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1644 Definitions for Sepsis and Organ Faikire (Bone et a!) accplsccm consensus conference Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis THE ACCP/SCCM CONSENSUS CONFERENCE COMMITTEE: RogerC. Bone, M.D., FG.C.P, Chairman RobertA. Balk, M.D., F.C.C.P Frank B. Cerra, M.D. R. Philip Dellinger, M. D. , F. C. C.P An American College ofChest Physicians/Society of Critical Care Medicine Consensus Conference was held in North- brook in August 1991 with the goal of agreeing on a set of definitions 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 proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dys- function syndrome were also offered. The use of severity Alan M. Fein, M.D., F.C.C.P William A. Knaus; M.D. Roland M. H. Schein, M.D. William j Sibbald, M.D. , F. C.C.P scoring methods when dealing with septic patients was recommended as an adjunctive tool 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) MODS = multiple organ dysfunction syndrome; SIRS systemic inflammatory response syndrome n American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Chicago in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. It was the goal of this conference to provide both a conceptual and a practical framework to define the systemic inflammatory response to infection, a progressive, injurious process that falls under the generalized term “sepsis” and includes sepsis-associated organ dysfunc- tions as well. We expect that the broad definitions proposed in this report will improve our ability to make early bedside detection of the disease possible, and thus allow early therapeutic intervention. In For editorial comment see page 1481 addition, the standardization ofresearch protocols will be possible, as will improved dissemination and appli- cation ofinformation derived from clinical studies. We hope that the continuing research on the inflammatory response to infection will allow us to understand the cellular and immunologic mechanisms that cause sep- sis and related organ dysfunctions and, sometimes, death. We recognize the limitations of the definitions we have proposed and urge further studies to validate these clinical concepts, critical phases, and measures Reprint requests: Dr. Bone, Rush-Presbyterian St. b.ske Medical Center, 1753 West Congress Parkway, Chicago 60612 of inflammation by using more sophisticated risk stratification and other tools of evaluation. Two other issues are also addressed in this article and serve to round out the discussion of the causes and treatment of sepsis: (1) the utilization of severity- of-illness scoring systems that allow the consistent evaluation, description, and risk prognostication of patients with sepsis; and (2) guidelines for the use of innovative therapies in severe sepsis. SEPSIS The systemic response to infection has been termed sepsis. 1.2 Sepsis is an increasingly common cause of morbidity and mortality, particularly in elderly, im- munocompromised, and critically ill patients.’ Sep- sis has been reported to be the most common cause of death in the noncoronary intensive care unit.46 Its rising incidence, new etiologies, and appearance in new populations of patients have been related to changing demographics and the increased use of more potent and broader-spectrum antibiotics, immunosup- pressive agents, and invasive technology in the treat- ment of inflammatory, infectious, and neoplastic dis- eases.34 Recent clinical trials have been undertaken to evaluate both conventional and innovative therapies in the treatment ofsepsis.7’#{176} However, interpretations of these results have been obscured by the use of varying definitions for the following terms: infection, bactenmia, sepsis, septicemia, septic syndrome, and Downloaded From: http://journal.publications.chestnet.org/ on 05/29/2014

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  • 1644 Definitions for Sepsis and Organ Faikire (Bone et a!)

    accplsccm consensus conferenceDefinitions for Sepsis and Organ Failure andGuidelines for the Use of Innovative Therapies inSepsis

    THE ACCP/SCCM CONSENSUS CONFERENCE COMMITTEE:RogerC. Bone, M.D., FG.C.P, ChairmanRobertA. Balk, M.D., F.C.C.PFrank B. Cerra, M.D.R. Philip Dellinger, M. D. , F. C. C.P

    An American College ofChest Physicians/Society of CriticalCare Medicine Consensus Conference was held in North-brook in August 1991 with the goal of agreeing on a set ofdefinitions that could be applied to patients with sepsis andits sequelae. New definitions were offered for some terms,while others were discarded. Broad definitions of sepsisand the systemic inflammatory response syndrome wereproposed, along with detailed physiologic parameters bywhich a patient may be categorized. Definitions for severesepsis, septic shock, hypotension, and multiple organ dys-function syndrome were also offered. The use of severity

    Alan M. Fein, M.D., F.C.C.PWilliam A. Knaus; M.D.Roland M. H. Schein, M.D.William j Sibbald, M.D. , F. C.C.P

    scoring methods when dealing with septic patients wasrecommended as an adjunctive tool to assess mortality.Appropriate methods and applications for the use andtesting of new therapies were recommended. The use ofthese terms and techniques should assist clinicians andresearchers who deal with sepsis and its sequelae.

    (Chest 1992; 101:1644-55)

    MODS = multiple organ dysfunction syndrome; SIRSsystemic inflammatory response syndrome

    n American College of Chest Physicians/Society ofCritical Care Medicine Consensus Conference

    was held in Chicago in August 1991 with the goal ofagreeing on a set of definitions that could be appliedto patients with sepsis and its sequelae. It was thegoal of this conference to provide both a conceptualand a practical framework to define the systemicinflammatory response to infection, a progressive,injurious process that falls under the generalized termsepsis and includes sepsis-associated organ dysfunc-tions as well. We expect that the broad definitionsproposed in this report will improve our ability tomake early bedside detection of the disease possible,and thus allow early therapeutic intervention. In

    For editorial comment see page 1481

    addition, the standardization ofresearch protocols willbe possible, as will improved dissemination and appli-cation ofinformation derived from clinical studies. Wehope that the continuing research on the inflammatoryresponse to infection will allow us to understand thecellular and immunologic mechanisms that cause sep-sis and related organ dysfunctions and, sometimes,death. We recognize the limitations of the definitionswe have proposed and urge further studies to validatethese clinical concepts, critical phases, and measures

    Reprint requests: Dr. Bone, Rush-Presbyterian St. b.ske MedicalCenter, 1753 West Congress Parkway, Chicago 60612

    of inflammation by using more sophisticated riskstratification and other tools of evaluation.

