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Vol.
6,
No.
4
CLINICAL
MICROBIOLOGY
REVIEWS,
October
1993,
p.
443
444
0893-8512/93/040443-02$02.00/0
Letter
to
the
Editor
Gram-Negative
Sepsis:
What
Dilemma?
Bone
reviewed
the
syndrome
of
gram-negative
sepsis
with
an
emphasis
on
aspects
of
its
clinical
management
and
the
promise
of
antiendotoxin
immunotherapy
(3).
He
suggested
that
the
triggering
of
mediators
by
bacterial
endotoxin,
which
antimicrobial
therapy
fails
to
address,
is
the
basis
for
the
continuing
high
mortality
and
complications
associated
with
this
condition.
The
new
terminology
presented
is
an
important
step
toward
progress
in
this
area,
as
it
is
based
on
the
recognition
that
patient
outcome
in this
syndrome
is
more
closely
related
to
the
degree
of
organ
damage
than
to
the
documentation
of
infection
(i.e.,
bacteremia)
by
the
microbiology
laboratory.
For
example,
in
the
Veterans
Administration
systemic
sepsis
study,
alterations
in
mental
state
were
a
powerful
predictor
of
outcome
(odds
ratio
for
mortality,
2.36;
P
<
0.0001)
whereas
gram-negative
bacteremia
was
not
(odds
ratio
for
mortality,
1.32;
P
was
not
significant
[12]).
As
a
conse-
quence,
recent
efforts
have
focused
on
the
mediators
of
the
sepsis
cascade,
with
particular
attention
to
endotoxin.
From
three
perspectives,
however,
the
role
of
endotoxin
in
the
sepsis
syndrome
is
far
from
clear.
First,
the
neologism
"endotoxinemia"
emphasizes
that
the
detection
of
endo-
toxin
in
blood
(previously
termed
"endotoxemia")
does
not
automatically
imply
"toxemia"
(10).
Second,
experimental
data
demonstrate
that
antibiotics
do
in
fact
induce
the
release
of
endotoxin
in
patients
(5,
9).
However,
it
is
difficult
to
find
documented
cases
in
which
this
release
of
endotoxin
could
be
of
any
clinical
conse-
quence
(6).
Third,
the
effects
of
endotoxin
cannot
account
for
the
multiple
organ
failure
(MOF)
paradoxes.
The
process
may
involve
multiple
organs;
the
lag
period;
the
lack
of
microbi-
ological
documentation
for
many
clinically
septic
patients,
even
those
with
a
fatal
outcome;
and
the
lack
of
response
to
currently
applied
therapy
(4).
There
is
increasing
recognition
that
mechanisms,
such
as
lipopolysaccharide-binding
proteins
(11),
which
mediate
much
of
the
response
to
endotoxin
in
sepsis,
are
regulated.
Hence,
the
mass
action
response
that
follows
the
acute
administration
of
endotoxin
to
volunteers
may
not
accu-
rately
represent
the
pathophysiology
of
sepsis.
In
particular,
these
acute
effects
of
endotoxin
cannot
explain
the
MOF
paradoxes.
It
is
difficult
to
establish
the
experimental
evidence
on
which
Bone
has
based
the
assertion
that
monoclonal
antien-
dotoxin
antibodies
bind
to
endotoxin
or
neutralize
its
ad-
verse
effects,
as
much
of
his
cited
literature
does
not
correspond
to
pertinent
entries
in
his
list
of
references.
Moreover,
there
is
now
in
vitro
(13)
and
in
vivo
(2)
evidence
to
refute
this
assertion.
In
the
clinical
evaluations
of
both
E5
and
HA-1A,
no
overall
benefit
was
noted.
Rather,
the
benefit
was
confined
to
subgroups
of
patients
that
were
defined
only
in
retrospect.
Hence,
the
value
of
antiendotoxin
therapy
(1)
and
the
mechanism
of
its
benefit
(7)
are
questionable.
This
is
not
to
deny
that
these
immunotherapeutic
ap-
proaches
may
yet
have
an
important
role
in
that
subgroup
of
patients
which
we
are
not
yet
able
to
identify
prospec-
tively.
However,
reappraisal
of
the
concept
of
endotoxin
suggests
that
its
role
in
the
mediation
of
sepsis
is
unproven,
and
other
components
of
gram-negative
bacteria,
for
exam-
ple,
L-forms
(8),
have
yet
to
be
examined.
REFERENCES
1.
Baumgartner,
J.-D.
1991.
Immunotherapy
with
antibodies
to
core
lipopolysaccharide:
a
critical
appraisal.
Infect.
Dis.
