Defining Sepsis

Jean-LouisVincent, MD, PhD*, Hakan Atalan Korkut, MD

KEYWORDS
 Infection  Septic shock  Inflammatory response

The word definition has its roots in the Latin term, definire, meaning to limit or to place boundaries. It first was used in the sense of providing a meaning for words in the mid-16th century (Online Etymology Dictionary). A quick search in various English-language dictionaries provides the following definitions of definition: A statement of the exact meaning of a word or the nature or scope of something (Oxford English Dictionary) A statement expressing the essential nature of something (Merriam-Webster) A description of a thing by its properties (Webster) The clear determination of the limits of anything, as of a disease process (Dorlands Illustrated Medical Dictionary) Importantly, definitions can range from the very simple to the much more detailed and complex, and this will depend not only on what is being defined, but also the purpose for which the definition is required. Definitions in medicine help provide a relatively concise and clear description of the condition in question, enabling a diagnosis to be determined precisely and rapidly. Without a specific definition, it is difficult to make a diagnosis, choose an appropriate therapy, select homogeneous groups of patients for clinical trials, or clearly assess the effect of new interventions on a specific disease process. In recent years, attempts have been made to standardize definitions for various conditions within intensive care medicine, so that the same definition is used each time the condition in question is discussed, whether in individual patient care or for clinical trial purposes. For some conditions it has been relatively easy to develop a working and widely accepted definition; however, sepsis has

proved much more difficult to define for several reasons, including the complex nature of the septic process and the huge variety of patients it can affect.

DEFINING SEPSIS
Clinicians recognize sepsis as an important cause of mortality in the intensive care setting. Increasingly, it is becoming clear that early recognition and accurate diagnosis of a patient with sepsis are imperative, as early resuscitation and antibiotic therapy are key to ensuring the best possible outcome for that patient.1,2 To be able to achieve early diagnosis, however, one needs a good understanding of the concepts underlying sepsis and, ideally, good working definitions. And therein lies a problem. Sepsis is a complex disease state, or syndrome, that can affect many diverse groups of patients, originate from multiple sites, be triggered as a result of infection by many different microorganisms, and present with assorted symptoms and signs. There is no single sign, symptom, or test with 100% specificity and sensitivity for sepsis. Hence, while acute myocardial infarction can be defined relatively simply for most patients according to typical symptoms (eg, chest pain, breathlessness, nausea), signs (eg, ST elevation on EKG), and biomarkers (raised creatine kinase or troponin levels), the situation for patients who have sepsis is much more complex. Over the years, there has been much discussion about how best to define sepsis, and the following section will run through the developments in this field in chronologic order to the current situation in which, perhaps, the focus is beginning to shift more to the importance of the concept of sepsis rather than to any specific definition.

Department of Intensive Care, Erasme Hospital, Universite Libre de Bruxelles, 808, Route de Lennik, 1070 Brussels, Belgium * Corresponding author. E-mail address: jlvincen@ulb.ac.be (J-L. Vincent). Clin Chest Med 29 (2008) 585590 doi:10.1016/j.ccm.2008.06.001 0272-5231/08/$ see front matter 2008 Elsevier Inc. All rights reserved.

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A Little History
The word sepsis is derived from a Greek word meaning decay or putrefaction, and the term originally was used with no knowledge of the microbial origins of the condition. Indeed, although some of the first descriptions of bacteria were made in the 1680s, it was another 200 years before the link between bacteria and infection finally began to be realized, and only in 1914 did Schottmueller3 report that the release of pathogenic germs into the bloodstream was responsible for systemic symptoms and signs, thus changing the modern understanding of the term sepsis.4 SIRS was defined as being the presence of at least two of four clinical criteria:6 1. Body temperature greater than 38  C or less than 36  C 2. Heart rate greater than 90 beats/min 3. Respiratory rate greater than 20 breaths/min or hyperventilation with a PaCO2 less than 32 mm Hg 4. White blood cell count greater than 12,000/ mm3, less than 4000/mm3, or with greater than 10% immature neutrophils Sepsis was defined as the presence of SIRS with a confirmed infectious process. Sepsis associated with organ dysfunction, hypoperfusion abnormality, or sepsis-induced hypotension was called severe sepsis, and septic shock was defined as severe sepsis with sepsis-induced hypotension persisting despite adequate fluid resuscitation. Worldwide, many adopted the SIRS approach rapidly, and it has been used to define populations of patients in many interventional clinical trials. A study in 2005 reported that 69% of clinical trials in sepsis published after the consensus conference used the consensus conference definitions as standard.7 Nevertheless, in a survey of 1058 physicians conducted in 2000, only 5% (22% of the intensivists) gave the ACCP/SCCM definition when asked to define sepsis;8 only 17% of physicians agreed on any one definition for sepsis, and six different definitions were mentioned by at least 1 in 10 physicians. Indeed, the SIRS criteria have been criticized for being too sensitive and nonspecific, limiting their clinical usefulness.9 It is true that most ICU patients and many general ward patients meet the SIRS criteria;1014 for example, in the Sepsis Occurrence in Acutely ill Patients (SOAP) study, 93% of ICU admissions had at least two SIRS criteria at some point during their ICU stay.14 Moreover, each of the SIRS criteria can be present in many varied conditions, so that a label of SIRS provides little information about the underlying disease process. For example: Fever can be present in sepsis, after myocardial infarction or pulmonary embolism, or postoperatively Tachycardia and tachypnea may be present in heart failure, anemia, respiratory failure, hypovolemia, and sepsis A raised white blood cell count can be present in many other diseases encountered in ICU patients, including trauma, heart failure, pancreatitis, hemorrhage, and pulmonary edema.

