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Sepsis and the systemic

inflammatory response
syndrome: Definitions,
epidemiology, and prognosis

Author Section Editor Deputy Editor

Remi Neviere, MD Polly E Parsons, MD Kevin C Wilson, MD

Last literature review version 17.3: September 2009 | This topic last updated:
June 3, 2009 (More)

INTRODUCTION — Sepsis is a clinical syndrome that complicates severe infection and

is characterized by systemic inflammation and widespread tissue injury. In this
syndrome, tissues remote from the original insult display the cardinal signs of
inflammation, including vasodilation, increased microvascular permeability, and
leukocyte accumulation. Although inflammation is an essential host response, current
beliefs regarding the onset and progression of sepsis center upon a "dysregulation" of
the normal response, with a massive and uncontrolled release of proinflammatory
mediators creating a chain of events that leads to widespread tissue injury.

Noninfectious disorders (eg, acute pancreatitis or pulmonary contusion) may also be

complicated by tissue injury secondary to activation of the inflammatory system. The
term systemic inflammatory response syndrome (SIRS) is used in this setting to refer
to the consequences of a dysregulated host inflammatory response when infection is
not present.

We therefore distinguish between an underlying disease (infection or pancreatitis) and

the host's response (sepsis or SIRS). This distinction is important clinically since it is
the latter, not the primary disease, that is responsible for the multiple organ
dysfunction syndrome (MODS). MODS is the usual explanation for the high mortality
rates associated with these syndromes.

The definition, epidemiology, and risk factors of sepsis and SIRS are reviewed here.
The pathophysiology and treatment are discussed separately. ( See "Pathophysiology
of sepsis" and see "Management of severe sepsis and septic shock in adults" ).

DEFINITIONS — The American College of Chest Physicians (ACCP) and Society of

Critical Care Medicine (SCCM) convened a consensus panel in 1992 to define SIRS,
sepsis, severe sepsis, and septic shock [ 1-3] . The last three are clinical diagnoses and
do not require a positive blood culture. In a large study, the incidence of positive blood
cultures increased along the continuum — from 17 percent of patients with sepsis to 69
percent with septic shock [ 4] . However, the mortality rate within each category was
not influenced by the culture results.
Infection — Infection is characterized by an inflammatory response to
microorganisms, or the invasion of normally sterile host tissue by those organisms.

Bacteremia — Bacteremia is defined as the presence of viable bacteria in the blood.

Systemic inflammatory response syndrome (SIRS) — SIRS refers to the

consequences of a dysregulated host inflammatory response. It is clinically recognized
by the presence of two or more of the following ( show table 1 ):

Temperature >38.5ºC or <35ºC

Heart rate >90 beats/min
Respiratory rate >20 breaths/min or PaCO2 <32 mmHg
WBC >12,000 cells/mm3, <4000 cells/mm3, or >10 percent immature (band)
forms

SIRS can result from a variety of conditions, such as autoimmune disorders,

pancreatitis, vasculitis, thromboembolism, burns, or surgery.

Sepsis — In sepsis, the clinical signs that define SIRS are present and are due to
either a culture-proven infection or an infection identified by visual inspection ( show
table 1) [1] . The severity of sepsis is graded according to the associated organ
dysfunction and hemodynamic compromise.

The 1992 ACCP/SCCM definitions were revisited in 2001 during an International Sepsis
Definitions Conference convened by the SCCM, European Society of Intensive Care
Medicine (ESICM), ACCP, American Thoracic Society (ATS), and Surgical Infection
Society (SIS) [ 3] . A practical modification of the definitions has since been published,
including exact hemodynamic definitions of septic shock [ 5] . The definitions described
below are based upon these resources.