Clin.
N.
Am.
5:915-927.
2.
Baumgartner,
J.-D.,
D.
Heumann,
J.
Gerain,
P.
Weinbreck,
G.
E.
Grau,
and
M.
P.
Glauser.
1990.
Association
between
protective
efficacy
of
anti-lipopolysaccharide
(LPS)
antibodies
and
suppression
of
LPS-induced
tumour
necrosis
factor
alpha
and
interleukin
6.
Comparison
of
0
side
chain-specific
antibod-
ies
with
core
LPS
antibodies.
J.
Exp.
Med.
171:889-896.
3.
Bone,
R.
C.
1993.
Gram-negative
sepsis:
a
dilemma
of
modern
medicine.
Clin.
Microbiol.
Rev.
6:57-68.
4.
Deitch,
E.
A.
1990.
Multiple
organ
failure:
summary
and
over-
view,
p.
285-289.
In
E.
A.
Deitch
(ed.),
Multiple
organ
failure:
pathophysiology
and
basic
concepts
of
therapy.
Thieme
Medi-
cal
Publishers,
Inc.,
New
York.
5.
Hurley,
J.
C.
1991.
antibiotic
action
and
endotoxin.
Ph.D.
thesis.
University
of
Melbourne,
Parkville,
Victoria,
Australia.
6.
Hurley,
J.
C.
1992.
Antibiotic-induced
release
of
endotoxin:
a
reappraisal.
Clin.
Infect.
Dis.
15:840-854.
7.
Hurley,
J.
C.
Bacteremia,
endotoxemia
and
mortality
in
Gram
negative
sepsis.
J.
Infect.
Dis.,
in
press.
(Letter.)
8.
Hurley,
J.
C.
1993.
Reappraisal
of
the
role
of
endotoxin
in
the
sepsis
syndrome.
Lancet
341:1133-1135.
9.
Hurley,
J.
C.,
W.
J.
Louis,
F.
A.
Tosolini,
and
J.
B.
Carlin.
1991.
Antibiotic-induced
release
of
endotoxin
in
chronically
bacteriu-
ric
patients.
Antimicrob.
Agents
Chemother.
35:2388-2394.
10.
The
Lancet.
1992.
Endotoxaemia
or
endotoxinaemia?
Lancet
340:1323.
11.
Raetz,
C.
R.
H.,
R.
J.
Ulevitch,
S.
D.
Wright,
C.
H.
Sibley,
A.
Ding,
and
C.
F.
Nathan.
1991.
Gram
negative
endotoxin:
an
extraordinary
lipid
with
profound
effects
on
eukaryotic
signal
transduction.
FASEB
J.
5:2652-2660.
12.
Sprung,
C.
L.,
P.
N.
Peduzzi,
C.
H.
Shatney,
R.
M.
H.
Schein,
M.
F.
Wilson,
J.
N.
Sheagren,
L.
B.
Hinshaw,
and
The
Veterans
Administration
Systemic
Sepsis
Cooperative
Study
Group.
1990.
Impact
of
encephalopathy
on
mortality
in
the
sepsis
syndrome.
Crit.
Care
Med.
18:801-806.
13.
Warren,
H.
S.,
S.
F.
Amato,
C.
Fitting,
K.
M.
Black,
P.
M.
Loiselle,
M.
S.
Pasternack,
and
J.
M.
Cavaillon.
1993.
Assess-
ment
of
ability
of
murine
and
human
anti-lipid
A
monoclonal
antibodies
to
bind
and
neutralize
lipopolysaccharide.
J.
Exp.
Med.
177:83-97.
James
C.
Hurley
Division
of
Infectious
Diseases
Children's
Hospital
&
Medical
Center
4800
Sand
Point
Way
P.O.
Box
C5371
Seattle,
Washington
98105
Author's
Reply
The
dilemma
that
I
spoke
of
in
my
article
is
one
of
both
terminology
and
clinical
trial
conduct.
Problems
with
the
old
terminology
resulted
in
much
confusion,
as
various
individ-
uals
defined
such
a
clinical
entity
as
"sepsis"
in
different
ways.
The
terms
developed
by
the
ACCP/SCCM
Consensus
Conference
provide
a
standard
reference
and
should
resolve
some
of
this
confusion.
The
use
of
poorly
defined
terms
was
443
444
LETlTER
TO
THE
EDITOR
No.
of
Patients
80
70
60
50
40
30
20
10
0
(10
10-
20-
30-
40-
50-
60-
70-
80-
90-
ICU
Day
1
Mortality
Risk
SIRS
(N-503)
No
SIRS
(N-16)
FIG.
