Sepsis.

# Sepsis *The Lancet 2026* Seminar Sepsis Mervyn Singer, Derek C Angus, Djillali Annane, Michael Bauer, Andre C Kalil, Michael Klompas, Flavia R Machado, Greg S Martin, Adrienne G Randolph, Manu Shankar-Hari, Nathan I Shapiro, Greet Van den Berghe Sepsis is defined as a dysregulated host response to infection that leads to life-threatening organ dysfunction. The Lancet 2026; 407: 1276–88 infectious insult triggers a dysregulated immune response that variably activates and suppresses multiple body system Published Online functions. Susceptibility to either developing or succumbing to sepsis is influenced by pathogen load and virulence; February 26, 2026 site of infection; host factors, including genetics, biological variability, comorbidities, immunosuppression, and https://doi.org/10.1016/ extremes of age; and a wide range of external influences, such as social deprivation and local environment. Increasing S0140-6736(25)02422-5 appreciation of the underlying pathobiology has identified diering biological signatures with variable temporal Bloomsbury Intensive Care evolution. This variability highlights the requirement to individualise treatment with targeted interventions guided by Medicine Institute, Centre for rapidly accessible biomarkers. Although improved outcomes have been obtained with better prevention, early Respiratory Medicine, University College London, recognition, and treatment, sepsis is a major cause of global mortality and morbidity. All populations having the London, UK benefits currently enjoyed by a privileged few is imperative. This Seminar aims to unravel the complexity of the (Prof M Singer FRCP); Center for condition, describing epidemiology and pathophysiology, evolving fundamental shifts, patient management, current Clinical Research, Investigation, and Systems challenges, and future developments. Modeling of Acute Illness, Department of Critical Care Introduction Many challenges persist in clinical practice. Diagnosis Medicine, University of Sepsis is a syndrome defined conceptually as the can be problematic, especially at first presentation and in Pittsburgh, Pittsburgh, PA, USA (Prof D C Angus FRCP); IHU development of life-threatening organ dysfunction patients with multimorbidity and/or communication PROMETHEUS, Comprehensive resulting from a dysregulated host response to infection.1 issues. Infection might not be verified until positive Sepsis Centre, General This definition can apply to any pathogen—for example, microbiological results return. Nonetheless, causative Intensive Care Unit, Raymond COVID-19 disease when it leads to acute respiratory organisms are often unidentified; therefore, infection is Poincaré Hospital, Garches, France (Prof D Annane MD); failure. For clinical operationalisation, two newly acquired presumed and frequently overdiagnosed. Furthermore, School of Medicine Simone points on the Sequential Organ Failure Assessment score, acute organ dysfunction might be dicult to distinguish Veil, University of Versailles over and above the usual baseline of a patient, represent from pre-existing chronicity, and attributable to infection. Saint-Quentin-en-Yvelines, the minimum deterioration in organ function that Paris, France (Prof D Annane); Department of distinguishes sepsis from an uncomplicated infection.1 Epidemiology Anaesthesiology and Intensive This score incorporates six organ systems (brain, Sepsis epidemiology (figure 2) is realised with diagnostic Care Medicine, Jena University cardiovascular, respiratory, hepatic, renal, and coding, scrutiny of death certificates, and, in informatics- Hospital, Jena, Germany coagulation) and was updated in 2025.2 However, other rich settings, interrogation of electronic health-care (Prof M Bauer MD); Division of Infectious Diseases, organ systems are frequently aected, including record data. All approaches have limitations, with data Department of Internal gastrointestinal dysfunction, bone marrow depression, incompleteness and inaccuracies, diagnostic subjectivity, Medicine, University of myopathy, and peripheral neuropathy (figure 1). and temporal changes following sepsis awareness Nebraska Medical Center, Septic shock describes profound circulatory, cellular, campaigns, evolving definitions, and initiatives to Omaha, NE, USA (Prof A C Kalil MD); Department and metabolic irregularities that are associated with a improve coding.4–7 Nevertheless, clear consensus exists of Population Medicine, greater mortality risk than sepsis alone. The clinical that sepsis represents a major global health-care problem. Harvard Medical School and criteria include a vasopressor requirement to maintain a The Global Burden of Disease study extrapolated data Harvard Pilgrim Healthcare mean arterial pressure of 65 mm Hg or more and a from hospital diagnosis codes and death certificates to Institute, Boston, MA, USA (Prof M Klompas MD); serum lactate concentration of more than 2 mmol/L estimate 49 million sepsis cases and 11 million worldwide Department of Medicine, (18 mg/dL) despite correction of hypovolaemia.1 deaths in 2017.8 Incidence was higher in the young, old, Brigham and Women’s Equivalent definitions and criteria for children were and people with pre-existing medical conditions, with Hospital, Boston, MA, USA published in 2024.3 There, sepsis is characterised as a children accounting for 30% of deaths. Burden diered (Prof M Klompas); Escola Paulista de Medicina, 2 point or more rise in the Phoenix Sepsis score, which widely in dierent countries, with 85% of cases and Universidade Federal de São identifies dysfunction in respiratory, cardiovascular, deaths in resource-limited settings. Age-standardised Paulo, São Paulo, Brazil coagulation, and neurological systems. incidence and mortality rates inversely correlated with (F R Machado PhD); Division of sociodemographic index, and was 15-fold higher in Pulmonary, Allergy, Critical Care and Sleep Medicine, sub-Saharan Africa compared with western Europe. Department of Medicine, Search strategy and selection criteria Encouragingly, sepsis incidence was reported to have Emory University, Atlanta, GA, fallen by 37%, and mortality by 53%, between 1990 USA (Prof G S Martin MD); Grady We searched PubMed for articles published between Memorial Hospital, Atlanta, Jan 1, 1990 and June 1, 2025. The following search