Sepsis

• 1. Introduction

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  Sepsis affected about 49 million people in 2017, and 11 million of them died. That works out to one in every five deaths worldwide. The condition begins with an infection, yet the injury comes from the body's own dysregulated response to it. Tissues and organs suffer damage from the very defences meant to protect them. Several puzzles surround the illness. What turns an immune defence into a weapon aimed inward? Why can a patient in grave danger have no fever at all? And why do treatments that look sensible, sometimes backed by dramatic early results, so often fail when they are tested again?

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• 2. Inside the Cascade

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  Two phases define the biology of sepsis, and either one can kill. The early phase is marked by excessive inflammation, which sometimes becomes a cytokine storm. A prolonged period of weakened immune function may follow. Doctors separate sepsis from systemic inflammatory response syndrome, or SIRS, which appears without infection in people with burns, multiple serious injuries, or early pancreatitis. Sepsis nonetheless provokes a similar response.

  Four families of receptors in the innate immune system raise the alarm. They are the toll-like receptors, the C-type lectin receptors, the NOD-like receptors, and the RIG-I-like receptors. Each can spot pathogen-associated molecular patterns, such as lipopolysaccharides and flagellin on gram-negative bacteria, CpG bacterial DNA, or muramyl dipeptide in the cell wall of gram-positive bacteria. Whenever a pattern meets a receptor, signals cascade through the cell. Transcription factors, including nuclear factor-kappa B and activator protein-1, then turn up the genes for both pro-inflammatory and anti-inflammatory cytokines.

  Lipid A, a component of lipopolysaccharide that is also called endotoxin, is thought to drive much of the sepsis caused by gram-negative bacteria. Gram-positive bacteria can set it off through lipoteichoic acid in their cell walls. Some bacterial exotoxins act as superantigens, which bind major histocompatibility complex molecules and T-cell receptors at once, without any antigen presentation. That forced contact makes T-cells release a flood of cytokines.

  Neutrophil extracellular traps, called NETs, form only when a neutrophil dies, and they clear bacteria from the bloodstream. Platelets may play a key role in steering the response. Systemic inflammation, injury to the vessel lining, and disordered clotting activate them early. The activated platelets then interact with white blood cells and vessel-lining cells, amplifying both inflammation and clotting. That interaction feeds microvascular thrombosis and the progression to multiple organ dysfunction syndrome.

  Damage-associated molecular patterns, released by injured tissue, alert immune cells just as microbial signals do. The response then escapes control, because white blood cells are recruited all over the body instead of to the infection. Suppression follows. Interleukin 10 helps shift the proinflammatory T helper cell 1 response toward TH2, in what is called compensatory anti-inflammatory response syndrome. Lymphocytes then die by apoptosis, which deepens the suppression. Neutrophils, monocytes, macrophages, dendritic cells, CD4+ T cells, and B cells all undergo it, while regulatory T cells resist. Meanwhile, cytochrome c oxidase is inhibited, so tissues cannot use oxygen efficiently. This may be a "cell hibernation" mechanism that conserves oxygen.

  Acute respiratory distress syndrome, or ARDS, shows up in the lungs when leaky vessels let fluid flood the air sacs, causing pulmonary edema. Doctors count it as organ dysfunction when the ratio of arterial oxygen to inspired oxygen drops below 300. The liver, short of oxygen, struggles to transport bile salts, and jaundice turns the skin yellowish. Its production of clotting factors falters too, so blood clots poorly. In the kidneys, inadequate oxygen injures the cells lining the tubules, producing acute kidney injury and low or absent urine output. The heart suffers from impaired calcium transport and low ATP, which depress contractility and can cause heart failure. Cellular damage there can leak troponin, although the cause is not necessarily ischemic.

  Paralytic ileus and mucosal bleeding strike the gut, whose lining grows more permeable and upsets the balance of its microflora. In the brain, direct damage to cells and disturbed neurotransmission alter mental status. The result ranges from agitation and confusion to coma.

