Surviving

Sepsis

Campaign

International

guidelines

for

management

of

severe

sepsis

and

septic

shock

Objective

To

provide

an

update

to

the

original

Surviving

Sepsis

Campaign

clinical

management

guidelines

Surviving

Sepsis

Campaign

guidelines

for

management

of

severe

sepsis

and

septic

shock

published

in

Introduction

Severe

sepsis

-LRB-

acute

organ

dysfunction

secondary

to

infection

-RRB-

and

septic

shock

-LRB-

severe

sepsis

plus

hypotension

not

reversed

with

fluid

resuscitation

-RRB-

are

major

healthcare

problems

affecting

millions

of

individuals

around

the

world

each

year

killing

one

in

four

-LRB-

and

often

more

-RRB-

and

increasing

in

incidence

-LSB-

-RSB-

Similar

to

polytrauma

acute

myocardial

infarction

or

stroke

the

speed

and

appropriateness

of

therapy

administered

in

the

initial

hours

after

severe

sepsis

develops

are

likely

to

influence

outcome

In

an

international

group

of

experts

in

the

diagnosis

and

management

of

infection

and

sepsis

representing

organizations

published

the

first

internationally

accepted

guidelines

that

the

bedside

clinician

could

use

to

improve

outcomes

in

severe

sepsis

and

septic

shock

-LSB-

-RSB-

These

guidelines

represented

Phase

II

of

the

Surviving

Sepsis

Campaign

-LRB-

SSC

-RRB-

an

international

effort

to

increase

awareness

and

improve

outcomes

in

severe

sepsis

Joined

by

additional

organizations

the

group

met

again

in

and

to

update

the

guidelines

document

using

a

new

evidence-based

methodology

system

for

assessing

quality

of

evidence

and

strength

of

recommendations

-LSB-

-RSB-

These

recommendations

are

intended

to

provide

guidance

for

the

clinician

caring

for

a

patient

with

severe

sepsis

or

septic

shock

Recommendations

from

these

guidelines

can

not

replace

the

clinician

's

decision-making

capability

when

he

or

she

is

provided

with

a

patient

's

unique

set

of

clinical

variables

Most

of

these

recommendations

are

appropriate

for

the

severe

sepsis

patient

in

both

the

intensive

care

unit

-LRB-

ICU

-RRB-

and

non-ICU

settings

In

fact

the

committee

believes

that

currently

the

greatest

outcome

improvement

can

be

made

through

education

and

process

change

for

those

caring

for

severe

sepsis

patients

in

the

non-ICU

setting

and

across

the

spectrum

of

acute

care

It

should

also

be

noted

that

resource

limitations

in

some

institutions

and

countries

may

prevent

physicians

from

accomplishing

particular

recommendations

Methods

Sepsis

is

defined

as

infection

plus

systemic

manifestations

of

infection

-LRB-

Table

-RRB-

-LSB-

-RSB-

Severe

sepsis

is

defined

as

sepsis

plus

sepsis-induced

organ

dysfunction

or

tissue

hypoperfusion

The

threshold

for

this

dysfunction

has

varied

somewhat

from

one

severe

sepsis

research

study

to

another

An

example

of

typical

thresholds

identification

of

severe

sepsis

is

shown

in

Table

-LSB-

-RSB-

Sepsis

induced

hypotension

is

defined

as

a

systolic

blood

pressure

-LRB-

SBP

-RRB-

of

mm

Hg

or

mean

arterial

pressure

mm

Hg

or

a

SBP

decrease

mm

Hg

or

SD

below

normal

for

age

in

the

absence

of

other

causes

of

hypotension

Septic

shock

is

defined

as

sepsis

induced

hypotension

persisting

despite

adequate

fluid

resuscitation

Sepsis

induced

tissue

hypoperfusion

is

defined

as

either

septic

shock

an

elevated

lactate

or

oliguria

Table

of

the

Quality

of

Evidence

Underlying

methodologyARCTBDowngraded

RCT

or

upgraded

observational

studiesCWell-done

observational

studiesDCase

series

or

expert

opinion

Factors

that

may

decrease

the

strength

of

quality

of

planning

and

implementation

of

available

RCTs

suggesting

high

likelihood

of

of

results

-LRB-

including

problems

with

subgroup

analyses

-RRB-

Indirectness

of

evidence

-LRB-

differing

population

intervention

control

outcomes

comparison

-RRB-

Imprecision

of

likelihood

of

reporting

bias

Main

factors

that

may

increase

the

strength

of

magnitude

of

effect

-LRB-

direct

evidence

relative

risk

-LRB-

RR

-RRB-

with

no

plausible

confounders

-RRB-

Very

large

magnitude

of

effect

with

RR

and

no

threats

to

validity

-LRB-

by

two

levels

-RRB-

Dose

response

gradientRCT

randomized

controlled

trial

RR

relative

riskTable

Determining

Strong

vs.

Weak

RecommendationWhat

should

be

consideredRecommended

ProcessQuality

of

evidenceThe

lower

the

quality

of

evidence

the

less

likely

a

strong

recommendationRelative

importance

of

the

outcomesIf

values

and

preferences

vary

widely

a

strong

recommendation

becomes

less

likelyBaseline

risks

of

outcomesThe

higher

the

risk

the

greater

the

magnitude

of

benefitMagnitude

of

relative

risk

including

benefits

harms

and

burdenLarger

relative

risk

reductions

or

larger

increases

in

relative

risk

of

harm

make

a

strong

recommendation

more

or

less

likely

respectivelyAbsolute

magnitude

of

the

effectThe

larger

the

absolute

benefits

and

harms

the

greater

or

lesser

likelihood

respectively

of

a

strong

recommendationPrecision

of

the

estimates

of

the

effectsThe

greater

the

precision

the

more

likely

is

a

strong

recommendationCostsThe

higher

the

cost

of

treatment

the

less

likely

a

strong

recommendation

The

current

clinical

practice

guidelines

build

on

the

first

and

second

editions

from

-LRB-

see

below

-RRB-

and

-LSB-

-RSB-

The

publication

incorporated

a

MEDLINE

search

for

clinical

trials

in

the

preceding

years

supplemented

by

a

manual

search

of

other

relevant

journals

-LSB-

-RSB-

The

publication

incorporated

the

evidence

available

through

the

end

of

The

current

publication

is

based

on

an

updated

search

into

-LRB-

see

methods

and

rules

below

-RRB-

The

guidelines

were

coordinated

by

the

International

Sepsis

Forum

-LRB-

ISF

-RRB-

the

guidelines

were

funded

by

unrestricted

educational

grants

from

industry

and

administered

through

the

Society

of

Critical

Care

Medicine

-LRB-

SCCM

-RRB-

the

European

Society

of

Intensive

Care

Medicine

-LRB-

ESICM

-RRB-

and

ISF

Two

of

the

SSC

administering

organizations

receive

unrestricted

industry

funding

to

support

SSC

activities

-LRB-

ESICM

and

SCCM

-RRB-

but

of

this

funding

was

used

to

support

the

committee

meetings

It

is

important

to

distinguish

between

the

process

of

guidelines

revision

and

the

Surviving

Sepsis

Campaign

The

Surviving

Sepsis

Campaign

-LRB-

SSC

-RRB-

is

partially

funded

by

unrestricted

educational

industry

grants

including

those

from

Edwards

LifeSciences

Eli

Lilly

and

Company

and

Philips

Medical

Systems

SSC

also

received

funding

from

the

Coalition

for

Critical

Care

Excellence

of

the

Society

of

Critical

Care

Medicine

The

great

majority

of

industry

funding

has

come

from

Eli

Lilly

and

Company

Current

industry

funding

for

the

Surviving

Sepsis

Campaign

is

directed

to

the

performance

improvement

initiative

No

industry

funding

was

used

in

the

guidelines

revision

process

For

both

the

and

the

efforts

there

were

no

members

of

the

committee

from

industry

no

industry

input

into

guidelines

development

and

no

industry

presence

at

any

of

the

meetings

Industry

awareness

or

comment

on

the

recommendations

was

not

allowed

No

member

of

the

guideline

committee

received

any

honoraria

for

any

role

in

the

or

guidelines

process

The

committee

considered

the

issue

of

recusement

of

individual

committee

members

during

deliberation

and

decision

making

in

areas

where

committee

members

had

either

financial

or

academic

competing

interests

however

consensus

as

to

threshold

for

exclusion

could

not

be

reached

Alternatively

the

committee

agreed

to

ensure

full

disclosure

and

transparency

of

all

committee

members

potential

conflicts

at

time

of

publication

-LRB-

see

disclosures

at

the

end

of

this

document

-RRB-

The

guidelines

process

included

a

modified

Delphi

method

a

consensus

conference

several

subsequent

meetings

of

subgroups

and

key

individuals

teleconferences

and

electronically

based

discussions

among

subgroups

and

members

of

the

entire

committee

and

two

follow-up

nominal

group

meetings

in

Subgroups

were

formed

each

charged

with

updating

recommendations

in

specific

areas

including

corticosteroids

blood

products

activated

protein

C

renal

replacement

therapy

antibiotics

source

control

and

glucose

control

etc.

