Sepsis is a life-threatening condition in which the body's response to an infection damages its own tissues and organs. The immune system normally clears infection, but in sepsis its response becomes dysregulated, and the resulting organ dysfunction can progress to failure and death. Sepsis can follow infection by bacteria, viruses, or fungi, and it is a major contributor to deaths worldwide. Current international guidance cites roughly 49 million cases and 13 million sepsis-related deaths each year.
The condition matters because it is time-critical. Delayed recognition and treatment worsen outcomes, and many survivors carry physical, cognitive, and psychological impairments for years afterward. Its definition has changed several times since the mid-twentieth century, and the debate over how to define, detect, and treat it remains active. Clinical care is shaped by the infectious disease and critical care fields, by national and international guideline bodies, and by public health efforts to reduce incidence.
The entry traces the concept from its ancient origins and its modern definitions through the biology of the host response, the organisms and sources involved, risk and burden, recognition and diagnosis, septic shock, initial and ongoing treatment, antimicrobial stewardship, guideline development, long-term outcomes, prevention, and the questions that remain open.
Definition and terminology
The current international definition dates from the 2016 Third International Consensus Definitions (Sepsis-3). It holds that sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. The defining feature is therefore the damage done to organs by the body's own reaction, not the presence of the infection itself. A patient with a localized infection and no organ injury does not meet the definition, and host response that is proportionate and self-limiting does not count either.
For clinical use, the consensus turns organ dysfunction into a measurable quantity. Organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. The SOFA score grades six organ systems, on a scale of 0 to 4 depending on the degree of dysfunction using objective measurements. The original 2016 wording asked for an acute change from baseline, but subsequent validation studies have largely disregarded this requirement of an acute SOFA increase and often used an absolute score of 2 or more instead. This variation alters reported incidence, which is one reason the figures in the epidemiology section differ between studies.
The definition separates several related states that are often confused. Infection is the cause; sepsis is the organ-damaging response to it. Bacteremia, the presence of live bacteria in the bloodstream, can occur transiently after a dental procedure or a minor injury without any organ failure, and so it is not sepsis by itself. Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Septic shock is therefore a more severe category within sepsis, not a separate disease.
Etymology and the imprecision of lay terms
The word derives from ancient Greek. It comes from Ancient Greek σῆψις (sêpsis, "putrefaction"), from σήπω (sḗpō, "to make rotten"). Its English use as a medical term is much more recent. The English word, meaning "putrefaction, decomposition, rot," dates to 1876, from Modern Latin sepsis. The related adjective "septic" appeared around 1600, and the Greek origin of the word is discussed further in the historical section.
Lay expressions such as "blood poisoning" are imprecise for several reasons. Older dictionary definitions describe sepsis as a poisoned state caused by the absorption of pathogenic microorganisms and their products into the blood or other bodily tissue, which implies that a toxin in the blood is the main problem. Under the modern definition, the harm arises mainly from the host's dysregulated response, and bloodstream invasion is neither necessary nor sufficient. The older term "septicemia," introduced in French in 1837 and used in English from 1857, likewise centers on the blood, coined irregularly by French physician Pierre-Adolphe Piorry, and so it captures only part of the picture. For these reasons, clinicians and medical reference works generally use "sepsis" with the Sepsis-3 definition, and the term "blood poisoning" is best avoided in technical writing.
Historical development of the concept
The term descends from an ancient Greek word for rot, and early uses were descriptive rather than diagnostic. Some accounts identify Homer's epics as the earliest medical usage, where the word denoted putrefaction. Hippocrates, around 400 BC, described it as dangerous biological decay that he believed occurred in the colon and released substances causing "auto-intoxication". The core meaning of decay stayed in use for centuries. For much of the early modern period, the term still referred mainly to putrefaction, not to a disease with a defined cause.
That changed with the rise of microbiology. Louis Pasteur showed that single-celled organisms drove putrefaction, and he named them bacteria or microbes, correctly concluding that they were responsible for the formation of pus. This shift from rot to microbial cause is the conceptual link to the germ theory of disease. In 1837, French physician Pierre Piorry coined septicemia, a term for the presence of bacteria, fungi or viruses in the blood, which reflected the newer infection-centred view.
The first modern consensus definitions appeared in 1991. Systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock were initially defined by a consensus panel convened by the American College of Chest Physicians and the Society of Critical Care Medicine. In that framework, sepsis was SIRS due to infection, severe sepsis was sepsis with organ dysfunction, hypoperfusion, or hypotension, and septic shock was sepsis with hypotension persisting despite adequate fluid resuscitation. Some accounts date the first formal definition to 1992 rather than 1991, so the exact start of the SIRS-based framework varies by source.
The 2001 International Sepsis Definitions Conference kept this structure but changed its criteria. It retained sepsis as SIRS due to infection and severe sepsis as sepsis with acute organ dysfunction, but the SIRS criteria were greatly expanded and organ dysfunction variables were defined. The diagnostic requirement also loosened, from more than one of the original four signs to some item on the expanded list. Critics pointed out that because of high sensitivity and low specificity, Sepsis-1 was replaced by Sepsis-2 in 2001. The problem was that SIRS can accompany trauma, burns, surgery, or pancreatitis without any infection.
The 2016 Sepsis-3 definitions, proposed by a task force convened by national societies including the SCCM and the ESICM, abandoned SIRS as a diagnostic component and removed the term severe sepsis. The authors argued that SIRS lacks specificity, because it may also occur in noninfectious states such as trauma, burns, surgery, or pancreatitis. They also stated that sepsis is more complex than infection and inflammation, and that the host's response, including both proinflammatory and anti-inflammatory activity, is central. Despite the change, SIRS has not disappeared from practice. Many hospitals continue to use SIRS-based screening in emergency departments and on general medical floors because of its higher sensitivity.
The guideline movement began alongside these definitional debates. In 2002, the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, and the International Sepsis Forum launched the Surviving Sepsis Campaign. Its founding document, the Barcelona Declaration, set out a plan to inform the public and government agencies, develop guidelines, and reduce mortality in sepsis. The first guidelines followed in 2004, and they included 52 recommendations. These recommendations translated definitions into bedside practice. For example, they called for intravenous antibiotic therapy to start within the first hour of recognizing severe sepsis, after appropriate cultures were obtained. The campaign then turned guideline content into sepsis change bundles for initial resuscitation (6 hours) and management (24 hours), created as a performance improvement tool.
Later critics questioned how much of this rested on solid evidence. One critique stated that most of the recommendations of these guidelines are not evidence-based, and that the core recommendations were principally based on the results of a small, single-center study. The guidelines were subsequently revised in 2008 and 2012, with updates in 2008 and again in 2012 reflecting continual innovations in sepsis care.
Pathophysiology: the dysregulated host response
Sepsis begins with the immune system detecting an invading microorganism. Pattern-recognition receptors of the innate immune system bind conserved microbial molecules, such as bacterial lipopolysaccharide, flagellin and lipoteichoic acid, as well as viral nucleic acids. Damage-associated molecular patterns released from injured host cells activate the same receptors, which leads to an uncontrolled release of cytokines, activation of coagulation pathways, and cellular injury. The initial response is normally self-limiting. Sepsis occurs when its magnitude and timing go wrong, and its intensity and scope vary with the type, load and virulence of the pathogen, patient comorbidities, immune fitness, age, and nutritional status.
Hyperinflammation and immunoparalysis
The early phase involves inflammatory mediators, activation of complement and coagulation, and the release of alarmins by necrotic cell death. The older model held that an anti-inflammatory compensation phase followed the initial surge. Newer studies instead describe a subsequent immunoparalysis phase, and in many patients the two processes overlap from the onset. Hyper-inflammation and immunoparalysis can coexist from the onset of sepsis. Immunoparalysis is marked by cell depletion, apoptosis, and T-cell exhaustion, and by a diminished capacity to produce pro-inflammatory cytokines upon stimulation and reduced expression of cell-surface molecules such as HLA-DR. In practice, reduced HLA-DR on antigen-presenting cells means the immune system presents fewer antigens to the adaptive response. Blood counts reflect this shift: leukocytosis with marked increases in neutrophils and monocytes in the first 2–4 days is followed quickly by lymphopenia. Clinically, this state predisposes patients to persistent infection, secondary nosocomial infections, viral reactivation, impaired pathogen clearance, and prolonged organ failure.
