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accplsccm consensus conference

Definitions
Guidelines
Sepsis
THE

ACCP/SCCM

RogerC.

RobertA.
Frank

Balk,

M.D.,

B. Cerra,

M.D.

R. Philip
An

M. D.

College

Medicine

CONFERENCE
Chairman

Alan

F. C. C.P

ofChest

of Critical

Physicians/Society

Consensus

held in Northof agreeing


on a set of
was

Conference

in August
1991 with the goal
that could be applied
to patients
with sepsis and
its sequelae.
New definitions
were
offered
for some terms,
while
others were discarded.
Broad
definitions
of sepsis
and the systemic
inflammatory
response
syndrome
were
brook

definitions

along
a patient

proposed,

which
sepsis,

septic

function

with

shock,

were

n American
was

held

physiologic

College
Care

and

also

offered.

of Chest

Medicine

in Chicago

parameters

M. Fein,

Roland
William

M. H. Schein,
M.D.
j Sibbald,
M.D. , F. C.C.P

scoring

methods

1991

of

Conference
with

the

MODS

= multiple
inflammatory

of

inflammation

stratification

goal

of

be applied
It was the

Two
and
and

thus

allow
For

addition,

early

editorial

the generalized

of the

disease

therapeutic
comment

the standardization

term

possible,

to infection

intervention.
see

page

In

protocols

will

cellular
sis and

and immunologic
related
organ

allow

us to understand

mechanisms
dysfunctions

death.
We recognize
the limitations
we have proposed
and urge further
these

clinical

concepts,

critical

Reprint
Center,

requests:
Dr. Bone, Rush-Presbyterian
1753 West Congress Parkway, Chicago

the

that cause sepand, sometimes,


of the
studies

phases,

definitions
to validate

and
St.

measures

b.ske

60612

1644

Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2016

Medical

by

sophisticated

issues

using

more

tools

are

SIRS

risk

of evaluation.

also

addressed

in this

article

the discussion
of the causes
(1) the utilization
of severity-

scoring
systems
that allow
the consistent
description,
and risk prognostication
with

The

sepsis;

and

therapies

systemic
1.2

(2) guidelines

in severe

response

Sepsis

is an

morbidity
and
munocompromised,
sis has

1481

ofresearch

will

was

for the

of

use

of

sepsis.

SEPSIS

sepsis.

be possible,
as will improved
dissemination
and application ofinformation
derived
from clinical
studies.
We
hope that the continuing
research
on the inflammatory
response

patients

syndrome;

and other

other

patients

sepsis
and includes
sepsis-associated
organ dysfunctions
as well.
We expect
that the broad
definitions
proposed
in this report
will improve
our ability
to
and

septic

tool

organ
dysfunction
response
syndrome

serve
to round
out
treatment
of sepsis:

innovative

under

detection

with

an adjunctive

as

systemic

injurious

bedside

dealing

to assess mortality.
Appropriate
methods
and
applications
for the use and
testing
of new therapies
were recommended.
The use of
these
terms
and
techniques
should
assist
clinicians
and
researchers
who deal with sepsis and its sequelae.
(Chest
1992; 101:1644-55)

of-illness
evaluation,

early

when

recommended

goal of this conference


to provide
both a conceptual
and a practical
framework
to define
the systemic
inflammatory
response
to infection,
a progressive,

make

M.D.

by

Physicians/Society
Consensus

in August

that falls

F.C.C.P

A. Knaus;

for severe
multiple
organ
dysThe use of severity

agreeing
on a set of definitions
that could
to patients
with sepsis
and its sequelae.

process

M.D.,

William

Definitions

hypotension,

syndrome

Critical

detailed

may be categorized.

in

COMMITTEE:

F.C.C.P

Dellinger,

American

Care

CONSENSUS
FG.C.P,

M.D.,

Bone,

for Sepsis and Organ Failure and


for the Use of Innovative Therapies

been

has been

of inflammatory,

eases.34
Recent
to evaluate
both
in the treatment
of these
results
varying
bactenmia,

cause

to be the

most

common

of
imSep-

cause

noncoronary
intensive
care unit.46
new etiologies,
and appearance
of patients
have
been
related

changing
demographics
and the increased
potent
and broader-spectrum
antibiotics,
pressive
agents,
and invasive
technology
ment

termed

common

mortality,
particularly
in elderly,
and critically
ill patients.

reported

of death in the
rising
incidence,
new
populations

to infection
increasingly

infectious,

Its
in
to

use of more
immunosupin the treat-

and

neoplastic

dis-

clinical
trials have been
undertaken
conventional
and innovative
therapies
ofsepsis.7#{176} However,
interpretations
have been
obscured
by the use of

definitions
sepsis,

for the

following

septicemia,
Definitions

for Sepsis

septic

terms:

infection,

syndrome,

and Organ

and

Faikire (Bone et a!)

septic

shock.72

been

the

An additional

application

syndrome

to

source

of the

noninfectious

terms

of confusion
sepsis

has

and

inflammatory

states.

13.14

and

simplification

of this

advance
these
processes,
will offer recommendations

termino1ogy37

To

this consensus
conference
for the standardization

of

eliminate
cians

of terminology

confusion
and

quelae.
ability

32

blood

in communication

researchers
By

protocols

should

sepsis

terms,

is significantly

definitions

for both

concerning

standardizing

to compare

interventions

is necessary

such

and

evaluate

as general

clini-

cell

guidelines

design
of future
investigations
into
diagnostic
and treatment
modalities.

potential

than

less than

4,000/cu

than

10

other

known

chemotherapy,

include
tissue

percent

mm,

changes

from

causes

greater

baseline

for

such

induced

white
12,000/

neutrophils
should
in the

represent
absence

abnormalities,

neutropenia,

systemic
with

of less

or the presence

immature

physiologic

Rationale:
The
seen
in association
conditions.
produce

by a PaCO2

as a count

the

Recommendation

a count

than

than 90
by a
minute,

such

alteration

new

clinical

greater

in the

an acute

in the

following

(4) an alteration

se-

following

and

count,

more

of the

temperature

as indicated

Hg;

These

therapeutic
The

of

mm

(bands).

its

as sepsis,

improved.

be used

and

to

one

than 36#{176}C;
(2) a heart rate greater
minute;
(3) tachypnea,
manifested
rate greater
than
20 breaths
per

or hyperventilation,

cu mm,

standardization

than

(1) a body

38#{176}Cor less

than

terminology.
The

to, more

beats
per
respiratory

Several
editorials
and position
papers
have recently
attempted
to provide
a framework
for the standardization

not limited
manifestations:

septic

and

pancreatitis,

ischemia,

hemorrhagic

response
is
of clinical

multiple
shock,

as

leukopenia.

inflammatory
a large
number

Besides
the infectious
insults
that
SIRS,
noninfectious
pathologic
causes

injury,

of

such

may
may

trauma

and

immune-mediated

The term sepsi


in popular
usage,
implies
a clinical
response
arising
from infection.
It is apparent
that a

organ injury, and the exogenous


administration
of such
putative
mediators
of the inflammatory
process
as

similar,

or even

tumor

absence
systemic
describe

ofinfection.
We therefore
propose
the phrase
inflammatory
response
syndrome
(SIRS)
to
this inflammatory
process,
independent
of

identical,

response

its cause (Fig 1).


