Sepsis is a heterogeneous clinical syndrome that encompasses infections of many different types and severity. Not surprisingly, it has confounded most attempts to apply a single definition, which has also limited the ability to develop a set of reliable diagnostic criteria. It is perhaps best defined as the different clinical syndromes produced by an immune response to infection that causes harm to the body beyond that of the local effects of the infection.
Key points
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Sepsis is a heterogeneous clinical syndrome that has defied attempts to create an exact definition or develop specific clinical diagnostic criteria.
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Sepsis is characterized by the immune response to an infection that creates harmful effects beyond the local site of the infection.
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The difficulty in defining sepsis has created significant challenges in the determination of reliable epidemiologic data for the disease.
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Despite an increased incidence, the mortality for sepsis has decreased over the past several decades.
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According to the most recent publication on the definitions for sepsis and septic shock, sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection.
Introduction
The syndrome of sepsis includes an incredibly wide variety of infections and clinical presentations, from the 85-year-old patient with a urinary tract infection with mild confusion to the 18-year-old patient with multiorgan failure from meningitis. Any attempt to define sepsis must incorporate these disparate and heterogeneous manifestations under 1 syndromic banner. The incredible difficulty of this task is reflected in the interplay between conceptual, diagnostic, and research definitions of sepsis.
It is generally accepted that worldwide sepsis represents a large burden of illness, morbidity, and mortality. In 2011, it was estimated that sepsis represented the most expensive single condition treated in US hospitals and accounted for more than $20 billion dollars in health care costs (5.2% of aggregate US hospital costs). A 2009 study estimated that more than 3 million cases of sepsis occur annually in the United States and result in more than 200,000 deaths. It is clear that the incidence of sepsis has increased. It is believed that increases in the aging population along with an increase in patients that have select comorbidities, such as immunosuppressive conditions, may account for the increased incidence of disease. In addition to the increased elderly population and patients with complex comorbidities, it is also postulated that increased awareness of the condition has contributed to the increase in the incidence of sepsis. Despite an increased incidence of sepsis, mortality has decreased. In fact, mortality rates in the 3 most recent studies comparing the use of an early goal-directed therapy protocol with current usual care ranged from 19% to 29%. This is markedly reduced from the mortality rate of greater than 46% in the original 2001 early goal-directed therapy study.
This article discusses the evolution of sepsis definitions that have been published over the past several decades, with attention to the most recent publication by Singer and colleagues.
Sepsis 1: an initial definition
Sepsis is generally accepted to be an advanced, life-threatening infection that produces organ dysfunction and increases morbidity and mortality. The first formal definition of sepsis came in 1992, when a consensus conference defined sepsis as “the systemic response to infection.” The conference committee believed that much of the harm and damage to the body in sepsis is not the result of the microorganism causing infection, but rather the damage to various organs that are distant from the actual site of infection. Importantly, this is not necessarily owing to a systemic infection itself (ie, bacteremia), but rather to the patient’s immune system response to the infection. An example of this process is the development of the acute respiratory distress syndrome in a patient with a foot abscess. One would not be expected to detect bacteria in sputum cultures that match those in wound cultures from the abscess itself.
Based on the understanding of sepsis at that time, the 1992 conference committee felt that this systemic response to infection was the result of overwhelming inflammation. They named this response the systemic inflammatory response syndrome (SIRS). SIRS is the presence of at least 2 of the 4 criteria listed in Box 1 . Importantly, the committee emphasized that the SIRS criteria needed to be both (1) a change from the patient’s baseline and (2) part of the systemic response to the presence of an infectious process. This highlighted that the presence of SIRS was not unique to sepsis, but rather could be present in many other inflammatory conditions, such as pancreatitis, ischemia, trauma and tissue injury, hemorrhagic shock, and immune-mediated organ injury ( Fig. 1 ).
Defined as the presence of at least 2 of the following 4 criteria:
Body temperature greater than 38°C or less than 36°C
Heart rate greater than 90 bpm
Tachypnea: RR >20 breaths per minute; or
Hyperventilation: Pa co 2 less than 32 mm Hg
WBC greater than 12,000/mm 3 or less than 4000/mm 3 or greater than 10% immature neutrophils
Abbreviations: bpm, beats per minute; Pa co 2 , partial pressure CO 2 in arterial blood gas sample; RR, respiratory rate; WBC, white blood cell count.
Importantly, the conference committee also recognized that the syndrome of sepsis encompassed a wide range of clinical severities. The committee stated that, as SIRS develops and progresses untreated, it produces organ dysfunction. As such, they identified 2 discrete clinical conditions that were important indicators of the progression of sepsis toward death. The first of these clinical conditions was severe sepsis, defined as a subset of patients with sepsis who also had organ dysfunction, hypoperfusion abnormalities, or sepsis-induced hypotension ( Box 2 ). Finally, the 1992 committee defined septic shock as those patients with severe sepsis who also had sepsis-induced hypotension and evidence of hypoperfusion or organ dysfunction that persisted despite adequate fluid resuscitation.