Sepsis Syndrome
In 1989, Bone and colleagues5 made a notable attempt to define severe sepsis and proposed the term sepsis syndrome. Sepsis syndrome was defined as hypothermia (temperature less than 96  F [35.5  C]) or hyperthermia (greater than 101  F [38.3  C]), tachycardia (greater than 90 beats/min), tachypnea (greater than 20 breaths/min), clinical evidence of an infection site, and at least one end-organ demonstrating inadequate perfusion or dysfunction expressed as poor or altered cerebral function, hypoxemia (PaO2 less than 75 torr), elevated plasma lactate, or oliguria (urine output less than 30 mL/h or 0.5 mL/kg body weight/h without corrective therapy). There were several problems with this definition, including the fact that not all patients with severe sepsis will have tachycardia or tachypnea, and that altered cerebral function is difficult to quantify. This definition thus largely has been replaced by the term severe sepsis.

Systemic Inflammatory Response Syndrome

Following on from the sepsis syndrome, in 1991 the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM)6 convened a consensus conference of 35 experts in an attempt to create a set of standardized definitions for patients who have sepsis. It had been realized for some time that sepsis was the result of an inflammatory response to infection, but that this systemic response could occur in response to other conditions, including acute pancreatitis, trauma, ischemia/reperfusion injury, and burns. The goal of the conference, therefore, was to provide a framework to define the systemic inflammatory response and to differentiate that occurring because of infection (ie, sepsis) from that occurring as a result of other processes (systemic inflammatory response syndrome [SIRS]).

Defining Sepsis
Indeed, presence of the SIRS criteria generally reflects an appropriate adaptive response to a physiologic insult rather than an abnormality, and SIRS in itself should not be considered as a disease entity.15 Importantly, the list of signs and markers suggested by the Sepsis Definitions Conference participants should be considered as a guide to diagnosis. Not all patients with sepsis will have all the markers included on the list, and many patients without sepsis will have several. The unexplained presence of several of the listed signs in a patient, however, should be used to raise suspicion of sepsis and to encourage a repeated, or more thorough, search for an infectious focus (Fig. 2). As research continues, and more potential markers are identified, this list likely will need to be adapted and expanded. A detailed evaluation of the individual biomarkers is provided in the article by Levy in this issue.

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2001 Sepsis Definitions Conference

With advances in the understanding of the pathophysiology of sepsis, development of new biomarkers, and continuing dissatisfaction with the ACPP/SCCM definitions, particularly the clinical validity of the SIRS criteria, a consensus sepsis definitions conference of 29 international experts in the field of sepsis was held in December 2001, under the auspices of the SCCM, the European Society of Intensive Care Medicine (ESICM), the ACCP, and the Surgical Infection Societies (SIS).16 The conference participants concluded that the definitions of sepsis, severe sepsis, and septic shock, as defined in the 1991 North American Consensus Conference,6 remain useful both in clinical practice and for research purposes, but that the diagnostic criteria for SIRS were overly sensitive and nonspecific. The participants suggested that an expanded list of signs and symptoms of sepsis might reflect the clinical response to infection better (Fig. 1). By these new definitions (Box 1), sepsis is defined as the presence of infection plus some of the listed signs and symptoms of sepsis. Severe sepsis is defined as sepsis complicated by organ dysfunction, and septic shock as severe sepsis with acute circulatory failure characterized by persistent arterial hypotension unexplained by other causes.
SIRS
Fever/hypothermia Tachycardia Tachypnea Altered white blood cell count

