critical care

A New for
Sepsis: Hypothesis
Pathogenesis of the Disease Process*
Roger C. Rone, MD, PhD (honorary), Master FCCP;f Charles J. Grodzin, MD;

and Robert A. Balk, MD, FCCP

and its innovative

(CHEST 1997; 112:235-43) sepsis sequelae, therapies were

and clinical trials

developed were
begun. Although
Abbreviations:
CARS=compensatory anti-inflammatory re
these trials were of the most advanced experimental
sponse syndrome; IFN^interferon; IL=interleukin; MARS = design, double-blind, randomized, and placebo con
mixed
antagonists response syndrome; MODS=multiple organ trolled, all such trials thus far have failed to
sepsis
dysfunction syndrome; SIRS=systemic inflammatory
show efficacy or
have had harmful, ambiguous, or
response syndrome; TNF=tumor necrosis factor
negative results.4 Pharmacologic interventions to
infection.
Sepsisis the
systemic response to severe
date have not improved the outcome in sepsis and
SIRS. The trials have shown how effective certain
The incidence of sepsis continues to increase. agents can be at the cellular or animal model stage
and its the of
Sepsis sequelae are
leading causes
but how ineffective these same agents can be when
death in medical and surgical ICUs.12 According to applied in clinical trials.4
the Centers for Disease Control and Prevention, the While trials addressed the proinflammatory phase of
incidence of sepsis continues to increase and is now sepsis and SIRS, there was no evidence that the
was dominant when
the third leading cause of infectious death (Fig 1). proinflammatory phase drugs
and its
Sepsis sequelae represent progressive were given. This may mean more to us as we learn
of the illness.a to
more about
compensatory anti-inflammatory re
stages same
systemic response
infection mediated via
macrophage-derived cyto-kines that sponses and mixed proinflammatory and anti-inflam
in the human with The
target end-organ receptors in
response to
matory responses sepsis.
failed initial clinical trials tested efficacy of clinical

injury or infection. Much confusion has

trials for sepsis and provided some insight into the
existed
of the cascade.
regarding terminology for sepsis. An American Col complexity immuno-inflammatory
of Chest of Critical Care This article looks at what we know about this com
lege Physicians/Society
Medicine Consensus Conference3 held in 1991 plex immuno-inflammatory cascade, and a new
hy
to relate it to
agreed to a new set of definitions that could be pothesis sepsis.
readily applied to patients in different stages of
sepsis (Table 1). New discoveries made in the last
several years have validated the conceptual appro and
Sepsis, SIRS, CARS, MARS
priateness of these terms, which has led to wide
acceptance. However, new discoveries also suggest When the American College of Chest Physicians

that we need to push these concepts further. and Society of Critical Care Medicine convened a
The
pathophysiologic state of the
systemic inflam Consensus Conference in 1991 to address the prob

matory response syndrome (SIRS) has been studied lem of confusion over use of proper terms and
terms
definitions, the bacteremia, septicemia, sepsis,
extensively. We characterize SIRS as an abnormal sepsis syndrome, and
septic shock were
being used
reaction in remote
generalized inflammatory organs
almost interchangeably, which led to confusion and
from the initial insult. When the process is due to an
terms
imprecise understanding of sepsis and related disor
infection, the sepsis and SIRS are
synony
ders. Members of the Consensus Conference agreed
mous. On the basis of the current understanding of
to a new set of definitions that could be readily
to in different of
*From
the Department of Internal Medicine, Sections of Pulmo applied patients stages sepsis:
nary and Critical Care Medicine, Rush-Presbyterian-St. Luke's bacteremia, SIRS, sepsis, severe
sepsis, septic shock,
and
Medical Center, Rush Medical College, Chicago. multiple organ dysfunction syndrome (MODS).
Deceased.
Manuscript received April 28, 1997; accepted April 29.

CHEST/112/1 /JULY, 1997

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 1980
? 1992

Lung AIDS Sepsis Urinary Heart Hepato TB

tract biliary
Figure 1. Leading causes
of infectious death according to the Centers for Disease Control and

Prevention.