terms and 2017. However, comparative estimates for the USA, GA, USA (Prof G S Martin); obtained with an electronic health-care record approach were used: “sepsis” , “septic shock”, and “bacteremia/ Department of Anesthesiology, between 2009 and 2014, found that sepsis cases were Critical Care, and Pain bacteraemia”. Only studies published in English were 88% higher and deaths 55% higher than those reported Medicine, Boston Children’s considered, with a particular focus on pathophysiology, Hospital, Boston, MA, USA epidemiology, and randomised controlled trials. in the Global Burden of Disease study, with unchanged (Prof A G Randolph MD); incidence and mortality.9 1276 Seminar The higher burden of sepsis in resource-limited settings relates to poor sanitation, low vaccine coverage, Encephalopathy overstretched primary care, delays in seeking health care, Autonomic dysfunction limited hospital access, shortages of health-care personnel, overcrowding, and insucient intensive care unit (ICU) beds.10,11 Antimicrobial resistance (AMR) is common due Acute lung injury (ARDS) to antibiotic overuse, a scarcity of stewardship Cardiomyopathy programmes, and high nosocomial infection rates.8 Vascular hyporeactivity Sepsis cases are mainly community-acquired. Hospital- Hepatic dysfunction acquired sepsis accounts for 10–15% of cases, but is Immune dysfunction Gut dysfunction associated with worse outcomes.12,13 A large multinational Acute kidney injury point prevalence study done in ICUs reported an overall in-hospital mortality of 30·3%.13 Mortality from septic shock exceeds 40%.1 The most common sites of infection Haematological dysfunction are the respiratory tract, abdomen, bloodstream, and Myopathy (coagulopathy and bone marrow urinary tract.8,13 Diarrhoeal illnesses predominate in low- depression) resource settings. Bacterial organisms, particularly Gram-negative bacilli, most often cause sepsis, followed by viruses, fungi, and protozoa, alone or in combination with bacteria.13 In resource-limited settings, malaria, leptospirosis, melioidosis, typhus, tuberculosis disease, Neuropathy and viral infections, including dengue, measles, and influenza, are prevalent.8 Pathophysiology Figure 1: Organ dysfunctions in sepsis The host response to infection requires recognition of Created in BioRender. Singer, M (2025) https://BioRender.com/l1o1l55. ARDS=acute respiratory distress syndrome. the invading pathogen, its constituents (eg, DNA, lipopolysaccharides, and peptidoglycans), and other danger signals produced by both the immune system and non-immune cells, such as the epithelium and The host Pathogens endothelium.14 Both cell surface (eg, toll-like) and • Extremes of age • Virulence mechanism factors • Race and genetic susceptibility • Antimicrobial resistance patterns intracellular (eg, nucleotide-binding oligomerisation • Immunosuppression • Co-infection (eg, HIV, tuberculosis, and domain-like) pattern recognition receptors identify • Lifestyle CMV) • Chronic illness pathogen-associated molecular patterns, triggering host • Gut dysbiosis immune responses aimed at clearing the infection. • Critical illness Society • Invasive devices However, these responses can inadvertently aect host • Poverty and malnutrition cellular functionality, resulting in cell injury with the • Poor sanitation and hygiene • Inadequate vaccination coverage release of damage-associated molecular patterns, such as The heathcare system • Absence of health insurance DNA, mitochondria, and heat shock proteins.14,15 Damage- • Few primary care providers • Underfunding of health care • Low public awareness • Delays in seeking health care associated molecular patterns also act as danger signals, • Geographical barriers to access • Low health literacy amplifying the host immune response. The net result is • Resource limitations activation of pro-inflammatory pathways, in combination • Workforce shortage • Low ICU capacity with immune dysfunction, including leukocyte anergy, • Suboptimal quality of care Other • Low prioritisation by policy makers lymphopenia, depletion of regulatory T cells and • Health care-associated infections • Poor implementation of national action plans • Inadequate long-term follow-up myeloid-derived suppressor cells, and reduced HLA-DR • Absence of context-specific guidelines for low-resource settings isotype expression by antigen-presenting cells. The • Challenges to doing high-quality studies altered functionality of both the innate and adaptive • Insufficient investment in research immune systems increases susceptibility to secondary focused on low-resource settings infection from either external or intrinsic sources. Intrinsic sources include bowel microorganisms, such as Figure 2: Risk factors for infection and progression to sepsis ICU=intensive care unit. CMV=cytomegalovirus. Gram-negative bacteria and fungi16 and viral reactivation.17 Such infections impact recovery and can cause late deaths. mechanisms that reduce the pathogen burden. Tolerance Department of Anesthesiology, The dysregulated immune response has been reframed is an evolutionarily conserved defence strategy that limits and Department of Pediatrics, as altered homoeostasis, with pathological disruption of disease severity without directly aecting pathogen Harvard Medical School, Boston, MA, USA immune-driven resistance, disease tolerance, resilience, burden.19 Resilience, with respect to the immune system, (Prof A G Randolph); Centre for and resolution (figure 3).18 Resistance refers to eector is the capacity to rapidly restore the pre-illness regulated Critical Illness Research, King’s Seminar Pathogens, PAMPs, Recognition via Factors influencing Functional versus dysfunctional host response and DAMPs extracellular and host response (with examples) intracellular PRRs Pro- Excessive Inflammatory inflammatory inflammation tissue injury Resistance Resolution Responses of inflammation mediating Tolerance resilience Susceptibility to Anti- Immune secondary infections inflammatory impairments Damage by pathogen Hyper- Energy reprioritisation (for fight or metabolic flight), pyrexia generation Nutrient deprivation and Catabolism Repair resource mobilisation Muscle wasting, gut Anabolism (autocannibalism) mucosal atrophy, etc Bioenergetic and Arousal Recovery metabolic shutdown pathways ► Organ dormancy Hypo- Responses mediating metabolic resilience Figure 3: Reframing conceptual fundamentals underlying immune and non-immune responses DAMPs=damage-associated molecular patterns. cfDNA=cell-free DNA. mtDNA=mitochondrial DNA. HSP=heat shock protein. LPS=lipopolysaccharide. NLR=nucleotide-binding oligomerisation domain-like receptor. PAMPs=pathogen-associated molecular patterns. PRRs=pathogen recognition receptors. ROS=reactive oxygen species. TLR=toll-like receptor. College London, London, UK state while limiting the inflammatory cost to the host. survival, while attempting to prevent excessive (Prof M Shankar-Hari PhD); Resolution is the regulated process that restores tissue inflammation and allow pro-resolving pathways to Department of Emergency homoeostasis following inflammation. This model mediate a return to homoeostasis.22,23 Altered Medicine, Beth Israel represents competing host defence strategies. For example, neuroendocrine–immune crosstalk contributes to organ Deaconess Medical Center, Harvard Medical School, low pathogen loads can be dealt with by a resistance dysfunction.24 Coagulopathy occurs, with both pro- Boston, MA, USA response, whereas a high pathogen load induces energy- thrombotic and increased bleeding tende ncies, although (Prof N I Shapiro MD); Clinical saving catabolic and maintenance responses, such as overt disseminated intravascular coagu lation is Division, and Laboratory of autophagy and tolerance.20 As every organ has a dierent increasingly rare.25 Thrombin generation amplifies the Intensive Care Medicine, Department of Cellular and immune architecture, the site of infection also influences inflammatory response. At the cellular level, organelle Molecular Medicine, KU clinical outcomes.21 injury and dysfunction are apparent—for example, Leuven, Leuven, Belgium The dysregulated immune response triggers multiple endoplasmic reticulum stress and mitochondrial (Prof G Van den Berghe MD) downstream eects, including altered neural control dysfunction. Mitochondrial dysfunction is hallmarked Correspondence to: mechanisms, endothelial activation, and loss of by an availability, but decreased use, of oxygen Prof Mervyn Singer, Bloomsbury Intensive Care Medicine vasoregulatory control, with alterations in macrovascular (cytopathic dysoxia), aecting ATP production.26 Institute, Centre for Respiratory and microvascular blood flow aecting tissue perfusion Notably, other than gut epithelium and immune cells, Medicine, University College (figure 4). Metabolic substrate use initially increases and cell death is not a major feature of organ dysfunction in London, London WC1E 6BT, UK then falls, shifting from glucose towards fat and protein. sepsis;27,28 thus, even poorly regenerative organs can m.singer@ucl.ac.uk Marked endocrine changes occur early, with an regain functionality. Nonetheless, activation of various increased release of most pituitary hormones, increased cell death pathways can potentially be targeted to impact circulating concentrations of cortisol and outcomes.29 catecholamines, and peripheral inactivation of anabolic From an evolutionary perspective, an excessive insult in hormones.22,23 These endocrine responses induce the pre-ICU era would have rapidly progressed to death. catabolism to generate metabolic substrates and Nowadays, early deaths can be avoided or delayed by haemodynamic modifications that are essential for organ support. This prolongation has revealed dierent 1278 sesnopser tsoH Pathogen factors Pathogen load, site of Immune Bacteria infection, virulence response DNA LPS Peptidoglycans NLR Fungi β-glucan Release of pro-inflammatory Viruses and anti-inflammatory DNA mediators RNA TLR Host signals cfDNA Non-immune mtDNA ROS (bioenergetic– ROS Host factors metabolic) HSP Age, comorbidities, response medication, genetics and environment Seminar phases of the septic illness, from an early, adaptive fight- Pathogen plus PAMPs Cell injury plus DAMPs or-flight response with an increase in metabolic rate to a subacute bioenergetic shutdown of several organ systems to economise energy expenditure, followed by either Pathogen recovery or persisting organ dysfunction (figure 3).26 recognition receptors Persisting organ dysfunction is a pathophysiological state that exceeds any natural time course that would have enabled evolution to select survival pathways. Initially, beneficial metabolic, endocrine, and bioenergetic Activation of adaptations become potentially deleterious in prolonged transcription factors Cellular and humoral immune response critical illness,22,30–32 an example of which is the uniform Pro-inflammatory and suppression of all hypothalamus–pituitary axes.22,23,32,33 anti-inflammatory Processes underlying host resilience, including mediators, reactive oxygen species, metabolic, bioenergetic, and endocrine adaptations that eicosanoids, etc contribute to recovery are poorly characterised. Diagnosis Sepsis is a time-sensitive condition: prompt identification and treatment are key. No single best screening tool Endocrine Epithelial exists as settings and presentations vary. Most approaches alert to signs and symptoms of infection, including Metabolic Neural Coagulation markers of systemic inflammation,34,35 clinical deterioration with bedside early warning scores such as the National Early Warning Score-2 and quick Sequential Bioenergetic Endothelial Organ Failure Assessment,36–38 and illness severity (organ dysfunction and lactate).39,40 Manual screening tools are Macrovascular and inecient, and automated tools built in to many microvascular electronic health record systems are also not failsafe, and often alert excessively, causing alarm fatigue.41–43 Accurate and timely diagnosis of infection is a major challenge, especially in low-resource settings. Diagnostic Organ dysfunction precision is essential to administer the appropriate anti- infective agents and, if needed, early and eective source control. However, current diagnostics are far from failsafe. Patients with sepsis can present atypically—for example, apyrexial or with normal or marginally elevated inflammatory biomarkers.44,45 Bacterial infection is verified in only 60–70% of patients treated for bacterial sepsis.13,46,47 Non-identification of a pathogen does not necessarily exclude sepsis, and a positive culture might reflect colonisation rather than infection. Overdiagnosis Figure 4: Schematic of sepsis pathophysiology, highlighting substantial crosstalk is commonplace, as sepsis mimics can present with Created in BioRender. Singer, M (2025) https://BioRender.com/n99wt2j. DAMPs=damage-associated molecular clinical and laboratory features similar to sepsis.48–50 patterns. PAMPs=pathogen-associated molecular patterns. Examples of such non-infectious inflammatory conditions include pulmonary embolism, heart failure, both potential sites of infection and organs directly or acute lymphomas, drug reactions, and allergic reactions. indirectly aected by the septic process. Identifying the An erroneous label of sepsis exposes the patient to site of infection optimises the type, dosing, and duration unnecessary treatment and can distract from diagnosing of antibiotics51 and the need for source control—for and treating the true cause. example, abscess drainage, viscus perforation repair, and A comprehensive approach maximises diagnostic indwelling device removal.52 precision and improves outcomes. A detailed history Microbiological and radiological evaluations identify evaluates the risks for specific types of infection and the organism and infection site. Blood cultures should includes individual comorbidities, such as immuno- ideally be collected before initiating antibiotics. A suppression, environmental exposures (eg, recent positive blood culture enables the most targeted admission to hospital), and geographical and travel antibiotic approach; however, positivity occurs in only locations to establish community exposure to specific 20–30% of patients with sepsis,12 and the lag time can be pathogens. Thorough physical examination assesses several days. Guided by the likely site of infection, Seminar from such tests is particularly relevant in borderline Screening and diagnosis cases of sepsis, in which most uncertainty resides. Rapid • Pathogen identification and susceptibilities host response biomarkers measuring mRNA or proteins (cultures, molecular tests, etc) • Point-of-care tests (blood gases, lactate, can reasonably discriminate bacterial from non-bacterial electrolytes, glucose, etc) Initial interventions infections, but are likelihood-based rather than • Biochemistry and haematology tests • Antibiotics conclusive.57–59 • Host response markers • Fluid • Imaging for site of infection (eg, x-ray, CT, • Consider need for vasopressors or inotropes ultrasonography, MRI) • Consider need for oxygen and ventilatory Management • Echocardiography (myocardial depression, support endocarditis, etc) • Consider need for source control Debates are still ongoing about best treatment (figure 5), especially with prospective trials oering neutral or even conflicting results across a wide range of interventions, Considerations Other support such as fluid therapy, vasoactive drugs, nutrition, and • Alternative diagnoses (sepsis mimics) • Consider renal replacement therapy Sepsis • Therapies for specific patient groups (eg, • Nutrition immunomodulation.60 Promising initial results have not corticosteroids) • Thromboprophylaxis been reproduced in larger multicentre studies:61,62 even with • Glycaemic control • Physiotherapy and mobilisation sepsis caused by a single pathogen (SARS-CoV-2), Monitoring • Psychological support (patient and family) multicentre studies generated inconsistent findings.63,64 • Vital signs These inconsistencies are multifactorial and are in part • Advanced haemodynamics related to study design and performance and the • Gas exchange, ventilator settings • Conscious level, delirium populations being treated.65,66 Short-term gains, such as • Fluid balance, serial weights elevating blood pressure with a specific agent, do not • Laboratory tests (haematology, including coagulation studies, necessarily translate into longer-term outcome benefits. biochemistry, and others as indicated There is increasing recognition that the individual patient’s —eg, antibiotic concentrations) underlying biological signature (subphenotype) can predict a beneficial, harmful, or neutral response to therapy Figure 5: Sepsis management summary (eg, corticosteroids).67,68 Such signatures might prove useful Created in BioRender. Singer, M (2025) https://BioRender.com/dx0h1z2. in guiding therapy and improving outcomes.66,69 samples, such as sputum, bronchoalveolar lavage, urine, The Surviving Sepsis Campaign (SSC) oers regularly pleural fluid, cerebrospinal fluid, and pus are taken to updated evidence-based guidelines to assist patient increase the likelihood of identifying the specific management.70 In view of the aforementioned issues and infection. Multiplex PCR platform assays that detect the resulting dearth of high-quality or even moderate- specific pathogen molecular patterns are now quality evidence, the strength of recommendations is commercially available for various body fluids, with mainly graded as weak. A revised version is expected most oering a selection of AMR genes. These panels in 2026. provide a rapid diagnosis that can facilitate early, targeted antimicrobials.53–56 Prospective randomised trials are still Prompt intervention scarce and have yet to show clear outcome benefits.54–56 Intervention in the proximal part of the illness course is Such platforms might yield false-positive results due to the best way to mitigate progressive organ dysfunction their high sensitivity in, for example, detecting and poor outcomes. SSC guidelines emphasise key commensals and contaminants, and will not detect less actions, such as prompt intravenous antibiotic common microorganisms. The choice of radiological administration and circulatory (intravenous fluid ± procedure (x-ray, CT, or MRI) depends on local vasopressors) support within the first hours. availability and is directed by the most likely site or sites of infection, as assessed by bedside evaluation. Control and eradication of infection Ultrasonography (including echocardiography) might be Timely antibiotic administration is the only component of indicated from history and examination findings. sepsis resuscitation bundles that is consistently associated Blood tests are also taken for urgent identification of with lower mortality.71,72 However, a balance should be markers of systemic inflammation (eg, white