Defining and Diagnosing
Sepsis
Michael C. Scott, MD
KEYWORDS
Sepsis Severe sepsis Septic shock SOFA qSOFA
KEY POINTS
Sepsis is a heterogeneous clinical syndrome that has defied attempts to create an exact
definition or develop specific clinical diagnostic criteria.
Sepsis is characterized by the immune response to an infection that creates harmful ef-
fects beyond the local site of the infection.
The difficulty in defining sepsis has created significant challenges in the determination of
reliable epidemiologic data for the disease.
Despite an increased incidence, the mortality for sepsis has decreased over the past
several decades.
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 mani-
festations 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).1 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.2 It is clear that the incidence of sepsis
has increased. It is believed that increases in the aging population along with an
The author has nothing to disclose.
Adult Intensive Care Unit, Saint Agnes Hospital, 900 S. Caton Ave, Baltimore, MD 21229, USA
E-mail address: mikescott@umem.org
Emerg Med Clin N Am 35 (2017) 1–9
http://dx.doi.org/10.1016/j.emc.2016.08.002 emed.theclinics.com
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2 Scott
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 postu-
lated that increased awareness of the condition has contributed to the increase in
the incidence of sepsis.3 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 orig-
inal 2001 early goal-directed therapy study.4–7
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 pro-
duces organ dysfunction and increases morbidity and mortality. The first formal defi-
nition of sepsis came in 1992, when a consensus conference defined sepsis as “the
systemic response to infection.”8 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 infec-
tion. 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 bac-
teria 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 inflamma-
tion. 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 1.8 Importantly, the com-
mittee emphasized that the SIRS criteria needed to be both (1) a change from the pa-
tient’s baseline and (2) part of the systemic response to the presence of an infectious
process.8 This highlighted that the presence of SIRS was not unique to sepsis, but
Box 1
Systemic inflammatory response syndrome
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: PaCO2 less than 32 mm Hg
WBC greater than 12,000/mm3 or less than 4000/mm3 or greater than 10% immature
neutrophils
Abbreviations: bpm, beats per minute; PaCO2, partial pressure CO2 in arterial blood gas sample;
RR, respiratory rate; WBC, white blood cell count.
Data from Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and
guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference
Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest
1992;101(6):1644–55.
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Defining and Diagnosing Sepsis 3
rather could be present in many other inflammatory conditions, such as pancreatitis,
ischemia, trauma and tissue injury, hemorrhagic shock, and immune-mediated organ
injury8 (Fig. 1).
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.8 As such, they
identified 2 discrete clinical conditions that were important indicators of the progres-
sion 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, hypoper-
fusion abnormalities, or sepsis-induced hypotension8 (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.8
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
Fig. 1. The interrelationship between systemic inflammatory response syndrome (SIRS),
sepsis, and infection. (From Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and or-
gan failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM
Consensus Conference Committee. American College of Chest Physicians/Society of Critical
Care Medicine. Chest 1992;101(6):1645; with permission.)
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Box 2
Severe sepsis
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
Data from Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guide-
lines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference
Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest
1992;101(6):1644–55.
Rivers and colleagues4 used the definitions put forth in this first sepsis definitions con-
ference to evaluate an intense treatment protocol for patients with sepsis. The remark-
able 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.5–7,9,10 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.
SEPSIS 2: AN UPDATED DEFINITION
Shortly after the early goal-directed therapy publication by Rivers and colleagues, a
second sepsis definitions conference was held to update the initial work published
in 1992. Interestingly, there was no mention of the Rivers trial, or the research defini-
tions of severe sepsis and septic shock used by Rivers and colleagues, in the updated
version. Instead, the committee upheld the initial definition of sepsis as a “clinical
syndrome defined by the presence of both infection and a systemic inflammatory
response syndrome.”11 However, the committee did feel that the SIRS criteria lacked
sufficient specificity to identify patients with sepsis. As a result, the committee broad-
ened the list of clinical and laboratory findings to facilitate the usefulness of criteria for
the bedside clinician.11 The expanded list of sepsis criteria are listed in Box 3. It is
important to note that these criteria were chosen based on expert opinion. In fact,
the authors state that, in the “day-to-day reality, a bedside clinician does not use rigid
criteria to diagnose sepsis, but instead, the clinician identifies a myriad of symptoms,
and regardless of an evident infection declares the patient to look septic.”11 In addi-
tion, the committee members specifically emphasized that these additional criteria
are not specific to infection and must be interpreted in light of the provider’s opinion
on whether an infection is present and whether that infection is the cause of these
abnormalities.