We now to add the anti- in those disorders that often associated with
propose compensatory are

and the of
inflammatory response syndrome (CARS), organ dysfunction, pattern systemic cytokine
mixed release is dissimilar. How, then,
antagonists response syndrome (MARS) to can SIRS and
this set of clinical definitions (Table 2).
MODS be
Multiple organ dysfunction
trauma
occurs in about 30% of
explained?
patients with sepsis, and it also can be found in
patients, patients with acute pancreatitis and
other
diseases such as systemic vasculitides, and in
The Cytokine Cascade
burn victims.59 How7 of
The systemic response to infection is mediated via
dysfunction multiple organs can

be such disorders the that end-

produced by disparate puzzled macrophage-derived cytokines target
clinicians and investigators for Almost a de in to infection.
years. organ receptors response injury or

cade
ago, it was suggested that multiple organ The infection or is a
inflammatory response to
injury
dysfunction may result not from infection per se, but highly conserved and regulated reaction of the or
from a
generalized inflammatory reaction.10 Evi ganism. After
recognition that a
response is
required,
dence
today suggests that a massive inflammatory the
organism (eg, a human
being) produces soluble

reaction
resulting from systemic cytokine release is
protein and
lipid proinflammatory molecules that
the common
pathway underlying multiple organ activate cellular defenses, then produces similar
dysfunction. Also, it is now
known that most patients anti-inflammatory molecules to attenuate and halt
the Molecules known or
have evidence of dysfunction in one or more organs proinflammatory response.
before failure presumed at this time to be
proinflammatory and
anti-
long organ develops.
listed in Table 3.
Unfortunately, the more we learn about this in inflammatory are
Presumption
of is based data of it is
flammatory response, the more difficult it becomes activity on
varying quality;
to
pinpoint a
specific cytokine, or a
specific reaction,
likely that some molecules will eventually drop from
the "cause" of SIRS. Indeed, it has become clear
as
that is
this list, and others will be added.
cytokine release a
normal, healthy part of the is the
Normally cytokine response regulated by
to insult or infection.
body's response Cytokines are
intricate network of and anti-in
proinflammatory
and of
highly pleiotropic, they appear capable pro
flammatory mediators. The initial inflammatory re
different effects the
ducing markedly depending on
sponse is kept in check by down-regulating produc
hormonal milieu.
nearby Furthermore, the body has tion and
counteracting the effects of cytokines already
a network of
highly complex, rigidly regulated recep produced. The picture that emerges from analysis of
tor and other that
antagonists regulatory agents data from
patients with
sepsis is that a

mixture of and anti-in

continuously modulate the effects of cytokine re complex proinflammatory
lease. Adding to our confusion is the fact that flammatory molecules
may be
present.1112 Standard

systemic cytokine release can occur in a variety of models of

disorders without leading to organ dysfunction. Even
pathophysiologic sepsis
do not such
explain a
picture.13
236 Critical Care

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 Table 1.Standard and Table and
Definitionsfor Sepsis Organ 2.Proposed Definitionsfor Sepsis Organ

Failure Failure
Terminology Definition CARS HLA-DR on monocytes <30% and diminished
of
ability monocytes to
produce inflammatory
Infectk Microbial phenomenon characterized by an
IL-6
to the of cytokines, such as
TNF-a or
(Kox WJ, Bone
inflammatory response presence
RC, Krausch D, et al. Arch Intern Med 1997; 157:
the invasion of
microorganisms or
normally
389-93).
sterile host tissue by those organisms.
Bacteremia Presence of viable bacteria in the blood. MARS Features of SIRS in a patient with CARS.
SIRS The
systemic inflammatory response to a wide

variety of severe
clinical insults, manifested by
two or more
of the following conditions: (1)
temperature >38C or
<36C; (2) heart rate proinflammatory reaction (SIRS) or a
compensatory
rate >20 A
>90 beats/min; (3) respiratory anti-inflammatory reaction (CARS) will ensue.