This systemic
inflammatory
following

a wide

variety

can

response

of insults

1. The

in the

and

can

interrelationship

be

includes,

seen
but

is

BORNE
between

systemic

necrosis

factor

and other

cytokines.

A frequent
complication
ofSIRS
is the development
of organ
system
dysfunction,
including
such
welldefined
renal

BLOOD
FIGURE

arise

clinical
failure,

conditions
and

as acute

multiple

drome
(MODS).
The
consensus
conference,

organ

lung

injury,

shock,

dysfunction

term MODS
also stems from
and its definition
will be

synthis
dis-

INFECTION
inflammatory

response

syndrome

(SIRS),

sepsis,

and

infection.

CHEST

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I 101

I 6 I JUNE,

1992

1645

cussed
It is
iology
stitute

later in this report.


likely that similar
pathogenesis
and pathophysunderlie
the various
clinical
entities
that conSIRS . Future
definitions
may take into account

the pathogenetic
response.
Further

mechanism
in descriptions
work is needed
to characterize

clinical
and prognostic
associated
sequelae.

When
stance,

SIRS

is the

the term

result

of a confirmed

sepsis.

sepsLs

In this

represents

to the presence
Rationale:
Sepsis
has been
systemic
inflammatory
response

of the

pathogenetic
of

the

to improved

mechanisms
systemic

involved

response

to

causes
of SIRS.
mechanisms
will

it

and verbal
relates
to

organisms.
presence

presence

of viable

of viruses,

in the blood
(ie, viremia,

bacteria

fungi,

in the

parasites,

and

should
be described
in a
fungemia,
parasitemia,

However,

this

term

interpretation.
Septicemia
describe
the entire
spectrum
that may infect
the blood.
term
Sepsis
infection.

of sepsis

has

in the past
their
toxins
been

same

SIRS, and include,


one of the following:

but

used

in a variety
difficulties

and

as
in

the
the

clinically

as
a

as those

of ways,
in data

usage.
response
manifestations

previously

are not limited


(1) a temperature

known

causes

for such

defined
to, more
greater

to

Severe
organ

sepsis

than
than

38#{176}Cor less than 36#{176}C;(2) an elevated


heart
rate
greater
than
90 beats
per minute;
(3) tachypnea,
manifested
by a respiratory
rate greater
than
20
1646

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along

prognosis

is defined

dysfunction,

this

continuum

include

as sepsis

hypoperfusion

hypotension.

the follow-

Table
= microbial

response

Systemic

presence

minute;
<32

mm

Hg;

ofviable

<32

>38#{176}C or
and

mm,

or >10%

cell

may

include,

Septic

shock=

fluid

but

are

alteration

cell

not

sepsis-induced
along

malities

that

include,

oliguria,

or an acute

may

inotropic

at the time

that

Sepsis-induced
or a reduction
other

causes

Multiple

organ

with
but

alteration

perfusion
of 40

rate

by two

>90

or
(1)

beats

minute

count

per

or PaCO,

>12,00Wcu

mm,

forms.

organ

dysfunction,

and

hypoper-

perfusion

to lactic

abnormali-

acidosis,

oliguria,

hypotension

despite

presence

of perfusion

are

not

limited

in mental

a systolic
Hg

from

may

adequate
abnor-

to, lactic

status.

agents

abnormalities
mm

mm,

of infection:

the

or vasopressor

hypotension

per

status.

with

resuscitation

>12,000/cu

per

(band)

limited

beats

or PaCO,

forms

heart

blood

in mental

>90

manifested

breaths

The

conditions:

minute

a result

>20

Severe sepsis= sepsis associated


with
fusion, or hypotension.
Hypoperfusion
ties

rate

count

as

immature

systemic

insults.

following

(band)

<36#{176}C; (2)

white

invasion

the

clinical

per

to infection,

rate

Hg;

or an acute

(SIRS)=

breaths

conditions

inflamma-

in the blood.

ofthe

blood

an
or the

of severe

immature

response

(3) respiratory
mm

bacteria

>20

(4) white

following

temperature
minute;

rate

or >10%

the

pres-

organisms.

by two or more

systemic

of

by

syndrome

to a variety

and

mm,

= the

by those

response

(3) respiratory

<4,000/cu

by the

>38#{176}Cor <36#{176}C;
(2) heart

(1) temperature

Sepsi.s

tissue

is manifested

altera-

1 -Definitions
characterized

response

acute

is defined

of microorganisms

inflammatory

inflammatory

and

presence

host

with
or sep-

abnormali-

oliguria,

phenomenon

to the
sterile

associated

abnormality,

Hypoperfusion

ties include
lactic acidosis,
tion of mental
status.
Sepsis-induced
hypotension

receiving

for

stages
affect

ing:

<4,000/cu

also does not adequately


of pathogenic
organisms
We therefore
suggest
that

be eliminated
from current
is the systemic
inflammatory
In association
with infection,
are the

immature

manifestations

represent
a continuum
of
severity.
The degree
of
affect
prognosis.
Some

recognizable

that may adversely

more

has been
defined
microorganisms
or

ofother

and its sequelae


and pathophysiologic
may
independently

response

and in the medical


literature
which
has added
to confusion

this

Sepsis
clinical

BaCt#{128}I-emia = the

to the presence
of
of normally
sterile

etc).

blood.

