1. Nabil Abouchala, MD, FCCP, FACP Consultant, Pulmonary and Critical Care Medicine King Faisal Hospital & Research Center Riyadh, Saudi Arabia

2. Organizations involved Number of participants ProcessPublication First 2001 1 (ISF)9EBM: A-EIntensive care medicine (ICM) supplement, 2001 Second 2004 3 (ISF, ESIM, SCCM) 24EBM: A-ECCM & ICM, 2004 Third 2008 1655GRADECCM & ICM, 2008 Fourth 2012 30 ( ISF, ESIM, SCCM, WFSICCM, WFPICCS, WFCCN, ISF, Sepsis Alliance, IFEM, APP, GSS, CSCC, …) 68GRADECCM & ICM, 2012

4. Crit Care Med 2013; 41:580–637

5. 1. Initial Resuscitation and Infection Issues 2. Hemodynamic Support and Adjunctive Therapy ​ 3. Other Supportive Therapy of Severe Sepsis 4. Special Considerations in Pediatrics ​​

6. 1. Initial Resuscitation and Infection Issues 2. Hemodynamic Support and Adjunctive Therapy ​ 3. Other Supportive Therapy of Severe Sepsis 4. Special Considerations in Pediatrics ​​

7. 1. Initial Resuscitation and Infection Issues 2. Hemodynamic Support and Adjunctive Therapy ​ 3. Other Supportive Therapy of Severe Sepsis 4. Special Considerations in Pediatrics ​​

8. A. Initial ResuscitationB. Screening for Sepsis & Performance ImprovementC. DiagnosisD. Antimicrobial TherapyE. Source ControlF. Infection prevention 1. Initial Resuscitation & Infection Issues

9. Sepsis Bundle A. Initial Resuscitation RRT and Use of Sepsis Bundle Protocol B. Screening for Sepsis & Performance Improvement Use of the 1,3 beta-D-glucan assay, mannan and anti-mannan antibody assays C. Diagnosis Use of an echinocandin if candidemia is suspected Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics D. Antimicrobial TherapyE. Source Control Oral chlorhexidine gluconate (CHG) for prevention of VAP F. Infection prevention 1. Initial Resuscitation & Infection Issues

10. JAMA. 2010;303(8):739

12.  Initial fluid challenge ≥ 1000 mL of crystalloids or minimum of 30 mL/kg of crystalloids in the 1 st 4-6 hours  (Strong recommendation; Grade 1C).  Crystalloids is the initial fluid for resuscitation  (Strong recommendation; Grade 1A).  Adding albumin to the initial fluid resuscitation  (Weak recommendation; Grade 2B).  Against hydroxyethyl starches (hetastarches) with MW >200 dalton  (Strong recommendation; Grade 1B).

13. Timing of Antibiotic Administration

14. Septic Shock: Timing of Antibiotics Kumar Crit Care Med 2006 0.0.20.40.60.80 1.00 % Survival % Total receiving antibiotics 0 -.5.5 – 1.01 - 22 - 33-44 - 55 - 66 - 99 - 1212 - 2424 - 36> 36 Percent Time, hrs 14 ICUs; n = 2,731 Only 50% of patients in Septic Shock received antibiotics w/in 6 hrs. Only 50% of patients in Septic Shock received antibiotics w/in 6 hrs.

15. 1. Initial Resuscitation and Infection Issues 2. Hemodynamic Support and Adjunctive Therapy ​ 3. Other Supportive Therapy of Severe Sepsis 4. Special Considerations in Pediatrics ​​

16. G. Fluid Therapy of Severe SepsisH. VasopressorsI. Inotropic TherapyJ. Corticosteroids 2. Hemodynamic Support and Adjunctive Therapy

