REVIEW

CURRENT
OPINION Oxygen extraction and perfusion markers in severe
sepsis and septic shock: diagnostic, therapeutic
and outcome implications
Emanuel P. Rivers a, Angel Coz Yataco b, Anja Kathrina Jaehne a,
Jasreen Gill a, and Margaret Disselkamp b

Purpose of review
The purpose of this study is to review the recent literature examining the clinical utility of markers of
systemic oxygen extraction and perfusion in the diagnosis, treatment and prognosis of severe sepsis and
septic shock.
Recent findings
When sepsis is accompanied by conditions in which systemic oxygen delivery does not meet tissue
oxygen demands, tissue hypoperfusion begins. Tissue hypoperfusion leads to oxygen debt, cellular
injury, organ dysfunction and death. Tissue hypoperfusion can be characterized using markers of
tissue perfusion (central venous oxygen saturation and lactate), which reflect the interaction between
systemic oxygen delivery and demands. For the last two decades, studies and quality initiatives
incorporating the early detection and interruption of tissue hypoperfusion have been shown to
improve mortality and altered sepsis care. Three recent trials, while confirming an all-time improvement
in sepsis mortality, challenged the concept that rapid normalization of markers of perfusion confers
outcome benefit. By defining and comparing haemodynamic phenotypes using markers of tissue perfusion,
we may better understand which patients are more likely to benefit from early goal-directed haemodynamic
optimization.
Summary
The phenotypic haemodynamic characterization of patients using perfusion markers has diagnostic,
therapeutic and outcome implications in severe sepsis and septic shock. However, irrespective of
haemodynamic phenotype, the outcome reflects the quality of care provided at the point of presentation.
Utilizing these principles may allow more objective interpretation of resuscitation trials and translate these
findings into current practice.
Keywords
haemodynamic phenotypes, lactate, oxygen extraction, perfusion markers, severe sepsis/septic shock

INTRODUCTION the signal fidelity of intervention outcome trials

Maintenance of tissue normoxia, reversal of tissue
hypoxia and avoidance of tissue dysoxia are essen-
tial to prevent oxygen debt, cell injury, organ failure
and death. Oxygen extraction and perfusion
markers define the presence of illness, quantify
severity, provide a clinical road map to guide inter-
ventions and provide prognostication. The ability to
characterize patients according to a distinct haemo-
dynamic phenotype decreases patient heterogeneity
and clarifies patient selection and results of related
outcome trials [1]. By controlling for these factors,
may be improved.
a
Department of Emergency Medicine, Henry Ford Hospital, Wayne State
University, Detroit, Michigan and bDepartment of Internal Medicine,
Pulmonary and Critical Care Medicine, University of Kentucky, Lexington,
Kentucky, USA
Correspondence to Emanuel P. Rivers, MD, MPH, 270-Clara Ford
Pavilion, Henry Ford Hospital, 2799 West Grand Boulevard Detroit,
MI 48202, USA. Tel: +1 313 916 1801; fax: +1 313 916 7437;
e-mail: erivers1@hfhs.org
Curr Opin Crit Care 2015, 21:381–387
DOI:10.1097/MCC.0000000000000241

