Sepsis: A New Hypothesis for Pathogenesis of the Disease Process

Roger C. Bone, Charles J. Grodzin and Robert A. Balk Chest 1997;112;235-243 DOI 10.1378/chest.112.1.235 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/112/1/235.citation

Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright1997by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

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

(CHEST 1997; 112:235-43)

Abbreviations: CARS=compensatory anti-inflammatory re sponse syndrome; IFN^interferon; IL=interleukin; MARS mixed antagonists response syndrome; MODS=multiple organ dysfunctionTNF=tumor SIRS=systemic inflammatory response syndrome; necrosis factor syndrome;
=

its sequelae are leading causes of Sepsis death in medical and surgical ICUs.12 According to the Centers for Disease Control and Prevention, the incidence of sepsis continues to increase and is now the third leading cause of infectious death (Fig 1). Sepsis and its sequelae represent progressive stages of the same illness.a systemic response to infection mediated via macrophage-derived cytokines that target end-organ receptors in response to injury or infection. Much confusion has existed Col regardingChest terminology for sepsis. An American Care of of Critical Physicians/Society lege Medicine Consensus Conference3 held in 1991 agreed to a new set of definitions that could be readily applied to patients in different stages of sepsis (Table 1). New discoveries made in the last several years have validated the conceptual appro priateness of these terms, which has led to wide acceptance. However, new discoveries also suggest that we need to push these concepts further. The pathophysiologic state of the systemic inflam matory response syndrome (SIRS) has been studied extensively. We characterize SIRSinas an abnormal generalized inflammatory reaction organs remote from the initial insult. When the process is due to an infection, the terms sepsis and SIRS are synony mous. On the basis of the current understanding of
*From the Department of Internal Medicine, Sections of Pulmo nary and Critical Care Medicine, Rush-Presbyterian-St. Luke's Medical Center, Rush Medical College, Chicago. Deceased.

response Sepsisandthe systemicsepsis the The incidence of

is

to

severe

infection.

continues to increase.

developed and clinical trials were begun. Although these trials were of the most advanced experimental and placebo con design, double-blind, randomized, far have failed to all such sepsis trials thus trolled, show efficacy or have had harmful, ambiguous, or negative results.4 Pharmacologic interventions to date have not improved the outcome in sepsis and SIRS. The trials have shown how effective certain agents can be at the cellular or animal model stage but how ineffective these same agents can be when applied in clinical trials.4 the While trials addressed proinflammatory phase of sepsis and SIRS, there was no evidence that the proinflammatory phase was dominant when drugs were given. This may mean more to us as we learn more about compensatory anti-inflammatory re sponses and mixed proinflammatory and anti-inflam matory responses in the human with sepsis. The failed initial clinical trials tested efficacy of clinical trials for sepsis and provided some insight into the complexity of the immuno-inflammatory cascade. This article looks at what we know about this com plex immuno-inflammatory cascade, and a new hy pothesis to relate it to sepsis.
Sepsis, SIRS, CARS, and MARS
When the American College of Chest Physicians and Society of Critical Care Medicine convened a Consensus Conference in 1991 to address the prob lem of confusion over use of proper terms and definitions, the terms bacteremia, septicemia, sepsis, sepsis syndrome, and septic shock were being used almost interchangeably, which led to confusion and imprecise understanding of sepsis and related disor ders. Members of the Consensus Conference agreed to a new set of definitions that could be readily applied to patients in different stages of sepsis:

sepsis and

its

sequelae,

innovative

therapies

were

Manuscript received April 28, 1997; accepted April 29.

bacteremia, SIRS, sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS).
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 1980 ? 1992

Lung
Figure 1. Prevention.

