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COPYRIGHT 2012 EDIZIONI MINERVA MEDICA
E X PE RT O P I N I O N
Early interventions in severe sepsis and septic shock:

a review of the evidence one decade later
E. P. RIVERS 1, M. KATRANJI 2, K. A. JAEHNE 1, S. BROWN
G. ABOU DAGHER 1, C. CANNON 3, V. COBA 1
1Department
of Emergency Medicine and Surgery, Henry Ford Hospital, Wayne State University, Detroit, MI, USA;
of Medicine, Pulmonary and Critical Care Medicine, Pontiac Osteopathic Hospital, Pontiac, MI, USA;
3Department of Emergency Medicine, University of Kansas, Medical Center, Kansas City, KS, USA
2Department
ABSTRACT
The outcomes of acute myocardial infarction, trauma, and stroke have improved by implementing processes that
provide early diagnosis and aggressive interventions at the most proximal point of disease presentation. A common
feature in these conditions is the implementation of early intervention strategies. One decade ago, a similar approach
to sepsis began when a prospective randomized trial compared early goal-directed therapy (EGDT) to standard care
using specific criteria for the early identification of high risk patients with infection. The components of EGDT were
derived from expert consensus opinion to produce a protocol to reverse the hemodynamic perturbations of hypovolemia, vasodysregulation, myocardial suppression and increased metabolic demands for patients with severe sepsis in
the intensive care unit (ICU). However, EGDT was provided at the most proximal phase of disease presentation in the
Emergency Department (ED). With EGDT, a reduction in mortality of over 16% was shown over standard care. Since
the EGDT study was published a decade ago, significant emphasis worldwide has been placed on a comprehensive
approach to the first 6 hours of sepsis management which is commonly referred to as the resuscitation bundle (RB).
The RB consists of early diagnosis, risk stratification using lactate levels, hemodynamic response after a fluid challenge,
antibiotics, source control and hemodynamic optimization or EGDT. This review will examine one decade of evidence
for the components of the RB examining its impact on systemic inflammation, the progression of organ failure, health
care resource consumption and mortality in severe sepsis and septic shock. (Minerva Anestesiol 2012;78:712-24)
Key words: Sepsis - Shock, septic - Lactatic acid - Resuscitation.
epsis represents a continuum beginning with

a host-pathogen interaction that triggers a
complex interplay between pro-inflammatory,
anti-inflammatory and apoptotic mediators.1
As the disease progresses, organ dysfunction can
result from circulatory insufficiency from hypovolemia, myocardial depression, increased metabolic demands and vasoregulatory perfusion abnormalities. These hemodynamic perturbations
lead to an imbalance between systemic oxygen
supply and demand, leading to global tissue hypoxia and shock. These pathogenic events significantly contribute to the morbidity and mortality in early sepsis.2, 3
712
A critical decrease in systemic oxygen delivery

(DO2) is followed by an increase in the systemic
oxygen extraction ratio (O2ER) and a decrease
in central venous oxygen saturation (ScvO2) or
mixed venous oxygen saturation (SvO2). This increase in OER is a compensatory mechanism to
match systemic oxygen demands. When the limit of this compensatory mechanism (OER>50 to
60%) is reached, anaerobic metabolism ensures
leading to lactate production.4 In this critical delivery dependent or hypodynamic phase, lactate
concentrations are inversely related to DO2 and
ScvO2/SvO2 (Figure 1).5 This phase can occur
with normal vital signs and is commonly referred
MINERVA ANESTESIOLOGICA
June 2012
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies

Early interventions in severe sepsis and septic shock
Figure 1.Oxygen delivery and consumption.
to as occult shock, where the patient outwardly

appears less ill. As a result organ dysfunction and
sudden cardiopulmonary collapse are complications associated with this phase if unrecognized
or left untreated.2, 6, 7 This state predominantly
characterizes the early sepsis presentation (Figure
2) and is an important distinction from previous
unsuccessful sepsis resuscitation trials performed
in the ICU setting.8-11
After adequate resuscitation, a hyperdynamic
phase follows the hypodynamic phase. Compensated sepsis is characterized by an elevated
ScvO2/SvO2 and normal lactate. Later an elevated lactate and elevated ScvO2/SvO2 denote
pathologic delivery dependence or delivery independence and is associated with increased mortality.12 The failure to increase OER and thus increase systemic oxygen consymption (VO2) may
be secondary to impairment of microvascular
oxygen perfusion or mitochondrial dysfunction.
Origin of the resuscitation
bundle (RB) components
The RB and its components are not novel
strategies. Wilson et al. wrote a series of expert
opinions beginning in 1976 that comprised the
tenets of early sepsis management (Figure 2).13
These recommendations included the following:
early identification of high risk patients, appropriate cultures, source control, and appropriate
antibiotic administration. This was followed by
strategies aimed at early hemodynamic optimization of oxygen delivery guided by preload
(central venous pressure or surrogate, fluids),
afterload (mean arterial pressure, vasopressors),
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RIVERS
arterial oxygen content (packed red blood cells,

oxygen), and contractility (inotropes) if ScvO2
remained low (Figure 2).
In the 2001 publication, these components
which were also recommended by a consensus of
expert opinion 14 were applied at the most proximal
site of hospital presentation mirroring the approach
to trauma, stroke and acute myocardial infarction.14
This approach called early good-directed therapy
(EGDT) was tested against standard care in a randomized control trial resulting in a mortality benefit of over 16%. In order to avoid the ethical issues
(withholding life saving therapy), the control or
standard care arm also received continuous central
venous pressure (CVP), arterial blood pressure and
urine output monitoring. This was not a standard
of care in emergency department (ED) throughout
the United States at the time where baseline mortality was estimated to be over 50%. In regards to the
success of the EGDT group, it must be emphasized
that control group therapy also reduced mortality
(46.5%) compared to the historical care mortality
which was over 50%.15 Over the last decade the
various components of EGDT or the resuscitation
bundle have been examined, validated and incorporated into evidence based guidelines.16, 17
Early risk stratification using blood
pressure and lactate levels
EGDT begins with early identification of high
risk patients based on hypotension (systolic blood
pressure <90 mmHg) and a lactate level >4 mmol/L
(Figure 2). Although it is intuitive, a hypotensive
episode is associated with an increase risk for sudden and unexpected death.18 After Aduen et al. established the general prognostic value of a lactate
of 4 mM/L on hospital admission; multiple studies
have confirmed the risk stratification of this level
for illness severity and mortality in both the prehospital and in-hospital setting.19-23
Antibiotic therapy
Once patients are identified, source control
and appropriate cultures should be obtained.24
While there are no prospective outcome trials
to support early administration of antibiotics,
the animal and retrospective human literature
713
RIVERS
714
Figure 2.The early goal directed therapy algorithm.
regarding the benefits of early and appropriate

antibiotic administration is present in both animal and multiple human studies of sepsis.25-28
The time period for the combination of antibi-
otics and early hemodynamic optimization has

been shown to be approximately 3-6 hours to
archive the best outcomes in human studies.26, 29
Hutchinson et al. showed that early antibiotic
June 2012