Definition of Infection
Although precise definitions of sepsis still are debated, few would argue that sepsis is the host response to infection; hence, a definition of infection is integral to the definition of sepsis. For general purposes, infection is defined as a pathologic process caused by the invasion of normally sterile tissue or fluid or body cavity by pathogenic or potentially pathogenic microorganisms.16 More precise definitions exist that have been used widely in clinical trials,17 but there are no definitions for specific infections as related to the patient who has sepsis. Therefore, a consensus conference was organized by the International Sepsis Forum to provide definitions for specific infections, specifically for use in clinical studies of sepsis.18 The panel of 28 international experts in the fields of intensive care medicine, infectious diseases,
Signs of Sepsis General signs and symptoms
Rigor fever (sometimes hypothermia) Tachypnea/respiratory alkalosis Positive fluid balance edema

General inflammatory reaction

Altered white blood cell count Increased CRP, IL-6, PCT concentrations

Hemodynamic alterations
Arterial hypotension Tachycardia Increased cardiac output/low SVR/high SvO2 Altered skin perfusion Decreased urine output Hyperlactatemia increased base deficit

Signs of organ dysfunction

Hypoxemia Coagulation abnormalities Altered mental status Hyperglycemia Thrombocytopenia, DIC Altered liver function (hyperbilirubinemia) Intolerance to feeding (altered GI motility)

Fig. 1. The Sepsis Definitions Conference16 suggested that the systemic inflammatory response syndrome criteria be replaced by a longer list of possible signs and symptoms of sepsis. Although none of these is specific of sepsis, the unexplained presence of several in combination should raise suspicion of sepsis.

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Intra-abdominal infections Urosepsis Surgical wound infections The main aim of these definitions is to facilitate patient selection for clinical trial inclusion; by classifying patients into prospectively defined infection categories, treatments could be targeted more specifically. Such definitions, however, potentially could be used as a framework for guiding diagnostic or therapeutic decisions.

Box 1 Currently proposed definitions of infection and sepsis Infection: a pathologic process caused by the invasion of normally sterile tissue or fluid or body cavity by pathogenic or potentially pathogenic microorganisms Sepsis: the systemic response to infection. Sepsis is defined as the presence of several clinical, hematologic, biochemical, and immunologic variables (see Fig. 1) associated with an infection. Severe sepsis: sepsis complicated by organ dysfunction Septic shock: refers to a state of acute circulatory failure characterized by arterial hypotension despite adequate fluid resuscitation, so that vasopressor therapy is necessary to restore a minimally acceptable arterial pressure. Hypotension is defined by a systolic arterial pressure below 90 mm Hg or a reduction of more than 40 mm Hg from baseline, and it is associated with signs of altered tissue perfusion such as oliguria, altered mental status, or altered skin perfusion and a metabolic marker (ie, increased blood lactate levels)
Data from Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:12506.

Beyond Definitions
In addition to concerns about defining sepsis, participants at the Sepsis Definitions Conference were concerned that there was no mechanism for characterizing or staging the host response to infection.16 Sepsis can be considered as a global concept covering a large group of more specific diseases related to the type of microorganism, the degree of immunologic response, the genetic make-up of the individual, and multiple other factors.19,20 As further advances in the understanding of the pathophysiology of sepsis are made, and potential therapeutic targets are identified, the global definition or concept of sepsis will need to be expanded by a mechanism or system that allows specific individual characteristics and profiles to be determined so that therapies can be targeted more appropriately and outcomes improved. Very few of the many randomizedcontrolled studies of potential new sepsis interventions that have been conducted over the last 20 years have yielded positive results. One reason for this is that the definitions of sepsis have been too broad, allowing very heterogeneous groups of patients to be included.21 Similarly, in acute respiratory distress syndrome (ARDS), the introduction of precise definitions in 199422 was not associated with any increased success in clinical trials of new therapies for patients who had ARDS. As discussed already by Abraham and colleagues23 in 2000, a key problem with the consensus conference definitions for sepsis and ARDS was that they were descriptive rather than mechanistic, based on clinical, laboratory, and radiological abnormalities, with little reference to the biochemical, immunologic, or pathophysiological changes that occur in individual patients. Whether the recent call for all studies in patients who have acute renal failure to use the risk, injury failure, loss, end-stage kidney disease criteria definition as developed by the Acute Dialysis Quality Initiative will result in more positive trial results or will prove ineffective in the search for new therapies for acute renal failure remains to be seen.

and clinical microbiology developed definitions for the six most frequent causes of infections in septic patients: Pneumonia Bloodstream infections (including infective endocarditis) Intravascular catheter-related sepsis
INFECTED ORGAN? SIGNS OF SEPSIS ?
Fever WBC, CRP, PCT shock, organ failure etc Pneumonia Peritonitis Meningitis etc

MICROBIOLOGICAL FINDINGS?
Blood cultures BAL samples Drain specimens etc

INFECTION ANTIBIOTICS ? SOURCE CONTROL ?

