Sepsis

critical careSepsis: A New Hypothesis forPathogenesis 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 response syndrome; IFN^interferon; IL=interleukin; MARS =mixed antagonists response syndrome; MODS=multiple organdysfunction syndrome; SIRS=systemic inflammatory responsesyndrome; TNF=tumor necrosis factor

Sepsis is the systemic response to severe infection.The incidence of sepsis continues to increase.Sepsis and its sequelae are the leading causes ofdeath in medical and surgical ICUs.12 According tothe Centers for Disease Control and Prevention, theincidence of sepsis continues to increase and is nowthe third leading cause of infectious death (Fig 1).

Sepsis and its sequelae represent progressivestages of the same illness.a systemic response toinfection mediated via macrophage-derived cyto-kines that target end-organ receptors in response toinjury or infection. Much confusion has existedregarding terminology for sepsis. An American College of Chest Physicians/Society of Critical CareMedicine Consensus Conference3 held in 1991agreed to a new set of definitions that could bereadily applied to patients in different stages ofsepsis (Table 1). New discoveries made in the lastseveral years have validated the conceptual appropriateness of these terms, which has led to wideacceptance. However, new discoveries also suggestthat we need to push these concepts further.The pathophysiologic state of the systemic inflam

matory response syndrome (SIRS) has been studiedextensively. We characterize SIRS as an abnormalgeneralized inflammatory reaction in organs remotefrom the initial insult. When the process is due to aninfection, the terms sepsis and SIRS are synonymous. On the basis of the current understanding of*From the Department of Internal Medicine, Sections of Pulmonary and Critical Care Medicine, Rush-Presbyterian-St. Luke'sMedical Center, Rush Medical College, Chicago.Deceased.Manuscript received April 28, 1997; accepted April 29.

sepsis and its sequelae, innovative therapies weredeveloped and clinical trials were begun. Althoughthese trials were of the most advanced experimentaldesign, double-blind, randomized, and placebo controlled, all such sepsis trials thus far have failed toshow efficacy or have had harmful, ambiguous, ornegative results.4 Pharmacologic interventions todate have not improved the outcome in sepsis andSIRS. The trials have shown how effective certainagents can be at the cellular or animal model stagebut how ineffective these same agents can be whenapplied in clinical trials.4While trials addressed the proinflammatory phase

of sepsis and SIRS, there was no evidence that theproinflammatory phase was dominant when drugswere given. This may mean more to us as we learnmore about compensatory anti-inflammatory responses and mixed proinflammatory and anti-inflammatory responses in the human with sepsis. Thefailed initial clinical trials tested efficacy of clinicaltrials for sepsis and provided some insight into thecomplexity of the immuno-inflammatory cascade.This article looks at what we know about this complex immuno-inflammatory cascade, and a new hypothesis to relate it to sepsis.

Sepsis, SIRS, CARS, and MARSWhen the American College of Chest Physicians

and Society of Critical Care Medicine convened aConsensus Conference in 1991 to address the problem of confusion over use of proper terms anddefinitions, the terms bacteremia, septicemia, sepsis,sepsis syndrome, and septic shock were being usedalmost interchangeably, which led to confusion andimprecise understanding of sepsis and related disorders. Members of the Consensus Conference agreedto a new set of definitions that could be readilyapplied to patients in different stages of sepsis:bacteremia, SIRS, sepsis, severe sepsis, septic shock,and multiple organ dysfunction syndrome (MODS).

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1980? 1992

Lung AIDS Sepsis Urinary Heart Hepato TBtract biliary

Figure 1. Leading causes of infectious death according to the Centers for Disease Control andPrevention.

We propose now to add the compensatory anti-inflammatory response syndrome (CARS), andmixed antagonists response syndrome (MARS) tothis set of clinical definitions (Table 2).

Multiple organ dysfunction occurs in about 30% ofpatients with sepsis, and it also can be found intrauma patients, patients with acute pancreatitis andother diseases such as systemic vasculitides, and inburn victims.59 How7 dysfunction of multiple organscan be produced by such disparate disorders puzzledclinicians and investigators for years. Almost a decade ago, it was suggested that multiple organdysfunction may result not from infection per se, butfrom a generalized inflammatory reaction.10 Evidence today suggests that a massive inflammatoryreaction resulting from systemic cytokine release isthe common pathway underlying multiple organdysfunction. Also, it is now known that most patientshave evidence of dysfunction in one or more organslong before organ failure develops.

