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The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

Mervyn Singer,MD,FRCP;Clifford S.Deutschman,MD,MS;Christopher Warren Seymour,MD,MSc;Manu Shankar-Hari,MSc,MD,FFICM;Djillali Annane,MD,PhD;Michael Bauer,MD;Rinaldo Bellomo,MD;Gordon R.Bernard,MD;Jean-Daniel Chiche,MD,PhD;Craig M.Coopersmith,MD;Richard S.Hotchkiss,MD;Mitchell M.Levy,MD;John C.Marshall,MD;Greg S.Martin,MD,MSc;

Steven M.Opal,MD;Gordon D.Rubenfeld,MD,MS;Tom van der Poll,MD,PhD;Jean-Louis Vincent,MD,PhD;Derek C.Angus,MD,MPH

Editorial page 757

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Author Affiliations:Author

affiliations are listed at the end of this article.

Group Information:The Sepsis Definitions Task Force members are the authors listed above.

Corresponding Author:Clifford S.Deutschman,MD,MS,Departments of Pediatrics and Molecular Medicine,Hofstra–Northwell School of Medicine,Feinstein Institute for Medical Research,269-0176th Ave,New Hyde Park,NY 11040(cdeutschman@https://www.wendangku.net/doc/5914365418.html, ).

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S epsis,a syndrome of physiologic,pathologic,and bio-chemical abnormalities induced by infection,is a major

public health concern,accounting for more than$20bil-lion(5.2%)of total US hospital costs in2011.1The reported inci-dence of sepsis is increasing,2,3likely reflecting aging populations with more comorbidities,greater recognition,4and,in some coun-tries,reimbursement-favorable coding.5Although the true inci-dence is unknown,conservative estimates indicate that sepsis is a leading cause of mortality and critical illness worldwide.6,7Further-more,there is increasing awareness that patients who survive sep-sis often have long-term physical,psychological,and cognitive dis-abilities with significant health care and social implications.8

A1991consensus conference9developed initial definitions that focused on the then-prevailing view that sepsis resulted from a host’s systemic inflammatory response syndrome(SIRS)to infection(Box1).Sepsis complicated by organ dysfunction was termed severe sepsis,which could progress to septic shock, defined as“sepsis-induced hypotension persisting despite adequate fluid resuscitation.”A2001task force,recognizing limi-tations with these definitions,expanded the list of diagnostic cri-teria but did not offer alternatives because of the lack of support-ing evidence.10In effect,the definitions of sepsis,septic shock, and organ dysfunction have remained largely unchanged for more than2decades.

The Process of Developing New Definitions

Recognizing the need to reexamine the current definitions,11the European Society of Intensive Care Medicine and the Society of Critical Care Medicine convened a task force of19critical care, infectious disease,surgical,and pulmonary specialists in January 2014.Unrestricted funding support was provided by the societies, and the task force retained complete autonomy.The societies each nominated cochairs(Drs Deutschman and Singer),who selected members according to their scientific expertise in sepsis epidemiology,clinical trials,and basic or translational research.

The group engaged in iterative discussions via4face-to-face meetings between January2014and January2015,email corre-spondence,and voting.Existing definitions were revisited in light of an enhanced appreciation of the pathobiology and the avail-ability of large electronic health record databases and patient cohorts.

An expert consensus process,based on a current under-standing of sepsis-induced changes in organ function,morphol-ogy,cell biology,biochemistry,immunology,and circulation (collectively referred to as pathobiology),forged agreement on updated definition(s)and the criteria to be tested in the clinical arena(content validity).The distinction between definitions and clinical criteria is discussed below.The agreement between potential clinical criteria(construct validity)and the ability of the criteria to predict outcomes typical of sepsis,such as need for intensive care unit(ICU)admission or death(predictive validity,a form of criterion validity),were then tested.These explorations were performed in multiple large electronic health record data-bases that also addressed the absence(missingness)of individual elements of different organ dysfunction scores and the question of generalizability(ecologic validity).12A systematic literature review and Delphi consensus methods were also used for the definition and clinical criteria describing septic shock.13 When compiled,the task force recommendations with sup-porting evidence,including original research,were circulated to major international societies and other relevant bodies for peer review and endorsement(31endorsing societies are listed at the end of this article).

Issues Addressed by the Task Force

The task force sought to differentiate sepsis from uncomplicated infection and to update definitions of sepsis and septic shock to be consistent with improved understanding of the pathobiology.A definition is the description of an illness concept;thus,a definition of sepsis should describe what sepsis“is.”This chosen approach allowed discussion of biological concepts that are currently incom-pletely understood,such as genetic influences and cellular abnor-malities.The sepsis illness concept is predicated on infection as its trigger,acknowledging the current challenges in the microbiologi-cal identification of infection.It was not,however,within the task force brief to examine definitions of infection.