This expanded list of clinical and laboratory findings was the precursor for the
clinical definition of severe sepsis used by the Surviving Sepsis Campaign (SSC)
to identify patients who should receive their sepsis resuscitation bundle.12,13 This
tool uses history suggestive of infection, the presence of SIRS criteria (with altered
mental status or hyperglycemia being additional criteria), and organ dysfunction
(defined by the presence of any of hypotension, hypoxia, elevated creatinine/oliguria,
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Defining and Diagnosing Sepsis 5
Box 3
Expanded list of sepsis criteria from the 2001 consensus conference
Sepsis is defined as infection plus some of the following:
Hyperthermia or hypothermia
Tachycardia or tachypnea
Altered mental status
Edema or positive fluid balance
Elevated glucose (without a history of diabetes)
Leukocytosis or leukopenia or bandemia
Elevated C-reactive protein level or procalcitonin level
Hypotension
Low mixed venous oxygen saturation or cardiac index
Hypoxia
Oliguria or elevated creatinine level
Coagulation abnormalities
Ileus
Thrombocytopenia
Elevated bilirubin level
Elevated lactate level
Decreased capillary refill time
Data from Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international
sepsis definitions conference. Intensive Care Med 2003;29(4):530–8.
thrombocytopenia, coagulopathy, elevated bilirubin, or elevated lactate) to identify a
severe sepsis population. Although some authors have criticized the SSCs broader
definition of severe sepsis as being significantly divergent from the definitions used
in large sepsis trials,4–7 it should be noted that the SSC bundles do use a more narrow
research definition (ie, lactate of 4 mmol/L or mean arterial pressure of <65 mm Hg
after fluid administration) to define the subset of severe sepsis patients that need to
proceed to the more advanced form of the SSC resuscitation bundle.13,14 Importantly,
there are also trials that suggest the possibility that implementation of the SSC
screening tool and resuscitation bundles correlates with decreased mortality in this
patient population.13,14
CENTERS FOR MEDICARE AND MEDICAID SERVICES
In October 2015, the US Centers for Medicare and Medicaid Services implemented a
quality measure called the Sepsis Bundle Project. The Sepsis Bundle Project details
a specific metric for patients with severe sepsis and septic shock, with diagnostic
criteria for severe sepsis that have a significant overlap with those used in the SSC
bundles.13 Although the US Centers for Medicare and Medicaid Services definition
of sepsis may not be evidence based, it is important for providers to be familiar with
these specific criteria, because provider reimbursement may be tied to the achieve-
ment of these metrics.
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6 Scott
It is not surprising that coding for sepsis diagnoses has been fraught with questions,
inconsistencies, and controversies. Until 2003, there was no International Statistical
Classification of Diseases and Related Health Problems (ICD) code specific to sepsis,
SIRS, severe sepsis, or septic shock. Although coding for an infection plus an organ
dysfunction could substitute for severe sepsis, or coding for an infection plus shock
could approximate septic shock, the closest thing to code for sepsis that was not
complicated by organ dysfunction or shock was to code for septicemia (ICD-9 code
0.38.**). Although the coding literature specifically delineates that equating septicemia
(a systemic infection) with sepsis is erroneous, it continues to recommend using the
0.38 code for a systemic infection as the principal diagnostic code in sepsis, severe
sepsis, or septic shock, despite the existence now of the secondary diagnoses spe-
cific to these conditions.15 Even after creating diagnostic codes specific to these sys-
temic responses, the coding agencies still recommend coupling them with a code for a
systemic infection in essentially all cases.
As imagined, it seems that sepsis coding is far from uniformly accepted by bedside
clinicians. Aside from the potential problems created with regard to tracking quality
and reimbursement, this messy coding practice also makes it nearly impossible to
accurately determine any population-wide epidemiology of sepsis. It has been noted
many times and in multiple geographic areas that using coding data to determine
sepsis incidence or mortality rates creates a situation where the rates can vary by a
factor as high as 3.5, depending on which coding extraction method is used.2,16–18
SEPSIS 3: A NEW DEFINITION
Recently, the Society of Critical Care Medicine and the European Society of Intensive
Care Medicine sponsored a 19-member Task Force to update the definitions of sepsis
and septic shock. The results and recommendations of this task force where pub-
lished in a February 2016 issue of the Journal of the American Medical Association.19
The recommendations of this task force marked a significant change from the confer-
ences held in 1992 and 2001. Owing to an increased understanding of the harmful
systemic response to infection, members of the multidisciplinary task force proposed
that sepsis now be defined as “life threatening organ dysfunction caused by a dysre-
gulated host response to infection.”19 This underscores the current belief that the
presence of a systemic inflammatory response does not necessarily reflect an inap-
propriate, dysregulated host response, and that this dysregulation is better identified
by organ dysfunction. In proposing this definition, the authors emphasized that sepsis,
in the absence of organ dysfunction, hypotension, and hypoperfusion, is a clinically
distinct entity from severe sepsis or septic shock and may not necessarily warrant
the same aggressive therapeutic approach. With the new proposed definitions and
criteria, the authors eliminated the term “severe sepsis,” because this term in previous
definitions is made up by patients now defined simply by the term “sepsis.” This
means that the group of “uncomplicated sepsis” patients identified by previous defi-
nitions would not qualify under any cohort on the spectrum that is the syndrome of
sepsis. Instead, these patients would simply qualify as having an infection.