10 percent
these

of normally

characterized

phenomenon

host tissue by those


Bacteremia
is the

Septicemia
presence
of

than

identify

be determined
whether
they are
systemic
response
to the presence

Recommendation

tory

response
the invasion

The

sepsis,
it should
part of the direct

Infection

1):

is a microbial

other pathogens
similar
manner

of more

To help

sis-induced

the written
infection
as

by an inflammatory
microorganisms
or

blood.

pro-

management.

to improve
concerning

(Table

presence

neutrophils.

severity

recommend
the adoption
of the following
and definitions
for several
commonly

used terms
infection

or the

clinically

In an attempt
communication
SIRS,
we
nomenclature

clinical
studies

in the

inflammatory

therapeutic

Recommendation

as indicated

inflam-

of infection.
well
recognized
as a
to an active infectious

infection,
as well as the noninfectious
An improved
understanding
of these
lead

or hyperventilation,

baseline
in the absence
abnormalities.

circum-

in the host. The use of a broad-based


of the septic
process
may facilitate

duction

its

infectious

clinical

the systemic

response

process
definition

and

minute

ofan infectious
process.
Also, the physiologic
changes
measured
should
represent
an acute
alteration
from

it is termed

matory

of the
the

of SIRS

per

by a PaCO2 ofless
than 32 mm Hg; and (4) an alteration
in the white
blood cell count,
such as a count greater
than 12,000/cu
mm, a count
less than 4,000/cu
mm;

Recommendation

process,

significance

breaths

acidosis,

Patients

who

are

not be hypotensive

are measured.
blood

pressure

baseline

<90

in the

mm

Hg

absence

of

for hypotension.
dysfunction

organ

function

in an

cannot

be maintained

syndmme(MODS)
acutely

ill patient

without

intervention.

Defindions

for Sepsis

presence
such

and Organ

that

of altered
homeostasis

Failure (Bone eta!)

ence
of a systolic
blood
pressure
Hg or its reduction
by 40 mm
baseline

in the absence

(eg, cardiogenic
Septic

causes

as sepsis-induced

for hypotension

of

severe

sepsis

hypotension,

Patients

sor agents
they

may

manifest

is

persisting

inotropic

de-

with
the
or organ
by the

abnormalities
still be considered

time

Recent,

spective

studies

a continuum

of sepsis

and inflammatory
with
infection
organ
remia

large-scale,
have

of severity
and

urge

multicenter,
suggested

for the

The

both

there

is

infectious

became

The condition
begins
leads
to sepsis
with

system
dysfunction
and septic
shock.7#{176} Bacteand hypotension
may
occur
as a part of this
While
recognizing
that the disease
process

utilize

other

more
tools

of

concepts,
critical
that are impor-

SYNDROME

ofmorbidity

and mortality

organ
failure
has paralleled
imlife-support
technologies
available
to an intensive
care unit (ICU).
for the monitoring
and support

sustaining

that

death.
in these

of sepsis.

incidence

admitted
technologies

life-threatening

critical

retrospective

a major

underlying
thereof,
but

that
and

DYSFUNCTION

established,

found

studies

treatment

multiple
in the

cases,

inherent

the clinical
of inflammation

ORGAN

of patients

severe
are

stratification

clinical

increasing

to patients
As newer

pro-

that

encompassing

components.
potentially

tant

that

further

risk

caused
by
provements

shock.

Rationale:

we

MULTIPLE

or organ
to have

in the most

limitations

evaluation
to validate
phases,
and measures

or vasopres-

be hypotensive

hypoperfusion
yet they would

dysfunction,

septic

receiving

no longer

and,

of the

definitions,

and

spite
adequate
fluid
resuscitation,
along
presence
of hypoperfusion
abnormalities
dysfunction.

dysfunction

Because
sophisticated

shock).
is a subset

shock

defined

ofother

organ

of less than 90 mm
Hg or more
from

threat

to

illness

clinical
survival

studies

was

illness,
or even
a single
rather
a process
ofprogressive

not

the

complication
physiologic

forms
a continuum
of severity,
an analysis
of several
clinical
trials has indicated
that definable
phases
exist
on that continuum
which
characterize
populations
at

failure
of several
interdependent
organ
systems.
The terms
progressive
or sequential
organ
failure,
multiple
organ
frilure,m
and multiple
systeims
organ
f ailure were thereby introduced
to describe
an evolving clinical
syndrome
that was characterized
by the

increased

development

process.

such
with

risk of morbidity

phase
organ

should
system

and

be termed
dysfunction.

mortahty.72
severe
Some

used the term


of the septic

septic
syndmme
to describe
process.
However,
the

syndrome

been

tory

has

states

and

and
the term

applied

it now
134
We,
syndrome

septic

this
term

to a variety

appears

to be

therefore,
no longer

One

sepsis
or sepsis
have previously
phase
septic

of inflammaboth

confusing

recommend
be used.

that

These
critical
stages
in the septic
process
are likely
to have independent
prognostic
implications;18.19
however,
this hypothesis
has not been
tested
in largescale,
may

prospective,
be

multicenter

a more

patients
likely
The development

appropriate

trials.

Risk

approach

assessment

to identifying

tools is encouraged.
Previous
studies
have shown
septic
shock,
as defined
above,
is associated
increased
mortality.
11.19.22

that
with

We have

provided
for the

framework

matory
of these
detection

Conventional
to accurately

terminology
characterize

cal descriptions

ofthe

in an arbitrary

and

both a conceptual
definition
of the

and a practical
systemic
inflam-

response
to infection
(sepsis).
The application
broad definitions
will improve
early bedside
and permit
early intervention
in sepsis.
In

this

abnormalities

organ

is considered
syndrome.

failure

for the

concept
either

most

part,

of organ failure,
present
or absent,

tion,

a continuum

static
tions

criteria
preclude

have

been

of physiologic

predicated

studies

of

for

on the

event
that
organ dysfunc-

derangements.

descripchanging

the syndrome
issue,
if it is not
future

multiple

is

The

epidemiologic
ofdynamically

that characterizes
clinically.
This

clinical

emerged
Criteria

organ function
have
one study to another

addressed,
could
potentially
hinder
in the treatment
of this syndrome.
Early

inadequate
Thus, cmi-

fashion.

a dichotomous
rather
than

used in current
the possibility

to an

syndrome

retrospective

defining
abnormalities
of specific
also been widely
dissimilar
from

organ function
is encountered

Conclusion

unexplained

but also of the application


of these
technologies
increasingly
high-risk
patient
population.