The task force recognized that sepsis is a syndrome without, at present,a validated criterion standard diagnostic test.There is currently no process to operationalize the definitions of sepsis and septic shock,a key deficit that has led to major variations in reported incidence and mortality rates(see later discussion).The task force determined that there was an important need for fea-tures that can be identified and measured in individual patients and sought to provide such criteria to offer uniformity.Ideally, these clinical criteria should identify all the elements of sepsis (infection,host response,and organ dysfunction),be simple to obtain,and be available promptly and at a reasonable cost or bur-den.Furthermore,it should be possible to test the validity of these criteria with available large clinical data sets and,ultimately, prospectively.In addition,clinical criteria should be available to provide practitioners in out-of-hospital,emergency department, and hospital ward settings with the capacity to better identify patients with suspected infection likely to progress to a life-threatening state.Such early recognition is particularly important because prompt management of septic patients may improve outcomes.4

In addition,to provide a more consistent and reproducible pic-ture of sepsis incidence and outcomes,the task force sought to in-tegrate the biology and clinical identification of sepsis with its epi-demiology and coding.

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Identified Challenges and Opportunities Assessing the Validity of Definitions

When There Is No Gold Standard

Sepsis is not a specific illness but rather a syndrome encompassing a still-uncertain pathobiology.At present,it can be identified by a constellation of clinical signs and symptoms in a patient with sus-pected infection.Because no gold standard diagnostic test exists, the task force sought definitions and supporting clinical criteria that were clear and fulfilled multiple domains of usefulness and validity.

Improved Understanding of Sepsis Pathobiology

Sepsis is a multifaceted host response to an infecting pathogen that may be significantly amplified by endogenous factors.14,15The original conceptualization of sepsis as infection with at least2of the4SIRS criteria focused solely on inflammatory excess.How-ever,the validity of SIRS as a descriptor of sepsis pathobiology has been challenged.Sepsis is now recognized to involve early activa-tion of both pro-and anti-inflammatory responses,16along with major modifications in nonimmunologic pathways such as cardio-vascular,neuronal,autonomic,hormonal,bioenergetic,metabolic,

and coagulation,14,17,18all of which have prognostic significance. Organ dysfunction,even when severe,is not associated with sub-stantial cell death.19

The broader perspective also emphasizes the significant bio-logical and clinical heterogeneity in affected individuals,20with age,underlying comorbidities,concurrent injuries(including sur-gery)and medications,and source of infection adding further complexity.21This diversity cannot be appropriately recapitulated in either animal models or computer simulations.14With further validation,multichannel molecular signatures(eg,transcriptomic, metabolomic,proteomic)will likely lead to better characterization of specific population subsets.22,23Such signatures may also help to differentiate sepsis from noninfectious insults such as trauma or pancreatitis,in which a similar biological and clinical host response may be triggered by endogenous factors.24Key concepts of sepsis describing its protean nature are highlighted in Box2.

Variable Definitions

A better understanding of the underlying pathobiology has been accompanied by the recognition that many existing terms(eg,sep-sis,severe sepsis)are used interchangeably,whereas others are redundant(eg,sepsis syndrome)or overly narrow(eg,septicemia). Inconsistent strategies in selecting International Classification of Diseases,Ninth Revision(ICD-9),and ICD-10codes have com-pounded the problem.

Sepsis

The current use of2or more SIRS criteria(Box1)to identify sepsis was unanimously considered by the task force to be unhelpful. Changes in white blood cell count,temperature,and heart rate reflect inflammation,the host response to“danger”in the form of infection or other insults.The SIRS criteria do not necessarily indi-cate a dysregulated,life-threatening response.SIRS criteria are present in many hospitalized patients,including those who never develop infection and never incur adverse outcomes(poor dis-criminant validity).25In addition,1in8patients admitted to criti-cal care units in Australia and New Zealand with infection and new organ failure did not have the requisite minimum of2SIRS criteria to fulfill the definition of sepsis(poor concurrent validity)yet had protracted courses with significant morbidity and mortality.26 Discriminant validity and convergent validity constitute the2 domains of construct validity;the SIRS criteria thus perform poorly on both counts.

Organ Dysfunction or Failure

Severity of organ dysfunction has been assessed with various scor-ing systems that quantify abnormalities according to clinical find-ings,laboratory data,or therapeutic interventions.Differences in these scoring systems have also led to inconsistency in reporting. The predominant score in current use is the Sequential Organ Fail-ure Assessment(SOFA)(originally the Sepsis-related Organ Failure Assessment27)(Table1).28A higher SOFA score is associated with an increased probability of mortality.28The score grades abnormal-ity by organ system and accounts for clinical interventions.How-ever,laboratory variables,namely,Pa O

,platelet count,creatinine level,and bilirubin level,are needed for full computation.Further-more,selection of variables and cutoff values were developed by consensus,and SOFA is not well known outside the critical care community.Other organ failure scoring systems exist,including systems built from statistical models,but none are in common use.

Septic Shock

Multiple definitions for septic shock are currently in use.Further details are provided in an accompanying article by Shankar-Hari et al.13A systematic review of the operationalization of current definitions highlights significant heterogeneity in reported mortality.This heterogeneity resulted from differences in the clinical variables chosen(varying cutoffs for systolic or mean blood pressure±diverse levels of hyperlactatemia±vasopressor use±concurrent new organ dysfunction±defined fluid resuscita-tion volume/targets),the data source and coding methods,and enrollment dates.

