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CLINICAL FEATURES

Adrenergic Support in Septic Shock: A Critical Review

Pedro Póvoa, MD, PhD 1
António H. Carneiro, MD 2
1
Hospital de São Francisco Xavier,
Centro Hospitalar de Lisboa
Ocidental, Medical Sciences Faculty,
New University of Lisbon, Lisboa,
Portugal; 2Hospital Geral de Santo
António, Porto, Portugal, Instituto
de Ciências Biomédicas Abel Salazar,
University of Porto, Porto, Portugal
Abstract: The definition of septic shock includes sepsis-induced hypotension despite adequate
fluid resuscitation, along with the presence of organ perfusion abnormalities, and ultimately cell
dysfunction. To restore adequate organ perfusion and cell homeostasis, cardiac output should be
restored with volume infusion plus vasopressor agents as indicated. Appropriate arterial pres-
sure for each individual patient and proper arterial oxygen content are key elements to restoring
perfusion. Tissue perfusion can be monitored by markers of organ and mitochondrial function,
namely urine output, level of consciousness, peripheral skin perfusion, central or mixed venous
oxygen saturation, and lactate. The hemodynamic effects of the different vasopressor agents
depend on the relative affinity to adrenergic receptors. Those with predominant α-agonist activity
produce more vasoconstriction (inoconstrictors) while those with predominant β-agonist stimu-
lation increase cardiac performance (inodilators). The debate about whether one vasopressor
agent is superior to another is still ongoing. The Surviving Sepsis Campaign guidelines refer to
either norepinephrine or dopamine as the first-choice vasopressor agent to correct hypotension
in septic shock. However, recent data from observational and controlled trials have challenged
these recommendations concerning different adrenergic agents. As a result, our view on the
prescription of vasopressors has changed from a probably oversimplified “one-size-fits-all”
approach to a multimodal approach in vasopressor selection.
Keywords: dobutamine; dopamine; epinephrine; norepinephrine; septic shock; vasopressin

Correspondence: Pedro Póvoa, MD, PhD,
Unidade de Cuidados Intensivos
Polivalente,
Hospital de São Francisco Xavier,
Estrada do Forte do Alto do Duque,
1449-005 Lisboa, Portugal.
Tel: + 351 21 0431104
Fax: + 351 21 3017533
E-mail: povoap@netcabo.pt
Introduction
Sepsis, as a complex immune response to aggression, activates and/or depresses
numerous systems within the body including neural, immune, hormonal, bioenergetic,
and metabolic pathways.1,2 The activity levels of these systems vary both with illness
severity and over time. Disturbance of pathway components is independently associ-
ated with a heightened mortality risk, yet these interactions and temporal relationships
remain poorly understood.2,3 Therefore, a systematic approach is needed to interpret
these regulations.
A considerable body of evidence has implicated mitochondrial dysfunction as a
common denominator in sepsis pathophysiology. Multiple organ dysfunctions that char-
acterize sepsis are accompanied by impaired cellular oxygen uptake, despite adequate
tissue perfusion, and cellular oxygen consumption is thought to be impaired primarily
at the level of the mitochondria, ultimately leading to decreased energy production.4
Mitochondria have a central role in energy production, namely adenosine triphosphate
(ATP) synthesis, after glucose and fatty acids, depending on the individual tissue and
on nutritional status, although significant amounts of lactate are also oxidized by the
heart, liver, and brain.2 These findings support the concept that septic organ failure
represents a state of “tissue dysoxia” or “cytopathic hypoxia,” ie, a cellular inability