Neutrophils, NETs and the "cytokine storm"
Neutrophils show a dual pattern. Early in sepsis, neutrophils originating from the bone marrow expand and include immature and delayed-apoptosis cells. Later, neutrophils continually present impaired chemotaxis and antibacterial capacity, reduced oxidative burst, decreased intracellular myeloperoxidase, and excessive neutrophil extracellular traps. Neutrophil extracellular traps (NETs) are web-like structures composed of decondensed DNA, histones, myeloperoxidase and other granule proteins that can ensnare bacteria in the circulation. When NET release is excessive, endothelial cells may shift toward a pro-inflammatory and pro-coagulant phenotype. Plasma levels of NET markers such as myeloperoxidase and citrullinated histone H3 rise with sepsis severity and are higher in patients who die, which makes them candidate biomarkers for NET-related harm.
The term "cytokine storm" describes the early, overwhelming release of cytokines that is proposed to cause fever, shock, respiratory failure, and early death due to multiple organ dysfunction. Its use is contested. Measured cytokine concentrations in many septic patients are modest, the concept is partly imported from the COVID-19 literature, where it was linked to a subgroup of patients with a cytokine storm syndrome, which seems to be responsible for multi-organ failure, and many patients show immunosuppression rather than uncontrolled inflammation. Current reviews increasingly treat hyperinflammation and suppression as parallel, time-dependent programs rather than as one storm.
Variability and the search for endotypes
Patients differ widely in their host responses because of genetic background, comorbidity, the causative organism, and the stage of illness at which they are assessed. This heterogeneity has motivated the search for sepsis endotypes that divide patients into groups with distinct immune profiles and outcomes. Candidate stratification markers include monocyte HLA-DR expression and lymphocyte counts, alongside PD-1/PD-L1, CD86 and IL-10. Single-cell studies suggest that immune low-response states lie along myeloid and lymphoid continua in which distinct regulatory circuits dominate across patients and time windows. Dysfunction of mitochondria within immune cells is one proposed contributor: monocytes and macrophages lose antigen-presenting capacity, neutrophils develop impaired migration and antimicrobial activity, and T cells acquire exhaustion-like phenotypes. Whether endotype-guided treatment will improve outcomes remains unresolved, because earlier immunomodulatory trials targeting a single mediator have largely failed.
Mechanisms of organ dysfunction
Endothelial injury and capillary leak
The endothelium, the single layer of cells lining the blood vessels, is among the first structures to fail. Across much of the vascular bed, microbial products and host-derived signals weaken these lining cells, so water and plasma proteins pass into the surrounding tissue 2-8. This leak is an active process. Intracellular stress signalling makes the actin cytoskeleton contract and the junctions between endothelial cells loosen, opening gaps through which plasma seeps out 5-1,5-2. The endothelial glycocalyx, a carbohydrate-rich coat on the luminal surface, is also stripped during sepsis. Enzymes such as heparanase-1 and matrix metalloproteinases remove its components, and their plasma concentrations rise with disease severity 8-2,8-6.
As plasma leaves the circulation, the remaining blood becomes more viscous and moves more slowly, which lowers hydrostatic pressure and reduces perfusion of downstream tissue 4-1,4-2. Hypotension that persists despite fluid replacement arises when leakage occurs alongside unchecked vasodilation 3-2. Clinically, the combination appears as edema, low serum albumin, hypotension, and hemoconcentration, the picture of capillary leak.
Microvascular thrombosis and disseminated intravascular coagulation
Disturbances of hemostasis are nearly universal in sepsis, ranging from isolated thrombocytopenia to overt consumptive coagulopathy in which platelets and clotting proteins are used up 13-1. The mechanism involves coagulation being switched on while fibrinolysis is suppressed and natural anticoagulants are depleted, so fibrin accumulates in the microcirculation and contributes to organ dysfunction 17-2,17-3,17-4. This process is classified as disseminated intravascular coagulation (DIC) when it becomes overt.
Current models describe the process as thromboinflammation, in which activated neutrophils interact with platelets and injured endothelium while clotting and clot breakdown fall out of balance 14-4. Clots lodged in small vessels choke off perfusion to downstream tissue 14-3. In DIC, these microthrombi tend to lodge in postcapillary venules, whereas in related thrombotic microangiopathies they form mainly in arterioles 18-3.
Cellular oxygen use and mitochondrial dysfunction
Oxygen delivery may look adequate while cells still cannot use the oxygen they receive. Fink introduced the term cytopathic hypoxia for this state, in which cells fail to make enough ATP despite sufficient molecular oxygen 19-9. Within the cell, mitochondria are the main site of this failure. Inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium imbalance, and metabolic stress all act on mitochondria 22-3. Energy stores fall, membrane potential is lost, and reactive oxygen and nitrogen species are produced in excess 22-5.
Whether mitochondrial failure drives organ damage or instead follows from poor tissue oxygenation remains unresolved 21-12. In one prospective ICU cohort that measured mitochondrial oxygen tension non-invasively, values were lower in the acute phase and had returned to control levels by six months, suggesting that much of the restriction is reversible 21-10,21-5.
Organ-specific injury
The kidney is one of the organs most often affected. Sepsis-associated acute kidney injury closely tracks the severity of sepsis and follows the same microthrombotic and inflammatory routes 14-5. In the lungs, damage to the alveolar-capillary barrier produces acute respiratory distress syndrome, in which protein-rich fluid fills the air spaces and impairs gas exchange. Hepatic involvement is frequent and worsens prognosis 23-3. In the brain, sepsis-associated encephalopathy ranges from delirium to coma and can occur without direct invasion of the central nervous system by microbes. After prolonged critical illness, some patients develop ICU-acquired weakness, a neuromuscular impairment in which limb muscle and nerve function decline.
Causative pathogens and sources of infection
Bacterial agents
Bacteria are the most common cause of sepsis. Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes are among the leading causes, and they also account for the largest number of deaths attributable to bloodstream infection. Among the leading causative agents of sepsis are bacterial pathogens such as those named above, along with fungal pathogens of the Candida species. Bacterial pathogens lead cases of bloodstream infections. Gram-negative and gram-positive organisms both matter, and their relative importance has shifted over time. Early descriptions of sepsis were linked to gram-negative bacteria because the condition was thought to be a response to endotoxin, a molecule considered fairly specific to those organisms. In the United States, gram-positive organisms overtook gram-negative ones as the most common cause of sepsis in the early to mid-1980s.
The distribution also depends on the site of infection. In a nationwide prospective cohort from Japan, the most common pathogen was Escherichia coli (21.5%), followed by Klebsiella pneumoniae (9.0%). Gram-positive bacteria were the dominant pathogen in bone and soft tissue infection and in cardiovascular infection, but were rarely identified in urinary tract infection. Gram-negative bacteria were the predominant pathogens in abdominal infection and urinary tract infection. The same cohort found that the highest mortality, 47.5%, was observed in patients infected with methicillin-resistant Staphylococcus aureus, a finding that links the organism to resistance and to poor outcome.
Fungal and viral agents
Fungal sepsis is less common but clinically important. Candida species are the most frequent fungal pathogens in the critical care setting, with a strong association with hospital-acquired infection. Estimates of the fungal share of sepsis vary widely. One account puts fungi at about 5% of all cases of severe sepsis, although the incidence of fungal infections is increasing, while another suggests ~20% of sepsis is caused by fungi. Fungal sepsis is also associated with high mortality, with one estimate ranging from 40-60%.
Viral sepsis is recognized but less frequently identified. Viruses are less frequently regarded as the cause of sepsis and are often deemed as facilitators to infection by secondary agents. The viruses considered causes of sepsis include Herpes simplex virus, Enterovirus, Influenza, Adenovirus, Dengue virus, and recently the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Sources of infection
Sepsis usually arises from a localized infection that spreads into the bloodstream. Common sites include the lungs, urinary tract, skin, and abdomen, for example appendicitis, or other parts of the body. Infections of the skin and soft tissue are particularly relevant in people with diabetes or lymphedema, because the edematous tissue or poor circulation provides a favorable environment for opportunistic pathogens, and such infections may result in severe cellulitis or related sequelae that lead to sepsis.
Device-related sources are a major route in hospitals. Some of these infections can be acquired in a hospital setting and can result from certain types of surgery, such as abdominal procedures, immune suppression due to cancer or transplantation therapy, immune deficiency diseases, and exposure through intravenous catheters. Catheter-related bloodstream infection therefore represents a characteristic hospital-acquired form.
Culture-negative and polymicrobial cases
A substantial share of cases involve more than one organism. In the Japanese cohort, 1352 causative pathogens were identified in 928 patients, and a polymicrobial infection with two or more causative pathogens was present in 200 patients. Many cases remain culture-negative. Documenting the pathogenic microorganisms clinically significant to sepsis has proven difficult, and causative microorganisms are typically detected by culturing blood, sputum, urine, wound secretions, or catheter surfaces. Sepsis can also be triggered by toxins even when no identifiable bacteria are present, which is one reason that a negative culture does not exclude sepsis.
Community-acquired and hospital-acquired sepsis
The organisms and sources differ between community-onset and hospital-onset cases. Community-onset sepsis is most often associated with pneumonia, urinary, and abdominal infections, where gram-negative organisms predominate in the Japanese data. Hospital-acquired sepsis is more often linked to devices, surgery, and immunosuppression, and fungal infections are concentrated in this group. This may represent a general increase in nosocomial (hospital-acquired) cases of sepsis, or it may reflect effective treatment of bacterial infections, which allowed fungal infections to grow without competition. The bloodstream isolates in one review were led by coagulase-negative Staphylococcus, followed by Klebsiella pneumoniae, and Staphylococcus aureus.
Risk factors and vulnerable populations
Sepsis can arise in anyone who develops an infection, but it is far more likely in people whose immune defenses or physiological reserve are limited. A 2020s meta-analysis of risk factors in hospitalized patients found that age, comorbidities, and clinical severity indicators were consistently associated with higher sepsis incidence.
The two ends of the age range carry the greatest vulnerability, for different reasons. In neonates, immune function is immature: neutrophil activity is impaired, complement activity is low, and bacteria are poorly opsonized, so infections can spread quickly. In the BARNARDS birth cohort across seven low- and middle-income countries, most laboratory-confirmed cases appeared within the first three days of life, and preterm birth, perinatal asphyxia, and multiple births were among the associated factors. In older adults, the baseline is immunosenescence, a gradual decline of immune function that reduces output of naive T cells and B cells, slows the migration of neutrophils to sites of infection, and coexists with chronic low-grade inflammation. Advanced age (60 years or older) was associated with higher sepsis odds in the same meta-analysis. Much of the worse outcome in older patients is attributed to accumulated comorbidity and frailty rather than to chronological age alone, a distinction that bears on decisions about intensive care.
Immunocompromised patients form a second high-risk group. Those receiving chemotherapy, living with HIV, recovering from transplantation, or taking long-term corticosteroids are more susceptible to infection and to its progression to sepsis. Their infections often originate from catheters, from translocation of gut bacteria, or from opportunistic fungal and viral pathogens. Immunosuppression is not a single state: inherited immunodeficiencies, medications, and comorbidities each impair different components of host defense. Chronic conditions add to this burden. Diabetes, cancer, chronic obstructive pulmonary disease, and kidney disease were all consistently linked to sepsis risk in the meta-analysis, and malnutrition, which weakens immune function, is a further contributor, particularly in older adults.
Medical interventions are a major and modifiable source of risk. Invasive devices such as endotracheal tubes, urinary catheters, and central venous catheters were associated with healthcare-associated infection and sepsis in pediatric intensive care cohorts, with endotracheal tubes carrying the highest hazard in one analysis. Major surgery produces a similar exposure: postoperative sepsis is a common complication in surgical intensive care patients, and surgical stress, prolonged intubation, poor nutrition, and indwelling catheters have all been identified as contributors. Patients receiving mechanical circulatory support showed a sepsis incidence of about 20% in one cohort, with prior heart failure and previous cardiac surgery linked to higher risk. Extended intensive care stays compound these exposures.
Social and structural factors shape who is most affected. Low- and middle-income countries account for nearly all neonatal deaths, and neonatal sepsis is among the leading causes of those deaths there, with recent estimates of roughly 3 million cases and 570,000 neonatal deaths a year. Single-site data illustrate the gradient: in a Ghanaian teaching hospital, the recorded prevalence of neonatal sepsis was about 71% among neonates of mothers younger than 20 and about 52% among those of mothers aged 30 or older, and about 68% when mothers had no formal education compared with about 38% for those with tertiary education. Limited access to clean birth practices, chlorhexidine cord care, and timely antenatal and facility-based obstetric services leaves these risks largely unaddressed. Pregnancy itself raises the risk of maternal sepsis, which is one reason that obstetric care capacity is central to prevention in public health planning.
Epidemiology and global burden
Estimates of sepsis burden are mostly modelled rather than counted directly. Sepsis is not a standalone category in standard Global Burden of Disease (GBD) estimates, so the 2020 GBD analysis instead used the underlying infections as the starting point, calculated sepsis-specific case-fatality rates from hospital records, and back-calculated incidence from death counts.They modelled sepsis case-fatality rates from hospital discharge records for each of the underlying causes and used these case-fatality rates as divisors to calculate sepsis incidence from death counts. Its estimate for 2017 was about 48.9 million cases and 11.0 million sepsis-related deaths, which corresponded to roughly one death in five worldwide.An estimated 48·9 million incident cases of sepsis were recorded worldwide and 11·0 million sepsis-related deaths were reported, representing 19·7% The WHO similarly places sepsis at about 20% of all global deaths.
Over the period 1990–2017, the same analysis found a decline. Estimated cases fell from 60.2 million in 1990 to 48.9 million in 2017, and deaths fell by 30% to 11.0 million.In 1990, there were an estimated 60.2 million sepsis cases and 15.7 million deaths; by 2017, incidence had dropped by 19% to 48.9 million cases and deaths by 30% to 11.0 million. The study's authors described these rates as improving, while noting that sepsis remained a major cause of health loss. The burden is also very unevenly distributed. Approximately 85% of sepsis-related deaths occurred in low- and middle-income countries (LMICs),with approximately 85% of all sepsis-related deaths in LMICs. Age-standardized incidence was highest in sub-Saharan Africa, Oceania and South Asia.Sepsis has an age-standardized incidence rate of 677.5 cases per 100,000 people worldwide, with sub-Saharan Africa, Oceania, and South Asia having the highest rates
Children carry a disproportionate share of the burden. Almost half (20 million) of all estimated sepsis cases worldwide occurred in children under 5 years of age. The neonatal component is especially concentrated in LMICs, where nearly all newborn deaths occur. One GBD 2016/2017-based estimate put neonatal sepsis at 1.3 (95% CI 0.8 to 2.3) million annual incident cases of neonatal sepsis worldwide, resulting in 203 000 (95% CI 178 700 to 267 100) sepsis-attributable deaths. Prospective cohort data from seven LMICs illustrate the scale of the problem at the facility level. In the BARNARDS study, the incidence of clinically suspected neonatal sepsis was 166.0 per 1000 livebirths, and laboratory-confirmed sepsis was 46.9 per 1000 livebirths.The incidence of clinically suspected sepsis was 166·0 (95% CI 97·69–234·24) per 1000 livebirths, laboratory-confirmed sepsis was 46·9 (19·04–74·79) per 1000 livebirths Maternal sepsis, which arises from infections acquired during pregnancy, childbirth or the postpartum period, is also one of the most common causes of maternal mortality in LMICs
Germany offers a well-documented national example, although the figures depend heavily on the method used. A 2026 review states that in Germany, approximately 279,000 patients develop sepsis annually, with reported in-hospital mortality approaching 40%, depending on data source and case mix. This case count matches nationwide hospital DRG statistics for 2013, when the figure was 279,530 cases and in-hospital mortality was 24.3%. Over 2007–2013, DRG-based counts had risen from 200,535 cases, and the share of patients with severe sepsis increased from 27% to 41%.The number of cases of sepsis rose by an average of 5.7% per year, from 200 535 in 2007 to 279 530 in 2013, corresponding to an increase in the adjusted in-hospital incidence from 256 to 335 cases per 100 000 persons per year. Chart-review data from ten German hospitals yield much higher numbers: current estimates of more than 500,000 sepsis cases annually and more than 140,000 sepsis-related deaths are based on chart review information from a sample of 10,334 inpatient cases aged ≥ 15 years treated during 2015–2017 in ten German hospitals
Reported figures vary for several reasons. The first is case definition. Before the GBD analysis, the most recent global estimate was 19.4 million cases and 5.3 million deaths, based on hospitalized adults in seven high-income countries; the authors of the newer work noted that the older figures were at least half the true level, mainly because the new analysis included LMIC data."These estimates are at least double the figures we had previously assumed, likely because this study included data from low- and middle-income countries," The second is coding. Hospital statistics based on microbiological sepsis codes considerably underestimate the incidence derived from clinical sepsis codes. The third is case mix and setting. The German DRG data, for instance, were limited to ICU and severe cases in one earlier analysis, so cases without organ dysfunction on regular wards were largely unrecorded. Population factors also shape the curves: incidence peaked overall in early childhood, and again, among older adults. In-hospital mortality in German data also rose nearly linearly with age from age 40 onward. Finally, hospital-acquired infection contributes substantially, as for every 1000 hospitalized patients, an estimated 15 patients will develop sepsis as a complication of receiving health care.