administration was associated with a significantly reduced hospital length of stay and hospital
costs.30
Central venous pressure and fluid therapy
While some question the accuracy of CVP
in assessing volume status; equivalent outcomes
have been shown when compared to the pulmonary artery catheter for assessment of fluid
status in acute lung injury.31 CVP measurement
is indicative of fluid responsiveness in the lower ranges and a CVP >10 is the upper limit for
algorithms of fluid challenges.32 CVP has been
shown to have a significant association with 30day mortality.33 Ferrer et al.34 and Boyd et al.
concluded a negative impact on survival when
CVP was used as a guide to fluid management.35
The use of CVP appears to be time sensitive.
Early, aggressive fluid therapy which is associated
with improved outcomes must be distinguished
from late aggressive fluid therapy.36 The administered volume in the EGDT group within the first
6 hours was significantly greater compared to
standard therapy group, but over 72 hours there
were no differences in the amount of fluid between the two groups. In a meta-analysis, the use
of albumin is associated with lower mortality.37
Mean arterial pressure and vasopressor use
The mean arterial blood pressure target in
EGDT is supported by Varpula and Dunser et
al.33, 38 They examined hemodynamic variables
in septic shock patients during the first 24-48
h of treatment and found a MAP below 60-65
mmHg to be most predictive of 28-30-day mortality and organ function. It is preferable that
this endpoint be met with fluid versus vasopressor therapy. EGDT is associated with greater volume administration and diminished vasopressor
use over first 6 hours of resuscitation. However,
an equal amount of fluid is used over the first
72 hours of hospitalization. In the absence of diminished early volume therapy, there was an increase in the incidence of sudden hemodynamic
deterioration and vasopressor use.
These observations reveal that hypotension
is more refractory to fluid administration at the
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later stage of disease presentation. It may be because of this that administration and duration of
vasopressors also correlates with worse outcome.
Levy et al. has shown that the delayed use of vasopressor therapy for cardiovascular support is
incrementally associated with a significantly
higher mortality than any other organ failure
beyond the first 24 hours of sepsis.3 One of the
attributes of early volume therapy is a significant
reduction in vasopressor therapy which further
reduced need for vasopressin and corticosteroid
therapy.3,14, 39-41 De Backer et al. showed that
there was no significant difference in the rate of
death between patients treated with dopamine
as the first-line vasopressor agent and those who
were treated with norepinephrine, however, the
use of dopamine was associated with a greater
number of adverse events.42
Central venous and tissue oxygen saturation
Many of the salutary effects of ScvO2 monitoring are based on its ability to detect imbalances of DO2 to VO2 in the delivery dependent phase even with normal vitals signs.6 In the
presence of a low value, therapeutic maneuvers
to increase DO2 or decrease VO2 are required to
normalize this number. Thus, ScvO2 becomes a
trigger for increasing inspired oxygen concentration (arterial hypoxia), red blood cell transfusion
(decreased arterial oxygen content), inotrope
therapy (myocardial suppression), and mechanical ventilation (increased oxygen demands).43-46
Multiple studies have compared ScvO2 with
SvO2 showing that there is an absolute difference
(5%) between the two sites.47, 48 While there is
a difference, the clinical utility of both sites is
comparable and validated by outcome studies.48
In a multicenter study, Pope et al. found that the
failure to reach a ScvO2 greater than 70% within
the first six hours is associated with significantly
increased (14%) mortality.12 Castellanos-Ortega
et al. examined all of the sepsis bundle elements
at 6 and 24 hours of sepsis and found that the
attainment of an ScvO2 >70% had the statistically most significant impact on survival than
all other bundle elements.49 In a meta-analysis
examining five studies comprising over 11000
patients, it was shown that patients reaching this
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endpoint were twice as likely to survive than patients without reaching this endpoint.50 ScvO2
remains significantly predictive of outcome 47
hours after the onset of acute lung injury and
up to 48 hours in the ICU phase of sepsis.33, 51
Further evidence exists showing that continuous
ScvO2 monitoring is superior to intermittent
monitoring.52 Tissue oxygenation (StO2) can
be obtained using near-infrared spectroscopy
using a probe applied to the thenar portion of
the hand. Napoli showed that while a statistically significant relationship existed between
StO2 and ScvO2, StO2 appears to systematically
overestimate lower ScvO2 values and underestimate at higher ScvO2 values.53 Mesquida et al.
found that StO2 values below 75% predicted
low ScvO2 values with high specificity, but this
predictive value did not hold for StO2 values
above 75%. In examining this variable in early
resuscitation, Colin et al. found masseter tissue
oxygen saturation predictive of 28-day mortality.54 Thus, StO2 might be useful very early in
resuscitation, before ScvO2 is available.55
Hemoglobin threshold and red
blood cell transfusion
Anemia in early severe sepsis and septic shock
results from a combination of pre-existing disease, acute volume resuscitation, impaired bone
marrow response and a proposed decrease in the
sensitivity of erythropoietin receptors.56 Anemia
leads to a compensatory increase in systemic
oxygen extraction to systemic oxygen needs.
When this compensatory response is inadequate,
the physiologic rationale for transfusion of red
blood cells (RBCs) during this delivery dependent physiology (increased lactate and low ScvO2)
is warranted. This concept has been supported
by Vallet et al. who found that mortality is optimized when an ScvO2 of 69.5% is used as a trigger for transfusion.43 Because hemoglobin concentrations may vary in the central, peripheral
and microvascular circulations, the oxygen carrying capacity and rheological characteristics of
a specific region is unpredictable. For instance,
findings suggest that the sublingual microcirculation is globally unaltered by RBC transfusion
in septic patients yet can improve in patients
716
with altered capillary perfusion at baseline.57