    Two other issues are also addressed in this articleand serve to round out the discussion of the causesand treatment of sepsis: (1) the utilization of severity-of-illness scoring systems that allow the consistentevaluation, description, and risk prognostication ofpatients with sepsis; and (2) guidelines for the use ofinnovative therapies in severe sepsis.

    SEPSIS

    The systemic response to infection has been termedsepsis. 1.2 Sepsis is an increasingly common cause ofmorbidity and mortality, particularly in elderly, im-munocompromised, and critically ill patients. Sep-sis has been reported to be the most common causeof death in the noncoronary intensive care unit.46 Itsrising incidence, new etiologies, and appearance innew populations of patients have been related tochanging demographics and the increased use of morepotent and broader-spectrum antibiotics, immunosup-pressive agents, and invasive technology in the treat-ment of inflammatory, infectious, and neoplastic dis-eases.34 Recent clinical trials have been undertakento evaluate both conventional and innovative therapiesin the treatment ofsepsis.7#{176} However, interpretationsof these results have been obscured by the use ofvarying definitions for the following terms: infection,bactenmia, sepsis, septicemia, septic syndrome, and

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  • BLOOD BORNE INFECTION

    CHEST I 101 I 6 I JUNE, 1992 1645

    septic shock.72 An additional source of confusion hasbeen the application of the terms sepsis and septicsyndrome to noninfectious inflammatory states. 13.14Several editorials and position papers have recentlyattempted to provide a framework for the standardi-zation and simplification of this termino1ogy37 Toadvance these processes, this consensus conferencewill offer recommendations for the standardization ofterminology.

    The standardization of terminology is necessary toeliminate confusion in communication for both clini-cians and researchers concerning sepsis and its se-quelae. By standardizing terms, such as sepsis, theability to compare protocols and evaluate therapeuticinterventions is significantly improved. The followingdefinitions should be used as general guidelines in thedesign of future investigations into potential newdiagnostic and treatment modalities.

    Recommendation 1

    The term sepsi in popular usage, implies a clinicalresponse arising from infection. It is apparent that asimilar, or even identical, response can arise in theabsence ofinfection. We therefore propose the phrasesystemic inflammatory response syndrome (SIRS) todescribe this inflammatory process, independent ofits cause (Fig 1).

    This systemic inflammatory response can be seenfollowing a wide variety of insults and includes, but is

    not limited to, more than one of the following clinicalmanifestations: (1) a body temperature greater than38#{176}Cor less than 36#{176}C;(2) a heart rate greater than 90beats per minute; (3) tachypnea, manifested by arespiratory rate greater than 20 breaths per minute,or hyperventilation, as indicated by a PaCO2 of lessthan 32 mm Hg; and (4) an alteration in the whiteblood cell count, such as a count greater than 12,000/cu mm, a count less than 4,000/cu mm, or the presenceof more than 10 percent immature neutrophils(bands). These physiologic changes should representan acute alteration from baseline in the absence ofother known causes for such abnormalities, such aschemotherapy, induced neutropenia, and leukopenia.

    Rationale: The systemic inflammatory response isseen in association with a large number of clinicalconditions. Besides the infectious insults that mayproduce SIRS, noninfectious pathologic causes mayinclude pancreatitis, ischemia, multiple trauma andtissue injury, hemorrhagic shock, immune-mediatedorgan injury, and the exogenous administration of suchputative mediators of the inflammatory process astumor necrosis factor and other cytokines.

    A frequent complication ofSIRS is the developmentof organ system dysfunction, including such well-defined clinical conditions as acute lung injury, shock,renal failure, and multiple organ dysfunction syn-drome (MODS). The term MODS also stems from thisconsensus conference, and its definition will be dis-

    FIGURE 1. The interrelationship between systemic inflammatory response syndrome (SIRS), sepsis, andinfection.

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  • 1646 Defindions for Sepsis and Organ Failure (Bone eta!)

    cussed later in this report.It is likely that similar pathogenesis and pathophys-

    iology underlie the various clinical entities that con-stitute SIRS . Future definitions may take into accountthe pathogenetic mechanism in descriptions of theresponse. Further work is needed to characterize theclinical and prognostic significance of SIRS and itsassociated sequelae.

    Recommendation 2

    When SIRS is the result of a confirmed infectiousprocess, it is termed sepsis. In this clinical circum-stance, the term sepsLs represents the systemic inflam-matory response to the presence of infection.

    Rationale: Sepsis has been well recognized as asystemic inflammatory response to an active infectiousprocess in the host. The use of a broad-based clinicaldefinition of the septic process may facilitate studiesof the pathogenetic mechanisms involved in the pro-duction of the systemic inflammatory response toinfection, as well as the noninfectious causes of SIRS.An improved understanding of these mechanisms willlead to improved therapeutic management.

    Recommendation 3

    In an attempt to improve the written and verbalcommunication concerning infection as it relates toSIRS, we recommend the adoption of the followingnomenclature and definitions for several commonlyused terms (Table 1):

    infection is a microbial phenomenon characterizedby an inflammatory response to the presence ofmicroorganisms or the invasion of normally sterilehost tissue by those organisms.

    Bacteremia is the presence of viable bacteria in theblood. The presence of viruses, fungi, parasites, andother pathogens in the blood should be described in asimilar manner (ie, viremia, fungemia, parasitemia,etc).

    Septicemia has been defined in the past as thepresence of microorganisms or their toxins in theblood. However, this term has been used clinicallyand in the medical literature in a variety of ways,which has added to confusion and difficulties in datainterpretation. Septicemia also does not adequatelydescribe the entire spectrum of pathogenic organismsthat may infect the blood. We therefore suggest thatthis term be eliminated from current usage.

