™ Guidelines for Management of Severe Sepsis/Septic Shock Bekele Afessa, MD

™ Slide 3 Dellinger RP, Levy MM, Carlet JM, et al. for the International Surviving Sepsis Campaign Guidelines Committee Crit Care Med. 2008;36: Intensive Care Med. 2008;34: Available free online at: ubmedid= Surviving Sepsis Campaign: Guidelines for Management of Severe Sepsis/Septic Shock

™ Slide 4 Sepsis-induced Tissue Hypoperfusion Persistent hypotension Elevated lactate Hypoxemia Oliguria or increase in creatinine Coagulation abnormalities Ileus Thrombocytopenia Elevated bilirubin Levy MM et al. CCM 2003;31:1250

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™ Slide 7 A Melting Pot of Shock Etiologies Hypovolemic Distributive Cardiogenic Obstructive Cytotoxic Dellinger RP. CCM 2003;31:946

™ Slide 8 Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003;31: Pre-Fluid Resuscitation

™ Slide 9 Diastolic Size of Ventricles 10 days post-shock Diastole Systole Diastole Systole Images used with permission from Joseph E. Parrillo, MD

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™ Slide 12 Early Goal Directed Therapy Rivers E et al. NEJM 2001;345:1368

™ Slide 13 Importance of Early Goal for 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: In-hospital mortality (all patients) Standard therapy EGDT 28-day mortality 60-day mortality NNT to prevent 1 event (death) = 6-8 Mortality (%)

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™ Slide 16 Fluid Therapy Boluses of 1,000 mL crystalloid or 300 to 500 mL colloid every 30 minutes Target CVP 8 mm Hg Target higher CVP of 12 mm Hg in certain conditions

™ Slide 17 Bicarbonate Therapy Bicarbonate therapy not recommended to improve hemodynamics in patients with lactate-induced pH >7.15 Cooper et al. Ann Intern Med. 1990;112: Mathieu et al. Crit Care Med. 1991;19:

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™ Slide 20 Vasopressors for Septic Shock Indications Drug of choice Norepinephrine or dopamine No place for “low dose” dopamine

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™ Slide 23 Effects on Splanchnic Circulation 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:

™ Slide 24 Vasopressin in Septic Shock Elevated in early septic shock, normal later Indication Dose 0.03 units/min. It may decrease stroke volume. Watch for side effects

™ Slide 25 Changing pH Has Limited Value TreatmentBeforeAfter NaHCO3 (2 mEq/kg) pH PAOP1517 Cardiac output % NaCl pH PAOP1417 Cardiac output Cooper DJ et al. Ann Intern Med. 1990;112:

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™ Slide 28 Resuscitation in Septic Shock Fluid to achieve CVP 8 – 12 mm Hg If central venous oxygen saturation < 70% or mixed venous oxygen saturation < 65% despite fluid and CVP 8 – 12 mm Hg, –PRBC to keep Hct > 30% –Dobutamine infusion (up to a maximum of 20 μg·kg- 1·min-1)

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™ Slide 31 Looking for a Source Identify common causes of ICU-acquired infections Obtain cultures before antibiotics Testing Procedures

™ Slide 32 Antibiotics IV antibiotic within the first hour (premixed supply) Initially (adequate and appropriate) Observe for adverse consequences De-escalate within 48 – 72 hours Be aware of non-infectious causes Be aware of negative blood cultures Duration of therapy 7-10 days for most

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™ Slide 35 Infection Source Control Dellinger RP. Crit Care Med 2004;32:858

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™ Slide 38 Steroid Therapy 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:

™ Slide 39 P =.045 Figure 2 and Figure 3, page 648, reproduced with permission from Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26: Figure 2 and Figure 3, page 727, reproduced with permission from Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: A prospective, randomized, double-blind, single- center study. Crit Care Med. 1999;27: P =.007

™ Slide 40 CORTICUS Study Sprung CL et al. NEJM 2008;358:111 Kaplan-Meier Curves Hydrocortisone Vs Placebo

™ Slide 41 Steroids For septic shock poorly responsive to fluid and vasopressors ACTH stimulation not recommended If non-hydrocortisone corticosteroid is used, fludrocortisone 50 μg daily is added Dose of hydrocortisone mg/day, which can be weaned off when vasopressors are no longer needed

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™ Slide 44 Results: 28-day All-cause Mortality % 24.7% Placebo (n - 840) Drotrecogin alfa (activated) (n = 850) Mortality (%) 6.1% absolute reduction in mortality Primary analysis results 2-sided p-value 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:

™ Slide 45 Patient Criteria for Recombinant Human Activated Protein C Full support patient High risk of death – Any of the following: –APACHE II  25 –Sepsis-induced multiple organ failure –Septic shock

™ Slide 46 Recombinant Human Activated Protein C: Contraindications Risk of bleeding Hemorrhagic stroke Head trauma, intracranial or spinal surgery Intracranial mass or herniation Presence of epidural catheter Recent surgery Intracranial lesion Low APACHE II score

™ Slide 47 Sepsis Resuscitation Bundle Serum lactate measured. Blood cultures obtained prior to antibiotic administration. At presentation, broad-spectrum antibiotics administered Management of hypotension Management of persistent arterial hypotension refractory to volume resuscitation

™ Slide 48 Sepsis Management Bundle Low-dose steroids administered for septic shock in accordance with a standardized ICU policy. Drotrecogin alfa (activated) administered in accordance with a standardized ICU policy. Glucose control maintained > lower limit of normal, but <150 mg/dL (8.3 mmol/L). For mechanically ventilated patients, inspiratory plateau pressures maintained <30 cm H2O.

™ Slide 49 Copyright restrictions may apply. Ferrer, R. et al. JAMA 2008;299: The Impact of Sepsis Resuscitation and Management Bundles

™ Slide 50

™ Slide 51 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.

™ Slide 52 Self Assessment Ready to test your knowledge? Take the Review Skip the Review

™ Slide 53 References Levy MM et al SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definition Conference. Crit Care Med 2003;31: 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: 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: Annane D, Sebille 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: Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003;31:

™ Slide 54 References Bochud PY, Bonten M, Marchetti O, et al. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004;32:S495-S512. Marshall JC, Maier RV, Jimenez M, et al. Source control in the management of severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004;32:S513-S526. Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomized trial. Lancet 2007;370: Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. NEJM 5008;358:

™ Slide 55 References Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. NEJM 2008;358; Dellinger RP et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock:2008. Crit Care Med. 2008;36: Ferrer R, Artigas A, Levy MM, et al. Improvement in process of care and outcome after multicenter severe sepsis educational program in Spain. JAMA 2008;299: