Version May 2024
INTRODUCTION — Sepsis is a clinical syndrome that has physiologic, biologic, and biochemical abnormalities caused by a dysregulated host response to infection. Sepsis and the inflammatory response that ensues can lead to multiple organ dysfunction syndrome and death.
The epidemiology, definitions, risk factors, clinical presentation, diagnosis, and outcomes of sepsis are reviewed here. The pathophysiology and treatment of sepsis are discussed separately. (See "Pathophysiology of sepsis" and "Evaluation and management of suspected sepsis and septic shock in adults".)
EPIDEMIOLOGY
Incidence — In the late 1970s, it was estimated that 164,000 cases of sepsis occurred in the United States (US) each year [1]. Since then, rates of sepsis in the US and elsewhere have on balance increased although many of these are derived from academic institutions or on claims-based analyses [2-9]:
●One national database analysis of discharge records from hospitals in the US estimated an annual rate of more than 1,665,000 cases of sepsis between 1979 and 2000 [2].
●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 [3].
●A retrospective analysis of an international database reported a global incidence of 437 per 100,000 person-years for sepsis between the years 1995 and 2015, although this rate was not reflective of contributions from low- and middle-income countries [6]. The Global Burden of Disease Study reported that in 2017, an estimated 48.9 million incident cases of sepsis were reported [7]. Approximately 11 million deaths were reported, representing 19.7 percent of all global deaths. Nearly one-half of all sepsis-related deaths occur in the setting of an underlying injury or non-communicable disease. While incidence and mortality varied across regions, the overall mortality decreased by almost 53 percent between 1990 and 2017. Moreover, this study highlights the need for greater prevention and treatment of sepsis, particularly in areas of the world with the lowest socio-demographic index.
●In an analysis of 27 academic hospitals, between 2005 and 2014 rates of septic shock determined by clinical criteria increased from 12.8 to 18.6 per 1000 hospital admissions and mortality decreased from 55 to 51 percent [8]. Similar trends were noted when the International Classification of Diseases 9th edition (ICD 9) codes were used except the decrease in mortality was more dramatic.
●In contrast, a 2017 study reports stable rates of sepsis between 2009 and 2014 [9]. This study used clinical electronic health record (EHR) data (and the sepsis definitions described above (see 'Sepsis' below)) from 7 million hospitalizations in 409 US hospitals and compared it to traditional claims-based analysis (International Classification of diseases, Ninth Revision, Clinical Modification codes for severe sepsis or septic shock) and direct chart review. It was estimated that using EHR-based data, admission rates due to sepsis remained unchanged over the study period at 6 percent while in-hospital mortality decreased by 3 percent. In contrast, claims-based analyses suggested a 10 percent increase in incidence and a 7 percent reduction in mortality. When compared with direct chart review (thought to be the most sensitive method of detecting incidence) of 510 randomly selected cases, it was estimated that EHR-based analyses missed 20 percent of sepsis cases, while claims-based analysis missed 40 percent. A meta-analysis of 10 studies that did not include this major trial also reported that SIRS was superior to qSOFA for the diagnosis of sepsis but qSOFA was a better predictor of in-hospital mortality [10].
Reasons for a possible increased rate of sepsis include advancing age, immunosuppression, and multidrug-resistant infection [4,11-14]. It may also 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 African-American males [1,15].
The incidence is also greatest during the winter, probably due to the increased prevalence of respiratory infections [16].
Older patients ≥65 years of age account for the majority (60 to 85 percent) of all episodes of sepsis; with an increasing aging population, it is likely that the incidence of sepsis will continue to increase in the future [1,4,17,18].
Pathogens — Bacteria have been shown to be the predominant pathogen of sepsis among patients with pathogens detected, while sepsis caused by viruses is underdiagnosed worldwide.
The contribution of various infectious organisms to the burden of sepsis has changed over time [19-21]. 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 [1]. In approximately one-half of cases of sepsis, an organism is not identified (culture negative sepsis) [22].
The viruses, which can cause severe disease, include influenza A and B, respiratory syncytial virus, coronavirus, human metapneumovirus, parainfluenza virus types 1 to 3, adenovirus, enteroviruses, and rhinovirus [23]. As well as for commonly detected viruses, emerging novel virus infections can also result in sepsis and have raised global health concerns; these include severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East Respiratory Syndrome-coronavirus (MERS-CoV), and SARS-CoV-2, which caused the outbreak of the coronavirus disease 2019 (COVID-19) [23].
Disease severity — The severity of disease appears to be increasing [24]. In one retrospective analysis, the proportion of patients with sepsis who also had at least one dysfunctional organ increased from 26 to 44 percent between 1993 and 2003 [25,26]. The most common manifestations of severe organ dysfunction were acute respiratory distress syndrome, acute renal failure, and disseminated intravascular coagulation [27]. However, it is unclear as to whether the rising incidence of sepsis and septic shock reflects the overall increased incidence of sepsis or altered definitions of sepsis over time.
DEFINITIONS — Sepsis exists on a continuum of severity ranging from infection and bacteremia to sepsis and septic shock, which can lead to multiple organ dysfunction syndrome (MODS) and death. The definitions of sepsis and septic shock have rapidly evolved since the early 1990s [28-33]. The systemic inflammatory response syndrome (SIRS) is no longer included in the definition since it is not always caused by infection. The definitions for sepsis that we provide below reflect expert opinion from task forces generated by national societies including the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Importantly, such definitions are not diagnostic of sepsis since they do not comprehensively include specific criteria for the identification of infection. However, clinicians should be aware that SCCM/ESICM definitions are not unanimously accepted. For example, the Center for Medicare and Medicaid Services (CMS) still continues to support the previous definition of SIRS, sepsis, and severe sepsis. (See 'Diagnosis' below.)
Early sepsis — Infection and bacteremia may be early forms of infection that can progress to sepsis. However, there is no formal definition of early sepsis. Nonetheless, despite the lack of definition, monitoring those suspected of having sepsis is critical for its prevention. Despite an aggressive education campaign regarding the early identification of sepsis, one study has reported that alert systems designed to prompt an evaluation for sepsis may misclassify patients’ inflammation as having sepsis; alert systems also led to a higher rate of antibiotic use and Clostridioides difficile infection and did not affect 30 day mortality [34].
Infection and bacteremia — All patients with infection or bacteremia are at risk of developing sepsis and represent early phases in the continuum of sepsis severity:
●Infection is defined as the invasion of normally sterile tissue by organisms resulting in infectious pathology.
●Bacteremia is the presence of viable bacteria in the blood.
Identification of early sepsis (qSOFA, NEWS) — Societal guidelines place emphasis on the early identification of infected patients who may go on to develop sepsis as a way to decrease sepsis-associated mortality [31-33,35,36]. The two most commonly used scores are the quick Sequential (Sepsis-related) Organ Failure Assessment score (qSOFA) score (calculator 1) and the National Early Warning Score (NEWS) score (calculator 2). We and others prefer NEWS [35].
NEWS is an aggregate scoring system derived from six physiologic parameters and is preferred among most physicians (calculator 2):
●Respiration rate
●Oxygen saturation
●Systolic blood pressure
●Pulse rate
●Level of consciousness or new confusion
●Temperature
The aggregate score represents the risk of death from sepsis and indicates the urgency of the response:
●0 to 4 – low risk (a score of 3 in any individual parameter is low-medium)
●5 to 6 – medium risk
●7 or more – high risk
The qSOFA score (calculator 1) is a modified version of the Sequential (Sepsis-related) Organ Failure Assessment score (SOFA) score. A score ≥2 is associated with poor outcomes due to sepsis.
The qSOFA score is easy to calculate since it only has three components, each of which are readily identifiable at the bedside and are allocated one point:
●Respiratory rate ≥22/minute
●Altered mentation
●Systolic blood pressure ≤100 mmHg
Because data of the value of qSOFA is conflicting, we believe that further studies that demonstrate improved clinically meaningful outcomes due to the use of qSOFA compared to clinical judgement are warranted before it can be routinely used to diagnose sepsis or predict those at risk of death from sepsis. The qSOFA score was originally validated in 2016 as most useful in patients suspected as having sepsis outside of the intensive care unit (ICU) [33]. It has since been prospectively studied in several settings including the emergency department (ED) [37-43] and ICU [44-46] with conflicting data regarding its ability to accurately diagnose or predict the risk of death in these populations. In addition, data describing its comparative performance with other predictors of mortality, such as systemic inflammatory response syndrome criteria (SIRS) or national early warning score (NEWS), are also conflicting [40-43]. In a retrospective review of several scores in ED patients with sepsis, NEWS was the most accurate predictor (area under the receiver operating characteristic [AUROC] curve 0.904, 95% CI 0.805–0.913) [36]. On balance, qSOFA may not be as robust as originally thought and clinicians need to keep in mind that it was originally designed not as a diagnostic tool but rather as a predictive tool that calculates the risk of death from sepsis.
As qSOFA requires only a clinical examination, whether qSOFA could be applied to different types of infection, location within the hospital (ED, ward, ICU), and countries is under question. The value of qSOFA in low- and middle-income countries (LMICs) has been addressed in one analysis of 6218 hospitalized patients derived from eight cohort studies and one randomized trial in LMICs [47]. In that analysis. higher qSOFA scores were associated with a higher risk of death, but predictive validity varied significantly among cohorts, limiting the interpretation of the results.
The full SOFA score is described separately. (See "Predictive scoring systems in the intensive care unit", section on 'Sequential (sepsis-related) Organ Failure Assessment (SOFA)' and 'Sepsis' below.)
Artificial intelligence (AI) has the potential to detect sepsis symptoms hours before traditional methods. AI systems examine medical records to identify patients at risk of sepsis. As an example, Targeted Real-Time Early Warning System (TREWS) is a bedside tool which combines the patient's medical history with their symptoms and laboratory results, to alert the clinicians to the risk of sepsis and suggests a treatment protocols, such as fluid therapy and antibiotics [48,49]. TREWS was reported to result in a 3 percent reduction in sepsis-related mortality when a provider responded to and confirmed the alert within three hours of the alert compared with patients whose alert was not confirmed by a provider within three hours. However, only 38 percent of evaluated alerts were cases of provider-confirmed sepsis suggesting limited specificity of the system. Preliminary data on deep learning systems such as Sepsis Prediction and Optimization of Therapy (SPOT) and Sepsis Watch, which facilitate timely rapid responses to initiate life-saving therapy, have also been reported to lead to an almost 10 percent reduction in mortality for patients with severe sepsis [50].
Sepsis — A 2016 SCCM/ESICM task force has defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis-3) as evidenced by the following:
●Organ dysfunction – Organ dysfunction is defined by the 2016 SCCM/ESICM task force as an increase of two or more points in the SOFA score (calculator 3). The validity of this score was derived from critically ill patients with suspected sepsis by interrogating over a million intensive care unit (ICU) electronic health record encounters from ICUs both inside and outside the United States [31-33]. ICU patients were suspected as having infection if body fluids were cultured and they received antibiotics. Predictive scores (SOFA, systemic inflammatory response syndrome [SIRS], and Logistic Organ Dysfunction System [LODS]) were compared for their ability to predict mortality. Among critically ill patients with suspected sepsis, the predictive validity of the SOFA score for in-hospital mortality was superior to that for the SIRS criteria (area under the receiver operating characteristic curve 0.74 versus 0.64). Patients who fulfill these criteria have a predicted mortality of ≥10 percent. Although the predictive capacity of SOFA and LODS were similar, SOFA is considered easier to calculate, and was therefore recommended by the task force.
Importantly, the SOFA score is an organ dysfunction score. It is not diagnostic of sepsis nor does it identify those whose organ dysfunction is truly due to infection but rather helps identify patients who potentially have a high risk of dying from infection. In addition, it does not determine individual treatment strategies nor does it predict mortality based upon demographics (eg, age) or underlying condition (eg, stem cell transplant recipient versus postoperative patient). SOFA and other predictive scores are discussed separately. (See "Predictive scoring systems in the intensive care unit", section on 'Sequential (sepsis-related) Organ Failure Assessment (SOFA)'.)
In addition, the SOFA score may overestimate the risk of in-hospital mortality in Black patients. In one database of over 111,000 ICU encounters representing over 95 ,000 patients, mortality was lower among Black individuals compared with White individuals with equivalent SOFA scores (odds ratio [OR] 0.98, 95% CI 0.97-0.99) [51]. This led to inequitable resource allocation for patients, which may be more important during times of bed crisis and limited resources. Separate analyses from a different group have confirmed the same findings [52].
●Infection – There are no clear guidelines to help the clinician identify the presence of infection or to causally link an identified organism with sepsis. In our experience, for this component of the diagnosis, the clinician is reliant upon clinical suspicion derived from the signs and symptoms of infection as well as supporting radiologic and microbiologic data and response to therapy. (See 'Clinical presentation' below and 'Diagnosis' below.)
The term severe sepsis, which originally referred to sepsis that was associated with tissue hypoperfusion (eg, elevated lactate, oliguria) or organ dysfunction (eg, elevated creatinine, coagulopathy) [29,35], and the term systemic inflammatory response syndrome (SIRS (table 1)) are no longer used since the 2016 sepsis and septic shock definitions include patients with evidence of tissue hypoperfusion and organ dysfunction. However, the Center for Medicare and Medicaid Services (CMS) still continues to support the previous definition of SIRS, sepsis, and severe sepsis.