Severe sepsis — Severe sepsis exists if there is sepsis plus at least one of the
following signs of organ hypoperfusion or dysfunction ( show table 1 ):

Areas of mottled skin

Capillary refilling requires three seconds or longer
Urine output <0.5 mL/kg for at least one hour, or renal replacement therapy
Lactate >2 mmol/L
Abrupt change in mental status
Abnormal electroencephalographic (EEG) findings
Platelet count <100,000 platelets/mL
Disseminated intravascular coagulation
Acute lung injury or acute respiratory distress syndrome (ARDS)
Cardiac dysfunction, as defined by echocardiography or direct measurement of
the cardiac index

Septic shock — Septic shock exists if there is severe sepsis plus one or both of
the following ( show table 1 ):

Systemic mean blood pressure is <60 mmHg (or <80 mmHg if the patient has
baseline hypertension) despite adequate fluid resuscitation.
 Maintaining the systemic mean blood pressure >60 mmHg (or >80 mmHg if the
patient has baseline hypertension) requires dopamine >5 mcg/kg per min,
norepinephrine <0.25 mcg/kg per min, or epinephrine <0.25 mcg/kg per min
despite adequate fluid resuscitation.

Adequate fluid resuscitation is defined as infusion of 20 to 30 mL/kg of starch, infusion

of 40 to 60 mL/kg of saline solution, or a measured pulmonary capillary wedge
pressure (PCWP) of 12 to 20 mmHg. Septic shock is one type of vasodilatory or
distributive shock. It results from a marked reduction in systemic vascular resistance,
often associated with an increase in cardiac output. ( See "Shock in adults: Types,
presentation, and diagnostic approach" ).

Refractory septic shock — Refractory septic shock exists if maintaining the

systemic mean blood pressure >60 mmHg (or >80 mmHg if the patient has baseline
hypertension) requires dopamine >15 mcg/kg per min, norepinephrine >0.25 mcg/kg
per min, or epinephrine >0.25 mcg/kg per min despite adequate fluid resuscitation
(show table 1 ).

Multiple organ failure — Multiple organ failure refers to the presence of altered
organ function in an acutely ill patient such that homeostasis cannot be maintained
without intervention. The multiple organ dysfunction syndrome (MODS) is classified as
either primary or secondary.

Primary MODS is the result of a well-defined insult in which organ dysfunction

occurs early and can be directly attributable to the insult itself (eg, renal failure
due to rhabdomyolysis).

Secondary MODS is organ failure not in direct response to the insult itself, but
as a consequence of a host response (eg, acute respiratory distress syndrome
in patients with pancreatitis). In the context of the definitions of sepsis and
SIRS, MODS represents the more severe end of the spectrum of severity of
illness characterized by SIRS/sepsis.

Although there are no universally applicable criteria for the definition of individual
organ dysfunction in MODS, Marshall critically evaluated the definitions of MODS
adopted in the clinical literature and provided a rationale for the physiologic descriptors
commonly used to define this syndrome [ 6] . Increasing abnormalities in the following
organ-specific parameters correlated with a higher mortality in the ICU:

PO2/FiO2 ratio
Serum creatinine
Platelet count
Glasgow coma score
Serum bilirubin
Pressure-adjusted heart rate, defined by heart rate multiplied by the ratio of
central venous pressure and mean arterial pressure

EPIDEMIOLOGY — In the late 1970s, it was estimated that 164,000 cases of sepsis
occurred in the United States each year [ 7-9] . This has dramatically increased, with
more recent estimates suggesting that more than 650,000 cases of sepsis are
more recent estimates suggesting that more than 650,000 cases of sepsis are
diagnosed annually ( show figure 1 ) [7,10] . Sepsis occurs in approximately 2 percent
of hospitalized patients and up to 75 percent of ICU patients, with a mortality rate of
20 to 50 percent [ 7,11-15] . Despite an 8 percent per year increase in the incidence of
sepsis, hospital case-fatality rates have declined ( show figure 2 ) [7,11,12] .

Continuum of severity — Among patients with sepsis, the severity of disease

appears to be increasing. In one large retrospective analysis, the proportion of
patients with sepsis plus organ dysfunction (ie, severe sepsis) increased from 26
to 44 percent over a ten-year period [ 11,12] . Despite this, hospital case-fatality
rates declined. The trends of increasing incidence and improved survival have
also been observed for septic shock.

Mortality rates increase stepwise according to disease severity. In one study, the
mortality rate of SIRS, sepsis, severe sepsis, and septic shock was 7, 16, 20, and 46
percent, respectively [ 16] . Compared to critically ill patients who are not septic,
patients with septic shock remain at an increased risk of death [ 7,17] . A substantial
portion of sepsis cases develop and are managed outside of the ICU [ 18,19] .