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Cardiovascular system
KEY POINTS
 Severe sepsis and septic shock have distinct
haemodynamic phenotypes that have associated
mortalities.
 The mortality of these distinct phenotypes can be altered
with early diagnostic and therapeutic interventions.
 The combination of a normal lactate and decreased
ScvO2, increased lactate and low ScvO2 (early),
increased lactate and low ScvO2 (delayed), increased
lactate and high ScvO2 is incrementally associated with
increased mortality.
 These haemodynamic phenotypes require different
interventions in order to reverse the hypoxic or
dysoxic state.
 These haemodynamic phenotypes have clinical utility
and can aid in the comparison and interpretation of
future sepsis intervention trials.
THE EARLY HAEMODYNAMIC
PATHOGENESIS OF SEVERE SEPSIS AND
SEPTIC SHOCK
Animal and human models of early sepsis have
repeatedly shown that circulatory insufficiency
results in an imbalance between systemic oxygen
delivery (DO2) and consumptive demands (VO2).
Depending on the severity of insult and comorbid-
ities, there is decrease in DO2 as a result of decreased
intravascular volume, loss of vasomotor tone,
myocardial depression and increased metabolic
demands (i.e. fever and increased work of breathing).
As a result, the untreated haemodynamic picture of
early sepsis is hypotension, a decrease in central/
mixed venous oxygen saturation (ScvO2/SvO2), and
decreased central venous pressure (CVP) and cardiac
index followed by lactate production [2–4].
Unlike the experimental animal model, in
humans, the onset and duration of infection is
frequently unknown and thus the temporal pro-
gression from sepsis to severe sepsis and septic
shock. Upon presentation, patients will present
along a continuum of disease whose illness severity
may be cryptic or obvious. The characterization of
patients from a haemodynamic, oxygen transport
and utilization perspective provides a clinical phe-
notype. This is potentially of diagnostic, therapeutic
and prognostic utility to the treating clinician and
future research studies.
THE CONCEPT OF EARLY INTERVENTION
In the last two decades, a convergence of the basic
principles of early detection, antimicrobial therapy,
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source control, risk stratification and an early bal-
ance between DO2 and VO2 led to a fundamental
change in sepsis management called early goal-
directed therapy (EGDT) in 2001 [5]. EGDT was a
standard operating procedure (SOP) based on com-
ponents recommended by expert opinion and hae-
modynamic optimization studies over 50 years prior
to its conception and publication. The mortality
benefit of EGDT has been robustly replicated for
over a decade, leading to the general adoption as
basis of early care in septic patients by the Surviving
&
Sepsis Campaign (SCC) [6 ]. This adoption has led to
universal decline in sepsis mortality over the last
decade and a change in the haemodynamic pheno-
type.
Seven years after the EGDT publication and
dissemination of SCC guidelines, a recent triad of
clinical trials that incorporated many aspects of
EGDT as usual or control care ‘re-examined’ EGDT
&& &&
[7 –9 ]. Although it was an SOP, some investi-
gators considered EGDT a controversial haemo-
dynamic optimization study using a 50-year-old
haemodynamic technology and principles called
central venous oximetry [10,11]. These trials con-
cluded that an early resuscitation targeting CVP and
ScvO2 of 70% did not improve outcomes compared
&& &&
with ‘usual care’ [7 –9 ]. Although these trials add
an important insight, rendering the understanding
of the early pathogenesis to vital signs and physical
examination may not advance the scientific under-
standing of this disease. Before the findings of these
trials are translated into practice, the clinician
should examine these trials on the basis of the
physiology of oxygen transport and utilization. This
physiology provides the perfusion parameters that
allow objective comparisons and clarity regarding
the patient populations. This is important not only
for patient management but also for the future
interpretation of trials that include haemodynamic
optimization [1].
THE HAEMODYNAMIC PHENOTYPES OF
SEVERE SEPSIS AND SEPTIC SHOCK
The clinical and haemodynamic phenotypes are
defined by markers of perfusion (lactate and ScvO2)
into various stages that have diagnostic, therapeutic
and outcome implications (Fig. 1).
Normal lactate and low ScvO2
An early decrease in DO2 is accompanied by a low
ScvO2 [3]. This occurs prior to Stage A (Fig. 1) and in
non-ICU settings. Because this phase can frequently
manifest before lactate production, it can go un-
recognized because central venous or pulmonary
Volume 21  Number 5  October 2015
 Oxygen extraction and perfusion markers in severe sepsis and septic shock Rivers et al.