To standardize the assessment of organ dysfunction, the Task Force members pro-
pose that provider use the Sequential Organ Failure Assessment (SOFA) score. The
components of the SOFA score are listed in Box 4. Patients who have an increase
of 2 or more points above their baseline SOFA score would be classified as having or-
gan dysfunction.19 The recommendation to adopt the SOFA score was the result of a
comparison of the performance of the SIRS criteria, the SOFA, and the Logistic Organ
Dysfunction System.20 The comparison found SOFA and Logistic Organ Dysfunction
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Defining and Diagnosing Sepsis 7
Box 4
Sequential Organ Failure Assessment (SOFA) score
Respiration: low PaO2:FiO2 ratio
Coagulation: thrombocytopenia
Liver: elevated bilirubin
Cardiovascular: hypotension
Central nervous system: altered mental status
Renal: elevated creatinine or low urine output
Data from Singer M, Deutschman CS, Seymour CW, et al. The third international consensus def-
initions for sepsis and septic shock (sepsis-3). JAMA 2016;315(8):801–10.
System to have the best receiver operating curve with regard to in-hospital mortality
prediction in patients in the intensive care unit (ICU). The Task Force felt that the
SOFA score was less complicated and more widely used than the Logistic Organ
Dysfunction System, and therefore it was chosen as the best definition of organ
dysfunction to define the new term of sepsis. Because the SOFA score is not widely
used, if at all, outside of the ICU, the task force retrospectively derived a new score,
the quick SOFA (qSOFA) score. The qSOFA score is composed of 3 variables: the res-
piratory rate (1 point if >22/min), systolic blood pressure (1 point if <100 mm Hg), and
mentation (1 point if the Glasgow Coma Scale is <15). When applied, the receiver
operating curve of qSOFA in patients outside the ICU approached that of SOFA for
ICU patients. Thus, the task force recommended implementation of the qSOFA score
as a method to quickly identify adult patients with suspected infection who are likely to
have poor outcomes.19 Importantly, the qSOFA score has not been validated pro-
spectively, a primary concern of critics of these newly proposed definitions. Similar
to the term severe sepsis, the task force recommended that the SIRS criteria no longer
be used to screen patients for suspected sepsis.
Finally, the task force proposed that septic shock be defined as “a subset of sepsis
in which underlying circulatory and cellular metabolism abnormalities are profound
enough to substantially increase mortality.”19 After examining the mortality associated
with 6 different proposed clinical criteria to define a clinical population of septic
shock,21 the committee decided on the following clinical criteria to define septic
shock: persistent hypotension requiring vasopressors to maintain a mean arterial
pressure of greater than or equal to 65 mm Hg and a serum lactate of greater than
2 mmol/L despite adequate volume resuscitation.19
Although a significant number of national and international organizations endorsed
these definitions as part of the peer review and publishing process, some groups did
not endorse the new definitions. Perhaps most notably, the American College of Chest
Physicians (ACCP), a title sponsor of the first 2 iterations of the definitions at the con-
ferences held in 1991 and 2001, published a statement in opposition to the newly pro-
posed definitions.22 They cite a number of concerns with the new definitions that are
especially noteworthy. First, the ACCP is concerned with changing definitions that
have previously been shown to predict mortality and that have been used in studies
to apply interventions that have reduced global sepsis mortality.22 Second, the
ACCP is concerned with the recommendation to stop using the SIRS criteria, and
the resultant shift that does not recognize the start of the continuum of the sepsis
syndrome until the patient has progressed to organ dysfunction. Specifically, they
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8 Scott
hypothesize that this shift could lead to failure to recognize the signs of potentially le-
thal infection until the combination is significantly more likely to be deadly.22
Finally, the ACCP specifically calls for a reconvening of the definitions conference,
specifically with greater representation from emergency medicine and hospitalist
physicians, to address a principle concern that the new definition deemphasizes
intervention at earlier stages of sepsis when the syndrome is actually at its most
treatable.22
SUMMARY
The syndrome of sepsis covers a myriad of infections and the wide range of clinical
severity those infections produce. The breadth and heterogeneity of the clinical en-
tities contained in this syndrome, and the evolution of the understanding of the syn-
drome, have led to multiple different, and to some extent competing, definitions
over the past decades. This has come to a head recently with the submission of a
new, revised definition for the syndrome, which has been met with significant resis-
tance by some parts of the medical community.
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