62 011510e
© Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809

to use oxygen rather than a lack of its availability.2 Together,
such data have led to the formulation of the hypothesis that
septic organ failure results from a depression in mitochon-
drial function, with key effectors being cytokine-induced
oxidant nitrosative species and changes in hormone levels.
To some, this represents a damage-induced energetic failure
of mitochondria.1
However, histological studies of failing organs show rela-
tively preserved tissue compared with the severity of the cor-
respondent organ dysfunction. This lack of evident cell death
enables a relatively rapid recovery of failed organs. Thus, an
interpretative hypothesis suggests that organ failure actually
represents an adaptive and functional metabolic suppression,
determined by the lack of efficient energy production.3
Organ tissue oxygenation response to sepsis reflects
local oxygen supply-demand balance and varies in the face
of decreased oxygen delivery (DO2) and potential micro-
vascular abnormalities.2 Both macro- and microcirculatory
abnormalities occur early in sepsis and, if not promptly cor-
rected, can amplify the inflammatory response with possibly
greater impact on later mitochondrial dysfunction.2 We can
therefore conclude that optimization of DO2 is a key point
in sepsis management, provided it occurs in parallel with
infection treatment.5,6 For practical proposes, the elements
to consider for optimal DO2 are cardiac output and blood
oxygen content. In sepsis, these elements are influenced by
several expected alterations:7
• Increased capillary permeability, induced by inflam-
matory mediators, which provokes runaway of intra-
vascular fluid to interstitial space
• Vasodilatation (arterial and venous) in the hyperdy-
namic phase, provoking an enlargement of the vascular
continent with relative insufficiency of vascular content
• Myocardial depression
• Changes in cardiac rhythm that can influence cardiac
output
Based on these concepts, interventions have been pro-
posed that focus on optimizing DO2, considered to be essen-
tial for the availability of appropriate oxygen consumption
and energy production.8,9
Organ Blood Flow and Perfusion Pressure
Blood flow and perfusion pressure of each organ are regulated
by 2 systems. The systemic or “extrinsic” system regulates
the systemic circulation. It results from the activity of differ-
ent neurohormonal systems such as the autonomic nervous
system and the renin-angiotensin-aldosterone system.10
© Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809
Septic Shock
Furthermore, each organ possesses its own autoregulation,
depending on the tone of the afferent arteriole of capillary
beds. Preservation of an adequate systemic blood pressure is
crucial for adequate tissue perfusion. Over a wide range of
mean arterial pressure (MAP), the autoregulatory range, the
organ blood flow remains constant, that is to say, organ blood
flow is independent of the systemic blood pressure.11 When
the MAP falls below this autoregulatory threshold, blood flow
decreases, causing tissue ischemia due to reduced nutrient
supply and DO2, and as a consequence, organ dysfunction
(Figure 1). Below that critical MAP level, organ blood flow
becomes linearly dependent of MAP.12
The primary hemodynamic defect in hypovolemic, car-
diogenic, and obstructive forms of shock is a decrease in
cardiac output.7 In contrast, the underlying pathophysiology
of septic shock, related to the inflammatory response, encom-
passes several interactions between pathological vasodilata-
tion, increased pulmonary vascular resistance, relative and
absolute hypovolemia, decreased myocardial contractility,
and altered blood flow distribution.7
Therefore, the supportive approach of septic shock
includes an aggressive fluid resuscitation, and if hypoten-
sion persists, patients should be treated with vasopressors.
Goals of Resuscitation and
Monitoring in Septic Shock
According to the Surviving Sepsis Campaign guidelines,9 the
initial (first 6 hours) goals of resuscitation of severe sepsis
and septic shock patients include (level of evidence 1C):
1. Central venous pressure (CVP) between 8 to 12 mm Hg
(ⱖ 12 mm Hg if mechanically ventilated)
2. MAP ⬎ 65 mm Hg
3. Urine output ⱖ 0.5 mL/kg/h
4. Central venous (superior vena cava) oxygen saturation
(ScvO2) ⱖ 70% or mixed venous oxygen saturation
(SvO2) ⱖ 65%
These recommendations were originally suggested by
expert opinion for intensive care unit (ICU) patients13 and
later applied to an earlier presentation in the emergency
department for the first 6 hours of septic shock approach.8
Rivers et al8 showed a 14% reduction in vasopressor use in
patients managed with this approach.
The assessment of intravascular volume status as well as
individual preload responsiveness is done with a traditional
cardiac filling pressure, CVP. However, the use of CVP or
even pulmonary artery occlusion pressure, which are static
hemodynamic variables, is controversial because of the poor
63
Pedro Póvoa and António H. Carneiro
Figure 1. Relation between mean arterial pressure and organ blood flow.
Autoregulatory threshold
100%
Organ blood flow (%)
80%
60%
40%
20%
0%
0 20 40 60 80
Mean arterial pressure (mm Hg)
predictive value of cardiac response to volume challenge.14,15
In contrast, dynamic variables, such as pulse pressure varia-
tion or stroke volume variation, are preferable because they
give more information about the responsiveness of the car-
diovascular system and cardiac reserve,16 although no study
has yet assessed the effect on outcomes of resuscitation using
dynamic versus static variables. Moreover, dynamic variables
also have limitations: they cannot be used in spontaneously
breathing patients, in patients mechanically ventilated with
low tidal volumes (⬍ 8 mL/kg), or in patients with atrial
fibrillation. As a result, static variables could still be useful
in some patients.17
If hypotension persists after adequate fluid resuscita-
tion, vasopressors should be initiated. Increasing MAP with
vasopressors could improve organ perfusion pressure but
simultaneously carries a risk of regional vasoconstriction.
Mean arterial pressure is commonly used as a surrogate
marker of organ perfusion pressure in patients in shock. The
recommended MAP is only an indicative value because the
MAP sufficient to maintain a reasonable organ perfusion
is likely to vary between patients. Nevertheless, a MAP of
~65 mm Hg has been shown in 2 studies to be equivalent to
higher values.18,19
In each individual septic shock patient, the optimal MAP
is still unknown. However, a vasopressor support should only
be used to achieve a MAP necessary to restore organ perfu-
sion. A good surrogate marker is urine output, in other words,
the glomerular perfusion pressure. The target MAP depends
mainly on blood pressure measurement.20,21 Clinically, the
individual MAP should be kept at the lowest possible level
to maintain urine output, usually between 60 to 65 mm Hg.
Unfortunately, certain patients remain oliguric despite an
adequate resuscitation, which could indicate renal damage.
The SvO2 is an indirect measurement of the global
oxygen extraction ratio, ie, oxygen consumption.22 If oxygen
64
consumption remains constant, SvO2 has a direct relation-
ship with DO2. Even though the ScvO2 and SvO2 are not
exactly the same, for clinical purposes, changes over time
in ScvO2 have proved to be appropriate.23 A low SvO2 sug-
gests increased oxygen extraction and, consequently, an
incomplete resuscitation, prompting interventions to increase
DO2. A randomized trial has shown that using ScvO2 as
part of the resuscitation protocol, aiming at a value ⬎ 70%,
was associated with a significant reduction in mortality.8 In
contrast, a normal or high SvO2, when associated with an
100 increased blood lactate concentration, usually reflects a defect
in the cellular oxygen utilization with decreased oxygen
extraction.24 The extraction defect in septic patients could
result from microcirculatory shunting, interstitial edema, or
mitochondrial dysfunction.
Another frequently overlooked limitation is that to
implement these measures, septic shock patients need an
arterial line, a central venous catheter (either subclavian or
jugular), and a urinary catheter. In shock, measurement of
blood pressure using indirect measurement devices, such as
a sphygmomanometer, is inaccurate. An arterial line permits
a more accurate measurement and, in addition, allows the
beat-to-beat analysis necessary to tailor the vasopressor sup-
port.25 Moreover, the dynamic variables, like pulse pressure
variation, result from continuous readings of arterial line
tracings. These patients should have a central venous catheter
inserted as soon as possible to assess CVP, ScvO2, and to
administer vasopressor support.9 Nevertheless, the routine
use of pulmonary artery catheters is not recommended in
the management of septic shock patients26 since all of the
randomized trials as well as the systematic reviews have
failed to demonstrate any outcome benefit.27,28
Vasopressor and Inotropic Support
in Septic Shock
It is widely accepted that vasopressors should be initiated
when appropriate fluid resuscitation fails to restore an
adequate blood pressure. The aim is to maintain or restore
organ perfusion pressure in life-threatening hypotension,
even when hypovolemia has not yet been resolved.29 Many
vasopressors have been used since the 1940s. However,
very few controlled studies have been performed to assess
the relative efficacy of the different vasopressors as well as
their effect on outcomes.30
The vascular tone is regulated by the activity of the
sympathetic nervous system via endogenous catechol-
amines (dopamine, norepinephrine, and epinephrine) and
the renin-angiotensin-aldosterone system (vasopressin
© Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809
 Septic Shock

