Sepsis and The Systemic Inflammatory Response Syndrome - Definitions, Epidemiology, and Prognosis

Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis
07/08/15 10:38
Official reprint from UpToDate

www.uptodate.com 2015 UpToDate
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Remi Neviere, MD
Section Editor
Polly E Parsons, MD
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Geraldine Finlay, MD
Disclosures: Remi Neviere, MD Nothing to disclose. Polly E Parsons, MD Nothing to disclose. Geraldine Finlay, MD Nothing to disclose.
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Literature review current through: Jul 2015. | This topic last updated: Jun 19, 2015.
INTRODUCTION Sepsis is a clinical syndrome that complicates severe infection. It is characterized by the cardinal
signs of inflammation (vasodilation, leukocyte accumulation, increased microvascular permeability) occurring in tissues
that are remote from the infection. Systemic inflammatory response syndrome (SIRS) is an identical clinical syndrome
that complicates a noninfectious insult (eg, acute pancreatitis, pulmonary contusion). Current theories about the onset
and progression of sepsis and SIRS focus on dysregulation of the inflammatory response, including the possibility that a
massive and uncontrolled release of proinflammatory mediators initiates a chain of events that lead to widespread tissue
injury. This response can lead to multiple organ dysfunction syndrome (MODS), which is the cause of the high mortality
associated with these syndromes.
The definitions, epidemiology, risk factors, and outcomes of sepsis and SIRS are reviewed here. The pathophysiology
and treatment of sepsis are discussed separately. (See "Pathophysiology of sepsis" and "Evaluation and management of
severe sepsis and septic shock in adults".)
DEFINITIONS Systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock were
initially defined in 1991 by a consensus panel convened by the American College of Chest Physicians (ACCP) and
Society of Critical Care Medicine (SCCM) [1]. These definitions were reconsidered in 2001 during an International
Sepsis Definitions Conference that included representatives from the ACCP, SCCM, American Thoracic Society (ATS),
European Society of Intensive Care Medicine (ESICM), and Surgical Infection Society (SIS), and again in 2012 by the
SCCM and ESICM [2,3]. A practical modification of the definitions has been published, which provides exact
hemodynamic definitions for sepsis and septic shock [4].
SIRS is a clinical syndrome that is a form of dysregulated inflammation. The term SIRS has routinely been associated
with both infectious processes (sepsis) and noninfectious insults, such as an autoimmune disorder, pancreatitis,
vasculitis, thromboembolism, burns, or surgery. SIRS was previously defined as two or more abnormalities in
temperature, heart rate, respiration, or white blood cell count [2]. However, in practice, its clinical definition and
pathophysiology are equivocal such that SIRS and early sepsis cannot be readily distinguished. Thus, when SIRS is
suspected it should prompt an evaluation for a septic focus.
The definitions that we provide below are based upon these resources and represent a continuum of early infection
through multiple organ dysfunction syndrome (MODS).
Infection Infection is the invasion of normally sterile tissue by organisms.
Bacteremia Bacteremia is the presence of viable bacteria in the blood.
Sepsis Sepsis is the clinical syndrome that results from a dysregulated inflammatory response to an infection that is
non resolving and deleterious, often leading to organ dysfunction. Sepsis is defined as the presence (probable or
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documented) of infection together with systemic manifestations of infection. Diagnostic criteria for sepsis include
infection (documented or suspected) and some of the following [2,3,5]:
General variables
Temperature >38.3 or <36C
Heart rate >90 beats/min or more than two standard deviations above the normal value for age
Tachypnea, respiratory rate >20 breaths/min
Altered mental status
Significant edema or positive fluid balance (>20 mL/kg over 24 hours)
Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of diabetes
Inflammatory variables
Leukocytosis (WBC count >12,000 microL1) or leukopenia (WBC count <4000 microL1)
Normal WBC count with greater than 10 percent immature forms
Plasma C-reactive protein more than two standard deviations above the normal value
Plasma procalcitonin more than two standard deviations above the normal value
Hemodynamic variables
Arterial hypotension (systolic blood pressure SBP <90 mmHg, MAP <70 mmHg, or an SBP decrease >40
mmHg in adults or less than two standard deviations below normal for age)
Organ dysfunction variables
Arterial hypoxemia (arterial oxygen tension [PaO2]/fraction of inspired oxygen [FiO2] <300)
Acute oliguria (urine output <0.5 mL/kg/hr for at least two hours despite adequate fluid resuscitation)
Creatinine increase >0.5 mg/dL or 44.2 micromol/L
Coagulation abnormalities (international normalized ratio [INR] >1.5 or activated partial thromboplastin time
[aPTT] >60 seconds)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count <100,000 microL1)
Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 micromol/L)
Tissue perfusion variables
Hyperlactatemia (>1 mmol/L)
Decreased capillary refill or mottling
Severe sepsis Severe sepsis refers to sepsis-induced tissue hypoperfusion or organ dysfunction with any of the
following thought to be due to the infection [2,3]:
Sepsis-induced hypotension
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Lactate above upper limits of laboratory normal

Urine output <0.5 mL/kg/hr for more than two hours despite adequate fluid resuscitation
Acute lung injury with PaO2/FIO2 <250 in the absence of pneumonia as infection source
Acute lung injury with PaO2/FIO2 <200 in the presence of pneumonia as infection source
Creatinine >2 mg/dL (176.8 micromol/L)
Bilirubin >4 mg/dL (34.2 micromol/L)
Platelet count <100,000 microL1
Coagulopathy (INR >1.5)
Sepsis-induced hypotension is defined as a systolic blood pressure (SBP) <90 mmHg or mean arterial pressure (MAP)
<70 mmHg or a SBP decrease >40 mmHg or less than two standard deviations below normal for age in the absence of
other causes of hypotension.