breaths/min or PaC02 <32 mm Hg; and (4)

WBC count >12,000/mm3, <4,000/mm3, or rangeof clinical sequelae may then follow. These
>10% immature (band) forms. sequelae can be remembered by using the mne
Sepsis The
systemic inflammatory response to infection.
monic CHAOS (Fig 2).
In association with infection, manifestations of Currently, our concept of the pathogenesis of
sepsis are the same as those previously defined sepsis is undergoing evolution, based in part on
for SIRS. It should be determined whether
of the direct
animal models or human exposure to endotoxin, in
they are a
part systemic response
hopes of finding a "magic bullet" for sepsis.4 The
to the presence of an infectious process and
magic bullet to definitively treat sepsis has been
represent an acute alteration from baseline in
the absence of other known causes for such vigorously sought, but has not been found. More
Severe sepsis abnormalities.
associated with
than a dozen pharmacologic magic bullet candidates
Sepsis organ dysfunction,
have failed to improve outcome of sepsis in random
hypoperfusion, or
hypotension. Hypoperfusion
ized, placebo-controlled clinical trials. Magic bullet
and perfusion abnormalities may include, but
are
not limited to, lactic acidosis, oliguria, or an trials were based on an assumption that antagonism
acute alteration in mental status. of a single proinflammatory mediator can modulate
shock
Septic A subset of severe sepsis and defined as sepsis-
the cascade of events that constitutes sepsis in a
induced fluid
hypotension despite adequate heterogeneous group of patients. Hindsight indicates
resuscitation along with the presence of perfusion
abnormalities that include, but are
not
that this was simplistic, but evidence available at that
may
time was
limited to, lactic acidosis, oliguria, or an interpreted to suggest that such a strategy
acute alteration in mental status. Patients should be successful. Similarly, available evidence suggested that neutralization of endotoxin would

receiving inotropic or vasopressor agents may

be the time
no
longer hypotensive by they prevent the
proinflammatory response, but clinical
manifest hypoperfusion abnormalities or organ
trials of monoclonal antiendotoxin antibodies were
dysfunction, yet they would still be considered
not successful.1518 The design of clinical trials man
to have septic shock.
MODS Presence of altered organ function in an acutely dated that patients enrolled in the trial meet some
criteria for
ill patient such that homeostasis cannot having sepsis, ignoring any preexisting
be maintained without intervention.
Sepsis-induced condition that might have induced proinflammatory
A systolic BP <90 mm Hg or a reduction of >40 mm
mediators.19 Animal studies suggested that an endo-
hypotension Hg from baseline in the absence of other should be before or
toxin-neutralizing drug given shortly
for
causes
hypotension. after the inflammatory stimulus, but interspe-
cies variation in immunomodulation and other dif

These mediators initiate overlapping processes

ferences in animal models compared to the critically

ill ICU patient make it difficult to generalize animal

that directly influence the endothelium, cardiovascu
lar, hemodynamic, and coagulation mechanisms. The
studies to humans.20
release of many of these vasoregulators is often local.
of the Why Previous Theories Were Inadequate
Evolving concepts septic response give more

to the of local
weight importance cytokine produc
tion, not in
contradistinction to
systemic production We have understood that a massive inflammatory
but as of the total reaction underlies both SIRS and MODS, but now we
part septic-response picture.414
The duration of illness also may alter the mix of must understand that this reaction is only half the
mediators, leading to a state of metabolic disorders picture. It is now clear that quite rapidly after the
in which the body has no control over its own first proinflammatory mediators are
released, the
inflammatory response. If balance cannot be estab body mounts a
compensatory anti-inflammatory re

lished and homeostasis is not restored, a massive

action to
(CARS) the initial proinflammatory re-

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 Table 3.Partial List and Molecules
ofProinflammatory Anti-inflammatory
Molecules
Proinflammatory Anti-inflammatory Molecules