Season — The incidence of sepsis is greatest during the winter, which appears
related to the increased likelihood of a respiratory source [ 20] .

Race and ethnicity — It also varies among racial and ethnic groups, with
African-American males at greatest risk ( show figure 3 ) [7] .

Organisms — The contribution of various infectious organisms to the burden of

disease has changed over time. Although the number of cases of Gram negative
sepsis remains substantial, Gram positive bacteria are more frequently
identified among patients in the United States. The incidence of fungal sepsis,
though lower than that of bacterial sepsis, has increased steadily over the past
decade ( show figure 4 ) [7] .

Population characteristics — The population at risk of developing sepsis is large. At

any given moment, approximately 50 percent of ICU patients have a nosocomial
infection [ 21] . Clinical trials conducted over the last two decades have provided
important insights about which patients develop sepsis [ 18,22-25] . Important risk
factors include:

Bacteremia. Medical patients with bacteremia commonly have hemodynamic

consequences of infection including SIRS, sepsis, severe sepsis, or septic shock
(95 percent) [ 26] .

Advanced age (≥ 65 years). The incidence of sepsis is disproportionately

increased in elderly patients and age is an independent predictor of mortality.
Elderly nonsurvivors die earlier during hospitalization and elderly survivors
more frequently require skilled nursing or rehabilitation after hospitalization [ 27]
.

Impaired immune system function. Comorbidities that cause host-defense

depression (neoplasms, renal or hepatic failure, AIDS) are common in septic
patients.
 patients.

Community acquired pneumonia (CAP). Among patients with CAP, severe sepsis
and septic shock will either develop or be present at admission in approximately
48 and 5 percent of patients, respectively [ 28] .

Continuum of severity — Simple categorical descriptions of sepsis patients (eg,

shock/nonshock, bacteremic/nonbacteremic, gram-positive/gram-negative) do not
adequately characterize illness severity or accurately define the mortality risk.
Multicenter, prospective studies of sepsis have suggested that there is a continuum of
severity that has both infectious and inflammatory components. The clinical spectrum
usually begins with infection that potentially leads to sepsis, organ dysfunction (ie,
severe sepsis), and septic shock.

While recognizing that the disease process forms a continuum of severity, clinical trials
have found that definable phases exist on this continuum that characterize populations
at increased risk of morbidity and mortality. As an example, one study evaluated the
natural history of 2527 patients with SIRS [ 16] :

48 percent developed part of the sepsis continuum, including sepsis (26

percent), severe sepsis (18 percent), or septic shock (4 percent)

The incidence of positive blood cultures increased along the continuum: 17

percent with sepsis to 69 percent with septic shock. Although the cause of
culture-negative disease was often not established, the mortality rate within a
category was not influenced by the culture results

The mortality rate increased progressively along the continuum: 7 percent with
SIRS alone, 16 percent with sepsis, 20 percent with severe sepsis, and 46
percent with septic shock

The most common manifestations of severe organ dysfunction were acute

respiratory distress syndrome, acute renal failure, and disseminated
intravascular coagulation. Survival was reduced in patients with these
complications

Clinical trials in the 1980s and 1990s confirmed the prognostic importance of the
definitions of the different sepsis syndromes. Patients with sepsis die at a significantly
lower rate than those with severe sepsis or septic shock on admission or those who
develop shock subsequent to study entry [ 22-25,29] .

Categorical definitions, such as SIRS, severe sepsis, and septic shock, have important
limitations [ 3,30] . They identify patients with a variable baseline or pretreatment risk,
which contributes to the large range in mortality within a category in published trials.
Furthermore, some patients with clinical evidence of sepsis may not fulfill the exact
criteria for a categorical definition such as the sepsis syndrome. These limitations have
led to recognition of the importance of physiologic derangements and individual patient
characteristics in determining the outcome from sepsis [ 3] .

