Professional Documents
Culture Documents
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
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
phases,
definitions
to validate
and
St.
measures
b.ske
60612
1644
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
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,
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
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
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
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
I 101
I 6 I JUNE,
1992
1645
cussed
It is
iology
stitute
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
but
used
in a variety
difficulties
and
as
in
the
the
clinically
as
a
as those
of ways,
in data
usage.
response
manifestations
previously
known
causes
for such
defined
to, more
greater
to
Severe
organ
sepsis
than
than
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
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
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
more
has been
defined
microorganisms
or
ofother
response
this
Sepsis
clinical
BaCt#{128}I-emia = the
to the presence
of
of normally
sterile
etc).
blood.
10 percent
these
of normally
characterized
phenomenon
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-
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
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
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
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
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
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
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
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
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
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-
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
it is increasingly
being
end point
of severity
scoring
a score representing
the degree
for care
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
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.
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
(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
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
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
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-
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
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
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
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
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
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,
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
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
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-
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
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
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
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,
CHEST
patients
bleeding,
trials. Overutilization
if the identification
is not an expert
on
care
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
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
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:
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
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
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Center
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Medical
School,
Madison
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Professor
of Surgery,
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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,
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Department
of Medicine,
St. Vincents
Hospital
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Center
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DepartHospital,
Houston
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I 101
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