Clinical presentation and bedside recognition
Early sepsis is hard to recognize because its first signs are nonspecific. Fever or hypothermia, tachycardia, tachypnea, altered mental status, mottled skin, and falling urine output also occur in many other acute illnesses. Bedside suspicion therefore rests on combining these findings with a suspected or documented infection and with evidence that organs are failing.
The SOFA score
The Sepsis-3 operational criterion is built on the Sequential Organ Failure Assessment (SOFA) score, which grades six organ systems from 0 to 4 and sums the results. The systems are respiratory (PaO₂/FiO₂ ratio), coagulation (platelet count), liver (bilirubin), cardiovascular (mean arterial pressure or vasopressor dose), central nervous system (Glasgow Coma Scale), and renal (creatinine or urine output). Each system is scored independently and the six are summed; there is no weighting between systems. A rise of 2 or more points from baseline is taken as organ dysfunction. The baseline score is assumed to be zero unless the patient already had known preexisting organ dysfunction before the infection began.
Several practical limits apply. The task force did not intend SOFA as a tool for managing individual patients, but as a way to characterize septic patients. Several components depend on laboratory tests, so they can lag behind a patient's deterioration, and the cardiovascular component can be shifted by treatment itself. Because arterial blood gas, coagulation, and chemistry values are usually drawn in intensive care, SOFA is mainly an ICU tool rather than a ward screen.
The qSOFA prompt
To provide a bedside alternative, the task force proposed qSOFA, which scores respiratory rate of 22/min or more, altered mentation, and systolic blood pressure of 100 mm Hg or less. Adults with suspected infection who meet at least 2 of these criteria are more likely to have poor outcomes typical of sepsis. Its intended use was to flag patients at risk of a prolonged ICU stay or in-hospital death, which the task force linked to a mortality risk above 10%.
Its sensitivity as a stand-alone screen is poor. In a meta-analysis, the pooled sensitivity for predicting a sepsis diagnosis was 65% for early warning scores, similar to 70% for SIRS ≥2, and higher than 37% for qSOFA ≥2. Emergency department data show a similar pattern, and the 2021 Surviving Sepsis Campaign guidelines recommended against using qSOFA as a single screening tool for sepsis. Triage-based scoring performs worse still. In one cohort, the triage version identified a remarkably low percentage (17.9%) of patients who went on to meet sepsis criteria, require admission, and more often than not need ICU-level care.
SIRS and early warning scores in practice
The SIRS criteria were removed from the Sepsis-3 definition, but they remain widespread in clinical workflows. Hospital sepsis alerts are often built using SIRS criteria, although the white blood cell count criterion is subject to a laboratory lag that can delay identification. SIRS uses respiratory rate, heart rate, temperature, and white cell count, and is scored as positive when at least two of four criteria are met.
Early warning scores such as NEWS, NEWS2, and MEWS rely mainly on vital signs and level of consciousness. In the United Kingdom, the National Early Warning Score is the most common screening method, while in the United States SIRS is commonly applied for sepsis and the Modified Early Warning Score for general deterioration. The 2024 meta-analysis found that early warning scores had similar or superior diagnostic accuracy to SIRS or qSOFA in predicting sepsis diagnosis and in-hospital mortality, which calls into question the value of SIRS or qSOFA where early warning scores are already in use. Some hospitals instead combine tools. In one study, combining SIRS criteria with the Modified Early Warning Score captured three times more sepsis diagnoses while triggering 46% fewer false-positive alerts. Current guidance also treats these scores as aids to be used together with additional tools such as lactate measurement.
Diagnosis and laboratory assessment
Sepsis is a clinical diagnosis and should not be ruled in or ruled out using a single biomarker or diagnostic test. Laboratory results therefore support bedside judgment and do not replace it. The main tests are blood cultures, serum lactate, inflammatory biomarkers, rapid pathogen identification, and, increasingly, computational early-warning tools.
Blood cultures
Blood cultures are the central microbiological test. The 2026 Surviving Sepsis Campaign guideline recommends collecting blood cultures as soon as possible and ideally before the administration of antimicrobial therapy, a strong recommendation resting on low-certainty evidence. Practice documents generally call for two culture sets, each comprising 4 bottles (2 aerobic and 2 anaerobic), with a total blood volume of approximately 30 to 40 mL. Collection should not delay treatment: cultures are taken early unless collection would delay antibiotic administration.
The limits of culture yield are substantial. The guideline panel notes that a pathogen is identified in approximately 60–70% of patients with sepsis, although blood cultures are positive in only approximately 10–20% of patients, which means that many infections are documented from other sites or not microbiologically confirmed at all. Yield depends on the pretest probability of bacteremia, number of sets collected, the blood volume collected, the use of anaerobic bottles, and prior antibiotic use. Cultures drawn after treatment has begun tend to grow fewer organisms, and they have been associated with higher costs and longer hospital stays.
Serum lactate
Lactate has a defined role in the septic shock definition. Under Sepsis-3, patients with septic shock can be identified with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and a serum lactate level >2 mmol/L (18 mg/dL) despite adequate volume resuscitation. Lactate rises through tissue hypoxia, aerobic glycolysis, or decreased clearance (e.g., hepatic dysfunction). Because the liver is the major organ responsible for lactate elimination, impaired liver function can raise values independently of tissue perfusion. Lactate is also non-specific: it may be elevated by a panoply of serious conditions (including any shock state, physiologic stress, beta-agonists, seizures, or hepatic dysfunction). For prognosis, a lactate level greater than 4 mmol/L is an independent predictor of septic shock mortality in Surviving Sepsis Campaign database analyses, while one cohort found that the lactate criterion added substantial mortality risk mainly above 6 mmol/L. The Sepsis-3 task force advised against using lactate to judge therapeutic response or illness severity.
Biomarkers
Procalcitonin (PCT) and C-reactive protein (CRP) are widely measured but only moderately discriminating. In a systematic review and meta-analysis, the overall area under the summary ROC curve for procalcitonin was 0.85, with a sensitivity and specificity of 0.80 and 0.77, whereas for CRP the area was 0.73 and specificity 0.61. The authors summarized the value as a moderate degree of value of PCT and CRP for the diagnosis of sepsis in adult patients. PCT rises sharply within 2–4 h after exposure to bacterial endotoxin, reaches a plateau within 6–8 h, and returns to normal after 24 h. CRP has poorer specificity because in the absence of systemic infection, CRP may be elevated in various prenatal circumstances such as fetal distress, stress delivery, and maternal fever. Neither marker reliably separates sepsis from non-infectious systemic inflammation, and the 2021 Surviving Sepsis Campaign guidelines even discouraged the use of PCT to assist in the diagnosis and initial management of sepsis.
Rapid pathogen identification and resistance testing
Molecular methods, including multiplex nucleic acid amplification panels run directly on positive blood culture bottles, can identify common bacteria and detect resistance determinants such as the mecA gene in Staphylococcus aureus or carbapenemase genes in Enterobacterales. Rapid phenotypic susceptibility methods work in a similar time frame. These tools aim to shorten the interval from sampling to targeted therapy, which is the period when patients are most likely to receive ineffective empirical treatment. The benefit for patient-level outcomes is less consistent across studies than the benefit for turnaround time, and results depend on the local laboratory workflow and the ability to act on them. The 2026 guideline recommends de-escalation of antimicrobial therapy over no de-escalation when a confirmed microbiological diagnosis and susceptibility profile is available, which is where rapid results have the most direct clinical use.
