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The Sepsis Continuum

Use of Vasopressors in
Sepsis Resuscitation
:Guideline Update 2012
.

SIRS

Sepsis

Severe
Sepsis

Septic
Shock

A clinical response

arising from a
nonspecific insult,
with 2 of the
following:
T >38oC or <36oC
HR >90 beats/min
RR >20/min
WBC >12,000/mm3
or <4,000/mm3 or
>10% bands

Sepsis with Refractory

SIRS with a
organ failure hypotension
presumed
or confirmed
infectious
process
SIRS = systemic inflammatory
response syndrome
Chest 1992;101:1644.

Severe sepsis definition = sepsis-induced

tissue hypoperfusion or organ dysfunction

Septic shock ; a complex interaction

Crit Care Med 2013; 41:580637

-pathologic vasodilation
-relative and absolute hypovolemia
-myocardial dysfunction
-altered blood flow distribution

Rational to treat absolute hypovolemia

resulting from plasma extravasation with
aggressive fluid challenge

Sepsis initiates coagulation by activating endothelium to expression of TF

coagulation cascademicrovascular thrombi & obstruction distal
ischemia & tissue hypoxia

Systemic vasodilationmay be
primarily counteracted by early initiation
of vasopressor support

-clinical consequences of the changes in coagulation caused by sepsis are

levels of markers of DIC & widespread organ dysfunction

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Sepsis-induced cardiac dysfunction

Early aggressive, goal-directed

therapy improves the outcome of
patients who have severe sepsis &
present to ER
Early identification of patients at
high risk for cardiovascular collapse
& Early therapeutic intervention to
restore a balance between oxygen
delivery & demand
Echocardiographic studies suggest that 40% to 50% of patients
with prolonged septic shock develop myocardial depression
Crit Care Med 2007; 35:15991608

N Engl J Med 2001;345:1368-77

N Engl J Med 2001;345:1368-77

N Engl J Med 2001;345:1368-77

Surviving Sepsis Campaign (SSC)

and the Institute for Healthcare
Improvement recommend
implementation of

6-hr resuscitation bundle

N Engl J Med 2001;345:1368-77

29/08/56

SURVIVING SEPSIS CAMPAIGN BUNDLES

Fluid Therapy

Crit Care Med 2013; 41:580637

Fluid challenge technique

Fluid Therapy of Severe Sepsis

Large amounts of fluids
Limited period of time
Close monitoring

PRO
CON
MAY BE
SHOULD BE

Patients response
Avoid pulmonary edema
Crit Care Med 2013; 41:580637

Will cardiac output increase

with fluid loading?
-

blood pressure
SvO2
heart rate
blood lactate
2mmHg

2mmHg

The change in CO. should be in the range of 300 ml/min

Current Opinion in Critical Care 2005, 11:264270

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Vasopressors

The changes in aortic blood flow induced

by PLR are highly predictive of preload
responsiveness in ventilated patients, even
in the presence of spontaneous respiratory
efforts or arrhythmias
Crit Care Med 2006; 34:14021407

Vasopressor therapy initially to

target a mean arterial pressure
(MAP) of 65 mm Hg (grade 1C)
Norepinephrine as the first choice
vasopressor (grade 1B)

Effects of perfusion pressure on tissue

perfusion in septic shock
Crit Care Med 2000;28:27292732

Objective: To examine the effect of titrating

NE to different levels of MAP on systemic and
regional indices of perfusion
Patients: 10 pts. with the diagnosis of septic
shock who required pressor agents to maintain
a MAP 60 mm Hg after fluid resuscitation to
a PAOP 12 mm Hg
Interventions: NE was titrated to MAP of 65, 75,
and 85 mm Hg in 10 patients with septic shock

Surviving Sepsis Campaign: International guidelines for management of severe

sepsis and septic shock: 2012
Crit Care Med 2013; 41:580637

Conclusions: Increasing the MAP

from 65 mm Hg to 85 mm Hg with
NE does not significantly affect
- systemic oxygen metabolism
- skin microcirculatory blood flow
- urine output
- splanchnic perfusion

The aim of vasopressor therapy

is to improve tissue perfusion
pressure while avoiding
excessive vasoconstriction
Crit Care Med 2000;28:27292732

Adequate fluid resuscitation is

a fundamental aspect of
the hemodynamic management
of patients with septic shock

but using vasopressors early as

an emergency measure in patients
with severe shock is frequently
necessary

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Adequate driving pressure & flow

>> sustain organ homeostasis

Norepinephrine Compared With Dopamine

in Severe Sepsis Summary of Evidence

Brain: Reversal of consciousness

Heart: Improvement of BP, PR
no signs of myocardial
ischemia
Kidney: Urine output > 0.5ml/kg/hr
Skin : warm, good skin perfusion

Reversal of lactic acidosis

Does my patient need an increase in CO. ??