Sepsis-induced tissue hypoperfusion is defined as infection-induced hypotension, elevated lactate, or oliguria.
Septic shock Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation,
which may be defined as infusion of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). Septic shock
is a type of vasodilatory or distributive shock [2,3]. In other words, it results from a marked reduction in systemic vascular
resistance, often associated with an increase in cardiac output. (See "Definition, classification, etiology, and
pathophysiology of shock in adults".)
Multiple organ dysfunction syndrome Multiple organ dysfunction syndrome (MODS) refers to progressive organ
dysfunction in an acutely ill patient, such that homeostasis cannot be maintained without intervention. It is at the severe
end of the severity of illness spectrum of both SIRS and sepsis. MODS can be classified as 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 that is not in direct response to the insult itself, but is a consequence of the
hosts response (eg, acute respiratory distress syndrome in patients with pancreatitis)
There are no universally accepted criteria for individual organ dysfunction in MODS. However, progressive abnormalities
of the following organ-specific parameters are commonly used to diagnose MODS and scoring systems are used to
predict ICU mortality [6]:
PaO2/FiO2 ratio
Platelet count
Serum bilirubin
Serum creatinine (or urine output)
Glasgow coma score
Hypotension
RISK FACTORS The population at risk of developing sepsis is large. At any given moment, approximately 50 percent
of ICU patients have a nosocomial infection and, therefore, are at high risk for sepsis [7]. Other risk factors include the
following [8-12]:
Bacteremia Patients with bacteremia often develop systemic consequences of infection. In a study of 270 blood
cultures, 95 percent of positive blood cultures were associated with sepsis, severe sepsis, or septic shock [13].
Advanced age (65 years) The incidence of sepsis is disproportionately increased in older adult patients and age
is an independent predictor of mortality due to sepsis. Moreover, older adult non-survivors tend to die earlier during
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hospitalization and older adult survivors more frequently require skilled nursing or rehabilitation after hospitalization
[14].
Immunosuppression Comorbidities that depress host-defense (eg, neoplasms, renal failure, hepatic failure, AIDS,
asplenism) and immunosuppressant medications are common among patients with sepsis, severe sepsis, or septic
shock. (See "Clinical features and management of sepsis in the asplenic patient".)
Diabetes and cancer Diabetes and some cancers may alter the immune system, result in an elevated risk for
developing sepsis, and increase the risk of nosocomial sepsis.
Community acquired pneumonia Severe sepsis and septic shock develop in approximately 48 and 5 percent,
respectively, of patients with community-acquired pneumonia [15].
Genetic factors Both experimental and clinical studies have confirmed that genetic factors can increase the risk
of infection. In few cases, monogenic defects underlie vulnerability to specific infection, but genetic factors are
typically genetic polymorphisms. Genetic studies of susceptibility to infection have initially focused on defects of
antibody production, or a lack of T cells, phagocytes, natural killer cells, or complement. Recently, genetic defects
have been identified that impair recognition of pathogens by the innate immune system, increasing susceptibility to
specific classes of microorganisms [16].
EPIDEMIOLOGY
Incidence In the late 1970s, it was estimated that 164,000 cases of sepsis occurred in the United States (US) each
year [17]. Since then, rates of sepsis in the US and elsewhere have dramatically increased as supported by the following
studies [18-20]:
One national database analysis of discharge records from hospitals in the United States estimated an annual rate
of more than 1,665,000 cases of sepsis between 1979 and 2000 (figure 1) [18].
Another retrospective population-based analysis reported increased rates of sepsis and septic shock from 13 to 78
cases per 100,000 between 1998 and 2009 [19].
