Early Goal Directed

Therapy
Remzi Ba, MD, FCCP
Anadolu Health Center

Summary

Sepsis and epidemiology

Pivotal study (Rivers et al.)
SSC and other studies
Conclusions

Sepsis

Incidence %0.3

Worldwide 18 million cases/yr (2000)

High risk of death:

Annual increase %1.5

1400 deaths/day worldwide

135,000 European and 215,000 American
deaths/y

Cost

EU 7.6 billion, US 17.4 billion

Angus DC et al. Crit Care Med 2001; 29: 1303
10.
Bone RC et al. Chest 1992; 101: 164455

Mortality in Sepsis
Conditio
n
Sepsis

Mortality

AMI

%2.7-9.6

Stroke

%9.3

%28-50

Sepsis
Infection,* documented or suspected, and some of the
following:

General variables

Fever (core temperature 38.3C [101.0F])

Hypothermia (core temperature 36C [96.8F])
Pulse rate 90 beats/min or 2 SD above the normal value for age
Tachypnea (respiratory rate 20 breaths/min)
Altered mental status
Significant edema or positive fluid balance (20 mL/kg during 24
h)
Hyperglycemia (plasma glucose 120 mg/dL or 7.7 mmol/L) in
the absence of diabetes

Inflammatory variables

Leukocytosis (WBC count 12,000/mm3)

Leukopenia (WBC count 4,000/mm3)
Normal WBC count with 10% immature forms
Plasma C-reactive protein 2 SD above the normal value
Plasma procalcitonin 2 SD above the normal value

Severe Sepsis

Sepsis accompanied by organ dysfunction,

hypoperfusion or hypotension
Hemodynamic variables

Organ dysfunction variables

Arterial hypotension (SBP 90 mm Hg, MAP 70 mm Hg, or an SBP

decrease 40 mm Hg in adults or 2 SD below normal for age)
SvO2 >70%
Cardiac index> 3.5 L/min/m2
Arterial hypoxemia (PaO2/FIO2 300)
Acute oliguria (urine output 0.5 mL/kg/h for at least 2 h)
Creatinine increase 0.5 mg/dL
Coagulation abnormalities (INR 1.5 or aPTT 60 s)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count 100,000/mL)
Hyperbilirubinemia (plasma total bilirubin 4 mg/dL or 70 mmol/L)

Tissue perfusion variables

Hyperlactatemia (2 mmol/L)
Decreased capillary refill or mottling

2001 International Sepsis Definitions Confer

Shock / Septic Shock

A failure of the cardiovascular system to

maintain effective tissue perfusion,
causing cellular dysfunction and acute
organ system failure

Macrocirculation :

Microcirculation

persistent arterial hypotension

(SBP <90 mmHg, MAP <60, or a reduction in SBP >40 mm
Hg from baseline despite adequate volume resuscitation

Septic shock: acute circulatory failure

unexplained by other causes

2001 International Sepsis Definitions Confer

Sepsis : Late Findings

PE

Altered mental status

Delayed capillary refill
Cold extremities /skin

Vital signs (hypotension, tachycardia etc)

CVP
Urine output

Inadequate for early detection of global tissue hypoxia

Rady et al. Am J Emerg Med 1996;14:218-225
Cortez et al. Arch Surg 1977;112:471-476

Tissue Oxygenation
Oxygen Delivery
Utilization

Oxygen

Tissue Oxygenation
Oxygen Delivery
Utilization

Oxygen

O2 delivery (DO2) =
Cardiac output (CO) X Arterial O2 content
(CaO2)
CaO2= Hb X Sa02 X 1.34 X

Oxygen transport and

utilization

Rivers, E. P. et al. CMAJ 2005;173:1054-1065Copyright 2005 CMA Media Inc. or its licensors

SvO2

Reflects a balance between DO2 and VO2

Surrogate for the cardiac index as a
target for hemodynamic therapy
In the absence of PAC, SvO2 can be
replaced by ScvO2
Reinhart Intensive Care Med (2004) 30:1572
1578
Gattinoni et al NEJM 1995;333:1025-1032
Reinhart et al. Chest 1989;95:1216-1221

Physiological Changes in
Sepsis

Dellinger RP. Cardiovascular management of septic shock. Crit Care Med 2003;31:946-955.