VO2
(b) Lactate (c)
VO2
DO2 SvO2
DO2 Lactate
NI SvOo2
NI Lactate

VO2

VO2 Lactate DO2

(a) DO2 (d)
SvO2
Lactate VO2
Lactate
DO2 SvO2
Lactate

Haemodynamic Treatment and

Stage Lactate SvO2 /ScvO2 MAP Mortality (%)
Derangements Comments

Hypovolaemia, Normal â 15% (12), 23% (29) Volume,

vasodilatation, vasopressors, correct
A myocardial suppression, â 21% (21), 24.9% anaemia, inotropic
increased metabolic á Normal (27), 35.2% (28) therapy, mechanical
demands (cryptic shock) ventilation

19.0% (21), 20%

â
Resuscitated, (56) Hyperdynamic,
B compensated and Normal - á Normal vasopressors, low-dose
7.7% (55), 11.8%
vasodilatory Normal corticosteroids
(61), 21% (48)

Continued DO2 37.9% (61), 40% Decrease VO2 and

C dependency, increased á â â (48), 42.9% (55), further augmentation
metabolic demands 48% (27), 51% (12) of DO2

Microcirculatory or OER
34% (48), 40%
defections and
(12), 41.7% (61), Microcirculatory
D impairment of VO2 á á â
52.3% (26), 60.3% rescue, source control
Decreased VO2
(28)
(dysoxic)

FIGURE 1. The haemodynamic phenotypes of severe sepsis and septic shock. OER, oxygen extraction ratio.

artery catheter placement for measurement of
ScvO2/SvO2 usually has not been performed. This
haemodynamic picture is usually triggered by a
hypotensive episode and more commonly reversed
with early fluid therapy or other interventions to
increase DO2 and/or decrease VO2. The incidence of
patients admitted to the ICU with a normal lactate
and low ScvO2 has been reported to be 33–37%
&&
[12 ]. The corresponding mortality is 15–23%, with
the higher mortality associated with unresolved
hypotension refractory to fluid therapy [13]. This
is the most ‘benign’ haemodynamic phenotype,
with minimal interventions necessary if resolved
at this stage.
Elevated lactate and low ScvO2 (Early)
Stage A in Fig. 1 is the DO2-dependent phase that
frequently begins with normal vital signs, which is
referred to as occult or cryptic shock (Fig. 1, Stage A)
[3,5,14–16]. A critical decrease in DO2 is followed by
an increase in the systemic oxygen extraction ratio
(OER) or decreased ScvO2/SvO2 as a compensatory
&&
mechanism to maintain VO2 [12 ,17]. Anaerobic