Septic shock — Septic shock is a type of vasodilatory or distributive shock. Septic shock is defined as sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone [31]. Clinically, this includes patients who fulfill the criteria for sepsis (see 'Sepsis' above) who, despite adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg and have a lactate >2 mmol/L (>18 mg/dL). Per predictions from the SOFA score (calculator 3), patients who fulfill these criteria for septic shock have a higher mortality than those who do not (≥40 versus ≥10 percent). (See "Predictive scoring systems in the intensive care unit", section on 'Sequential (sepsis-related) Organ Failure Assessment (SOFA)'.)
Others — Multiple organ dysfunction syndrome (MODS) and systemic inflammatory response syndrome (SIRS) are terms frequently used in practice that need to be distinguished from sepsis.
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 infectious (sepsis, septic shock) and noninfectious conditions (eg, SIRS from pancreatitis). 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 host's 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 are also used in scoring systems (eg, SOFA (calculator 3) or LODS) to predict ICU mortality [53-55] (see "Predictive scoring systems in the intensive care unit"):
●Respiratory – Partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio
●Hematology – Platelet count
●Liver – Serum bilirubin
●Renal – Serum creatinine (or urine output)
●Brain – Glasgow coma score
●Cardiovascular – Hypotension and vasopressor requirement
In general, the greater the number of organ failures, the higher the mortality, with the greatest risk being associated with respiratory failure requiring mechanical ventilation. (See "Acute respiratory distress syndrome: Prognosis and outcomes in adults".)
Systemic inflammatory response syndrome — The use of systemic inflammatory response syndrome (SIRS) criteria to identify those with sepsis has fallen out of favor since it is considered by many experts that SIRS criteria are present in many hospitalized patients who do not develop infection, and their ability to predict death is poor when compared with other scores such as the SOFA score [33,56,57]. SIRS is considered a clinical syndrome that is a form of dysregulated inflammation. It was previously defined as two or more abnormalities in temperature, heart rate, respiration, or white blood cell count [29]. SIRS may occur in several conditions related, or not, to infection. Noninfectious conditions classically associated with SIRS include autoimmune disorders, pancreatitis, vasculitis, thromboembolism, burns, or surgery.
Pregnancy — The usual scoring systems (eg, SOFA, SIRS) have excluded pregnant women because pregnancy physiology is different and normal pregnancy parameters overlap with criteria for sepsis [58] such that some experts have proposed use of pregnancy-specific scores. As an example, the sepsis in obstetrics score is a score that incorporates clinical criteria, modified for parameters expected to change in pregnancy, that predicted risk of admission to the intensive care unit with a score of six or greater [59]. Further validation of this score is needed before it can be routinely used in this population. Guidelines have been proposed by some experts for potential diagnostic parameters but have not been universally accepted or validated [60].
COVID-19 — Patients critically ill with COVID-19 satisfy the diagnostic criteria for sepsis and exhibit a phenotype and pathology with both similarities and differences to that of sepsis caused by other pathogens. Patients with severe COVID-19 suffer from multi-organ dysfunction, representing the common manifestations that characterize sepsis [61]. (See "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult" and "COVID-19: Management of the intubated adult".)
RISK FACTORS — The importance of identifying risk factors for sepsis was highlighted in one epidemiologic study that reported that risk factors for septic shock were the fifth leading cause of years of productive life lost due to premature mortality [62]. Risk factors for sepsis include the following [63-71]:
●Intensive care unit admission – Approximately 50 percent of intensive care unit (ICU) patients have a nosocomial infection and are, therefore, intrinsically at high risk for sepsis [72].
●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, or septic shock [67].
●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 hospitalization and older adult survivors more frequently require skilled nursing or rehabilitation after hospitalization [68].
●Immunosuppression – Comorbidities that depress host-defense (eg, neoplasms, renal failure, hepatic failure, AIDS, asplenism) and immunosuppressant medications are common among patients with sepsis, or septic shock. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function".)
●Diabetes and obesity – Diabetes and obesity may alter the immune system, resulting in an elevated risk for developing sepsis. Both obesity and type 2 diabetes are associated with an increased risk of recurrent, nosocomial, and secondary infections that lead to sepsis. Individuals with obesity have a higher risk of community acquired pneumonia, biliary disease, cutaneous infections, and aspiration pneumonia during hospitalizations. In ICU, patients with obesity may have a higher risk of infectious complications that lead to sepsis, ventilator-associated pneumonia, central venous catheter–related infections, and increased mortality compared with normal weight patients [73].