  Tumor necrosis factor, interleukin 1, and interleukin 6 can switch on clotting factors in the cells lining blood vessels. The damaged surface loses its anticoagulant properties and promotes antifibrinolysis. Clots then form in small vessels, and multiple organs fail.

  Three processes help explain the fall in blood pressure. The body overproduces vessel-dilating chemicals such as nitric oxide, it lacks the vessel-constricting hormone vasopressin, and ATP-sensitive potassium channels switch on. In severe sepsis and septic shock, this chain of events produces a type of circulatory failure called distributive shock.

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• 3. Changing Culprits

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  Before antibiotics arrived in the 1950s, gram-positive bacteria were the main cause of sepsis. From the 1960s to the 1980s, gram-negative bacteria took the lead. After the 1980s, gram-positive bacteria, most commonly staphylococci, are thought to cause more than 50% of cases.

  Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species are other bacteria often implicated. Fungi account for approximately 5% of severe sepsis and septic shock cases. The usual culprit there is Candida yeast, a frequent hospital-acquired infection. Parasitic sepsis most often comes from Plasmodium, which causes malaria, along with Schistosoma and Echinococcus. In children, viral pathogens and diarrhoeal illnesses are common causes.

  Between 40 and 60% of infections that lead to sepsis start in the lungs. Another 15-30% begin in the abdomen, and a similar 15-30% in the bladder, kidney, skin, or soft tissue. Both the site and the pathogen vary with geographic region. A pathogen is found in 60-70% of cases. Risk factors include being very young or very old, an immune system weakened by cancer, diabetes, or the absence of a spleen, major trauma, and burns.

  Some authors propose that Streptococcus pneumoniae, Staphylococcus aureus, and other normally harmless residents of the microbiome sometimes start sepsis as an adaptive strategy rather than an accident. In their account, the trigger is a sudden fall in the host's chances of survival. The microbe then benefits by monopolizing the future cadaver, using its biomass as a decomposer, and spreading through soil or water to form partnerships with new hosts. Proteus, Clostridium, Lactobacillus, and Bacteroides are among the microbes the authors consider flexible enough for such a switch. They accept that not all cases of sepsis arise this way.

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• 4. Racing the Clock

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  Fever is the most common presenting symptom in sepsis, yet the elderly and people with weakened immune systems may have none. The very young and old can also show a low or normal temperature and no sign of which infection is responsible. In other patients the clues follow the source, such as a cough with pneumonia or painful urination with a kidney infection. Early signs include a rapid heart rate, decreased urination, and high blood sugar. Established sepsis adds confusion, edema, metabolic acidosis, and low blood pressure from decreased systemic vascular resistance. Cardiac output rises, and disordered clotting may lead to organ failure.

  A pulse pressure above 70 mmHg is correlated with better odds of survival in sepsis. Pulse pressure is the gap between the top and bottom blood-pressure numbers. Early in the illness the bottom number falls and the gap widens, which also predicts that a patient will respond to intravenous fluids. As circulatory compromise advances, the top number drops too, and the gap narrows. The fall in pressure can cause lightheadedness. In septic shock, circulating levels of copper and vitamin C are lower, a sign of oxidative stress.

  Three hours is the first deadline. Within it, diagnostic studies should include white blood cell counts, serum lactate, and cultures, drawn before antibiotics as long as that delays the drugs by no more than 45 minutes. At least two sets of blood cultures are needed, using bottles for organisms that need air and those that do not. One set should be drawn through the skin and one through each vascular access device, such as an IV catheter, that has been in place for more than 48 hours. Bacteria are present in the blood in only about 30% of cases. Polymerase chain reaction is another possible method of detection. Cultures of urine, cerebrospinal fluid, wounds, or respiratory secretions are added if those sites are suspected. Some hospitals use alerts generated from electronic health records to flag potential cases early.