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Cardiovascular system
metabolism ensues when the limit of this compen-
satory mechanism (OER >50%) is reached, leading
to lactate production [18]. In this critical DO2-
dependent phase, lactate concentrations are inver-
sely related to DO2 and ScvO2/SvO2 (Fig. 1, Stage A)
[3].
This phase is also often present prior to or early
upon admission to the ICU. Because of the cryptic
nature of the severity of this illness, sudden cardi-
opulmonary organ failure (i.e. arrhythmias, respir-
atory failure, overt shock or cardiac arrest) may be
seen in up to 20% of patients in this critical phase
[4,19–25]. In the absence of lactate screening, many
of these patients would otherwise be sent to general
practice floors and succumb to these complications
or death. The early detection of cryptic shock has
been associated with a mortality reduction up to
&& && &&
10% [5,21,26 ,27,28 ,29 ].
Normal lactate and normal ScvO2
Stage B in Fig. 1 indicates adequate resuscitation to a
DO2-independent phase (normal lactate and normal
ScvO2/SvO2). Patients in this group typically have
responded to interventions with an increased
cardiac output and a normal OER. This state may
be accompanied by a normal blood pressure or a low
systemic vascular resistance necessitating low-dose
vasopressor administration. An initially low ScvO2
that is corrected within 6 h (based on hypotension
or a lactate > 4 mmol/l) carries a corresponding
&& &&
mortality reduction from 27.5 to 15% [12 ,29 ].
Interventions needed for continued haemodynamic
optimization are minimal in this phase.
Elevated lactate and low ScvO2 (Late)
Stage C in Fig. 1 has been defined as pathological
supply dependency, wherein even in the presence of
an increased DO2, there is continued evidence of
global tissue hypoxia (increased lactate and low
ScvO2) [14,22,30,31]. These patients may exhibit
variable cardiac outputs, vascular resistance and a
low ScvO2 [14,22,30–32]. The goals are still to
improve DO2 (increase oxygen levels, haemoglobin
or cardiac output) or decrease VO2.
Progressive hypoxaemia secondary to acute lung
injury decreases DO2 and frequently accompanies
sepsis. The compensatory increase in work of breath-
ing can consume 20–40% of DO2 (compared with
less than 5% in resting state) [33,34]. A persistently
low ScvO2 can signal cardiopulmonary decompen-
sation and the need for ventilator support [33–36].
Not only is mechanical ventilation associated with
increased mortality, but this intervention also alters
the haemodynamic phenotype. The introduction of
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ventilator support and sedation increases ScvO2 and
diminishes the incidence of low ScvO2 upon ICU
admission [37,38].
Myocardial dysfunction can be present in up to
15% of patients in septic shock [39–41]. This can be
even more pronounced in patients with prior
cardiovascular comorbidities. These patients will
have an impaired ability to increase DO2 appro-
priately to meet systemic demands. Although
these patients may receive life-saving mechanical
ventilation, adverse heart–lung interactions may
necessitate more cardiovascular manipulation. The
combination of a low ScvO2, increased CVP and
increased lactate is indicative of haemodynamically
significant myocardial dysfunction [19]. This hae-
modynamic phenotype is associated with increased
&&
mortality if unrecognized [42 ,43–48].
If ScvO2/SvO2 remains low for all 6 h of resusci-
tation, the mortality increases to 40% [48], and if
present upon ICU admission, mortality is 51%
&&
[12 ]. ScvO2 is predictive of outcome 47 h after
the onset of acute lung injury and its normalization
is associated with a mortality reduction from 38 to
23% [40].
Elevated lactate and increased ScvO2
Stage D in Fig. 1 represents the impairment of OER
(decreases VO2) secondary to microcirculatory
defects or impaired cellular respiration (cytopathic
tissue hypoxia). Patients in this stage have an elev-
ated ScvO2 and increased lactate (impaired clear-
ance), which are associated with high mortality
[48,49]. The mortality of an elevated lactate and
ScvO2 at least 70% initially and after 6 h is 33 and
31%, respectively. If this scenario is present upon
ICU admission, the mortality approaches 40%
&&
[12 ]. When hypotension requiring vasopressors
becomes an accompanying feature, the mortality
of this stage increases from 46.1 to 60.3%
&& &&
[26 ,29 ,50]. Treatment of this phenotype remains
difficult and is the subject of intense research.
Hypotension
Hypotension is an important element of cardio-
vascular insufficiency and generally potentiates
the mortality of all the described phenotypes
&&
[13,29 ,51–53]. Cardiovascular insufficiency is the
most lethal organ dysfunction within the first 24 h of
onset in septic shock [54]. However, although hypo-
tension is considered an essential feature of shock, its
&&
impact on outcome can be variable [28 ,53,55–57].
Septic or vasoplegic shock is defined as a patient
who is vasopressor dependent after presumed
adequate fluid resuscitation. However, vasopressor
Volume 21  Number 5  October 2015
 Oxygen extraction and perfusion markers in severe sepsis and septic shock Rivers et al.

Table 1. Baseline haemodynamic variables at enrolment of intervention trials

Refractory Lactate Lactate Hospital

hypotension (%) >4 mmol/l (%) ScvO2 (%) (mmol/l) mortality (%)