While there are many publications that incriminate RBC transfusions with worse outcome, a
recent large observational study found that RBC
transfusion was associated with decreased mortality rates.58 Further studies are needed to support the current recommendation for a hemoglobin of 10 mg/dL during septic shock.59
Myocardial dysfunction and inotrope therapy
The early recognition of myocardial dysfunction requiring inotropic use was found to be at a
12.9% greater frequency in the EGDT versus the
control group in the original EGDT study and
this incidence is consistent with previous findings by Parrillo et al.60 Grissom et al. established
that physical examination findings of inadequate
circulation are not useful for predicting low cardiac index or ScvO2.51 Afessa et al. examined 962
patients using a propensity score for each bundle
element and found that compliance with lactate
measurement and inotrope administration was
independently associated with decreased risk of
mortality.61 Shah et al. performed a retrospective review of 183 sepsis episodes in patients
with pre-existing echocardiograms (prior to the
sepsis event) documenting systolic dysfunction.
In the 135 patients who did not meet EGDT
adherence requirements, the mortality rate was
36.3% and in the 48 patients who met EGDT
adherence requirements, the mortality rate was
16.67%, P<0.05.44
Decreasing systemic oxygen consumption
The indications for ventilatory support include hypoxia, hypercarbia, severe metabolic
acidosis, altered mental status and the look of
impending demise. A persistently low ScvO2
may signal cardiopulmonary decompensation
and the need for ventilator support.45, 62 Furthermore, the work of breathing can be eliminated which consumes 20-40% of systemic oxygen
delivery.63-65 In patients with severe adult respiratory distress syndrome; early administration of
a neuromuscular blocking agent improves outcome and decreases duration of mechanical ventilation.66 The outcome benefit may be related
June 2012

to early restoration of the balance between DO2

and VO2.
Lactate clearance
Nguyen et al. found that the clearance of lactate over the first six hours after presentation was
associated with a significant decrease in pro- and
anti-inflammatory biomarkers, improved organ function and reduced mortality.42, 43 This
was based on previous investigations using lactate clearance over 24 and 72 hours in the ICU
setting.67 In a recent prospective multicenter
trial of EGDT implementation, Nguyen et al.
showed that when patients received EGDT, the
mortality reduction was further enhanced when
retrospectively grouped by improving levels of
lactate clearance.68 Jones et al. declared that lactate clearance is equivalent to ScvO2 using the
EGDT algorithm in a noninferiority study.69 In
this study, patients assigned to the ScvO2 group
were resuscitated to normalize central venous
pressure, mean arterial pressure, and ScvO2
of 70% while patients in the lactate clearance
group were resuscitated to normalize central
venous pressure, mean arterial pressure, and
achieve a lactate clearance of at least 10%. The
study protocol was continued until all goals were
achieved or for up to six hours. They concluded
that lactate clearance guided resuscitation was
non-inferior or equivalent to a ScvO2 guided
resuscitation based on no difference in mortality. Compared to the EGDT study, the patients
enrolled by Jones et al. were of a lower illness
severity, in a more supply independent phase at
baseline (ScvO2 and lower lactate levels at study
baseline), more frequently in vasodilatory shock
(vasopressor dependent) and less mechanically
ventilated, Figure 1. More importantly, only
30 interventions were made in only 10% of the
patient population. It is these patients (delivery
dependent or hypodynamic phase) that require
additional interventions such as supplemental
oxygen, packed red blood cells, inotropes and
mechanical ventilation which are physiologically triggered by ScvO2. These interventions reduce sudden cardiopulmonary complications by
50%; an issue not addressed by Jones et al. These
events signal reaching the critical OER (low
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ScvO2) where the production of lactate exceeds