    Sepsis is the systemic inflammatory response toinfection. In association with infection, manifestationsof sepsis are the same as those previously defined forSIRS, and include, but are not limited to, more thanone of the following: (1) a temperature greater than38#{176}Cor less than 36#{176}C;(2) an elevated heart rategreater than 90 beats per minute; (3) tachypnea,manifested by a respiratory rate greater than 20

    breaths per minute or hyperventilation, as indicatedby a PaCO2 ofless than 32 mm Hg; and (4) an alterationin the white blood cell count, such as a count greaterthan 12,000/cu mm, a count less than 4,000/cu mm;or the presence of more than 10 percent immatureneutrophils. To help identify these manifestations assepsis, it should be determined whether they are apart of the direct systemic response to the presenceofan infectious process. Also, the physiologic changesmeasured should represent an acute alteration frombaseline in the absence ofother known causes for suchabnormalities.

    Recommendation 4

    Sepsis and its sequelae represent a continuum ofclinical and pathophysiologic severity. The degree ofseverity may independently affect prognosis. Someclinically recognizable stages along this continuumthat may adversely affect prognosis include the follow-ing:

    Severe sepsis is defined as sepsis associated withorgan dysfunction, hypoperfusion abnormality, or sep-sis-induced hypotension. Hypoperfusion abnormali-ties include lactic acidosis, oliguria, and acute altera-tion of mental status.

    Sepsis-induced hypotension is defined by the pres-

    Table 1 -Definitions

    Infection = microbial phenomenon characterized by an inflamma-tory response to the presence of microorganisms or the invasionof normally sterile host tissue by those organisms.

    BaCt#{128}I-emia = the presence ofviable bacteria in the blood.Systemic inflammatory response syndrome (SIRS)= the systemic

    inflammatory response to a variety of severe clinical insults. Theresponse is manifested by two or more ofthe following conditions:(1) temperature >38#{176}Cor 90 beats perminute; (3) respiratory rate >20 breaths per minute or PaCO,12,000/cu mm,10% immature (band) forms

    Sepsi.s = the systemic response to infection, manifested by two ormore of the following conditions as a result of infection: (1)temperature >38#{176}C or 90 beats perminute; (3) respiratory rate >20 breaths per minute or PaCO,12,00Wcu mm,10% immature (band) forms.

    Severe sepsis= sepsis associated with organ dysfunction, hypoper-fusion, or hypotension. Hypoperfusion and perfusion abnormali-ties may include, but are not limited to lactic acidosis, oliguria,or an acute alteration in mental status.

    Septic shock= sepsis-induced with hypotension despite adequatefluid resuscitation along with the presence of perfusion abnor-malities that may include, but are not limited to, lactic acidosis,oliguria, or an acute alteration in mental status. Patients who arereceiving inotropic or vasopressor agents may not be hypotensiveat the time that perfusion abnormalities are measured.

    Sepsis-induced hypotension a systolic blood pressure

  • CHEST I 101 I 6 I JUNE. 1992 1647

    ence of a systolic blood pressure of less than 90 mmHg or its reduction by 40 mm Hg or more frombaseline in the absence ofother causes for hypotension(eg, cardiogenic shock).

    Septic shock is a subset of severe sepsis and isdefined as sepsis-induced hypotension, persisting de-spite adequate fluid resuscitation, along with thepresence of hypoperfusion abnormalities or organdysfunction. Patients receiving inotropic or vasopres-sor agents may no longer be hypotensive by the timethey manifest hypoperfusion abnormalities or organdysfunction, yet they would still be considered to haveseptic shock.

    Rationale: Recent, large-scale, multicenter, pro-spective studies of sepsis have suggested that there isa continuum of severity encompassing both infectiousand inflammatory components. The condition beginswith infection and potentially leads to sepsis withorgan system dysfunction and septic shock.7#{176} Bacte-remia and hypotension may occur as a part of thisprocess. While recognizing that the disease processforms a continuum of severity, an analysis of severalclinical trials has indicated that definable phases existon that continuum which characterize populations atincreased risk of morbidity and mortahty.72 Onesuch phase should be termed severe sepsis or sepsiswith organ system dysfunction. Some have previouslyused the term septic syndmme to describe this phaseof the septic process. However, the term septicsyndrome has been applied to a variety of inflamma-tory states and it now appears to be both confusingand 134 We, therefore, recommend thatthe term septic syndrome no longer be used.

    These critical stages in the septic process are likelyto have independent prognostic implications;18.19 how-ever, this hypothesis has not been tested in large-scale, prospective, multicenter trials. Risk assessmentmay be a more appropriate approach to identifyingpatients likely to develop morbidity and mortality.The development and refinement of such evaluationtools is encouraged. Previous studies have shown thatseptic shock, as defined above, is associated withincreased mortality. 11.19.22

    Conclusion

    We have provided both a conceptual and a practicalframework for the definition of the systemic inflam-matory response to infection (sepsis). The applicationof these broad definitions will improve early bedsidedetection and permit early intervention in sepsis. Inaddition, the standardization ofresearch protocols willbe enhanced, as will application ofinformation derivedfrom clinical studies. We believe that the early iden-tification of the inflammatory response to infectionwill enhance our understanding of the cellular andimmunologic mechanisms that can cause sepsis and

    organ dysfunction and, in the most severe cases, death.Because of the limitations that are inherent in thesedefinitions, we urge further studies that utilize moresophisticated risk stratification and other tools ofevaluation to validate the clinical concepts, criticalphases, and measures of inflammation that are impor-tant for the clinical treatment of sepsis.