Fig. 2. In clinical practice, the presence of signs of sepsis in a patient is one factor that leads to a search for infection requiring treatment with appropriate antibiotics and effective source control; local signs of infection or positive microbiological cultures are also important clues.

Defining Sepsis
Sepsis is a process that has many different facets, and grouping all patients with sepsis together is too simplistic. A new, more specific approach to defining the sepsis patient is needed, that takes into account the numerous factors involved in an individuals response to infection. The PIRO (predisposing factors, infection, response, organ dysfunction) system has been suggested as a means of describing patients who have sepsis,16 much as the TNM (tumor, node, metastases) staging system allows the degree of disease to be staged in patients who have cancer. Defining cancer has faced many of the same problems as defining sepsis, in that cancer can affect many different groups of patients, originate in many different organ systems, and have varied means of presentation, with no single marker or sign common to all patients who have cancer. As is likely to be the case in sepsis, treatments in cancer need to be individualized with no one cure for all cancers. Improved characterization of individual patients using a grading system could help determine which therapies are likely to be most beneficial at an individual level. The PIRO grading system is discussed in more detail in the article by Levy elsewhere in this issue.
5. Bone RC, Fisher CJ, Clemmer TP, et al. Sepsis syndrome: a valid clinical entity. Crit Care Med 1989;17: 38993. 6. ACCP-SCCM Consensus Conference. Definitions of sepsis and multiple organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:86474. 7. Trzeciak S, Zanotti-Cavazzoni S, Parrillo JE, et al. Inclusion criteria for clinical trials in sepsis: did the American College of Chest Physicians/Society of Critical Care Medicine consensus conference definitions of sepsis have an impact? Chest 2005;127: 2425. 8. Poeze M, Ramsay G, Gerlach H, et al. An international sepsis survey: a study of doctors knowledge and perception about sepsis. Crit Care 2004;8: R40913. 9. Vincent JL. Dear Sirs, Im sorry to say that I dont like you. Crit Care Med 1997;25:3724. 10. Pittet D, Rangel-Frausto S, Li N, et al. Systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock: incidence, morbidities, and outcomes in surgical ICU patients. Intensive Care Med 1995;21:3029. 11. Rangel Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 1995;273:11723. 12. Salvo I, de Cian W, Musicco M, et al. The Italian SEPSIS study: preliminary results on the incidence and evolution of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med 1995;21:S2449. 13. Bossink AW, Groeneveld J, Hack CE, et al. Prediction of mortality in febrile medical patients: how useful are systemic inflammatory response syndrome and sepsis criteria? Chest 1998;113:153341. 14. Sprung CL, Sakr Y, Vincent JL, et al. An evaluation of systemic inflammatory response syndrome signs in the Sepsis Occurrence in Acutely Ill Patients (SOAP) study. Intensive Care Med 2006;32:4217. 15. Marshall J. Both the disposition and the means of cure: Severe SIRS, sterile shock, and the ongoing challenge of description. Crit Care Med 1997;25: 17656. 16. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;31:12506. 17. Garner JS, Jarvis WR, Emori TG, et al. CDC definitions for nosocomial infections. Am J Infect Control 1988;16:12840. 18. Calandra T, Cohen J. The International Sepsis Forum Consensus Conference on definitions of infection in the intensive care unit. Crit Care Med 2005;33: 153848. 19. Marshall JC, Vincent JL, Fink MP, et al. Measures, markers, and mediators: toward a staging system for clinical sepsis. A report of the Fifth Toronto

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SUMMARY
Although the notion of sepsis as a concept is important in clinical practice and for clinical trials, specific definitions of sepsis are difficult to develop and have not proved to be of great benefit for developing new therapies. New strategies need to be introduced to define the sepsis patient rather than sepsis per se. Such systems will allow specific individual characteristics and profiles to be determined, so that therapies can be targeted more appropriately and outcomes improved.

REFERENCES
1. Rivers E, Nguyen B, Havstad S, et al. Early goaldirected therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345: 136877. 2. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34: 158996. 3. Schottmueller H. Wesen und Behandlung der Sepsis. Inn Med 1914;31:25780. 4. Vincent JL, Abraham E. The last 100 years of sepsis. Am J Respir Crit Care Med 2006;173:25663.

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Sepsis Roundtable, Toronto, Ontario, Canada, October 2526, 2000. Crit Care Med 2003;31:15607. 20. Marshall JC. Sepsis research: where have we gone wrong? Crit Care Resusc 2006;8:2413. 21. Carlet J, Cohen J, Calandra T, et al. Sepsis: time to reconsider the concept. Crit Care Med 2008;36:9646. 22. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:81824. 23. Abraham E, Matthay MA, Dinarello CA, et al. Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation. Crit Care Med 2000;28:2325.