17. IsoproterenolDobutamineDopamineEpinephrineNorepinephrinePhenylephrine Beta Alpha

18.  Norepinephrine as the first choice  ( Grade 1B)  Adding or substituting epinephrine when an additional drug is needed  (Strong recommendation; Grade 1B).  Vasopressin 0.03 units/min may be added  (Weak recommendation; Grade 2A)  Dopamine only in highly selected patients at very low risk of arrhythmias or low heart rate  (Weak recommendation; Grade 2C).  Dobutamine infusion be started or added with low cardiac output) or ongoing signs of hypoperfusion, even after adequate intravascular volume  (Strong recommendation; Grade 1C)

20. Adequate fluid resuscitation …

21. Crit Care Med 2007; 35:64–68

23. CHEST 2008; 134:172–178

25. PLR mimics fluid challenge Unlike fluid challenge, no fluid is infused and the effects are reversible and transient

26. Normal Heart Failing Heart

28. SVV = SV max – SV min / SV mean MV with TV >8 ML/Kg, no spontaneous breathing NSR Difficult to interpret with: spont breathing, arrhythmias, TV too low, lung compliance too low, on HFV Limitation:

29. Preload Stroke Volume 0 0 Higher PVI = More likely to respond to fluid administration 24 % 10 % Lower PVI = Less likely to respond to fluid administration Maxime Cannesson, MD, PhD

30. Crystalloids = Albumin Against the use of hydroxyethyl starches Hemodynamic response based on Dynamic assessment G. Fluid Therapy of Severe Sepsis Norepinephrine is 1 st choice Epinephrine 2 nd Dopamine only in highly selected cases Phenylephrine is not recommended Low-dose dopamine should not be used for renal protection H. VasopressorsI. Inotropic Therapy Not using IV hydrocortisone to treat adult septic shock unless … Use Hydrocortisone at 200 mg/day, preferably as IV infusion, to be tapered off J. Corticosteroids 2. Hemodynamic Support and Adjunctive Therapy Target MAP ≥ 65 …

31. 1. Initial Resuscitation and Infection Issues 2. Hemodynamic Support and Adjunctive Therapy ​ 3. Other Supportive Therapy of Severe Sepsis 4. Special Considerations in Pediatrics ​​

32. K. Blood Product Administration Target Hemoglobin (7-9 g/dl) unless …L. Immunoglobulins: Not recommendedM. Selenium: Not recommendedN. History of Recommendations Regarding Use of Recombinant Activated Protein CO. Mechanical Ventilation of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)P. Sedation, Analgesia, and Neuromuscular Blockade in SepsisQ. Glucose ControlR. Renal Replacement TherapyS. Bicarbonate TherapyT & U. Prophylaxis: Deep Vein Thrombosis and Stress UlcerV. NutritionW. Setting Goals of Care 3. Other Supportive Therapy of Severe Sepsis

33. K. Blood Product Administration Target Hemoglobin (7-9 g/dl) unless … L. Immunoglobulins: Not recommended M. Selenium: Not recommended N. History of Recommendations Regarding Use of Recombinant Activated Protein C R. Renal Replacement Therapy S. Bicarbonate Therapy 3. Other Supportive Therapy of Severe Sepsis

36. -6.5% +1.2%

37. K. Blood Product Administration Target Hemoglobin (7-9 g/dl) unless … L. Immunoglobulins: Not recommended M. Selenium: Not recommended N. History of Recommendations Regarding Use of Recombinant Activated Protein C O. Mechanical Ventilation of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS) P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis Q. Glucose Control R. Renal Replacement Therapy S. Bicarbonate Therapy T & U. Prophylaxis: Deep Vein Thrombosis and Stress Ulcer V. Nutrition W. Setting Goals of Care 3. Other Supportive Therapy of Severe Sepsis