Norepinephrine may be more effective at reversing hypotension

Dopamine may be particularly useful in patients with
compromised systolic function
Crit Care Med 2013; 41:580637

Safety about the administration of

low-dose dopamine ?
:Transient decrease in T-cell function

Dopamine was
associated with an
increased risk of death
(RR, 1.12; CI,1.011.20;
p =.035)

:Decreases growth-hormone
secretion negative nitrogen
balance in critical illness
:proarrhythmic effect

In the two trials that reported arrhythmias, these were more

frequent with dopamine than with norepinephrine
(RR, 2.34; CI, 1.46 3.77; p = .001)
Crit Care Med 2012; 40:725730

Crit Care Med 2006; 34:589597

Crit Care Med 2006; 34:589597

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But no clinical study has

definitely indicated that
one catecholamine is
superior to another, so
that at present no agent
should be preferred
over the other

Epinephrine (added to and potentially

substituted for norepinephrine) when
an additional agent is needed to
maintain adequate blood pressure
(grade 2B)

Surviving Sepsis Campaign: International guidelines for management of severe

sepsis and septic shock: 2012
Crit Care Med 2013; 41:580637

to compare the efficacy and safety of

norepinephrine plus dobutamine (whenever
needed) with those of epinephrine alone in
septic shock
prospective,
double-blind
septic shock
participating

multicentre, randomised,
study was done in 330 pts with
admitted to one of 19
ICU in France
Lancet 2007; 370: 67684

Lancet 2007; 370: 67684

Lancet 2007; 370: 67684

There is no evidence for

a difference in efficacy and safety
between epinephrine alone &
norepinephrine plus dobutamine
for the management of septic shock
Should be the first alternative to norepinephrine!
Lancet 2007; 370: 67684

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Prospective, double-blind, randomised

controlled trial
Setting: 4 Australian university-affiliated
multidisciplinary ICUs
280 patients were randomised to receive
either epinephrine or norepinephrine.

Kaplan-Meier estimates for probability of

achievement of MAP goal between epinephrine
and norepinephrine
Epinephrine was associated with the
development of significant but transient
metabolic effects that prompted the withdrawal of
18/139 (12.9%) patients from the study by
attending clinicians

Intensive Care Med (2008) 34:22262234

Vasopressin 0.03 units/minute can be added

to norepinephrine (NE) with intent of either
raising MAP or decreasing NE dosage (UG)
Low dose vasopressin is not recommended as the
single initial vasopressor for treatment of sepsisinduced hypotension and vasopressin doses higher
than 0.03-0.04 units/minute should be reserved for
salvage therapy (failure to achieve adequate MAP
with other vasopressor agents) (UG)

Intensive Care Med (2008) 34:22262234

Vasopressin is a direct vasoconstrictor

without inotropic or chronotropic effects
may result in CO and
hepatosplanchnic flow
most published reports exclude
patients from treatment with vasopressin
if the CI is < 2 or 2.5 L/min/m2, and it
should be used with caution in patients
with cardiac dysfunction

Surviving Sepsis Campaign: International guidelines for management of severe

sepsis and septic shock: 2012
Crit Care Med 2013; 41:580637

relative vasopressin deficiency in septic shock

infusion of low-dose vasopressin

(0.01 0.04 units/min yielding
plasma levels of 20100 pg/mL)

restores plasma levels to values

found during comparable
degrees of hypotension from
other origins (2030 pg/mL)
Crit Care Clin 22 (2006) 187 197

Crit Care Med 2007 Vol. 35, No. 9 (Suppl.)