Unfortunately, the more we learn about this inflammatory response, the more difficult it becomesto pinpoint a specific cytokine, or a specific reaction,as the "cause" of SIRS. Indeed, it has become clearthat cytokine release is a normal, healthy part of thebody's response to insult or infection. Cytokines arehighly pleiotropic, and they appear capable of producing markedly different effects depending on thenearby hormonal milieu. Furthermore, the body hasa highly complex, rigidly regulated network of receptor antagonists and other regulatory agents thatcontinuously modulate the effects of cytokine release. Adding to our confusion is the fact thatsystemic cytokine release can occur in a variety ofdisorders without leading to organ dysfunction. Even

in those disorders that are often associated withorgan dysfunction, the pattern of systemic cytokinerelease is dissimilar. How, then, can SIRS andMODS be explained?

The Cytokine CascadeThe systemic response to infection is mediated via

the macrophage-derived cytokines that target end-organ receptors in response to injury or infection.The inflammatory response to infection or injury is ahighly conserved and regulated reaction of the organism. After recognition that a response is required,the organism (eg, a human being) produces solubleprotein and lipid proinflammatory molecules thatactivate cellular defenses, then produces similaranti-inflammatory molecules to attenuate and haltthe proinflammatory response. Molecules known orpresumed at this time to be proinflammatory andanti-inflammatory are listed in Table 3. Presumptionof activity is based on data of varying quality; it islikely that some molecules will eventually drop fromthis list, and others will be added.Normally cytokine response is regulated by the

intricate network of proinflammatory and anti-inflammatory mediators. The initial inflammatory response is kept in check by down-regulating production and counteracting the effects of cytokinesalready produced. The picture that emerges fromanalysis of data from patients with sepsis is that acomplex mixture of proinflammatory and anti-inflammatory molecules may be present.1112 Standardpathophysiologic models of sepsis do not explainsuch a picture.13

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Table 1.Standard Definitions for Sepsis and OrganFailure

Table 2.Proposed Definitions for Sepsis and OrganFailure

Terminology DefinitionInfectk

BacteremiaSIRS

Sepsis

Severe sepsis

Septic shock

MODS

Sepsis-inducedhypotension

Microbial phenomenon characterized by aninflammatory response to the presence ofmicroorganisms or the invasion of normallysterile host tissue by those organisms.

Presence of viable bacteria in the blood.The systemic inflammatory response to a wide

variety of severe clinical insults, manifested bytwo or more of the following conditions: (1)temperature >38C or 90 beats/min; (3) respiratory rate >20breaths/min or PaC02 12,000/mm3, 10% immature (band) forms.

The systemic inflammatory response to infection.In association with infection, manifestations ofsepsis are the same as those previously definedfor SIRS. It should be determined whetherthey are a part of the direct systemic responseto the presence of an infectious process andrepresent an acute alteration from baseline inthe absence of other known causes for suchabnormalities.

Sepsis associated with organ dysfunction,hypoperfusion, or hypotension. Hypoperfusionand perfusion abnormalities may include, butare not limited to, lactic acidosis, oliguria, or anacute alteration in mental status.

A subset of severe sepsis and defined as sepsis-induced hypotension despite adequate fluidresuscitation along with the presence ofperfusion abnormalities that may include, butare not limited to, lactic acidosis, oliguria, or anacute alteration in mental status. Patientsreceiving inotropic or vasopressor agents mayno longer be hypotensive by the time theymanifest hypoperfusion abnormalities or organdysfunction, yet they would still be consideredto have septic shock.

Presence of altered organ function in an acutelyill patient such that homeostasis cannot bemaintained without intervention.

A systolic BP 40mm Hg from baseline in the absence of othercauses for hypotension.

These mediators initiate overlapping processesthat directly influence the endothelium, cardiovascular, hemodynamic, and coagulation mechanisms. Therelease of many of these vasoregulators is often local.Evolving concepts of the septic response give moreweight to the importance of local cytokine production, not in contradistinction to systemic productionbut as part of the total septic-response picture.414The duration of illness also may alter the mix of

mediators, leading to a state of metabolic disordersin which the body has no control over its owninflammatory response. If balance cannot be established and homeostasis is not restored, a massive

CARS

MARS

HLA-DR on monocytes

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

TNF-aIL-10IL-2IL-6IL-8IL-15Neutrophil elastaseIFN-7Protein kinaseMCP-1*MCP-2Leukemia inhibitory factor

(D-factor)

ThromboxanePlatelet activating factorSoluble adhesion moleculesVasoactive neuropeptidesPhospholipase A2Tyrosine kinasePlasminogen activator inhibitor-1Free radical generationNeopterinCD14ProstacyclinProstaglandins

IL-1 raIL-4IL-10IL-13Type II IL-1 receptorTransforming growth factor-pEpinephrineSoluble TNF-a receptorsLeukotriene B4-receptor antagonismSoluble recombinant CD-14LPS binding protein*

^MCP^monocyte chemoattractant protein; LPS=lipopolysaccharide.

sponse.13 The anti-inflammatory reaction may be aslarge as, and sometimes even larger than, the proinflammatory response. The goal of this anti-inflammatory reaction is to down-regulate synthesis ofproinflammatory mediators and to modulate theireffects, thereby restoring homeostasis.