blood struck between the harms associated with administering count, C-reactive protein, and procalcitonin), electrolyte unnecessary antibiotics to patients with non-bacterial disturbances, and organ dysfunction. Lactate sepsis or non-infectious mimics (eg, encouragement of measurement is useful for risk stratification and AMR) and multiple direct complications, including assessing treatment response.40 The absence of deleterious eects on the microbiome.16,73 Risk hyperlactataemia does not necessarily exclude substantial stratification can help clinicians navigate the tension disease severity or risk of death.1 Numerous host between early antibiotics versus limiting overtreatment. response biomarkers, either singly or in combination, of The association between time-to-antibiotics and mortality inflammation, coagulation, and immunological pathways is strongest and most consistent in patients with septic have been proposed. However, none are absolute shock.72,74,75 However, this association is weak or absent in diagnostics at present.34,35 The lack of diagnostic surety non-shocked patients unless delays exceed 5–6 hours,72,74 a 1280 Seminar finding verified by prospective studies.76,77 If the diagnosis of bacterial sepsis is unclear, clinicians can investigate Empirical antibiotics within 1 h (unless definitive alternative diagnosis) whether a patient who is non-shocked is infected and, if so, whether the infection is most likely to be bacterial or Antibiotics within 3 h non-bacterial before administering antibacterials (targeted to site if possible) (figure 6). SSC guidelines recommend administering antibiotics within 3 h if concern for infection persists, as per the precautionary principle.70 UK guidelines stratify response time by the bedside National Early Warning Score-2 score, with 1, 3, and 6 h windows, depending on severity.78 Such time windows are maxima; once a decision Likelihood of bacterial infection is made to give antibiotics, prescription or administration Figure 6: Timing of antibiotic initiation and illness severity should not be delayed.70,78,79 Created in BioRender. Singer, M (2025) https://BioRender.com/y9ci3ya. NEWS2=National Early Warning Score-2. Antibiotic choice should be informed by the patient- specific likelihood of infection by a resistant organism. An increasingly positive fluid balance is associated with a Physicians usually overestimate the risk for drug-resistant progressively higher mortality risk.88,89 Once stabilised, organisms,80 although resistance rates are higher with fluid accumulation should be reversed with restricted hospital-onset sepsis and in many resource-limited fluid inputs and, if needed, judicious use of diuretics or settings.81,82 To reduce the risk of AMR and other antibiotic- renal replacement therapy. This approach might be related complications, antibiotic de-escalation, including a challenging in low-resource settings, where patients who shift to a narrow-spectrum antibiotic, should be are critically ill are frequently managed outside the ICU, implemented once the pathogen and its antimicrobial with low respiratory and renal support capacity to deal susceptibilities are known. Future advances in rapid with complications arising from fluid overload.90,91 diagnostics might facilitate increased initial use of narrow- Vasopressor infusion should begin, via peripheral spectrum antibiotics. Multiple prospective studies show access, if necessary, within the first hour in cases of life- equal ecacy with shorter antibiotic courses:83–85 in threatening hypotension or when hypotension persists general, 5–7 day courses are sucient unless the infection despite initial fluid resuscitation. Norepinephrine is the is deep-seated or a specific pathogen requires an extended current recommended first-line agent,70 although in low- course. As with early antibiotics, prompt, adequate source resource settings, epinephrine or dopamine are control is associated with reduced mortality.76,86 Results reasonable alternatives. Early vasopressor use might vary between studies; therefore, some room for discretion improve haemodynamics by mobilising the unstressed exists to vary source control time targets depending on the venous volume and avoiding excess fluid loading. Due to patient substrate, clinical syndrome, and the complexity potentially harmful eects from high doses of and safety of providing source control. catecholamines,92 a multimodal approach is recom- mended, ensuring an adequate intravascular volume, Organ support maintaining a mean arterial pressure generally within the Signs suggestive of organ hypoperfusion—for example, 65–70 mm Hg range, and adding vasopressin as a second- protracted capillary refill time, livedo, altered line vasopressor70 and low-dose hydrocortisone (50 mg consciousness, oliguria, hypotension, and hyper- four times per day) to improve vascular responsiveness to lactataemia—should prompt early resuscitation eorts. catecholamines. Inotropes might be required for ongoing Most patients with sepsis are hypovolaemic, albeit to hypoperfusion related to sepsis-induced myocardial varying degrees, because of decreased fluid intake, dysfunction. increased losses (eg, sweating, vomiting, and diarrhoea), In patients with respiratory failure (acute respiratory and increased vascular leak, resulting in fluid distress syndrome), support can initially be given with redistribution from intravascular to extravascular high-flow nasal oxygen or non-invasive ventilation. compartments. In the initial resuscitation phase, up to Patients with more severe respiratory failure usually 30 mL/kg of intravenous crystalloids (preferably balanced require sedation and mechanical ventilation and, electrolyte solutions) might be needed. Frequent occasionally, extracorporeal support. Although mechanical re-evaluation is necessary to establish regular fluid ventilation carries its own complications (ventilator- requirements. Resuscitation should be based on the induced lung injury), delayed intubation can increase clinical context and assessments of fluid responsiveness, oxygen consumption and result in self-inflicted lung ideally with dynamic measures, such as capillary refill and injury by spontaneous hyper ventilation.93 A lung- passive leg raising.87 A fluid challenge in adults represents protective approach