EGDT [5]a 51.1–54.6 79–80 48.6–49.2 6.9–7.7 30.5–46.5

Holst et al. [58 ] All n/a 68–69 2.4–2.7 43–45
&&

ProCESS [7 ]b 53.5–55.6 59.0–60.7 71 4.8–5.0 18.2–21.0

&&

ARISE [9 ]b 69.8–70.0 46.3–46.5 72.7 4.2–4.4 14.5–15.7

&&

ProMISE [8 ]b 54.1–55.6 63.7–65.4 70.1 5.1–5.2 24.0–25.0

&&

Jones et al. [59]a 74–82 39 74 3.9–4.2 16.7–22.0

ARISE, Australasian Resuscitation in Sepsis Evaluation; EGDT, early goal-directed therapy; n/a, not available; ProCESS, Protocolised Care for Early Septic Shock;
ProMISE, Protocolised Management in Sepsis.
a
Refractory hypotension to 20–30 ml/kg of intravenous fluids.
b
Refractory hypotension to 1 l bolus of intravenous fluids.

dependency is a function of fluid responsiveness
and the amount of volume given. There is variability
in this definition when it is based on a 1 l versus
20–30 ml/kg fluid bolus.
Thus, the introduction of vasopressor therapy
creates a vasoplegic phenotype, which may be a
function of volume and clinician judgement. This
also provides a confounding variable for the use of
corticosteroids, which are recommended for this
phase of septic shock. Patients who are hypotensive
with near normal lactate levels have generally
higher ScvO2, fewer organ failures and lower mortal-
ities than patients who are hypotensive with elev-
&&
ated lactates [28 ,53,55–57]. There is outcome
variability in patients who are vasopressor depend-
ent to septic shock.
conclude that, the physiologic need to augment
DO2 with red blood cells was minimal, which is
consistent with the study’s conclusion of no out-
&
come benefit [60,61 ].
Recent trials examining EGDT conclude no
benefit of augmenting early resuscitation with
&& &&
ScvO2 [7 –9 ]. The conclusion recommending lac-
tate clearance as a substitute for ScvO2 by Jones et al.
[59] was also derived from studies of similar haemo-
dynamic phenotypes. The haemodynamic pheno-
types of patients enrolled in these trials differ from
those in the original trial of EGDT (Table 1). The
results and conclusions of these trials apply to a
different stage and illness severity based on haemo-
dynamic phenotype (Table 1).

USING HAEMODYNAMIC PHENOTYPES
TO INTERPRET RECENT SEPSIS
INTERVENTION STUDIES
Comparing related clinical trials by haemodynamic
phenotype can provide objective comparisons of
enrolment characteristics, therapies received and
the interpretation of reported outcomes. For
example, sepsis studies heavily comprising patients
with an increased lactate, low ScvO2, hypotension,
mechanical ventilation and cardiopulmonary
comorbidities represent some of the most lethal
&&
subgroups [12 ]. These patients require more inter-
ventions to optimize DO2 (i.e. oxygen, fluid, blood,
inotropic therapy or mechanical ventilation).
Although it is associated with high mortality, this
phenotype can be reversed when treated early
&&
[12 ,48].
&&
In a recent trial [58 ], patients were randomized
to a haemoglobin of 7 or 9 g/dl. At enrollment,
patients had near normal lactate and ScvO2 (tissue
normoxia) (Table 1). Using the haemodynamic prin-
ciples of perfusion to interpret this trial, we can
LIMITATIONS
Irrespective of the haemodynamic phenotype,
mortality is dependent upon the care provided
[27]. The use of other parameters such as lactate
clearance, direct measurement of VO2 and micro-
circulatory indices may further improve upon the
individual discrimination of the haemodynamic
phenotype.
CONCLUSION
The haemodynamic phenotypes of severe sepsis and
septic shock are a multidimensional interaction of
oxygen extraction (ScvO2), perfusion (lactate) and
blood pressure, which distinctly reflect mortality.
This phenotypic characterization provides objective
information to compare resuscitation studies and
interpret the conclusions. This individual haemo-
dynamic characterization decreases heterogeneity
and improves the fidelity of enrolment character-
istics. This may improve the clarity of results and
conclusions in clinical outcome trials in severe sep-
sis and septic shock.

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Cardiovascular system
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 21  Number 5  October 2015
 Oxygen extraction and perfusion markers in severe sepsis and septic shock Rivers et al.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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extraction early in the course of sepsis.
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