AIDS

Sepsis Urinary
tract

Heart

Hepato TB

biliary

Leading causes

of infectious death

according to the

Centers for Disease Control and

add the compensatory antiinflammatory response syndrome (CARS), and mixed antagonists response syndrome (MARS) to this set of clinical definitions (Table 2). Multiple organ dysfunction occurs in about 30% of patients with sepsis, and it also can be found in trauma patients, patients with acute pancreatitis and other diseases such as systemic vasculitides, and in burn victims.59 How7 dysfunction of multiple organs can be produced by such disparate disorders puzzled clinicians and investigators for years. Almost a de cade ago, it was suggested that multiple organ dysfunction may result not from infection per se, but from a generalized inflammatory reaction.10 Evi dence today suggests that a massive inflammatory reaction resulting from systemic cytokine release is the common pathway underlying multiple organ dysfunction. Also, it is now known that most patients have evidence of dysfunction in one or more organs long before organ failure develops. we Unfortunately, the moremore learn about this in the difficult it becomes flammatory aresponse, to pinpoint specific cytokine, or a specific reaction, as the "cause" of SIRS. Indeed, it has become clear that cytokine release is a normal, healthy part of the body's response to insult or infection. Cytokines are highly pleiotropic, and they appear capable of pro ducing hormonal different effects depending on the markedly milieu. Furthermore, the body has nearby a highly complex, rigidly regulated network of recep tor antagonists and other regulatory agents that continuously modulate the effects of cytokine re lease. Adding to our confusion is the fact that systemic cytokine release can occur in a variety of disorders without leading to organ dysfunction. Even
We propose
now

to

in

those disorders that are often associated with organ dysfunction, the pattern of systemic cytokine release is dissimilar. How, then, can SIRS and MODS be explained?
The Cytokine Cascade

The systemic response to infection is mediated via the macrophage-derived cytokines that target endorgan receptors in response to injury or infection. The inflammatory response to infection or injury is a highly conserved and regulated reaction of the or ganism. After recognition that a response is required, the organism (eg, a human being) produces soluble protein and lipid proinflammatory molecules that activate cellular defenses, then produces similar anti-inflammatory molecules to attenuate and halt the proinflammatory response. Molecules known or presumed at this time to be proinflammatory and anti-inflammatory are listed in Table 3. Presumption of activity is based on data of varying quality; it is likely that some molecules will eventually drop from this list, and others will be added. Normally cytokine response is regulated by the intricate network of proinflammatory and anti-in flammatory mediators. The initial inflammatory re sponse is kept in check by down-regulating produc tion and counteracting the effects of cytokines already produced. The picture that emerges from analysis of data from patients with sepsis is that a complex mixture of proinflammatory and anti-in flammatory molecules may be present.1112 Standard pathophysiologic models of sepsis do not explain such a picture.13
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Table 1.Standard Definitions for Sepsis and Organ Failure

Table
CARS

2.Proposed Definitions for Sepsis and Organ Failure

HLA-DR
on

Terminology
Infectk

Definition

Microbial phenomenon characterized by an inflammatory response to the presence of

Presence of viable bacteria in the blood.

Bacteremia SIRS

microorganisms or the invasion of normally sterile host tissue by those organisms.

of the

MARS

cytokines, such as TNF-a or IL-6 (Kox WJ, Bone RC, Krausch D, et al. Arch Intern Med 1997; 157: 389-93). Features of SIRS in a patient with CARS.

ability of monocytes to produce inflammatory

monocytes <30% and diminished

The

systemic inflammatory response to a wide variety of severe clinical insults, manifested by

two
or more

Sepsis

WBC count >12,000/mm3, <4,000/mm3, or >10% immature (band) forms. The systemic inflammatory response to infection. In association with infection, manifestations of

or <36C; (2) heart rate temperature >90 beats/min; (3) respiratory rate >20 breaths/min or PaC02 <32 mm Hg; and (4)

>38C

following conditions: (1)

sepsis are the same as those previously defined

for SIRS. It should be determined whether
to

Severe

sepsis

the presence of an infectious process and represent an acute alteration from baseline in the absence of other known causes for such abnormalities. Sepsis associated with organ dysfunction,

they are a part of the direct systemic response

Septic shock

MODS

Sepsis-induced hypotension

alteration in mental status. sepsis and defined as sepsisinduced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may no longer be hypotensive by the time they manifest hypoperfusion abnormalities or organ dysfunction, yet they would still be considered to have septic shock. Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention. A systolic BP <90 mm Hg or a reduction of >40 mm Hg from baseline in the absence of other causes for hypotension.
acute

hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an

A subset of severe

These mediators initiate overlapping processes that directly influence the endothelium, cardiovascu lar, hemodynamic, and coagulation mechanisms. The release of many of these vasoregulators is often local. Evolving concepts of the septic response give more weight tointhe importance of local cytokine produc tion, not contradistinction to systemic production but as part of the total septic-response picture.414 The duration of illness also may alter the mix of mediators, leading to a state of metabolic disorders in which the body has no control over its own inflammatory response. If balance cannot be estab lished and homeostasis is not restored, a massive