●Cancer – Malignancy is one of the most common comorbidities among patients with sepsis. Analysis of a subgroup of patients with cancer in the 1979–2001 National Hospital Discharge Survey found cancer of all types increased the risk of developing sepsis almost 10-fold [74].
●Community acquired pneumonia – Severe sepsis (as defined by the old definition) and septic shock develop in approximately 48 and 5 percent, respectively, of patients hospitalized with community-acquired pneumonia [69].
●Previous hospitalization – Hospitalization is thought to induce an altered human microbiome, particularly in patients who are treated with antibiotics. Previous hospitalization has been associated with a three-fold increased risk of developing sepsis in the subsequent 90 days [70]. Patients with hospitalizations for infection-related conditions, especially Clostridium difficile infection, are at greatest risk.
●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 [71].
CLINICAL PRESENTATION — Patients with suspected or documented sepsis typically present with hypotension, tachycardia, fever, and leukocytosis. As severity worsens, signs of shock (eg, cool skin and cyanosis) and organ dysfunction develop (eg, oliguria, acute kidney injury, altered mental status) [29,35]. Importantly, the presentation is nonspecific such that many other conditions (eg, pancreatitis, acute respiratory distress syndrome) may present similarly. Presentations of common conditions associated with sepsis are in the table (table 2). Detailed discussion of the clinical features of shock are discussed separately. (See "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock", section on 'Clinical manifestations'.)
Symptoms and signs — The symptoms and signs of sepsis are nonspecific but may include the following:
●Symptoms and signs specific to an infectious source (eg, cough and dyspnea may suggest pneumonia, pain and purulent exudate in a surgical wound may suggest an underlying abscess).
●Arterial hypotension (eg, systolic blood pressure [SBP] <90 mmHg, mean arterial pressure [MAP] <70 mmHg, an SBP decrease >40 mmHg, or less than two standard deviations below normal for age).
●Temperature >38.3 or <36ºC.
●Heart rate >90 beats/min or more than two standard deviations above the normal value for age.
●Tachypnea, respiratory rate >20 breaths/minute.
●Signs of end-organ perfusion:
•Warm, flushed skin may be present in the early phases of sepsis. As sepsis progresses to shock, the skin may become cool due to redirection of blood flow to core organs. Decreased capillary refill, cyanosis, or mottling may indicate shock.
•Additional signs of hypoperfusion include altered mental status, obtundation or restlessness, and oliguria or anuria.
•Ileus or absent bowel sounds are often an end-stage sign of hypoperfusion.
These findings may be modified by preexisting disease or medications. As examples, older patients, diabetic patients, and patients who take beta-blockers may not exhibit an appropriate tachycardia as blood pressure falls. In contrast, younger patients frequently develop a severe and prolonged tachycardia and fail to become hypotensive until acute decompensation later occurs, often suddenly. Patients with chronic hypertension may develop critical hypoperfusion at a higher blood pressure than healthy patients (ie, relative hypotension).
Clinical findings of COVID-19 are discussed separately. (See "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult", section on 'Clinical features in critically ill patients'.)
Laboratory signs — Similarly, laboratory features are nonspecific and may be associated with abnormalities due to the underlying cause of sepsis or to tissue hypoperfusion or organ dysfunction from sepsis. They include the following:
●Leukocytosis (white blood cell [WBC] count >12,000 microL–1) or leukopenia (WBC count <4000 microL–1).
●Normal WBC count with greater than 10 percent immature forms.
●Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence of diabetes.
●Plasma C-reactive protein more than two standard deviations above the normal value.
●Arterial hypoxemia (arterial oxygen tension [PaO2]/fraction of inspired oxygen [FiO2] <300).
●Acute oliguria (urine output <0.5 mL/kg/hour 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).
●Thrombocytopenia (platelet count <100,000 microL–1).
●Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 micromol/L).
●Adrenal insufficiency (eg, hyponatremia, hyperkalemia), and the euthyroid sick syndrome can also be found in sepsis.
●Hyperlactatemia (higher than the laboratory upper limit of normal) – An elevated serum lactate (eg, >2 mmol/L) can be a manifestation of organ hypoperfusion in the presence or absence of hypotension and is an important component of the initial evaluation, since elevated lactate is associated with poor prognosis [35,75-77]. A serum lactate level ≥4 mmol/L is consistent with, but not diagnostic of, septic shock. Additional laboratory studies that help characterize the severity of sepsis include a low platelet count, and elevated international normalized ratio, creatinine, and bilirubin. Although arterial and venous lactate correlate, arterial lactate measurements are more accurate and preferred [78].
