Septic shock

 

Clinical Review & Education

SpecialCommunication | CARINGFORTHECRITICALLYILLPATIENT
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

Author Video Interview, Author Audio Interview, and JAMA Report Video at jama.com

Related articles pages 762 and 775

CME Quiz at jamanetworkcme.com and CME Questions page 816

       

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, 269-01 76th Ave, New Hyde Park, NY 11040 (cdeutschman@nshs.edu).

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IMPORTANCE Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.

OBJECTIVE Toevaluateand,asneeded,updatedefinitionsforsepsisandsepticshock.

PROCESS Ataskforce(n=19)withexpertiseinsepsispathobiology,clinicaltrials,and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment).

KEYFINDINGSFROMEVIDENCESYNTHESIS Limitationsofpreviousdefinitionsincludedan excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant.

RECOMMENDATIONS Sepsisshouldbedefinedaslife-threateningorgandysfunctioncaused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with

a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg
or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.

CONCLUSIONSANDRELEVANCE Theseupdateddefinitionsandclinicalcriteriashouldreplace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.

JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287

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Clinical Review & Education Special Communication

Consensus Definitions for Sepsis and Septic Shock

Sepsis, a syndrome of physiologic, pathologic, and bio- chemical abnormalities induced by infection, is a major public health concern, accounting for more than $20 bil- lion (5.2%) of total US hospital costs in 2011.1 The reported inci- dence of sepsis is increasing,2,3 likely reflecting aging populations with more comorbidities, greater recognition,4 and, in some coun- tries, reimbursement-favorable coding.5 Although the true inci- dence is unknown, conservative estimates indicate that sepsis is a leading cause of mortality and critical illness worldwide.6,7 Further- 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

A 1991 consensus conference9 developed initial definitions that focused on the then-prevailing view that sepsis resulted from a host’s systemic inflammatory response syndrome (SIRS) to infection (Box 1). 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.” A 2001 task 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.10 In effect, the definitions of sepsis, septic shock, and organ dysfunction have remained largely unchanged for more than 2 decades.

The Process of Developing New Definitions

Recognizing the need to reexamine the current definitions,11 the European Society of Intensive Care Medicine and the Society of Critical Care Medicine convened a task force of 19 critical 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 via 4 face-to-face meetings between January 2014 and January 2015, 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).12 A 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 (31 endorsing 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.

Box 1. SIRS (Systemic Inflammatory Response Syndrome)

Two or more of:
Temperature >38°C or <36°C

Heart rate >90/min
Respiratory rate >20/min or PaCO2 <32 mm Hg (4.3 kPa)

White blood cell count >12 000/mm3 or <4000/mm3 or >10% immature bands

From Bone et al.9

 

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Consensus Definitions for Sepsis and Septic Shock

Special Communication

Clinical Review & Education

Box 2. Key Concepts of Sepsis

• Sepsis is the primary cause of death from infection, especially if not recognized and treated promptly. Its recognition mandates urgent attention.

• Sepsis is a syndrome shaped by pathogen factors and host factors (eg, sex, race and other genetic determinants, age, comorbidities, environment) with characteristics that evolve over time. What differentiates sepsis from infection is an aberrant or dysregulated host response and the presence of organ dysfunction.

• Sepsis-induced organ dysfunction may be occult; therefore,
its presence should be considered in any patient presenting with infection. Conversely, unrecognized infection may be the cause of new-onset organ dysfunction. Any unexplained organ dysfunction should thus raise the possibility of underlying infection.

• The clinical and biological phenotype of sepsis can be modified by preexisting acute illness, long-standing comorbidities, medication, and interventions.

• Specific infections may result in local organ dysfunction without generating a dysregulated systemic host response.

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.14,15 The original conceptualization of sepsis as infection with at least 2 of the 4 SIRS 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,16 along with major modifications in nonimmunologic pathways such as cardio- vascular, neuronal, autonomic, hormonal, bioenergetic, metabolic, and coagulation,14,17,18 all 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,20 with age, underlying comorbidities, concurrent injuries (including sur- gery) and medications, and source of infection adding further complexity.21 This diversity cannot be appropriately recapitulated in either animal models or computer simulations.14 With further validation, multichannel molecular signatures (eg, transcriptomic, metabolomic, proteomic) will likely lead to better characterization of specific population subsets.22,23 Such 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.24 Key concepts of sepsis describing its protean nature are highlighted in Box 2.

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-10 codes have com- pounded the problem.

Sepsis

The current use of 2 or more SIRS criteria (Box 1) 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).25 In addition, 1 in 8 patients admitted to criti-

cal care units in Australia and New Zealand with infection and new organ failure did not have the requisite minimum of 2 SIRS 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 the 2 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) (Table 1).28 A higher SOFA score is associated with an increased probability of mortality.28 The score grades abnormal- ity by organ system and accounts for clinical interventions. How- ever, laboratory variables, namely, PaO2, 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.13 A 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.

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Clinical Review & Education Special Communication

Consensus Definitions for Sepsis and Septic Shock

 

Table 1. Sequential [Sepsis-Related] Organ Failure Assessment Scorea

 

System

Respiration

PaO2/FIO2, mm Hg (kPa)

Coagulation Platelets, ×103/μL

Liver

Bilirubin, mg/dL (μmol/L)

Cardiovascular

Central nervous system

Glasgow Coma Scale scorec

Renal

Creatinine, mg/dL (μmol/L)

Urine output, mL/d

Score
0 1

2

<300 (40)

<100

2.0-5.9 (33-101)

Dopamine <5 or dobutamine (any dose)b

10-12

2.0-3.4 (171-299)

3

<200 (26.7) with respiratory support

<50

6.0-11.9 (102-204)

Dopamine 5.1-15
or epinephrine ≤0.1
or norepinephrine ≤0.1b

6-9

3.5-4.9 (300-440) <500

4

<100 (13.3) with respiratory support

<20

>12.0 (204)

Dopamine >15 or epinephrine >0.1
or norepinephrine >0.1b

<6

>5.0 (440)

<200

  

≥400 (53.3)

≥150

<1.2 (20)
MAP ≥70 mm Hg

15

<1.2 (110)

<400 (53.3)

<150

1.2-1.9 (20-32) MAP <70 mm Hg

13-14

1.2-1.9 (110-170)

                

Abbreviations: FIO2, fraction of inspired oxygen; MAP, mean arterial pressure; PaO2, partial pressure of oxygen.

a Adapted from Vincent et al.27

A Need for Sepsis Definitions for the Public and for Health Care Practitioners

Despite its worldwide importance,6,7 public awareness of sepsis is poor.29 Furthermore, 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 (Box 3). 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 of 10%. 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) that focus attention toward the likely ana- 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-

b Catecholamine doses are given as μg/kg/min for at least 1 hour.

c Glasgow Coma Scale scores range from 3-15; higher score indicates better neurological function.

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 the 2001 task force, many bedside examination findings and routine laboratory test results are indicative of inflammation or organ dysfunction.10 The 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)9 or organ dysfunction (eg, SOFA,27,28 Logistic 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 of 21 bedside and laboratory criteria proposed by the 2001 task force.10

Full details are found in the accompanying article by Seymour et al.12 In brief, electronic health record data of 1.3 million encoun- ters at 12 community and academic hospitals within the Univer- sity of Pittsburgh Medical Center health system in southwestern Pennsylvania were studied. There were 148 907 patients with suspected infection, identified as those who had body fluids sampled for culture and received antibiotics. Two outcomes— hospital mortality and mortality, ICU stay of 3 days 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

  

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Consensus Definitions for Sepsis and Septic Shock

Special Communication Clinical Review & Education

Box 3. New Terms and Definitions

• Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

• Organ dysfunction can be identified as an acute change in total SOFA score 2 points consequent to the infection.