Each

subgroup

was

responsible

for

updating

the

evidence

-LRB-

into

with

major

additional

elements

of

information

incorporated

into

the

evolving

manuscript

throughout

and

-RRB-

A

separate

search

was

performed

for

each

clearly

defined

question

The

committee

chair

worked

with

subgroup

heads

to

identify

pertinent

search

terms

that

always

included

at

a

minimum

sepsis

severe

sepsis

septic

shock

and

sepsis

syndrome

crossed

against

the

general

topic

area

of

the

subgroup

as

well

as

pertinent

key

words

of

the

specific

question

posed

All

questions

of

the

previous

guidelines

publications

were

searched

as

were

pertinent

new

questions

generated

by

general

topic

related

search

or

recent

trials

Quality

of

evidence

was

judged

by

pre-defined

Grades

of

Recommendation

Assessment

Development

and

Evaluation

-LRB-

GRADE

-RRB-

criteria

-LRB-

see

below

-RRB-

Significant

education

of

committee

members

on

the

GRADE

approach

was

performed

via

email

prior

to

the

first

committee

meeting

and

at

the

first

meeting

Rules

were

distributed

concerning

assessing

the

body

of

evidence

and

GRADE

experts

were

available

for

questions

throughout

the

process

Subgroups

agreed

electronically

on

draft

proposals

that

were

presented

to

committee

meetings

for

general

discussion

In

January

the

entire

group

met

during

the

SCCM

Critical

Care

Congress

in

San

Francisco

California

USA

The

results

of

that

discussion

were

incorporated

into

the

next

version

of

recommendations

and

again

discussed

using

electronic

mail

Recommendations

were

finalized

during

nominal

group

meetings

-LRB-

composed

of

a

subset

of

the

committee

members

-RRB-

at

the

SCCM

-LRB-

Orlando

-RRB-

and

International

Symposium

on

Intensive

Care

and

Emergency

Medicine

-LRB-

Brussels

-RRB-

meetings

with

recirculation

of

deliberations

and

decisions

to

the

entire

group

for

comment

or

approval

At

the

discretion

of

the

chair

and

following

adequate

discussion

competing

proposals

for

wording

of

recommendations

or

assigning

strength

of

evidence

were

resolved

by

formal

voting

On

occasions

voting

was

performed

to

give

the

committee

a

sense

of

distribution

of

opinions

to

facilitate

additional

discussion

The

manuscript

was

edited

for

style

and

form

by

the

writing

committee

with

final

approval

by

section

leads

for

their

respective

group

assignment

and

then

by

the

entire

committee

The

development

of

guidelines

and

grading

of

recommendations

for

the

guideline

development

process

were

based

on

a

system

proposed

by

Sackett

in

during

one

of

the

first

American

College

of

Chest

Physicians

-LRB-

ACCP

-RRB-

conferences

on

the

use

of

antithrombotic

therapies

-LSB-

-RSB-

The

revised

guidelines

recommendations

are

based

on

the

Grades

of

Recommendation

Assessment

Development

and

Evaluation

-LRB-

GRADE

-RRB-

system

a

structured

system

for

rating

quality

of

evidence

and

grading

strength

of

recommendation

in

clinical

practice

-LSB-

-RSB-

The

SSC

Steering

Committee

and

individual

authors

collaborated

with

GRADE

representatives

to

apply

the

GRADE

system

to

the

SSC

guidelines

revision

process

The

members

of

GRADE

group

were

directly

involved

either

in

person

or

via

e-mail

in

all

discussions

and

deliberations

amongst

the

guidelines

committee

members

as

to

grading

decisions

Subsequently

the

SSC

authors

used

written

material

prepared

by

the

GRADE

group

and

conferred

with

GRADE

group

members

who

were

available

at

the

first

committee

meeting

and

subsequent

nominal

group

meetings

GRADE

representatives

were

also

used

as

a

resource

throughout

subgroup

deliberation

The

GRADE

system

is

based

on

a

sequential

assessment

of

the

quality

of

evidence

followed

by

assessment

of

the

balance

between

benefits

versus

risks

burden

and

cost

and

based

on

the

above

development

and

grading

of

a

management

recommendations

-LSB-

-RSB-

Keeping

the

rating

of

quality

of

evidence

and

strength

of

recommendation

explicitly

separate

constitutes

a

crucial

and

defining

feature

of

the

GRADE

approach

This

system

classifies

quality

of

evidence

as

high

-LRB-

Grade

A

-RRB-

moderate

-LRB-

Grade

B

-RRB-

low

-LRB-

Grade

C

-RRB-

or

very

low

-LRB-

Grade

D

-RRB-

Randomized

trials

begin

as

high

quality

evidence

but

may

be

downgraded

due

to

limitations

in

implementation

inconsistency

or

imprecision

of

the

results

indirectness

of

the

evidence

and

possible

reporting

bias

-LRB-

see

Table

-RRB-

Examples

of

indirectness

of

the

evidence

include

population

studied

interventions

used

outcomes

measured

and

how

these

relate

to

the

question

of

interest

Observational

-LRB-

non-randomized

-RRB-

studies

begin

as

low-quality

evidence

but

the

quality

level

may

be

upgraded

on

the

basis

of

large

magnitude

of

effect

An

example

of

this

is

the

quality

of

evidence

for

early

administration

of

antibiotics

The

GRADE

system

classifies

recommendations

as

strong

-LRB-

Grade

-RRB-

or

weak

-LRB-

Grade

-RRB-

The

grade

of

strong

or

weak

is

considered

of

greater

clinical

importance

than

a

difference

in

letter

level

of

quality

of

evidence

The

committee

assessed

whether

the

desirable

effects

of

adherence

will

outweigh

the

undesirable

effects

and

the

strength

of

a

recommendation

reflects

the

group

's

degree

of

confidence

in

that

assessment

A

strong

recommendation

in

favor

of

an

intervention

reflects

that

the

desirable

effects

of

adherence

to

a

recommendation

-LRB-

beneficial

health

outcomes

less

burden

on

staff

and

patients

and

cost

savings

-RRB-

will

clearly

outweigh

the

undesirable

effects

-LRB-

harms

more

burden

and

greater

costs

-RRB-

A

weak

recommendation

in

favor

of

an

intervention

indicates

that

the

desirable

effects

of

adherence

to

a

recommendation

probably

will

outweigh

the

undesirable

effects

but

the

panel

is

not

confident

about

these

tradeoffs

either

because

some

of

the

evidence

is

low-quality

-LRB-

and

thus

there

remains

uncertainty

regarding

the

benefits

and

risks

-RRB-

or

the

benefits

and

downsides

are

closely

balanced

While

the

degree

of

confidence

is

a

continuum

and

there

is

a

lack

of

a

precise

threshold

between

a

strong

and

a

weak

recommendation

the

presence

of

important

concerns

about

one

or

more

of

the

above

factors

makes

a

weak

recommendation

more

likely

A

strong

recommendation

is

worded

as

we

recommend

and

a

weak

recommendation

as

we

suggest

The

implications

of

calling

a

recommendation

strong

are

that

most

well-informed

patients

would

accept

that

intervention

and

that

most

clinicians

should

use

it

in

most

situations

There

may

be

circumstances

in

which

a

strong

recommendation

can

not

or

should

not

be

followed

for

an

individual

patient

because

of

that

patient

's

preferences

or

clinical

characteristics

which

make

the

recommendation

less

applicable

It

should

be

noted

that

being

a

strong

recommendation

does

not

automatically

imply

standard

of

care

For

example

the

strong

recommendation

for

administering

antibiotics

within

one

hour

of

the

diagnosis

of

severe

sepsis

although

desirable

is

not

currently

standard

of

care

as

verified

by

current

practice

-LRB-

personal

communication

Mitchell

Levy

from

first

patients

entered

internationally

into

the

SSC

performance

improvement

data

base

-RRB-

The

implication

of

a

weak

recommendation

is

that

although

a

majority

of

well-informed

patients

would

accept

it

-LRB-

but

a

substantial

proportion

would

not

-RRB-

clinicians

should

consider

its

use

according

to

particular

circumstance

Differences

of

opinion

among

committee

members

about

interpretation

of

evidence

wording

of

proposals

or

strength

of

recommendations

were

resolved

using

a

specifically

developed

set

of

rules

We

will

describe

this

process

in

detail

in

a

separate

publication

In

summary

the

main

approach

for

converting

diverse

opinions

into

a

recommendation

was

to

give

a

recommendation

a

direction

-LRB-

for

or

against

the

given

action

-RRB-

a

majority

of

votes

were

to

be

in

favor

of

that

direction

with

no

more

than

preferring

the

opposite

direction

-LRB-

there

was

a

neutral

vote

allowed

as

well

-RRB-

to

call

a

given

recommendation

strong

rather

than

weak

at

least

strong

votes

were

required

if

fewer

than

of

votes

indicated

strong

preference

the

recommendation

was

assigned

a

weak

category

of

strength

We

used

a

combination

of

modified

Delphi

Process

and

Nominal

-LRB-

Expert

-RRB-

Group

techniques

to

ensure

both

depth

and

breadth

of

review

The

entire

review

group

-LRB-

together

with

their

parent

organizations

as

required

-RRB-

participated

in

the

larger

iterative

modified

Delphi

process

The

smaller

working

group

meetings

which

took

place

in

person

functioned

as

the

Nominal

Groups

If

a

clear

consensus

could

not

be

obtained

by

polling

within

the

Nominal

Group

meetings

the

larger

group

was

specifically

asked

to

use

the

polling

process

This

was

only

required

for

corticosteroids

and

glycemic

control

The

larger

group

had

the

opportunity

to

review

all

outputs

In

this

way

the

entire

review

combined

intense

focused

discussion

-LRB-

Nominal

Group

-RRB-

with

broader

review

and

monitoring

using

the

Delphi

process

Note

Refer

to

condensed

adult

recommentations.Table

Resuscitation

and

Infection

IssuesInitial

resuscitation

-LRB-

first

hours

-RRB-

Strength

of

recommendation

and

quality

of

evidence

have

been

assessed

using

the

GRADE

criteria

presented

in

brackets

after

each

guideline

For

added

clarity

Indicates

a

strong

recommendation

or

we

recommend

indicates

a

weak

recommendation

or

we

suggest

Begin

resuscitation

immediately

in

patients

with

hypotension

or

elevated

serum

lactate

do

not

delay

pending

ICU

admission

-LRB-

-RRB-

Resuscitation

goals

-LRB-

-RRB-

Central

venous

pressure

-LRB-

CVP

-RRB-

mm

Hg

Mean

arterial

pressure

mm

Hg

Urine

output

Central

venous

-LRB-

superior

vena

cava

-RRB-

oxygen

saturation

or

mixed

venous

If

venous

saturation

target

not

achieved

-LRB-

-RRB-

consider

further

fluid

transfuse

packed

red

blood

cells

if

required

to

hematocrit

of

and/or

dobutamine

infusion

max

A

higher

target

CVP

of

mm

Hg

is

recommended

in

the

presence

of

mechanical

ventilation

or

pre-existing

decreased

ventricular

compliance.Diagnosis

Obtain

appropriate

cultures

before

starting

antibiotics

provided

this

does

not

significantly

delay

antimicrobial

administration

-LRB-

-RRB-

Obtain

two

or

more

blood

cultures

-LRB-

BCs

-RRB-

One

or

more

BCs

should

be

percutaneous

One

BC

from

each

vascular

access

device

in

place

h

Culture

other

sites

as

clinically

indicated

Perform

imaging

studies

promptly

in

order

to

confirm

and

sample

any

source

of

infection

if

safe

to

do

so

-LRB-

-RRB-

Antibiotic

therapy

Begin

intravenous

antibiotics

as

early

as

possible

and

always

within

the

first

hour

of

recognizing

severe

sepsis

-LRB-

-RRB-

and

septic

shock

-LRB-

-RRB-

Broad-spectrum

one

or

more

agents

active

against

likely

bacterial/fungal

pathogens

and

with

good

penetration

into

presumed

source

-LRB-

-RRB-

Reassess

antimicrobial

regimen

daily

to

optimise

efficacy

prevent

resistance

avoid

toxicity

minimise

costs

-LRB-

-RRB-

Consider

combination

therapy

in

Pseudomonas

infections

-LRB-

-RRB-

Consider

combination

empiric

therapy

in

neutropenic

patients

-LRB-

-RRB-

Combination

therapy

no

more

than

days

and

deescalation

following

susceptibilities

-LRB-

-RRB-

Duration

of

therapy

typically

limited

to

days

longer

if

response

slow

undrainable

foci

of

infection

or

immunologic

deficiencies

-LRB-

-RRB-

Stop

antimicrobial

therapy

if

cause

is

found

to

be

non-infectious

-LRB-

-RRB-

Source

identification

and

control

A

specific

anatomic

site

of

infection

should

be

established

as

rapidly

as

possible

-LRB-

-RRB-

and

within

first

hrs

of

presentation

-LRB-

-RRB-

Formally

evaluate

patient

for

a

focus

of

infection

amenable

to

source

control

measures

-LRB-

eg

abscess

drainage

tissue

debridement

-RRB-

-LRB-

-RRB-

Implement

source

control

measures

as

soon

as

possible

following

successful

initial

resuscitation

-LRB-

-RRB-

Exception

infected

pancreatic

necrosis

where

surgical

intervention

best

delayed

-LRB-

-RRB-

Choose

source

control

measure

with

maximum

efficacy

and

minimal

physiologic

upset

-LRB-

-RRB-

Remove

intravascular

access

devices

if

potentially

infected

-LRB-

-RRB-

Table

Support

and

Adjunctive

TherapyFluid

therapyStrength

of

recommendation

and

quality

of

evidence

have

been

assessed

using

the

GRADE

criteria

presented

in

brackets

after

each

guideline

For

added

clarity

Indicates

a

strong

recommendation

or

we

recommend

indicates

a

weak

recommendation

or

we

suggest

Fluid-resuscitate

using

crystalloids

or

colloids

-LRB-

-RRB-

Target

a

CVP

of

mm

Hg

-LRB-

mm

Hg

if

mechanically

ventilated

-RRB-

-LRB-

-RRB-

Use

a

fluid

challenge

technique

while

associated

with

a

haemodynamic

improvement

-LRB-

-RRB-

Give

fluid

challenges

of

ml

of

crystalloids

or

ml

of

colloids

over

min

More

rapid

and

larger

volumes

may

be

required

in

sepsis-induced

tissue

hypoperfusion

-LRB-

-RRB-

Rate

of

fluid

administration

should

be

reduced

if

cardiac

filling

pressures

increase

without

concurrent

hemodynamic

improvement

-LRB-

-RRB-

Vasopressors

Maintain

MAP

mm

Hg

-LRB-

-RRB-

Norepinephrine

or

dopamine

centrally

administered

are

the

initial

vasopressors

of

choice

-LRB-

-RRB-

Epinephrine

phenylephrine

or

vasopressin

should

not

be

administered

as

the

initial

vasopressor

in

septic

shock

-LRB-

-RRB-

Vasopressin

units/min

maybe

subsequently

added

to

norepinephrine

with

anticipation

of

an

effect

equivalent

to

norepinephrine

alone

Use

epinephrine

as

the

first

alternative

agent

in

septic

shock

when

blood

pressure

is

poorly

responsive

to

norepinephrine

or

dopamine

-LRB-

-RRB-

Do

not

use

low-dose

dopamine

for

renal

protection

-LRB-

-RRB-

In

patients

requiring

vasopressors

insert

an

arterial

catheter

as

soon

as

practical

-LRB-

-RRB-

Inotropic

therapy

Use

dobutamine

in

patients

with

myocardial

dysfunction

as

supported

by

elevated

cardiac

filling

pressures

and

low

cardiac

output

-LRB-

-RRB-

Do

not

increase

cardiac

index

to

predetermined

supranormal

levels

-LRB-

-RRB-

Steroids

Consider

intravenous

hydrocortisone

for

adult

septic

shock

when

hypotension

remains

poorly

responsive

to

adequate

fluid

resuscitation

and

vasopressors

-LRB-

-RRB-

ACTH

stimulation

test

is

not

recommended

to

identify

the

subset

of

adults

with

septic

shock

who

should

receive

hydrocortisone

-LRB-

-RRB-

Hydrocortisone

is

preferred

to

dexamethasone

-LRB-

-RRB-

Fludrocortisone

-LRB-

μg

orally

once

a

day

-RRB-

may

be

included

if

an

alternative

to

hydrocortisone

is

being

used

which

lacks

significant

mineralocorticoid

activity

Fludrocortisone

is

optional

if

hydrocortisone

is

used

-LRB-

-RRB-

Steroid

therapy

may

be

weaned

once

vasopressors

are

no

longer

required

-LRB-

-RRB-

Hydrocortisone

dose

should

be

mg/day

-LRB-

-RRB-

Do

not

use

corticosteroids

to

treat

sepsis

in

the

absence

of

shock

unless

the

patient

's

endocrine

or

corticosteroid

history

warrants

it

-LRB-

-RRB-

Recombinant

human

activated

protein

C

-LRB-

rhAPC

-RRB-

Consider

rhAPC

in

adult

patients

with

sepsis-induced

organ

dysfunction

with

clinical

assessment

of

high

risk

of

death

-LRB-

typically

APACHE

II

or

multiple

organ

failure

-RRB-

if

there

are

no

contraindications

-LRB-

-RRB-

Adult

patients

with

severe

sepsis

and

low

risk

of

death

-LRB-

eg

APACHE

II

or

one

organ

failure

-RRB-

should

not

receive

rhAPC

-LRB-

-RRB-

Table

Supportive

Therapy

of

Severe

SepsisBlood

product

administrationStrength

of

recommendation

and

quality

of

evidence

have

been

assessed

using

the

GRADE

criteria

presented

in

brackets

after

each

guideline

For

added

clarity

Indicates

a

strong

recommendation

or

we

recommend

indicates

a

weak

recommendation

or

we

suggest

Give

red

blood

cells

when

hemoglobin

decreases

to

g/dl

-LRB-

g/L

-RRB-

to

target

a

hemoglobin

of

g/dl

in

adults

-LRB-

-RRB-

A

higher

hemoglobin

level

may

be

required

in

special

circumstances

-LRB-

e.

g.

myocardial

ischaemia

severe

hypoxemia

acute

haemorrhage

cyanotic

heart

disease

or

lactic

acidosis

-RRB-

Do

not

use

erythropoietin

to

treat

sepsis-related

anemia

Erythropoietin

may

be

used

for

other

accepted

reasons

-LRB-

-RRB-

Do

not

use

fresh

frozen

plasma

to

correct

laboratory

clotting

abnormalities

unless

there

is

bleeding

or

planned

invasive

procedures

-LRB-

-RRB-

Do

not

use

antithrombin

therapy

-LRB-

-RRB-

Administer

platelets

when

-LRB-

-RRB-

counts

are

-LRB-

-RRB-

regardless

of

bleeding

counts

are

to

-LRB-

-RRB-

and

there

is

significant

bleeding

risk

Higher

platelet

counts

-LRB-

-LRB-

-RRB-

-RRB-

are

required

for

surgery

or

invasive

procedures.Mechanical

ventilation

of

sepsis-induced

acute

lung

injury

-LRB-

ALI

-RRB-

ARDS

Target

a

tidal

volume

of

ml/kg

-LRB-

predicted

-RRB-

body

weight

in

patients

with

ALI/ARDS

-LRB-

-RRB-

Target

an

initial

upper

limit

plateau

pressure

cm

Consider

chest

wall

compliance

when

assessing

plateau

pressure

-LRB-

-RRB-

Allow

to

increase

above

normal

if

needed

to

minimize

plateau

pressures

and

tidal

volumes

-LRB-

-RRB-

Positive

end

expiratory

pressure

-LRB-

PEEP

-RRB-

should

be

set

to

avoid

extensive

lung

collapse

at

end

expiration

-LRB-

-RRB-

Consider

using

the

prone

position

for

ARDS

patients

requiring

potentially

injurious

levels

of

or

plateau

pressure

provided

they

are

not

put

at

risk

from

positional

changes

-LRB-

-RRB-

Maintain

mechanically

ventilated

patients

in

a

semi-recumbent

position

-LRB-

head

of

the

bed

raised

to

-RRB-

unless

contraindicated

-LRB-

-RRB-

between

-LRB-

-RRB-

Non

invasive

ventilation

may

be

considered

in

the

minority

of

ALI/ARDS

patients

with

mild-moderate

hypoxemic

respiratory

failure

The

patients

need

to

be

hemodynamically

stable

comfortable

easily

arousable

able

to

protect/clear

their

airway

and

expected

to

recover

rapidly

-LRB-

-RRB-

Use

a

weaning

protocol

and

a

spontaneous

breathing

trial

-LRB-

SBT

-RRB-

regularly

to

evaluate

the

potential

for

discontinuing

mechanical

ventilation

-LRB-

-RRB-

SBT

options

include

a

low

level

of

pressure

support

with

continuous

positive

airway

pressure

cm

or

a

T-piece

Before

the

SBT

patients

should

be

arousable

be

haemodynamically

stable

without

vasopressors

have

no

new

potentially

serious

conditions

have

low

ventilatory

and

end-expiratory

pressure

requirement

require

levels

that

can

be

safely

delivered

with

a

face

mask

or

nasal

cannula

Do

not

use

a

pulmonary

artery

catheter

for

the

routine

monitoring

of

patients

with

ALI/ARDS

-LRB-

-RRB-

Use

a

conservative

fluid

strategy

for

patients

with

established

ALI

who

do

not

have

evidence

of

tissue

hypoperfusion

-LRB-

-RRB-

Sedation

analgesia

and

neuromuscular

blockade

in

sepsis

Use

sedation

protocols

with

a

sedation

goal

for

critically

ill

mechanically

ventilated

patients

-LRB-

-RRB-

Use

either

intermittent

bolus

sedation

or

continuous

infusion

sedation

to

predetermined

end

points

-LRB-

sedation

scales

-RRB-

with

daily

interruption/lightening

to

produce

awakening

Re-titrate

if

necessary

-LRB-

-RRB-

Avoid

neuromuscular

blockers

-LRB-

NMBs

-RRB-

where

possible

Monitor

depth

of

block

with

train

of

four

when

using

continuous

infusions

-LRB-

-RRB-

Glucose

control

Use

IV

insulin

to

control

hyperglycemia

in

patients

with

severe

sepsis

following

stabilization

in

the

ICU

-LRB-

-RRB-

Aim

to

keep

blood

glucose

mg/dl

-LRB-

mmol/L

-RRB-

using

a

validated

protocol

for

insulin

dose

adjustment

-LRB-

-RRB-

Provide

a

glucose

calorie

source

and

monitor

blood

glucose

values

every

hrs

-LRB-

hrs

when

stable

-RRB-

in

patients

receiving

intravenous

insulin

-LRB-

-RRB-

Interpret

with

caution

low

glucose

levels

obtained

with

point

of

care

testing

as

these

techniques

may

overestimate

arterial

blood

or

plasma

glucose

values

-LRB-

-RRB-

Renal

replacement

Intermittent

hemodialysis

and

continuous

veno-venous

haemofiltration

-LRB-

CVVH

-RRB-

are

considered

equivalent

-LRB-

-RRB-

CVVH

offers

easier

management

in

hemodynamically

unstable

patients

-LRB-

-RRB-

Bicarbonate

therapy

Do

not

use

bicarbonate

therapy

for

the

purpose

of

improving

hemodynamics

or

reducing

vasopressor

requirements

when

treating

hypoperfusion-induced

lactic

acidemia

with

pH

-LRB-

-RRB-

Deep

vein

thrombosis

-LRB-

DVT

-RRB-

prophylaxis

Use

either

low-dose

unfractionated

heparin

-LRB-

UFH

-RRB-

or

low-molecular

weight

heparin

-LRB-

LMWH

-RRB-

unless

contraindicated

-LRB-

-RRB-

Use

a

mechanical

prophylactic

device

such

as

compression

stockings

or

an

intermittent

compression

device

when

heparin

is

contraindicated

-LRB-

-RRB-

Use

a

combination

of

pharmacologic

and

mechanical

therapy

for

patients

who

are

at

very

high

risk

for

DVT

-LRB-

-RRB-

In

patients

at

very

high

risk

LMWH

should

be

used

rather

than

UFH

-LRB-

-RRB-

Stress

ulcer

prophylaxis

Provide

stress

ulcer

prophylaxis

using

blocker

-LRB-

-RRB-

or

proton

pump

inhibitor

-LRB-

-RRB-

Benefits

of

prevention

of

upper

GI

bleed

must

be

weighed

against

the

potential

for

development

of

ventilator-associated

pneumonia.Consideration

for

limitation

of

support

Discuss

advance

care

planning

with

patients

and

families

Describe

likely

outcomes

and

set

realistic

expectations

-LRB-

-RRB-

I.

Management

of

Severe

Sepsis

A.

Initial

Resuscitation

We

recommend

the

protocolized

resuscitation

of

a

patient

with

sepsis-induced

shock

defined

as

tissue

hypoperfusion

-LRB-

hypotension

persisting

after

initial

fluid

challenge

or

blood

lactate

concentration

equal

to

or

greater

than

mmol/L

-RRB-

This

protocol

should

be

initiated

as

soon

as

hypoperfusion

is

recognized

and

should

not

be

delayed

pending

ICU

admission

During

the

first

hrs

of

resuscitation

the

goals

of

initial

resuscitation

of

sepsis-induced

hypoperfusion

should

include

all

of

the

following

as

one

part

of

a

treatment

protocol

Central

venous

pressure

-LRB-

CVP

-RRB-

mm

HgMean

arterial

pressure

-LRB-

MAP

-RRB-

mm

HgUrine

output

mL.kg

hr

venous

-LRB-

superior

vena

cava

-RRB-

or

mixed

venous

oxygen

saturation

or

respectively

-LRB-

Grade

-RRB-

Rationale

Early

goal-directed

resuscitation

has

been

shown

to

improve

survival

for

emergency

department

patients

presenting

with

septic

shock

in

a

randomized

controlled

single-center

study

-LSB-

-RSB-

Resuscitation

directed

toward

the

previously

mentioned

goals

for

the

initial

period

of

the

resuscitation

was

able

to

reduce

mortality

rate

The

consensus

panel

judged

use

of

central

venous

and

mixed

venous

oxygen

saturation

targets

to

be

equivalent

Either

intermittent

or

continuous

measurements

of

oxygen

saturation

were

judged

to

be

acceptable

Although

blood

lactate

concentration

may

lack

precision

as

a

measure

of

tissue

metabolic

status

elevated

levels

in

sepsis

support

aggressive

resuscitation

In

mechanically

ventilated

patients

or

patients

with

known

pre-existing

decreased

ventricular

compliance

a

higher

target

CVP

of

mm

Hg

is

recommended

to

account

for

the

impediment

to

filling

-LSB-

-RSB-

Similar

consideration

may

be

warranted

in

circumstances

of

increased

abdominal

pressure

or

diastolic

dysfunction

-LSB-

-RSB-

Elevated

central

venous

pressures

may

also

be

seen

with

pre-existing

clinically

significant

pulmonary

artery

hypertension

Although

the

cause

of

tachycardia

in

septic

patients

may

be

multifactorial

a

decrease

in

elevated

pulse

rate

with

fluid

resuscitation

is

often

a

useful

marker

of

improving

intravascular

filling

Recently

published

observational

studies

have

demonstrated

an

association

between

good

clinical

outcome

in

septic

shock

and

MAP

mm

Hg

as

well

as

central

venous

oxygen

saturation

-LRB-

measured

in

superior

vena

cava

either

intermittently

or

continuously

-RRB-

of

-LSB-

-RSB-

Many

recent

studies

support

the

value

of

early

protocolized

resuscitation

in

severe

sepsis

and

sepsis-induced

tissue

hypoperfusion

-LSB-

-RSB-

Studies

of

patients

with

shock

indicate

that

runs

lower

than

central

venous

oxygen

saturation

-LRB-

-RRB-

-LSB-

-RSB-

and

that

an

early

goal

directed

resuscitation

protocol

can

be

established

in

a

non-research

general

practice

venue

-LSB-

-RSB-

There

are

recognized

limitations

to

ventricular

filling

pressure

estimates

as

surrogates

for

fluid

resuscitation

-LSB-

-RSB-

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

-LRB-

and

even

to

microcirculation

changes

-RRB-

-LSB-

-RSB-

Technologies

currently

exist

that

allow

measurement

of

flow

at

the

bedside

-LSB-

-RSB-

Future

goals

should

be

making

these

technologies

more

accessible

during

the

critical

early

resuscitation

period

and

research

to

validate

utility

These

technologies

are

already

available

for

early

ICU

resuscitation

We

suggest

that

during

the

first

hrs

of

resuscitation

of

severe

sepsis

or

septic

shock

if

or

of

or

respectively

is

not

achieved

with

fluid

resuscitation

to

the

CVP

target

then

transfusion

of

packed

red

blood

cells

to

achieve

a

hematocrit

of

and/or

administration

of

a

dobutamine

infusion

-LRB-

up

to

a

maximum

of

μg.kg

min

-RRB-

be

utilized

to

achieve

this

goal

-LRB-

Grade

-RRB-

Rationale

The

protocol

used

in

the

study

cited

previously

targeted

an

increase

in

to

-LSB-

-RSB-

This

was

achieved

by

sequential

institution

of

initial

fluid

resuscitation

then

packed

red

blood

cells

and

then

dobutamine

This

protocol

was

associated

with

an

improvement

in

survival

Based

on

bedside

clinical

assessment

and

personal

preference

a

clinician

may

deem

either

blood

transfusion

-LRB-

if

Hct

is

less

than

-RRB-

or

dobutamine

the

best

initial

choice

to

increase

oxygen

delivery

and

thereby

elevate

When

fluid

resuscitation

is

believed

to

be

already

adequate

The

design

of

the

afore

mentioned

trial

did

not

allow

assessment

of

the

relative

contribution

of

these

two

components

-LRB-

i.

e.

increasing

content

or

increasing

cardiac

output

-RRB-

of

the

protocol

on

achievement

of

improved

outcome

B.