and angiotensin). So far, in clinical practice, endogenous
as well as synthetic catecholamines, and vasopressin and
its synthetic analog, terlipressin, have been used and
evaluated.31
These vasopressors have the ability to increase blood
pressure; however, their use in clinical practice is always
associated with concerns related to the potential increase
in vasoconstriction, which may cause further deterioration
in the perfusion pressure.32 This is true in inadequately
volume-resuscitated patients, and reinforces the need for
adequate fluid resuscitation before vasopressors can safely
be prescribed.
During septic shock there are important changes in vascu-
lar control at the microvascular level that are characterized by
decreased responsiveness to vasoconstrictor agents, mainly
mediated by nitric oxide. The administration of vasopressors
at “common” pharmacological doses to restore the target
MAP results in serum concentrations reaching 100 times the
physiological levels.33 Consequently, vasopressor support
will counterbalance this impaired adrenergic responsiveness
of microvessels in septic shock patients.
Adrenergic Agents
The hemodynamic effects of the different adrenergic agents
depend on their relative affinity to the adrenergic receptors,
ranging from pure α-agonists to pure β-agonists. Those with
predominant α-agonist activity produce more vasoconstric-
tion and are classified as inoconstrictors (eg, norepinephrine,
epinephrine, and dopamine), whereas those with predomi-
nant β-agonist stimulation increase cardiac performance
and are called inodilators (eg, dobutamine, dopexamine,
and isoproterenol) (Table 1, Figure 2).33,34 Only dopamine,
norepinephrine, epinephrine, and dobutamine will be detailed
in this article.
Dopamine
Dopamine has been classified by several experts as the
“complete” catecholamine35 because, depending on the
dose, it could have D1A, β1, β2, and α1 activity (Figure 3).9
Dopamine is the immediate precursor of norepinephrine
through the enzyme dopamine β-hydroxylase. About 50%
5 μg/kg/min, the so-called “dopaminergic” dose, dopamine
activates dopaminergic receptors, leading to the vasodilata-
tion of renal and mesenteric vascular beds. With intermediate
dosages, between 5 to 10 μg/kg/min, dopamine also activates
β-adrenergic receptors, leading to positive inotropic and chro-
notropic effects on the myocardium. Attempting to increase
the dopamine inotropic effect by increasing its dosage
⬎ 10 μg/kg/min usually results in tachycardia, tachyarritmia,
and increasing α1-adrenergic stimulation and, therefore,
systemic vasoconstriction. Because norepinephrine levels
parallel dopamine infusion rate, at high doses (⬎ 20 μg/kg/
min), the effects of dopamine are almost indistinguishable
from those of norepinephrine.36
Norepinephrine
Norepinephrine is the endogenous mediator of sym-
pathetic nervous system. It is a potent α-adrenergic
agonist and, to a lesser extent, a β1-adrenergic agonist
(Table 1, Figure 2). At low doses, norepinephrine is an
inotropic agent via stimulation of β1-receptors and also
a vasoconstrictor by activation of α1-receptors, leading
to an increase in systemic blood pressure with minimal
or absent tachycardia.29,34 At high doses, vasoconstric-
tion predominates due to predominant activation of
α1-receptors.
Given this systemic vasoconstrictive effect of norepi-
nephrine at high doses, acute renal failure secondary to
renal vasoconstriction could be precipitated. However,
septic shock patients present a marked vasodilatation
related to α-adrenergic hyporesponsiveness, and therefore
to infusion of norepinephrine; although it causes some
renal vasoconstriction, the net effect of increasing MAP
is the restoration of renal perfusion pressure followed by
increase in urine output, increase in creatinine clearance
and, consequently, a decrease in serum creatinine.20,21
Table 1. Affinity of Catecholamines for Adrenergic Receptors
Dose α1art α1ven β1 β2 D1A