38. O. Mechanical Ventilation of Sepsis-Induced (ARDS) 3. Other Supportive Therapy of Severe Sepsis 1. Target a TV of 6 mL/kg predicted body weight (grade 1A vs. 12 mL/kg) 2. Plateau pressures be measured in patients with ARDS be ≤30 cm H2O (grade 1B) 3. (PEEP) be applied (grade 1B) 4. Higher rather than lower levels of PEEP for moderate or severe ARDS (grade 2C) 5. Recruitment maneuvers be used with severe refractory hypoxemia (grade 2C) 6. Prone positioning be used Pao2/Fio2 ratio ≤ 100 mm (grade 2B) 7. HOB elevated to 30-45 (grade 1B) 8. (NIV) be used in minority of patients in whom the benefits of NIV (grade 2B) 9. Weaning protocol be in place 10. Against the routine use of the pulmonary artery catheter (grade 1A) 11. A conservative rather than liberal fluid strategy (grade 1C) 12. not using beta 2-agonists for treatment of sepsis-induced ARDS (grade 1B)

39. ARMA Trial InterventionControl TV (4-6 ml/Kg) PEEP 8.5 TV (10-12 ml/Kg) PEEP 8.6 Reducing from 12 to 6 ml/kg VT saved lives NNT 12 14000 Lives Saved/Year Reducing from 12 to 6 ml/kg VT saved lives NNT 12 14000 Lives Saved/Year

40. Consequences of Fluid Overload

43. FACTT: Fluid management Protocols Conservative: Conservative: CVP < 4 and PAOP < 8 CVP < 4 and PAOP < 8 Liberal: Liberal: CVP 10 -14 and PAOP 14 -18 CVP 10 -14 and PAOP 14 -18

44. Wet First –Dry later Approach that combines both adequate initial fluid resuscitation followed by conservative late-fluid management was associated with improved survival Approach that combines both adequate initial fluid resuscitation followed by conservative late-fluid management was associated with improved survival CHEST 2009; 136:102–109

45. Wet First –Dry later CHEST 2009; 136:102–109

47. JAMA. 2010;303(9):865-873

48. Higher PEEP is better in Moderate to Severe ARDS (PO2/FiO2 ≤ 200 mmHg) JAMA. 2010;303(9):865-873

49. Higher PEEP is better in Moderate to Severe ARDS (PO2/FiO2 ≤ 200 mmHg) Death in ICU  6.3 % NNT 16 Days off the MV-5 days Death in ICU  6.3 % NNT 16 Days off the MV-5 days JAMA. 2010;303(9):865-873

52. Survival with PAL

53. (NMBAs) be avoided if possible without ARDS Short course of NMBA (<48 hours) for early ARDS + Pao2/Fio2<150 mm Hg P. Sedation, Analgesia, and Neuromuscular Blockade in SepsisQ. Glucose Control PPIs rather than H2RA (grade 2D) T & U. Prophylaxis: Deep Vein Thrombosis and Stress Ulcer V. Nutrition 3. Other Supportive Therapy of Severe Sepsis

56. Rice at al. for the NHLBI ARDS Clinical Trials Network. JAMA. 2012

57. (NMBAs) be avoided if possible without ARDS Short course of NMBA (<48 hours) for early ARDS + Pao2/Fio2<150 mm Hg P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis Target an upper BG 140-180 mg/dL rather than ≤ 110 mg/dL (grade 1A) Q. Glucose Control PPIs rather than H2RA (grade 2D) T & U. Prophylaxis: Deep Vein Thrombosis and Stress Ulcer Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day) No specific immunomodulating supplementation V. Nutrition 3. Other Supportive Therapy of Severe Sepsis

58.  BE Goal Directed:  More and faster fluid  No hetastarch  Earlier Inotropes  Use norepineprine and epinephrine over dopamine  Lactic acid clearance  Dynamic SVV is better than CVP  Antimicrobials:  Fast <1 hr, consider early antifungals, use biomarkers to deescalate or stop  ARDS:  Wet first, dry later  Higher PEEP  Glucose control  Not so tight (140-180 mg/dl = 8-10 mmol/l)  Nutrition  Underfeed first week  No supplement