Machine learning and artificial intelligence early-warning systems
Machine learning and artificial intelligence models trained on electronic health record data, such as vital signs, laboratory values, and nursing observations, can flag patients who are deteriorating before clinicians recognize sepsis. Their appeal lies in identifying high-risk patients earlier than rule-based screens. Concerns center on several points. Models often perform well in the hospital where they were developed but lose accuracy elsewhere, so external validation across different populations and documentation practices is essential. Training labels are frequently derived from coded diagnoses or retrospective criteria, which may not match clinical definitions. High rates of false alerts can produce alert fatigue, leading staff to ignore warnings, and an alert that is ignored offers no benefit.
Septic shock
Septic shock is the most severe subset of sepsis. The Sepsis-3 task force describes it as a condition in which circulatory, cellular and metabolic disturbances are profound enough to carry a higher risk of death than sepsis alone (Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone.).
The clinical definition has two components. A patient must still need a vasopressor to keep mean arterial pressure at 65 mmHg or higher, and serum lactate must stay above 2 mmol/L after adequate volume resuscitation (Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level >2 mmol/L (18mg/dL) despite adequate volume resuscitation.). The lactate threshold is a practical cut-point rather than a biological boundary. In one ICU cohort, lactate threshold of 2 mmol/L may be too low to point out patients with actual increased ICU mortality. The stricter Sepsis-3 criteria also changed how many patients were classified: in a cohort of 632 septic patients, 482 (76.3%) had septic shock according to Sepsis-2 and 300 patients (48.4%) according to Sepsis-3 definition, and the Sepsis-3 group had a higher ICU mortality (38.9 vs. 34.0%).
Mortality is the main reason for separating septic shock from sepsis. Sepsis-3 reports that this combination is associated with hospital mortality rates greater than 40%. Other summaries give a wider range, noting that overall mortality is roughly 25 to 30% in sepsis and approximately 40 to 60% in septic shock, with a wide range depending on patient characteristics. The figures differ by population, period and data source.
Mechanisms of shock physiology
Septic shock combines three processes. The first is vasoplegia. Inflammatory mediators produce widespread vasodilation, and excess nitric oxide production by inducible nitric oxide synthase is a major contributor. Blood pressure falls even when the circulating volume is adequate, which is why vasopressors are needed. The second is myocardial depression. Inflammatory signals reduce the contractility of the heart, so stroke volume and cardiac output can fall. The third is capillary leak. Endothelial injury lets fluid and protein move from the vascular space into tissues, so the effective intravascular volume shrinks. This explains why additional fluid helps some patients but becomes less effective as leak accumulates.
Lactate reflects these disturbances but does not measure tissue oxygen alone. The lactate level being a crude surrogate for cellular and metabolic abnormalities is the basis for its inclusion in the definition. In sepsis, the inflammatory response appears to be associated with an increase in glycolysis and impaired pyruvate dehydrogenase activity. Lactate can therefore rise even in the presence of adequate tissue oxygenation, which points to impaired use of oxygen by mitochondria rather than to oxygen delivery alone.
Distinguishing septic shock from other shock states
Because hypotension has many causes, septic shock is diagnosed only after other forms of shock are considered. Cardiogenic shock results from pump failure, with low cardiac output and usually high systemic vascular resistance and elevated filling pressures. Hypovolemic shock results from blood or fluid loss, with a small, underfilled circulation. Septic shock may coexist with either. Early septic shock often shows vasodilation with preserved or high cardiac output, but myocardial depression can lower output, and a patient may be both vasodilated and underfilled, or vasodilated and fluid-overloaded.
Bedside ultrasound is used to sort these possibilities. Echocardiography assesses left and right ventricular function and can detect pericardial effusion or tamponade. Measurement of the inferior vena cava and lung ultrasound help estimate volume status and identify pulmonary congestion. Hemodynamic monitoring adds cardiac output estimates, measures of fluid responsiveness and titration of vasopressors and fluids to optimize central venous oxygen saturation and preload, and to lower serum lactate levels. Because the patient's state can change within hours, these assessments are repeated rather than performed once.
Time-critical initial management
Early sepsis care is organized around an "hour-one" bundle. The Surviving Sepsis Campaign (SSC) developed the one-hour bundle in 2018, after the three-hour window was associated with a significant increase of in-hospital mortality. The revision folded earlier three-hour and six-hour bundles into a single hour-1 bundle, with the purpose of starting interventions as quickly as possible. The steps run from lactate measurement and blood cultures drawn before antibiotics, through broad-spectrum antibiotics and fluid boluses, to vasopressors for hypotension that persists after fluid.
The bundle descends from early goal-directed therapy (EGDT), a six-hour protocol that adjusted fluids, vasopressors, inotropes and red cell transfusions to reach targets for blood pressure, central venous pressure, central venous oxygen saturation and hemoglobin. EGDT was found to reduce hospital mortality from 46.5 to 30.5%, prompting its adoption by many institutions worldwide. That result came from a single-center study, and the effect was not confirmed when the approach was tested in larger settings.
Three large randomized trials addressed this question: ProCESS in the United States, ARISE in Australasia and ProMISe in England. From March 2008 through July 2014, the three trials enrolled 4211 patients at 138 hospitals. Their control-group mortality was lower than the investigators had anticipated, and they failed to show that EGDT reduced mortality to a greater extent than usual care, although no harm was associated with the intervention strategies. Subsequent guidance has therefore moved away from rigid protocols. The 2026 SSC update is read as a shift from a fixed protocolization standard towards precision-focused care, and its authors describe management that is individualized to physiology rather than driven by fixed targets.
Antibiotic timing is now stratified by diagnostic certainty. The 2026 guideline recommends that for adults with possible, probable, or definite septic shock, antimicrobial therapy be administered immediately, ideally within 1 hr of recognition. For probable or definite sepsis without shock, the same immediacy is advised. Commentators differ on the window for possible sepsis without shock: one summary describes a stricter time frame of within 3 h for possible sepsis without shock, while another notes that antibiotics are recommended only within one hour for patients in shock and that, for low-likelihood patients without shock, deferring antimicrobial therapy while continuing to closely monitor the patient is suggested. Critics worry that rigid timeframes could disrupt workflows and paradoxically increase inappropriate broad-spectrum antibiotic use.
Fluid resuscitation remains contested in its dosing. For adults with sepsis-induced hypoperfusion or septic shock, the guideline suggests administering at least 30 mL/kg of IV crystalloid in the first 3 hr. The recommendation is conditional and rests on low certainty evidence, and clinicians are asked to consider individual characteristics and to reassess frequently. Reassessment often relies on dynamic measures; preferably using dynamic measures such as passive leg raise is one example. Balanced crystalloids are suggested over 0.9% saline for most adults. Repeated lactate values are used to steer resuscitation, but fluid administration should be individualized after initial fluid bolus and monitoring of lactate decrement, rather than continuing fluids until lactate normalization is achieved. For vasopressors, norepinephrine remains first line, and it can be started through a peripheral line. Vasopressors are generally added after fluid if hypotension persists, although immediate concurrent administration of vasopressors together with IV crystalloid fluid may be warranted on a case-by-case basis in unstable shock.
Source control runs in parallel with antibiotics and resuscitation. It includes draining an abscess or other collection, removing an infected central venous catheter, and operating on a perforation or necrotic tissue that antibiotics cannot reach effectively. Timing is decided case by case, balancing the urgency of removing the source against the patient's physiological stability and the risks of surgery during shock.
Ongoing organ support and adjunctive therapies
After initial resuscitation, care shifts to sustaining perfusion and supporting failing organs. Vasopressors are the central tool. The 2021 Surviving Sepsis Campaign (SSC) guidelines gave a strong recommendation for norepinephrine as the first-line agent over dopamine, epinephrine and selepressin. The 2026 update still prefers norepinephrine over vasopressin or angiotensin II, but with lower certainty of evidence. For septic shock with concomitant cardiac dysfunction, it allows either norepinephrine or epinephrine as first line. When norepinephrine doses keep climbing, the 2021 guidance favored adding vasopressin rather than escalating norepinephrine further, and the 2026 update suggests the same with moderate certainty. If mean arterial pressure (MAP) remains inadequate on both agents, epinephrine may be added.
The usual MAP target of 65 mmHg has been questioned, particularly in older adults. A large trial (SEPSIS-PAM) comparing 65–70 mmHg with 80–85 mmHg found no difference in mortality, although patients with chronic hypertension in the higher-target group needed renal replacement therapy less often. The OPTPRESS trial in Japan, which enrolled patients aged 65 and older, was stopped early for harm: 90-day mortality was 39.3% with the higher target and 28.6% with the control target. A lower-target trial in older patients did not link reduced vasopressor exposure with higher mortality. The 2026 guideline suggests an initial MAP range of 60–65 mmHg in septic shock patients aged 65 and older rather than higher ranges. Observational analyses in older patients have proposed somewhat higher optimal ranges, so the question remains open.