Diagnosis

We

recommend

obtaining

appropriate

cultures

before

antimicrobial

therapy

is

initiated

if

such

cultures

do

not

cause

significant

delay

in

antibiotic

administration

To

optimize

identification

of

causative

organisms

we

recommend

at

least

two

blood

cultures

be

obtained

prior

to

antibiotics

with

at

least

one

drawn

percutaneously

and

one

drawn

through

each

vascular

access

device

unless

the

device

was

recently

-LRB-

h

-RRB-

inserted

Cultures

of

other

sites

-LRB-

preferably

quantitative

where

appropriate

-RRB-

such

as

urine

cerebrospinal

fluid

wounds

respiratory

secretions

or

other

body

fluids

that

may

be

the

source

of

infection

should

also

be

obtained

before

antibiotic

therapy

if

not

associated

with

significant

delay

in

antibiotic

administration

-LRB-

Grade

-RRB-

Rationale

Although

sampling

should

not

delay

timely

administration

of

antibiotics

in

patients

with

severe

sepsis

-LRB-

example

lumbar

puncture

in

suspected

meningitis

-RRB-

obtaining

appropriate

cultures

prior

to

their

administration

is

essential

to

confirm

infection

and

the

responsible

pathogen

-LRB-

s

-RRB-

and

to

allow

de-escalation

of

antibiotic

therapy

after

receipt

of

the

susceptibility

profile

Samples

can

be

kept

in

the

refrigerator

or

frozen

if

processing

can

not

be

performed

immediately

Immediate

transport

to

a

microbiological

lab

is

necessary

Because

rapid

sterilization

of

blood

cultures

can

occur

within

a

few

hours

after

the

first

antibiotic

dose

obtaining

those

cultures

before

starting

therapy

is

essential

if

the

causative

organism

is

to

be

identified

Two

or

more

blood

cultures

are

recommended

-LSB-

-RSB-

In

patients

with

indwelling

catheters

-LRB-

for

h

-RRB-

at

least

one

blood

culture

should

be

drawn

through

each

lumen

of

each

vascular

access

device

Obtaining

blood

cultures

peripherally

and

through

a

vascular

access

device

is

an

important

strategy

If

the

same

organism

is

recovered

from

both

cultures

the

likelihood

that

the

organism

is

causing

the

severe

sepsis

is

enhanced

In

addition

if

the

culture

drawn

through

the

vascular

access

device

is

positive

much

earlier

than

the

peripheral

blood

culture

-LRB-

i.

e.

hrs

earlier

-RRB-

the

data

support

the

concept

that

the

vascular

access

device

is

the

source

of

the

infection

-LSB-

-RSB-

Quantitative

cultures

of

catheter

and

peripheral

blood

are

also

useful

for

determining

whether

the

catheter

is

the

source

of

infection

Volume

of

blood

drawn

with

the

culture

tube

should

be

at

least

mL

-LSB-

-RSB-

Quantitative

-LRB-

or

semi-quantitative

-RRB-

cultures

of

respiratory

tract

secretions

are

recommended

for

the

diagnosis

of

ventilator-associated

pneumonia

-LSB-

-RSB-

Gram

stain

can

be

useful

in

particular

for

respiratory

tract

specimens

to

help

decide

the

micro-organisms

to

be

targeted

The

potential

role

of

biomarkers

for

diagnosis

of

infection

in

patients

presenting

with

severe

sepsis

remains

at

present

undefined

The

procalcitonin

level

although

often

useful

is

problematic

in

patients

with

an

acute

inflammatory

pattern

from

other

causes

-LRB-

e.

g.

post-operative

shock

-RRB-

-LSB-

-RSB-

In

the

near

future

rapid

diagnostic

methods

-LRB-

polymerase

chain

reaction

micro-arrays

-RRB-

might

prove

extremely

helpful

for

a

quicker

identification

of

pathogens

and

major

antimicrobial

resistance

determinants

-LSB-

-RSB-

We

recommend

that

imaging

studies

be

performed

promptly

in

attempts

to

confirm

a

potential

source

of

infection

Sampling

of

potential

sources

of

infection

should

occur

as

they

are

identified

however

some

patients

may

be

too

unstable

to

warrant

certain

invasive

procedures

or

transport

outside

of

the

ICU

Bedside

studies

such

as

ultrasound

are

useful

in

these

circumstances

-LRB-

Grade

-RRB-

Rationale

Diagnostic

studies

may

identify

a

source

of

infection

that

requires

removal

of

a

foreign

body

or

drainage

to

maximize

the

likelihood

of

a

satisfactory

response

to

therapy

However

even

in

the

most

organized

and

well-staffed

healthcare

facilities

transport

of

patients

can

be

dangerous

as

can

placing

patients

in

outside-unit

imaging

devices

that

are

difficult

to

access

and

monitor

Balancing

risk

and

benefit

is

therefore

mandatory

in

those

settings

C.

Antibiotic

Therapy

We

recommend

that

intravenous

antibiotic

therapy

be

started

as

early

as

possible

and

within

the

first

hour

of

recognition

of

septic

shock

-LRB-

-RRB-

and

severe

sepsis

without

septic

shock

-LRB-

-RRB-

Appropriate

cultures

should

be

obtained

before

initiating

antibiotic

therapy

but

should

not

prevent

prompt

administration

of

antimicrobial

therapy

-LRB-

Grade

-RRB-

Rationale

Establishing

vascular

access

and

initiating

aggressive

fluid

resuscitation

is

the

first

priority

when

managing

patients

with

severe

sepsis

or

septic

shock

However

prompt

infusion

of

antimicrobial

agents

should

also

be

a

priority

and

may

require

additional

vascular

access

ports

-LSB-

-RSB-

In

the

presence

of

septic

shock

each

hour

delay

in

achieving

administration

of

effective

antibiotics

is

associated

with

a

measurable

increase

in

mortality

-LSB-

-RSB-

If

antimicrobial

agents

can

not

be

mixed

and

delivered

promptly

from

the

pharmacy

establishing

a

supply

of

premixed

antibiotics

for

such

urgent

situations

is

an

appropriate

strategy

for

ensuring

prompt

administration

In

choosing

the

antimicrobial

regimen

clinicians

should

be

aware

that

some

antimicrobial

agents

have

the

advantage

of

bolus

administration

while

others

require

a

lengthy

infusion

Thus

if

vascular

access

is

limited

and

many

different

agents

must

be

infused

bolus

drugs

may

offer

an

advantage

We

recommend

that

initial

empirical

anti-infective

therapy

include

one

or

more

drugs

that

have

activity

against

all

likely

pathogens

-LRB-

bacterial

and/or

fungal

-RRB-

and

that

penetrate

in

adequate

concentrations

into

the

presumed

source

of

sepsis

-LRB-

Grade

-RRB-

Rationale

The

choice

of

empirical

antibiotics

depends

on

complex

issues

related

to

the

patient

's

history

including

drug

intolerances

underlying

disease

the

clinical

syndrome

and

susceptibility

patterns

of

pathogens

in

the

community

in

the

hospital

and

that

previously

have

been

documented

to

colonize

or

infect

the

patient

There

is

an

especially

wide

range

of

potential

pathogens

for

neutropenic

patients

Recently

used

antibiotics

should

generally

be

avoided

Clinicians

should

be

cognizant

of

the

virulence

and

growing

prevalence

of

oxacillin

-LRB-

methicillin

-RRB-

resistant

Staphylococcus

aureus

-LRB-

ORSA

or

MRSA

-RRB-

in

some

communities

and

healthcare

associated

settings

-LRB-

especially

in

the

United

States

-RRB-

when

they

choose

empiric

therapy

If

the

prevalence

is

significant

and

in

consideration

of

the

virulence

of

this

organism

empiric

therapy

adequate

for

this

pathogen

would

be

warranted

Clinicians

should

also

consider

whether

Candidemia

is

a

likely

pathogen

when

choosing

initial

therapy

When

deemed

warranted

the

selection

of

empiric

antifungal

therapy

-LRB-

e.

g.

fluconazole

amphotericin

B

or

echinocandin

-RRB-

will

be

tailored

to

the

local

pattern

of

the

most

prevalent

Candida

species

and

any

prior

administration

of

azoles

drugs

-LSB-

-RSB-

Risk

factors

for

candidemia

should

also

be

considered

when

choosing

initial

therapy

Because

patients

with

severe

sepsis

or

septic

shock

have

little

margin

for

error

in

the

choice

of

therapy

the

initial

selection

of

antimicrobial

therapy

should

be

broad

enough

to

cover

all

likely

pathogens

There

is

ample

evidence

that

failure

to

initiate

appropriate

therapy

-LRB-

i.

e.

therapy

with

activity

against

the

pathogen

that

is

subsequently

identified

as

the

causative

agent

-RRB-

correlates

with

increased

morbidity

and

mortality

-LSB-

-RSB-

Patients

with

severe

sepsis

or

septic

shock

warrant

broad-spectrum

therapy

until

the

causative

organism

and

its

antibiotic

susceptibilities

are

defined

Restriction

of

antibiotics

as

a

strategy

to

reduce

the

development

of

antimicrobial

resistance

or

to

reduce

cost

is

not

an

appropriate

initial

strategy

in

this

patient

population

All

patients

should

receive

a

full

loading

dose

of

each

antimicrobial

However

patients

with

sepsis

or

septic

shock

often

have

abnormal

renal

or

hepatic

function

and

may

have

abnormal

volumes

of

distribution

due

to

aggressive

fluid

resuscitation

Drug

serum

concentration

monitoring

can

be

useful

in

an

ICU

setting

for

those

drugs

that

can

be

measured

promptly

An

experienced

physician

or

clinical

pharmacist

should

be

consulted

to

ensure

that

serum

concentrations

are

attained

that

maximize

efficacy

and

minimize

toxicity

-LSB-

-RSB-

We

recommend

that

the

antimicrobial

regimen

be

reassessed

daily

to

optimize

activity

to

prevent

the

development

of

resistance

to

reduce

toxicity

and

to

reduce

costs

-LRB-

Grade

-RRB-

Rationale

Although

restriction

of

antibiotics

as

a

strategy

to

reduce

the

development

of

antimicrobial

resistance

or

to

reduce

cost

is

not

an

appropriate

initial

strategy

in

this

patient

population

once

the

causative

pathogen

has

been

identified

it

may

become

apparent

that

of

the

empiric

drugs

offers

optimal

therapy

i.

e.

there

may

be

another

drug

proven

to

produce

superior

clinical

outcome

which

should

therefore

replace

empiric

agents

Narrowing

the

spectrum

of

antibiotic

coverage

and

reducing

the

duration

of

antibiotic

therapy

will

reduce

the

likelihood

that

the

patient

will

develop

superinfection

with

pathogenic

or

resistant

organisms

such

as

Candida

species

Clostridium

difficile

or

vancomycin-resistant

Enterococcus

faecium

However

the

desire

to

minimize

superinfections

and

other

complications

should

not

take

precedence

over

the

need

to

give

the

patient

an

adequate

course

of

therapy

to

cure

the

infection

that

caused

the

severe

sepsis

or

septic

shock

We

suggest

combination

therapy

for

patients

with

known

or

suspected

Pseudomonas

infections

as

a

cause

of

severe

sepsis

-LRB-

Grade

-RRB-

We

suggest

combination

empiric

therapy

for

neutropenic

patients

with

severe

sepsis

-LRB-

Grade

-RRB-

When

used

empirically

in

patients

with

severe

sepsis

we

suggest

that

combination

therapy

should

not

be

administered

for

more

than

to

days

De-escalation

to

the

most

appropriate

single

therapy

should

be

performed

as

soon

as

the

susceptibility

profile

is

known

-LRB-

Grade

-RRB-

Rationale

Although

no

study

or

meta-analysis

has

convincingly

demonstrated

that

combination

therapy

produces

a

superior

clinical

outcome

for

individual

pathogens

in

a

particular

patient

group

combination

therapies

do

produce

in

vitro

synergy

against

pathogens

in

some

models

-LRB-

although

such

synergy

is

difficult

to

define

and

predict

-RRB-

In

some

clinical

scenarios

such

as

the

two

above

combination

therapies

are

biologically

plausible

and

are

likely

clinically

useful

even

if

evidence

has

not

demonstrated

improved

clinical

outcome

-LSB-

-RSB-

Combination

therapy

for

suspected

known

Pseudomonas

pending

sensitivities

increases

the

likelihood

that

at

least

one

drug

is

effective

against

that

strain

and

positively

affects

outcome

-LSB-

-RSB-

We

recommend

that

the

duration

of

therapy

typically

be

days

longer

courses

may

be

appropriate

in

patients

who

have

a

slow

clinical

response

undrainable

foci

of

infection

or

who

have

immunologic

deficiencies

including

neutropenia

-LRB-

Grade

-RRB-

If

the

presenting

clinical

syndrome

is

determined

to

be

due

to

a

noninfectious

cause

we

recommend

antimicrobial

therapy

be

stopped

promptly

to

minimize

the

likelihood

that

the

patient

will

become

infected

with

an

antibiotic

resistant

pathogen

or

will

develop

a

drug

related

adverse

effect

-LRB-

Grade

-RRB-

Rationale

Clinicians

should

be

cognizant

that

blood

cultures

will

be

negative

in

more

than

of

cases

of

severe

sepsis

or

septic

shock

yet

many

of

these

cases

are

very

likely

caused

by

bacteria

or

fungi

Thus

the

decisions

to

continue

narrow

or

stop

antimicrobial

therapy

must

be

made

on

the

basis

of

clinician

judgment

and

clinical

information

D.

Source

Control

We

recommend

that

a

specific

anatomic

diagnosis

of

infection

requiring

consideration

for

emergent

source

control

for

example

necrotizing

fasciitis

diffuse

peritonitis

cholangitis

intestinal

infarction

be

sought

and

diagnosed

or

excluded

as

rapidly

as

possible

-LRB-

Grade

-RRB-

and

within

the

first

hours

following

presentation

-LRB-

Grade

-RRB-

We

further

recommend

that

all

patients

presenting

with

severe

sepsis

be

evaluated

for

the

presence

of

a

focus

of

infection

amenable

to

source

control

measures

specifically

the

drainage

of

an

abscess

or

local

focus

of

infection

the

debridement

of

infected

necrotic

tissue

the

removal

of

a

potentially

infected

device

or

the

definitive

control

of

a

source

of

ongoing

microbial

contamination

-LRB-

Grade

-RRB-

-LRB-

see

Appendix

A

for

examples

of

potential

sites

needing

source

control

-RRB-

We

suggest

that

when

infected

peripancreatic

necrosis

is

identified

as

a

potential

source

of

infection

definitive

intervention

is

best

delayed

until

adequate

demarcation

of

viable

and

non-viable

tissues

has

occurred

-LRB-

Grade

-RRB-

We

recommend

that

when

source

control

is

required

the

effective

intervention

associated

with

the

least

physiologic

insult

be

employed

e.

g.

percutaneous

rather

than

surgical

drainage

of

an

abscess

-LRB-

Grade

-RRB-

We

recommend

that

when

intravascular

access

devices

are

a

possible

source

of

severe

sepsis

or

septic

shock

they

be

promptly

removed

after

establishing

other

vascular

access

-LRB-

Grade

-RRB-

Rationale

The

principles

of

source

control

in

the

management

of

sepsis

include

a

rapid

diagnosis

of

the

specific

site

of

infection

and

identification

of

a

focus

of

infection

amenable

to

source

control

measures

-LRB-

specifically

the

drainage

of

an

abscess

the

debridement

of

infected

necrotic

tissue

the

removal

of

a

potentially

infected

device

and

the

definitive

control

of

a

source

of

ongoing

microbial

contamination

-RRB-

-LSB-

-RSB-

Foci

of

infection

readily

amenable

to

source

control

measures

include

an

intra-abdominal

abscess

or

gastrointestinal

perforation

cholangitis

or

pyelonephritis

intestinal

ischemia

or

necrotizing

soft

tissue

infection

and

other

deep

space

infection

such

as

an

empyema

or

septic

arthritis

Such

infectious

foci

should

be

controlled

as

soon

as

possible

following

successful

initial

resuscitation

-LSB-

-RSB-

accomplishing

the

source

control

objective

with

the

least

physiologic

upset

possible

-LRB-

e.

g.

percutaneous

rather

than

surgical

drainage

of

an

abscess

-LSB-

-RSB-

endoscopic

rather

than

surgical

drainage

of

biliary

tree

-RRB-

and

removing

intravascular

access

devices

that

are

potentially

the

source

of

severe

sepsis

or

septic

shock

promptly

after

establishing

other

vascular

access

-LSB-

-RSB-

A

randomized

controlled

trial

comparing

early

vs.

delayed

surgical

intervention

for

peripancreatic

necrosis

showed

better

outcomes

with

a

delayed

approach

-LSB-

-RSB-

However

areas

of

uncertainty

such

as

definitive

documentation

of

infection

and

appropriate

length

of

delay

exist

The

selection

of

optimal

source

control

methods

must

weigh

benefits

and

risks

of

the

specific

intervention

as

well

as

risks

of

transfer

-LSB-

-RSB-

Source

control

interventions

may

cause

further

complications

such

as

bleeding

fistulas

or

inadvertent

organ

injury

Surgical

intervention

should

be

considered

when

lesser

interventional

approaches

are

inadequate

or

when

diagnostic

uncertainty

persists

despite

radiological

evaluation

Specific

clinical

situations

require

consideration

of

available

choices

patient

's

preferences

and

clinician

's

expertise

E.

Fluid

Therapy

We

recommend

fluid

resuscitation

with

either

natural/artificial

colloids

or

crystalloids

There

is

no

evidence-based

support

for

one

type

of

fluid

over

another

-LRB-

Grade

-RRB-

Rationale

The

SAFE

study

indicated

albumin

administration

was

safe

and

equally

effective

as

crystalloid

-LSB-

-RSB-

There

was

an

insignificant

decrease

in

mortality

rates

with

the

use

of

colloid

in

a

subset

analysis

of

septic

patients

-LRB-

p

-RRB-

Previous

meta-analyses

of

small

studies

of

ICU

patients

had

demonstrated

no

difference

between

crystalloid

and

colloid

fluid

resuscitation

-LSB-

-RSB-

Although

administration

of

hydroxyethyl

starch

may

increase

the

risk

of

acute

renal

failure

in

patients

with

sepsis

variable

findings

preclude

definitive

recommendations

-LSB-

-RSB-

As

the

volume

of

distribution

is

much

larger

for

crystalloids

than

for

colloids

resuscitation

with

crystalloids

requires

more

fluid

to

achieve

the

same

end

points

and

results

in

more

edema

Crystalloids

are

less

expensive

We

recommend

fluid

resuscitation

initially

target

a

CVP

of

at

least

mm

Hg

-LRB-

mm

Hg

in

mechanically

ventilated

patients

-RRB-

Further

fluid

therapy

is

often

required

-LRB-

Grade

-RRB-

We

recommend

that

a

fluid

challenge

technique

be

applied

wherein

fluid

administration

is

continued

as

long

as

the

hemodynamic

improvement

-LRB-

e.

g.

arterial

pressure

heart

rate

urine

output

-RRB-

continues

-LRB-

Grade

-RRB-

We

recommend

fluid

challenge

in

patients

with

suspected

hypovolemia

be

started

with

at

least

mL

of

crystalloids

or

mL

of

colloids

over

min

More

rapid

administration

and

greater

amounts

of

fluid

may

be

needed

in

patients

with

sepsis

induced

tissue

hypoperfusion

-LRB-

see

initial

resuscitation

recommendations

-RRB-

-LRB-

Grade

-RRB-

We

recommend

the

rate

of

fluid

administration

be

reduced

substantially

when

cardiac

filling

pressures

-LRB-

CVP

or

pulmonary

artery

balloon-occluded

pressure

-RRB-

increase

without

concurrent

hemodynamic

improvement

-LRB-

Grade

-RRB-

Rationale

Fluid

challenge

must

be

clearly

separated

from

simple

fluid

administration

it

is

a

technique

in

which

large

amounts

of

fluids

are

administered

over

a

limited

period

of

time

under

close

monitoring

to

evaluate

the

patient

's

response

and

avoid

the

development

of

pulmonary

edema

The

degree

of

intravascular

volume

deficit

in

patients

with

severe

sepsis

varies

With

venodilation

and

ongoing

capillary

leak

most

patients

require

continuing

aggressive

fluid

resuscitation

during

the

first

hours

of

management

Input

is

typically

much

greater

than

output

and

input/output

ratio

is

of

no

utility

to

judge

fluid

resuscitation

needs

during

this

time

period

F.

