1. 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

2. 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.

3. 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.

4. 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.

5. 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

6. 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:

7. 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:

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

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

10. ◦ 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:

11. Treatment Administered
N Engl J Med, 2001;345:

12. MOrtality
10-20%
Sudden
Death!

13. 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:

14. 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:

15. Sepsis induced vasodilatationNE
Lower amount of fluid required to fill the tank

16. Vasoconstriction

17. 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