. Critical Area –Semi ICU

39. Blood Gas with Lactate Analysis Machine

40. Critical Area –SCVO2 Monitor

41. Pre-sep Catheter

42. Protocol

43. Special Sheet

44. Case Demonstration • 57 male, underline DM • Conscious disturbance, fever • RR 32 PR 123 BT 38.7 BP 70/40 mmHg • One touch: high • pH 7.1; HCO3- :12 • WBC 8900, Band 22%, CRP: 9 • Hb 10.4 • Lactate > 12

46. CVP: 7 cm H2O

47. SCVO2 : 49%

48. Initial Treatment • Fluid: HAES 500 + NS 2000 • Vasopressor: Dopamine  Levophed • Abx: Augmentin (susp LRTI) • Continuous insulin

49. 2 hours later • CVP 8 cm H2O • SBP 73 mmHg • Lactate > 12 • Glucose 950

50. Treatment Adjustment • Fluid: NS 4000 • Vasopressor: Pitressin 3 amp in 500 cc NS run 24 hrs (0.04u/min) • Steroids: Dexamethasone 2mg IV • Increase continuous RI dose