Early Goal Therapy in Severe Sepsis & Septic Shock Nabil Abouchala, MD, FCCP, FACP Consultant, Pulmonary and Critical Care Medicine King Faisal Hospital & Research Center Riyadh, Saudi Arabia 1

SIRS = Systemic Inflammatory Response Syndrome Sepsis: Defining a Disease Continuum Infection/ Trauma SIRS Sepsis Severe Sepsis A clinical response arising from a nonspecific insult, including  2 of the following: Temperature 38oC or 36oC HR 90 beats/min Respirations 20/min WBC count 12,000/mm3 or 4,000/mm3 or >10% immature neutrophils SIRS with a presumed or confirmed infectious process SIRS = Systemic Inflammatory Response Syndrome Adapted from: Bone RC, et al. Chest 1992;101:1644 Opal SM, et al. Crit Care Med 2000;28:S81 2 Draft. For internal use only. Confidential, Eli Lilly and Company, 2001.

Sepsis: Defining a Disease Continuum Infection/ Trauma SIRS Sepsis Severe Sepsis Sepsis with 1 sign of organ failure Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic CNS Metabolic acidosis Shock Bone et al. Chest 1992;101:1644; Wheeler and Bernard. N Engl J Med 1999;340:207 3 Draft. For internal use only. Confidential, Eli Lilly and Company, 2001.

Mortality Increases in Septic Shock Patients Incidence Mortality 7-17% Sepsis 400,000 20-53% Severe Sepsis 300,000 Septic Shock 53-63% Balk, R.A. Crit Care Clin 2000;337:52 4 Draft. For internal use only. Confidential, Eli Lilly and Company, 2001.

Sepsis Bundle A. Initial Resuscitation Serum Lactate Measured Resuscitation Bundle Serum Lactate Measured Blood Culture Obtained Prior to Antibiotic Administration Broad-Spectrum Antibiotics Administered within 1 Hour of ED Admission Fluid Resuscitation (30 ML/Kg) for Hypotension or Lactate >4mmol/L Vasopressors for Ongoing Hypotension Maintain Adequate Central Venous Pressure (CVP ≥ 8) Maintain Adequate Central Venous Oxygen Saturation (ScvO2 ≥ 70%) Re-measure Serum Lactate

Early Goal-directed Therapy in the Treatment of Severe Sepsis and Septic Shock To Examine whether Early Goal Directed Therapy (EGDT) before admission to the ICU is superior to standard hemodynamic therapy in patients with sever sepsis and septic shock #Citing articles 2469 N Engl J Med, 2001;345:1368-77

Protocol for Early Goal-Directed Therapy Central venous and arterial catheterization Crystalloid Colloid CVP 8 -12 mm Hg Vasoactive agents MAP ³65 and £90 mm Hg Transf. of RBC until Hct ³30% Inotropic agents ScvO2 ³70% The protocol was as follows: A 500-ml bolus of crystalloid was given every 30 minutes t achieve a central venous pressure of 8 to 12 mm Hg. If the mean arterial pressure was less than 65 mm Hg, vasopressors were given t maintain a mean arterial pressure of at least 65 mm Hg.If the mean arterial pressure was greater than 90 mm Hg,vasodilators were given until it was 90 mm Hg or be- low. If the central venous oxygen saturation was less than 70 per- cent,red cells were transfused t achieve a hematocrit of at least 30 percent. After the central venous pressure,mean arterial pressure, and hematocrit were thus optimized,if the central venous oxygen saturation was less than 70 percent, dobutamine administration was started at a dose of 2.5 µg per kilogram of b dy weight per min- ute,a dose that was increased by 2.5 µg per kilogram per minute every 30 minutes until the central ven us xygen saturation was 70 percent or higher or until a maximal d se of 20 µg per kilogram per minute was given. Dobutamine was decreased in dose or discon- tinued if the mean arterial pressure was less than 65 mm Hg or if the heart rate was ab ve 120 beats per minute.T decrease xygen consumption,patients in whom hemodynamic ptimization could not be achieved received mechanical ventilation and sedatives. Goals achieved Hospital admission N Engl J Med, 2001;345:1368-77

Venous Oxygen Saturation Alternative of using mixed venous oxyhemoglobin saturation from pulmonary artery catheter instead of central venous O2 saturation from CVP catheter

ScvO2 closely paralleled SvO2 but averaged 5 – 7% higher ScvO2 > SvO2 (5-7%) Reinhart K, et al. Intensive Care Med. 2004;30:1572-1578.

◦ If venous O2 saturation target not achieved: (2C) Consider further fluid Tansfuse packed red blood cells if required to hematocrit of ≥30% and/or Dobutamine infusion max 20 µg.kg−1 .min−1 Rivers E, Nguyen B, Havstad S, et al. 2001;345:1368-1377.

Treatment Administered N Engl J Med, 2001;345:1368-77

MOrtality 10-20% Sudden Death!

In-hospital mortality (all patients) The Importance of Early Goal-Directed Therapy for Sepsis-induced Hypoperfusion In-hospital mortality (all patients) 10 20 30 40 50 60 Standard therapy EGDT 28-day mortality 60-day mortality NNT to prevent 1 event (death) = 6 - 8 Mortality (%) Rivers E, Nguyen B, Havstad S, et al. 2001;345:1368-1377.

Results 37 Observational studies showing improved outcomes with early quantitative resuscitation between 2001 and 2011 Mortality EGT : 30.5 % Standard: 46.5 % Absolute Risk Reduction NNT = 16% 7 Multicenter trial of 314 patients with severe sepsis in eight Chinese centers (2010). This trial reported a 17.7% absolute reduction multicenter trial of 314 patients with severe sepsis in eight Chinese centers (14). This trial reported a 17.7% absolute reduction in 28-day mortality (survival rates, 75.2% vs. 57.5%) N Engl J Med, 2001;345:1368-77

Sepsis induced vasodilatation NE Lower amount of fluid required to fill the tank

Vasoconstriction

Early NE + Fluids Late NE + Fluids Fluids NE LPS Crit Care Med 2007; 35:1736–1740 Early NE + Fluids Late NE + Fluids Fluids NE LPS