and,

to develop
morbidity
and mortality.
and refinement
of such evaluation

of otherwise

oforgan
function
in critically
ill patients.
The phenomenon that these terms describe
is clearly
increasing
in
prevalence,
as a result
not only of improvements
in
life-support
technology
(both medications
and devices)

as it
soon

advances

organ

failure

addition,
the standardization
ofresearch
protocols
will
be enhanced,
as will application
ofinformation
derived
from clinical
studies.
We believe
that the early iden-

identified
occult
infection
as the
most
important
clinical
correlate
of the syndrome.m
However,
recent
work has shown
that organ system
dysfunction
can evolve
in the absence
of an untreated
focus
of
invasive
infection
and can be reproduced
expen-

tification

mentally

of the

will enhance
immunologic

inflammatory

our understanding
mechanisms
that

response

to

infection

of the cellular
can cause
sepsis

and
and

endogenously
Futhermore,

by

the

infusion

of a diverse

CHEST

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spectrum

of

derived
mediators
of inflammation.#{176}
recent
work has demonstrated
a complex
I 101

I 6 I JUNE.

1992

1647

interrelationship
failure
of one
that

hastens

Our

may

among
individual
organs,
establish
an amplification

injury

must be recognized:
1. MODS
describes

to another.

understanding

dysfunction
improving.

such that
process

of the

and
failure
In contrast,

pathophysiology

in critically
descriptions

2.

ology
of this
syndrome
remain
meager.
Available
reports
focus
primarily
on disease
that is severe,
perhaps
at a point in the disease
course
where
interventions
may no longer be anticipated
to have potential

although
process

The
must

recognition
of early
organ
abnormalities
be improved
so that treatment
can

purpose

conceptual

of

this

framework

statement

for future

is

to

studies

detection

of

altered

ill patient

constitutes

be termed
terminology

multiple
organ
dyifunction

phenomenon

in which

clinical

factors
at varying
time
tional and host-related.

organ

function

a syndrome
dysfunction
identifies

organ

in

that

is not

MODS

The
as a
capable

as a continuum

over

of change

organ

dysfunction

a normal
cardiac
output
who exhibits
evidence
tion (eg, lactic
The proposed

acidosis).
acronym

time.

is found

An

in the

and systemic
of inadequate

example

also identifies

of

patient

oxygen
tissue

with

delivery
oxygena-

multiple

Recommendation

should

syndrome.
this process

function

the

This process,
which
may
be more readily
identified

dysfunction
is proposed
progressive

organ

as a syndrome.
In this context,
MODS
to describe
a pattern
of multiple
and
symptoms
and signs that are thought
to

may

be described
MODS

Rationale:

as being

either

develops

which

organ

directly
primary

interven-

the dynamic
nature
Thus,
the following

of the
points

result

dysfunction

oftrauma

(eg, pulmonary

ipation

ofan
in

syndrome

is not

(Fig

both

1648

Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2016

onset

and

can

renal

be

host

of

failure

due to
the partic-

inflammatory

progression

of the

as it is in secondary

MODS
develops,
itself,
but as the

and

is identified

activation

inciting

MODS

not in direct
consequence

response
of a host

the context

of SIRS.

within

process,
and describes
that is characterized
of the

inflammatory

by

reaction

an
a
in

the initial insult. When the process


the terms
sepsis
and SIRS
are

injury

or event,

to complicate

Since
Death

and

contusion,

and excessive
the

as evident

criteria

quantifying
the
prised
by MODS
comprehensive
clinically
test

severe

and

is most

commonly

infection.

Recommendation

and secondary

early

dis-

Primary
insult in

synonymous.
Given
that SIRS/sepsis
is a continuous
process,
MODS
may be understood
to represent
the
more severe
end of the spectrum
of severity
of illness
that
characterizes
S I RS/sepsis.
Thus,
secondary
MODS
usually
evolves
after a latent period
following

seen

different
causes
and results
ofprimary
dysfunction
syndrome
(MODS).

relatively

2).

response,

the

Recovery

two

or the coagulopathy
In primary
MODS,

abnormal

response

organs remote
from
is due to infection,

MOD$

by

occurs

due to rhabdomyolysis,
multiple
transfusions).

generalized

condary

primary

attributable
to the insult itself. An example
MODS
is organ dysfunction
as the immediate

SIRS is also a continuous


abnormal
host response

organ

both

tinct,
but not mutually
exclusive,
pathways.
MODS
is the direct
result of a well-defined

terminology
emphasizes
process
under
discussion.

multiple

periods,

or secondary.

Secondary
to the insult

2. The

ofthe disease.
by numerous

be pathogenetically
related.
Rationale:
In contrast
to the static descriptions
that
have been
used previously,
the proposed
change
in

FIGURE

be

of this

in organ
function
over
time
can be
as an important
element
in prognostica-

out reference
to the natural course
MODS
is subject
to modulation

4.

of maintaining
homeostasis.
be absolute
or relative,
can
relative

evolution

Recommendation

acutely

in the

tion. When applied


to MODS,
existing
measures
ofillness
severity
provide
only a snapshot
in time
of this dynamic
process,
and are generally
with-

phenomenon
of organ
system
dysfunction
in critical
illness,
and to lay the foundations
for common
terminology
and criteria
to describe
the syndrome.

The

stages

contin-

available.

syndrome.

propose

ofthe

ofthis

are not currently

at earlier

3. Changes
viewed

for success.
The

descriptions

dysfunc-

uous

initiated

specific

oforgan

tion,
of organ

ill patients
is
of the epidemi-

a continuum

that

are

individual
cannot

universally

applicable

organ
dysfunctions
be proposed
at this

and continuously
and validate
optimal

updated
criteria

in

comtime,
a

data base to
for describ-

Definitions for Sepsis and Organ Failure (Bone et a!)

ing this

syndrome

Rationale:
mendation
serve
ment

must

Data

be established.
insufficient

are

of universally

as a validated
of criteria

applicable

operational
for measuring

should
empiric

not occur
a priori,
process
in which

against

outcome.

of individual

a recom-

criteria
template.
organ

that could

so, the

groups

predicted

can be defined
practice.