The increased rate of sepsis is thought to be a consequence of advancing age, immunosuppression, and multidrugresistant infection [20-24]. It is also likely to be due to the increased detection of early sepsis from aggressive sepsis
education and awareness campaigns, although this hypothesis is unproven.
The incidence of sepsis varies among the different racial and ethnic groups, but appears to be highest among AfricanAmerican males (figure 2) [17]. The incidence is also greatest during the winter, probably due to the increased
prevalence of respiratory infections [25]. Older patients 65 years of age account for the majority (60 to 85 percent) of all
episodes of severe sepsis which, with an increasing aging population, is likely to increase in the future [17,20,26,27].
Pathogens The contribution of various infectious organisms to the burden of sepsis has changed over time [3,28-30].
Gram positive bacteria are most frequently identified in patients with sepsis in the United States, although the number of
cases of Gram negative sepsis remains substantial. The incidence of fungal sepsis has increased over the past decade,
but remains lower than bacterial sepsis [3,17].
Disease severity The severity of disease appears to be increasing [31]. In one retrospective analysis, the proportion
of patients with sepsis who also had at least one dysfunctional organ (ie, severe sepsis) increased from 26 to 44 percent
over a ten-year period [32,33]. The most common manifestations of severe organ dysfunction were acute respiratory
distress syndrome, acute renal failure, and disseminated intravascular coagulation [34].
MORTALITY AND PROGNOSIS Sepsis has a high mortality rate. Estimates range from 10 to 52 percent
[17,20,32,35-44]. Mortality rates increase linearly according to the disease severity of sepsis [44]. In one study, the
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mortality rates of SIRS, sepsis, severe sepsis, and septic shock were 7, 16, 20, and 46 percent, respectively [34].
Mortality appears to be lower in younger patients (<44 years) without comorbidities (<10 percent) [20].
Several studies have reported decreasing mortality rates over time [17,20,32,39,45,46]. As an example, a 12-year study
of 101,064 patients with severe sepsis and septic shock from 171 ICUs in Australia and New Zealand reported a 50
percent risk reduction (from 35 to 18 percent) in in-hospital mortality from 2000 to 2012 [20]. This persisted after
adjusting for multiple variables including underlying disease severity, comorbidities, age, and the rise in incidence of
sepsis over time. This suggested that the reduction in mortality observed in this study was less likely due to the
increased detection of early sepsis and possibly due to improved therapeutic strategies for sepsis. However, despite
improved compliance with practice guidelines for the treatment of sepsis (also known as sepsis bundles) there is
conflicting evidence as to whether sepsis bundles truly improve mortality [19,39,41,47-50].
Following discharge from the hospital, sepsis carries an increased risk of death as well as an increased risk of further
sepsis and recurrent hospital admissions. Most deaths occur within the first six months but the risk remains elevated at
one-year [51-57]. Patients who survive sepsis are more likely to be admitted to acute care and/or long term care facilities
in the first year after the initial hospitalization, and also appear to have a persistent decrement in their quality of life
[38,53-55]. The most common diagnoses associated with readmission at 90 days in one database analysis of 3494
hospital admissions included heart failure, pneumonia, acute exacerbations of chronic obstructive pulmonary disease,
and urinary tract infections [56].
PROGNOSTIC FACTORS Clinical characteristics that impact the severity of sepsis and, therefore, the outcome
include the hosts response to infection, the site and type of infection, and the timing and type of antimicrobial therapy.
Host response Anomalies in the host's inflammatory response may indicate increased susceptibility to severe
disease and mortality. As examples, the failure to develop a fever (or hypothermia) and leukopenia, a patients
comorbidities, and hypocoagulability have all been associated with poor outcomes [58-61].
Failure to develop a fever (defined as a temperature below 35.5C) was more common among non-survivors of sepsis
than survivors (17 versus 5 percent) in one study of 519 patients with sepsis [58]. Leukopenia (a white blood cell count
less than 4000/mm3) was similarly more frequent among non-survivors than survivors (15 versus 7 percent) in study of
612 patients with Gram negative sepsis [60].
A patients comorbidities and functional health status are also important determinants of outcome in sepsis [58]. Risk
factors for mortality include new-onset atrial fibrillation [62], an age above 40 years [26], and comorbidities such as AIDS
[63], liver disease [64], cancer [65], alcohol dependence [64], and/or immune suppression [63,66]. Age is probably a risk
factor for mortality because of its association with comorbid illnesses, impaired immunologic responses, malnutrition,
increased exposure to potentially resistant pathogens in nursing homes, and increased utilization of medical devices,
such as indwelling catheters and central venous lines [17,26,67].
Inability to clot has also been associated with increased mortality. In one prospective study of 260 patients with severe
sepsis, indicators of hypocoagulability using standard and functional levels of fibrinogen, were associated with a six-fold
increase in the risk of death, particularly in patients treated with hydroxyethyl starch [61].