Consensus Definitions for Sepsis and Septic Shock Special Communication Clinical Review&Education

A Need for Sepsis Definitions for the Public

and for Health Care Practitioners

Despite its worldwide importance,6,7public awareness of sepsis is poor.29Furthermore,the various manifestations of sepsis make di-agnosis difficult,even for experienced clinicians.Thus,the public needs an understandable definition of sepsis,whereas health care practitioners require improved clinical prompts and diagnostic ap-proaches to facilitate earlier identification and an accurate quanti-fication of the burden of sepsis.

Results/Recommendations

Definition of Sepsis

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection(Box3).This new defini-tion emphasizes the primacy of the nonhomeostatic host response to infection,the potential lethality that is considerably in excess of a straightforward infection,and the need for urgent recognition.As described later,even a modest degree of organ dysfunction when infection is first suspected is associated with an in-hospital mortal-ity in excess of10%.Recognition of this condition thus merits a prompt and appropriate response.

Nonspecific SIRS criteria such as pyrexia or neutrophilia will con-tinue to aid in the general diagnosis of infection.These findings complement features of specific infections(eg,rash,lung consoli-dation,dysuria,peritonitis)thatfocusattentiontowardthelikelyana-tomical source and infecting organism.However,SIRS may simply reflect an appropriate host response that is frequently adaptive.Sep-sis involves organ dysfunction,indicating a pathobiology more com-plex than infection plus an accompanying inflammatory response alone.The task force emphasis on life-threatening organ dysfunc-tion is consistent with the view that cellular defects underlie physi-ologic and biochemical abnormalities within specific organ sys-tems.Under this terminology,“severe sepsis”becomes superfluous. Sepsis should generally warrant greater levels of monitoring and in-tervention,including possible admission to critical care or high-dependency facilities.

Clinical Criteria to Identify Patients With Sepsis

The task force recognized that no current clinical measures reflect the concept of a dysregulated host response.However,as noted by the2001task force,many bedside examination findings and routine laboratory test results are indicative of inflammation or organ dysfunction.10The task force therefore evaluated which clinical criteria best identified infected patients most likely to have sepsis.This objective was achieved by interrogating large data sets of hospitalized patients with presumed infection, assessing agreement among existing scores of inflammation (SIRS)9or organ dysfunction(eg,SOFA,27,28Logistic Organ Dysfunction System30)(construct validity),and delineating their correlation with subsequent outcomes(predictive validity).In addition,multivariable regression was used to explore the perfor-mance of21bedside and laboratory criteria proposed by the2001 task force.10

Full details are found in the accompanying article by Seymour et al.12In brief,electronic health record data of1.3million encoun-ters at12community and academic hospitals within the Univer-sity of Pittsburgh Medical Center health system in southwestern Pennsylvania were studied.There were148907patients with suspected infection,identified as those who had body fluids sampled for culture and received antibiotics.Two outcomes—hospital mortality and mortality,ICU stay of3days or longer,or both—were used to assess predictive validity both overall and across deciles of baseline risk as determined by age,sex,and comorbidity.For infected patients both inside and outside of the

IO2

Pa O2,partial pressure of oxygen.

a Adapted from Vincent et al.27c Glasgow Coma Scale scores range from3-15;higher score indicates better neurological function.

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ICU,predictive validity was determined with 2metrics for each criterion:the area under the receiver operating characteristic curve (AUROC)and the change in outcomes comparing patients with a score of either 2points or more or fewer than 2points in the different scoring systems 9,27,30across deciles of baseline risk.These criteria were also analyzed in 4external US and non-US data sets containing data from more than 700000patients (cared for in both community and tertiary care facilities)with both community-and hospital-acquired infection.

In ICU patients with suspected infection in the University of Pittsburgh Medical Center data set,discrimination for hospital mor-tality with SOFA (AUROC =0.74;95%CI,0.73-0.76)and the Logis-tic Organ Dysfunction System (AUROC =0.75;95%CI,0.72-0.76)was superior to that with SIRS (AUROC =0.64;95%CI,0.62-0.66).The predictive validity of a change in SOFA score of 2or greater was similar (AUROC =0.72;95%CI,0.70-0.73).For patients outside the ICU and with suspected infection,discrimination of hospital mortality with SOFA (AUROC =0.79;95%CI,0.78-0.80)or change in SOFA score (AUROC =0.79;95%CI,0.78-0.79)was similar to that with SIRS (AUROC =0.76;95%CI,0.75-0.77).