of its activity is indirect through its biotransformation to Dopamine Low dose 0 +++ +++ +++++ ++++

norepinephrine. As a result, during dopamine infusion, even High dose ++++ +++ +++++

at a low dose (3 μg/kg/min), plasma norepinephrine concen- Norepinephrine +++++ +++++ +++ ? 0

tration increases likewise.36 Epinephrine Low dose + + ++++ ++++ 0

The effects of the infusion rate (in μg/kg/min) of dopa- High dose ++++ ++++
mine are the result of the different receptor interactions as Dobutamine 5 μg/kg/min + ? ++++ ++ 0
dose increases (Figure 3).29,34 At a low dose, between 0 to Adapted from Curr Opin Anaesthesiol.31

© Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809 65

Pedro Póvoa and António H. Carneiro

Figure 2. Graphic representation of the relative α-adrenergic and β-adrenergic effects of different catecholamines used to treat patients with shock.

100%

80%

60%

Affinity
α
β
40%

20%

0%
ol

e
e

e
in

in

in

in
in

in
n
re

am

am

am

hr
hr

hr
te

ep

ep

ep
ex

ut

op
ro

in

in

yl
ob
op

D
op

en
Ep

ep
D
D
Is

Epinephrine
Epinephrine is produced and released by the adrenal medulla.
At low doses, epinephrine is a potent nonselective β1- and
β2-receptor agonist providing a positive inotropic effect with
an increase in cardiac output without marked vasoconstric-
tion (Table 1, Figure 2).31,32 However, epinephrine has potent
chronotropic, dromotropic, and bathmotropic actions, leading
to an increase in myocardial work and oxygen consump-
tion that may augment the risk of ischemia and malignant
arrhythmias. At higher doses (0.15–0.3 μg/kg/min) the
α-receptors are activated, resulting in potent vasoconstriction
and increased systemic blood pressure.
For a long time, clinicians hesitated to use epinephrine
because it has been associated with potential detrimental
effects of regional blood flow, in particular, decreased
splanchnic blood flow and increased blood lactate. Con-
sequently, epinephrine was reserved for cases of extreme
hemodynamic collapse.31
Ph
or
N
Dobutamine
Dobutamine is a synthetic analog of dopamine and is a potent
β-agonist (Table 1, Figure 2).29 With a dose range between
5 to 25 μg/kg/min, dobutamine is an inodilator with positive
inotropic effects (β1-receptor activation) and arterial vaso-
dilatation (β2-receptor activation). In addition, dobutamine
possesses significant chronotropic and bathmotropic activi-
ties that result not only from the cardiac β1- and β2-receptor
activation but also from the baroreflex response to arterial
vasodilatation. In patients with septic shock, dobutamine
should always be given in association with a vasopressor. It
should never be given alone in hypotensive patients.9
Other Vasopressor Agents
During hypovolemic shock (particularly secondary to bleed-
ing) and cardiogenic shock, vasopressin is greatly increased,
contributing to the maintenance of blood pressure. However,
for reasons not completely understood, in early septic shock,

Figure 3. Graphic representation of the predominant effects of dopamine infusion.