• The baseline SOFA score can be assumed to be zero in patients not known to have preexisting organ dysfunction.

• A SOFA score 2 reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection. Even patients presenting with modest dysfunction can deteriorate further, emphasizing the seriousness of this condition and the need for prompt and appropriate intervention, if not already being instituted.

• In lay terms, sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs.

• Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the hospital can be promptly identified at the bedside with qSOFA, ie, alteration in mental status, systolic blood pressure 100 mm Hg, or respiratory rate 22/min.

• Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.

• Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP 65 mm Hg and having a serum lactate level
>2 mmol/L (18 mg/dL) despite adequate volume resuscitation.

With these criteria, hospital mortality is in excess of 40%.

Abbreviations: MAP, mean arterial pressure; qSOFA, quick SOFA; SOFA: Sequential [Sepsis-related] Organ Failure Assessment.

 

ICU, predictive validity was determined with 2 metrics for each criterion: the area under the receiver operating characteristic curve (AUROC) and the change in outcomes comparing patients with a score of either 2 points or more or fewer than 2 points in the different scoring systems9,27,30 across deciles of baseline risk. These criteria were also analyzed in 4 external US and non-US data sets containing data from more than 700 000 patients (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 2 or 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 2 points 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 2 or more had an overall

mortality risk of approximately 10% in a general hospital popula- tion with presumed infection.12 This is greater than the overall mor- tality rate of 8.1% for ST-segment elevation myocardial infarction,31 a 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 2 or 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 patient. Components 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 2 of 3 clinical variables— Glasgow Coma Scale score of 13 or less, systolic blood pressure of 100 mm 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.12 This 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 100 mm 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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Box 4. qSOFA (Quick SOFA) Criteria

Respiratory rate 22/min
Altered mentation
Systolic blood pressure 100 mm Hg

Clinical Review & Education Special Communication

Consensus Definitions for Sepsis and Septic Shock

Scale score less than 15 and will reduce the measurement burden. Although qSOFA is less robust than a SOFA score of 2 or 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 (Box 3). The 2001 task force defi- nitions described septic shock as “a state of acute circulatory failure.”10 The task force favored a broader view to differentiate sep- tic shock from cardiovascular dysfunction alone and to recognize the importance of cellular abnormalities (Box 3). 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.13 First, 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 than 65 mm 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, whereas 2 (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.32 Hyperlactatemia is, however, a reasonable marker of illness severity, with higher levels predictive of higher mortality.33 Criteria 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.34 Other aspects of management, such as sedation and volume status assessment, are also potential confounders in the hypotension- vasopressor relationship.

By Delphi consensus process, 3 variables 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 of 28 150 infected patients with at least 2 SIRS criteria and at least 1 organ dysfunction criterion. Hypotension was defined as a mean arterial pressure less than 65 mm Hg, the only available cutoff. A total of 18 840 patients with vasopressor therapy, hypotension, or hyperlactatemia (>2 mmol/L [18 mg/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 < .001 compared with the referent group) in patients with fluid- resistant hypotension requiring vasopressors and hyperlactatemia (42.3% and 49.7% at thresholds for serum lactate level of >2 mmol/L [18 mg/dL] or >4 mmol/L [36 mg/dL], respectively) compared with either hyperlactatemia alone (25.7% and 29.9% mortality for those with serum lactate level of >2 mmol/L [18 mg/dL] and >4 mmol/L [36 mg/dL], respectively) or with fluid- resistant hypotension requiring vasopressors but with lactate level of 2 mmol/L (18 mg/dL) or less (30.1%).