Because SOFA is better known and simpler than the Logistic Organ Dysfunction System,the task force recommends using a change in baseline of the total SOFA score of 2points or more to represent organ dysfunction (Box 3).The baseline SOFA score should be assumed to be zero unless the patient is known to have preexisting (acute or chronic)organ dysfunction before the onset of infection.Patients with a SOFA score of 2or more had an overall

mortality risk of approximately 10%in a general hospital popula-tion with presumed infection.12This is greater than the overall mor-tality rate of 8.1%for ST-segment elevation myocardial infarction,31a condition widely held to be life threatening by the community and by clinicians.Depending on a patient’s baseline level of risk,a SOFA score of 2or greater identified a 2-to 25-fold increased risk of dying compared with patients with a SOFA score less than 2.12

As discussed later,the SOFA score is not intended to be used as a tool for patient management but as a means to clinically char-acterize a septic https://www.wendangku.net/doc/5914365418.html,ponents of SOFA (such as creatinine or bilirubin level)require laboratory testing and thus may not promptly capture dysfunction in individual organ systems.Other elements,such as the cardiovascular score,can be affected by iat-rogenic interventions.However,SOFA has widespread familiarity within the critical care community and a well-validated relationship to mortality risk.It can be scored retrospectively,either manually or by automated systems,from clinical and laboratory measures often performed routinely as part of acute patient management.The task force noted that there are a number of novel biomarkers that can identify renal and hepatic dysfunction or coagulopathy earlier than the elements used in SOFA,but these require broader validation before they can be incorporated into the clinical criteria describing sepsis.Future iterations of the sepsis definitions should include an updated SOFA score with more optimal variable selection,cutoff values,and weighting,or a superior scoring system.

Screening for Patients Likely to Have Sepsis

A parsimonious clinical model developed with multivariable logistic regression identified that any 2of 3clinical variables—Glasgow Coma Scale score of 13or less,systolic blood pressure of 100mm Hg or less,and respiratory rate 22/min or greater—offered predictive validity (AUROC =0.81;95%CI,0.80-0.82)similar to that of the full SOFA score outside the ICU.12This model was robust to multiple sensitivity analyses including a more simple assessment of altered mentation (Glasgow Coma Scale score <15)and in the out-of-hospital,emergency department,and ward settings within the external US and non-US data sets.

For patients with suspected infection within the ICU,the SOFA score had predictive validity (AUROC =0.74;95%CI,0.73-0.76)superior to that of this model (AUROC =0.66;95%CI,0.64-0.68),likely reflecting the modifying effects of interventions (eg,vaso-pressors,sedative agents,mechanical ventilation).Addition of lac-tate measurement did not meaningfully improve predictive validity but may help identify patients at intermediate risk.

This new measure,termed qSOFA (for quick SOFA)and incor-porating altered mentation,systolic blood pressure of 100mm Hg or less,and respiratory rate of 22/min or greater,provides simple bedside criteria to identify adult patients with suspected infection who are likely to have poor outcomes (Box 4).Because predictive validity was unchanged (P =.55),the task force chose to empha-size altered mentation because it represents any Glasgow Coma

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Scale score less than15and will reduce the measurement burden. Although qSOFA is less robust than a SOFA score of2or greater in the ICU,it does not require laboratory tests and can be assessed quickly and repeatedly.The task force suggests that qSOFA criteria be used to prompt clinicians to further investigate for organ dys-function,to initiate or escalate therapy as appropriate,and to con-sider referral to critical care or increase the frequency of monitor-ing,if such actions have not already been undertaken.The task force considered that positive qSOFA criteria should also prompt consideration of possible infection in patients not previously recog-nized as infected.

Definition of Septic Shock

Septic shock is defined as a subset of sepsis in which underlying cir-culatory and cellular metabolism abnormalities are profound enough to substantially increase mortality(Box3).The2001task force defi-nitions described septic shock as“a state of acute circulatory failure.”10The task force favored a broader view to differentiate sep-tic shock from cardiovascular dysfunction alone and to recognize the importance of cellular abnormalities(Box3).There was unanimous agreement that septic shock should reflect a more severe illness with a much higher likelihood of death than sepsis alone.

Clinical Criteria to Identify Septic Shock

Further details are provided in the accompanying article by Shankar-Hari et al.13First,a systematic review assessed how cur-rent definitions were operationalized.This informed a Delphi pro-cess conducted among the task force members to determine the updated septic shock definition and clinical criteria.This process was iterative and informed by interrogation of databases,as sum-marized below.

The Delphi process assessed agreements on descriptions of terms such as“hypotension,”“need for vasopressor therapy,”“raised lactate,”and“adequate fluid resuscitation”for inclusion within the new clinical criteria.The majority(n=14/17;82.4%)of task force members voting on this agreed that hypotension should be de-noted as a mean arterial pressure less than65mm Hg according to the pragmatic decision that this was most often recorded in data sets derived from patients with sepsis.Systolic blood pressure was used as a qSOFA criterion because it was most widely recorded in the elec-tronic health record data sets.

A majority(11/17;64.7%)of the task force agreed,whereas2

(11.8%)disagreed,that an elevated lactate level is reflective of cel-lular dysfunction in sepsis,albeit recognizing that multiple factors, such as insufficient tissue oxygen delivery,impaired aerobic respi-ration,accelerated aerobic glycolysis,and reduced hepatic clear-ance,also contribute.32Hyperlactatemia is,however,a reasonable marker of illness severity,with higher levels predictive of higher mortality.33Criteria for“adequate fluid resuscitation”or“need for vasopressor therapy”could not be explicitly specified because these are highly user dependent,relying on variable monitoring modalities and hemodynamic targets for treatment.34Other aspects of management,such as sedation and volume status assessment,are also potential confounders in the hypotension-vasopressor relationship.

