1. Surviving Sepsis 2008 Guidelines Therapy Across the Sepsis Continuum MAZEN KHERALLAH, MD, FCCP INFECTIOUS DISEASE AND CRITICAL CARE MEDICINE

2. Sepsis SIRSSevere SepsisSeptic ShockInfection Chest 1992;101:1644 Therapy Across the Sepsis Continuum  A clinical response arising from a nonspecific insult, with  2 of the following:  T >38 o C or <36 o C  HR >90 beats/min  RR >20/min  WBC >12,000/mm 3 or 10% bands Microorganism invading sterile tissue SIRS with a presumed or confirmed infectious process Sepsis with organ failure  Vascular collapse  Renal  Hemostasis  Lung  LA Refractory hypotension

3. Surviving Sepsis Campaign Launched in Fall 2002 as a collaborative effort of European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine Goal: reduce sepsis mortality by 25% in the next 5 years Guidelines revealed at SCCM in Feb 2004  Critical Care Medicine March 2004 32(3):858-87.  Website: survivingsepsis. org

4. THE SEVERE SEPSIS BUNDLES: SSC/IHI 6 Hour Bundle Measure serum lactate Blood Cultures prior to antibiotics Broad spectrum antibiotics within 3 hours of presentation, 1 hour in hospital Initial fluid resuscitation with 20-40 mL/kg crystalloid (or equivalent colloid) if hypotensive (SBP 4 mmol/L Vasopressors If septic shock or lactate > 4 mmol/L: CVP and ScvO 2 or SvO 2 measured CVP maintained 8-12 mm Hg Inotropes (and/or PRBCs if Hct 8 mmHg 24 Hour Bundle Glucose control maintained < 150 mg/dL Drotrecogin alfa (activated) administered in accordance with hospital guidelines Steroids given for septic shock requiring continued use of vasopressors for > 6 hours Lung protective strategy with plateau pressures < 30 cm H 2 O for mechanically ventilated patients http://www.ihi.org

5. Key Components: Prevent Complications of Critical Illness Prophylaxis for DVT Stress ulcer prophylaxis Prevention of nosocomial pneumonia by elevation of head to 45 degrees Facilitate extubation by daily interruption of sedation and early SBT Narrowing of antibiotic spectrum when appropriate

6. SUMMARY: SEPSIS GUIDELINES 2008 Strong Recommendation (1): Recommended DVT Prophylaxis H2 Blocker PUD Prophylaxis No Routine Use of SGC ADCB Glycemic Control Consider Limiting Support BC prior to Abx Antibiotics within 1 hr for Septic Shock EGDT and Protocolized Resuscitation Antibiotics within 1 hr in No septic Shock Patients De-escalation Antibiotic Therapy 7-10 day Antibiotic Duration Source Control Fluid Challenge Dopamine or Norepinephrine Limit P plateau <30 cm H2O PEEP Conservative Fluid in ALI with no Shock No Renal Dose Dopamine No High Dose Steroids Weaning Protocol/SBT Avoid NMB PPI PUD Prophylaxis Crystalloid = Colloid Limited Transfusion Low VT for ALI HOB >45 Intermittent = Continuous sedation No Antithrombin II No Erythropoietin

7. SUMMARY: SEPSIS GUIDELINES 2008 Weak Recommendation (2): Suggested APC in high risk and non-surgical ADCB equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis Wean Steroids Low dose steroids for septic shock B/S < 150 APC for high risk and surgical PRBCs or Dobutamine ACTH test not to be done Prone Position in ARDS NIV for ALI/ARDS mild/moderate hypoxemia

8. Sepsis SIRSSevere SepsisSeptic ShockInfection Antibiotics and Source Control Therapy Across the Sepsis Continuum  Drainage  Debridement  Device removal  Resection  Amputation Chest 2000;118(1):146 *

9. Mortality* Associated With Initial Inadequate Therapy in Critically Ill Patients With Serious Infections in the ICU 0%20%40%60%80%100 % Luna, 1997 Ibrahim, 2000 Kollef, 1998 Kollef, 1999 Rello, 1997 Alvarez-Lerma,1996 Initial adequate therapy Initial inadequate therapy *Mortality refers to crude or infection-related mortality. Mortality* Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394. Rello J et al. Am J Respir Crit Care Med 1997;156:196-200. Kollef MH et al. Chest 1999; 115:462-474 Kollef MH et al. Chest 1998;113:412-420. Ibrahim EH at al. Chest 2000;118:146-155. Luna CM et al. Chest 1997;111:676-685.