and

in a manner

that

that

in

currently

patients

goal
tant

A common

SCORING

theme

in the

levels

and,

more
more

of

that

many

complex
illnesses
of chronic
and
presentation

of these

by

and

the

possible

life-support
ever,

present
verity,

and

without

that

uum is essential
The rationale

have

or host

our

that the
thanjust

with
along

of new

diagnostic

presents

how-

description

of that

of new

where,

insights

into

regard,

imporrisks of

along

resides.
factors

or existing

determined.
measurements

the

This will
so that the

therapy

can

It is also hoped
of patient
risk will

disease

processes

and

can more accurately


use of new therapies,

it is increasingly

being

end point
of severity
scoring
a score representing
the degree

for care

they can serve


also be updated

both
of these
syndromes
a continuum
of illness
Se-

an accurate

A specific

be
that
lead

serve

as a

monitor
such as
recognized

can be more
of physiologic

outcomes,
such as hospital
mortality.37
These
probability estimates
can be calculated
at the time a patient

and

emphasized,

consistently

disturbance.
Severity
scoring
can be used, in conjunction with other
risk factors
(eg, disease
etiology
or
patient
selection
criteria),
to anticipate
and evaluate

The recognition
would
not have

advanced

It is also

impact

precisely
precise

In this

more

response

introduction

and MODS.
syndromes

capabilities.

that patients
somewhere

patient

proposed

syndromes,
such as SIRS
and treatment
of these
been

who

may be suffering
from a combination
acute
disease.
The nature
of disease

is changing,

is exemplified

patients

of disease

is

to identify

tool with which clinicians


patients
and guide
the
monoclonal
antibodies.

this consensus
statement
is that we are treating
more
severely
ill patients
at later stages
of illness.
It is also
apparent

treated

and descriptions.

thereby,

incremental

reflects

sections

complexity

being

in evaluations

patients

SYSTEM

previous

two

increased

of severity
scoring
systems
is to use these
patient
variables
to describe
the relative

to new
SEVERITY-OF-ILLNESS

the

continuum
of severity,
the patient
reduce
the variation
due to patient

accuracy

of variables,

is to ensure
represented

The assigndysfunction

but should
result
from an
specific
variables
are tested

By doing

variables,

ofabnormality
current
clinical

to justify

describing
alternative

contin-

to appropriate
usage of these terms.
for using scoring
systems,
therefore,

or for entry

into

a clinical

as a pretreatment
during
the course

the course
of
for the evaluation

illness
and
of response.

ods for calculating


these dynamic
are not as developed,
however,

trial;

thus,

control.
They
can
of therapy,
thereby
providing
an
The meth-

probability
as are those

estimates
for initial

RISK DISTRIBUTIONS
OF 519 ICU ADMISSIONS
FOR SEPSIS
ACCORDING
TO CATEGORICAL
DEFINITION
OF SEPTIC
SYNDROME
*
N OF CASES

10

20

30

40

DAY 1 HOSPITAL

SEPTIC
SHOCK
FIGURE

criteria

WITH

Care

3. Risk distribution
for sepsis
syndrome

OR WITHOUT

60

70

MORTALITY

NO DEFINITION(N211)

SYNDROME

(Bone,Crit

50

80

90

RISK

DEFINITION

(N.308)*

SEPTIC

Med 1989;17:389)
of 519

sepsis

(see reference

patients
who
40 for further

either
met
details).

(n

308)

or did

not

meet

CHEST

Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2016

(n = 211)

I 101

the

I 6 I JUNE,

1992

1649

RISK DISTRIBUTIONS
OF 519 ICU ADMISSIONS
FOR SEPSIS
ACCORDING
TO THE DEFINITION
OF SEPTIC INFLAMMATORY
RESPONSE
SYNDROME
No. of Patient8

80
70
60
50
40
30
20
10
0

--

1O

-----.--..-

10-

30.-

or presentation

FIGURE

4. Risk

criteria

for SIRS.

distribution

the

scoring

or probability

proposed
viewed

definition
the application

Icu

Day

SIRS

(N503)

of the

value

of combining
risk

for

surgical
ICU.#{176} These
initial
microbial
source
pneumonia,
but were
suffering

primarily

represent
the new

a subgroup
definitions,

ate (Fig

1).

estimation

with

from

As

as defined
risk
meeting

substantially
cent) patients
In contrast,

this

newly

they

the

distribution
on the initial

were

3, according

by Bone

et al.

It can

risks

were

the 308 (59 percent)


for this syndrome
is not
that for the 211 (41 per-

application

percent

of the

therefore,
is an increase
classffied
by the definition.

new

4 illus-

was applied
to
clinical
diagnosis
(503/519).

What

definition

has

in the number
This is important,

1650

Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2016

equivalent

of

met

(sepsis
syndrome)
although
their

to those

exesti-

of patients

who

Figure
5 demonstrates
that,
for the 503
meeting
the criteria
for SIRS,
the estimated
risks calculated
on the initial
day of ICU

Finally,

patients
mortality

treatment

accurately

hospital

predicted

mortality

capability
used
in

rates.

ofseverity
combination

This

scoring
with

the

subsequent

demonstrates

actual
the

current

and risk estimation


when
a broad,
encompassing

definition
like SIRS.
Further
details
on these
are available#{176}
and will be the subject
of a

These

report

from

led

to the

findings

Because

seen

of

SIRS definition
with a primary
96.9

be

they

included.#{176}

this

consensus

following

conference.

recommendations.

Recommendation

to whether
of sepsis

to whether

the previous
definition
many
of these
patients,

clinical
methods

of hospital
day of ICU

90-

(N16)

as in Figure

mated

group
rerisk esti-

who did not fulfill the criteria.


the result
depicted
in Figure

it identified

initial

patients

80-

Risk

since
cluded

ofpatients
with sepsis for whom
such as SIRS, would be appropri-

distribution
the criteria
different
from

trates
that when
the
the same 519 patients

achieved,
patients

70-

subsequent

syndrome,

of sepsis,

sepsis

severity

such,

----.--

60-

No SIRS

with a primary
to medical
and

infection.

50-

1 Mortality

patients
frequently
lacked
an
of infection,
such as bacterial
still identified
and treated
as

3 illustrates
risk calculated

the

519

the

SIRS,
the study
of hospital
mortality

treatment
for these 519 patients,
according
the patient
met criteria
for the definition

patients

same

initial

mation
to a group of519
adult patients
diagnosis
of sepsis
upon
admission

that

40-

risk assessment.