By Delphi consensus process,3variables were identified (hypotension,elevated lactate level,and a sustained need for vaso-pressor therapy)to test in cohort studies,exploring alternative combinations and different lactate thresholds.The first database interrogated was the Surviving Sepsis Campaign’s international multicenter registry of28150infected patients with at least2SIRS criteria and at least1organ dysfunction criterion.Hypotension was defined as a mean arterial pressure less than65mm Hg,the only available cutoff.A total of18840patients with vasopressor therapy,hypotension,or hyperlactatemia(>2mmol/L[18mg/dL]) after volume resuscitation were identified.Patients with fluid-resistant hypotension requiring vasopressors and with hyperlacta-temia were used as the referent group for comparing between-group differences in the risk-adjusted odds ratio for mortality.Risk adjustment was performed with a generalized estimating equation population-averaged logistic regression model with exchangeable correlation structure.

Risk-adjusted hospital mortality was significantly higher (P<.001compared with the referent group)in patients with fluid-resistant hypotension requiring vasopressors and hyperlactatemia (42.3%and49.7%at thresholds for serum lactate level of >2mmol/L[18mg/dL]or>4mmol/L[36mg/dL],respectively) compared with either hyperlactatemia alone(25.7%and29.9% mortality for those with serum lactate level of>2mmol/L [18mg/dL]and>4mmol/L[36mg/dL],respectively)or with fluid-resistant hypotension requiring vasopressors but with lactate level of2mmol/L(18mg/dL)or less(30.1%).

With the same3variables and similar categorization,the unad-justed mortality in infected patients within2unrelated large elec-tronic health record data sets(University of Pittsburgh Medical Center[12hospitals;2010-2012;n=5984]and Kaiser Permanente Northern California[20hospitals;2009-2013;n=54135])showed reproducible results.The combination of hypotension,vasopressor use,and lactate level greater than2mmol/L(18mg/dL)identified patients with mortality rates of54%at University of Pittsburgh

California(n=8051).These rates were higher than the mortality rates of25.2%(n=147)and18.8%(n=3094)in patients with hypotension alone,17.9%(n=1978)and6.8%(n=30209)in patients with lactate level greater than2mmol/L(18mg/dL)alone, and20%(n=5984)and8%(n=54135)in patients with sepsis at University of Pittsburgh Medical Center and Kaiser Permanente Northern California,respectively.

The task force recognized that serum lactate measurements are commonly,but not universally,available,especially in developing countries.Nonetheless,clinical criteria for septic shock were devel-oped with hypotension and hyperlactatemia rather than either alone becausethecombinationencompassesbothcellulardysfunctionand cardiovascular compromise and is associated with a significantly higher risk-adjusted mortality.This proposal was approved by a ma-jority(13/18;72.2%)of voting members13but warrants revisiting.The Controversies and Limitations section below provides further dis-cussion about the inclusion of both parameters and options for when lactate level cannot be measured.

Recommendations for ICD Coding

and for Lay Definitions

In accordance with the importance of accurately applying diagnos-tic codes,Table2details how the new sepsis and septic shock clini-

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cal criteria correlate with ICD-9-CM and ICD-10codes.The task force also endorsed the recently published lay definition that

“sepsis is a life-threatening condition that arises when the body’s response to infection injures its own tissues,”which is consistent with the newly proposed definitions described above.35To trans-mit the importance of sepsis to the public at large,the task force emphasizes that sepsis may portend death,especially if not recog-nized early and treated promptly.Indeed,despite advances that include vaccines,antibiotics,and acute care,sepsis remains the pri-mary cause of death from infection.Widespread educational cam-paigns are recommended to better inform the public about this lethal condition.

Controversies and Limitations

There are inherent challenges in defining sepsis and septic shock. First and foremost,sepsis is a broad term applied to an incom-pletely understood process.There are,as yet,no simple and unam-biguous clinical criteria or biological,imaging,or laboratory features that uniquely identify a septic patient.The task force recognized the impossibility of trying to achieve total consensus on all points. Pragmatic compromises were necessary,so emphasis was placed on generalizability and the use of readily measurable identifiers that could best capture the current conceptualization of underlying mechanisms.The detailed,data-guided deliberations of the task force during an18-month period and the peer review provided by bodies approached for endorsement highlighted multiple areas for discussion.It is useful to identify these issues and provide justifica-tions for the final positions adopted.

Thenewdefinitionofsepsisreflectsanup-to-dateviewofpatho-biology,particularly in regard to what distinguishes sepsis from un-complicated infection.The task force also offers easily measurable clinical criteria that capture the essence of sepsis yet can be trans-lated and recorded objectively(Figure).Although these criteria cannot be all-encompassing,they are simple to use and offer con-sistency of terminology to clinical practitioners,researchers,admin-istrators,and funders.The physiologic and biochemical tests re-quired to score SOFA are often included in routine patient care,and scoring can be performed retrospectively.