compensatory proinflammatory reaction (SIRS) or a will ensue. A anti-inflammatory reaction (CARS) follow. These range of clinical sequelae may then sequelae can be remembered by using the mne monic CHAOS (Fig 2). Currently, our concept of the pathogenesis of sepsis is undergoing evolution, based in part on animal models or human exposure to endotoxin, in The hopes of finding a "magic bullet" for sepsis.4 been magic bullet to definitively treat sepsis has vigorously sought, but has not been found. More than a dozen pharmacologic magic bullet candidates have failed to improve outcome of sepsis in random ized, placebo-controlled clinical trials. Magic bullet trials were based on an assumption that antagonism of a single proinflammatory mediator can modulate the cascade of events that constitutes sepsis in a heterogeneous group of patients. Hindsight indicates that this was simplistic, but evidence available at that time was interpreted to suggest that such a strategy should be successful. Similarly, available evidence would suggested that neutralization of endotoxin clinical prevent the proinflammatory response, but trials of monoclonal antiendotoxin antibodies were not successful.1518 The design of clinical trials man dated that patients enrolled in the trial meet some criteria for having sepsis, ignoring any preexisting condition that might have induced proinflammatory mediators.19 Animal studies suggested that an endotoxin-neutralizing drug should be given before or shortly after the inflammatory stimulus, but interspecies variation in immunomodulation and other dif ferences in animal models compared to the critically ill ICU patient make it difficult to generalize animal studies to humans.20
Why Previous Theories Were

Inadequate

We have understood that a massive inflammatory reaction underlies both SIRS and MODS, but now we must understand that this reaction is only half the picture. It is now clear that quite rapidly after the

first

body

proinflammatory mounts a
(CARS)
to

mediators

are

action

compensatory anti-inflammatory re
the initial

released, the

proinflammatory

re-

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

Proinflammatory Molecules
TNF-a

Anti-inflammatory Molecules
IL-1 ra IL-4 IL-10 IL-13 Type II IL-1

IL-10
IL-2 IL-6 IL-8 IL-15

Thromboxane Platelet activating factor Soluble adhesion molecules

Vasoactive

IFN-7

Neutrophil elastase

neuropeptides Phospholipase A2 Tyrosine kinase Plasminogen activator inhibitor-1

Free radical

Protein kinase MCP-1* MCP-2

Neopterin
CD14

generation

Transforming growth factor-p Epinephrine

LPS

receptor

Soluble TNF-a receptors Leukotriene B4-receptor antagonism Soluble recombinant CD-14

Leukemia inhibitory factor

(D-factor)

Prostacyclin Prostaglandins LPS=lipopolysaccharide.

binding protein*

^MCP^monocyte chemoattractant protein;

proinflammatory mediators and to modulate their effects, thereby restoring homeostasis. It has recently become possible to differentiate ongoing CARS from SIRS immunophysiology. Zedler et al21 detailed a technique of stimulating peripheral blood mononuclear cells from severely injured burn patients for the purpose of cell surface antigen staining and intracellular interferon-gamma (IFN-7) and interleukin-4 (IL-4) detection. IL-4, an anti-inflammatory cytokine, was found in excess (el evated 16-fold) in the presence of downregulated IL-2 and IFN-7. IL-4 thus served as a marker for the "THrTH2 switch," a major characteristic of the CARS response to injury (TH is the T helper cell). In most healthy persons, the body is able to achieve a balance between proinflammatory and anti-inflamC
H
A
Cardiovascular compromise (usually manifesting as shock; in this setting SIRS predominates).
Homeostasis (return to health; this represents a balance of SIRS and CARS).

sponse.13 The anti-inflammatory reaction may be as large as, and sometimes even larger than, the proin flammatory response.toThe goal of this anti-inflam matory reaction is down-regulate synthesis of

matory mediators and homeostasis is restored (Fig 2). In some patients, however, a variety of forces conspire to upset this balance, resulting in SIRS and
MODS.

Apoptosis (neither SIRS nor CARS predominates).

Organ dysfunction (single or multiple; SIRS predominates).
Suppression of the immune system (anergy and/or increased susceptibility to infection; CARS predominates).

O
S

Figure 2. Mnemonic of CHAOS.