TNF-a Thromboxane IL-1 ra

IL-10 Platelet activating factor IL-4
IL-2 Soluble adhesion molecules IL-10
IL-6 Vasoactive
IL-8 neuropeptides IL-13
IL-1
IL-15 Phospholipase A2 Type II receptor
Neutrophil elastase Tyrosine kinase Transforming growth factor-p
Plasminogen activator inhibitor-1 Epinephrine
IFN-7 Free radical generation Soluble TNF-a receptors
Protein kinase
MCP-1* Neopterin Leukotriene
B4-receptor antagonism
MCP-2
CD14 Soluble recombinant CD-14
LPS
Leukemia inhibitory factor Prostacyclin binding protein*
(D-factor) Prostaglandins
^MCP^monocyte chemoattractant protein; LPS=lipopolysaccharide.

matory mediators and homeostasis is restored (Fig

The reaction be as
sponse.13 anti-inflammatory may
sometimes even In some
large as, and larger than, the proin 2). patients, however, a
variety of forces
The of this anti-inflam in
flammatory response. goal conspire to upset this balance, resulting SIRS and
matory reaction is to down-regulate synthesis of
MODS.
proinflammatory mediators and to modulate their The theories put forth to explain the development
effects, thereby restoring homeostasis. of SIRS have generally not taken this compensatory
It has recently become possible to differentiate
CARS from SIRS anti-inflammatory reaction into consideration. Many of
ongoing immunophysiology. the anti-inflammatory mediators were discovered
Zedler et al21 detailed a technique of stimulating and characterized only in the last few years, and to
peripheral blood mononuclear cells from severely
some extent, this may have led to overstatement of
injured burn patients for the purpose of cell surface the media
and intracellular
dangers presented by proinflammatory
antigen staining interferon-gamma
tors. It might almost be said that proinflammatory
(IFN-7) and interleukin-4 (IL-4) detection. IL-4, an

anti-inflammatory cytokine, was

found in excess
(el mediators became "bad guys," without taking into
in account that excessive levels can be harmful, but
evated 16-fold) the presence of downregulated
IL-2 and IFN-7. IL-4 thus served as a marker for the lower levels are required to combat pathogenic
"THrTH2 switch," a
major characteristic of the organisms and to
promote healing.
to T In Most of the evidence for the role of proinflamma
CARS response injury (TH is the helper cell).
most healthy persons, the body is able to achieve a tory mediators in the pathogenesis of SIRS and
balance between and anti-inflam- MODS came from studies using animal models,
proinflammatory which endotoxin in
experiments or
proinflammatory
into
mediators were
injected human volunteers, and
of levels of media
analysis serum
proinflammatory
C Cardiovascular tors in patients with sepsis, burn injury, or other
compromise (usually manifesting
as
severe
injuries (Fig 3). We now know that these
shock; in this setting SIRS predominates).
studies may not truly reflect what happens in criti
cally ill patients with sepsis or
SIRS. As noted earlier,
H Homeostasis (return to health; this
represents a balance of SIRS and a marked interspecies variation in cytokine release
CARS).
makes it difficult to extrapolate results of animal
A SIRS nor
Apoptosis (neither CARS predominates). studies to humans. More importantly, these experi

ments were performed on healthy animals and gen

or erally included a relatively short observation peri
O Organ dysfunction (single multiple;
od.22 Studies of human volunteers were performed
SIRS in
healthy subjects; the amount of stimulus
injected
predominates). was
sublethal; and, again, the follow-up period was
of the
S Suppression immune system (anergy
and/or increased susceptibility to
brief.23 In contrast, SIRS and MODS develop over

ill or
infection; CARS predominates).
time in
severely injured patients who have

disorders.24
multiple preexisting
Figure 2. Mnemonic of CHAOS. Serum levels of immunomodulating mediators

238 Critical Care

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 result of an immediate insult such as trauma and not