Hemodynamic patterns of
early severe sepsis and
septic shock

Otero, R. M. et al. Chest 2006;130:1579-1595

Yksek kapiller dansite

Dk kapiller dansite

Orthogonal polarization spectral imaging in severe sepsis and septic

What to do to achieve a
balance between systemic
oxygen delivery and oxygen
Resuscitation strategy : goaldemand?

oriented manipulation of cardiac

preload, afterload, and contractility
Normalized values for mixed
venous oxygen saturation, arterial
lactate concentration, base deficit,
and pH

Open, randomized, partially blinded

Primary efficacy end point: In-hospital
mortality
Secondary end points:

the resuscitation end points

organ-dysfunction scores
coagulation-related variables
administered treatments
the consumption of health care resources

Rivers E et al. N Engl J Med 2001;345:1368-1377

EGDT

Fluid infusion - titrated incrementally based on

CVP monitoring; CVP target, 812 mm Hg
substituted for PAOP
Transfusion trigger was set for a target Hb of 10
g/dL if Scvo2 was <70% after CVP of 812 mm
Hg was achieved
If MAP, CVP, and hemoglobin level at goal values,
and Scvo2 still < 70%, give dobutamine
Scvo2 provided an indirect measurement of the
DO2 consumption ratio; Scvo2 was used to
titrate therapies, rather than routinely increasing
CI

Rivers E et al. N Engl J Med 2001;345:1368-1377

Set up of Rivers study

Rivers E et al. N Engl J Med 2001;345:1368-1377

Rivers EGDT protocol

Rivers E et al. N Engl J Med 2001;345:1368-1377

Treatments Administered

Rivers E et al. N Engl J Med 2001;345:1368-1377

Rivers E et al. N Engl J Med 2001;345:1368-1377

Vital Signs, Resuscitation End Points, Organ-Dysfunction Scores, and Coagulation Variables

Rivers E et al. N Engl J Med 2001;345:1368-1377

Comparing the PaO2/fraction of inspired oxygen (FIO2) ratios between the EGDT
and standard-care groups

Otero, R. M. et al. Chest 2006;130:1579-1595

Kaplan-Meier
Estimates of Mortality

Rivers E et al. N Engl J Med 2001;345:1368-1377

EGDT and Mortality

Mortalite (%)

1 lm engellemek iin gereken NNT = 6-8

33 %
reduction
in 60 d
mortality

60
50

Standart tedavi
EHYT

40
30
20
10
0

60-gn
Hastaned
28-gn
mortalite
e
mortalite
mortalite
(btn
Rivers E, Nguyen B, Havstadhastalar)
S, et al. Early goal-directed therapy in the treatment of severe
sepsis and septic shock. N Engl J Med 2001; 345:1368-1377

In-Hospital Survival of Patients in the Treatment and Control Groups

Hayes M et al. N Engl J Med 1994;330:1717-1722

Gattinoni Survival

Gattinoni L et al. N Engl J Med 1995;333:1025-1032

Hemodynamic Optimization
Trials before Rivers
Variables

Setting

Astiz et al10 /1988

Gattinoni et al27 /1995

Hayes et al26 /1994

Rivers et al12 /2001

Early ICU

ICU

ICU

ED or Pre-ICU

<6

Up to 72

Up to 24

<2

5.3 0.5

NA

2.23.5

6.97.7

MAP, mm Hg

68 2

NA

NA

7476

SvO2, %

57 2

67.3

NA

48.649.2

NA

10.6

Optimized

5.36.1

2.7 0.2

3.73.8

3.23.4

1.71.9

2,394 178

708735

NA

1,1811,192

Enrollment time, h
Lactate, mmol/L

CVP, mm Hg
Cardiac index,
L/min/m2
SVRI, dyne s cm5
m2

The endothelial response

to oxygen deprivation

Karimova et.al. Intensive Care Med 2001;27:19-31

www.ihi.org

Feasibility study of
EGDT in 24 patients
in ED

Critical Care Medicine 35(4),April 2007,pp 1105-1

The effect of EGDT on

inflammation

Otero, R. M. et al. Chest 2006;130:1579-1595

EGDT effect on coagulation

defects (d-dimer)

Otero, R. M. et al. Chest 2006;130:1579-1595

Lactate clearance and d-dimer

Otero, R. M. et al. Chest 2006;130:1579-1595

An Outcome Survey of
Sepsis Initiatives With
EGDTPreimplementation
Postimplementation
Patients (n)

1,298

Patients (n=671) /
mean mortality% + SD
[95% CI]

44.8 + 7.8
0.410.49

Patients (n=627) /
mean mortality% + SD
[95% CI] + SD

24.5 + 5.5
0.210.28

For all centers reporting mortality data: RR,

0.54; OR, 0.39; RRR, 45%; ARR, 20.3%;
NNT, 5
Otero, R. M. et al. Chest 2006;130:1579-1595

EGDT: Conclusions

Early resuscitation therapy designed to

improve the oxygen supply/ demand balance
improves outcome in sepsis
( Grade B )

Monitoring of venous oxygen saturations is

a necessary part of the early resuscitation of
patients with severe sepsis or septic shock
( Grade B)

EGDT: Conclusion

EGDT feasible as a bundle in

community and academic centers
Significant reductions in

Morbidity
Mortality NNT ~5-7
vasopressor use
health-care resource consumption

Unclear which component works

Thank you