The initial,retrospective analysis indicated that qSOFA could

be a useful clinical tool,especially to physicians and other practi-tioners working outside the ICU(and perhaps even outside the hospital,given that qSOFA relies only on clinical examination find-ings),to promptly identify infected patients likely to fare poorly. However,because most of the data were extracted from extracted US databases,the task force strongly encourages prospective vali-dation in multiple US and non-US health care settings to confirm its robustness and potential for incorporation into future iterations of the definitions.This simple bedside score may be particularly rel-evant in resource-poor settings in which laboratory data are not readily available,and when the literature about sepsis epidemiol-ogy is sparse.

Neither qSOFA nor SOFA is intended to be a stand-alone defi-nition of sepsis.It is crucial,however,that failure to meet2or more qSOFA or SOFA criteria should not lead to a deferral of investigation or treatment of infection or to a delay in any other aspect of care deemed necessary by the practitioners.qSOFA can be rapidly scored at the bedside without the need for blood tests,and it is hoped that it will facilitate prompt identification of an infection that poses a greater threat to life.If appropriate laboratory tests have not already been undertaken,this may prompt testing to identify biochemical organ dysfunction.These data will primarily aid patient management but will also enable subsequent SOFA scoring.The task force wishes to stress that SIRS criteria may still remain useful for the identification of infection.

Some have argued that lactate measurement should be man-dated as an important biochemical identifier of sepsis in an infected patient.Because lactate measurement offered no meaningful change in the predictive validity beyond2or more qSOFA criteria in the identification of patients likely to be septic,the task force could not justify the added complexity and cost of lactate measurement alongside these simple bedside criteria.The task force recommen-dations should not,however,constrain the monitoring of lactate as a guide to therapeutic response or as an indicator of illness severity. Abbreviations:ICD,International Classification of Diseases;MAP,mean arterial pressure;SOFA,Sequential[Sepsis-related]Organ Failure Assessment.27

a Included training codes.

b Suspected infection could be defined as the concomitant administration of oral or parenteral antibiotics and sampling of body fluid cultures(blood,urine, cerebrospinal fluid,peritoneal,etc).For example,if the culture is obtained,the antibioti

c is require

d to b

e administered within72hours,whereas i

f the antibiotic is first,the culture is required within24hours.12

c Considers a perio

d as great as48hours befor

e and up to24hours after onset o

f infection,although sensitivity analyses have tested windows as short as

3hours before and3hours after onset of infection.12

d With th

e specified period around suspected infection,assess for shock criteria, using any vasopressor initiation(eg,dopamine,norepinephrine,epinephrine, vasopressin,phenylephrine),any lactate level>2mmol/L(18mg/dL),and mean arterial pressure<65mm Hg.These criteria require adequate fluid resuscitation as defined by the Surviving Sepsis Campaign guidelines.4

Consensus Definitions for Sepsis and Septic Shock Special Communication Clinical Review&Education

Our approach to hyperlactatemia within the clinical criteria for

septic shock also generated conflicting views.Some task force members suggested that elevated lactate levels represent an important marker of“cryptic shock”in the absence of hypotension. Others voiced concern about its specificity and that the nonavail-ability of lactate measurement in resource-poor settings would preclude a diagnosis of septic shock.No solution can satisfy all https://www.wendangku.net/doc/5914365418.html,ctate level is a sensitive,albeit nonspecific,stand-alone indicator of cellular or metabolic stress rather than“shock.”32How-ever,the combination of hyperlactatemia with fluid-resistant hypo-tension identifies a group with particularly high mortality and thus offers a more robust identifier of the physiologic and epide-miologic concept of septic shock than either criterion alone.Identi-fication of septic shock as a distinct entity is of epidemiologic rather than clinical importance.Although hyperlactatemia and hypoten-sion are clinically concerning as separate entities,and although the proposed criteria differ from those of other recent consensus statements,34clinical management should not be affected.The greater precision offered by data-driven analysis will improve reporting of both the incidence of septic shock and the associated mortality,in which current figures vary4-fold.3The criteria may also enhance insight into the pathobiology of sepsis and septic shock.In settings in which lactate measurement is not avail-able,the use of a working diagnosis of septic shock using hypoten-sion and other criteria consistent with tissue hypoperfusion (eg,delayed capillary refill36)may be necessary.

The task force focused on adult patients yet recognizes the need to develop similar updated definitions for pediatric populations and the use of clinical criteria that take into account their age-dependent variation in normal physiologic ranges and in patho-physiologic responses.Implications

The task force has generated new definitions that incorporate an up-to-date understanding of sepsis biology,including organ dys-function(Box3).However,the lack of a criterion standard,similar to its absence in many other syndromic conditions,precludes unambiguous validation and instead requires approximate estima-tions of performance across a variety of validity domains,as out-lined above.To assist the bedside clinician,and perhaps prompt an escalation of care if not already instituted,simple clinical criteria (qSOFA)that identify patients with suspected infection who are likely to have poor outcomes,that is,a prolonged ICU course and death,have been developed and validated.