Corticosteroids are used in patients who still need vasopressors. The 2021 guidelines suggested intravenous corticosteroids for ongoing vasopressor requirement, with hydrocortisone at 200 mg per day, given as 50 mg every six hours or as a continuous infusion, as the typical regimen. The 2026 update suggests intravenous corticosteroids for adults with septic shock more broadly. The evidence rests mainly on trials such as ADRENAL and APROCCHSS, which reported differing mortality results, and the benefit of adding fludrocortisone is uncertain. Mechanical ventilation for sepsis-associated acute respiratory failure follows lung-protective principles: low tidal volumes based on predicted body weight (about 6 mL/kg), limits on plateau pressure, and avoidance of excessive oxygen, with oxygen targets set to avoid both hypoxemia and hyperoxia.
Renal replacement therapy (RRT) timing remains contested. In the IDEAL-ICU trial of patients with septic shock and severe acute kidney injury, 90-day mortality was 58% with early initiation and 54% with delayed initiation, a difference that was not significant; 38% of the delayed group never required RRT. A 2026 systematic review found that early RRT in sepsis-associated acute kidney injury was linked to lower 28-day mortality, but this advantage disappeared at 90 days and did not change multi-organ dysfunction scores. A 2026 retrospective cohort analysis from the MIMIC-IV database, by contrast, associated early continuous RRT with higher 60-day mortality. Once shock has resolved, cumulative positive fluid balance is generally considered harmful, so clinicians often try to remove excess fluid with diuretics or ultrafiltration; trials of deliberately restrictive fluid strategies have produced mixed results.
Several adjunctive treatments have been tested without clear benefit. High-dose intravenous vitamin C was studied in small trials and in the larger LOVIT trial, none of which showed a clear improvement in outcomes. Albumin has moved from a conditional suggestion in 2021, for patients who had received large volumes of crystalloid, toward a more restrictive position in 2026. The 2026 guideline suggests crystalloids alone over crystalloids supplemented with albumin, with moderate certainty of evidence. Albumin may still be appropriate for patients who have already received large crystalloid volumes or who have cirrhosis, and it should be avoided in traumatic brain injury.
Antimicrobial stewardship and resistance
Because the causative organism is rarely known at the bedside, treatment of sepsis starts with empirical, broad-spectrum antibiotics chosen to cover the most likely bacterial pathogens and the suspected source. The next step is narrowing the regimen as microbiological results return. The 2026 Surviving Sepsis Campaign guideline makes this explicit: when a confirmed organism and its susceptibility profile are known, it recommends de-escalation rather than continuing the original broad regimen, although the certainty of evidence is very low.For adults with sepsis or septic shock, we "recommend" de-escalation of antimicrobial therapy over no de-escalation when a confirmed microbiological diagnosis and susceptibility profile is available. Certainty of evidence: Very low Narrowing therapy is therefore one of the few stewardship steps the guideline ranks among its strong recommendations, and it is framed as complementary to early treatment rather than a reason to delay it.Critics have argued that rapid antibiotic delivery leads to overprescription and rising resistance, but studies have not found evidence of overtreatment when clinicians give antibiotics more quickly.
The central pressure on empirical prescribing is antimicrobial resistance. Broad-spectrum empirical use is considered a possible driver of resistance in sepsis, and resistant infections are harder to treat, prolong hospital stays and add to morbidity, mortality and economic cost.Antimicrobial resistance may increase due to the use of broad-spectrum antibiotics as empirical therapy in patients with sepsis or septic shock. Resistance leads to difficult-to-treat infections, longer hospital stays, increased morbidity and mortality, and has an impact on the global economy. Methicillin-resistant Staphylococcus aureus (MRSA) illustrates the dilemma: because it resists beta-lactams, clinicians must decide case by case whether local prevalence and patient risk justify adding agents from other classes. Carbapenem-resistant Enterobacterales (CRE) show the same tension more sharply. In one cohort of 1,190 sepsis episodes, CRE infection was associated with higher 30-day mortality than that of patients with other infections (63.8% versus 33.4%), and patients with CRE were much less likely to receive active empirical therapy, at 13.0% versus 49.8%.A lower rate of appropriate empirical therapy was administered to patients with CRE infections than to patients with other identified pathogens: 9 (13.0%) of 69 total versus 250 (49.8%) of 502 A later bacteremia study attributed most of the excess mortality to illness severity and inappropriate initial therapy rather than to carbapenem resistance itself, and reported that early appropriate therapy improved survival regardless of resistance profile.Mortality was driven primarily by illness severity and inappropriate empirical antimicrobial therapy rather than carbapenem resistance itself. Early appropriate empirical therapy independently improved survival regardless of resistance profile.
The 2026 guideline also narrows empirical coverage in other directions. It suggests against empirical antifungal therapy for adults with sepsis or septic shock, a conditional recommendation resting on low-certainty evidence.The guidelines now suggest against using empirical antifungal therapy in patients with sepsis or septic shock (conditional recommendation, low-certainty evidence) The advice is not absolute: antifungal coverage remains a case-by-case decision in patients with fungal risk factors, including immunosuppression, prolonged antibiotic exposure, prolonged hospitalization and intra-abdominal sources.Empiric antifungal therapy should be considered on a case-by-case basis in selected patients with sepsis or septic shock and risk factors for fungal infection, including immunosuppression, prolonged use of antibiotics, prolonged hospitalization, and intra-abdominal sources of infection. A similar logic applies to anaerobes: empirical anaerobic coverage is discouraged for infections such as most pneumonias and urinary tract infections, partly because anaerobic agents alter the microbiome and have been associated with higher mortality.The 2026 guidelines include a new conditional recommendation against empiric antianaerobic coverage for infections unlikely to be caused by anaerobic pathogens—for example, respiratory and urinary tract infections, based on evidence that antianaerobic antibiotics alter the microbiome and may be associated with increased mortality.
Duration is the other major stewardship lever, and biomarker-guided stopping is the best-studied approach. Biomarkers such as procalcitonin are used to decide when to stop treatment. In the ADAPT-Sepsis trial, which enrolled 2,760 critically ill adults in 41 UK intensive care units, the PCT protocol reduced antibiotic duration significantly (mean difference 0.88 days, p=0.01) without increasing 28-day all-cause mortality within the noninferiority safety margin of 5.4%. The CRP-guided arm did not clearly reduce use.CRP-guided care did not clearly reduce antibiotic use and exceeded the noninferiority safety margin of 5.4%. The absolute saving was modest, and adherence to the algorithm was imperfect.However, algorithm adherence was suboptimal, and the absolute reduction in antibiotic duration with procalcitonin was only 1 day. A pooled analysis of 19 trials with 6,382 patients estimated a shorter course of about two days, with moderate certainty.Moderate certainty evidence from 19 trials, involving 6382 patients, indicated that procalcitonin-guided protocols probably reduced antibiotic therapy by, on average, 2.0 days (95%CI -2.6 to -1.4) compared with standard care. Earlier meta-analytic work, however, found no survival benefit in the subset of trials restricted to sepsis.Death was the primary outcome in only one study and a survival benefit was not observed in the subset specified as sepsis (10 RCTs; RR, 0.94; 95% CI, 0.85-1.03; I^2 = 0%) Commentators have also noted that higher baseline severity scores weaken the reduction in antibiotic exposure, which suggests the benefit is not uniform across sepsis phenotypes.Meta-regression indicated that higher baseline sequential organ failure assessment scores attenuated the reduction in antibiotic exposure. The 2026 guideline additionally favors prolonged infusion of beta-lactams after an initial loading dose over bolus dosing, and suggests clinical evaluation alone over procalcitonin plus clinical evaluation when deciding whether to start treatment.For adults with possible or probable sepsis or septic shock, we "suggest" using clinical evaluation alone over procalcitonin plus clinical evaluation to decide whether to start antimicrobial therapy.
In low-resource settings, the stewardship agenda meets a different problem. Where blood culture, susceptibility testing and biomarker assays are scarce, empirical choices depend on local resistance patterns rather than on patient-specific results, and restrictive prescribing rules can leave patients without effective drugs when they need them. The World Health Organization's AWaRe classification attempts to reconcile these goals by encouraging "Access" agents as first-line choices and reserving "Watch" and "Reserve" agents for specific indications.