Vasopressors

We

recommend

mean

arterial

pressure

-LRB-

MAP

-RRB-

be

maintained

mm

Hg

-LRB-

Grade

-RRB-

Rationale

Vasopressor

therapy

is

required

to

sustain

life

and

maintain

perfusion

in

the

face

of

life-threatening

hypotension

even

when

hypovolemia

has

not

yet

been

resolved

Below

a

certain

mean

arterial

pressure

autoregulation

in

various

vascular

beds

can

be

lost

and

perfusion

can

become

linearly

dependent

on

pressure

Thus

some

patients

may

require

vasopressor

therapy

to

achieve

a

minimal

perfusion

pressure

and

maintain

adequate

flow

-LSB-

-RSB-

The

titration

of

norepinephrine

to

as

low

as

MAP

mm

Hg

has

been

shown

to

preserve

tissue

perfusion

-LSB-

-RSB-

In

addition

pre-existing

comorbidities

should

be

considered

as

to

most

appropriate

MAP

target

For

example

a

MAP

of

mm

Hg

might

be

too

low

in

a

patient

with

severe

uncontrolled

hypertension

and

in

a

young

previously

normotensive

a

lower

MAP

might

be

adequate

Supplementing

end

points

such

as

blood

pressure

with

assessment

of

regional

and

global

perfusion

such

as

blood

lactate

concentrations

and

urine

output

is

important

Adequate

fluid

resuscitation

is

a

fundamental

aspect

of

the

hemodynamic

management

of

patients

with

septic

shock

and

should

ideally

be

achieved

before

vasopressors

and

inotropes

are

used

but

using

vasopressors

early

as

an

emergency

measure

in

patients

with

severe

shock

is

frequently

necessary

When

that

occurs

great

effort

should

be

directed

to

weaning

vasopressors

with

continuing

fluid

resuscitation

We

recommend

either

norepinephrine

or

dopamine

as

the

first

choice

vasopressor

agent

to

correct

hypotension

in

septic

shock

-LRB-

administered

through

a

central

catheter

as

soon

as

one

is

available

-RRB-

-LRB-

Grade

-RRB-

We

suggest

that

epinephrine

phenylephrine

or

vasopressin

should

not

be

administered

as

the

initial

vasopressor

in

septic

shock

-LRB-

Grade

-RRB-

Vasopressin

units/min

may

be

subsequently

added

to

norepinephrine

with

anticipation

of

an

effect

equivalent

to

norepinephrine

alone.We

suggest

that

epinephrine

be

the

first

chosen

alternative

agent

in

septic

shock

that

is

poorly

responsive

to

norepinephrine

or

dopamine

-LRB-

Grade

-RRB-

Rationale

There

is

no

high-quality

primary

evidence

to

recommend

one

catecholamine

over

another

Much

literature

exists

that

contrasts

the

physiologic

effects

of

choice

of

vasopressor

and

combined

inotrope/vasopressors

in

septic

shock

-LSB-

-RSB-

Human

and

animal

studies

suggest

some

advantages

of

norepinephrine

and

dopamine

over

epinephrine

-LRB-

the

latter

with

the

potential

for

tachycardia

as

well

as

disadvantageous

effects

on

splanchnic

circulation

and

hyperlactemia

-RRB-

and

phenylephrine

-LRB-

decrease

in

stroke

volume

-RRB-

There

is

however

no

clinical

evidence

that

epinephrine

results

in

worse

outcomes

and

it

should

be

the

first

chosen

alternative

to

dopamine

or

norepinephrine

Phenylephrine

is

the

adrenergic

agent

least

likely

to

produce

tachycardia

but

as

a

pure

vasopressor

would

be

expected

to

decrease

stroke

volume

Dopamine

increases

mean

arterial

pressure

and

cardiac

output

primarily

due

to

an

increase

in

stroke

volume

and

heart

rate

Norepinephrine

increases

mean

arterial

pressure

due

to

its

vasoconstrictive

effects

with

little

change

in

heart

rate

and

less

increase

in

stroke

volume

compared

with

dopamine

Either

may

be

used

as

a

first-line

agent

to

correct

hypotension

in

sepsis

Norepinephrine

is

more

potent

than

dopamine

and

may

be

more

effective

at

reversing

hypotension

in

patients

with

septic

shock

Dopamine

may

be

particularly

useful

in

patients

with

compromised

systolic

function

but

causes

more

tachycardia

and

may

be

more

arrhythmogenic

-LSB-

-RSB-

It

may

also

influence

the

endocrine

response

via

the

hypothalamic-pituitary

axis

and

have

immunosuppressive

effects

Vasopressin

levels

in

septic

shock

have

been

reported

to

be

lower

than

anticipated

for

a

shock

state

-LSB-

-RSB-

Low

doses

of

vasopressin

may

be

effective

in

raising

blood

pressure

in

patients

refractory

to

other

vasopressors

and

may

have

other

potential

physiologic

benefits

-LSB-

-RSB-

Terlipressin

has

similar

effects

but

is

long

lasting

-LSB-

-RSB-

Studies

show

that

vasopressin

concentrations

are

elevated

in

early

septic

shock

but

with

continued

shock

concentration

decreases

to

normal

range

in

the

majority

of

patients

between

and

hrs

-LSB-

-RSB-

This

has

been

called

relative

vasopressin

deficiency

because

in

the

presence

of

hypotension

vasopressin

would

be

expected

to

be

elevated

The

significance

of

this

finding

is

unknown

The

recent

VASST

trial

a

randomized

controlled

trial

comparing

norepinephrine

alone

to

norepinephrine

plus

vasopressin

at

units

per

minute

showed

no

difference

in

outcome

in

the

intent

to

treat

population

An

a

priori

defined

subgroup

analysis

showed

that

the

survival

of

patients

receiving

less

than

μg/min

norepinephrine

at

the

time

of

randomization

was

better

with

vasopressin

It

should

be

noted

however

that

the

pre-trial

rationale

for

this

stratification

was

based

on

exploring

potential

benefit

in

the

μg

or

greater

norepinephrine

requirement

population

Higher

doses

of

vasopressin

have

been

associated

with

cardiac

digital

and

splanchnic

ischemia

and

should

be

reserved

for

situations

where

alternative

vasopressors

have

failed

-LSB-

-RSB-

Cardiac

output

measurement

to

allow

maintenance

of

a

normal

or

elevated

flow

is

desirable

when

these

pure

vasopressors

are

instituted

We

recommend

that

low

dose

dopamine

not

be

used

for

renal

protection

-LRB-

Grade

-RRB-

Rationale

A

large

randomized

trial

and

meta-analysis

comparing

low-dose

dopamine

to

placebo

found

no

difference

in

either

primary

outcomes

-LRB-

peak

serum

creatinine

need

for

renal

replacement

urine

output

time

to

recovery

of

normal

renal

function

-RRB-

or

secondary

outcomes

-LRB-

survival

to

either

ICU

or

hospital

discharge

ICU

stay

hospital

stay

arrhythmias

-RRB-

-LSB-

-RSB-

Thus

the

available

data

do

not

support

administration

of

low

doses

of

dopamine

solely

to

maintain

renal

function

We

recommend

that

all

patients

requiring

vasopressors

have

an

arterial

line

placed

as

soon

as

practical

if

resources

are

available

-LRB-

Grade

-RRB-

Rationale

In

shock

states

estimation

of

blood

pressure

using

a

cuff

is

commonly

inaccurate

use

of

an

arterial

cannula

provides

a

more

appropriate

and

reproducible

measurement

of

arterial

pressure

These

catheters

also

allow

continuous

analysis

so

that

decisions

regarding

therapy

can

be

based

on

immediate

and

reproducible

blood

pressure

information

G.

Inotropic

Therapy

We

recommend

a

dobutamine

infusion

be

administered

in

the

presence

of

myocardial

dysfunction

as

suggested

by

elevated

cardiac

filling

pressures

and

low

cardiac

output

-LRB-

Grade

-RRB-

We

recommend

against

the

use

of

a

strategy

to

increase

cardiac

index

to

predetermined

supranormal

levels

-LRB-

Grade

-RRB-

Rationale

Dobutamine

is

the

first-choice

inotrope

for

patients

with

measured

or

suspected

low

cardiac

output

in

the

presence

of

adequate

left

ventricular

filling

pressure

-LRB-

or

clinical

assessment

of

adequate

fluid

resuscitation

-RRB-

and

adequate

mean

arterial

pressure

Septic

patients

who

remain

hypotensive

after

fluid

resuscitation

may

have

low

normal

or

increased

cardiac

outputs

Therefore

treatment

with

a

combined

inotrope/vasopressor

such

as

norepinephrine

or

dopamine

is

recommended

if

cardiac

output

is

not

measured

When

the

capability

exists

for

monitoring

cardiac

output

in

addition

to

blood

pressure

a

vasopressor

such

as

norepinephrine

may

be

used

separately

to

target

specific

levels

of

mean

arterial

pressure

and

cardiac

output

Two

large

prospective

clinical

trials

that

included

critically

ill

ICU

patients

who

had

severe

sepsis

failed

to

demonstrate

benefit

from

increasing

oxygen

delivery

to

supranormal

targets

by

use

of

dobutamine

-LSB-

-RSB-

These

studies

did

not

target

specifically

patients

with

severe

sepsis

and

did

not

target

the

first

hours

of

resuscitation

The

first

hours

of

resuscitation

of

sepsis

induced

hypoperfusion

need

to

be

treated

separately

from

the

later

stages

of

severe

sepsis

-LRB-

see

initial

resuscitation

recommendations

-RRB-

H.

Corticosteroids

We

suggest

intravenous

hydrocortisone

be

given

only

to

adult

septic

shock

patients

after

blood

pressure

is

identified

to

be

poorly

responsive

to

fluid

resuscitation

and

vasopressor

therapy

-LRB-

Grade

-RRB-

Rationale

One

french

multi-center

randomized

controlled

trial

-LRB-

RCT

-RRB-

of

patients

in

vasopressor-unresponsive

septic

shock

-LRB-

hypotension

despite

fluid

resuscitation

and

vasopressors

-RRB-

showed

a

significant

shock

reversal

and

reduction

of

mortality

rate

in

patients

with

relative

adrenal

insufficiency

-LRB-

defined

as

post-adrenocorticotropic

hormone

-LRB-

ACTH

-RRB-

cortisol

increase

μg/dL

or

less

-RRB-

-LSB-

-RSB-

Two

additional

smaller

RCTs

also

showed

significant

effects

on

shock

reversal

with

steroid

therapy

-LSB-

-RSB-

However

a

recent

large

European

multicenter

trial

-LRB-

CORTICUS

-RRB-

which

has

been

presented

in

abstract

form

but

not

yet

published

failed

to

show

a

mortality

benefit

with

steroid

therapy

of

septic

shock

-LSB-

-RSB-

CORTICUS

did

show

a

faster

resolution

of

septic

shock

in

patients

who

received

steroids

The

use

of

the

ACTH

test

-LRB-

responders

and

nonresponders

-RRB-

did

not

predict

the

faster

resolution

of

shock

Importantly

unlike

the

French

trial

which

only

enrolled

shock

patients

with

blood

pressure

unresponsive

to

vasopressor

therapy

the

CORTICUS

study

included

patients

with

septic

shock

regardless

of

how

the

blood

pressure

responded

to

vasopressors

Although

corticosteroids

do

appear

to

promote

shock

reversal

the

lack

of

a

clear

improvement

in

mortality-coupled

with

known

side

effects

of

steroids

such

as

increased

risk

of

infection

and

myopathy-generally

tempered

enthusiasm

for

their

broad

use

Thus

there

was

broad

agreement

that

the

recommendation

should

be

downgraded

from

the

previous

guidelines

-LRB-

Appendix

B

-RRB-

There

was

considerable

discussion

and

consideration

by

the

committee

on

the

option

of

encouraging

use

in

those

patients

whose

blood

pressure

was

unresponsive

to

fluids

and

vasopressors

while

strongly

discouraging

use

in

subjects

whose

shock

responded

well

to

fluids

and

pressors

However

this

more

complex

set

of

recommendations

was

rejected

in

favor

of

the

above

single

recommendation

-LRB-

see

Appendix

B

-RRB-

We

suggest

the

ACTH

stimulation

test

not

be

used

to

identify

the

subset

of

adults

with

septic

shock

who

should

receive

hydrocortisone

-LRB-

Grade

-RRB-

Rationale

Although

one

study

suggested

those

who

did

not

respond

to

ACTH

with

a

brisk

surge

in

cortisol

-LRB-

failure

to

achieve

or

μg/dL

increase

in

cortisol

mins

post-ACTH

administration

-RRB-

were

more

likely

to

benefit

from

steroids

than

those

who

did

respond

the

overall

trial

population

appeared

to

benefit

regardless

of

ACTH

result

and

the

observation

of

a

potential

interaction

between

steroid

use

and

ACTH

test

was

not

statistically

significant

-LSB-

-RSB-

Furthermore

there

was

no

evidence

of

this

distinction

between

responders

and

nonresponders

in

a

recent

multicenter

trial

-LSB-

-RSB-

Commonly

used

cortisol

immunoassays

measure

total

cortisol

-LRB-

protein-bound

and

free

-RRB-

while

free

cortisol

is

the

pertinent

measurement

The

relationship

between

free

and

total

cortisol

varies

with

serum

protein

concentration

When

compared

to

a

reference

method

-LRB-

mass

spectrometry

-RRB-

cortisol

immunoassays

may

over

or

underestimate

the

actual

cortisol

level

affecting

the

assignment

of

patients

to

responders

or

nonresponders

-LSB-

-RSB-

Although

the

clinical

significance

is

not

clear

it

is

now

recognized

that

etomidate

when

used

for

induction

for

intubation

will

suppress

the

HPA

axis

-LSB-

-RSB-

We

suggest

that

patients

with

septic

shock

should

not

receive

dexamethasone

if

hydrocortisone

is

available

-LRB-

Grade

-RRB-

Rationale

Although

often

proposed

for

use

until

an

ACTH

stimulation

test

can

be

administered

we

no

longer

suggest

an

ACTH

test

in

this

clinical

situation

-LRB-

see

above

-RRB-

Furthermore

dexamethasone

can

lead

to

immediate

and

prolonged

suppression

of

the

HPA

axis

after

administration

-LSB-

-RSB-

We

suggest

the

daily

addition

of

oral

fludrocortisone

-LRB-

μg

-RRB-

if

hydrocortisone

is

not

available

and

the

steroid

that

is

substituted

has

no

significant

mineralocorticoid

activity

Fludrocortisone

is

considered

optional

if

hydrocortisone

is

used

-LRB-

Grade

-RRB-

Rationale

One

study

added

μg

of

fludrocortisone

orally

-LSB-

-RSB-

Since

hydrocortisone

has

intrinsic

mineralcorticoid

activity

there

is

controversy

as

to

whether

fludrocortisone

should

be

added

We

suggest

clinicians

wean

the

patient

from

steroid

therapy

when

vasopressors

are

no

longer

required

-LRB-

Grade

-RRB-

Rationale

There

has

been

no

comparative

study

between

a

fixed

duration

and

clinically

guided

regimen

or

between

tapering

and

abrupt

cessation

of

steroids

Three

RCTs

used

a

fixed

duration

protocol

for

treatment

-LSB-

-RSB-

and

in

two

RCTs

therapy

was

decreased

after

shock

resolution

-LSB-

-RSB-

In

four

RCTs

steroids

were

tapered

over

several

days

-LSB-

-RSB-

and

in

two

RCTs

-LSB-

-RSB-

steroids

were

withdrawn

abruptly

One

cross-over

study

showed

hemodynamic

and

immunologic

rebound

effects

after

abrupt

cessation

of

corticosteroids

-LSB-

-RSB-

It

remains

uncertain

whether

outcome

is

affected

by

tapering

of

steroids

or

not

We

recommend

doses

of

corticosteroids

comparable

to

mg

hydrocortisone

daily

not

be

used

in

severe

sepsis

or

septic

shock

for

the

purpose

of

treating

septic

shock

-LRB-

Grade

-RRB-

Rationale

Two

randomized

prospective

clinical

trials

and

a

meta-analyses

concluded

that

for

therapy

of

severe

sepsis

or

septic

shock

high-dose

corticosteroid

therapy

is

ineffective

or

harmful

-LSB-

-RSB-

Reasons

to

maintain

higher

doses

of

corticosteroid

for

medical

conditions

other

than

septic

shock

may

exist

We

recommend

corticosteroids

not

be

administered

for

the

treatment

of

sepsis

in

the

absence

of

shock

There

is

however

no

contraindication

to

continuing

maintenance

steroid

therapy

or

to

using

stress

does

steroids

if

the

patient

's

endocrine

or

corticosteroid

administration

history

warrants

-LRB-

Grade

-RRB-

Rationale

No

studies

exist

that

specifically

target

severe

sepsis

in

the

absence

of

shock

that

offer

support

for

use

of

stress

doses

of

steroids

in

this

patient

population

Steroids

may

be

indicated

in

the

presence

of

a

prior

history

of

steroid

therapy

or

adrenal

dysfunction

A

recent

preliminary

study

of

stress

dose

level

steroids

in

community

acquired

pneumonia

is

encouraging

but

needs

confirmation

-LSB-

-RSB-

I.

Recombinant

Human

Activated

Protein

C

-LRB-

rhAPC

-RRB-

We

suggest

that

adult

patients

with

sepsis

induced

organ

dysfunction

associated

with

a

clinical

assessment

of

high

risk

of

death

most

of

whom

will

have

APACHE

II

or

multiple

organ

failure

receive

rhAPC

if

there

are

no

contraindications

-LRB-

Grade

except

for

patients

within

days

of

surgery

where

it

is

Grade

-RRB-

Relative

contraindications

should

also

be

considered

in

decision

making.We

recommend

that

adult

patients

with

severe

sepsis

and

low

risk

of

death

most

of

whom

will

have

APACHE

II

or

one

organ

failure

do

not

receive

rhAPC

-LRB-

Grade

-RRB-

Rationale

The

evidence

concerning

use

of

rhAPC

in

adults

is

primarily

based

on

two

randomized

controlled

trials

-LRB-

RCTs

-RRB-

PROWESS

-LRB-

adult

patients

stopped

early

for

efficacy

-RRB-

-LSB-

-RSB-

and

ADDRESS

-LRB-

stopped

early

for

futility

-RRB-

-LSB-

-RSB-

Additional

safety

information

comes

from

an

open-label

observational

study

ENHANCE

-LSB-

-RSB-

The

ENHANCE

trial

also

suggested

early

administration

of

rhAPC

was

associated

with

better

outcomes

PROWESS

involved

patients

and

documented

in

absolute

total

mortality

reduction

with

a

relative

risk

reduction

-LRB-

RRR

-RRB-

of

CI

number

needed

to

treat

-LRB-

NNT

-RRB-

-LSB-

-RSB-

Controversy

associated

with

the

results

focused

on

a

number

of

subgroup

analyses

Subgroup

analyses

have

the

potential

to

mislead

due

to

the

absence

of

an

intent

to

treat

sampling

bias

and

selection

error

-LSB-

-RSB-

The

analyses

suggested

increasing

absolute

and

relative

risk

reduction

with

greater

risk

of

death

using

both

higher

APACHE

II

scores

and

greater

number

of

organ

failures

-LSB-

-RSB-

This

led

to

drug

approval

for

patients

with

high

risk

of

death

-LRB-

such

as

APACHE

II

-RRB-

and

more

than

one

organ

failure

in

Europe

The

ADDRESS

trial

involved

patients

judged

to

have

a

low

risk

of

death

at

the

time

of

enrollment

day

mortality

from

all

causes

was

on

placebo

vs.

on

APC

relative

risk

-LRB-

RR

-RRB-

CI

-LSB-

-RSB-

Again

debate

focused

on

subgroup

analyses

analyses

restricted

to

small

subgroups

of

patients

with

APACHE

II

score

over

or

more

than

one

organ

failures

which

failed

to

show

benefit

however

these

patient

groups

also

had

a

lower

mortality

than

in

PROWESS

Relative

risk

reduction

of

death

was

numerically

lower

in

the

subgroup

of

patients

with

recent

surgery

-LRB-

n

-RRB-

in

the

PROWESS

trial

-LRB-

placebo

vs.