●Plasma procalcitonin more than two standard deviations above the normal value (not routinely performed in many centers) – Elevated serum procalcitonin levels are associated with bacterial infection and sepsis [79-81]. Despite this, a meta-analysis of 18 studies found that procalcitonin did not readily distinguish sepsis from nonseptic systemic inflammation (sensitivity of 71 percent and specificity of 71 percent) [80]. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'De-escalation and duration of antibiotics'.)
●Mid-regional pro-Adrenomedullin (MR-proADM) has been used to predict occurrence and worsening of organ failure in critically ill patients. Yet controversial, monitoring of MR-proADM levels may improve the diagnosis of bacterial infection and contribute to prognosis and antibiotic therapy effectiveness [82].
Laboratory findings of COVID-19 are discussed separately. (See "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult", section on 'Laboratory findings'.)
Imaging — There are no radiologic signs that are specific to the identification of sepsis other than those associated with infection in a specific site (eg, pneumonia on chest radiography, fluid collection on computed tomography of the abdomen).
Microbiology — The identification of an organism in culture in a patient who fulfills the definition of sepsis (see 'Sepsis' above) is highly supportive of the diagnosis of sepsis but is not necessary. The rationale behind its lack of inclusion in the diagnostic criteria for sepsis is that a culprit organism is frequently not identified in up to 50 percent of patients who present with sepsis nor is a positive culture required to make a decision regarding treatment with empiric antibiotics [22,83]. Blood cultures are also frequently negative with one study reporting positive blood cultures in 31.4 percent of patients prior to the administration of antimicrobials [84]. The importance of obtaining early cultures (including blood cultures) is described separately. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Initial investigations'.)
DIAGNOSIS — A limitation of the definitions above (see 'Definitions' above) is that they cannot identify patients whose organ dysfunction is truly secondary to an underlying infection. Thus, a constellation of clinical, laboratory, radiologic, physiologic, and microbiologic data is typically required for the diagnosis of sepsis and septic shock. The diagnosis is often made empirically at the bedside upon presentation, or retrospectively when follow-up data returns (eg, positive blood cultures in a patient with endocarditis) or a response to antibiotics is evident. Importantly, the identification of a culprit organism, although preferred, is not always feasible since in many patients no organism is ever identified. In some patients this may be because they have been partially treated with antibiotics before cultures are obtained.
Although septic shock has a specific hemodynamic profile on pulmonary artery catheterization (PAC) (table 3), PACs are difficult to interpret and rarely placed in patients with suspected sepsis. (See "Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults" and "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock", section on 'Pulmonary artery catheterization'.)
The evaluation and diagnosis of shock is discussed separately. (See "Evaluation of and initial approach to the adult patient with undifferentiated hypotension and shock".)
PROGNOSIS
In-hospital morbidity and mortality — Sepsis has a high mortality rate. Rates depend upon how the data are collected but estimates range from 10 to 52 percent [1,4,15,25,56,85-94]. Data derived from death certificates report that sepsis is responsible for 6 percent of all deaths while administrative claims data suggest higher rates [94]. Mortality rates increase linearly according to the disease severity of sepsis [56]. In one study, the mortality rates of SIRS, sepsis, and septic shock were 7, 16, and 46 percent, respectively [27]. In another study, the mortality associated with sepsis was ≥10 percent while that associated with septic shock was ≥40 percent [31]. Mortality appears to be lower in younger patients (<44 years) without comorbidities (<10 percent) [4].
Several studies have reported decreasing mortality rates over time [1,4,25,89,95-97]. As an example, a 12-year study of 101,064 patients with sepsis and septic shock from 171 intensive care units (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 [4]. 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 [98-100].
During hospital admission, sepsis may increase the risk of acquiring a subsequent hospital-related infection. One prospective observational study of 3329 admissions to the ICU reported that ICU-acquired infections occurred in 13.5 percent admissions of patients with sepsis compared with 15 percent of non-sepsis ICU admissions [101]. Patients admitted with sepsis also developed more ICU-acquired infections including infection with opportunistic pathogens, hinting at possible immune suppression. In patients with a sepsis admission diagnosis, secondary infections were mostly catheter-related blood stream infections (26 percent), pneumonia (25 percent), or abdominal infections (16 percent), compared with patients with non-sepsis admission where pneumonia was the most common ICU-acquired infection (48 percent). In both groups, patients who developed ICU-acquired infection were more severely ill on admission (eg, higher Acute Physiologic and Chronic Health Evaluation [APACHE] IV and Sequential Organ Failure Assessment scores and more shock on admission) and had higher mortality at day 60. However, the contribution of developing a secondary infection was small.