Infection
of condition such
a
consequence a
preexisting as

pancreatitis.19

Endotoxin and
other microbial toxins
\ Relating Clinical Responses

Some patients with sepsis, extensive burns,

sive traumatic injury, or other severe insults show

Cascade
to Cytokine

mas

little or no evidence of a systemic inflammatory

l
reaction or
organ dysfunction, although their recov ery
be because of the of their
may protracted severity
underlying illness. In three other categories, how
ever, are patients with sepsis or severe
other insult

state who develop the following: a mild form of SIRS and

Proinflammatory some evidence of dysfunction in one or two organs
with cytokine release early in their clinical course that usually resolves
rapidly; a massive systemic inflammatory reaction developing
and rapidly after the initial insult, with death
other often within few from
proinflammatory following days profound
a

shock; and a less severe initial course, but marked

mediators deterioration several days or more after the original

l
insult, with outright failure of one or more
organs

and death in some but not all patients.

Clinical trials have usually excluded patients with

mild of
symptoms organ dysfunction or
symptoms

Sepsis/SIRS that last for <24 or 48 h. While this was perhaps

believed necessary to the design and conduct of

I
these trials, the underlying hypothesis may have

been faulty. We should have looked better at the

proinflammatory and anti-inflammatory response to
severe insult and asked whether the inflammatory
was of an
response appropriate magnitude and if it
Shock and
multiorgan was
appropriately down-regulated. When down-reg

dysfunction and ulation is not adequate, is there a progression of

severities? Rangel-Frausto et al28 published the first
possible large study to confirm that
patients progress through

death stages of the septic process, from mild to severe.

Figure 3. Old for A New Theory of SIRS, CARS, MARS, and

paradigm sepsis.
MODS
Immunomodulation is a complex, overlapping net
of because immu-
present problems interpretation work of interactions among agents that work to
noassays can
detect only free, circulating mediators,
gether to overcome severe assaults on the body.
not mediators bound to cells or receptors.12'2526 Paradoxically, they also work to the
body's disadvan
Therefore, the amount of mediator reported may not
tage and cause the disruptions we call SIRS and
MODS. We have
be the amount present. Bioassays used to measure the presented a hypothesis-based ex planation
for the events ob in
functional activity of cytokine often lack speci apparently paradoxical served the
in the
ficity and may over-report the amount of mediator critically ill (Fig 4). The five stages
present.27 Other points to consider are the following: development of
multiple organ dysfunction are

(1) analysis of serum level is usually performed once

as follows: (1) local reaction at the site of injury or
a
day or
less often, although mediator release is
infection; (2) initial systemic response; (3) massive
most
phasic; and (2) analyses have assumed that the systemic inflammation; (4) excessive immunosup-
of mediators is direct
presence proinflammatory a
pression; and (5) immunologic dissonance.29

CHEST / 112 / 1 / JULY, 1997

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 Initial insult
(bacterial,
viral, traumatic,
thermal)
Systemic spillover of Systemic spillover of

pro-inflammatory mediators anti-inflammatory mediators

Cardiovascular Homeo Apoptosis Organ Suppression

compromise stasis (cell death) dysfunction of the
(shock) immune
system
SIRS CARS and Death with SIRS CARS
predominates SIRS minimal predominates predominates
balanced inflammation

Figure 4. New
concepts for the clinical sequelae of sepsis, SIRS, CARS, and MARS. (This figure is
an
adaptation of Figure 1 by Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 1996;
24:1125-28.)
substances12-30'32 work to diminish monocytic major
1
Stage histocompatibility complex class II
expression, im