Site of infection The site of infection in patients with sepsis may be an important determinant of outcome, with sepsis
from a urinary tract infection generally being associated with the lowest mortality rates [58,68]. One study found that
mortality from sepsis was 50 to 55 percent when the source of infection was unknown, gastrointestinal, or pulmonary,
compared to only 30 percent when the source of infection was the urinary tract [68]. Another retrospective, multicenter
cohort study of nearly 8000 patients with septic shock reported similar results with the highest mortality in those with
sepsis from ischemic bowel (78 percent) and the lowest rates in those with obstructive uropathy-associated urinary tract
infection (26 percent) [43].
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Approximately 50 percent of patients with severe sepsis are bacteremic at the time of diagnosis according to one study
[69]. This is consistent with a study of 85,750 hospital admissions, which found that the incidence of positive blood
cultures increased along a continuum, ranging from 17 percent of patients with sepsis to 69 percent with septic shock
[70]. However, the presence or absence of a positive blood culture does not appear to influence the outcome,
suggesting that prognosis is more closely related to the severity of sepsis than the severity of the underlying infection
[70,71].
Type of infection Sepsis due to nosocomial pathogens has a higher mortality than sepsis due to communityacquired pathogens [72,73]. 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 1.532.36), and pseudomonas (odds ratio 1.6, 95% CI 1.04-2.47), as well as polymicrobial infections (odds ratio 1.69, 95% CI
1.24-2.30) [72,74]. When bloodstream infections become severe (ie, severe sepsis or septic shock), the outcome is
similar regardless of whether the pathogens are Gram-negative or Gram-positive bacteria [9,75].
Antimicrobial therapy Studies have shown that appropriate antibiotic therapy (ie, antibiotics to which the pathogen is
sensitive) has a beneficial impact on bacteremic sepsis [60,71]. In one report, for example, early institution of adequate
antibiotic therapy was associated with a 50 percent reduction in the mortality rate compared to antibiotic therapy to which
the infecting organisms were resistant [60]. In contrast, prior antibiotic therapy (ie, antibiotics within the past 90 days)
may be associated with increased mortality, at least among patients with Gram negative sepsis [76]. This is probably
because patients who have received prior antibiotic therapy are more likely to have higher rates of antibiotic resistance,
making it less likely that appropriate antibiotic therapy will be chosen empirically.
Restoration of perfusion Failure to aggressively try to restore perfusion early (ie, failure to initiate early goal-directed
therapy) may also be associated with mortality [77]. This is discussed in detail separately. (See "Evaluation and
management of severe sepsis and septic shock in adults", section on 'Interventions to restore perfusion'.)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to
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the keyword(s) of interest.)
Basics topic (see "Patient information: Sepsis in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS
Sepsis is the consequence of a dysregulated inflammatory response to an infectious insult. (See 'Introduction'
above.)
Sepsis exists on a continuum of severity: infection is the invasion of normally sterile tissue by organisms;
bacteremia is the presence of viable bacteria in the blood; sepsis is defined as the presence (probable or
documented) of infection together with systemic manifestations of infection; severe sepsis refers to sepsis plus
sepsis-induced organ dysfunction; and septic shock is defined as sepsis-induced hypotension persisting despite
adequate fluid resuscitation. (See 'Definitions' above.)
Systemic inflammatory response syndrome (SIRS) is a syndrome that is the consequence of a dysregulated
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inflammatory response to an infectious or non-infectious insult. It can be due to and is often indistinguishable from
early sepsis such that a source of sepsis should be sought when it is suspected. (See 'Definitions' above.)
Multiple organ dysfunction syndrome refers to progressive deterioration of organ function in an acutely ill patient. It
is the most severe end of the spectrum for both sepsis and SIRS. (See 'Multiple organ dysfunction syndrome'
above.)
Risk factors for sepsis include a nosocomial infection, bacteremia, advanced age, immunosuppression, and
community-acquired pneumonia. Genetic defects have also been identified that may increase susceptibility to
specific classes of microorganisms. (See 'Risk factors' above.)
The incidence and severity of sepsis appear to be increasing, with Gram positive bacteria being the pathogens that
are most commonly isolated from patients with sepsis. Mortality due to sepsis is high, but appears to have
decreased. (See 'Epidemiology' above.)
Poor prognostic factors include the inability to mount a fever, leukopenia, age >40 years, certain comorbidities (eg,
AIDS, hepatic failure, cirrhosis, cancer, alcohol dependence, immunosuppression), a non-urinary source of
infection, a nosocomial source of infection, and inappropriate antibiotic coverage. (See 'Prognostic factors' above.)
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treatment in 612 patients. Am J Med 1980; 68:344.

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