μg/kg/min
0 3–5 8–10 ⬎ 20

D1A β1 +++ α1 ++++

β2 ++

66 © Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809


vasopressin levels are elevated and subsequently begin to
decrease, sometimes markedly, reaching almost undetectable
levels.37 Furthermore, the administration of vasopressin has
been shown to restore vascular tone and blood pressure in
patients with vasodilatory shock.38 As a result, the rationale
for giving vasopressin to vasodilatory shock patients is
based on the concept of relative vasopressin insufficiency,39
the potential synergism with adrenergic agents,40 and the
vasopressin-mediated restoration of vascular tone.41
Vasopressin
Vasopressin is a hormone produced in the neurohypophysis. It
regulates fluid and electrolyte balance and, in addition, arterial
blood pressure and organ perfusion pressure through a sys-
temic action.42 There are 2 types of vasopressin receptors: the
V2-receptor, located in the kidney, responsible for the regula-
tion of water and sodium reabsorption, and the V1-receptor,
located in the vascular smooth muscle, which contributes to the
regulation of vascular tone and increased blood pressure.43 Con-
sequently, the administration of vasopressin in “physiological”
doses (~0.03–0.04 U/min) can increase blood pressure, mainly
mediated by inhibition of inducible nitric oxide synthase.
Terlipressin
Terlipressin is a semi-synthetic analog of vasopressin with a
greater affinity for V1-receptors compared with V2-receptors
(2:1 ratio). Thus, in septic shock, its administration is associated
with a greater effect in arterial and organ perfusion pressure,
particularly in the kidney.44 Simultaneously, cardiac output
usually decreases from high to “physiological” values.43 The
terlipressin molecule has a prolonged half-life (∼6 hours), much
higher than that of vasopressin (∼6 minutes). Terlipressin can
be used either as a bolus or continuous infusion.
Vasopressor Support in Septic Shock
The current recommendations from the Surviving Sepsis
Campaign9 on vasopressor support in septic shock are
detailed below.
1. Either norepinephrine or dopamine is the first-choice
vasopressor agent to correct hypotension in septic
shock (level of evidence 1C).
2. Epinephrine, phenylephrine, or vasopressin should
not be administered as the initial vasopressor in septic
shock (level of evidence 2C). Vasopressin 0.03 U/min
may be subsequently added to norepinephrine, with
anticipation of an effect equivalent to that of norepi-
nephrine alone.
© Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809
Septic Shock
3. Epinephrine should be the first chosen alternative
agent in septic shock that is poorly responsive to
norepinephrine or dopamine (level of evidence 2B).
4. Low-dose dopamine should not be used for renal
protection (level of evidence 1A).
5. Dobutamine infusion is recommended in the presence
of myocardial dysfunction, as suggested by elevated
cardiac filling pressures and low cardiac output (level
of evidence 1C).
6. Avoid use of strategy to increase cardiac index to
predetermined supranormal levels (level of evidence
1B).
In clinical practice, low-dose dopamine increases renal
blood flow and can induce diuresis. For a long time, the
protective renal effects of the so-called “dopaminergic”
doses of dopamine were debated. This dispute was resolved
by a large (N = 328) randomized controlled trial evaluating
the effect of low-dose dopamine on the development of
renal failure in a general ICU population with early renal
dysfunction.45 Patients were randomly assigned to receive
either dopamine at 2 μg/kg/min or placebo. No protective
effect of dopamine on renal function was found. Finally, in
a meta-analysis (58 studies; N = 2149 patients), low-dose
dopamine did not prevent mortality, the onset of acute renal
failure, or the need for dialysis.46 Accordingly, the current
evidence does not support the administration of dopamine
for renal protection.
Observational Studies of Catecholamines
in Septic Shock
Several observational studies in septic shock patients have
investigated the impact of different vasopressor agents on
mortality.47–52 Two of these deserve an additional comment
because they were used in large cohorts of septic shock
patients.50,52
The Sepsis Occurrence in Acutely Ill Patients (SOAP)
study was designed to assess the incidence of sepsis and the
characteristics of critically ill patients in European ICUs.53
In a second study from the SOAP database, authors assessed
the impact of vasopressor support on outcomes of patients
with septic shock (N = 462).50 The authors showed that
septic shock patients treated with dopamine had a tendency
for higher hospital mortality (43.4% vs 35.4%; P = 0.079).
The administration of dopamine was associated with a
tendency for a lower 30-day survival (P = 0.09), as was
epinephrine, which had a significant negative impact on
outcome (P = 0.045). Neither norepinephrine nor dobutamine
67
Pedro Póvoa and António H. Carneiro
was associated with altered 30-day survival (P = 0.391 and
P = 0.541, respectively). In a multivariate logistic regression
model, dopamine administration in septic shock patients was
significantly associated with poor outcome (odds ratio [OR],
95% confidence interval [CI], 2.05, 1.27–3.37; P = 0.005).
Our study, the Sepsis Adquirida na Comunidade e
internada em Unidade de Cuidados Intensivos (SACiUCI)—
Portuguese Community-Acquired Sepsis Study, was
designed to characterize the epidemiology of community-
acquired sepsis in patients admitted to Portuguese ICUs and,
in addition, assess the level of compliance with Surviving
Sepsis Campaign recommendations.54 Our data52 suggest
that norepinephrine administration may be associated with a
worse outcome than dopamine, either used as a single agent
(mortality 46.7% vs 20.3%; P ⬍ 0.001) or in combination
(mortality 52% vs 38.5%; P = 0.002), while the administra-
tion of dopamine seemed to have a beneficial effect. The use
of dobutamine, always in combination with norepinephrine,
dopamine, or both, was associated with a nonsignificant
increase in mortality (52.2% vs 41.1%; P = 0.057). To
assess the impact of the adrenergic support on mortality
during the first 5 days of ICU stay, we then performed a
multivariate, logistic-forward, stepwise regression analysis
with ICU mortality as the dependent factor. Norepinephrine
administration (adjusted OR, 95% CI, 3.821, 1.837–7.948;
P ⬍ 0.001) was found to be independently associated with
a higher risk of death in patients with septic shock. Finally,
we performed a Cox regression analysis to assess the hazard
ratios (HRs) of the administration of each of the studied
agents (dopamine, norepinephrine, and dobutamine) to
define its independent effect on mortality. The use of dopa-
mine showed a trend toward a lower mortality in our group
of septic shock patients, reaching a marginal significance
(HR = 0.742; 95% CI, 0.552–0.999; P = 0.049). In contrast,
the use of norepinephrine and dobutamine was associated
with an increased risk of death, with an HR of 3.532 (95%
CI, 2.01–6.204; P ⬍ 0.001) and 1.548 (95% CI,1.148–2.088;
P = 0.004), respectively. After adjustment of the regression
model to the clinical severity assessed with the Simplified
Acute Physiology Score II, Cox proportional hazard analy-
sis revealed that the administration of norepinephrine still
remained significantly associated with an increased risk of
death, with an adjusted HR of 2.501 (95% CI, 1.413–4.425;
P ⬍ 0.002).
Our study shares some limitations with the SOAP study,
namely the observational design, which may have caused dif-
ferences in vasopressor choice because sicker patients may
have received more norepinephrine than dopamine. However,
68
there is another important distinction between the 2 studies
that could have resulted in the observed differences.50,52
In the SOAP study,49 only 6.7% (N = 31) of septic shock
patients received dopamine alone at any dose, while 39.2%
(N = 181) received dopamine alone or in combination with
another vasopressor; in the SACiUCI study,52 more septic
shock patients received dopamine, 14.4% (N = 66) alone at
any dose, and 50.5% (N = 231) alone or in combination with
another vasopressor.
Comparative Studies of Vasopressors
in Septic Shock
In recent years, several randomized controlled trials of
vasopressor support in septic shock have been conducted
that have brought some light to this debate.
Comparing of Norepinephrine with Epinephrine
For a long time, physicians hesitated to use epinephrine as a
vasopressor agent because it was associated with a decrease
in splanchnic blood flow, an increase in gastric mucosal
PCO2, and a decrease in gastric pHi (ie, epinephrine has a
marked influence on oxygen supply to the splanchnic cir-
culation).31,32 In addition, epinephrine was associated with
an increase both in systemic and regional lactate levels.
Epinephrine administration increased blood pressure in
patients who were unresponsive to other vasopressors, and
this effect was mediated primarily by an increase in cardiac
index and stroke volume.32
Annane et al55 performed a randomized controlled trial
comparing norepinephrine plus dobutamine versus epi-
nephrine alone in the management of septic shock, titled
the Norepinephrine Plus Dobutamine Versus Epinephrine
Alone for the Management of Septic Shock (CATS) study.
This was a multicenter study (19 French ICUs) in which 330
septic shock patients were included (161 epinephrine vs 169
norepinephrine ± dobutamine). Vasopressors were titrated to
achieve and maintain a MAP ⱖ 70 mm Hg and the primary
outcome measure was 28-day all-cause mortality. At day
28, the mortality rate was similar in the epinephrine and
norepinephrine ± dobutamine groups (40% vs 34%, respec-
tively; P = 0.31). Intensive care unit mortality (47% vs 44%;
P = 0.69) and hospital mortality (52% vs 49%; P = 0.51)
were also similar. In addition, the clinical course of septic
shock patients was comparable in both groups, assessed
by the time to hemodynamic success (log-rank, P = 0.67),
time to vasopressor withdrawal (log-rank, P = 0.09), and
time course of Sequential Organ Failure Assessment score.
Even though epinephrine was associated with a delay in the
© Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809