This approach has important epidemiologic and investigative implications.The proposed criteria should aid diagnostic categori-zation once initial assessment and immediate management are completed.qSOFA or SOFA may at some point be used as entry criteria for clinical trials.There is potential conflict with cur-rent organ dysfunction scoring systems,early warning scores, ongoing research studies,and pathway developments.Many of these scores and pathways have been developed by consensus, whereas an important aspect of the current work is the interroga-tion of data,albeit retrospectively,from large patient populations. The task force maintains that standardization of definitions and clinical criteria is crucial in ensuring clear communication and a more accurate appreciation of the scale of the problem of sep-sis.An added challenge is that infection is seldom confirmed microbiologically when treatment is started;even when micro-biological tests are completed,culture-positive“sepsis”is observed in only30%to40%of cases.Thus,when sepsis epide-

Figure.Operationalization of Clinical Criteria Identifying Patients With Sepsis and Septic Shock

The baseline Sequential[Sepsis-related]Organ Failure Assessment(SOFA)score should be assumed to be zero unless the patient is known to have preexisting (acute or chronic)organ dysfunction before the onset of infection.qSOFA indicates quick SOFA;MAP,mean arterial pressure.

Clinical Review&Education Special Communication Consensus Definitions for Sepsis and Septic Shock

808JAMA February23,2016Volume315,https://www.wendangku.net/doc/5914365418.html,

miology is assessed and reported,operationalization will neces-sarily involve proxies such as antibiotic commencement or a clini-cally determined probability of infection.Future epidemiology studies should consider reporting the proportion of microbiology-positive sepsis.

Greater clarity and consistency will also facilitate research and more accurate coding.Changes to ICD coding may take several years to enact,so the recommendations provided in Table2demon-strate how the new definitions can be applied in the interim within the current ICD system.

The debate and discussion that this work will inevitably generate are encouraged.Aspects of the new definitions do indeed rely on expert opinion;further understanding of the biol-ogy of sepsis,the availability of new diagnostic approaches,and enhanced collection of data will fuel their continued reevaluation and revision.

Conclusions

These updated definitions and clinical criteria should clarify long-used descriptors and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing it.This process,however,remains a work in progress.As is done with soft-ware and other coding updates,the task force recommends that the new definition be designated Sepsis-3,with the1991and2001it-erations being recognized as Sepsis-1and Sepsis-2,respectively,to emphasize the need for future iterations.

ARTICLE INFORMATION

Author Affiliations:Bloomsbury Institute of Intensive Care Medicine,University College London,London,United Kingdom(Singer); Hofstra–Northwell School of Medicine,Feinstein Institute for Medical Research,New Hyde Park, New York(Deutschman);Department of Critical Care and Emergency Medicine,University of Pittsburgh School of Medicine,Pittsburgh, Pennsylvania(Seymour);Department of Critical Care Medicine,Guy’s and St Thomas’NHS Foundation Trust,London,United Kingdom (Shankar-Hari);Department of Critical Care Medicine,University of Versailles,France(Annane); Center for Sepsis Control and Care,University Hospital,Jena,Germany(Bauer);Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University,Melbourne,and Austin Hospital, Melbourne,Victoria,Australia(Bellomo);Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University,Nashville,Tennessee (Bernard);Réanimation Médicale-H?pital Cochin, Descartes University,Cochin Institute,Paris,France (Chiche);Critical Care Center,Emory University School of Medicine,Atlanta,Georgia (Coopersmith);Washington University School of Medicine,St Louis,Missouri(Hotchkiss);Infectious Disease Section,Division of Pulmonary and Critical Care Medicine,Brown University School of Medicine,Providence,Rhode Island(Levy,Opal); Department of Surgery,University of Toronto, Toronto,Ontario,Canada(Marshall);Emory University School of Medicine and Grady Memorial Hospital,Atlanta,Georgia(Martin);Trauma, Emergency&Critical Care Program,Sunnybrook Health Sciences Centre,Toronto,Ontario,Canada (Rubenfeld);Interdepartmental Division of Critical Care,University of Toronto(Rubenfeld); Department of Infectious Diseases,Academisch Medisch Centrum,Amsterdam,the Netherlands (van der Poll);Department of Intensive Care, Erasme University Hospital,Brussels,Belgium (Vincent);Department of Critical Care Medicine, University of Pittsburgh and UPMC Health System, Pittsburgh,Pennsylvania(Angus);Associate Editor, JAMA(Angus).

Author Contributions:Drs Singer and Deutschman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design:All authors.Acquisition,analysis,or interpretation of data:All

authors.

Drafting of the manuscript:Singer,Deutschman,

Seymour,Shankar-Hari,Angus.

Critical revision of the manuscript for important

intellectual content:All authors.

Statistical analysis:Shankar-Hari,Seymour.

Obtained funding:Deutschman,Chiche,

Coopersmith.

Administrative,technical,or material support:

Singer,Deutschman,Chiche,Coopersmith,

Levy,Angus.

Study supervision:Singer,Deutschman.

Drs Singer and Deutschman are joint first authors.

Conflict of Interest Disclosures:All authors have

completed and submitted the ICMJE Form for

Disclosure of Potential Conflicts of Interest.