Prior to development of SIRS or MODS is some pair antigen presenting activity, and reduce the
insult such as a nidus of infection, a traumatic injury of cells to
ability produce inflammatory cytokines.
(including a
surgical wound), a
burn injury, or

that release of of Local levels of both proinflammatory and anti-in

pancreatitis prompts a
variety mediators can be
flammatory substantially higher
mediators in the microenvironment. The body's ini
tial
response is to induce a proinflammatory state in than are later
found systemically33,38 (Table 3).
which mediators have multiple overlapping effects
2
designed
whatever
to limit new damage and to ameliorate Stage
damage has already occurred. Theydestroy If the
original insult is
sufficiently severe, first
damaged tissue, promote the growth of new tissue, proinflammatory and later
anti-inflammatory media

and combat pathogenic organisms, neoplastic cells, tors will appear in the systemic circulation via a
and of mechanisms. The of
foreign antigens20-24 (Table 3). variety presence proinflam
A
compensatory anti-inflammatory response soon
matory mediators in the circulation is part of the
ensures that the effects of these proinflammatory normal response to infection and serves as a warning
mediators do not become destructive. IL-4, IL-10, signal that the microenvironment cannot control the
IL-11, IL-13, soluble tumor necrosis factor (TNF-ot) initiating insult. The
proinflammatory mediators
IL-1 recruit T
receptors, receptor antagonists, transforming help neutrophils, cells and B cells,
growth factor-(3, and other, as
yet undiscovered
platelets, and coagulation factors to the site of injury or

240 Critical Care

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 infection.24 This cascade stimulates a compensatory
5
systemic anti-inflammatory response, which nor
mally
Stage
quickly down-regulates the initial
proinflam The final stage of MODS is what we have elected
if clinical to call "immunologic dissonance."54 It is an inappro
matory response. Few, any, significant
and be priate, out-of-balance response ofthe immunomodu-
signs symptoms are
produced. Organs may In some it results from
latory system. patients,
the
affected by inflammatory cascade, but persistent, overwhelming inflammation that
may
in
significant organ dysfunction is rare. persist patients with SIRS and MODS, with
increased risk of death.115557
3 In some
patients, persistent immune
suppression
Stage Loss of of the causes immunologic dissonance. Studies have shown
regulation proinflammatory re
not
only that
monocyte deactivation
persists in
many
sponse results in a massive systemic reaction mani patients, but that such
persistent deactivation
greatly
fest as the clinical findings of SIRS. Underlying the increases the risk of death.51 In patients with persis
clinical
pathophysiologic changes that
findings are
tent immune suppression, the cause of organ failure
include the following: (1) progressive endothelial may be inhibition of the
synthesis of the
proinflam
dysfunction, leading to increased microvascular per matory agents needed to allow the organs to recover.
meability;3943 (2) platelet sludging that blocks the In
patients with immunologic dissonance, it may be
microcireulation,44 causing maldistribution of blood possible to
regain organ function if the
body can

its balance.
in
flow and possibly ischemia, which turn may cause
recover
reperfusion injury45 and induction of heat shock
proteins;46 (3) activation of the coagulation system
and
impairment ofthe
protein C-protein S
inhibitory Conclusions
pathway;47 and (4) profound vasodilation, fluid tran- Balance between proinflammatory and anti-in
forces
sudation, and maldistribution of blood flow may flammatory could conceivably be lost: (1)
in
result profound shock.4849 Organ dysfunction and, ultimately, failure result from these changes unless
when
infection, burn injury, hemorrhage, etc, is so

severe that the insult alone is sufficient to prompt

homeostasis is quickly restored. SIRS and MODS; or
(2) when patients are
"pre

Stage 4
to SIRS and MODS severe
printed" develop by preexisting
illness. (3) Most of the preexisting conditions

It is possible that a compensatory anti-inflamma are associated with abnormal cytokine levels.19
reaction can be with a The of rests on our under
tory inappropriate, resulting hypothesis prepriming

immunosuppression. What some

investigators have standing that a patient at risk for SIRS or MODS already
has a clinical and is not
called "immune significant history,
"window of imparalysis,"5051 and
human volunteer.
munodeficiency,"52 "compensatory we describe as clinically analogous to a
healthy
anti-inflammatory response syndrome" (CARS).4
CARS is the body's response to inflammation and is
more than
just immune-paralysis. CARS may explain References
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