With the same 3 variables and similar categorization, the unad- justed mortality in infected patients within 2 unrelated large elec- tronic health record data sets (University of Pittsburgh Medical Center [12 hospitals; 2010-2012; n = 5984] and Kaiser Permanente Northern California [20 hospitals; 2009-2013; n = 54 135]) showed reproducible results. The combination of hypotension, vasopressor use, and lactate level greater than 2 mmol/L (18 mg/dL) identified patients with mortality rates of 54% at University of Pittsburgh Medical Center (n = 315) and 35% at Kaiser Permanente Northern California (n = 8051). These rates were higher than the mortality rates of 25.2% (n = 147) and 18.8% (n = 3094) in patients with hypotension alone, 17.9% (n = 1978) and 6.8% (n = 30 209) in patients with lactate level greater than 2 mmol/L (18 mg/dL) alone, and 20% (n = 5984) and 8% (n = 54 135) 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 because the combination encompasses both cellular dysfunction and 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 members13 but 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, Table 2 details how the new sepsis and septic shock clini-

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Consensus Definitions for Sepsis and Septic Shock

Special Communication Clinical Review & Education

cal criteria correlate with ICD-9-CM and ICD-10 codes. 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.35 To 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 an 18-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.

The new definition of sepsis reflects an up-to-date view of patho- 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 meet 2 or 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

Table 2. Terminology and International Classification of Diseases Coding Current Guidelines

 

and Terminology

1991 and 2001 consensus terminology9,10

2015 Definition

2015 Clinical criteria

Recommended primary ICD codesa

ICD-9

ICD-10a

Framework for implementation for coding and research

Sepsis

Severe sepsis Sepsis-induced hypoperfusion

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection

Suspected or documented infection and
an acute increase of ≥2 SOFA points (a proxy for organ dysfunction)

995.92

R65.20

Septic Shock

Septic shock13

Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality

Sepsisa
and
vasopressor therapy needed to elevate MAP ≥65 mm Hg
and
lactate >2 mmol/L (18 mg/dL) despite adequate fluid resuscitation13

785.52 R65.21

       

Identify suspected infection by using concomitant orders

for blood cultures and antibiotics (oral or parenteral) in a specified periodb
Within specified period around suspected infectionc:
1. Identify sepsis by using a clinical criterion for life-threatening organ dysfunction

2. Assess for shock criteria, using administration of vasopressors, MAP <65 mm Hg, and lactate >2 mmol/L (18 mg/dL)d

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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 antibiotic is required to be administered within 72 hours, whereas if the antibiotic is first, the culture is required within 24 hours.12

c Considers a period as great as 48 hours before and up to 24 hours after onset of infection, although sensitivity analyses have tested windows as short as
3 hours before and 3 hours after onset of infection.12

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

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 beyond 2 or 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.

 

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

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

 

Patient with suspected infection

  

qSOFA ≥2? (see A )

Yes

SOFA ≥2? (see B )

Yes

Sepsis

No

No

Sepsis still No suspected?

Yes

             

Despite adequate fluid resuscitation, 1. vasopressors required to maintain MAP ≥65 mm Hg
AND

2. serum lactate level >2 mmol/L? Yes

Septic shock

No

 

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.

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 con- cerns. Lactate level is a sensitive, albeit nonspecific, stand-alone indicator of cellular or metabolic stress rather than “shock.”32 How- 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,34 clinical 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 vary 4-fold.3 The 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 (Box 3). 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 only 30% to 40% of cases. Thus, when sepsis epide-

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Monitor clinical condition; reevaluate for possible sepsis if clinically indicated

Monitor clinical condition; reevaluate for possible sepsis if clinically indicated

Assess for evidence of organ dysfunction

A qSOFA Variables Respiratory rate Mental status
Systolic blood pressure

 

B SOFA Variables

PaO2/FiO2 ratio

Glasgow Coma Scale score

Mean arterial pressure

Administration of vasopressors with type and dose rate of infusion

Serum creatinine or urine output Bilirubin
Platelet count

Consensus Definitions for Sepsis and Septic Shock

Special Communication Clinical Review & Education

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 Table 2 demon- 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 the 1991 and 2001 it- erations being recognized as Sepsis-1 and 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-Hôpital 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.

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 Nestlé and 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 August 25, 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

Study concept and design: All authors.

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Consensus Definitions for Sepsis and Septic Shock

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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