Dr Singer reports serving on the advisory boards of

InflaRx,Bayer,Biotest,and Merck and that his

institution has received grants from the European

Commission,UK National Institute of Health

Research,Immunexpress,DSTL,and Wellcome

Trust.Dr Deutschman reports holding patents on

materials not related to this work and receiving

travel/accommodations and related expenses for

participation in meetings paid by the Centers for

Disease Control and Prevention,World Federation

of Societies of Intensive and Critical Care,

Pennsylvania Assembly of Critical Care Medicine/PA

Chapter,Society of Critical Care Medicine

(SCCM)/Penn State–Hershey Medical Center,

Society of Critical Care Medicine,Northern Ireland

Society of Critical Care Medicine,International

Sepsis Forum,Department of Anesthesiology,

Stanford University,Acute Dialysis Quality Initiative,

and European Society of Intensive Care Medicine

(ESICM).Dr Seymour reports receiving personal

fees from Beckman Coulter and a National

Institutes of Health(NIH)grant awarded to his

institution.Dr Bauer reports support for travel to

meetings for the study from ESICM,payment for

speaking from CSL Behring,grants to his institution

from Jena University Hospital,and patents held by

Jena University Hospital.Dr Bernard reports grants

from AstraZeneca for activities outside the

submitted work.Dr Chiche reports consulting for

Nestléand Abbott and honoraria for speaking from

GE Healthcare and Nestlé.Dr Coopersmith reports

receiving grants from the NIH for work not related

to this article.Dr Coopersmith also reports bring

president-elect and president of SCCM when the

task force was meeting and the article was being

drafted.A stipend was paid to Emory University for

his time spent in these roles.Dr Hotchkiss reports

consulting on sepsis for GlaxoSmithKline,Merck,

and Bristol-Meyers Squibb and reports that his

institution received grant support from Bristol-

Meyers Squibb and GlaxoSmithKline,as well as the

NIH,for research on sepsis.Dr Marshall reports

serving on the data and safety monitoring board

(DSMB)of AKPA Pharma and Spectral Medical

Steering Committee and receiving payment for

speaking from Toray Ltd and Uni-Labs.Dr Martin

reports serving on the board for SCCM and Project

Help,serving on the DSMB for Cumberland

Pharmaceuticals and Vanderbilt University,serving

on the medical advisory board for Grifols and

Pulsion Medical Systems,and grants to his

institution from NIH,the Food and Drug

Administration,Abbott,and Baxter.Dr Opal reports

grants from GlaxoSmithKline,Atoxbio,Asahi-Kasei,

Ferring,Cardeas,and Arsanis outside the submitted

work;personal fees from Arsanis,Aridis,Bioaegis,

Cyon,and Battelle;and serving on the DSMB for

Achaogen,Spectral Diagnostics,and Paratek.No

other disclosures were reported.

Funding/Support:This work was supported in part

by a grant from the Society of Critical Care Medicine

(SCCM)and the European Society of Intensive Care

Medicine(ESICM).

Role of the Funder/Sponsor:These funding bodies

appointed cochairs but otherwise had no role in the

design and conduct of the work;the collection,

management,analysis,and interpretation of the

data;preparation of the manuscript;or decision to

submit the manuscript for publication.As other

national and international societies,they were

asked for comment and endorsement.

Disclaimer:Dr Angus,JAMA Associate Editor,had

no role in the evaluation of or decision to publish

this article.

Endorsing Societies:Academy of Medical Royal

Colleges(UK);American Association of Critical Care

Nurses;American Thoracic Society(endorsed

August25,2015);Australian–New Zealand

Intensive Care Society(ANZICS);Asia Pacific

Association of Critical Care Medicine;Brasilian

Society of Critical Care;Central American and

Caribbean Intensive Therapy Consortium;Chinese

Society of Critical Care Medicine;Chinese Society of

Critical Care Medicine–China Medical Association;

Critical Care Society of South Africa;Emirates

Intensive Care Society;European Respiratory

Society;European Resuscitation Council;European

Society of Clinical Microbiology and Infectious

Consensus Definitions for Sepsis and Septic Shock Special Communication Clinical Review&Education

Diseases and its Study Group of Bloodstream Infections and Sepsis;European Society of Emergency Medicine;European Society of Intensive Care Medicine;European Society of Paediatric and Neonatal Intensive Care;German Sepsis Society;Indian Society of Critical Care Medicine;International Pan Arabian Critical Care Medicine Society;Japanese Association for Acute Medicine;Japanese Society of Intensive Care Medicine;Pan American/Pan Iberian Congress of Intensive Care;Red Intensiva(Sociedad Chilena de Medicina Crítica y Urgencias);Sociedad Peruana de Medicina Critica;Shock Society;Sociedad Argentina de Terapia Intensiva;Society of Critical Care Medicine;Surgical Infection Society;World Federation of Pediatric Intensive and Critical Care Societies;World Federation of Critical Care Nurses; World Federation of Societies of Intensive and Critical Care Medicine.

Additional Contributions:The task force would like to thank Frank Brunkhorst,MD,University Hospital Jena,Germany;Theodore J.Iwashyna,MD, PhD,University of Michigan;Vincent Liu,MD,MSc, Kaiser Permanente Northern California;Thomas Rea,MD,MPH,University of Washington;and Gary Phillips,MAS,Ohio State University;for their invaluable assistance,and the administrations and leadership of SCCM and ESICM for facilitating its work.Payment was provided to the Center for Biostatistics,Ohio State University,to support the work of Mr Phillips.

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