APC

-RRB-

-LSB-

-RSB-

when

compared

to

the

overall

study

population

-LRB-

placebo

vs.

APC

-RRB-

-LSB-

-RSB-

In

the

ADDRESS

trial

patients

with

recent

surgery

and

single

organ

dysfunction

who

received

APC

had

significantly

higher

day

mortality

rates

-LRB-

vs.

p

n

-RRB-

-LSB-

-RSB-

Serious

adverse

events

did

not

differ

in

the

studies

-LSB-

-RSB-

with

the

exception

of

serious

bleeding

which

occurred

more

often

in

the

patients

treated

with

APC

vs.

-LRB-

PROWESS

p

-RRB-

-LSB-

-RSB-

vs.

-LRB-

ADDRESS

p

-RRB-

-LSB-

-RSB-

-LRB-

ENHANCE

open

label

-RRB-

-LSB-

-RSB-

The

pediatric

trial

and

implications

are

discussed

in

the

pediatric

consideration

section

of

this

manuscript

-LRB-

see

Appendix

C

for

absolute

contraindications

to

use

of

rhAPC

and

prescribing

information

for

relative

contraindications

-RRB-

Intracranial

hemorrhage

-LRB-

ICH

-RRB-

occurred

in

the

PROWESS

trial

in

-LRB-

placebo

-RRB-

and

-LRB-

APC

-RRB-

-LRB-

n.

s.

-RRB-

-LSB-

-RSB-

in

the

ADDRESS

trial

-LRB-

placebo

-RRB-

vs.

-LRB-

APC

-RRB-

-LRB-

n.

s.

-RRB-

-LSB-

-RSB-

in

ENHANCE

-LSB-

-RSB-

Registry

studies

of

rhAPC

report

higher

bleeding

rates

than

randomized

controlled

trials

suggesting

that

the

risk

of

bleeding

in

actual

practice

may

be

greater

than

reported

in

PROWESS

and

ADDRESS

-LSB-

-RSB-

The

two

RCTs

in

adult

patients

were

methodologically

strong

precise

and

provide

direct

evidence

regarding

death

rates

The

conclusions

are

limited

however

by

inconsistency

that

is

not

adequately

resolved

by

subgroup

analyses

-LRB-

thus

the

designation

of

moderate

quality

evidence

-RRB-

Results

however

consistently

fail

to

show

benefit

for

the

subgroup

of

patients

at

lower

risk

of

death

and

consistently

show

increases

in

serious

bleeding

The

RCT

in

pediatric

severe

sepsis

failed

to

show

benefit

and

has

no

important

limitations

Thus

for

low

risk

and

pediatric

patients

we

rate

the

evidence

as

high

quality

For

adult

use

there

is

probable

mortality

reduction

in

patients

with

clinical

assessment

of

high

risk

of

death

most

of

whom

will

have

APACHE

II

or

multiple

organ

failure

There

is

likely

no

benefit

in

patients

with

low

risk

of

death

most

of

whom

will

have

APACHE

II

or

single

organ

dysfunction

The

effects

in

patients

with

more

than

one

organ

failure

but

APACHE

II

are

unclear

and

in

that

circumstance

one

may

use

clinical

assessment

of

the

risk

of

death

and

number

of

organ

failures

to

support

decision

There

is

a

certain

increased

risk

of

bleeding

with

administration

of

rhAPC

which

may

be

higher

in

surgical

patients

and

in

the

context

of

invasive

procedures

Decision

on

utilization

depends

upon

assessing

likelihood

of

mortality

reduction

versus

increases

in

bleeding

and

cost

-LRB-

see

appendix

D

for

nominal

committee

vote

on

recommendation

for

rhAPC

-RRB-

A

European

Regulatory

mandated

randomized

controlled

trial

of

rhAPC

vs.

placebo

in

patients

with

septic

shock

is

now

ongoing

-LSB-

-RSB-

J.

Blood

Product

Administration

Once

tissue

hypoperfusion

has

resolved

and

in

the

absence

of

extenuating

circumstances

such

as

myocardial

ischemia

severe

hypoxemia

acute

hemorrhage

cyanotic

heart

disease

or

lactic

acidosis

-LRB-

see

recommendations

for

initial

resuscitation

-RRB-

we

recommend

that

red

blood

cell

transfusion

occur

when

hemoglobin

decreases

to

g/dL

-LRB-

g/L

-RRB-

to

target

a

hemoglobin

of

g/dL

-LRB-

g/L

-RRB-

in

adults

-LRB-

Grade

-RRB-

Rationale

Although

the

optimum

hemoglobin

for

patients

with

severe

sepsis

has

not

been

specifically

investigated

the

Transfusion

Requirements

in

Critical

Care

trial

suggested

that

a

hemoglobin

of

g/dL

-LRB-

g/L

-RRB-

when

compared

to

g/dL

-LRB-

g/L

-RRB-

was

not

associated

with

increased

mortality

rate

in

adults

-LSB-

-RSB-

Red

blood

cell

transfusion

in

septic

patients

increases

oxygen

delivery

but

does

not

usually

increase

oxygen

consumption

-LSB-

-RSB-

This

transfusion

threshold

of

g/dL

-LRB-

g/L

-RRB-

contrasts

with

the

early

goal-directed

resuscitation

protocol

that

uses

a

target

hematocrit

of

in

patients

with

low

-LRB-

measured

in

superior

vena

cava

-RRB-

during

the

first

hrs

of

resuscitation

of

septic

shock

We

recommend

that

erythropoietin

not

be

used

as

a

specific

treatment

of

anemia

associated

with

severe

sepsis

but

may

be

used

when

septic

patients

have

other

accepted

reasons

for

administration

of

erythropoietin

such

as

renal

failure-induced

compromise

of

red

blood

cell

production

-LRB-

Grade

-RRB-

Rationale

No

specific

information

regarding

erythropoietin

use

in

septic

patients

is

available

but

clinical

trials

in

critically

ill

patients

show

some

decrease

in

red

cell

transfusion

requirement

with

no

effect

on

clinical

outcome

-LSB-

-RSB-

The

effect

of

erythropoietin

in

severe

sepsis

and

septic

shock

would

not

be

expected

to

be

more

beneficial

than

in

other

critical

conditions

Patients

with

severe

sepsis

and

septic

shock

may

have

coexisting

conditions

that

do

warrant

use

of

erythropoietin

We

suggest

that

fresh

frozen

plasma

not

be

used

to

correct

laboratory

clotting

abnormalities

in

the

absence

of

bleeding

or

planned

invasive

procedures

-LRB-

Grade

-RRB-

Rationale

Although

clinical

studies

have

not

assessed

the

impact

of

transfusion

of

fresh

frozen

plasma

on

outcomes

in

critically

ill

patients

professional

organizations

have

recommended

fresh

frozen

plasma

for

coagulopathy

when

there

is

a

documented

deficiency

of

coagulation

factors

-LRB-

increased

prothrombin

time

international

normalized

ratio

or

partial

thromboplastin

time

-RRB-

and

the

presence

of

active

bleeding

or

before

surgical

or

invasive

procedures

-LSB-

-RSB-

In

addition

transfusion

of

fresh

frozen

plasma

in

nonbleeding

patients

with

mild

abnormalities

of

prothrombin

time

usually

fails

to

correct

the

prothrombin

time

-LSB-

-RSB-

There

are

no

studies

to

suggest

that

correction

of

more

severe

coagulation

abnormalities

benefits

patients

who

are

not

bleeding

We

recommendagainst

antithrombin

administration

for

the

treatment

of

severe

sepsis

and

septic

shock

-LRB-

Grade

-RRB-

Rationale

A

phase

III

clinical

trial

of

high-dose

antithrombin

did

not

demonstrate

any

beneficial

effect

on

all-cause

mortality

in

adults

with

severe

sepsis

and

septic

shock

High-dose

antithrombin

was

associated

with

an

increased

risk

of

bleeding

when

administered

with

heparin

-LSB-

-RSB-

Although

a

post

hoc

subgroup

analysis

of

patients

with

severe

sepsis

and

high

risk

of

death

showed

better

survival

in

patients

receiving

antithrombin

antithrombin

can

not

be

recommended

at

this

time

until

further

clinical

trials

are

performed

-LSB-

-RSB-

In

patients

with

severe

sepsis

we

suggest

that

platelets

should

be

administered

when

counts

are

-LRB-

-RRB-

regardless

of

apparent

bleeding

Platelet

transfusion

may

be

considered

when

counts

are

-LRB-

-RRB-

and

there

is

a

significant

risk

of

bleeding

Higher

platelet

counts

-LRB-

-LRB-

-RRB-

-RRB-

are

typically

required

for

surgery

or

invasive

procedures

-LRB-

Grade

-RRB-

Rationale

Guidelines

for

transfusion

of

platelets

are

derived

from

consensus

opinion

and

experience

in

patients

undergoing

chemotherapy

Recommendations

take

into

account

the

etiology

of

thrombocytopenia

platelet

dysfunction

risk

of

bleeding

and

presence

of

concomitant

disorders

-LSB-

-RSB-

II

Supportive

Therapy

of

Severe

Sepsis

A.

Mechanical

Ventilation

of

Sepsis-Induced

Acute

Lung

Injury

-LRB-

ALI

-RRB-

Acute

Respiratory

Distress

Syndrome

-LRB-

ARDS

-RRB-

We

recommend

that

clinicians

target

a

tidal

volume

of

ml/kg

-LRB-

predicted

-RRB-

body

weight

in

patients

with

ALI/ARDS

-LRB-

Grade

-RRB-

We

recommend

that

plateau

pressures

be

measured

in

patients

with

ALI/ARDS

and

that

the

initial

upper

limit

goal

for

plateau

pressures

in

a

passively

inflated

patient

be

cm

Chest

wall

compliance

should

be

considered

in

the

assessment

of

plateau

pressure

-LRB-

Grade

-RRB-

Rationale

Over

the

past

yrs

several

multi-center

randomized

trials

have

been

performed

to

evaluate

the

effects

of

limiting

inspiratory

pressure

through

moderation

of

tidal

volume

-LSB-

-RSB-

These

studies

showed

differing

results

that

may

have

been

caused

by

differences

between

airway

pressures

in

the

treatment

and

control

groups

-LSB-

-RSB-

The

largest

trial

of

a

volume

and

pressure-limited

strategy

showed

a

decrease

of

all-cause

mortality

in

patients

with

ALI

or

ARDS

ventilated

with

tidal

volumes

of

mL/kg

of

predicted

body

weight

-LRB-

PBW

-RRB-

as

opposed

to

mL/kg

and

aiming

for

a

plateau

pressure

cm

-LSB-

-RSB-

The

use

of

lung

protective

strategies

for

patients

with

ALI

is

supported

by

clinical

trials

and

has

been

widely

accepted

but

the

precise

choice

of

tidal

volume

for

an

individual

patient

with

ALI

may

require

adjustment

for

such

factors

as

the

plateau

pressure

achieved

the

level

of

PEEP

chosen

the

compliance

of

the

thoracoabdominal

compartment

and

the

vigor

of

the

patient

's

breathing

effort

Some

clinicians

believe

it

may

be

safe

to

ventilate

with

tidal

volumes

higher

than

ml/kg

PBW

as

long

as

the

plateau

pressure

can

be

maintained

cm

-LSB-

-RSB-

The

validity

of

this

ceiling

value

will

depend

on

breathing

effort

as

those

who

are

actively

inspiring

generate

higher

trans-alveolar

pressures

for

a

given

plateau

pressure

than

those

who

are

passively

inflated

Conversely

patients

with

very

stiff

chest

walls

may

require

plateau

pressures

higher

than

cm

to

meet

vital

clinical

objectives

One

retrospective

study

suggested

that

tidal

volumes

should

be

lowered

even

with

plateau

pressures

that

are

cm

-LSB-

-RSB-

An

additional

observational

study

suggested

that

knowledge

of

the

plateau

pressures

was

associated

with

lower

plateau

pressures

however

in

this

trial

plateau

pressure

was

not

independently

associated

with

mortality

rates

across

a

wide

range

of

plateau

pressures

that

bracketed

cm

-LSB-

-RSB-

The

largest

clinical

trial

employing

a

lung

protective

strategy

coupled

limited

pressure

with

limited

tidal

volumes

to

demonstrate

a

mortality

benefit

-LSB-

-RSB-

High

tidal

volumes

that

are

coupled

with

high

plateau

pressures

should

be

avoided

in

ALI/ARDS

Clinicians

should

use

as

a

starting

point

the

objective

of

reducing

tidal

volumes

over

hrs

from

its

initial

value

toward

the

goal

of

a

low

tidal

volume

-LRB-

mL

per

kilogram

of

predicted

body

weight

-RRB-

achieved

in

conjunction

with

an

end-inspiratory

plateau

pressure

cm

If

plateau

pressure

remains

after

reduction

of

tidal

volume

to

ml/kg/PBW

tidal

volume

should

be

reduced

further

to

as

low

as

ml/kg/PBW

-LRB-

see

Appendix

E

for

ARDSnet

ventilator

management

and

formula

to

calculate

predicted

body

weight

-RRB-

No

single

mode

of

ventilation

-LRB-

pressure

control

volume

control

airway

pressure

release

ventilation

high

frequency

ventilation

etc.

-RRB-

has

been

consistently

shown

advantageous

when

compared

with

any

other

that

respects

the

same

principles

of

lung

protection

We

recommend

that

hypercapnia

-LRB-

allowing

to

increase

above

its

pre-morbid

baseline

so-called

permissive

hypercapnia

-RRB-

be

allowed

in

patients

with

ALI/ARDS

if

needed

to

minimize

plateau

pressures

and

tidal

volumes

-LRB-

Grade

-RRB-

Rationale

An

acutely

elevated

may

have

physiologic

consequences

that

include

vasodilation

as

well

as

an

increased

heart

rate

blood

pressure

and

cardiac

output

Allowing

modest

hypercapnia

in

conjunction

with

limiting

tidal

volume

and

minute

ventilation

has

been

demonstrated

to

be

safe

in

small

nonrandomized

series

-LSB-

-RSB-

Patients

treated

in

larger

trials

that

have

the

goal

of

limiting

tidal

volumes

and

airway

pressures

have

demonstrated

improved

outcomes

but

permissive

hypercapnia

was

not

a

primary

treatment

goal

in

these

studies

-LSB-

-RSB-

The

use

of

hypercapnia

is

limited

in

patients

with

preexisting

metabolic

acidosis

and

is

contraindicated

in

patients

with

increased

intracranial

pressure

Sodium

bicarbonate

or

tromethamine

-LRB-

THAM

-RRB-

infusion

may

be

considered

in

selected

patients

to

facilitate

use

of

permissive

hypercarbia

-LSB-

-RSB-

We

recommend

that

positive

end-expiratory

pressure

-LRB-

PEEP

-RRB-

be

set

so

as

to

avoid

extensive

lung

collapse

at

end-expiration

-LRB-

Grade

-RRB-

Rationale

Raising

PEEP

in

ALI/ARDS

keeps

lung

units

open

to

participate

in

gas

exchange

This

will

increase

when

PEEP

is

applied

through

either

an

endotracheal

tube

or

a

face

mask

-LSB-

-RSB-

In

animal

experiments

avoidance

of

end-expiratory

alveolar

collapse

helps

minimize

ventilator

induced

lung

injury

-LRB-

VILI

-RRB-

when

relatively

high

plateau

pressures

are

in

use

One

large

multi-center

trial

of

the

protocol-driven

use

of

higher

PEEP

in

conjunction

with

low

tidal

volumes

did

not

show

benefit

or

harm

when

compared

to

lower

PEEP

levels

-LSB-

-RSB-

Neither

the

control

nor

experimental

group

in

that

study

however

was

clearly

exposed

to

hazardous

plateau

pressures

A

recent

multi-center

Spanish

trial

compared

a

high

PEEP

low-moderate

tidal

volume

approach

to

one

that

used

conventional

tidal

volumes

and

the

least

PEEP

achieving

adequate

oxygenation

A

marked

survival

advantage

favored

the

former

approach

in

high

acuity

patients

with

ARDS

-LSB-

-RSB-

Two

options

are

recommended

for

PEEP

titration

One

option

is

to

titrate

PEEP

-LRB-

and

tidal

volume

-RRB-

according

to

bedside

measurements

of

thoracopulmonary

compliance

with

the

objective

of

obtaining

the

best

compliance

reflecting

a

favorable

balance

of

lung

recruitment

and

overdistention

-LSB-

-RSB-

The

second

option

is

to

titrate

PEEP

based

on

severity

of

oxygenation

deficit

and

guided

by

the

required

to

maintain

adequate

oxygenation

-LSB-

-RSB-

-LRB-

see

Appendix

D.