To illustrate

Figure
mortality

--

20-

of

the

increasing

complexity

of

patient

presentation,
the use of new
terminology,
such
as
SIRS,
with its various
etiologies
(Fig
1) should
be
combined
with
risk stratification
or probability
risk
estimation
techniques
in order to measure
the position
of an individual
patient
along the continuum
of severity.
Rationale:
has been
more
stages

The

major

an increase

severely
of their

change

in patient

in the complexity

ill patients
are
illness.
Accurate

presentation
ofillness.

being
treated
identification

Also,
at later
of pre-

treatment
risk can improve
the precision
of the evaluation
of new therapies.
Such risk estimation
can also
Definitions

for Sepsis

and Organ

Faikire

(Bone

eta!)

be useful
and

in monitoring

in refining

the utilization

the

by identifying
appear
to be

indications

ofnew

risk levels
when
efficacious.
The use

model

therapies

for specific

treatments

for the

SIRS

and

model
process.

is a candidate

for

When
MODS,

patients
sequential

stratification
should

are identified
as
(daily
or more

or

be

probability

applied

to

having
SIRS
or
frequently)
risk

estimation

describe

the

course

of these

Rationale:

At

our

current

measurement

level

of

capabilities),

we

course
of SIRS
by relying
measurements
of physiologic

primarily
changes.

logic

subsequent

changes

the future,

correlate
it may

with

be possible

ment
to include
in measurement

metabolic
capabilities

outcome.
this

changes.
Such
may be especially

the

tion

yet to be determined.

of, MODS

have

Recommendation
Priority

scoring
This

and
will

allow

the

the

While
In

or metabolic
by, the
labeling

As emdescrip-

and

param-

unaffected

Ideally,
would

therapy

metabolic

by varia-

variables

involved

distinguish

control

or

from
response
effects,
and
for an individual
patient.

of such

model

systems

the

currently

severity
efforts.

variables

cause,

exist,

remain.
We
physiologic,
and

which

measurement

in use,

or the

such

cardiac

of a number

as the level
output,

style.
Very large
establish
whether

data bases
any reduced

retains

Despite

its validity.

vary

caused
difficulty
We also

of variables

ofoxygen

may

are curclinical,

are

inflammatory
response.
We have
and then reliably
identifying
diseases.

that

know

tion

consumpwith

practice

are also necessary


or streamlined
data

these

and other

to
set

substantial

obstacles,
it is becoming
apparent
that a small number
of variables
can accurately
capture
most of the mean-

of a comprehensive

RISK

examples

advances
impor-

to building
on
and descriptive

development

styles.

measure-

the course
of MODS.
exact criteria
for, and

be given
predictive

tions

independent,

as

is a complex
the pre-ICU

to time

number
of significant
problems
rently unable
to determine
which

3
should
other

respect

and

be

such

Conclusion

the

on sequential
These
physio-

in characterizing
phasized
previously,
taut

as SIRS,
describe

in physiologic
while
remaining

in practice

implica-

understanding
determine

to extend

with

have

of a comprehensive

such
must

disease-initiating
effects
would be path-independent

syndromes.

(and

development

interval

will

syndromes

and the changes


eters over time,
would

techniques

that
of new

a syndrome,
Such
a model

treatment
Recommendation

progression

investigation

MODS.
RatiOflal4:
The

certain
therapies
of this approach
is

particularly
important
when the patient
for, or a participant
in, a clinical
trial.

of disease

tions

DISTRIBUTIONS
OF
Admissions
With SIRS.

503 ICU

Actual

No. of Patients

Hospital

Mortality

(%)
100

80

90

70

80
60

70

50

60
H

40

50

40

30

30
20
20

10

10

10

10-

20-

30Day

ICU

FIGURE

relationship

hospital

Hospital

5. Risk distribution
between

mortality

risk

60Risk

Mortality

of 503 septic
of hospital

40501 Mortality

patients

mortality,

70-

80-

90-

No. of Patients
who met
calculated

the criteria
on

the

first

for SIRS.
day

of the

This
ICU

demonstrates
stay,

and

the
actual

rates.

CHEST

Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2016

I 101

I 6 I JUNE,

1992

1651

ingful

data

defining

present
in large
ment
that, while
response

physiologic

data
the

sets.
ideal
with

of patients

complex

SIRS,
does
not currently
attempting
to achieve.
GUIDELINES

FOR

Innovative

THE

OF

in severe

as

worth

SEPSIS

sepsis

targets a subgroup
with Gram-negative

ofthe septic population


(eg, patients
sepsis).
Patients
whose
underlying

disease
is not likely
to permit
them
study
should
be excluded,
as should
not candidates
for aggressive
medical

to survive
the
those
who are
therapy.
As our

ability to define
specific
subgroups
improves,
the entry
criteria
to future trials should
reflect
these changes.
The design
of trials in sepsis
research
should
entail
well-defined
end points,
including
the reporting
of

INNOVATIVE

SEVERE

the systemic

such

a goal

is

it

USE

IN

therapy
to alter

currently

illnesses,

exist,

THERAPIES

an attempt

response

This provides
encouragemodel
for describing
the

usually

involves

inflammatory

deaths

response

from

after

any cause,

study

through

enrollment.

a minimum

Overall

analysis
of adverse
outcomes
in the overall
well as in the treatment
group or any other

group,
group

remain

interest,

of results

have

Over

had

the

last

increasingly
impact
on

and

little

10

to

15

years,

sophisticated
the mortality

be reported.
We encourage
relevant
to the cost oftherapy

new

critical
care
rate of this

disease.
A variety
of innovative
mediators
of inflammation
clinical

trials,

continue.
who

meet

and

to gain

trials

and

the

should
therapies

that

for

the

statistical
The

various

results

as a guide

to the

to

of patients

power,

necessary.

clinical

increased

costs

becomes
innovative

clinically
therapies

expenses

for the health

ing

is likely

numbers

criteria

expensive.

impact
on the
determined.

of investigation

studies

rational

trials

use

of new

trials

and product

This

will

on the

total

product

being

care

majority
entail

consumer,

of health

care

if it

of these
significant

although

their

remains

to be

There
are well-established
guidelines
for conductclinical
tests,
including
adherence
to good

clinical

practice

and

the protection

ofhuman

These
guidelines
are particularly
trials that investigate
the causes
language
we

was

recommend

earlier

a central
the

in this

report

published

peer-reviewed

established

terminology

competently
innovative

compare
agents
in

comparison
standardized

ing

of data.