Defined as the presence of sepsis plus at least one of the following:
Organ dysfunction (not specifically defined)
Hypoperfusion abnormality, including but not limited to one of:
Lactic acidosis
Oliguria
Acute alteration in mental status
Sepsis-induced hypotension:
Systolic blood pressure <90 mm Hg or a reduction of greater than 40 mm Hg from baseline in the absence of a cause of hypotension besides sepsis
In addition, these initial terms and definitions were meant to clarify confusion that existed around the use of the words “sepsis” or “septic.” In fact, these terms were often used by providers interchangeably with the term “toxic” to describe a patient who seemed to be ill. Furthermore, the term “sepsis” was often used interchangeably with the term “septicemia.” Importantly, the committee recommended that the term “septicemia” no longer be used in everyday clinical discussion. This change was used to emphasize that sepsis is defined not by a systemic infection, but rather by a systemic immune response to infection, whether or not that infection was local or had spread systemically. Put another way, patients may have bacteremia, viremia, or fungemia without necessarily having sepsis.
A final goal of the 1992 conference committee was to standardize the framework for everyday clinical application and for research studies. The landmark sepsis study by Rivers and colleagues used the definitions put forth in this first sepsis definitions conference to evaluate an intense treatment protocol for patients with sepsis. The remarkable results of this study effectively solidified these inclusion criteria as the de facto definitions of severe sepsis and septic shock for the majority of the subsequent research. Importantly, they also established that severe sepsis and septic shock represent a distinct clinical entity from sepsis that has not progressed to organ dysfunction, hypoperfusion, or shock.
Introduction
The syndrome of sepsis includes an incredibly wide variety of infections and clinical presentations, from the 85-year-old patient with a urinary tract infection with mild confusion to the 18-year-old patient with multiorgan failure from meningitis. Any attempt to define sepsis must incorporate these disparate and heterogeneous manifestations under 1 syndromic banner. The incredible difficulty of this task is reflected in the interplay between conceptual, diagnostic, and research definitions of sepsis.
It is generally accepted that worldwide sepsis represents a large burden of illness, morbidity, and mortality. In 2011, it was estimated that sepsis represented the most expensive single condition treated in US hospitals and accounted for more than $20 billion dollars in health care costs (5.2% of aggregate US hospital costs). A 2009 study estimated that more than 3 million cases of sepsis occur annually in the United States and result in more than 200,000 deaths. It is clear that the incidence of sepsis has increased. It is believed that increases in the aging population along with an increase in patients that have select comorbidities, such as immunosuppressive conditions, may account for the increased incidence of disease. In addition to the increased elderly population and patients with complex comorbidities, it is also postulated that increased awareness of the condition has contributed to the increase in the incidence of sepsis. Despite an increased incidence of sepsis, mortality has decreased. In fact, mortality rates in the 3 most recent studies comparing the use of an early goal-directed therapy protocol with current usual care ranged from 19% to 29%. This is markedly reduced from the mortality rate of greater than 46% in the original 2001 early goal-directed therapy study.
This article discusses the evolution of sepsis definitions that have been published over the past several decades, with attention to the most recent publication by Singer and colleagues.
Sepsis 1: an initial definition
Sepsis is generally accepted to be an advanced, life-threatening infection that produces organ dysfunction and increases morbidity and mortality. The first formal definition of sepsis came in 1992, when a consensus conference defined sepsis as “the systemic response to infection.” The conference committee believed that much of the harm and damage to the body in sepsis is not the result of the microorganism causing infection, but rather the damage to various organs that are distant from the actual site of infection. Importantly, this is not necessarily owing to a systemic infection itself (ie, bacteremia), but rather to the patient’s immune system response to the infection. An example of this process is the development of the acute respiratory distress syndrome in a patient with a foot abscess. One would not be expected to detect bacteria in sputum cultures that match those in wound cultures from the abscess itself.
Based on the understanding of sepsis at that time, the 1992 conference committee felt that this systemic response to infection was the result of overwhelming inflammation. They named this response the systemic inflammatory response syndrome (SIRS). SIRS is the presence of at least 2 of the 4 criteria listed in Box 1 . Importantly, the committee emphasized that the SIRS criteria needed to be both (1) a change from the patient’s baseline and (2) part of the systemic response to the presence of an infectious process. This highlighted that the presence of SIRS was not unique to sepsis, but rather could be present in many other inflammatory conditions, such as pancreatitis, ischemia, trauma and tissue injury, hemorrhagic shock, and immune-mediated organ injury ( Fig. 1 ).