Definitions of sepsis, severe sepsis, and septic shock are based on clinical experience
(ie, "expert" advice) and the correlation of infection progression with appropriate
physiologic responses. However, these criteria may be inadequate for detection of
physiologic responses. However, these criteria may be inadequate for detection of
severe infections in routine daily practice. As an example, the well-established criteria
for SIRS fails to predict outcome among patients who present to the emergency
department with pneumonia [ 28] . In addition, a multicenter study of 1531 patients in
an ICU with infection found that categorizing an infectious process as sepsis or severe
sepsis did not predict prognosis [ 31] . The Surviving Sepsis Campaign Management
Guidelines Committee, the American College of Chest Physicians, and the Society of
Critical Care Medicine Consensus Conference Committee have proposed guidelines to
help identify patients who are at greater risk for sepsis [ 32] .

CHARACTERISTICS THAT INFLUENCE OUTCOME — Clinical characteristics that

relate to the severity of sepsis include an abnormal host response to infection, the site
and type of infection, the timing and type of antimicrobial therapy, and the
development of shock. ( See "Pathophysiology of sepsis" ).

Host response — Failure to develop a fever (or the occurrence of hypothermia) is

associated with increased fatality rates in patients with sepsis [ 30,33,34] . In an
analysis of 519 septic patients, for example, a temperature below 35.5ºC was found in
17 percent of nonsurvivors versus 5 percent of survivors [ 30] . Leukopenia (a white
blood cell count less than 4000/mm3) was also more frequent in nonsurvivors (15
versus 7 percent in survivors) [ 34] . Thus, failure to develop a febrile response and
the presence of leukopenia are characteristic of severe disease, and probably
represent anomalies in the host's inflammatory response.

Underlying disease — The presence of underlying diseases and the functional health
status of the patient are important determinants of outcome in severe sepsis [ 30] .
Risk factors for mortality from sepsis include age above 40 years and comorbid
conditions at the time of diagnosis of sepsis, such as AIDS, hepatic failure, cirrhosis,
cancer, alcohol dependence, and/or immune suppression [ 30,35-38] .

Age — Older patients are at increased risk of severe sepsis, in part because of
comorbid illness and impaired immunologic response to infection [ 7,10,39] .
Malnutrition, increased exposure to potentially resistant bacterial pathogens in nursing
homes, and utilization of medical devices including indwelling catheters and central
venous lines also contribute to this increased risk [ 39] . Older patients are at increased
risk of morbidity and mortality following the development of sepsis [ 7,10] . In the
United States, patients ≥ 65 years of age account for nearly 60 percent of all episodes
of severe sepsis. This percentage is likely to increase over the next 20 years [ 7,10,40]
.

Site of infection — The site of infection in patients with sepsis may be an important
determinant of outcome, with urosepsis being associated with lower mortality rates
[30,41] . One study, for example, found mortality rates from sepsis between 50 and 55
percent when the source of infection was unknown or was gastrointestinal or
pulmonary; in comparison, the mortality rate was only 30 percent when the source
was the urinary tract [ 41] .

Blood culture results — Approximately 50 percent of patients with severe sepsis

demonstrate bacteremia at the time of diagnosis [ 42] . However, the presence or
absence of a positive blood culture does not appear to influence outcome, suggesting
that the prognosis may be more related to the severity of sepsis rather than to the
that the prognosis may be more related to the severity of sepsis rather than to the
severity of any underlying infection [ 4] .

Microorganism — Nosocomial infections have higher mortality than

community-acquired infection (15 versus 10 percent) [ 43] . This likely reflects the
culprit microorganism, since increased mortality is associated with bloodstream
infections due to methicillin-resistant staphylococcus aureus (odds ratio 2.70, 95% CI
2.03-3.58), non-candidal fungus (odds ratio 2.66, 95% CI 1.27-5.58), candida (odds
ratio 2.32 95% CI 1.21-4.45), methicillin-sensitive staphylococcus aureus (odds ratio
1.9, 95% CI 1.53-2.36), polymicrobial (odds ratio 1.69, 95% CI 1.24-2.30), and
pseudomonas (odds ratio 1.6, 95% CI 1.04-2.47) [ 43] . When bloodstream infections
become severe (ie, severe sepsis or septic shock), gram-negative and gram-positive
bacteria have similar outcomes [ 22,44] .