should be taken in mechanically a bolus of 200–500 mL given over 5–10 min. ventilated patients with low tidal volumes (~6 mL/kg Prompt and adequate fluid resuscitation is crucial, predicted bodyweight) and a plateau pressure (end- although care should be taken to avoid fluid overload. inspiratory airway pressure when airflow ceases) of less Peripheral oedema reflects engorgement in other organs. than 30 cm H₂O.70 Deep sedation and neuromuscular )htaed fo ksir( ytireves ssenllI Shock NEWS2 score Hyperlactataemia Respiratory failure Altered mentation Intensive search for alternative diagnoses Targeted antibiotics after obtaining and confirmation of infection (if possible) additional information to guide before starting antibiotics antibiotic selection Seminar blockade should be limited to severe cases, and life at the expense of increased susceptibility to hyperoxaemia avoided. When appropriate, early ventilator opportunistic, community-acquired and hospital- and sedation adjustments to enable spontaneous breaths acquired infections that can evolve into sepsis.103 Notably, might avoid substantial respiratory muscle atrophy and despite the increased risk, not all immunocompromised facilitate weaning. conditions are associated with worse sepsis survival; Acute kidney injury is multifactorial, with contributions patients with suspected sepsis who received a solid-organ from hypoperfusion, inflammatory mediators, and transplant have higher survival rates than other patient mitochondrial dysfunction.94 Haemodynamic optimisation populations of equivalent illness severity, including alone might not reverse acute kidney injury. Early renal patients who were previously immunocompetent.104,105 replacement therapy does not improve outcomes and Diagnosing sepsis in this population is challenging as should be reserved for substantial hyperkalaemia, immunosuppressive agents can impair the typical host uraemia, or refractory acidosis.94 response to infection, resulting in, for example, the lack of fever.103,104 An absence of inflammatory signs and General supportive measures symptoms can hinder patient recognition of a severe General supportive measures are key for recovery. infection and clinician awareness of evolving sepsis. Patients, families, and caregivers should also be engaged The resulting delay to delivery of antimicrobials and early to discuss prognosis and goals of care, and to oer supportive care interventions can impact survival. The psychological support. Nutritional support can be enteral threshold to suspect sepsis and initiate appropriate and/or parenteral and should commence beyond the treatment should be low to truncate sepsis evolution acute phase; early, aggressive feeding is associated with and improve outcomes. Non-bacterial causes of increased harm.95–97 Optimal dose and formulation are sepsis—for example, fungal infections and endemic uncertain and overfeeding should be avoided. Enteral mycoses, such as Candida spp and histoplasmosis— nutrition should generally begin within 3–4 days in the should be considered. The reactivation of viruses, such absence of contraindications, such as ongoing shock or as cytomegalovirus and herpes simplex virus, which gastrointestinal complications.97 Parenteral nutrition occur in ICU patients who are both immunocompetent should be considered in cases of protracted insucient and immunocompromised, is less common. These enteral nutrition. Hyperglycaemia is commonplace in viruses are associated with worse survival outcomes— sepsis and is multifactorial due to insulin resistance, whether reactivation is simply a disease severity marker counter-regulatory hormones, and the use of therapies, or has a causal eect, thus requiring treatment, is such as corticosteroids, catecholamines, and parenteral unclear. nutrition. Intravenous insulin should be administered to patients with persistent hyperglycaemia. Neonates and children Muscle weakness can arise directly from the Most sepsis cases and related deaths aect the young and inflammatory, bioenergetic, and metabolic processes of the old. In 2017, the estimated 20·3 million sepsis cases sepsis, resulting in myopathy and/or peripheral in children under 5 years of age (with 2·9 million deaths) neuropathy.98 Muscle weakness is further compounded by make up 41·5% of all incident cases.8,106 The high nutritional deficiencies and autocannibalism, with the use incidence in young children is mainly driven by an of muscle protein by other organs and prolonged absence of protective adaptive immunity that develops immobility, particularly in patients requiring long-term via exposure to infection or immunisation.107 Vaccination mechanical ventilation. Mobilisation and physical against multiple viral and bacterial pathogens during rehabilitation can accelerate recovery, shorten time in early childhood is highly eective in decreasing the hospital, and confer long-term benefits for increased incidence of sepsis. functional independence. However, early mobilisation has Neonates are particularly susceptible to life-threatening no impact on mortality.99 Immobility combined with the infections.108 Worldwide, perinatal infections (mostly pro-coagulopathic tendency of sepsis100 puts patients at bacterial) and prematurity encompass almost half of all increased risk of deep vein thrombosis. Unless con- deaths in young children, with most occurring in low- traindicated, patients should receive thromb oprophylaxis resource countries. The 2024 definition of paediatric with subcutaneous low-molecular weight heparin.101 sepsis3 is similar to the adult sepsis definition, but no Similarly, stress ulcer prophylaxis in patients who are consensus definition for neonatal sepsis exists, hindering mechanically ventilated reduces the risk of gastrointestinal understanding and study design. Diagnosing neonatal bleeding.102 sepsis is challenging due to non-specific presenting signs, an inability to communicate symptoms, and low Special populations blood volumes that decrease culture sensitivity. Even in Patients who are immunosuppressed highly resourced countries, early onset sepsis aects 1 in Immunosuppressive therapies for malignancy, auto- 1000 newborns, mainly caused by Escherichia coli and immune diseases, and solid-organ and stem-cell Streptococcus agalactiae (group B streptococcus), and transplantations have improved quality and quantity of disproportionately burdening those born prematurely. 