-RRB-

Whichever

the

indicator-compliance

or

oxygenation-recruiting

maneuvers

are

reasonable

to

employ

in

the

process

of

PEEP

selection

Blood

pressure

and

oxygenation

should

be

monitored

and

recruitment

discontinued

if

deterioration

in

these

parameters

is

observed

A

PEEP

cm

is

usually

required

to

avoid

lung

collapse

-LSB-

-RSB-

We

suggest

prone

positioning

in

ARDS

patients

requiring

potentially

injurious

levels

of

or

plateau

pressure

who

are

not

at

high

risk

for

adverse

consequences

of

positional

changes

in

those

facilities

who

have

experience

with

such

practices

-LRB-

Grade

-RRB-

Rationale

Several

smaller

studies

and

one

larger

study

have

shown

that

a

majority

of

patients

with

ALI/ARDS

respond

to

the

prone

position

with

improved

oxygenation

-LSB-

-RSB-

One

large

multi-center

trial

of

prone

positioning

for

approximately

hrs/day

did

not

show

improvement

in

mortality

rates

in

patients

with

ALI/ARDS

however

a

post

hoc

analysis

suggested

improvement

in

those

patients

with

the

most

severe

hypoxemia

by

ratio

in

those

exposed

to

high

tidal

volumes

and

those

who

improved

exchange

as

a

result

of

proning

-LSB-

-RSB-

A

second

large

trial

of

prone

positioning

conducted

for

an

average

of

approximately

hours

per

day

for

days

in

adults

with

hypoxemic

respiratory

failure

of

low-moderate

acuity

confirmed

improvement

in

oxygenation

but

also

failed

to

show

a

survival

advantage

-LSB-

-RSB-

However

a

randomized

study

that

extended

the

length

of

time

for

proning

each

day

to

a

mean

of

hours

for

a

mean

of

days

supported

benefit

of

proning

with

randomization

to

supine

position

an

independent

risk

factor

for

mortality

by

multivariate

analysis

-LSB-

-RSB-

Prone

positioning

may

be

associated

with

potentially

life-threatening

complications

including

accidental

dislodgment

of

the

endotracheal

tube

and

central

venous

catheters

but

these

complications

can

usually

be

avoided

with

proper

precautions

A

-RRB-

Unless

contraindicated

we

recommend

mechanically

ventilated

patients

be

maintained

with

the

head

of

the

bed

elevated

to

limit

aspiration

risk

and

to

prevent

the

development

of

ventilator-associated

pneumonia

-LRB-

Grade

-RRB-

B

-RRB-

We

suggest

that

the

head

of

bed

is

elevated

approximately

degrees

-LRB-

Grade

-RRB-

Rationale

The

semirecumbent

position

has

been

demonstrated

to

decrease

the

incidence

of

ventilator-associated

pneumonia

-LRB-

VAP

-RRB-

-LSB-

-RSB-

Enteral

feeding

increased

the

risk

of

developing

VAP

of

the

patients

who

were

fed

enterally

in

the

supine

position

developing

VAP

-LSB-

-RSB-

However

the

bed

position

was

only

monitored

once

a

day

and

patients

who

did

not

achieve

the

desired

bed

elevation

were

not

included

in

the

analysis

-LSB-

-RSB-

A

recent

study

did

not

show

a

difference

in

in

incidence

of

VAP

between

patients

maintained

in

supine

and

semirecumbent

positions

-LSB-

-RSB-

In

this

study

patients

in

the

semirecumbent

position

did

not

consistently

achieve

the

desired

head

of

the

bed

elevation

and

the

head

of

bed

elevation

in

the

supine

group

approached

that

of

the

semirecumbent

group

by

day

-LSB-

-RSB-

When

necessary

patients

may

be

laid

flat

for

procedures

hemodynamic

measurements

and

during

episodes

of

hypotension

Patients

should

not

be

fed

enterally

with

the

head

of

the

bed

at

We

suggest

that

noninvasive

mask

ventilation

-LRB-

NIV

-RRB-

only

be

considered

in

that

minority

of

ALI/ARDS

patients

with

mild-moderate

hypoxemic

respiratory

failure

-LRB-

responsive

to

relatively

low

levels

of

pressure

support

and

PEEP

-RRB-

with

stable

hemodynamics

who

can

be

made

comfortable

and

easily

arousable

who

are

able

to

protect

the

airway

spontaneously

clear

the

airway

of

secretions

and

are

anticipated

to

recover

rapidly

from

the

precipitating

insult

A

low

threshold

for

airway

intubation

should

be

maintained

-LRB-

Grade

-RRB-

Rationale

Obviating

the

need

for

airway

intubation

confers

multiple

advantages

better

communication

lower

incidence

of

infection

reduced

requirements

for

sedation

Two

RCTs

demonstrate

improved

outcome

with

the

use

of

NIV

when

it

can

be

employed

successfully

-LSB-

-RSB-

Unfortunately

only

a

small

percentage

of

patients

with

life

threatening

hypoxemia

can

be

managed

in

this

way

We

recommend

that

a

weaning

protocol

be

in

place

and

mechanically

ventilated

patients

with

severe

sepsis

undergo

spontaneous

breathing

trials

on

a

regular

basis

to

evaluate

the

ability

to

discontinue

mechanical

ventilation

when

they

satisfy

the

following

criteria

a

-RRB-

arousable

b

-RRB-

hemodynamically

stable

-LRB-

without

vasopressor

agents

-RRB-

c

-RRB-

no

new

potentially

serious

conditions

d

-RRB-

low

ventilatory

and

end-expiratory

pressure

requirements

and

e

-RRB-

requirements

that

could

be

safely

delivered

with

a

face

mask

or

nasal

cannula

If

the

spontaneous

breathing

trial

is

successful

consideration

should

be

given

for

extubation

-LRB-

see

Appendix

E

-RRB-

Spontaneous

breathing

trial

options

include

a

low

level

of

pressure

support

continuous

positive

airway

pressure

-LRB-

cm

-RRB-

or

a

T-piece

-LRB-

Grade

-RRB-

Rationale

Recent

studies

demonstrate

that

daily

spontaneous

breathing

trials

in

appropriately

selected

patients

reduce

the

duration

of

mechanical

ventilation

-LSB-

-RSB-

Successful

completion

of

spontaneous

breathing

trials

leads

to

a

high

likelihood

of

successful

discontinuation

of

mechanical

ventilation

We

recommendagainst

the

routine

use

of

the

pulmonary

artery

catheter

for

patients

with

ALI/ARDS

-LRB-

Grade

-RRB-

Rationale

While

insertion

of

a

pulmonary

artery

catheter

may

provide

useful

information

on

a

patient

's

volume

status

and

cardiac

function

potential

benefits

of

such

information

may

be

confounded

by

differences

in

interpretation

of

results

-LSB-

-RSB-

lack

of

correlation

of

pulmonary

artery

occlusion

pressures

with

clinical

response

-LSB-

-RSB-

and

absence

of

a

proven

strategy

to

use

catheter

results

to

improve

patient

outcomes

-LSB-

-RSB-

Two

multi-center

randomized

trials

one

in

patients

with

shock

or

acute

lung

injury

-LSB-

-RSB-

and

one

in

patients

with

acute

lung

injury

-LSB-

-RSB-

failed

to

show

benefit

with

the

routine

use

of

pulmonary

artery

catheters

in

patients

with

acute

lung

injury

In

addition

other

studies

in

different

types

of

critically

ill

patients

have

failed

to

show

definitive

benefit

with

routine

use

of

the

pulmonary

artery

catheter

-LSB-

-RSB-

Well-selected

patients

remain

appropriate

candidates

for

pulmonary

artery

catheter

insertion

when

the

answers

to

important

management

decisions

depend

on

information

only

obtainable

from

direct

measurements

made

within

the

pulmonary

artery

To

decrease

days

of

mechanical

ventilation

and

ICU

length

of

stay

we

recommend

a

conservative

fluid

strategy

for

patients

with

established

acute

lung

injury

who

do

not

have

evidence

of

tissue

hypoperfusion

-LRB-

Grade

-RRB-

Rationale

Mechanisms

for

the

development

of

pulmonary

edema

in

patients

with

acute

lung

injury

include

increased

capillary

permeability

increased

hydrostatic

pressure

and

decreased

oncotic

pressure

-LSB-

-RSB-

Small

prospective

studies

in

patients

with

critical

illness

and

acute

lung

injury

have

suggested

that

less

weight

gain

is

associated

with

improved

oxygenation

-LSB-

-RSB-

and

fewer

days

of

mechanical

ventilation

-LSB-

-RSB-

Use

of

a

fluid

conservative

strategy

directed

at

minimizing

fluid

infusion

and

weight

gain

in

patients

with

acute

lung

injury

based

on

either

a

central

venous

catheter

or

a

pulmonary

artery

catheter

along

with

clinical

parameters

to

guide

treatment

strategies

led

to

fewer

days

of

mechanical

ventilation

and

reduced

length

of

ICU

stay

without

altering

the

incidence

of

renal

failure

or

mortality

rates

-LSB-

-RSB-

Of

note

this

strategy

was

only

used

in

patients

with

established

acute

lung

injury

some

of

whom

had

shock

present

Active

attempts

to

reduce

fluid

volume

were

conducted

only

during

periods

free

of

shock

B.

Sedation

Analgesia

and

Neuromuscular

Blockade

in

Sepsis

We

recommend

sedation

protocols

with

a

sedation

goal

when

sedation

of

critically

ill

mechanically

ventilated

patients

with

sepsis

is

required

-LRB-

Grade

-RRB-

Rationale

A

growing

body

of

evidence

indicates

that

the

use

of

protocols

for

sedation

of

critically

ill

ventilated

patients

can

reduce

the

duration

of

mechanical

ventilation

and

ICU

and

hospital

length

of

stay

-LSB-

-RSB-

A

randomized

controlled

clinical

trial

found

that

protocol

use

resulted

in

reduced

duration

of

mechanical

ventilation

reduced

lengths

of

stay

and

reduced

tracheostomy

rates

-LSB-

-RSB-

A

report

describing

the

implementation

of

protocols

including

sedation

and

analgesia

using

a

short-cycle

improvement

methodology

in

the

management

of

critically

ill

patients

demonstrated

a

decrease

in

the

cost

per

patient

day

and

a

decrease

of

ICU

length

of

stay

-LSB-

-RSB-

Furthermore

a

prospective

before-and-after

study

on

the

implementation

of

a

sedation

protocol

demonstrated

enhanced

quality

of

sedation

with

reduced

drug

costs

Although

this

protocol

also

may

have

contributed

to

a

longer

duration

of

mechanical

ventilation

ICU

discharge

was

not

delayed

-LSB-

-RSB-

Despite

the

lack

of

evidence

regarding

the

use

of

subjective

methods

of

evaluation

of

sedation

in

septic

patients

the

use

of

a

sedation

goal

has

been

shown

to

decrease

the

duration

of

mechanical

ventilation

in

critically

ill

patients

-LSB-

-RSB-

Several

subjective

sedation

scales

have

been

described

in

the

medical

literature

Currently

however

there

is

not

a

clearly

superior

sedation

evaluation

methodology

against

which

these

sedation

scales

can

be

evaluated

-LSB-

-RSB-

The

benefits

of

sedation

protocols

appear

to

outweigh

the

risks

We

recommend

intermittent

bolus

sedation

or

continuous

infusion

sedation

to

predetermined

end

points

-LRB-

e.

g.

sedation

scales

-RRB-

with

daily

interruption/lightening

of

continuous

infusion

sedation

with

awakening

and

retitration

if

necessary

for

sedation

administration

to

septic

mechanically

ventilated

patients

-LRB-

Grade

-RRB-

Rationale

Although

not

specifically

studied

in

patients

with

sepsis

the

administration

of

intermittent

sedation

daily

interruption

and

retitration

or

systemic

titration

to

a

predefined

end

point

have

been

demonstrated

to

decrease

the

duration

of

mechanical

ventilation

-LSB-

-RSB-

Patients

receiving

neuromuscular

blocking

agents

-LRB-

NMBAs

-RRB-

must

be

individually

assessed

regarding

discontinuation

of

sedative

drugs

because

neuromuscular

blocking

drugs

must

also

be

discontinued

in

that

situation

The

use

of

intermittent

vs.

continuous

methods

for

the

delivery

of

sedation

in

critically

ill

patients

has

been

examined

An

observational

study

of

mechanically-ventilated

patients

showed

that

patients

receiving

continuous

sedation

had

significantly

longer

durations

of

mechanical

ventilation

and

ICU

and

hospital

length

of

stay

-LSB-

-RSB-

Similarly

a

prospective

controlled

study

in

mechanically-ventilated

adults

receiving

continuous

intravenous

sedation

demonstrated

that

a

daily

interruption

in

the

continuous

sedative

infusion

until

the

patient

was

awake

decreased

the

duration

of

mechanical

ventilation

and

ICU

length

of

stay

-LSB-

-RSB-

Although

the

patients

did

receive

continuous

sedative

infusions

in

this

study

the

daily

interruption

and

awakening

allowed

for

titration

of

sedation

in

effect

making

the

dosing

intermittent

Systematic

-LRB-

protocolized

-RRB-

titration

to

a

predefined

end

point

has

also

been

shown

to

alter

outcome

-LSB-

-RSB-

Additionally

a

randomized

prospective

blinded

observational

study

demonstrated

that

although

myocardial

ischemia

is

common

in

critically

ill

ventilated

patients

daily

sedative

interruption

is

not

associated

with

an

increased

occurrence

of

myocardial

ischemia

-LSB-

-RSB-

Thus

the

benefits

of

daily

interruption

of

sedation

appear

to

outweigh

the

risks

These

benefits

include

potentially

shorter

duration

of

mechanical

ventilation

and

ICU

stay

better

assessment

of

neurologic

function

and

reduced

costs

We

recommend

that

NMBAs

be

avoided

if

possible

in

the

septic

patient

due

to

the

risk

of

prolonged

neuromuscular

blockade

following

discontinuation

If

NMBAs

must

be

maintained

either

intermittent

bolus

as

required

or

continuous

infusion

with

monitoring

the

depth

of

blockade

with

train-of-four

monitoring

should

be

used

-LRB-

Grade

-RRB-

Rationale

Although

NMBAs

are

often

administered

to

critically

ill

patients

their

role

in

the

ICU

setting

is

not

well

defined

No

evidence

exists

that

maintaining

neuromuscular

blockade

in

this

patient

population

reduces

mortality

or

major

morbidity

In

addition

no

studies

have

been

published

that

specifically

address

the

use

of

NMBAs

in

septic

patients

The

most

common

indication

for

NMBA

use

in

the

ICU

is

to

facilitate

mechanical

ventilation

-LSB-

-RSB-

When

appropriately

utilized

NMBAs

may

improve

chest

wall

compliance

prevent

respiratory

dyssynchrony

and

reduce

peak

airway

pressures

-LSB-

-RSB-

Muscle

paralysis

may

also

reduce

oxygen

consumption

by

decreasing

the

work

of

breathing

and

respiratory

muscle

blood

flow

-LSB-

-RSB-

However

a

randomized

placebo-controlled

clinical

trial

in

patients

with

severe

sepsis

demonstrated

that

oxygen

delivery

oxygen

consumption

and

gastric

intramucosal

pH

were

not

improved

during

profound

neuromuscular

blockade

-LSB-

-RSB-

An

association

between

NMBA

use

and

myopathies

and

neuropathies

has

been

suggested

by

case

studies

and

prospective

observational

studies

in

the

critical

care

population

-LSB-

-RSB-

The

mechanisms

by

which

NMBA

's

produced

or

contribute

to

myopathies

and

neuropathies

in

critically

ill

patients

are

presently

unknown

There

appears

to

be

an

added

association

with

the

concurrent

use

o

NMBA

's

and

steroids

Although

no

specific

studies

exist

specific

to

the

septic

patient

population

it

seems

clinically

prudent

based

on

existent

knowledge

that

NMBA

's

not

be

administered

unless

there

is

a

clear

indication

for

neuromuscular

blockade

that

can

not

be

safely

achieved

with

appropriate

sedation

and

analgesia

-LSB-

-RSB-

Only

one

prospective

randomized

clinical

trial

has

evaluated

peripheral

nerve

stimulation

vs.

standard

clinical

assessment

in

ICU

patients

Rudis

et

al.

-LSB-

-RSB-

randomized

critically

ill

patients

requiring

neuromuscular

blockade

in

the

ICU

to

receive

dosing

of

vecuronium

based

on

train-of-four

stimulation

or

clinical

assessment

-LRB-

control

-RRB-

The

peripheral

nerve

stimulation

group

received

less

drug

and

recovered

neuromuscular

function

and

spontaneous

ventilation

faster

than

the

control

group

Nonrandomized

observational

studies

have

suggested

that

peripheral

nerve

monitoring

reduces

or

has

no

effect

on

clinical

recovery

from

NMBAs

in

the

ICU

setting

-LSB-

-RSB-

Benefits

to

neuromuscular

monitoring

including

faster

recovery

of

neuromuscular

function

and

shorter

intubation

times

appear

to

exist

A

potential

for

cost

savings

-LRB-

reduced

total

dose

of

NMBAs

and

shorter

intubation

times

-RRB-

also

may

exist

although

this

has

not

been

studied

formally

C.

Glucose

Control

We

recommend

that

following

initial

stabilization

patients

with

severe

sepsis

and

hyperglycemia

who

are

admitted

to

the

ICU

receive

IV

insulin

therapy

to

reduce

blood

glucose

levels

-LRB-

Grade

-RRB-

We

suggest

use

of

a

validated

protocol

for

insulin

dose

adjustments

and

targeting

glucose

levels

to

the

mg/dl

range

-LRB-

Grade

-RRB-

We

recommend

that

all

patients

receiving

intravenous

insulin

receive

a

glucose

calorie

source

and

that

blood

glucose

values

be

monitored

every

hours

until

glucose

values

and

insulin

infusion

rates

are

stable

and

then

every

hours

thereafter

-LRB-

Grade

-RRB-

We

recommend

that

low

glucose

levels

obtained

with

point-of-care

testing

of

capillary

blood

be

interpreted

with

caution

as

such

measurements

may

overestimate

arterial

blood

or

plasma

glucose

values

-LRB-

Grade

-RRB-

Rationale

The

consensus

on

glucose

control

in

severe

sepsis

was

achieved

at

the

first

committee

meeting

and

subsequently

approved

by

the

entire

committee

-LRB-

see

Appendix

G

for

committee

vote

-RRB-

One

large

randomized

single

center

trial

in

a

predominantly

cardiac

surgical

ICU

demonstrated

a

reduction

in

ICU

mortality

with

intensive

IV

insulin

-LRB-

Leuven

Protocol

-RRB-

targeting

blood

glucose

to

mg/dl

-LRB-

for

all

patients

relative

and

absolute

mortality

reduction

and

for

those

with

day

ICU

length

of

stays

-LRB-

LOS

-RRB-

a

relative

and

absolute

mortality

reduction

-RRB-

-LSB-

-RSB-

A

reduction

in

organ

dysfunction

and

ICU

LOS

-LRB-

from

a

median

of

days

-RRB-

was

also

observed

in

the

subset

with

ICU

LOS

days

A

second

randomized

trial

of

intensive

insulin

therapy

using

the

Leuven

Protocol

enrolled

medical

ICU

patients

with

an

anticipated

ICU

LOS

of

days

in

three

MICUs

-LSB-

-RSB-

Overall

mortality

was

not

reduced

but

ICU

and

hospital

LOS

were

reduced

associated

with

earlier

weaning

from

mechanical

ventilation

and

less

acute

kidney

injury

In

patients

with

a

medical

ICU

LOS

days

hospital

mortality

was

reduced

with

intensive

insulin

therapy

-LRB-

versus

p

-RRB-

However

investigators

were

unsuccessful

in

predicting

ICU

LOS

and

patients

-LRB-

-RRB-

had

an

ICU

LOS

of

days

Furthermore

use

of

the

Leuven

Protocol

in

the

medical

ICU

resulted

in

a

nearly

three-fold

higher

rate

of

hypoglycemia

than

in

the

original

experience

-LRB-

versus

of

patients

-RRB-

-LSB-

-RSB-

One

large

before-and-after

observational

trial

showed

a

relative

and

absolute

reduction

in

mortality

and

a

reduction

in

median

ICU

LOS

-LSB-

-RSB-

In

a

subgroup

of

patients

with

septic

shock

there

was

an

absolute

mortality

reduction

of

and

a

relative

reduction

of

-LRB-

p

-RRB-

Two

additional

observational

studies

report

an

association

of

mean

glucose

levels

with

reductions

in

mortality

polyneuropathy

acute

renal

failure

nosocomial

bacteremia

and

number

of

transfusions

and

suggest

a

glucose

threshold

for

improved

mortality

lies

somewhere

between

and

mg/dl

-LSB-

-RSB-

However

a

large

observational

study

-LRB-

n

-RRB-

suggested

that

both

a

lower

mean

glucose

and

less

variation

of

blood

glucose

may

be

important

-LSB-

-RSB-

A

meta-analysis

of

trials

on

insulin

therapy

in

critically

ill

patients

including

randomized

trials

demonstrated

a

reduction

in

short

term

mortality

-LRB-

RR

confidence

interval

-RRB-

but

did

not

include

any

studies

of

insulin

therapy

in

medical

ICUs

-LSB-

-RSB-

Two

additional

multicenter

RCTs

of

intensive

insulin

therapy

one

focusing

on

patients

with

severe

sepsis

-LRB-

VISEP

-RRB-

and

the

second

on

medical

and

surgical

ICU

patients

failed

to

demonstrate

improvement

in

mortality

but

are

not

yet

published

-LSB-

-RSB-

Both

stopped

earlier

than

planned

because

of

high

rates

of

hypoglycemia

and

adverse

events

in

the

intensive

insulin

groups

A

large

RCT

that

is

planned

to

compare

targeting

mg/dl

-LRB-

mmol/L

-RRB-

versus

mg/dl

-LRB-

mmol/L

-RRB-

and

recruit

more

than

patients

-LRB-

Normoglycemia

in

Intensive

Care

Evaluation

and

Survival

Using

Glucose

Algorithm

Regulation

or

NICE-SUGAR

-RRB-

is

ongoing

-LSB-

-RSB-

Several

factors

may

affect

the

accuracy

and

reproducibility

of

point-of-care

testing

of

blood

capillary

blood

glucose

including

the

type

and

model

of

the

device

used

user

expertise

and

patient

factors

including

hematocrit

-LRB-

false

elevation

with

anemia

-RRB-

and

drugs

-LSB-

-RSB-

One

report

showed

overestimation

of

arterial

plasma

glucose

values

by

capillary

point-of-care

testing

sufficient

to

result

in

different

protocol-specified

insulin

dose

titration

The

disagreement

between

protocol-recommended

insulin

doses

was

largest

when

glucose

values

were

low

-LSB-

-RSB-

A

recent

review

of

published

insulin

infusion

protocols

for

critically

ill

patients

showed

wide

variability

in

insulin

dose

recommendations

and

variable

glucose

control

during

simulation

-LSB-

-RSB-

This

lack

of

consensus

about

optimal

dosing

of

IV

insulin

may

reflect

variability

in

patient

factors

-LRB-

severity

of

illness

surgical

vs.