focus

use

of this

clinical
the
the

conference,

terminology

in conjunction
may

with

it may

and

discussed
that

trials..#{176}The

make

it possible

predictors
disease
and

the

to

patients,

and
in

the

demonstrated
The interval

that

ensure

that

statistical

be noted

and

treatments
and
It is important

they

be

of

the clinician.
on the disease

considered;

the

for whom

cious

is important.

in septic
patients.
of entry criteria
and
intervention,
as well
lead time bias, should

of

in the clinical

trial

The

of the
should

identification

treatment

would

morbidity

occurred
in
and the safety
A patient

of pa-

be most

and

effica-

mortality

rates

the absence
profile ofthe
who

of the
product

is to be treated

therapy
should
have
a clinical
matches
the entrance
criteria
used
for that therapy.

criteria

(is,

rate),

rigid

ofconducting

for treating
to receive
consider-

The expected
impact
process
of the patient

also be appraised.

respiratory

data.

systems
should
be used in
risk to the extent
that the
has been
independently

prospective

the

that would
have
innovative
therapy

entrance

treated

the

analyzed.

tients

should

outcome,
source
of
are

analysis

In the approved
use of new therapies
sepsis,
the selection
of suitable
patients
these innovative
treatments
is an important
ation for
treatment

as
of

demonstrates

of clinical
the referral

to predict
outcome
between
fulfillment

in

prob-

reporting

analysis

to address
potential
such as underlying

use

to more

that

data
The

the comparability
ofnoninvestigational
patient
characteristics
among
groups.

used

facilitated
by
and report-

be anticipated

researchers
to report
and quality
oflife.

The

a detailed

with
an innovative
presentation
that

results
of efficacy
trials for
treatment
of sepsis.
The

of trials
would
also be
trial design,
data collection,
Further,

subjects.

important
in clinical
of sepsis.
The issue of

of the

also

administration
of experimental
as other indicators
of possible

significantly
investigated

available.
The
will, therefore,
cost

development

impose

should

be presented.

include

Severity-of-illness
scoring
the stratification
of patient
individual
scoring
system

multicenter
of these

should

should

adequately

are developed.

Multicenter
very

line

significant

be used

therapies
aimed
at the
have recently
undergone

appropriate

entry

are usually

are

this

To recruit

dysfunction,

as

well

high.

oforgan

days

mortality,

of a patient.
Such forms of therapy
are quite different
from supportive
therapy
or therapies
that are directed
at the causative
organism
(eg, antibiotics
or surgical
procedures).
Despite
the use of these
current
therapies, the morbidity
and mortality
rates in severe
sepsis
antibiotics

as the resolution

of28

hospital

a clinical

temperature,
limits

were

trial.

When

However,

for some

heart

rate,

set for the


objective

and

purpose
data have

allowed
a definitive
diagnosis
of the target
population
for which
the innovative
therapy
is intended,
exceptions

to the

listed

entrance

criteria

can

be made

For

lems with terminology


will only get worse as additional
agents
are tested,
either
alone or in combination.
The choice
of patients
for entry
into trials should

example,
in considering
a therapy
that utilizes
antibodies
raised against
endotoxin
for a patient
who has

be as selective

tachypnea,

as possible,

particularly

when

the trial

1652

Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2016

a positive

blood

culture

tachycardia,
Definitions

for Gram-negative
and

hypotension,

for Sepsis

and Organ

bacteria,
the

failure

Faikire (Bone et

a!)

to meet
trial

temperature

should

criteria

not

treatment.

Also,

from

be

used

as

since

the

Food

a previous

clinical

a reason

to

and Drug

Administra-

lion has access


to a larger
data base on any
agent,
FDA labeling
indicators
may be different
clinical
them.

trial

Patients
looked

entrance

criteria,

for whom

exclusion

include

those

who

old, those
who are
trolled
hemorrhage.
excluded
not

from

because

these

thus

given
from

in

preempt

criteria

might

be over-

vative

younger

than

18 years

cannot

therapy
be

suspected

ing may be considered,

risk
treatment

individual

may

For
offer

physician

tial risks

then

and

unproven

prior
to any
patients
who

must

clinical

therapy.
If
in nonex-

trials

may

excluded
above.

groups,
such
In the interim,

benefits

should

decision
to
are receiving

be considered

cost-containment

considerations

remembered
group

that

the

in

efficacy

mind;

to
and

it must

be

in

this

of treatment

is unknown.

information
about the
the appropriate
treat-

ment

utilization

method

can

culture
results
from suspected

be used.

The

and current
Gram
sites of infection

of previous

stains of specimens
are imperative
for

good
decision
making.
For example,
a patient
with
Gram stain evidence
ofStaphylococcus
as the probable
infecting
agent
is not likely
to benefit
from
the
utilization
These

of antiendotoxin
antibodies.
innovative
therapies
are typically

ized as having
patient
outcome,

a potentially
a substantial

important
impact

character-

influence
on health

costs, and a restrictive


set ofindications
characteristics
necessitate
an increased

who must
information

individuals
therapy.

determine
how and when
to use
should
be helpful
in the selection

who
This

ditional
studies
meet
changing

and marappropriate
or institu-

could

responsibility

potentially
may

benefit
also

from

necessitate

or documentation
in the
requirements
for the formal

it.
of
the
ad-

future
to
approval

clearance,

there

as in
redos-

are no available

is

therapies
will be
specific
populations
will
be identified

difficult

and

toxicity.
Equally
important
will not be underutilization
patient

groups

there

expensive
and
of patients.
through
the
is an important
of the target

is

no

anticipated

is the assurance
of the innovative

that

would

be

that there
therapy

likely

to

benefit.

Methods
of ensuring
proper
patient
selection
will
vary,
based on the character
of the particular
medical
institution.
Each hospital
must consider
its own situation and
the proper

devise
appropriate
innovative
therapy

Potential

mechanisms
the

placement

therapies.

methods
to ensure
that
for sepsis
is employed.

for

accomplishing

of physicians

of the particular
to guide
the
An approval

this

with

disorders
utilization

process

in

to be treated
of innovative

involving

therapy
is not delayed;
on-site
expertise
to off-site
expertise.
When
a specially

goal

expertise

these

cians may be warranted.