1282 Seminar Optimising and identifying interventions that eectively occur early during the intensive care stay and are prevent neonatal sepsis is a global imperative. detectable years later.121–123 Some of these changes are attributable to treatments given while in hospital and are Obstetric patients thus potentially modifiable. WHO defines obstetric sepsis as a life-threatening condition characterised as “organ dysfunction resulting Future prospects from infection during pregnancy, childbirth, post- Sepsis is a complex syndrome. As understanding abortion, or postpartum period for up to 42 days following continues to evolve, both definitions and management the end of a pregnancy.”109 The global cumulative guidelines will be updated. Important imperatives and incidence of maternal sepsis is 13·2 per 10 000 pregnancies, encouraging developments will arise in the years ahead. ranging from 6·3 per 10 000 in the Americas to 129·2 These include the need for an increasing emphasis on per 10 000 in Africa.110 Risk factors include an age of prevention and early intervention, tailoring evidence- 35 years or more, multiparity, diabetes, pre-eclampsia or based management to dierent health-care systems, eclampsia, hypertension, obesity, and caesarean delivery. including resource-limited settings,123,124 aftercare in A 2025 WHO systematic review identified 252 972 deaths survivors, an increasing role of artificial intelligence (AI) from maternal sepsis (6·6% of all maternal deaths), in patient management, accessibility to aordable two-thirds of which occurred postpartum.111 molecular biomarkers to accelerate accurate diagnosis, Diagnosing sepsis during pregnancy is challenging as and identifying tools to guide personalised interventions physiological, biochemical, and immunological changes, that can either halt the progression of sepsis or promote as well as eorts during labour, can obscure clinical recovery. signs.112 Pregnancy-adjusted sepsis screening tools only Most sepsis develops in the community, yet care only did better than non-pregnancy-adjusted tools after begins in the hospital. Better prevention in the 20 weeks gestation until 3 days postpartum, and high community could dramatically reduce the burden of false-positive rates were reported throughout.113 The main sepsis. A roadmap for the launch of such eorts in sepsis pregnancy-related sources are chorioamnionitis, was described in 2025,125 laying out some complementary endometritis, abortion due to sepsis, and mastitis; strategies, such as boosting vaccination rates, raising however, non-pregnancy-related infections should be awareness, implementing improved screening in considered—for example, wound infection, pyelo- outpatient settings, and targeted monitoring of high-risk nephritis, and pneumonia. As few prospective studies groups. exist, management guidelines are largely derived from The agenda for resuscitation and early management evidence drawn from the general adult population. should switch from trials attempting to fine-tune how to resuscitate to an implementation science platform Recovery addressing the question: how can evidence-based Recovery from sepsis implies a resolution of both the inciting infection, which generally occurs within the first days of onset, and the related organ dysfunctions. The acute recovery phase is often measured objectively as short-term mortality, collected at hospital discharge, or Patient centered Goal-concordant care collected within 30 days of admission to hospital. Valued by patients and Although mortality is an obviously important outcome, it family Quality of life (physical, cognitive, and psychological) Responsive to individual is not necessarily superior to other more patient-centred patient preferences Symptoms and stressors outcomes that capture the consequences of sepsis, such Hospital-free days as persisting organ dysfunction and impaired quality of life (figure 7).114–120 Approximately half of patients with Long-term mortality sepsis who survive to leave hospital make a complete or near-complete recovery, one in six have severe, persistent Hospital mortality physical disability or cognitive impairment, and one in three die within a year, half of which are directly related Organ failure-free days to sepsis complications.116 The long-term physical, cognitive, and psychological Pragmatic consequences of critical illness are collectively described Readily available as postintensive care syndrome.114,115 However, these Collected for routine clinical care complications are not restricted to intensive care Easily measured survivors, as shown by long COVID. Underlying No need for adjudication mechanisms are not fully understood, but involve environmentally induced epigenetic changes, such as Figure 7: Patient-centred versus pragmatic outcomes altered DNA methylation and telomere shortening that Created in BioRender. Singer, M (2025) https://BioRender.com/a1y8jmc. Seminar resuscitation be delivered promptly to everyone? Given rapidly, such that cardiovascular instability and life- that initial care is inadequate or delayed for many patients, threatening hypoxaemia have largely resolved within the establishing what strategies best help health systems to first 48–72 h. Patients then often face weeks of treatment ensure prompt care for all patients would likely yield in hospital, with ongoing organ dysfunction including, much larger benefits than further trials addressing but not limited to, delirium and cognitive issues, muscle questions such as the choice of fluid or vasopressor during weakness, failure to wean from mechanical ventilation initial resuscitation. Barriers to prompt resuscitation for and/or renal replacement therapy, and immuno- all patients are numerous, complex, and variable— uppression with an increased risk of secondary infection. ascertaining what solutions work most eciently in These conditions can extend well beyond hospital specific settings would be a major advance. In particular, discharge. Current care focuses on supporting this advance applies to resource-poor settings, where individualised recovery and preventing new complications. research capacity and collaboration should be enhanced. Recovery research is