normalization of arterial pH and lactate levels, the rate of
adverse events were similar.
In low-income countries, epinephrine continues to be
the first-line vasopressor agent because norepinephrine is
very expensive or simply not available.56 The CATS study
by Myburgh et al,57 in which some authors were from
countries where norepinephrine was unavailable, aimed
to compare epinephrine with norepinephrine in critically
ill patients. The study was conducted in 4 Australian ICUs
and included 280 shock patients (140 treated with epineph-
rine and 140 with norepinephrine), 56% of septic origin.
Similar to the CATS study, vasopressors were titrated to
achieve and maintain a MAP ⱖ 70 mm Hg. The endpoints
were the time to achievement of MAP goal for ⬎ 24 hours
without vasopressors (hours), and the 28-day and 90-day
mortality rates. There were no significant differences in the
above-mentioned endpoints among all the included patients
(P = 0.26, P = 0.48, and P = 0.49, respectively). In the sub-
groups of septic shock patients (N = 157), patients treated
with epinephrine showed similar time to achievement of
MAP goal compared with norepinephrine (35.1 hours vs
50.5 hours; P = 0.18), similar 28-day mortality (22.4% vs
29.3%; P = 0.76), and similar 90-day mortality (31.1% vs
36.6%; P = 0.85). As in the CATS study,55 in the present
study, epinephrine was associated with a significant increase
in lactate levels during the first 24 hours (especially the
first 16 hours), but thereafter lactate course was similar in
both groups.
From the data presented, it seems that epinephrine and
norepinephrine are similar as vasopressor agents in septic
shock patients with regard to hemodynamics, organ failure,
duration of therapy, and mortality.
Comparing Norepinephrine with Phenylephrine
Phenylephrine is an almost pure α1-agonist and, as a result,
is virtually only a vasoconstrictor agent. Its use as a vaso-
pressor has been shown to be associated with a decrease
in splanchnic blood flow and DO2, raising concerns about
its potential deleterious effect in septic shock patients. For
these reasons, the Surviving Sepsis Campaign guidelines9
recommend that phenylephrine not be used as a first-line
vasopressor in septic shock patients.
To clarify this issue, Morelli et al58 performed a small
randomized controlled trial to compare the effects of phen-
ylephrine or norepinephrine on systemic and regional hemo-
dynamic (splanchnic) blood flow in septic shock patients
(N = 32; 16 patients in each arm). Vasopressor agents were
titrated to achieve a MAP between 65 and 75 mm Hg; data
© Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809
Septic Shock
were collected at baseline and 12 hours after the start of the
infusion. Authors were unable to find any difference in the
investigated hemodynamic parameters, specifically those
related to the hepatosplanchnic perfusion assessed by the
blood clearance of indocyanine green, plasma disappear-
ance rate of indocyanine green, and gastric mucosal-arterial
CO2 partial pressure difference. Moreover, the blood arterial
lactate was virtually the same in both groups. As a result,
this pilot study was unable to demonstrate any difference
in hemodynamics, DO2, and regional blood flow between
phenylephrine and norepinephrine.
Comparing Norepinephrine with Dopamine
In the Surviving Sepsis Campaign guidelines9 either norepi-
nephrine or dopamine is recommended as first-choice vaso-
pressor agent to correct hypotension in septic shock. However,
data comparing norepinephrine with dopamine are scarce.
In the 1990s, Martin et al59 performed a single-center
study in 32 septic shock patients. Dopamine and norepi-
nephrine were titrated to achieve predefined hemodynamic
and oxymetric endpoints (systemic vascular resistance index
⬎ 1100 dynes*s/cm5*m2 and/or MAP ⱖ 80 mm Hg, cardiac
index ⱖ 4 L/min/m2, DO2 ⬎ 550 mL/min/m,2 and oxygen
consumption ⬎ 150 mL/min/m2). The success rate in patients
treated with dopamine was only 34%, whereas in those
receiving norepinephrine, the rate was 93%. The authors tried
norepinephrine in the 11 patients not responding to dopamine
and achieved the predefined goals in 10 patients. In addition,
lactate decreased more in the norepinephrine group. Although
the study was not sufficiently powered to evaluate mortality,
dopamine-treated patients presented a higher mortality (62.5%
vs 43.8% in the norepinephrine group).
In another single-center study comparing norepinephrine
with dopamine in septic shock patients (N = 66; 31 norepineph-
rine, 35 dopamine) titrated to achieve a MAP ⬎ 60 mm Hg
or systolic blood pressure ⬎ 90 mm Hg, the authors found
no difference in mortality rate (norepinephrine 41.8% vs
dopamine 40%).60 However, the incidence of dysrhythmias
needing intervention was significantly more frequent in the
dopamine-treated patients (31.4% vs 3.2%; P = 0.003).
Finally, a large multicenter randomized controlled trial
comparing norepinephrine with dopamine has been completed
but not yet published.61 Preliminary results have been presented