its clearance and the serum lactate levels begin
to rise.4 Therefore, SvO2 is more sensitive at detecting impending tissue hypoxia than lactate.
Continuous ScvO2 monitoring provides a real
time assessment, more efficient attainment of resuscitation endpoints and greater mortality benefit than intermittent sampling.47, 52 In an ICU
based study, Jansen et al. randomly allocated
patients with an elevated lactate (>3 mm/L) to
decrease lactate by 20% or more per two hours
for the initial eight hours in the lactate group.
In the control group, the treatment team had no
knowledge of lactate levels (except for the admission value). The lactate group received more
fluids and vasodilators. However, there were no
significant differences in lactate clearance between treatment groups. Hospital mortality was
significantly reduced from 43.5% in the control
group versus 33.9% in the lactate group. In the
lactate group, there was a decrease in organ failure, duration of inotrope therapy, mechanical
ventilation from 7-72 hours and ICU length of
stay.70 The lactate group treatment did not result in faster reduction of lactate when compared
with control group therapy. This might actually
argue against lactate as a target of hemodynamic
therapy. However, given that ScvO2 monitoring
was mandatory in the lactate group and facultative in the control group, this study could not
exclude the possibility that this had an impact
on the observed outcome difference. The disturbances of lactate metabolism that occur during
sepsis are probably more complex than an isolated defect of cellular oxygenation.71 Further
a normal lactate in isolation does not exclude
the presence of tissue hypoperfusion. Twenty to
50% of septic shock patients will never elevate
lactate levels at presentation or during the clinical course and frequently develop multi-system
organ failure.72-74 These observations indicate
that using lactate and ScvO2 are complimentary
endpoints and not mutually exclusive.
Modified versions of the resuscitation bundle
Lin et al. employed a modified EGDT protocol in a medical ICU without the use of ScvO2
compared to a control group. Targeting CVP,
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Table I.Comparison of sepsis intervention studies using the resuscitation bundle compared to the original EGDT
study.8, 41, 49, 68, 80-128
Summary of implementation study
Number of patients
APACHE II score
Sex, % Males
Age (years)
Mortality before (SD)**
Relative risk reduction
Absolute risk reduction
NNT
Rivers et al.
Before or control
After
Control
EGDT
9527
24.24
58.15
63.84
46.8 (26)%
9884
24.2
57.3
62.9
29.1 (12)%
133
20.4
50.4
64.4
46.5%
130
21.4
50.8
67.1
30.5%
0.37
18.3%
5.45
0.34
16.0%
6.25
*Includes before and after and concurrent implementation studies. **The average mortality of each study. NNT=number needed to treat.
MAP, hemoglobin and urine output, not only

led to a significant decrease of the mortality rate,
but also to shortening the length of ICU stay,
duration of mechanical ventilator support and
duration of antibiotic administration. There was
more rapid reversal of shock and less delayed
vasopressor administration. For medical ICUs
without facility to monitor ScvO2, this modified therapeutic protocol provides an alternative that reduces mortality, ICU stay, ventilator
support duration, and tissue hypoperfusion associated major organ dysfunction. The authors
added that with ScvO2 measurement there was
a chance of improving clinical outcomes further.
Impact on inflammation, the
microcirculation and organ failure
The association between global tissue hypoxia
and inflammation has been well described in vivo
models. Boulos et al. have shown that SvO2 is
significantly associated with mitochondrial function and that inflammatory mediators in septic
patients can significantly alter mitochondrial
function.75 In a further analysis of EGDT patients, Rivers also showed that the persistence of
global tissue hypoxia (increased lactate and low
ScvO2) correlates significantly with the activity of
inflammatory mediators. In patients treated with
EGDT, alteration of the inflammatory cascade
is evidenced by significantly lower IL-8 levels.
When untreated, this pathogenic mechanism of
inflammation can lead to a second hit phenomenon of multi-organ failure and worsening
718
inflammation.76 The observation of a 15% reduction in mechanical ventilation over 72 hours is an