The theories put forth to explain the development of SIRS have generally not taken this compensatory anti-inflammatory reaction into consideration. Many of the anti-inflammatory mediators were discovered and characterized only in the last few years, and to some extent, this may have led to overstatement of the dangers presented by proinflammatory media tors. It might almost be said that proinflammatory mediators became "bad guys," without taking into account that excessive levels can be harmful, but lower levels are required to combat pathogenic organisms and to promote healing. Most of the evidence for the role of proinflamma tory mediators in the pathogenesis of SIRS and MODS came from studies using animal models, experiments in which endotoxin or proinflammatory mediators were injected into human volunteers, and analysis of serum levels of proinflammatory media tors in patients with sepsis, burn injury, or other severe injuries (Fig 3). We now know that these studies may not truly reflect what happens in criti cally ill patients with sepsis or SIRS. As noted earlier, a marked interspecies variation in cytokine release makes it difficult to extrapolate results of animal studies to humans. More importantly, these experi ments were performed on healthy animals and gen erally included a relatively short observation peri od.22 Studies of human volunteers were performed in healthy subjects; the amount of stimulus injected was sublethal; and, again, the follow-up period was brief.23 In contrast, SIRS and MODS develop over time in severely ill or injured patients who have multiple preexisting disorders.24 Serum levels of immunomodulating mediators
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Infection

Endotoxin and other microbial toxins

\ l

pancreatitis.19

result of an immediate insult such as trauma and not consequence of a preexisting condition such as
Relating Clinical Responses Cascade

to

Cytokine

with cytokine release and other proinflammatory mediators

Proinflammatory state

Sepsis/SIRS
Shock and multiorgan dysfunction and

l I

possible
death
sepsis.

systemic inflammatory reaction rapidly; a massive after the initial developing rapidly a few insult, with death often following within days from profound initial course, but marked shock; and a less severe deterioration several days or more after the original 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 symptoms of organ dysfunction or symptoms that last for <24 or 48 h. While this was perhaps believed necessary to the design and conduct of 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 response was of an appropriate magnitude and if it was appropriately down-regulated. When down-reg ulation is not adequate, is there a progression of severities? Rangel-Frausto et al28 published the first progress through large study to confirm that patientsmild to severe. from of the
stages

who develop the following: a mild form of SIRS and some evidence of dysfunction in one or two organs early in their clinical course that usually resolves

patients with sepsis, extensive burns, mas injury, or other severe insults show little or no evidence of a systemic inflammatory reaction or organ dysfunction, although their recov ery may be protracted because of the severity of their underlying illness. In three other categories, how ever, are patients with sepsis or other severe insult
Some
sive traumatic

septic process,
of

Figure 3. Old paradigm for

A New Theory

SIRS, CARS, MARS, and

MODS

present problems of interpretation because immunoassays can detect only free, circulating mediators, not mediators bound to cells or receptors.12'2526 Therefore, the amount of mediator reported may not be the amount present. Bioassays used to measure the functional activity of cytokine often lack speci ficity and may over-report the amount of mediator present.27 Other points to consider are the following: (1) analysis of serum level is usually performed once a day or less often, although mediator release is phasic; and (2) most analyses have assumed that the presence of proinflammatory mediators is a direct

systemic inflammation; (4) excessive immunosuppression; and (5) immunologic dissonance.29

CHEST / 112 / 1 / JULY, 1997

Immunomodulation is a complex, overlapping net work of interactions among agents that work to assaults gether to overcome severe to the on the body. work Paradoxically, they also body's disadvan tage and cause the disruptions we call SIRS and MODS. We have presented a hypothesis-based ex for planation the the apparently paradoxical events ob in served critically ill (Fig 4). The five stages in the development of multiple organ dysfunction are as follows: (1) local reaction at the site of injury or infection; (2) initial systemic response; (3) massive

239

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Initial insult

(bacterial,
viral, traumatic,

thermal)

Systemic spillover of pro-inflammatory mediators

Systemic spillover of anti-inflammatory mediators

Cardiovascular

compromise (shock)
SIRS

Homeo stasis

Apoptosis (cell death)

Death with
minimal

Organ dysfunction
SIRS

Suppression
of the immune

system

predominates

CARS and SIRS balanced

CARS

inflammation

predominates

predominates

24:1125-28.)