It has recently become possible to differentiateongoing CARS from SIRS immunophysiology.Zedler et al21 detailed a technique of stimulatingperipheral blood mononuclear cells from severelyinjured burn patients for the purpose of cell surfaceantigen staining and intracellular interferon-gamma(IFN-7) and interleukin-4 (IL-4) detection. IL-4, ananti-inflammatory cytokine, was found in excess (elevated 16-fold) in the presence of downregulatedIL-2 and IFN-7. IL-4 thus served as a marker for the"THrTH2 switch," a major characteristic of theCARS response to injury (TH is the T helper cell). Inmost healthy persons, the body is able to achieve abalance between proinflammatory and anti-inflam-

C Cardiovascular compromise (usually manifestingas shock; in this setting SIRS predominates).

H Homeostasis (return to health; this represents abalance of SIRS and CARS).

A Apoptosis (neither SIRS nor CARS predominates).

O Organ dysfunction (single or multiple;SIRS predominates).

S Suppression of the immune system (anergy and/orincreased susceptibility to infection; CARSpredominates).

Figure 2. Mnemonic of CHAOS.

matory mediators and homeostasis is restored (Fig2). In some patients, however, a variety of forcesconspire to upset this balance, resulting in SIRS andMODS.The theories put forth to explain the development

of SIRS have generally not taken this compensatoryanti-inflammatory reaction into consideration. Manyof the anti-inflammatory mediators were discoveredand characterized only in the last few years, and tosome extent, this may have led to overstatement ofthe dangers presented by proinflammatory mediators. It might almost be said that proinflammatorymediators became "bad guys," without taking intoaccount that excessive levels can be harmful, butlower levels are required to combat pathogenicorganisms and to promote healing.Most of the evidence for the role of proinflamma

tory mediators in the pathogenesis of SIRS andMODS came from studies using animal models,experiments in which endotoxin or proinflammatorymediators were injected into human volunteers, andanalysis of serum levels of proinflammatory mediators in patients with sepsis, burn injury, or othersevere injuries (Fig 3). We now know that thesestudies may not truly reflect what happens in critically ill patients with sepsis or SIRS. As noted earlier,a marked interspecies variation in cytokine releasemakes it difficult to extrapolate results of animalstudies to humans. More importantly, these experiments were performed on healthy animals and generally included a relatively short observation period.22 Studies of human volunteers were performedin healthy subjects; the amount of stimulus injectedwas sublethal; and, again, the follow-up period wasbrief.23 In contrast, SIRS and MODS develop overtime in severely ill or injured patients who havemultiple preexisting disorders.24Serum levels of immunomodulating mediators

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Infection

\Endotoxin and

other microbial toxins

lProinflammatory statewith cytokine release

andother proinflammatory

mediators

lSepsis/SIRS

IShock and multiorgan

dysfunction andpossibledeath

Figure 3. Old paradigm for sepsis.

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

result of an immediate insult such as trauma and nota consequence of a preexisting condition such aspancreatitis.19

Relating Clinical Responses to CytokineCascade

Some patients with sepsis, extensive burns, massive traumatic injury, or other severe insults showlittle or no evidence of a systemic inflammatoryreaction or organ dysfunction, although their recovery may be protracted because of the severity of theirunderlying illness. In three other categories, however, are patients with sepsis or other severe insultwho develop the following: a mild form of SIRS andsome evidence of dysfunction in one or two organsearly in their clinical course that usually resolvesrapidly; a massive systemic inflammatory reactiondeveloping rapidly after the initial insult, with deathoften following within a few days from profoundshock; and a less severe initial course, but markeddeterioration several days or more after the originalinsult, with outright failure of one or more organsand death in some but not all patients.

Clinical trials have usually excluded patients withmild symptoms of organ dysfunction or symptomsthat last for

Initial insult(bacterial,

viral, traumatic,thermal)

Systemic spillover ofpro-inflammatory mediators Systemic spillover

ofanti-inflammatory mediators

Cardiovascularcompromise

(shock)

SIRSpredominates

Homeostasis

CARS andSIRS

balanced

Apoptosis(cell death)

Death withminimal

inflammation

Organdysfunction

SIRSpredominates

Suppressionof theimmunesystem

CARSpredominates

Figure 4. New concepts for the clinical sequelae of sepsis, SIRS, CARS, and MARS. (This figure isan adaptation of Figure 1 by Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 1996;24:1125-28.)