medical

settings

etc

-RRB-

or

practice

patterns

-LRB-

e.

g.

approaches

to

feeding

IV

dextrose

-RRB-

in

the

environments

in

which

these

protocols

were

developed

and

tested

Alternatively

some

protocols

may

be

more

effective

than

other

protocols

This

conclusion

is

supported

by

the

wide

variability

in

hypoglycemia

rates

reported

with

protocols

-LSB-

-RSB-

Thus

the

use

of

a

validated

and

safe

intensive

insulin

protocol

is

important

not

only

for

clinical

care

but

also

for

the

conduct

of

clinical

trials

to

avoid

hypoglycemia

adverse

events

and

premature

termination

of

these

trials

before

the

efficacy

signal

if

any

can

be

determined

The

finding

of

reduced

morbidity

and

mortality

within

the

longer

ICU

length

of

stay

subsets

along

with

acceptable

cost

weighed

heavily

on

our

recommendation

to

attempt

glucose

control

after

initial

stabilization

of

the

patient

with

hyperglycemia

and

severe

sepsis

However

the

mortality

benefit

and

safety

of

intensive

insulin

therapy

-LRB-

goal

to

normalize

blood

glucose

-RRB-

has

been

questioned

by

recent

trials

and

we

recommend

maintaining

glucose

levels

mg/dl

until

recent

and

ongoing

trials

are

published

or

completed

Further

study

of

protocols

that

have

been

validated

to

be

safe

and

effective

for

controlling

blood

glucose

concentrations

and

blood

glucose

variation

in

the

severe

sepsis

population

are

needed

D.

Renal

Replacement

We

suggest

that

continuous

renal

replacement

therapies

and

intermittent

hemodialysis

are

equivalent

in

patients

with

severe

sepsis

and

acute

renal

failure

-LRB-

Grade

-RRB-

We

suggest

the

use

of

continuous

therapies

to

facilitate

management

of

fluid

balance

in

hemodynamically

unstable

septic

patients

-LRB-

Grade

-RRB-

Rationale

Although

numerous

nonrandomized

studies

have

reported

a

nonsignificant

trend

toward

improved

survival

using

continuous

methods

-LSB-

-RSB-

meta-analyses

-LSB-

-RSB-

report

the

absence

of

significant

difference

in

hospital

mortality

between

patients

who

receive

continuous

and

intermittent

renal

replacement

therapies

This

absence

of

apparent

benefit

of

one

modality

over

the

other

persists

even

when

the

analysis

is

restricted

to

only

randomized

studies

-LSB-

-RSB-

To

date

prospective

randomized

studies

have

been

published

-LSB-

-RSB-

Four

of

them

found

no

significant

difference

in

mortality

-LSB-

-RSB-

One

study

found

significantly

higher

mortality

in

the

continuous

treatment

group

-LSB-

-RSB-

but

imbalanced

randomization

had

led

to

a

higher

baseline

severity

of

illness

in

this

group

When

a

multivariable

model

was

used

to

adjust

for

severity

of

illness

no

difference

in

mortality

was

apparent

between

the

groups

-LSB-

-RSB-

It

is

important

to

note

that

most

studies

comparing

modes

of

renal

replacement

in

the

critically

ill

have

included

a

small

number

of

patients

and

some

major

weaknesses

-LRB-

randomization

failure

modifications

of

therapeutic

protocol

during

the

study

period

combination

of

different

types

of

continuous

renal

replacement

therapies

small

number

of

heterogenous

groups

of

patients

enrolled

-RRB-

The

most

recent

and

largest

randomized

study

-LSB-

-RSB-

enrolled

patients

and

found

no

significant

difference

in

survival

between

the

groups

Moreover

there

is

no

current

evidence

to

support

the

use

of

continuous

therapies

in

sepsis

independent

of

renal

replacement

needs

Concerning

the

hemodynamic

tolerance

of

each

method

no

current

evidence

exists

to

support

a

better

tolerance

with

continuous

treatments

Only

prospective

studies

-LSB-

-RSB-

have

reported

a

better

hemodynamic

tolerance

with

continuous

treatment

with

no

improvement

in

regional

perfusion

-LSB-

-RSB-

and

no

survival

benefit

-LSB-

-RSB-

Four

other

prospective

studies

did

not

find

any

significant

difference

in

mean

arterial

pressure

or

drop

in

systolic

pressure

between

the

methods

-LSB-

-RSB-

Concerning

fluid

balance

management

studies

report

a

significant

improvement

in

goal

achievement

with

continuous

methods

-LSB-

-RSB-

In

summary

current

evidence

is

insufficient

to

draw

strong

conclusions

regarding

the

mode

of

replacement

therapy

for

acute

renal

failure

in

septic

patients

Four

randomized

controlled

trials

have

addressed

whether

the

dose

of

continuous

renal

replacement

affects

outcomes

in

patients

with

acute

renal

failure

-LSB-

-RSB-

Three

found

improved

mortality

in

patients

receiving

higher

doses

of

renal

replacement

-LSB-

-RSB-

while

one

-LSB-

-RSB-

did

not

of

these

trials

was

conducted

specifically

in

patients

with

sepsis

Although

the

weight

of

current

evidence

suggests

that

higher

doses

of

renal

replacement

may

be

associated

with

improved

outcomes

these

results

may

not

be

easily

generalizable

The

results

of

very

large

multicenter

randomized

trials

comparing

the

dose

of

renal

replacement

-LRB-

ATN

in

the

United

States

and

RENAL

in

Australia

and

New

Zealand

-RRB-

will

be

available

in

and

will

greatly

inform

practice

E.

Bicarbonate

Therapy

We

recommendagainst

the

use

of

sodium

bicarbonate

therapy

for

the

purpose

of

improving

hemodynamics

or

reducing

vasopressor

requirements

in

patients

with

hypoperfusion-induced

lactic

acidemia

with

pH

-LRB-

Grade

-RRB-

Rationale

No

evidence

supports

the

use

of

bicarbonate

therapy

in

the

treatment

of

hypoperfusion-induced

lactic

acidemia

associated

with

sepsis

Two

randomized

blinded

crossover

studies

that

compared

equimolar

saline

and

bicarbonate

in

patients

with

lactic

acidosis

failed

to

reveal

any

difference

in

hemodynamic

variables

or

vasopressor

requirements

-LSB-

-RSB-

The

number

of

patients

with

pH

in

these

studies

was

small

Bicarbonate

administration

has

been

associated

with

sodium

and

fluid

overload

an

increase

in

lactate

and

and

a

decrease

in

serum

ionized

calcium

but

the

relevance

of

these

parameters

to

outcome

is

uncertain

The

effect

of

bicarbonate

administration

on

hemodynamics

and

vasopressor

requirements

at

lower

pH

as

well

as

the

effect

on

clinical

outcomes

at

any

pH

is

unknown

No

studies

have

examined

the

effect

of

bicarbonate

administration

on

outcomes

F.

Deep

Vein

Thrombosis

Prophylaxis

We

recommend

that

severe

sepsis

patients

receive

deep

vein

thrombosis

-LRB-

DVT

-RRB-

prophylaxis

with

either

-LRB-

a

-RRB-

low-dose

unfractionated

heparin

-LRB-

UFH

-RRB-

administered

b.i.d.

or

t.i.d.

or

-LRB-

b

-RRB-

daily

low-molecular

weight

heparin

-LRB-

LMWH

-RRB-

unless

there

are

contraindications

-LRB-

i.

e.

thrombocytopenia

severe

coagulopathy

active

bleeding

recent

intracerebral

hemorrhage

-RRB-

-LRB-

Grade

-RRB-

We

recommend

that

septic

patients

who

have

a

contraindication

for

heparin

use

receive

mechanical

prophylactic

device

such

as

graduated

compression

stockings

-LRB-

GCS

-RRB-

or

intermittent

compression

devices

-LRB-

ICD

-RRB-

unless

contraindicated

-LRB-

Grade

-RRB-

We

suggest

that

in

very

high-risk

patients

such

as

those

who

have

severe

sepsis

and

history

of

DVT

trauma

or

orthopedic

surgery

a

combination

of

pharmacologic

and

mechanical

therapy

be

used

unless

contraindicated

or

not

practical

-LRB-

Grade

-RRB-

We

suggest

that

in

patients

at

very

high

risk

LMWH

be

used

rather

than

UFH

as

LMWH

is

proven

superior

in

other

high-risk

patients

-LRB-

Grade

-RRB-

Rationale

ICU

patients

are

at

risk

for

DVT

-LSB-

-RSB-

Significant

evidence

exists

for

benefit

of

DVT

prophylaxis

in

ICU

patients

in

general

No

reasons

suggest

that

severe

sepsis

patients

would

be

different

from

the

general

patient

population

Nine

randomized

placebo

controlled

clinical

trials

of

DVT

prophylaxis

in

general

populations

of

acutely

ill

patients

exist

-LSB-

-RSB-

All

trials

showed

reduction

in

DVT

or

PE

The

prevalence

of

infection/sepsis

was

in

all

studies

in

which

this

was

ascertainable

with

a

prevalence

of

infection/sepsis

patients

in

the

study

that

included

ICU

patients

only

Benefit

of

DVT

prophylaxis

is

also

supported

by

meta-analyses

-LSB-

-RSB-

With

that

in

mind

DVT

prophylaxis

would

appear

to

have

a

high

grade

for

quality

of

evidence

-LRB-

A

-RRB-

As

the

risk

of

administration

to

the

patient

is

small

the

gravity

of

the

potential

result

of

not

administering

is

great

and

the

cost

is

low

the

grading

of

the

strength

of

the

recommendation

is

strong

The

evidence

supports

equivalency

of

LMWH

and

UFH

in

general

medical

populations

A

recent

meta-analysis

comparing

b.i.d.

and

t.i.d.

UFH

demonstrated

that

t.i.d.

UFH

produced

better

efficacy

and

b.i.d.

less

bleeding

-LSB-

-RSB-

Practitioners

should

use

underlying

risk

for

VTE

and

bleeding

to

individualize

choice

of

b.i.d.

versus

t.i.d.

The

cost

of

LMWH

is

greater

and

the

frequency

of

injection

is

less

UFH

is

preferred

over

LMWH

in

patients

with

moderate

to

severe

renal

dysfunction

Mechanical

methods

-LRB-

ICD

and

GCS

-RRB-

are

recommended

when

anticoagulation

is

contraindicated

or

as

an

adjunct

to

anticoagulation

in

the

very

high-risk

patients

-LSB-

-RSB-

In

very

high-risk

patients

LMWH

is

preferred

over

UFH

-LSB-

-RSB-

Patients

receiving

heparin

should

be

monitored

for

development

of

heparin-induced

thrombocytopenia

-LRB-

HIT

-RRB-

G.

Stress

Ulcer

Prophylaxis

-LRB-

SUP

-RRB-

We

recommend

that

stress

ulcer

prophylaxis

using

blocker

-LRB-

Grade

-RRB-

or

proton

pump

inhibitor

PPI

-LRB-

Grade

-RRB-

be

given

to

patients

with

severe

sepsis

to

prevent

upper

GI

bleed

Benefit

of

prevention

of

upper

GI

bleed

must

be

weighed

against

potential

effect

of

an

increased

stomach

pH

on

development

of

ventilator-associated

pneumonia

Rationale

Although

no

study

has

been

performed

specifically

in

patients

with

severe

sepsis

trials

confirming

the

benefit

of

stress

ulcer

prophylaxis

reducing

upper

GI

bleeds

in

general

ICU

populations

would

suggest

that

of

patients

enrolled

in

these

types

of

trials

have

sepsis

-LSB-

-RSB-

This

benefit

should

be

applicable

to

patients

with

severe

sepsis

and

septic

shock

In

addition

the

conditions

shown

to

benefit

from

stress

ulcer

prophylaxis

-LRB-

coagulopathy

mechanical

ventilation

hypotension

-RRB-

are

frequently

present

in

patients

with

severe

sepsis

and

septic

shock

-LSB-

-RSB-

Although

there

are

individual

trials

that

have

not

shown

benefit

from

SUP

numerous

trials

and

a

meta-analysis

show

reduction

in

clinically

significant

upper

GI

bleeding

which

we

consider

significant

even

in

the

absence

of

proven

mortality

benefit

-LSB-

-RSB-

The

benefit

of

prevention

of

upper

GI

bleed

must

be

weighed

against

the

potential

effect

of

increased

stomach

pH

on

greater

incidence

of

ventilator-associated

pneumonia

-LSB-

-RSB-

Those

severe

sepsis

patients

with

the

greatest

risk

of

upper

GI

bleeding

are

likely

to

benefit

most

from

stress

ulcer

prophylaxis

The

rationale

for

the

preference

for

suppression

of

acid

production

over

sulcrafate

was

based

on

the

study

of

patients

by

Cook

et

al

comparing

blockers

and

sucralfate

and

a

meta-analysis

-LSB-

-RSB-

studies

support

equivalency

between

blockers

and

PPIs

One

was

in

very

ill

ICU

patients

The

second

study

is

larger

and

demonstrates

non-inferiority

of

omeprazole

suspension

for

clinically

significant

stress

ulcer

bleeding

-LSB-

-RSB-

No

data

relating

to

utility

of

enteral

feeding

in

stress

ulcer

prophylaxis

exist

Patients

should

be

periodically

evaluated

for

continued

need

for

prophylaxis

H.

Selective

Digestive

Tract

Decontamination

-LRB-

SDD

-RRB-

The

guidelines

group

was

evenly

split

on

the

issue

of

SDD

with

equal

numbers

weakly

in

favor

and

against

recommending

the

use

of

SDD

-LRB-

see

appendix

H

-RRB-

The

committee

therefore

chose

not

to

make

a

recommendation

for

the

use

of

SDD

specifically

in

severe

sepsis

at

this

time

The

final

consensus

on

use

of

SDD

in

severe

sepsis

was

achieved

at

the

last

nominal

committee

meeting

and

subsequently

approved

by

the

entire

committee

-LRB-

see

Appendix

H

for

committee

vote

-RRB-

Rationale

The

cumulative

conclusion

from

the

literature

demonstrates

that

prophylactic

use

of

SDD

-LRB-

enteral

non-absorbable

antimicrobials

and

short-course

intravenous

antibiotics

-RRB-

reduces

infections

mainly

pneumonia

and

mortality

in

the

general

population

of

critically

ill

and

trauma

patients

-LSB-

-RSB-

without

promoting

emergence

of

resistant

Gram

negative

bacteria

Post

hoc

subgroup

analyses

-LSB-

-RSB-

of

two

prospective

blinded

studies

-LSB-

-RSB-

suggest

that

SDD

reduces

nosocomial

-LRB-

secondary

-RRB-

infections

in

ICU

patients

admitted

with

primary

infections

-LSB-

-RSB-

and

may

reduce

mortality

-LSB-

-RSB-

No

studies

of

SDD

specifically

focused

on

patients

with

severe

sepsis

or

septic

shock

The

use

of

SDD

in

severe

sepsis

patients

would

be

targeted

toward

preventing

secondary

infection

As

the

main

effect

of

SDD

is

in

preventing

ventilator-associated

pneumonia

-LRB-

VAP

-RRB-

studies

comparing

SDD

with

non-antimicrobial

interventions

such

as

ventilator

bundles

for

reducing

VAP

are

needed

Further

investigation

is

required

to

determine

the

comparative

efficacy

of

these

two

interventions

separately

or

in

combination

Although

studies

incorporating

enteral

vancomycin

in

the

regimen

appear

to

be

safe

-LSB-

-RSB-

concerns

persist

about

the

potential

for

emergence

of

resistant

Gram

positive

infections

I.

Consideration

for

Limitation

of

Support

We

recommend

that

advance

care

planning

including

the

communication

of

likely

outcomes

and

realistic

goals

of

treatment

be

discussed

with

patients

and

families

-LRB-

Grade

-RRB-

Rationale

Decisions

for

less

aggressive

support

or

withdrawal

of

support

may

be

in

the

patient

's

best

interest

-LSB-

-RSB-

Too

frequently

inadequate

physician/family

communication

characterizes

end-of-life

care

in

the

ICU

The

level

of

life

support

given

to

ICU

patients

may

not

be

consistent

with

their

wishes

Early

and

frequent

caregiver

discussions

with

patients

who

face

death

in

the

ICU

and

with

their

loved

ones

may

facilitate

appropriate

application

and

withdrawal

of

life-sustaining

therapies

A

recent

RCT

demonstrated

reduction

of

anxiety

and

depression

in

family

members

when

end-of-life

meetings

were

carefully

planned

conducted

included

advance

care

planning

and

provided

relevant

information

about

diagnosis

prognosis

and

treatment

-LSB-

-RSB-

III

Pediatric

Considerations

in

Severe

Sepsis

While

sepsis

in

children

is

a

major

cause

of

mortality

the

overall

mortality

from

severe

sepsis

in

children

is

much

lower

that

that

in

adults

estimated

at

about

-LSB-

-RSB-

The

definitions

for

severe

sepsis

and

septic

shock

in

children

are

similar

but

not

identical

to

the

definitions

in

adults

-LSB-

-RSB-

In

addition

to

age-appropriate

differences

in

vital

signs

the

definition

of

systemic

inflammatory

response

syndrome

requires

the

presence

of

either

temperature

or

leukocyte

abnormalities

The

presence

of

severe

sepsis

requires

sepsis

plus

cardiovascular

dysfunction

or

ARDS

or

or

more

other

organ

dysfunctions

-LSB-

-RSB-

A.