Guidelines, quality improvement, and implementation
From campaign to guideline series
The Surviving Sepsis Campaign (SSC) was launched in 2002 by the Society of Critical Care Medicine (SCCM), the European Society of Intensive Care Medicine (ESICM) and the International Sepsis Forum. The campaign was launched by the Society of Critical Care Medicine, the European Society of Intensive Care Medicine and the International Sepsis Forum in 2002. Its first guidelines, for severe sepsis and septic shock, appeared in 2004 with 52 recommendations, and the leadership committed to updates every four years. The 2008 edition broadened the scope to 85 recommendations while its core recommendations remained largely unchanged. The 2012 revision, which was published in Critical Care Medicine in early 2013, was a revision of the 2008 SSC guidelines for the management of severe sepsis and septic shock.
Funding and independence
Industry money has been a persistent point of debate. The 2004 process was sponsored by two device and drug companies, a fact that raised concerns about the integrity of the guidelines, and critics argued that the implementation effort also served a company's marketing aims. The campaign as a whole has relied on unrestricted industry educational grants, and most of that funding came from one company. Current industry funding for the Surviving Sepsis Campaign is directed to the performance improvement initiative. The committees stated that guideline writing was insulated from this money: no industry funding was used in the guidelines revision process, and since the inception of the SSC guidelines in 2004, no members of the committee represented industry.
The 2026 adult update
The adult guidelines were most recently revised in 2021, and the 2026 edition was released in March 2026. It contains 129 statements, 46 of which were not previously addressed, and more definitive recommendations. Among the new content, the authors addressed antibiotic optimisation, blood pressure targets in older adults, fluid removal after resuscitation, and continuity of care post-discharge—including psychological and physical rehabilitation. Specific changes include a conditional suggestion of an initial mean arterial pressure of 60-65 mm Hg over higher ranges for adults aged 65 or older, and an upgraded recommendation for prolonged infusion of beta-lactams for maintenance (after initial bolus) over conventional bolus infusion. A new conditional recommendation to screen patients for sepsis en route to the hospital was added, while the guidelines also acknowledge that there is no ideal sepsis screening tool.
The panel was broadly international. The 69-person guidelines panel had broad geographic diversity, representing 23 countries, with 38% of panelists currently or previously practicing in a low- or middle-income country. The guideline work was fully funded by Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM), with methodological support from the Guidelines in Intensive Care Medicine, Development, and Evaluation group, and there was no industry support. Adults and children receive two sets of guidelines, and the pediatric edition was first published in 2020.
Bundles and performance improvement
The campaign converted its recommendations into time-bound checklists. From these guidelines, sepsis change bundles for initial resuscitation (6 hours) and management (24 hours) were created as a performance improvement tool. These bundles were popularized as time stipulated bundles for resuscitation and maintenance. The campaign also analysed records from more than 30,000 patient records collected from around the world. Hospital programs built on these tools often include standardized "code sepsis" alerts and track bundle compliance as a quality metric. Whether such metrics reliably reflect patient outcomes remains disputed (see Controversies).
National adaptation: the German S3 guideline
National bodies typically adapt international recommendations to local practice. The German S3 guideline, which originated with a 2018 guideline of the German Sepsis Society, was updated in 2025. The update of the S3 guidelines "Sepsis—Prevention, diagnosis, treatment and follow-up care" was published on 25 July 2025. It was explicitly built on the international framework: The 2025 update is a targeted adaptation of the internationally recognized recommendations of the Surviving Sepsis Campaign from 2021. The new guideline addresses 29 new and 16 revised recommendations, with 43 recommendations remaining unchanged from the previous version. Its methods addressed 88 PICO questions, and the authors graded the evidence behind their recommendations as high for only 5 recommendations, moderate for 18 recommendations, low for 17 recommendations, and very low for 16. The authors concluded that these evidence gaps can only be closed through future multicenter, noncommercial clinical trials.
Long-term outcomes and post-sepsis care
Leaving hospital is not the end of the illness for many people who survive sepsis. Post-sepsis syndrome is the name for the physical and emotional problems many people experience after surviving sepsis. Estimates of how common it is vary. One patient-education source says it affects up to 50% of sepsis survivors, while another reports that about 40% of people who survive sepsis experience lingering effects, such as fatigue, memory or concentration problems, or emotional challenges. A population-level summary from the same literature describes roughly half of patients as recovering, about one in three dying within a year, and around one in six living with severe, persistent impairment.Post-sepsis syndrome is the working term for this cluster of problems, and it overlaps with post-intensive care syndrome, which describes the same kinds of impairment in ICU survivors more broadly.
Cognitive and psychological effects
Cognitive problems are among the best-documented outcomes. In one landmark cohort of adults aged 50 and older, the odds of moderate to severe cognitive impairment after severe sepsis were 3.34 times higher than before sepsis. A 2025 narrative review found that adult survivors report cognitive decline, including a higher risk of dementia. Delirium during mechanical ventilation is a recognized contributor; ICU delirium, which affects up to 80% of patients on ventilators, has been strongly associated with long-term cognitive and psychological impairment. Mental health problems are also reported by family members. The evidence for specific conditions such as post-traumatic stress disorder, depression, anxiety and suicidality is limited mixed evidence, so the magnitude of these risks remains uncertain. Older age and pre-existing comorbidities are consistently linked to worse long-term outcomes; long-term outcomes are strongly influenced by older age and underlying comorbidities, both of which independently predict increased risks of mortality, readmission, and functional decline over time.
Readmission, cardiovascular events and late mortality
A meta-analysis of 76 observational studies quantified the post-discharge burden. It reported a 1-year readmission rate as high as 44.0%, and the 5-year mortality rate reached 42.3%. Infection is the most frequent cause of return to hospital. In a nationwide Taiwanese cohort, sepsis survivors had higher risks of all-cause mortality (hazard ratio [HR], 2.18) and major adverse cardiovascular events (HR, 1.37) compared with matched controls, and these excess risks persisted for up to 5 years after discharge. A pooled analysis of adult survivors found a pooled cumulative incidence of major cardiovascular events of 9.0%, with heart failure and stroke also elevated relative to non-sepsis controls. Proposed mechanisms include sepsis-induced persistent endothelial dysfunction and coagulation activation, which are thought to raise the long-term risk of cardiovascular disease. Death and readmission are commonly attributed to infection, cancer and cardiovascular disease, and the authors of one Swedish cohort noted that the hazard ratios were larger among those without underlying comorbidities.
Post-ICU rehabilitation and follow-up
Current guidance on follow-up favors multidisciplinary care. Recommended approaches include cognitive screening, psychological assessment and rehabilitation activities, and these are usually organized within post-ICU programs. Access is uneven. Researchers note that in most health systems, and particularly in low- and middle-income countries, the emphasis of post-critical care follow-up remains predominantly physical, respiratory, renal or mobility outcomes. Because formal neuropsychological testing is often unavailable, proposed solutions include short outpatient cognitive screens, telemedicine-based post-discharge programs and caregiver-mediated cognitive tasks. Family caregivers carry part of this burden, given the mental health concerns reported among relatives of survivors. Cognitive and psychological rehabilitation has been proposed for inclusion in basic health service packages, and the authors argue that the economic costs of untreated impairment, including lost productivity, dependence, and re-hospitalisation, may exceed the cost of early detection.
Quality of life, return to work and pediatric outcomes
Findings on quality-of-life are mixed. While sepsis survivors frequently report poorer quality of life compared to the general population, studies have reported no difference in quality of life when comparing sepsis survivors with other critical illness survivors. Return-to-work outcomes were included among the endpoints of the 76-study meta-analysis, but the reported rates are heterogeneous across settings.
In children, outcomes depend strongly on age at illness. A 2025 review found that very preterm neonatal sepsis survivors reporting higher odds of neurodevelopmental disabilities, childhood sepsis survivors reporting delayed development. In a prospective case-control study of 50 children with sepsis-associated encephalopathy, 52% vs 32% in controls had low intelligence, and a decline in school performance (44%) was the most common behavioral change. In a small Ugandan cohort of infants with group B streptococcal sepsis, moderate to severe neurodevelopmental impairment occurred in 31% (5/16) in the GBS cohort compared with 8.5% (5/59) in the non-GBS cohort. A systematic review of neonatal sepsis reported that neonatal sepsis was consistently associated with adverse neurodevelopmental outcomes, with preterm infants and those with severe sepsis or comorbid conditions facing the highest risks. Because these effects can emerge after the first years of life, structured neurodevelopmental follow-up is widely recommended for pediatric survivors.