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RCT trial patients (who had septic shock and

were receiving a minimum of 5 g of NE/min) were
assigned to receive either low-dose vasopressin
(0.01- 0.03 U/min) or NE (5-15 g/min) in addition
to open-label vasopressors
The primary end point was the mortality rate 28 days after
the start of infusions
N Engl J Med 2008;358:877-87

Low-dose vasopressin did not reduce

mortality rates as compared with NE
among patients with septic shock who
were treated with catecholamine
vasopressors
N Engl J Med 2008;358:877-87

< 15 g/min NE

The effects of low-dose vasopressin

as a catecholamine-sparing drug,
not the effects in catecholamineunresponsive refractory shock

N Engl J Med 2008;358:877-87

Continuous infusion of
a relatively low dose of
TP (1.3 g/kg/h) was
effective in reversing
sepsis-induced
hypotension and in
reducing NE
requirements

45 septic shock patients with MAP < 65 mmHg were

randomized to receive continuous infusions of either
terlipressin (1.3 g/kg/h), vasopressin (0.03 U/min) or
norepinephrine (15 g/min; n = 15 per group)

In all groups, open-label norepinephrine was

added to achieve a mean arterial pressure
between 65 and 75 mmHg, if necessary
Critical Care 2009, 13:R130

Dopamine as an alternative vasopressor agent

to norepinephrine only in highly selected
patients (eg, patients with low risk of
tachyarrhythmias and absolute or relative
bradycardia) (grade 2C)

Critical Care 2009, 13:R130

Higher doses of vasopressin have been associated with cardiac,

digital, and splanchnic ischemia and should be reserved for
situations where alternative vasopressors have failed
Crit Care Med 2003; 31:13941398

Surviving Sepsis Campaign: International guidelines for management of severe

sepsis and septic shock: 2012
Crit Care Med 2013; 41:580637

29/08/56

Phenylephrine is not recommended in the treatment

of septic shock except in circumstances where

Low-dose dopaminenot be used for

renal protection(1A)

(a) Norepinephrine is associated with serious

arrhythmias
(b) Cardiac output is known to be high and blood
pressure persistently low
(c) As salvage therapy when combined
inotrope/vasopressor drugs and low dose
vasopressin have failed to achieve MAP target
(grade 1C)

All patients requiring vasopressors

have an arterial catheter placed as
soon as practical if resources are
available(UG)

Surviving Sepsis Campaign: International guidelines for management of severe

sepsis and septic shock: 2012
Crit Care Med 2013; 41:580637

Arterial catheter provides a more accurate

and reproducible measurement of arterial
pressure (also allows beat-to-beat analysis)

Surviving Sepsis Campaign: International guidelines for management of severe

sepsis and septic shock: 2012
Crit Care Med 2013; 41:580637

Inotropic Therapy

Anesthesiology 2005; 103:41928

Dobutamine infusion
administered in the presence
of myocardial dysfunction as
suggested by elevated cardiac
filling pressures and low C.O.

Dobutamine is the first-choice

inotrope for patients with measured or
suspected low CO in the presence of
adequate left ventricular filling
pressure & adequate MAP

If used in the presence of low BP,

it should be combined
with vasopressor therapy

Surviving Sepsis Campaign: International guidelines for management of severe

sepsis and septic shock: 2012
Crit Care Med 2013; 41:580637

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Against the use of a strategy

to increase Cardiac Index to
predetermined supranormal levels

Surviving Sepsis Campaign: International guidelines for management of severe

sepsis and septic shock: 2012
Crit Care Med 2013; 41:580637

P values are for the comparison of mortality rates among the three groups

N Engl J Med 1995;333:1025-32

There are recognized limitations to

ventricular filling pressure estimates
as surrogates for fluid resuscitation
However, measurement of CVP is
currently the most readily obtainable
target for fluid resuscitation

There may be advantages to targeting

fluid resuscitation to flow and perhaps to
volumetric indices (and even to
microcirculation changes)

arterial pulse contour analysis allow stroke volume

variation (SVV) to be tracked continuously

MICROCIRCULATION

TAKE HOME

volunteer

sepsis

10

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RECOMMENDATIONS FOR HEMODYNAMIC

SUPPORT OF SEPTIC PATIENTS

Vasopressors are indicated to

maintain MAP >65 mm Hg, both during
and following adequate fluid
resuscitation
Norepinephrine are the vasopressors
of choice in the treatment of septic
shock
Norepinephrine may be combined with
dobutamine when cardiac output is
being measured

Epinephrine, phenylephrine, &

vasopressin are not recommended as
first-line agents
Vasopressin may be considered for
salvage therapy
Low-dose dopamine is not
recommended for the purpose of renal
protection
Dobutamine is recommended as the
agent of choice to increase cardiac
output

Resuscitation
more earlymore effective
Monitor
in ICU & arterial cannulation
Clinical end points
MAP,HR, urine output, skin
perfusion, mental status, &
indexes of tissue perfusion
( blood lactate conc. & SvO2)

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