scarce, missing both foundational As mentioned previously, sepsis is an extraordinarily models and adequately nuanced clinical trials. heterogeneous syndrome that is dicult to clearly Although the onset of sepsis is widely regarded as an dierentiate from non-infectious inflammatory conditions, immunological occurrence, other mechanisms—for especially at the early stages of illness. Thus, considerable example, metabolic, bioenergetic, and disrupted research eorts are being expended on identifying neuroendocrine control—are more likely to cause delayed biomarkers for rapid, accurate detection of the sepsis- recovery.22,132 Organ dysfunction has been conceptualised defining dysregulated host response, and the underlying as a potentially reversible hibernation-like response.133,134 pathogen and its antimicrobial susceptibility. The global Therapies that can regenerate functioning mitochondria diagnostic market is predicted to reach US$6·8 billion and activate metabolism might be useful in this in 2029.126 Within the scope of biomarker development, a regard.135,136 However, the application of organ repair or further important requirement is the identification of regeneration strategies will require a precision approach. patients who would qualify for a host response-modifying As a useful lesson, non-targeted treatment with growth intervention to prevent deterioration or hasten recovery. hormone to promote anabolism and enhance recovery This need is highlighted by the repeated failure of multiple from critical illness doubled the mortality in two parallel clinical trials, when tested in unstratified populations, to randomised controlled trials.137 reproduce the benefits seen in preclinical models. Finally, the information available within high- Biomarkers, such as gene transcripts, proteins, metabolites, dimensional, patient-derived datasets renders the rapidly and cell surface markers, can help to identify patients with evolving tools related to AI as intriguing options for systemic biological signatures—for example, hyper- unsupervised identification of biomarker patterns directly inflammatory—or to indicate specific upregulated or from electronic health-care records. This application holds downregulated pathways.127 These biomarkers could be particularly true for cohorts of patients usually excluded used theragnostically to target patients responsive to a from randomised trials—eg, people with HIV or metastatic particular intervention (predictive enrichment) or avoid cancer.75 Barriers ranging from non-reproducibility of interventions in those likely to be harmed. Such therapies signatures to regulatory hurdles in applying AI in the might be either new, previously tested, or repurposed, such clinical context still exist.138,139 However, the application of as corticosteroids, immuno stimulators, and monoclonal AI tools in caring for the critically ill is likely to oer antibodies.69,127,128 This approach can be facilitated by breakthrough improvements in practical care and post-hoc analyses of existing biobanked materials from outcomes by early recognition, rapid initiation, and previous interventional trials or observational studies. adherence to structured interventions.139,140 A further heterogeneity surrounds the highly variable Contributors involvement of dierent organs. Although growing All authors contributed to the writing, review, and editing of this evidence indicates the importance of tissue-bound host Seminar. responses, clinical assessment still largely relies on blood Declaration of interests biomarkers, with possible divergent responses in organs, MS reports grant funding from the Wellcome Trust, the Medical Research Council, the National Institute for Health and Care Research, such as the lungs.129 An inflammatory injury could and Gentian; is a sepsis topic advisor for the UK National Institute for progress unrecognised by conventional blood chemistry, Health and Care Excellence; and consulting fees to himself or his as witnessed by the beneficial eects obtained with anti- institution for advisory board work or speaking engagements from inflammatory interventions during COVID-19 in the AOP Orphan Pharma, Aptarion, Bayer, Biotest, bioMérieux, deepull, Deltex, Matisse, Pfizer, Radiometer, Roche Diagnostics, Safeguard absence of a serum cytokine storm.130 This occurrence Biosystems, Sanofi, and Volition. DCA reports consulting fees from calls for novel diagnostic approaches, for example based Abionix, AM-Pharma, and Bayer. DA reports grant funding from the on the exhalome of the patient.131 Agence Nationale de la Recherche; honoraria for lectures from Baxter, Finding interventions that hasten resolution of organ Alexion, and Beckman Coulter; and sits on advisory boards for Hillrom, Janssen, Pfizer, Regeneron, Sanofi, Viatris, Volition, and Fabentech. dysfunction after successful resuscitation would MB reports consulting fees from Thermo Fisher, Bayer, and deepull. considerably reduce the cost and burden of sepsis. MK reports grant funding from the US Centers for Disease Control Nowadays, many patients are eectively resuscitated and Prevention and the US Agency for Healthcare Research and 1284 Seminar Quality; and royalties from UpToDate. FRM reports speaker fees from 18 Shankar-Hari M, Calandra T, Soares MP, et al. Reframing sepsis Baxter and Novartis. GSM reports grant funding from the National immunobiology for translation: towards informative subtyping and Institutes of Health and the National Science Foundation; advisory targeted immunomodulatory therapies. Lancet Respir Med 2024; board honoraria from Eagle Pharmaceuticals and Grifols; and is an 12: 323–36. editor for Critical Care Clinics and a section editor for UpToDate. 19 Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a AGR reports grant funding from the National Institutes of Health; defense strategy. Science 2012; 335: 936–41. royalties from UpToDate; and travel support from Thermo Fisher. 20 Bauer M, Weis S, Netea MG, Wetzker R. Remembering pathogen MS-H reports funding from the National Institute for Health and Care dose: long-term adaptation in innate immunity. Trends Immunol Research and the Chief Scientific Ocer, Scotland. GvdB reports grant 2018; 39: 438–45. funding from the European Research Council. 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