    MULTIPLE ORGAN DYSFUNCTION SYNDROME

    The increasing incidence ofmorbidity and mortalitycaused by multiple organ failure has paralleled im-provements in the life-support technologies availableto patients admitted to an intensive care unit (ICU).As newer technologies for the monitoring and supportof patients sustaining life-threatening critical illnessbecame established, retrospective clinical studiesfound that a major threat to survival was not theunderlying illness, or even a single complicationthereof, but rather a process ofprogressive physiologicfailure of several interdependent organ systems.The terms progressive or sequential organ failure,multiple organ frilure,m and multiple systeims organf ailure were thereby introduced to describe an evolv-ing clinical syndrome that was characterized by thedevelopment of otherwise unexplained abnormalitiesoforgan function in critically ill patients. The phenom-enon that these terms describe is clearly increasing inprevalence, as a result not only of improvements inlife-support technology (both medications and devices)but also of the application of these technologies to anincreasingly high-risk patient population.

    Conventional terminology is considered inadequateto accurately characterize this syndrome. Thus, cmi-cal descriptions ofthe organ failure syndrome emergedin an arbitrary and retrospective fashion. Criteria fordefining abnormalities of specific organ function havealso been widely dissimilar from one study to anotherand, for the most part, have been predicated on theconcept of organ failure, a dichotomous event that iseither present or absent, rather than organ dysfunc-tion, a continuum of physiologic derangements. Thestatic criteria used in current epidemiologic descrip-tions preclude the possibility ofdynamically changingorgan function that characterizes the syndrome as itis encountered clinically. This issue, if it is not soonaddressed, could potentially hinder future advancesin the treatment of this syndrome.

    Early clinical studies of multiple organ failureidentified occult infection as the most importantclinical correlate of the syndrome.m However,recent work has shown that organ system dysfunctioncan evolve in the absence of an untreated focus ofinvasive infection and can be reproduced expen-mentally by the infusion of a diverse spectrum ofendogenously derived mediators of inflammation.#{176}Futhermore, recent work has demonstrated a complex

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  • condary MOD$

    Recovery

    1648 Definitions for Sepsis and Organ Failure (Bone et a!)

    interrelationship among individual organs, such thatfailure of one may establish an amplification processthat hastens injury to another.

    Our understanding of the pathophysiology of organdysfunction and failure in critically ill patients isimproving. In contrast, descriptions of the epidemi-ology of this syndrome remain meager. Availablereports focus primarily on disease that is severe,perhaps at a point in the disease course where inter-ventions may no longer be anticipated to have potentialfor success.

    The purpose of this statement is to propose aconceptual framework for future studies ofthe clinicalphenomenon of organ system dysfunction in criticalillness, and to lay the foundations for common termi-nology and criteria to describe the syndrome.

    Recommendation 1

    The detection of altered organ function in theacutely ill patient constitutes a syndrome that shouldbe termed multiple organ dysfunction syndrome. Theterminology dyifunction identifies this process as aphenomenon in which organ function is not capableof maintaining homeostasis. This process, which maybe absolute or relative, can be more readily identifiedas a continuum of change over time. An example ofrelative organ dysfunction is found in the patient witha normal cardiac output and systemic oxygen deliverywho exhibits evidence of inadequate tissue oxygena-tion (eg, lactic acidosis).

    The proposed acronym also identifies multiple organdysfunction as a syndrome. In this context, MODSis proposed to describe a pattern of multiple andprogressive symptoms and signs that are thought tobe pathogenetically related.

    Rationale: In contrast to the static descriptions thathave been used previously, the proposed change interminology emphasizes the dynamic nature of theprocess under discussion. Thus, the following points

    Death

    FIGURE 2. The different causes and results ofprimary and secondarymultiple organ dysfunction syndrome (MODS).

    must be recognized:1. MODS describes a continuum oforgan dysfunc-

    tion, although specific descriptions ofthis contin-uous process are not currently available.

    2. The recognition of early organ abnormalitiesmust be improved so that treatment can beinitiated at earlier stages in the evolution of thissyndrome.

    3. Changes in organ function over time can beviewed as an important element in prognostica-tion. When applied to MODS, existing measuresofillness severity provide only a snapshot in timeof this dynamic process, and are generally with-out reference to the natural course ofthe disease.

    4. MODS is subject to modulation by numerousfactors at varying time periods, both interven-tional and host-related.

    Recommendation 2

    MODS may be described as being either primaryor secondary.

    Rationale: MODS develops by two relatively dis-tinct, but not mutually exclusive, pathways. PrimaryMODS is the direct result of a well-defined insult inwhich organ dysfunction occurs early and can bedirectly attributable to the insult itself. An example ofprimary MODS is organ dysfunction as the immediateresult oftrauma (eg, pulmonary contusion, renal failuredue to rhabdomyolysis, or the coagulopathy due tomultiple transfusions). In primary MODS, the partic-ipation ofan abnormal and excessive host inflammatoryresponse in both the onset and progression of thesyndrome is not as evident as it is in secondary MODS(Fig 2).

    Secondary MODS develops, not in direct responseto the insult itself, but as the consequence of a hostresponse, and is identified within the context of SIRS.SIRS is also a continuous process, and describes anabnormal host response that is characterized by ageneralized activation of the inflammatory reaction inorgans remote from the initial insult. When the processis due to infection, the terms sepsis and SIRS aresynonymous. Given that SIRS/sepsis is a continuousprocess, MODS may be understood to represent themore severe end of the spectrum of severity of illnessthat characterizes S I RS/sepsis. Thus, secondaryMODS usually evolves after a latent period followingthe inciting injury or event, and is most commonlyseen to complicate severe infection.

    Recommendation 3

    Since criteria that are universally applicable inquantifying the individual organ dysfunctions com-prised by MODS cannot be proposed at this time, acomprehensive and continuously updated data base toclinically test and validate optimal criteria for describ-

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  • RISK DISTRIBUTIONS OF 519 ICU ADMISSIONSFOR SEPSIS ACCORDING TO CATEGORICAL

    DEFINITION OF SEPTIC SYNDROME *N OF CASES

    0 10 20 30 40 50 60 70 80 90

    DAY 1 HOSPITAL MORTALITY RISK

    - NO DEFINITION(N211) DEFINITION (N.308)*

    SEPTIC SYNDROME WITH OR WITHOUT SEPTICSHOCK (Bone,Crit Care Med 1989;17:389)

    FIGURE 3. Risk distribution of 519 sepsis patients who either met (n 308) or did not meet (n = 211) thecriteria for sepsis syndrome (see reference 40 for further details).