in the 2009 International Symposium on Intensive Care and
Emergency Medicine. A total of 1679 patients with shock were
included. The authors found no difference in 28-day all-cause
mortality but, again, the incidence of severe arrhythmias was
more frequent in the dopamine-treated patients.
69
Pedro Póvoa and António H. Carneiro
Inotropic Support in Septic Shock
Dobutamine is an almost pure β-agonist that increases the
cardiac index through increment of both stroke volume and
heart rate. The Surviving Sepsis Campaign guidelines9 give
3 recommendations concerning the use of dobutamine:
1. During the first 6 hours of resuscitation of severe sep-
sis or septic shock, if ScvO2 or SvO2 of 70% or 65%,
respectively, is not achieved with fluid resuscitation to
the CVP target, then transfusion of packed red blood
cells to achieve a hematocrit of ⱖ 30% and/or admin-
istration of a dobutamine infusion (up to a maximum
of 20 μg/kg/min) should be used to achieve this goal
(level of evidence 2C).
2. Dobutamine infusion should be administered in the
presence of myocardial dysfunction as suggested
by elevated cardiac filling pressures and low cardiac
output (level of evidence 1C).
3. A strategy to increase cardiac index to predetermined
supranormal levels is not advised (level of evidence
1B).
As we have already pointed out, changes in ScvO2 and
SvO2 reflect changes in DO2. Consequently, a low ScvO2
and SvO2 indicate an inadequate DO2. Rivers et al,8 in a
randomized study of patients with severe sepsis and septic
shock, showed that an early (first 6 hours) goal-directed
therapy aiming at a ScvO2 ⬎ 70%, after an adequate fluid
resuscitation, achieved a MAP ⬎ 65 mm Hg and a hematocrit
ⱖ 30%, which was associated with a reduction in mortality.
It is important to point out that in the Rivers study,8 inotropic
support with dobutamine was required in only a marginal
group of patients (15%). Furthermore, ScvO2 monitoring
has been validated in other studies.62–67
In patients with suspected or measured low cardiac out-
put after adequate fluid resuscitation without hypotension,
dobutamine should be considered. In patients who remain
hypotensive after adequate fluid resuscitation, dobutamine
should always be administered in association with a vaso-
pressor (eg, norepinephrine).
Based on preliminary data from a study performed by
Shoemaker et al,68 the concept of supranormal hemodynamic
goals had become almost standard, without the necessary
scrutiny. However, in the 1990s, 2 randomized controlled
trials69,70 failed to demonstrate any benefit from this strategy,
namely the increase of DO2 to supranormal targets. As a
result, this approach is not recommended.
70
Other Drugs: Vasopressin and
Terlipressin
Vasopressin use may be considered in refractory shock,71
but is not recommended as a replacement of norepineph-
rine or dopamine as first-line vasopressor agent.9
To assess the role of vasopressin in septic shock,
Russell et al 72 performed a randomized multicenter
controlled trial in which patients already receiving a
minimum of 5 μg/min of norepinephrine were ran-
domly assigned to receive either low-dose vasopres-
sin (0.01–0.03 U/min) (N = 396) or norepinephrine
(5–15 μg/min) (N = 382) in addition to the open-label
vasopressors. Vasopressor infusions were titrated to
maintain a MAP of 65 to 75 mm Hg. The primary end-
point was the mortality rate at 28 days after the start
of the study infusion. The authors were unable to find
any difference in 28-day mortality between vasopressin
and norepinephrine (35.4% and 39.3%, respectively;
P = 0.26). However, in a prespecified subgroup with
less severe septic shock (norepinephrine 5–14 μg/min),
the mortality rate was significantly lower (26.5% vs
35.7%; P = 0.05).
Vasopressin is not available in several European
countries, such as Portugal. Although terlipressin has
been available since 2008, there are no randomized con-
trolled studies assessing its role in septic shock. We have
been using terlipressin in our ICU since 2008 for patients
with septic shock and refractory hypotension (norepi-
nephrine ⬎ 0.6 μg/kg/min). In septic shock patients
without known splanchnic and coronary ischemia, we
start terlipressin infusion with a 0.25 to 0.5 mg bolus
followed by a continuous perfusion (1–2 mg/d). The
response is assessed in terms of MAP, but the perfusion
status of the extremities should be frequently evaluated
to avoid irreversible ischemia. If digital ischemia ensues,
the dosage should be reduced or even stopped. Using this
approach, we were able to demonstrate a marked reduc-
tion in norepinephrine use and costs between 2007 and
2008, with a slight increase in terlipressin in a similar
cohort of patients.
Summary
Currently, it is not possible to recommend one vasopres-
sor over another to treat septic shock patients. According
to the Surviving Sepsis Campaign guidelines, norepi-
nephrine and dopamine are the first-choice vasopressors
in the treatment of septic shock. However, it is likely that
© Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809
 Septic Shock