1.
Risk
distribution
of
519
sepsis
patients
according
to
whether
they
met
criteria
for
SIRS.
Reproduced
with
permission
of
the
publishers
(1).
also
an
important
stumbling
block
to
clinical
researchers;
with
inclusion
criteria
and
disease
definitions
that
were
not
comparable,
and
without
the
ability
to
stratify
patients
by
the
severity
of
illness,
trial
results
were
very
difficult
to
interpret.
Nonstandard
terminology
made
it
especially
diffi-
cult
to
compare
results
from
study
to
study.
In
many
cases,
patients
with
high
risk
did
not
fulfill
the
criteria
for
sepsis
syndrome.
An
ACCP/SCCM
study
group
examined
the
risk
factors
and
classifications
of
519
patients
admitted
to
intensive
care
units
with
a
diagnosis
of
sepsis.
Figure
1
shows
that
503
of
these
519
patients
fulfilled
the
definition
for
septic
inflamma-
tory
response
syndrome
(SIRS)
and
indicates
their
risk
distributions
(1).
Figure
2
shows
those
503
patients
with
SIRS
stratified
by
mortality
risk,
along
with
their
eventual
mortality
(1).
These
data
demonstrate
the
difference
that
definitions
can
have
on
the
results
obtained
by
clinical
trials.
The
essential
issue
is
that,
because
of
the
equivocal
results
obtained
in
clinical
trials
to
date,
we
cannot
use
certain
pharmacological
agents
that
may,
nonetheless,
be
effective
treatments.
This
is
a
result
of
our
inability
to
prospectively
define
the
populations
that
might
benefit
from
their
use.
To
date,
this
factor
has
influenced
the
results
of
clinical
trials
of
monoclonal
antibodies
to
endotoxin
and
the
interleukin-1
receptor
antagonist.
For
example,
in
trials
of
the
interleu-
kin-1
receptor
antagonist,
when
a
population
with
an
ex-
pected
mortality
of
more
than
25%
was
used,
the
data
indicated
that
a
significant,
beneficial
effect
resulted
from
the
80
_
100
70
90
2°440~~~~~~~~~~~~8
O~~~~~~~~~~~~~~~~~
so
60-
70
60
10
2
3
40
50
s
30
-40
30
20
-20
10
10
410
10-
20-
30-
40-
50-
60-
70-
80-
90-
ICU
Day
1
Mortality
Risk
Hospital
Mortality
-
No.
of
Patients
FIG.
2.
Risk
distribution
of
503
septic
patients
who
met
the
criteria
for
SIRS.
This
demonstrates
the
relationship
between
risk
of
hospital
mortality,
calculated
on
the
first
day
of
stay
in
the
intensive
care
unit,
and
actual
hospital
mortality
rates.
Reproduced
with
permission
of
the
publishers
(1).
treatment.
However,
this
is
a
post
hoc
analysis
and
it
could
be
questioned.
In
such
a
case,
the
enrollment
of
large
numbers
of
patients
with
low
risk
would
make
the
hypothe-
sis
of
a
decreased
mortality
difficult
to
prove.
The
same
thing
was
seen
in
the
results
of
the
second
clinical
trial
of
E5,
a
monoclonal
antibody
against
endotoxin.
In
that
study,
the
placebo
group
had
a
lower
mortality
than
would
have
been
expected
on
the
basis
of
previous
studies.
It
is
hoped
that
future
studies
will
use
terminology
that
promotes
the
inclusion
of
larger
numbers
of
patients
who
are
appropriately
stratified.
This
should
allow
us
to
prospec-
tively
define
populations
likely
to
benefit
from
this
treatment
and
to
exclude
those
that
are
less
likely
to
benefit.
Addition-
ally,
it
would
greatly
improve
our
ability
to
interpret
and
compare
clinical
results.
REFERENCE
1.
Bone,
R.
C.,
R.
A.
Balk,
F.
B.
Cerra,
R.
P.
Dellinger,
A.
M.
Fein,
W.
A.
Knaus,
R.
M.
H.
Schein,
W.
J.
Sibbald,
et
al.
1992.
ACCP/SCCM
consensus
conference:
definitions
for
sepsis
and
organ
failure
and
guidelines
for
the
use
of
innovative
therapies
in
sepsis.
Chest
101:1644-1655.
(Also
published
in
Crit.
Care
Med.
20:864-874.)
Roger
C.
Bone
Rush-Presbyterian-St.
Luke's
Medical
Center
1653
West
Congress
Parkway
Chicago,
Illinois
60612-3864
CLIN.
MICROBIOL.
REV.