Prevention and public health
Prevention works at several levels: hospital infection control, vaccination, outpatient treatment of infections, maternity care, and health-system capacity. Because sepsis follows from infection, most of these measures aim to stop the infection before the host response becomes dysregulated. The WHO calls on health facilities to prevent health care-associated sepsis through hand hygiene and infection prevention and control (IPC) action. Hand hygiene is central because infections are most commonly transmitted in health care facilities on health care workers' hands. For invasive devices, guidance emphasizes hand hygiene before and after palpating catheter insertion sites, and before and after inserting, replacing, accessing, repairing, or dressing an intravascular catheter. Other measures include maximal sterile barrier precautions during central venous catheter insertion, chlorhexidine skin preparation with alcohol, and avoiding routine replacement of central venous catheters as a strategy to prevent infection. IPC is also regarded as one of the most effective approaches to combat the spread of antimicrobial resistance, which matters because resistant infections make empirical treatment harder.
Vaccination is a second pillar. Influenza and pneumococcal vaccination can prevent disease and potentially life-threatening complications like sepsis. Older adults are a priority group because they have an increased risk of severe disease, yet uptake remains low within the general public and the elderly population, while incidence rates of severe manifestations like sepsis are increasing. Vaccine benefit is not limited to preventing infection: the influenza vaccine often does not provide protection against infection, however, it does provide good efficacy against severe complications related to influenza. In children, a review of sepsis prevention policy notes that infections with Haemophilus influenzae type b and Streptococcus pneumoniae, leading causes of bacterial meningitis, pneumonia, and overwhelming infection in children, are now virtually 100% preventable through immunization. Vaccination also has a stewardship effect, since a meta-analysis reports a reduction of antibiotic use after vaccination.
Outpatient care and public awareness address the earlier stages of the pathway. Sepsis can happen as a result of any infection, so timely treatment of pneumonia, urinary, skin, and other common infections in primary care can interrupt progression. Awareness campaigns teach families and patients to recognize warning signs and to speak up; WHO's hand hygiene campaign, for example, encourages patients and advocacy groups to ask for 5 Moments of clean hands to prevent sepsis in health care.
Maternal and neonatal sepsis prevention relies heavily on delivery practices. There is strong evidence that clean delivery practices and handwashing during delivery reduce rates of neonatal sepsis in both home and health facility settings. The WHO's "six cleans" framework covers hand washing of the birth attendant before birth, a clean birth surface, a clean perineum, cutting of the umbilical cord with a clean implement, a clean cord tie, and a clean cloth for drying. Antenatal care contributes as well: in one case-control study, a higher number of antenatal care visits was associated with a lower likelihood of neonatal sepsis, and modifiable factors included prolonged labor or membrane rupture, forceps delivery, non-sterile vaginal examinations, and maternal urinary tract infections. In high-income settings, intrapartum antibiotic prophylaxis has been highly effective in reducing both early-onset neonatal bacterial and maternal sepsis. The link between hand cleaning and puerperal sepsis was recognized as early as the nineteenth century, when Ignaz Semmelweis demonstrated that an approach as simple as "cleaning hands" could prevent totally unnecessary deaths of mothers during delivery.
The burden of these preventable deaths is concentrated in low- and middle-income countries. Most neonatal deaths occur in countries from Sub-Saharan African regions and South Asia, generally in areas where poverty is rampant, and in many of these regions the main problem for mothers is access to quality antenatal health care, in addition to inadequate information about clean delivery practices, since most of the deliveries happen in home. Because skilled attendance at delivery is increasing in low- and middle-income countries, approaches such as risk-based antibiotic prophylaxis and improved hand washing during delivery are likely to be both cost-effective and feasible in these countries. Strengthening health-system capacity therefore means more than drugs: it requires trained attendants, clean delivery supplies, and facilities able to diagnose and treat infection promptly. At the policy level, Member States adopted a resolution on improving the prevention, diagnosis and treatment of sepsis at the Seventieth World Health Assembly in May 2017.
Controversies and unresolved questions
Debate over the Sepsis-3 framework has continued since its publication in 2016, and it operates on several levels. The first concerns the tools themselves. Both SOFA and qSOFA were conceived as mortality predictors, so critics argue that they describe prognosis better than they identify the infection-driven process that defines sepsis. Sensitivity is another point of contention. In an emergency department cohort in Norway, the score overlooked roughly two-thirds of patients admitted with severe sepsis. A prospective study of acute hepatobiliary infection described a different trade-off: qSOFA was highly specific but missed many cases, while SIRS criteria caught more of them at the cost of false positives (SIRS criteria have high sensitivity while qSOFA score has high specificity). Definitional edges add to the argument. Because isolated hypotension scores only 1 point on SOFA, patients whose main abnormality is low blood pressure fall outside the definition. Lactate, despite its sensitivity as a marker of severity in infection, sits outside the SOFA calculation.
The bedside use of qSOFA raises a practical hazard. A positive qSOFA risks being read as a sepsis diagnosis, which could lead clinicians to treat for sepsis patients who actually need an evaluation for other serious illnesses.
The question of whether sepsis is a single syndrome or a collection of diseases is unresolved. Subtyping advocates contend that one operational definition cannot capture how variably the condition presents and evolves. A recent narrative review found that heterogeneity recurs across bedside clinical phenotypes, longitudinal trajectories, immune-cell-defined endotypes, and omics-based and machine learning-derived classifications. The same review treats competing subphenotype schemes as complementary steps toward decisions at the bedside rather than as rival taxonomies (Sepsis subphenotyping should be interpreted as a staged framework for precision decision-making). Critics of uniform protocols point to immune states that range from hyperinflammation to immunoparalysis, which standardized strategies have not accounted for. Proposed responses include cytokine inhibition for hyperinflamed patients and immunostimulatory agents for those whose immunity appears exhausted. Corticosteroids illustrate the stakes: their efficacy and safety differ across molecular endotypes. Reviewers also stress that endotype-based tools must be reproducible, fast enough to inform decisions, and tested prospectively before they can guide therapy (Future progress requires reproducible, time-sensitive, clinically measurable treatable traits).
Disagreements over fluid volume, vasopressor timing, corticosteroid dosing, and mean arterial pressure targets follow similar lines. Large trials have not settled these questions for the whole population. The ProCESS trial found no benefit from early goal-directed therapy compared with usual care. Simulation work later suggested that the same protocol could be harmful in trials enriched for one subphenotype while beneficial in trials enriched for another. A single target or volume may therefore suit some patients and harm others, which is why older adults and patients with chronic hypertension or kidney disease are often discussed separately.
Few sepsis-specific drugs have emerged despite decades of testing. Since the early 1980s, numerous therapeutic agents have been evaluated in randomized controlled trials, yet none is currently approved specifically for the condition. One prominent example is eritoran, which targeted the endotoxin-driven immune response. In a phase 3 program involving nearly 2,000 patients, the drug was no better than placebo. Candidates that looked strong in animal studies and early human trials have repeatedly failed in larger studies. Explanations offered include trial designs that relied on animal evidence whose relevance to people was never established. Others point to mortality as the primary endpoint, treatment starts that came late in the illness, and targets that also serve essential host defence. Some authors now see the field moving toward narrower, individually matched interventions rather than blanket agents.
Performance measurement carries its own uncertainties. Mortality and bundle compliance are attractive quality indicators, but both are shaped by case mix and by how sepsis is coded, so a hospital that screens more widely may record more cases and more deaths without any change in care quality. Pressure to meet bundle deadlines can also encourage broad antibiotic use in patients whose infection is uncertain, which feeds the resistance problem described elsewhere in this entry. Long-term outcomes, including post-sepsis syndrome, remain less studied than the acute phase, and much of the research agenda is still open.
References
- The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) - PMCpmc.ncbi.nlm.nih.gov
- Sepsis 3.0: Progress or Peril?acdis.org
- Robustness of sepsis-3 criteria in critically ill patientslink.springer.com
- Methods for treating and detecting sepsis in humansimage-ppubs.uspto.gov
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- Septic - Etymology, Origin & Meaningetymonline.com
- SEPSIS definition in American Englishcollinsdictionary.com
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