example of preventing this second hit.73 Adjunctive therapies to further modulate the inflammatory response when used early may enhance the
beneficial effects of EGDT.77 Therapeutic efforts
targeting the microcirculation are in progress but
to date having not shown outcome benefit.78 Kiers et al. found that a delay in achieving hemodynamic goals of EGDT was significantly associated with the development of acute kidney injury
(P=0.02) and resulted in a 3.4% greater creatinine
level rise per hour (P=0.03) in patients admitted
from the hospital ward.79 In a subanalysis of patients enrolled in the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes
of Health, Acute Respiratory Distress Syndrome
Network, an improved SvO2 was significantly associated with improved mortality and decrease in
duration of mechanical ventilation.51 These findings support the observations of a decreased need
for mechanical ventilation over the first 72 hours
of presentation in the original EGDT trial.
Outcome evidence in adult patients
Over the last decade, the external validity
and generalizability of the RB containing varying versions of EGDT has been established in
multiple studies. These studies comprise over 50
publications containing over 18000 adult patients (Table I).8, 41, 49, 68, 80-128 The outcome benefit of these studies combined equal or exceed
the reduction in mortality found in the original
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trial. It has been stated that the original EGDT

study enrolled patients of higher illness severity
than that observed in other studies. However,
the mean age, baseline APACHE II scores and
mortality rate of these previous adult studies are
similar to the original EGDT study.129-131 These
outcomes results have been observed in community and tertiary care hospitals, ED and ICU
settings, medical and surgical patients.98 Studies
that are in the process of examining the components of EGDT can be found at www.clinicaltrials.gov.
Outcome evidence in pediatric patients
EGDT has shown to be beneficial in a prospective randomized pediatric trial.129, 132 A
recent study in children showed that fluid boluses significantly increased 48-hour mortality in
critically ill children with impaired perfusion in
these resource-limited settings in Africa.133 These
findings are a departure from previous trials
finding that aggressive fluid therapy and EGDT
improves mortality in pediatric sepsis.134, 135 The
difference between these studies may be multifactorial including the etiology of the infection
which was primarily malaria not bacterial. Peer
reviewed evidence based guidelines currently exist for the management of sepsis in the pediatric
patient.136 It is important to note that therapies
confirmed in adults are not necessarily translated
to pediatric patients.137
Health care resource consumption
The associated cost for sepsis in the United
States approaches over $ 50 billion per year or
2.5% of the health care expenditure, making
it the most expensive disease treated in hospital since 1997.138 EGDT has been shown to
decrease hospital related costs consistently by
20%.139, 140 The cost savings are largely driven by
a significant decrease in hospital length of stay
by five days per patient.141
Importance of timing
Does the effectiveness of the RB attenuate over
time? Coba et al. examined the impact of com-
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plying with the goals of EGDT on patient outcomes when completed beyond the six-hour recommendation period. Compliance was assessed
at 6, 18 and 24 hours after diagnosis of severe
sepsis or septic shock. The compliers at 18 h had
an absolute 10.2% significantly lower in-hospital mortality compared to the non-compliers at
18 h (37.1% vs. 47.3%). When adjusted for differences in baseline illness severity, the compliers
at 18 h had a greater reduction in predicted mortality of 26.8% versus 9.4% (P<0.01). This study
uniquely shows that when bundle completion is
extended to 18 hours, the mortality reduction
remains significant. Similar findings were noted
by Castellanos-Ortega et al.119
Challenges of implementation
Significant reductions in mortality have been
shown even with suboptimal compliance rates
approaching 51%.87 Without a continuous quality initiative (CQI), even these compliance rates
will not improve and will decrease over time.142
Multiple studies have shown that standardized
order sets, enhanced bedside monitor display,
Table II.Early goal directed therapy.
Decreases mortality (16-18%)
Decreases the progression of organ failure
Decreases the progression of acute kidney injury
Decreases need for mechanical ventilation
Modulates the early inflammatory response
Decreases health care costs (20%)
Decreased duration of mechanical ventilation
Decreased hospital length of stay
Is effective up to 18 hours after disease onset (in the ED and
ICU)
Decreases sudden cardiopulmonary complications
Is effective in community and tertiary care hospitals
Diagnostic components (associated with increased mortality):
Lactate > 4 mm/L
Systolic blood pressure <90 mmHg
Components (associated with improved outcomes):
Antibiotics within 1 to 3 hours
CVP >8 mmHg
MAP >65 mmHg
Hematocrit >30%
ScvO2 >70%
Threshold for red blood cell transfusion
Need for inotropic therapy
Indication for and response to mechanical ventilation
Is not equivalent to lactate clearance
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telemedicine and comprehensive CQI feedback