Stage 1Prior 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, orpancreatitis that prompts release of a variety ofmediators in the microenvironment. The body's initial response is to induce a proinflammatory state inwhich mediators have multiple overlapping effectsdesigned to limit new damage and to amelioratewhatever damage has already occurred. They destroydamaged 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 proinflammatorymediators do not become destructive. IL-4, IL-10,IL-11, IL-13, soluble tumor necrosis factor (TNF-ot)receptors, IL-1 receptor antagonists, transforminggrowth factor-(3, and other, as yet undiscovered

substances12-30'32 work to diminish monocytic majorhistocompatibility complex class II expression, impair antigen presenting activity, and reduce theability of cells to produce inflammatory cytokines.Local levels of both proinflammatory and anti-inflammatory mediators can be substantially higherthan are later found systemically33,38 (Table 3).Stage 2

If the original insult is sufficiently severe, firstproinflammatory and later anti-inflammatory mediators will appear in the systemic circulation via avariety of mechanisms. The presence of proinflammatory mediators in the circulation is part of thenormal response to infection and serves as a warningsignal that the microenvironment cannot control theinitiating insult. The proinflammatory mediatorshelp 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 compensatorysystemic anti-inflammatory response, which normally quickly down-regulates the initial proinflammatory response. Few, if any, significant clinicalsigns and symptoms are produced. Organs may beaffected by the inflammatory cascade, but significantorgan dysfunction is rare.

Stage 3Loss of regulation of the proinflammatory re

sponse results in a massive systemic reaction manifest as the clinical findings of SIRS. Underlying theclinical findings are pathophysiologic changes thatinclude the following: (1) progressive endothelialdysfunction, leading to increased microvascular permeability;3943 (2) platelet sludging that blocks themicrocireulation,44 causing maldistribution of bloodflow and possibly ischemia, which in turn may causereperfusion injury45 and induction of heat shockproteins;46 (3) activation of the coagulation systemand impairment of the protein C-protein S inhibitorypathway;47 and (4) profound vasodilation, fluid tran-sudation, and maldistribution of blood flow mayresult in profound shock.4849 Organ dysfunction and,ultimately, failure result from these changes unlesshomeostasis is quickly restored.

Stage 4It is possible that a compensatory anti-inflamma

tory reaction can be inappropriate, with a resultingimmunosuppression. What some investigators havecalled "immune paralysis,"5051 and "window of immunodeficiency,"52 we describe as "compensatoryanti-inflammatory response syndrome" (CARS).4CARS is the body's response to inflammation and ismore than just immune-paralysis. CARS may explainsuch anomalies as the burn patient's increased susceptibility to infection and even the anergy of thepancreatitis patient.2953 Recently, it has been shownthat treatment of patients with sepsis with IFN-y notonly restores the HLA-DR expression on monocytesbut reestablishes the ability of monocytes to secretethe cytokines IL-6 and TNF-a.29 One recent study55looked at a series of patients admitted to an ICU whomet the criteria for SIRS. All patients demonstratedCARS immunophysiology in that monocyte surfacehuman leukocyte antigen (HLA)-DR expression wasreduced to

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11 Pinsky MR, Vincent J-L, Deviere J, et al. Serum cytokinelevels in human septic shock: relation to multiple-systemorgan failure and mortality. Chest 1993; 103:565-75

12 Dinarello CA, Gelfand JA, Wolff SM. Anticytokine strategiesin the treatment of the systemic inflammatory responsesyndrome. JAMA 1993; 269:1829-35

13 Goldie AS, Fearon KCH, Ross JA, et al. Natural cytokineantagonists and endogenous antiendotoxin core antibodies insepsis syndrome. JAMA 1995; 274:172-77

14 Moore FA, Moore EE, Read RA. Postinjury multiple organfailure: role of extra-thoracic injury and sepsis in adultrespiratory distress syndrome. New Horizons 1993; 1:538-49

15 Bone RC, Balk RA, Fein AM, et al. A second large controlledclinical study of E5, a monoclonal antibody to endotoxin:results of a prospective, multicenter, randomized clinical trial.Crit Care Med 1995; 23:994-1006

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20 Zuckerman SH, Bendele AM. Regulation of serum tumornecrosis factor in glucocorticoid-sensitive and -resistant rodent endotoxin shock models. Infect Immun 1989;57:3009-13

21 Zedler S, Bone RC, v. Donnersmarck GH> et al. T-cellreactivity and its predictive role in immunosuppression afterburns (submitted)

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