    CHEST I 101 I 6 I JUNE, 1992 1649

    ing this syndrome must be established.Rationale: Data are insufficient to justify a recom-

    mendation of universally applicable criteria that couldserve as a validated operational template. The assign-ment of criteria for measuring organ dysfunctionshould not occur a priori, but should result from anempiric process in which specific variables are testedagainst outcome. By doing so, the predicted accuracyof individual variables, groups of variables, and levelsofabnormality can be defined in a manner that reflectscurrent clinical practice.

    SEVERITY-OF-ILLNESS SCORING SYSTEM

    A common theme in the two previous sections ofthis consensus statement is that we are treating moreseverely ill patients at later stages of illness. It is alsoapparent that many of these patients who have morecomplex illnesses may be suffering from a combinationof chronic and acute disease. The nature of diseasepresentation is changing, and patient or host responseis exemplified by the proposed introduction of newsyndromes, such as SIRS and MODS. The recognitionand treatment of these syndromes would not havebeen possible without our advanced diagnostic andlife-support capabilities. It is also emphasized, how-ever, that patients with both of these syndromespresent somewhere along a continuum of illness Se-verity, and that an accurate description of that contin-uum is essential to appropriate usage of these terms.

    The rationale for using scoring systems, therefore,

    is to ensure that the increased complexity of diseasein patients currently being treated is consistentlyrepresented in evaluations and descriptions. A specificgoal of severity scoring systems is to use these impor-tant patient variables to describe the relative risks ofpatients and, thereby, to identify where, along thecontinuum of severity, the patient resides. This willreduce the variation due to patient factors so that theincremental impact of new or existing therapy can bemore precisely determined. It is also hoped thatmore precise measurements of patient risk will leadto new insights into disease processes and serve as atool with which clinicians can more accurately monitorpatients and guide the use of new therapies, such asmonoclonal antibodies.

    In this regard, it is increasingly being recognizedthat the end point of severity scoring can be morethanjust a score representing the degree of physiologicdisturbance. Severity scoring can be used, in conjunc-tion with other risk factors (eg, disease etiology orpatient selection criteria), to anticipate and evaluateoutcomes, such as hospital mortality.37 These proba-bility estimates can be calculated at the time a patientpresents for care or for entry into a clinical trial; thus,they can serve as a pretreatment control. They canalso be updated during the course of therapy, therebydescribing the course of illness and providing analternative for the evaluation of response. The meth-ods for calculating these dynamic probability estimatesare not as developed, however, as are those for initial

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    1650 Definitions for Sepsis and Organ Faikire (Bone eta!)

    RISK DISTRIBUTIONS OF 519 ICU ADMISSIONSFOR SEPSIS ACCORDING TO THE DEFINITION

    OF SEPTIC INFLAMMATORY RESPONSE SYNDROMENo. of Patient8

    - -- -----.--..- -- ----.--

    1O 10- 20- 30.- 40- 50- 60- 70- 80- 90-

    Icu Day 1 Mortality Risk

    - SIRS (N503) No SIRS (N16)

    FIGURE 4. Risk distribution of the same 519 sepsis patients as in Figure 3, according to whether they metcriteria for SIRS.

    or presentation risk assessment.To illustrate the value of combining initial severity

    scoring or probability risk estimation with the newlyproposed definition for SIRS, the study group re-viewed the application of hospital mortality risk esti-mation to a group of519 adult patients with a primarydiagnosis of sepsis upon admission to medical andsurgical ICU.#{176} These patients frequently lacked aninitial microbial source of infection, such as bacterialpneumonia, but were still identified and treated assuffering primarily from infection. As such, theyrepresent a subgroup ofpatients with sepsis for whomthe new definitions, such as SIRS, would be appropri-ate (Fig 1).

    Figure 3 illustrates the distribution of hospitalmortality risk calculated on the initial day of ICUtreatment for these 519 patients, according to whetherthe patient met criteria for the definition of sepsissyndrome, as defined by Bone et al. It can be seenthat the risk distribution of the 308 (59 percent)patients meeting the criteria for this syndrome is notsubstantially different from that for the 211 (41 per-cent) patients who did not fulfill the criteria.

    In contrast, the result depicted in Figure 4 illus-trates that when the SIRS definition was applied tothe same 519 patients with a primary clinical diagnosisof sepsis, it identified 96.9 percent (503/519). Whatthis initial application of the new definition hasachieved, therefore, is an increase in the number ofpatients classffied by the definition. This is important,

    since the previous definition (sepsis syndrome) ex-cluded many of these patients, although their esti-mated risks were equivalent to those of patients whowere included.#{176}

    Finally, Figure 5 demonstrates that, for the 503patients meeting the criteria for SIRS, the estimatedmortality risks calculated on the initial day of ICUtreatment accurately predicted the subsequent actualhospital mortality rates. This demonstrates the currentcapability ofseverity scoring and risk estimation whenused in combination with a broad, encompassingclinical definition like SIRS. Further details on thesemethods are available#{176} and will be the subject of asubsequent report from this consensus conference.These findings led to the following recommendations.

    Recommendation 1

    Because of the increasing complexity of patientpresentation, the use of new terminology, such asSIRS, with its various etiologies (Fig 1) should becombined with risk stratification or probability riskestimation techniques in order to measure the positionof an individual patient along the continuum of sever-ity.