Antimicrobial therapy — The influence of antimicrobial therapy on the prognosis of

bacteremic and non-bacteremic sepsis is uncertain, although some studies have shown
a benefit of appropriate antibiotic therapy on bacteremic sepsis prognosis. In one
report, for example, early institution of adequate therapy was associated with a 50
percent reduction in fatality rate compared to that observed in patients treated with
antibiotics to which the infecting organisms were resistant [ 34] .

LONG-TERM SURVIVAL — Prospective studies indicate that most patients who die
following sepsis do so within the first six months [ 45,46] . In other words, mortality
tends to stabilize after six months according to the survival curves of patients with
sepsis (blood culture positive).

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GRAPHICS
Definitions of systemic inflammatory response syndrome (SIRS)
and different degrees of severity of sepsis

Condition Description
Two or more of the following conditions: temperature >38.5°C
Systemic
or <35.0°C; heart rate of >90 beats/min; respiratory rate of
inflammatory
>20 breaths/min or PaCO 2 of <32 mm Hg; and WBC count of
response
>12,000 cells/mL, <4000 cells/mL, or >10 percent immature
syndrome
(band) forms

SIRS in response to documented infection (culture or Gram

stain of blood, sputum, urine, or normally sterile body fluid
positive for pathogenic microorganism; or focus of infection
Sepsis
identified by visual inspection, eg, ruptured bowel with free air
or bowel contents found in abdomen at surgery, wound with
purulent discharge)

Sepsis and at least one of the following signs of organ

hypoperfusion or organ dysfunction: areas of mottled skin;
capillary refilling of 3 s; urinary output of <0.5 mL/kg for at
least 1 h or renal replacement therapy; lactate >2 mmol/L;
Severe sepsis
abrupt change in mental status or abnormal EEG findings;
platelet count of <100,000 cells/mL or disseminated
intravascular coagulation; acute lung injury/ARDS; and cardiac
dysfunction (echocardiography)
 Severe sepsis and one of the following conditions: systemic
mean BP of <60 mm Hg (<80 mm Hg if previous hypertension)
after 20 to 30 mL/kg starch or 40 to 60 mL/kg saline solution,
Septic shock or PCWP between 12 and 20 mm Hg; and need for dopamine of
>5 mcg/kg/min, or norepinephrine or epinephrine of <0.25
mcg/kg/min to maintain mean BP at >60 mm Hg (80 mm Hg if
previous hypertension)

Need for dopamine at >15 mcg/kg/min, or norepinephrine or

Refractory
epinephrine at >0.25 mcg/kg/min to maintain mean BP at >60
septic shock
mm Hg (80 mm Hg if previous hypertension)

WBC count: white blood cell count; BP: blood pressure.

Data from: Annane, D, Bellissant, E, Cavaillon, JM. Septic shock. Lancet 2005;
365:63.

Population-adjusted incidence of sepsis, according to sex, 1979 -

2000

Points represent the annual incidence rate, and I bars the standard error.
Data from: Martin, GS, Mannino, DM, Eaton, S, Moss, M. The epidemiology of
sepsis in the United States from 1979 through 2000. N Engl Med 2003;
348:1546.
Overall in-hospital mortality rate among patients
hospitalized for sepsis, 1979-2000

Mortality averaged 28 percent during the first six years of the study
and 18 percent during the last six years. The I bar represent the
standard error. Data from: Martin, GS, Mannino, DM, Eaton, S, Moss, M.
The epidemiology of sepsis in the United States from 1979 through
2000. N Engl Med 2003; 348:1546.
Population-adjusted incidence of sepsis, according to race, 1979 -
2000

Points represent the annual incidence rate, and I bars the standard error.
Data from: Martin, GS, Mannino, DM, Eaton, S, Moss, M. The epidemiology of
sepsis in the United States from 1979 through 2000. N Engl Med 2003;
348:1546.
 Number of cases of sepsis in the United States, according to
causative organism, 1979 - 2000

Points represent the number of cases for the given year, and I bars the
standard error. Data from: Martin, GS, Mannino, DM, Eaton, S, Moss, M. The
epidemiology of sepsis in the United States from 1979 through 2000. N Engl
Med 2003; 348:1546.

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