10. Sepsis SIRSSevere SepsisSeptic ShockInfection Early Goal Directed Therapy Antibiotics and Source Control Therapy Across the Sepsis Continuum Early Goal-Directed Therapy (EGDT): involves adjustments of cardiac preload, afterload, and contractility to balance O 2 delivery with O 2 demand: Fluids, Blood, and Inotropes Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. NEJM 2001;345:1368.  CVP > 8-12 mm Hg  MAP > 65 mm Hg  Urine Output > 0.5 ml/kg/hr  ScvO 2 > 70%  SaO 2 > 93%  Hct > 30% *

11. 49.2% 33.3% 0 10 20 30 40 50 60 Standard Therapy N=133 EGDT N=130 P = 0.01* *Key difference was in sudden CV collapse, not MODS Early Goal-Directed Therapy Results: 28 Day Mortality Vascular Collapse 21% vs 10% p=0.02 MODS 22% vs 16% P=0.27 NEJM 2001;345:1368-77. Mortality %

12. Sepsis SIRSSevere SepsisSeptic ShockInfection Insulin and Tight Glucose Control Early Goal Directed Therapy Antibiotics and Source Control Therapy Across the Sepsis Continuum * Van den Burghe, NEJM 2001;345:1359-1367.

13. Randomization Conventional Intensive >215 mg/dL 180 to 200 mg/dL (10.0 and 11.1 mmol/L) >110 mg/dL 80 to 110 mg/dL (4.4 to 6.1 mmol/L) Blood glucose level when insulin infusion was started Infusion adjusted to maintain blood glucose van den Berghe G, et al. NEJM 2001;345:1359-1367. Intensive Insulin Therapy in Critically Ill Patients 39 % Received insulin99% Received Insulin

14. Tight Glucose Control Improved Survival Van den Burghe, NEJM 2001;345:1359-1367.

15. Intensive Insulin Therapy in Critically Ill Patients: Mortality ICU Mortality was reduced by 42% In-Hospital Mortality was reduced by 34% Mortality (%) p = 0.01p < 0.04 (adjusted) N=783 N=765 ConventionalIntensive N=783 N=765 Van den Burghe, NEJM 2001;345:1359-1367.

16. Van den Berghe, G. et al. N Engl J Med 2006;354:449-461 Effect of Intensive Insulin Therapy on Morbidity In MICU Patients

17. Van den Berghe, G. et al. N Engl J Med 2006;354:449-461 Tight Glucose Control in the MICU: Effect on Mortality

18. Sepsis SIRSSevere SepsisSeptic ShockInfection Insulin and Tight Glucose Control Early Goal Directed Therapy Antibiotics and Source Control Chest 1992;101:1644 Therapy Across the Sepsis Continuum * Drotrecogin Alpha

19. Activated Protein C in Sepsis Activated Protein C:  Inactivates clotting factors  limiting the generation of thrombin  Inhibits production of inflammatory cytokines

20. Homeostasis  Fibrinolysis  Coagulation  Inflammation Endogenous Activated Protein C Modulates Coagulation, Fibrinolysis, and Inflammation in Severe Sepsis Activated Protein C Carvalho AC et al. J Crit Illness. 1994;9:51-75; Kidokoro A et al. Shock. 1996;5:223-8; Vervloet MG et al. Semin Thromb Hemost. 1998;24:33-44.

21. Results: 28-day All-cause Mortality 35 30 25 20 15 10 5 0 30.8% 24.7% Placebo (n - 840) Drotrecogin alfa (activated) (n = 850) Mortality (%) 6.1% absolute reduction in mortality Primary analysis results 2-sided p-value 0.005 Adjusted relative risk reduction 19.4% Increase in odds of survival 38.1% Adapted from Table 4, page 704, with permission from Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709.