    Rationale: The major change in patient presentationhas been an increase in the complexity ofillness. Also,more severely ill patients are being treated at laterstages of their illness. Accurate identification of pre-treatment risk can improve the precision of the eval-uation of new therapies. Such risk estimation can also

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  • 10 10- 20- 30- 40- 50- 60- 70- 80- 90-ICU Day 1 Mortality Risk

    CHEST I 101 I 6 I JUNE, 1992 1651

    be useful in monitoring the utilization ofnew therapiesand in refining the indications for specific treatmentsby identifying risk levels when certain therapiesappear to be efficacious. The use of this approach isparticularly important when the patient is a candidatefor, or a participant in, a clinical trial.

    Recommendation 2

    When patients are identified as having SIRS orMODS, sequential (daily or more frequently) riskstratification or probability estimation techniquesshould be applied to describe the course of thesesyndromes.

    Rationale: At our current level of understanding(and measurement capabilities), we determine thecourse of SIRS by relying primarily on sequentialmeasurements of physiologic changes. These physio-logic changes correlate with subsequent outcome. Inthe future, it may be possible to extend this measure-ment to include metabolic changes. Such advancesin measurement capabilities may be especially impor-taut in characterizing the course of MODS. As em-phasized previously, the exact criteria for, and descrip-tion of, MODS have yet to be determined.

    Recommendation 3

    Priority should be given to building on severityscoring and other predictive and descriptive efforts.This will allow the development of a comprehensive

    model of disease progression that will have implica-tions for the investigation of new syndromes such asSIRS and MODS.

    RatiOflal4: The development of a comprehensivemodel for a syndrome, such as SIRS, is a complexprocess. Such a model must describe the pre-ICUtreatment interval with respect to time and therapyand the changes in physiologic and metabolic param-eters over time, while remaining unaffected by varia-tions in practice styles. Ideally, the variables involvedwould be independent, would distinguish control ordisease-initiating effects from response effects, andwould be path-independent for an individual patient.

    Conclusion

    While examples of such model systems exist, anumber of significant problems remain. We are cur-rently unable to determine which physiologic, clinical,or metabolic variables cause, and which are causedby, the inflammatory response. We have difficultylabeling and then reliably identifying diseases. We alsoknow that the measurement of a number of variablescurrently in use, such as the level ofoxygen consump-tion or the cardiac output, may vary with practicestyle. Very large data bases are also necessary toestablish whether any reduced or streamlined data setretains its validity. Despite these and other substantialobstacles, it is becoming apparent that a small numberof variables can accurately capture most of the mean-

    RISK DISTRIBUTIONS OF503 ICU Admissions With SIRS.

    80

    70

    60

    50

    40

    30

    20

    10

    0

    No. of Patients Actual Hospital Mortality (%)100

    908070

    60H 50

    4030

    20

    10

    - Hospital Mortality No. of Patients

    FIGURE 5. Risk distribution of 503 septic patients who met the criteria for SIRS. This demonstrates therelationship between risk of hospital mortality, calculated on the first day of the ICU stay, and actualhospital mortality rates.

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  • 1652 Definitions for Sepsis and Organ Faikire (Bone et a!)

    ingful data defining physiologic response currentlypresent in large data sets. This provides encourage-ment that, while the ideal model for describing theresponse of patients with complex illnesses, such asSIRS, does not currently exist, it is a goal worthattempting to achieve.

    GUIDELINES FOR THE USE OF INNOVATIVE

    THERAPIES IN SEVERE SEPSIS

    Innovative therapy in severe sepsis usually involvesan attempt to alter the systemic inflammatory responseof a patient. Such forms of therapy are quite differentfrom supportive therapy or therapies that are directedat the causative organism (eg, antibiotics or surgicalprocedures). Despite the use of these current thera-pies, the morbidity and mortality rates in severe sepsisremain high. Over the last 10 to 15 years, newantibiotics and increasingly sophisticated critical carehave had little impact on the mortality rate of thisdisease.

    A variety of innovative therapies aimed at themediators of inflammation have recently undergoneclinical trials, and this line of investigation is likely tocontinue. To recruit appropriate numbers of patientswho meet the entry criteria for the various studiesand to gain significant statistical power, multicentertrials are usually necessary. The results of these trialsshould be used as a guide to the rational use of newtherapies that are developed.

    Multicenter clinical trials and product developmentare very expensive. This will impose significantlyincreased costs on the product being investigated if itbecomes clinically available. The majority of theseinnovative therapies will, therefore, entail significantexpenses for the health care consumer, although theirimpact on the total cost of health care remains to bedetermined.

    There are well-established guidelines for conduct-ing clinical tests, including adherence to goodclinical practice and the protection ofhuman subjects.These guidelines are particularly important in clinicaltrials that investigate the causes of sepsis. The issue oflanguage was a central focus of this conference, andwe recommend the use of the terminology discussedearlier in this report in conjunction with that used inpublished peer-reviewed clinical trials..#{176}The use ofestablished terminology may make it possible to morecompetently compare the results of efficacy trials forinnovative agents in the treatment of sepsis. Thecomparison of trials would also be facilitated bystandardized trial design, data collection, and report-ing of data. Further, it may be anticipated that prob-lems with terminology will only get worse as additionalagents are tested, either alone or in combination.

    The choice of patients for entry into trials shouldbe as selective as possible, particularly when the trial

    targets a subgroup ofthe septic population (eg, patientswith Gram-negative sepsis). Patients whose underlyingdisease is not likely to permit them to survive thestudy should be excluded, as should those who arenot candidates for aggressive medical therapy. As ourability to define specific subgroups improves, the entrycriteria to future trials should reflect these changes.