Figure 4. Strategy to optimize DO2 in severely septic patients.

Monitoring
Close and continuous monitoring (SaO2/PaO2, MAP, CVP, cardiac rhythm, urine output, level of consciousness, skin
perfusion, frequent evaluation of ScvO2, and blood lactate)

Hemodynamic Approach
If hypotension and/or lactate ⬎ 4 mmol/L,
volume infusion either crystalloids (20 mL/kg) or colloids (10 mL/kg)

Fluid Challenge Strategy

Define infusion fluid: crystalloids (500 mL for a 70-kg adult) or colloids (250 mL for a 70-kg adult)
Define infusion time: 30 min
Define intended MAP: 65–70 mm Hg
Define safety limits: CVP ⬍ 15 mm Hg (and 60 mL/kg crystalloids in the first 6 h)
Evaluate the dynamic response to the treatment measuring blood pressure and CVP every 10 min

Unsuccessful Test: Desired MAP has not been Successful Test: Desired MAP has been achieved
achieved within safety limits ⇒ patient is adequately without overcoming safety limits ⇒ the patient had
resuscitated so additional treatment is indicated, volume depletion and fluid challenge has
starting with vasopressors contributed to treatment

If Hb ⬍ 8 g/dL, transfuse to achieve Hb 8–10 g/dL

Vasopressors: eg, dopamine/norepinephrine (take into consideration arrhythmia and tachycardia)
Signs of low CO (echocardiography), consider inotrope: eg, dobutamine (in a septic shock setting, do not start
dobutamine without a vasopressor because of the risk of worsening hypotension)

If target blood pressure is not attained, consider epinephrine and terlipressin (1–2 mg IV daily perfusion)
If shock persists, consider hydrocortisone (50 mg IV 3 times daily)

Warning: Patients with risk of pulmonary or cerebral edema should have careful monitoring before, during, and after volume resuscitation.
Warning: Excessive vasopressor infusion without appropriate volume resuscitation risks to deteriorate tissue perfusion despite normalized hemodynamic parameters.
Hypotension is defined as a SBP < 90 mm Hg or MAP < 70 mm Hg or a SBP decrease > 40 mm Hg or > 2 SD below normal for age in the absence of other causes of
hypotension.
Abbreviations: CO, cardiac output; CVP, central venous pressure; DO2, oxygen delivery; Hb, hemoglobin; IV, intravenous; MAP, mean arterial pressure; PaO2, arterial
oxygen partial pressure; SaO2, arterial oxygen saturation; SBP, systolic blood pressure; SD, standard deviation; ScvO2, central venous blood oxygen saturation.

in the near future, both epinephrine and even phenyleph- It is more important to know what sort of person this
rine will also be considered first-line agents in the treat- disease has, than what sort of disease this person has.
ment of septic shock. Norepinephrine ± dobutamine or William Osler, 1849–1919.
epinephrine should also be considered in low-cardiac-
output states. Finally, vasopressin or terlipressin may Acknowledgments
be regarded for salvage therapy. We are indebted to all who participated in the Portuguese
Traditionally, the prescription of vasopressors was SACiUCI study.
viewed as a “one-size-fits-all” approach, which has
been shown to be oversimplified. The new paradigm Conflict of Interest Statement
of septic shock should follow a multimodal approach Pedro Póvoa, MD, PhD and António H. Carneiro, MD dis-
in vasopressor selection (Figure 4). close no conflicts of interest.

© Hospital Practice, Volume 38, Issue 1, February 2010, ISSN – 0018-5809 71

Pedro Póvoa and António H. Carneiro
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