22. D ROTRECOGIN A LFA (ACTIVATED) S IGNIFICANTLY I MPROVED S URVIVAL IN PROWESS 13% Absolute Reduction / p=0.0002 @ 28 days 11% Absolute Reduction / p=0.003 @ 90 days Subgroup analyses have the potential to mislead due to the absence of an intent to treat, sampling bias, and selection error

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24. Sepsis SIRSSevere SepsisSeptic ShockInfection Drotrecogin Alpha Insulin and Tight Glucose Control Early Goal Directed Therapy Steroids Antibiotics and Source Control Chest 1992;101:1644 Therapy Across the Sepsis Continuum *

25. Low Dose Steroid Treatment in Septic Shock: 28 Day Mortality (Non-responders vs. Responders) Low-dose SteroidsPlacebo Patients with Relative Adrenal Insuffiency (ACTH Test Non- responders) (77%) Patients Without Relative Adrenal Insufficiency (ACTH Test Responders) (23%) p = 0.04p = 0.96 N=114N=36N=34N=115 28-day Mortality Annane D, et. al. JAMA 2002;288(7):862.

26. PREVENT COMPLICATIONS Stress ulcer and DVT prophylaxis Narrow antibiotic spectrum Prevent VAP: 45 degree elevation Facilitate early discontinuation of mechanical ventilation: sedation interruption, early SBT

27. Sepsis SIRSSevere SepsisSeptic ShockInfection Insulin and Tight Glucose Control Early Goal Directed Therapy Steroids Antibiotics and Source Control Chest 1992;101:1644 Therapy Across the Sepsis Continuum * Drotrecogin Alpha

28. THE SEVERE SEPSIS BUNDLES: SSC/IHI 6 Hour Bundle Measure serum lactate Blood Cultures prior to antibiotics Broad spectrum antibiotics within 3 hours of presentation, 1 hour in hospital Initial fluid resuscitation with 20-40 mL/kg crystalloid (or equivalent colloid) if hypotensive (SBP 4 mmol/L Vasopressors If septic shock or lactate > 4 mmol/L: CVP and ScvO 2 or SvO 2 measured CVP maintained 8-12 mm Hg Inotropes (and/or PRBCs if Hct 8 mmHg 24 Hour Bundle Glucose control maintained < 150 mg/dL Drotrecogin alfa (activated) administered in accordance with hospital guidelines Steroids given for septic shock requiring continued use of vasopressors for > 6 hours Lung protective strategy with plateau pressures < 30 cm H 2 O for mechanically ventilated patients http://www.ihi.org

29. SCCM 2009: Sepsis Management "Bundles" Boost Guideline Implementation, Reduce Mortality 15,022 Patients 7% Absolute Risk Reduction 19% Relative Risk Reduction Society of Critical Care Medicine (SCCM) 38th Critical Care Congress. Late breaker. Presented February 2, 2009

30. Sepsis SIRSSevere SepsisSeptic ShockInfection Blood Sugar Level <150 mg/dl (8.3 mmol/L) CVP > 8-12 mm Hg MAP > 65 mm Hg Urine Output > 0.5 ml/kg/hr ScvO 2 > 70% SaO 2 > 93% Hct > 30% 300 mg hydrocortisone/day for non-responding septic shock 1 hour appropriate antibiotics and source control Therapy Across the Sepsis Continuum Drotrecogin Aapha for 2 organ dysfunction or septic shock with APACHE II >24 and not postop

31. Critical Care is A Promise ان الله يحب العبد اذا عمل عملا أن يتقنه

32. If you are admitted to our ICU with severe sepsis we will:  Get blood cultures and get lactic acid level ASAP  Start broad spectrum antibiotics within 1 hour  Control the source of infection  Use early goal directed therapy  Start steroid therapy when indicated  Tight control your blood sugar  Use our “Sepsis Bundle” to manage your sepsis

33. Thank You