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;

Stage 1
Prior to development of SIRS or MODS is some insult such as a nidus of infection, a traumatic injury (including a surgical wound), a burn injury, or pancreatitis that prompts release of a variety of mediators in the microenvironment. The body's ini tial response is to induce a proinflammatory state in which mediators have multiple overlapping effects designed to limit new damage and to ameliorate whatever damage has already occurred. They destroy damaged tissue, promote the growth of new tissue, and combat pathogenic organisms, neoplastic cells, and foreign antigens20-24 (Table 3). A compensatory anti-inflammatory response soon ensures that the effects of these proinflammatory mediators do not become destructive. IL-4, IL-10, IL-11, IL-13, soluble tumor necrosis factor (TNF-ot)
IL-1 receptor antagonists, transforming factor-(3, and other, as yet undiscovered growth

substances12-30'32 work to diminish monocytic major histocompatibility complex class II expression, im pair antigen presenting activity, and reduce the ability of cells to produce inflammatory cytokines. Local levels of both proinflammatory and anti-in flammatory mediators can be substantially higher than are later found systemically33,38 (Table 3).

Stage 2

original insult is sufficiently severe, first proinflammatory and later anti-inflammatory media tors will appear in the systemic circulation via a variety of mechanisms. The presence of proinflam mediators in the is

If the

receptors,
240

circulation part of the matory normal response to infection and serves as a warning signal that the microenvironment cannot control the initiating insult. The proinflammatory mediators help recruit neutrophils, T cells and B cells, platelets, and coagulation factors to the site of injury or
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infection.24 This cascade stimulates a compensatory systemic anti-inflammatory response, which nor mally quickly down-regulates the initial proinflam matory response. Few, if any, significant clinical signs and symptoms are produced. Organs may be affected by the inflammatory cascade, but significant organ dysfunction is rare.

Stage 5
The final stage of MODS is what we have elected call "immunologic dissonance."54 It is an inappro priate, out-of-balance response of the immunomodulatory system. In some patients, it results from persistent, overwhelming inflammation that may persist in patients with SIRS and MODS, with increased risk of death.115557
to

Stage 3

regulation of the proinflammatory re results in a massive systemic reaction mani sponse fest as the clinical findings of SIRS. Underlying the clinical findings are pathophysiologic changes that include the following: (1) progressive endothelial dysfunction, leading to increased microvascular per meability;3943 (2) platelet sludging that blocks the microcireulation,44 causing maldistribution of blood flow and possibly ischemia, which in turn may cause reperfusion injury45 and induction of heat shock proteins;46 (3) activation of the coagulation system and impairment of the protein C-protein S inhibitory pathway;47 and (4) profound vasodilation, fluid transudation, and maldistribution of blood flow may result in profound shock.4849 Organ dysfunction and, ultimately, failure result from these changes unless homeostasis is quickly restored.
Loss of

may be inhibition of the synthesis of the proinflam matory agents needed to allow the organs to recover. In patients with immunologic dissonance, it may be to possible its regain organ function if the body can recover balance.
Conclusions

patients, persistent immune suppression immunologic dissonance. Studies have shown not only that monocyte deactivation persists in many patients, but that such persistent deactivation greatly increases the risk of death.51 In patients with persis tent immune suppression, the cause of organ failure

In some causes

Stage 4
immunosuppression. What some investigators have called "immune paralysis,"5051 and "window of im munodeficiency,"52 we describe as "compensatory anti-inflammatory response syndrome" (CARS).4
It is possible that a compensatory anti-inflamma tory reaction can be inappropriate, with a resulting

Balance between proinflammatory and anti-in flammatory forces could conceivably be lost: (1) when infection, burn injury, hemorrhage, etc, is so severe that the insult alone is sufficient to prompt SIRS and MODS; or (2) when patients are "pre printed" to develop SIRS and MODS by preexisting severe illness. (3) Most of the preexisting conditions are associated with abnormal cytokine levels.19 The hypothesis of prepriming rests on our under that standinghas a a patient at risk for SIRS or MODS already significant clinical history, and is not clinically analogous to a healthy human volunteer.
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Sepsis: A New Hypothesis for Pathogenesis of the Disease Process Roger C. Bone, Charles J. Grodzin and Robert A. Balk Chest 1997;112; 235-243 DOI 10.1378/chest.112.1.235 This information is current as of August 18, 2011
Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/112/1/235.citation Cited Bys This article has been cited by 62 HighWire-hosted articles: http://chestjournal.chestpubs.org/content/112/1/235.citation#related-urls Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.

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