Long-term prognosis — Following discharge from the hospital, sepsis carries an increased risk of death (up to 20 percent) as well as an increased risk of further sepsis and recurrent hospital admissions (up to 10 percent are readmitted). Most deaths occur within the first six months but the risk remains elevated at two years [102-110]. 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 [88,97,104-106]. Quality of life also appears to be worse than non-sepsis survivors at ICU discharge and one month post ICU discharge [111].
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 [107]. Higher rates of readmission with subsequent infection and sepsis may be associated with previous hospitalization for an infection, particularly infection with clostridium difficile [70,112]. Another database analysis reported that a previous diagnosis of sepsis was a leading cause of readmissions when compared with myocardial infarction, chronic obstructive pulmonary disease, heart failure, and pneumonia [113]. Sepsis survivors may also be at increased risk of major cardiovascular events and stroke when compared with patients hospitalized with nonsepsis diagnosis [110,114]. (See "Hospital discharge and readmission".)
Prognostic factors — Clinical characteristics that impact the severity of sepsis and, therefore, the outcome include the host's response to infection, the site and type of infection, and the timing and type of antimicrobial therapy.
Prognosis of COVID-19 is discussed separately. (See "COVID-19: Epidemiology, clinical features, and prognosis of the critically ill adult", section on 'Prognosis'.)
Host-related — 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 the development of leukopenia, thrombocytopenia, hyperchloremia, a patient's comorbidities, age, hyperglycemia, hypocoagulability, and failure of procalcitonin to fall have all been associated with poor outcomes [115-122].
●Failure to develop a fever (defined as a temperature below 35.5ºC) was more common among non-survivors of sepsis than survivors (17 versus 5 percent) in one study of 519 patients with sepsis [115]. Leukopenia (a white blood cell count less than 4000/mm3) was similarly more frequent among non-survivors than survivors (15 versus 7 percent) in a study of 612 patients with Gram negative sepsis [117] and a platelet count <100,000/mm3 was found to be an early prognostic marker of 28-day mortality in another study of 1486 patients with septic shock [120]. In another retrospective analysis of critically ill septic patients, hyperchloremia (Cl ≥110 mEq/L) at 72 hours after ICU admission was independently associated with an increase in all-cause hospital mortality [119].
●A patient's comorbidities and functional health status are also important determinants of outcome in sepsis [115]. Risk factors for mortality include new-onset atrial fibrillation [123,124], an age above 40 years [17], and comorbidities such as AIDS [125], liver disease [126], cancer [127], alcohol dependence [126], immune suppression [125,128], and reduced or hyperdynamic left ventricular systolic dysfunction [129].
●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 [1,17,130].
●Admission hyperglycemia, was found in one prospective observational study of 987 patients with sepsis to be associated with an increased risk of death (hazard ratio 1.66) that was unrelated to the presence of diabetes [121].
●Inability to clot has also been associated with increased mortality. In one prospective study of 260 patients with 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 [118].
●Failure of procalcitonin level to fall in one study predicted mortality [122]. When procalcitonin did not decrease by more than 80 percent from baseline to day four in patients with severe sepsis, the 28-day mortality was reported to be higher (20 versus 10 percent).
Clinical host-related phenotypes have been proposed as a potential way to identify those most at risk of dying from sepsis. In a retrospective analysis of datasets, sepsis phenotypes were derived from over 20,000 patients who met the Sepsis-3 criteria (see 'Sepsis' above) and validated in a cohort of over 43,000 patients [131]. Four phenotypes were described. An alpha phenotype (patients on lowest dose of a vasopressor) had the lowest mortality at 5 percent while the beta phenotype (older patients with chronic illnesses and renal dysfunction) had a mortality of 13 percent, the gamma phenotype (patients with inflammation and pulmonary dysfunction) had a mortality of 24 percent, and the delta phenotype (patients with liver dysfunction and septic shock) had the highest mortality at 40 percent. Using simulation models it was predicted that clinical outcomes in randomized trials could be influenced by the inclusion of different proportions of the clinical phenotype. Significant differences in the distribution of many biomarkers were also demonstrated across the four phenotypes. Additional research is ongoing to understand the value of clinical phenotypes in sepsis.
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 [115,132]. One study found that mortality from sepsis was 50 to 55 percent when the source of infection was unknown, gastrointestinal, or pulmonary, compared with only 30 percent when the source of infection was the urinary tract [132]. 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) [93].
Approximately 50 percent of patients with sepsis are bacteremic at the time of diagnosis according to one study [133]. 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 [134]. 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 [134,135].