    The design of trials in sepsis research should entailwell-defined end points, including the reporting ofdeaths from any cause, through a minimum of28 daysafter study enrollment. Overall hospital mortality, aswell as the resolution oforgan dysfunction, should alsobe reported. We encourage researchers to report datarelevant to the cost oftherapy and quality oflife. Theanalysis of adverse outcomes in the overall group, aswell as in the treatment group or any other group ofinterest, should be presented. The reporting of resultsshould include a detailed analysis that demonstratesthe comparability ofnoninvestigational treatments andpatient characteristics among groups. It is importantto address potential predictors of clinical outcome,such as underlying disease and the referral source ofthe patients, and to ensure that they are treatedadequately in the statistical analysis of the data.Severity-of-illness scoring systems should be used inthe stratification of patient risk to the extent that theindividual scoring system has been independentlydemonstrated to predict outcome in septic patients.The interval between fulfillment of entry criteria andadministration of experimental intervention, as wellas other indicators of possible lead time bias, shouldbe noted and analyzed.

    In the approved use of new therapies for treatingsepsis, the selection of suitable patients to receivethese innovative treatments is an important consider-ation for the clinician. The expected impact of thetreatment on the disease process of the patient shouldbe considered; the prospective identification of pa-tients for whom the treatment would be most effica-cious is important. The morbidity and mortality ratesthat would have occurred in the absence of theinnovative therapy and the safety profile ofthe productshould also be appraised. A patient who is to be treatedwith an innovative therapy should have a clinicalpresentation that matches the entrance criteria usedin the clinical trial for that therapy. However, for someentrance criteria (is, temperature, heart rate, andrespiratory rate), rigid limits were set for the purposeofconducting a clinical trial. When objective data haveallowed a definitive diagnosis of the target populationfor which the innovative therapy is intended, excep-tions to the listed entrance criteria can be made . Forexample, in considering a therapy that utilizes anti-bodies raised against endotoxin for a patient who hasa positive blood culture for Gram-negative bacteria,tachypnea, tachycardia, and hypotension, the failure

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  • CHEST I 101 I 6 I JUNE, 1992 1653

    to meet temperature criteria from a previous clinicaltrial should not be used as a reason to withholdtreatment. Also, since the Food and Drug Administra-lion has access to a larger data base on any givenagent, FDA labeling indicators may be different fromclinical trial entrance criteria, and may thus preemptthem.

    Patients for whom exclusion criteria might be over-looked include those who are younger than 18 yearsold, those who are pregnant, and those with uncon-trolled hemorrhage. Such patients are frequentlyexcluded from clinical trials as a matter of protocol,not because of any anticipated risk to efficacy. Forthese excluded populations, treatment may offer asignificant benefit. The individual physician mustassess the risks or benefits of therapy for each patient.Patients with burns, neutropenia, and transplantedorgans may also be excluded from clinical trials dueto the potentially disparate effects of therapy. Ifinnovative therapy is found to be beneficial in nonex-cluded groups, then additional clinical trials may beappropriate for certain excluded groups, such as thethree groups mentioned above. In the interim, poten-tial risks and unproven benefits should be consideredprior to any decision to institute therapy. Finally,patients who are receiving less than full support arefrequently not included in clinical trials. A decision totreat such patients must be made with ethical andcost-containment considerations in mind; it must beremembered that the efficacy of treatment in thisgroup is unknown.

    For those therapies that are directed at bacterialinfections or the products of bacteria, such as endo-toxin, it is important to obtain information about thespecific etiologic agent so that the appropriate treat-ment method can be used. The utilization of previousculture results and current Gram stains of specimensfrom suspected sites of infection are imperative forgood decision making. For example, a patient withGram stain evidence ofStaphylococcus as the probableinfecting agent is not likely to benefit from theutilization of antiendotoxin antibodies.

    These innovative therapies are typically character-ized as having a potentially important influence onpatient outcome, a substantial impact on health carecosts, and a restrictive set ofindications for use. Thesecharacteristics necessitate an increased responsibilityon the part of the corporations developing and mar-keting the therapy to provide scientifically appropriateassistance and education to the clinicians or institu-tions who must determine how and when to use it.This information should be helpful in the selection ofindividuals who could potentially benefit from thetherapy. This responsibility may also necessitate ad-ditional studies or documentation in the future tomeet changing requirements for the formal approval

    of the therapy.In the absence of published data supporting altera-

    tions in the frequency or amount of an agent thatshould beadministered in innovative therapy, physi-cians should dose precisely as was done in the meth-odology ofthe clinical trial that showed efficacy. Unlesssupported by published literature, the effect of inno-vative therapy in the treatment of recurrent sepsiscannot be predicted. However, in those patientssuspected of having accelerated drug clearance, as incases of plasmapheresis and massive bleeding, redos-ing may be considered, although there are no availabledata on what effect, if any, these conditions have onthe bioavailability of the agent or on its therapeuticeffect.

    Most innovative therapies will be expensive andintended only for specific populations of patients.These populations will be identified through theresults ofclinical trials. Overutilization is an importantissue, particularly if the identification of the targetpopulation is difficult and there is no anticipatedtoxicity. Equally important is the assurance that therewill not be underutilization of the innovative therapyin patient groups that would be likely to benefit.Methods of ensuring proper patient selection willvary, based on the character of the particular medicalinstitution. Each hospital must consider its own situ-ation and devise appropriate methods to ensure thatthe proper innovative therapy for sepsis is employed.

    Potential mechanisms for accomplishing this goalinclude the placement of physicians with expertise inthe diagnoses of the particular disorders to be treatedin a position to guide the utilization of innovativetherapies. An approval process involving these physi-cians may be warranted. These physicians should bereadily available, so that treatment with innovativetherapy is not delayed; on-site expertise is preferableto off-site expertise. When a specially trained physi-cian is not available, the use of patient selectioncriteria checklists to assist the prescribing physicianmay be helpful. The checklists may also be useful forother situations in which the initial contact physicianis not an expert in sepsis and innovative therapy.