These
physicians
readily
available,
so that treatment
with

physi-

should
be
innovative

is preferable
trained
physi-

cian
is not available,
the use of patient
selection
criteria
checklists
to assist the prescribing
physician
may be helpful.
The checklists
may also be useful for
other situations
in which
the initial contact
physician
With the
tems should

in sepsis

and

tively
as a quality
assurance
the utilization
of innovative
checklists
may help prevent
ing for underutilization
important
for individual
in the
THE

use

innovative

input of physicians
be designed
and

of potentially

ACCP/SCCM

therapy.

and pharmacists,
sysimplemented
prospec-

mechanism
to evaluate
therapy.
Patient
selection
overutilization;
monitor-

is more difficult.
It is especially
physicians
to exercise
caution
deleterious

CONSENSUS

therapies.

CONFERENCE

COMMIT-

TEE:
Conference

Chairman:

Roger
C. Bone M.D.,
President
for Medical
Center,
Chicago

F.C.C.P,
Affairs,

Dean, Rush Medical


Rush-Presbyterian-St.

CHEST

Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2016

patients

bleeding,

trials. Overutilization
if the identification

is not an expert

on
care

for use. These


responsibility

on the part of the corporations


developing
keting the therapy
to provide
scientifically
assistance
and
education
to the clinicians
tions
This

population

the diagnoses
in a position

toxin,
it is important
to obtain
specific
etiologic
agent
so that

Unless
of innosepsis

those

massive

although

innovative
only
for
populations
ofclinical
particularly

include

For those
therapies
that are directed
at bacterial
infections
or the products
of bacteria,
such as endo-

in
drug

and

that
physimeth-

effect.

in

institute
therapy.
Finally,
less than full support
are

not

such

be

as the
poten-

included
in clinical
trials. A decision
patients
must be made
with ethical

frequently

treat

additional

for certain
mentioned

alteraagent

data on what effect,


if any, these
conditions
have on
the bioavailability
of the agent
or on its therapeutic

results
issue,

disparate
effects
of
is found to be beneficial

of an

of recurrent

accelerated

as a matter

The

supporting

However,

of having

trials

of protocol,

treatment

of plasmapheresis

to the potentially
innovative
therapy
groups,

in the
predicted.

anticipated

to efficacy.

data

or amount

odology
ofthe clinical
trial that showed
efficacy.
supported
by published
literature,
the effect

Most
intended
These

appropriate
three groups

of published

frequency

should
beadministered
in innovative
therapy,
cians should
dose precisely
as was done in the

assess the risks or benefits


of therapy
for each patient.
Patients
with burns,
neutropenia,
and transplanted
organs
may also be excluded
from clinical
trials due

cluded

the

cases

populations,

benefit.

may

tions

and those
with unconpatients
are frequently

clinical

excluded

are

pregnant,
Such

of any

significant

and

of the therapy.
In the absence

withhold

I 101

I 6 I JUNE,

College;
ViceLukes Medical

1992

1653

Session

Chairmen:

Robert A. Balk, M.D.


Rush-Presbyterian-St.
Frank B. Cerra, M.D.,

Cornelius

F.C.C.P,
Associate
Professor
of Medicine,
Lukes Medical Center,
Chicago

Professor
ofSurgery
and Director
of Critical
Care,
Department
of Surgery,
University
of Minnesota
Hospital,
Minneapolis
R. Philip
Dellinger,
M.D.,
F.C.C.P,
Associate
Professor
and Director of Critical
Care,
Department
of Medicine,
Baylor
College
of
Medicine,
Dallas
Alan
M. Fein,
M.D.,
FC.C.P,
Director,
Pulmonary
and Critical
Care
Medicine
Division,
and Associate
Professor
of Medicine,

SUNY
cola,

Health

Science

Center,

Winthrop-University

Hospital,

Mm-

Jerome

University
of Pennsylvania
Medical Center,
Dennts C. Maki, M.D., F.C.C.P,
Professor

New York, New York Medical College,


New York
Timothy
C. Rodell, M.D.
Vice President,
Operations

and Product
Development,
Cortech,
Inc, Denver;
Clinical
Assistant
Professor
of Medicine,
University
of Colorado
Health
Sciences
Center,
Denver
John
N.
Sheagren,
M.D.,
Chairman,
Department
of Internal
Medicine,
Illinois
Masonic
Medical
Center;
Professor
of Medicine,
University
of Illinois
College
of Medicine,
Chicago
Michael
Slices; M.D.,
F.C.C.P,
Assistant
Professor
and Director,
Respiratory
Care
Center,
Rush-Presbyterian-St.
Lukes Medical
Center,
Chicago
Charles L. Sprung,
M.D.
F.C.C.P,
Director,
Intensive
Care Unit,
Hadassah
Hebrew
University
Medical
Center,
Jerusalem,
Israel

C. Straube,

M.D.,

Director,

Infectious

Diseases,

Centocor,

Inc, Malvern,
Pa
Martin
I. Tobin,
M.D.,
F.C.C.P,
Professor
of Medicine,
Loyola
University
ofChicago
Stntch
School
of Medicine,
Maywood,
Ill
Gordon
M. Trenholme,
M.D.
Professor
ofMedicine,
Rush Medical
College,
Chicago
Douglas
Wagner,
M.D.,
Senior
Staff
Scientist,
ICU
Research,
George
Washington
University
Medical
Center,
Washington,
DC
C. Douglas Webb, Ph.D., Director,
Anti-Infectives,
RoerigfPfizer
Pharmaceuticals,
New York
Janice
C. Wherry,
M.D.,
Ph.D.,
Associate
Director,
Clinical
Research,
Cutter
Biological,
Miles,
Inc, Berkeley,
Calif
Herbert?
Wzedemann,
M.D.,
Chairman,
Department
of Pulmonary
and Critical
Care Medicine,
Cleveland
Clinic Foundation,
Cleveland

1654

Downloaded From: http://journal.publications.chestnet.org/ on 05/30/2016

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Physician,
Center
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ofWisconsin
Medical
School,
Madison
John C. Marshall,
M.D.
Assistant
Professor
of Surgery,
University
ofToronto,
and Toronto
Hospital,
Toronto
William W Merrill,
M.D.,
Chief,
Pulmonary
Section,
West Haven
VA Medical
Center,
West Haven,
Conn
John P Pribble,
Pharin.D.,
Assistant
Director
ofClinical
Research,
Synergen,
mc, Boulder,
Cob
Eric C. Rackou,
M.D.,
FC.C.P,
Professor and Chairman,
Department
of Medicine,
St. Vincents
Hospital
and Medical
Center
of

Assistant
Professor
of
Section,
DepartHospital,
Houston

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Faculty:

M.D.,
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