Type of infection — Sepsis due to nosocomial pathogens has a higher mortality than sepsis due to community-acquired pathogens [136,137]. Increased mortality is associated with bloodstream infections due to methicillin-resistant staphylococcus aureus (odds ratio [OR] 2.70, 95% CI 2.03-3.58), non-candidal fungus (OR 2.66, 95% CI 1.27-5.58), candida (OR 2.32, 95% CI 1.21-4.45), methicillin-sensitive staphylococcus aureus (OR 1.9, 95% CI 1.53-2.36), and pseudomonas (OR 1.6, 95% CI 1.04-2.47), as well as polymicrobial infections (OR 1.69, 95% CI 1.24-2.30) [136,138]. When bloodstream infections become severe (eg, septic shock), the outcome is similar regardless of whether the pathogens are Gram-negative or Gram-positive bacteria [64,139].
Antimicrobial therapy — Studies have shown that the early administration of appropriate antibiotic therapy (ie, antibiotics to which the pathogen is sensitive) has a beneficial impact on bacteremic sepsis [117,135]. In one report, 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 [117]. 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 [140]. 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. Empiric antibiotic regimens for patients with suspected sepsis are discussed separately. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Septic focus identification and source control'.)
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 [141]. A severely elevated lactate (>4 mmol/L) is associated with a poor prognosis in patients with sepsis with one study reporting a mortality of 78 percent in a population of critically ill patients, a third of whom had sepsis [77]. Restoration of perfusion is discussed in detail separately. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Initial resuscitative therapy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sepsis in children and adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient education: Sepsis in adults (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Sepsis is the consequence of a dysregulated inflammatory response to an infectious insult. Global rates of sepsis are as high as 437 per 100,000 person-years and sepsis appears to be responsible for 6 percent of US hospital admissions. Gram positive bacteria are the pathogens that are most commonly isolated from patients with sepsis. (See 'Introduction' above and 'Epidemiology' above.)
●Definitions – Sepsis exists on a continuum of severity ranging from infection (invasion of sterile tissue by organisms) and bacteremia (bacteria in the blood) to sepsis and septic shock, which can lead to multiple organ dysfunction syndrome (MODS) and death. A 2016 task force from the Society of Critical Care Medicine and European Society of Intensive Care Medicine (SCCM/ESICM) define sepsis and septic shock as the following (see 'Definitions' above):
•Sepsis – Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection; organ dysfunction is defined as an increase of two or more points in the sequential (sepsis-related) organ failure assessment (SOFA) score (calculator 3).
•Septic shock – Septic shock is defined as sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone; these abnormalities can be clinically identified as all of the following:
-Patients who fulfill the criteria for sepsis (above)
-Patients who, despite adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg
-Patients who have a lactate >2 mmol/L (>18 mg/dL)
However, clinicians should be aware that SCCM/ESICM definitions are not unanimously accepted. For example, the Center for Medicare and Medicaid Services (CMS) still continues to support the previous definition of systemic inflammatory response syndrome (SIRS (table 1)), sepsis, and severe sepsis.
●Risk factors – Risk factors for sepsis include intensive care unit (ICU) admission, a nosocomial infection, bacteremia, advanced age, immunosuppression, previous hospitalization (in particular hospitalization associated with infection), and community-acquired pneumonia. Genetic defects have also been identified that may increase susceptibility to specific classes of microorganisms. (See 'Risk factors' above.)
●Clinical presentation and diagnosis
•Patients with suspected or documented sepsis typically present with hypotension, tachycardia, fever, and leukocytosis. As severity worsens, signs of shock (eg, cool skin and cyanosis) and organ dysfunction develop (eg, oliguria, acute kidney injury, altered mental status) [29,35]. Importantly, the presentation is nonspecific such that many other conditions (eg, pancreatitis, acute respiratory distress syndrome) may present similarly. Presentations of common conditions associated with sepsis are in the table (table 2). (See 'Clinical presentation' above.)
•A constellation of clinical, laboratory, radiologic, physiologic, and microbiologic data is typically required for the diagnosis of sepsis and septic shock. The diagnosis is often made empirically at the bedside upon presentation, or retrospectively when follow-up data return or a response to antibiotics is evident. Importantly, the identification of a culprit organism, although preferred, is not always feasible since many patients have been partially treated with antibiotics before cultures are obtained. (See 'Diagnosis' above.)
●Prognosis – Sepsis has a high mortality rate that appears to be decreasing. Estimates range from 10 to 52 percent with rates increasing linearly according to the disease severity of sepsis. 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. 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 or late antibiotic coverage. (See 'Prognosis' above.)
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