Antibiotics

We

recommend

antibiotics

be

administered

within

one

hour

of

the

identification

of

severe

sepsis

after

appropriate

cultures

have

been

obtained

-LRB-

Grade

-RRB-

Early

antibiotic

therapy

is

as

critical

for

children

with

severe

sepsis

as

it

is

for

adults

B.

Mechanical

Ventilation

No

graded

recommendations

Due

to

low

functional

residual

capacity

young

infants

and

neonates

with

severe

sepsis

may

require

early

intubation

-LSB-

-RSB-

Drugs

used

for

intubation

have

important

side

effects

in

these

patients

for

example

concerns

have

been

raised

about

the

safety

of

using

etomidate

in

children

with

meningococcal

sepsis

because

of

adrenal

suppression

effect

-LSB-

-RSB-

The

principles

of

lung-protective

strategies

are

applied

to

children

as

they

are

to

adults

C.

Fluid

Resuscitation

We

suggest

initial

resuscitation

begin

with

infusion

of

crystalloids

with

boluses

of

mL/kg

over

minutes

titrated

to

clinical

monitors

of

cardiac

output

including

heart

rate

urine

output

capillary

refill

and

level

of

consciousness

-LRB-

Grade

-RRB-

Intravenous

access

for

fluid

resuscitation

and

inotrope/vasopressor

infusion

is

more

difficult

to

attain

in

children

than

in

adults

The

American

Heart

Association

along

with

the

American

Academy

of

Pediatrics

has

developed

pediatric

advanced

life

support

guidelines

for

emergency

establishment

of

intravascular

support

encouraging

early

intraosseous

access

-LSB-

-RSB-

On

the

basis

of

a

number

of

studies

it

is

accepted

that

aggressive

fluid

resuscitation

with

crystalloids

or

colloids

is

of

fundamental

importance

to

survival

of

septic

shock

in

children

-LSB-

-RSB-

Three

randomized

controlled

trials

compare

the

use

of

colloid

to

crystalloid

resuscitation

in

children

with

dengue

shock

-LSB-

-RSB-

No

difference

in

mortality

between

colloid

or

crystalloid

resuscitation

was

shown

Children

normally

have

a

lower

blood

pressure

than

adults

and

fall

in

blood

pressure

can

be

prevented

by

vasoconstriction

and

increasing

heart

rate

Therefore

blood

pressure

by

itself

is

not

a

reliable

end

point

for

assessing

the

adequacy

of

resuscitation

However

once

hypotension

occurs

cardiovascular

collapse

may

soon

follow

Hepatomegaly

occurs

in

children

who

are

fluid

overloaded

and

can

be

a

helpful

sign

of

adequacy

of

fluid

resuscitation

Large

fluid

deficits

typically

exist

and

initial

volume

resuscitation

usually

requires

mL/kg

but

can

be

much

higher

-LSB-

-RSB-

However

the

rate

of

fluid

administration

should

be

reduced

substantially

when

there

are

-LRB-

clinical

-RRB-

signs

of

adequate

cardiac

filling

without

hemodynamic

improvement

D.

Vasopressors/Inotropes

-LRB-

should

be

used

in

volume

loaded

patients

with

fluid

refractory

shock

-RRB-

We

suggest

dopamine

as

the

first

choice

of

support

for

the

pediatric

patient

with

hypotension

refractory

to

fluid

resuscitation

-LRB-

Grade

-RRB-

In

the

initial

resuscitation

phase

vasopressor

therapy

may

be

required

to

sustain

perfusion

pressure

even

when

hypovolemia

has

not

yet

been

resolved

Children

with

severe

sepsis

can

present

with

low

cardiac

output

and

high

systemic

vascular

resistance

high

cardiac

output

and

low

systemic

vascular

resistance

or

low

cardiac

output

and

low

systemic

vascular

resistance

shock

At

various

stages

of

sepsis

or

the

treatment

thereof

a

child

may

move

from

one

hemodynamic

state

to

another

Vasopressor

or

inotrope

therapy

should

be

used

according

to

the

clinical

state

of

the

child

Dopamine-refractory

shock

may

reverse

with

epinephrine

or

norepinephrine

infusion

-LSB-

-RSB-

We

suggest

that

patients

with

low

cardiac

output

and

elevated

systemic

vascular

resistance

states

-LRB-

cool

extremities

prolonged

capillary

refill

decreased

urine

output

but

normal

blood

pressure

following

fluid

resuscitation

-RRB-

be

given

dobutamine

-LRB-

Grade

-RRB-

The

choice

of

vasoactive

agent

is

determined

by

the

clinical

examination

For

the

child

with

a

persistent

low

cardiac

output

state

with

high

systemic

vascular

resistance

despite

fluid

resuscitation

and

inotropic

support

vasodilator

therapy

may

reverse

shock

-LSB-

-RSB-

When

pediatric

patients

remain

in

a

normotensive

low

cardiac

output

and

high

vascular

resistance

state

despite

epinephrine

and

vasodilator

therapy

the

use

of

a

phosphodiesterase

inhibitor

may

be

considered

-LSB-

-RSB-

In

the

case

of

extremely

low

systemic

vascular

resistance

despite

the

use

of

norepinephrine

vasopressin

use

has

been

described

in

a

number

of

case-reports

Thus

far

there

is

no

clear

evidence

for

the

use

of

vasopressin

in

pediatric

sepsis

-LSB-

-RSB-

E.

Therapeutic

End

Points

We

suggest

that

the

therapeutic

end

points

of

resuscitation

of

septic

shock

be

normalization

of

the

heart

rate

capillary

refill

of

secs

normal

pulses

with

no

differential

between

peripheral

and

central

pulses

warm

extremities

urine

output

kg

hr

and

normal

mental

status

-LSB-

-RSB-

-LRB-

Grade

-RRB-

Capillary

refill

may

be

less

reliable

in

a

cold

environment

Other

end

points

that

have

been

widely

used

in

adults

and

may

logically

apply

to

children

include

decreased

lactate

and

improved

base

deficit

or

CVP

of

mm

Hg

or

other

methods

to

analyze

cardiac

filling

Optimizing

preload

optimizes

cardiac

index

When

using

measurements

to

assist

in

identifying

acceptable

cardiac

output

in

children

with

systemic

arterial

hypoxemia

such

as

cyanotic

congenital

heart

disease

or

severe

pulmonary

disease

arterial-venous

oxygen

content

difference

is

a

better

marker

than

mixed

venous

hemoglobin

saturation

with

oxygen

As

noted

previously

blood

pressure

by

itself

is

not

a

reliable

end

point

for

resuscitation

If

a

thermodilution

catheter

is

used

therapeutic

end

points

are

cardiac

index

and

L.min

m

with

normal

coronary

perfusion

pressure

-LRB-

mean

arterial

pressure

central

venous

pressure

-RRB-

for

age

-LSB-

-RSB-

Using

clinical

endpoints

such

as

reversal

of

hypotension

and

restoration

of

capillary

refill

for

initial

resuscitation

at

the

community

hospital

level

before

transfer

to

a

tertiary

center

was

associated

with

significantly

improved

survival

rates

in

children

with

septic

shock

-LSB-

-RSB-

Development

of

a

transport

system

including

publicizing

to

local

hospitals

and

transport

with

mobile

intensive

care

services

significantly

decreased

the

case

fatality

rate

from

meningococcal

disease

in

the

United

Kingdom

-LSB-

-RSB-

F.

Approach

to

Pediatric

Septic

Shock

Figure

shows

a

flow

diagram

summarizing

an

approach

to

pediatric

septic

shock

-LSB-

-RSB-

Fig.

to

Pediatric

Shock

G.

Steroids

We

suggest

that

hydrocortisone

therapy

be

reserved

for

use

in

children

with

catecholamine

resistance

and

suspected

or

proven

adrenal

insufficiency

-LRB-

Grade

-RRB-

Patients

at

risk

for

adrenal

insufficiency

include

children

with

severe

septic

shock

and

purpura

-LSB-

-RSB-

children

who

have

previously

received

steroid

therapies

for

chronic

illness

and

children

with

pituitary

or

adrenal

abnormalities

Children

who

have

clear

risk

factors

for

adrenal

insufficiency

should

be

treated

with

stress

dose

steroids

-LRB-

hydrocortisone

-RRB-

Adrenal

insufficiency

in

pediatric

severe

sepsis

is

associated

with

a

poor

prognosis

-LSB-

-RSB-

No

strict

definitions

exist

but

absolute

adrenal

insufficiency

in

the

case

of

catecholamine-resistant

septic

shock

is

assumed

at

a

random

total

cortisol

concentration

μg/dL

-LRB-

nmol/L

-RRB-

A

post

or

ACTH

stimulation

test

increase

in

cortisol

of

μg/dL

-LRB-

mmol/L

-RRB-

has

been

used

to

define

relative

adrenal

insufficiency

The

treatment

of

relative

adrenal

insufficiency

in

children

with

septic

shock

is

controversial

A

retrospective

study

from

a

large

administrative

database

recently

reported

that

the

use

of

any

corticosteroids

in

children

with

severe

sepsis

was

associated

with

increased

mortality

-LRB-

OR

CI

-RRB-

-LSB-

-RSB-

While

steroids

may

have

been

given

preferentially

to

more

severely

ill

children

the

use

of

steroids

was

an

independent

predictor

of

mortality

in

multivariable

analysis

-LSB-

-RSB-

Given

the

lack

of

data

in

children

and

potential

risk

steroids

should

not

be

used

in

those

children

who

do

not

meet

minimal

criteria

for

adrenal

insufficiency

A

randomized

controlled

trial

in

children

with

septic

shock

is

very

much

needed

H.

Protein

C

and

Activated

Protein

C

We

recommendagainst

the

use

rhAPC

in

children

-LRB-

Grade

-RRB-

Protein

C

concentrations

in

children

reach

adult

values

at

the

age

of

yrs

This

might

indicate

that

the

importance

of

protein

C

supplementation

either

as

protein

C

concentrate

or

as

rhAPC

is

even

greater

in

young

children

than

in

adults

-LSB-

-RSB-

There

has

been

one

dose

finding

randomized

placebo-controlled

study

performed

using

protein

C

concentrate

This

study

was

not

powered

to

show

an

effect

on

mortality

rate

but

did

show

a

positive

effect

on

sepsis-induced

coagulation

disturbances

-LSB-

-RSB-

An

RCT

of

rhAPC

in

pediatric

severe

sepsis

patients

was

stopped

by

recommendation

of

the

Data

Monitoring

Committee

for

futility

after

enrollment

of

patients

all

cause

mortality

placebo

group

vs.

APC

group

Major

amputations

occurred

in

of

the

placebo

group

vs.

in

the

APC

group

-LSB-

-RSB-

Due

to

the

increased

risk

of

bleeding

-LRB-

vs.

in

the

pediatric

trial

-RRB-

and

lack

of

proof

of

efficacy

rhAPC

is

not

recommended

for

use

in

children

I.

DVT

Prophylaxis

We

suggest

the

use

of

DVT

prophylaxis

in

post-pubertal

children

with

severe

sepsis

-LRB-

Grade

-RRB-

Most

DVTs

in

young

children

are

associated

with

central

venous

catheters

Femoral

venous

catheters

are

commonly

used

in

children

and

central

venous

catheter-associated

DVTs

occur

in

approximately

of

children

with

a

femoral

central

venous

catheter

Heparin-bonded

catheters

may

decrease

the

risk

of

catheter-associated

DVT

and

should

be

considered

for

use

in

children

with

severe

sepsis

-LSB-

-RSB-

No

data

on

the

efficacy

of

unfractionated

or

low-molecular

weight

heparin

prophylaxis

to

prevent

catheter-related

DVT

in

children

in

the

ICU

exist

J.

Stress

Ulcer

Prophylaxis

No

graded

recommendations

Studies

have

shown

that

the

rate

of

clinically

important

gastrointestinal

bleeding

in

children

occurs

at

rates

similar

to

adults

-LSB-

-RSB-

As

in

adults

coagulopathy

and

mechanical

ventilation

are

risk

factors

for

clinically

important

gastrointestinal

bleeding

Stress

ulcer

prophylaxis

strategy

is

commonly

used

in

mechanically-ventilated

children

usually

with

blockers

Its

effect

is

not

known

K.

Renal

Replacement

Therapy

No

graded

recommendations

Continuous

veno-venous

hemofiltration

-LRB-

CVVH

-RRB-

may

be

clinically

useful

in

children

with

anuria/severe

oliguria

and

fluid

overload

but

no

large

RCTs

have

been

performed

comparing

CVVH

with

intermittent

dialysis

A

retrospective

study

of

critically

ill

children

reported

that

children

with

less

fluid

overload

before

CVVH

had

better

survival

especially

in

those

children

with

dysfunction

of

or

more

organs

-LSB-

-RSB-

CVVH

or

other

renal

replacement

therapy

should

be

instituted

in

children

with

anuria/severe

oliguria

before

significant

fluid

overload

occurs

L.

Glycemic

Control

No

graded

recommendations

In

general

infants

are

at

risk

for

developing

hypoglycemia

when

they

depend

on

intravenous

fluids

This

means

that

a

glucose

intake

of

mg.kg

min

or

maintenance

fluid

intake

with

glucose

NaCl

containing

solution

is

advised

Associations

have

been

reported

between

hyperglycemia

and

an

increased

risk

of

death

and

longer

length

of

stay

-LSB-

-RSB-

A

recent

retrospective

PICU

study

reported

associations

of

hyperglycemia

hypoglycemia

and

glucose

variability

with

length

of

stay

and

mortality

rates

-LSB-

-RSB-

No

studies

in

pediatric

patients

-LRB-

without

diabetes

mellitus

-RRB-

analyzing

the

effect

of

strict

glycemic

control

using

insulin

exist

In

adults

the

recommendation

is

to

maintain

a

serum

glucose

below

mg/dL

Insulin

therapy

to

avoid

long

periods

of

hyperglycemia

seems

sensible

in

children

as

well

but

the

optimal

goal

glucose

is

not

known

However

continuous

insulin

therapy

should

only

be

done

with

frequent

glucose

monitoring

in

view

of

the

risks

for

hypoglycemia

M.

Sedation/Analgesia

We

recommend

sedation

protocols

with

a

sedation

goal

when

sedation

of

critically

ill

mechanically

ventilated

patients

with

sepsis

is

required

-LRB-

Grade

-RRB-

Appropriate

sedation

and

analgesia

are

the

standard

of

care

for

children

who

are

mechanically

ventilated

Although

there

are

no

data

supporting

any

particular

drugs

or

regimens

it

should

be

noted

that

propofol

should

not

be

used

for

long

term

sedation

in

children

because

of

the

reported

association

with

fatal

metabolic

acidosis

-LSB-

-RSB-

N.

Blood

Products

No

graded

recommendations

The

optimal

hemoglobin

for

a

critically

ill

child

with

severe

sepsis

is

not

known

A

recent

multicenter

trial

reported

similar

outcomes

in

stable

critically

ill

children

managed

with

a

transfusion

threshold

of

gm/dl

compared

to

those

managed

with

a

transfusion

threshold

of

g/dL

-LSB-

-RSB-

Whether

a

lower

transfusion

trigger

is

safe

or

appropriate

in

the

initial

resuscitation

of

septic

shock

has

not

been

determined

O.

Intravenous

Immunoglobulin

We

suggest

that

immunoglobulin

may

be

considered

in

children

with

severe

sepsis

-LRB-

Grade

-RRB-

Administration

of

polyclonal

intravenous

immunoglobulin

has

been

reported

to

reduce

mortality

rate

and

is

a

promising

adjuvant

in

the

treatment

of

sepsis

and

septic

shock

in

neonates

A

recent

randomized

controlled

study

of

polyclonal

immunoglobulin

in

pediatric

sepsis

syndrome

patients

-LRB-

n

-RRB-

showed

a

significant

reduction

in

mortality

LOS

and

less

progress

to

complications

especially

DIC

-LSB-

-RSB-

P.

Extracorporeal

membrane

oxygenation

-LRB-

ECMO

-RRB-

We

suggest

that

use

of

ECMO

be

limited

to

refractory

pediatric

septic

shock

and/or

respiratory

failure

that

can

not

be

supported

by

conventional

therapies

-LRB-

Grade

-RRB-

ECMO

has

been

used

in

septic

shock

in

children

but

its

impact

is

not

clear

Survival

from

refractory

shock

or

respiratory

failure

associated

with

sepsis

is

in

neonates

and

in

children

In

one

study

analyzing

patients

with

meningococcal

sepsis

in

ECMO

eight

of

the

patients

survived

with

six

leading

functionally

normal

lives

at

a

median

of

yr

-LRB-

range

months

to

yrs

-RRB-

of

follow-up

Children

with

sepsis

on

ECMO

do

not

perform

worse

than

children

without

sepsis

at

long-term

follow-up

-LSB-

-RSB-

Although

the

pediatric

considerations

section

of

this

manuscript

offers

important

information

to

the

practicing

pediatric

clinician

for

the

management

of

critically

ill

children

with

sepsis

the

reader

is

referred

to

the

references

at

the

end

of

the

document

for

more

in-depth

descriptions

of

appropriate

management

of

pediatric

septic

patients

Summary

and

Future

Directions

The

reader

is

reminded

that

although

this

document

is

static

the

optimum

treatment

of

severe

sepsis

and

septic

shock

is

a

dynamic

and

evolving

process

New

interventions

will

be

proven

and

established

interventions

as

stated

in

the

current

recommendations

may

need

modification

This

publication

represents

an

ongoing

process

The

Surviving

Sepsis

Campaign

and

the

consensus

committee

members

are

committed

to

updating

the

guidelines

on

a

regular

basis

as

new

interventions

are

tested

and

published

in

the

literature

Although

evidence-based

recommendations

have

been

frequently

published

in

the

medical

literature

documentation

of

impact

on

patient

outcome

is

limited

-LSB-

-RSB-

There

is

however

growing

evidence

that

protocol

implementation

associated

with

education

and

performance

feedback

does

change

clinician

behavior

and

may

improve

outcomes

in

and

reduce

costs

in

severe

sepsis

-LSB-

-RSB-

Phase

III

of

the

Surviving

Sepsis

Campaign

targets

the

implementation

of

a

core

set

of

the

previous

recommendations

in

hospital

environments

where

change

in

behavior

and

clinical

impact

are

being

measured

The

sepsis

bundles

were

developed

in

collaboration

with

the

Institute

of

Healthcare

Improvement

-LSB-

-RSB-

Concurrent

or

retrospective

chart

review

will

identify

and

track

changes

in

practice

and

clinical

outcome

Software

and

software

support

is

available

at

no

cost

in

languages

allowing

bedside

data

entry

and

allows

creation

of

regular

reports

for

performance

feedback

The

Campaign

also

offers

significant

program

support

and

educational

materials

at

no

cost

to

the

user

-LRB-

-RRB-

Engendering

evidence-based

change

in

clinical

practice

through

multi-faceted

strategies

while

auditing

practice

and

providing

feedback

to

healthcare

practitioners

is

the

key

to

improving

outcomes

in

severe

sepsis

Nowhere

is

this

more

evident

than

in

the

worldwide

enthusiasm

for

Phase

III

of

the

Campaign

a

performance

improvement

program

using

SSC

guideline-based

sepsis

bundles

Using

the

guidelines

as

the

basis

the

bundles

have

established

a

global

best

practice

for

the

management

of

critically

ill

patients

with

severe

sepsis

As

of

November

over

patients

have

been

entered

into

the

SSC

central

database

representing

the

efforts

of

hospitals

in

countries

Change

in

practice

and

potential

effect

on

survival

are

being

measured

sepsis
septic shock
infection
grade
guidelines

severe sepsis
sepsis syndrome
evidence-based medicine
surviving sepsis campaign
sepsis bundles