    With the input of physicians and pharmacists, sys-tems should be designed and implemented prospec-tively as a quality assurance mechanism to evaluatethe utilization of innovative therapy. Patient selectionchecklists may help prevent overutilization; monitor-ing for underutilization is more difficult. It is especiallyimportant for individual physicians to exercise cautionin the use of potentially deleterious therapies.THE ACCP/SCCM CONSENSUS CONFERENCE COMMIT-TEE:

    Conference Chairman:Roger C. Bone M.D., F.C.C.P, Dean, Rush Medical College; Vice-President for Medical Affairs, Rush-Presbyterian-St. Lukes MedicalCenter, Chicago

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  • 1654 Definitions for Sepsis and Organ Faikan (Bone eta!)

    Session Chairmen:Robert A. Balk, M.D. , F.C.C.P, Associate Professor of Medicine,Rush-Presbyterian-St. Lukes Medical Center, ChicagoFrank B. Cerra, M.D., Professor ofSurgery and Director of CriticalCare, Department of Surgery, University of Minnesota Hospital,MinneapolisR. Philip Dellinger, M.D., F.C.C.P, Associate Professor and Direc-tor of Critical Care, Department of Medicine, Baylor College ofMedicine, DallasAlan M. Fein, M.D., FC.C.P, Director, Pulmonary and CriticalCare Medicine Division, and Associate Professor of Medicine,SUNY Health Science Center, Winthrop-University Hospital, Mm-cola, NYWilliam A Knaus, M.D., Director, PCU Research Unit, GeorgeWashington University, Washington, DCRoland M. H. Schein, M.D., Director of Critical Care Medicineand Associate Professor ofMedicine, Department ofVeterans AffairsMedical Center, University of Miami School of Medicine, MiamiWdhiamj Sibbald, M.D., FC.C.P, Chief, Program in Critical Care,and Professor of Medicine, University ofWestern Ontario, London,Ontario, Canada

    Faculty:

    Jerome H. Abram.s, M.D. ,Assistant Professor ofSurgery, Universityof Minnesota, MinneapolisGordon R. Bernard, M.D., F.C.C.P, Associate Professor of Mcdi-cine, Vanderbilt University Medical School, NashvilleJames W Biondi, M.D., Pulmonary and Critical Care Section, YaleUniversity School of Medicine, New HavenJames E. Calvin, Jr., M.D., Associate Professor ofMedicmne, Rush-Presbyterian-St. Lukes Medical Center, ChicagoRobert Demling, M.D., Professor of Surgery, Harvard MedicalSchool, BostonPatrick j Fahey, M.D., FC.C.P, Chief, Pulmonary and CriticalCare, Loyola University Medical Center, Maywood, IllCharles I. Firher Jr., M.D., Associate Professor and Director,Center for Critical Care Research, Case Western Reserve Univer-sity, ClevelandCory Franklin, M.D., Associate Professor of Medicine, Universityof Health Sciences/Chicago Medical School, North Chicago, IllKennethj Gorelick, M.D., Vice President, Medical and RegulatoryAffairs, Genelabs Technologies, mc, Redwood City, CalifMark A. Kelley, M.D., FC.C.P, Vice Dean, Clinical Affairs,University of Pennsylvania Medical Center, PhiladelphiaDennts C. Maki, M.D., F.C.C.P, Professor of Medicine and Head,Section of Infectious Diseases; Attending Physician, Center forTrauma and Life Support, University ofWisconsin Medical School,Madison

    John C. Marshall, M.D. ,Assistant Professor of Surgery, UniversityofToronto, and Toronto Hospital, TorontoWilliam W Merrill, M.D., Chief, Pulmonary Section, West HavenVA Medical Center, West Haven, ConnJohn P Pribble, Pharin.D., Assistant Director ofClinical Research,Synergen, mc, Boulder, CobEric C. Rackou, M.D., FC.C.P, Professor and Chairman, Depart-ment of Medicine, St. Vincents Hospital and Medical Center ofNew York, New York Medical College, New YorkTimothy C. Rodell, M.D. ,Vice President, Operations and ProductDevelopment, Cortech, Inc, Denver; Clinical Assistant Professorof Medicine, University of Colorado Health Sciences Center,DenverJohn N. Sheagren, M.D., Chairman, Department of InternalMedicine, Illinois Masonic Medical Center; Professor of Medicine,University of Illinois College of Medicine, ChicagoMichael Slices; M.D., F.C.C.P, Assistant Professor and Director,Respiratory Care Center, Rush-Presbyterian-St. Lukes MedicalCenter, ChicagoCharles L. Sprung, M.D. ,F.C.C.P, Director, Intensive Care Unit,Hadassah Hebrew University Medical Center, Jerusalem, IsraelRichard C. Straube, M.D., Director, Infectious Diseases, Centocor,Inc, Malvern, PaMartin I. Tobin, M.D., F.C.C.P, Professor of Medicine, LoyolaUniversity ofChicago Stntch School of Medicine, Maywood, IllGordon M. Trenholme, M.D. ,Professor ofMedicine, Rush MedicalCollege, ChicagoDouglas Wagner, M.D., Senior Staff Scientist, ICU Research,George Washington University Medical Center, Washington, DCC. Douglas Webb, Ph.D., Director, Anti-Infectives, RoerigfPfizerPharmaceuticals, New YorkJanice C. Wherry, M.D., Ph.D., Associate Director, Clinical Re-search, Cutter Biological, Miles, Inc, Berkeley, CalifHerbert? Wzedemann, M.D., Chairman, Department of Pulmonaryand Critical Care Medicine, Cleveland Clinic Foundation, Cleveland

    Cornelius H. Wortel, M.D., Adjunct Clinical Assistant Professor ofMedicine, Critical Care/Emergency Medicine Section, Depart-ment of Medicine, Ben Taub General Hospital, Houston

    EDITORS Nom: The editorial on page 1481 and this report appearsimultaneously in the June, 1992 issue of Critical Care Medicine(20: 724-26; 20: 864-74).

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