is feasible, modifies clinician behavior and is associated with decreased hospital mortality.41, 87,
103, 122, 126, 143
Conclusions
One decade later, multiple studies (Table II)
have not only validated the RB and its elements
but also provide evidence that this therapy
modulates inflammation, decreases organ failure
progression and conserves health care resource
consumption. This approach consistently saves 1
out of every 6 lives for patients presenting with
severe sepsis and septic shock. While implementation remains challenging, the RB remains one
of the most effective interventions in the management of severe sepsis and septic shock.
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Conflicts of interest.None related to this publication. Dr. Rivers receives research support from the National Institute of Health, Aggennix
and Alere Corporation. In the past four years, he has been a onetime consultant for Aggennix, Esai Pharmaceuticals Idaho Technologies,
Astra Zeneca, Massimo and Sangard. Dr. Rivers has never personally owned any patents or Early Interventions in Severe Sepsis and Septic
Shock: The Evidence One Decade Later received royalties, stock or research support associated with the EGDT study. Dr. Cannon has
received consulting fees from Eisai Pharmaceuticals.
Received on May 3, 2011 - Accepted for publication on March 21, 2012.
Corresponding author: E. P. Rivers, MD, MPH, Vice Chairman and Research Director, Department of Emergency Medicine, Senior Staff
Attending in Surgical Critical Care and Emergency Medicine, Clinical Professor, Wayne State University, 270-Clara Ford Pavilion, Henry
Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. E-mail: erivers1@hfhs.org
This article is freely available at www.minervamedica.it
724
June 2012

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COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

Early interventions in severe sepsis and septic shock:

epsis represents a continuum beginning with

A critical decrease in systemic oxygen delivery

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

Figure 1.Oxygen delivery and consumption.

to as occult shock, where the patient outwardly

arterial oxygen content (packed red blood cells,

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

Early interventions in severe sepsis and septic shock

Figure 2.The early goal directed therapy algorithm.

regarding the benefits of early and appropriate

otics and early hemodynamic optimization has

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

Early interventions in severe sepsis and septic shock

with altered capillary perfusion at baseline.57

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

to early restoration of the balance between DO2

ScvO2) where the production of lactate exceeds

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

Early interventions in severe sepsis and septic shock

MAP, hemoglobin and urine output, not only

inflammation.76 The observation of a 15% reduction in mechanical ventilation over 72 hours is an

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

trial. It has been stated that the original EGDT

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

Early interventions in severe sepsis and septic shock

telemedicine and comprehensive CQI feedback

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

sis bundles as processes of care: A meta-analysis. Aust Crit

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

Early interventions in severe sepsis and septic shock

saturation as goals of early sepsis therapy: a randomized

with hypoperfusion]. Zhonghua Wai Ke Za Zhi (Chinese

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

rez-Fernndez E, Duque M et al. Compliance with a sepsis

121. Casserly B, Baram M, Walsh P, Sucov A, Ward NS, Levy

COPYRIGHT 2012 EDIZIONI MINERVA MEDICA

Early interventions in severe sepsis and septic shock

to meeting early goal-directed therapy using telemedicine.

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