  Six hours brings a second checkpoint. If blood pressure stays low despite initial fluid resuscitation, or if the first lactate reading is 4 mmol/L (36 mg/dL) or higher, central venous pressure and central venous oxygen saturation should be measured. Lactate is measured again when the first reading was elevated. Evidence favouring point-of-care lactate testing over usual methods is poor. By twelve hours, clinicians must diagnose or exclude any infection needing emergency source control. Examples are a necrotizing soft tissue infection, inflammation of the abdominal cavity lining, a bile duct infection, or intestinal infarction. Free air on an abdominal X-ray or CT scan, a chest X-ray showing focal opacification, and petechiae, purpura, or purpura fulminans are all clues.

  Alcohol withdrawal, acute pancreatitis, burns, pulmonary embolism, thyrotoxicosis, anaphylaxis, adrenal insufficiency, and neurogenic shock can all mimic the systemic signs of sepsis. Hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis, or HLH, belong on the list as well.

  A 2013 review found moderate-quality evidence for using procalcitonin to tell sepsis from non-infectious causes of SIRS. The test showed 77% sensitivity and 79% specificity, so its authors cautioned that the level alone cannot settle the diagnosis. Newer literature recommends using it to direct antibiotic therapy. A 2012 systematic review judged soluble urokinase-type plasminogen activator receptor, or SuPAR, a nonspecific marker of inflammation that cannot diagnose sepsis. Higher levels did go with more deaths. Lactate checked about every 4 to 6 hours may guide treatment and is associated with lower mortality. A level above 4 mmol/L carries a mortality of 40%, while a level below 2 mmol/L carries less than 15%. Mitochondrial dysfunction is also a key feature of sepsis, and it can be assessed in peripheral blood mononuclear cells with a minimally invasive blood sample. A recent longitudinal study found that this function shifts during the first week of critical illness, hinting at a marker of progression and recovery.

  The first month of life changes the picture. Neonatal sepsis usually means a bacterial bloodstream infection, such as meningitis, pneumonia, pyelonephritis, or gastroenteritis, though fungi, viruses, or parasites can be responsible. Newborns may show no symptoms, and criteria based on circulatory compromise or respiratory failure come too late to help. When a newborn looks suspicious, antibiotics start immediately and are then narrowed to a specific organism or stopped once infection is ruled out. Even with early intervention, 13% of children who develop septic shock die.

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• 5. Shifting Definitions

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  In the fourth century BC, Hippocrates introduced the Greek word σήψις, meaning the process of decay or decomposition of organic matter. In the eleventh century, Avicenna used "blood rot" for diseases tied to severe purulent processes. Doctors had long observed severe systemic toxicity, yet the specific term sepsis for the condition arrived only in the 19th century.

  Septicemia and blood poisoning once referred to microorganisms or their toxins in the blood. Version 9 of the International Statistical Classification of Diseases, in use in the United States until 2013, relied on septicemia with modifiers, such as "Streptococcal septicemia." Version 10 converted all of these to sepsis, as in "Sepsis due to streptococcus." Current terms depend on the organism. Bacteremia means abnormal levels of bacteria in the blood, viremia means viruses, and fungemia means a fungus.

  Before a consensus in 2016, SIRS criteria defined sepsis. SIRS meant two or more abnormalities among body temperature, heart rate, respiratory rate or blood gas, and white blood cell count. Sepsis was SIRS in response to infection. Severe sepsis added organ dysfunction or poor tissue blood flow, shown by low blood pressure, elevated lactate, or decreased urine output. Septic shock was severe sepsis plus persistently low blood pressure despite intravenous fluids. A negative SIRS result made sepsis very unlikely, but a positive one meant only a moderate probability.

  The 2016 consensus replaced SIRS screening with the sequential organ failure assessment, or SOFA score, and a shortened version called qSOFA. The qSOFA criteria are a respiratory rate of at least 22 breaths per minute, a systolic blood pressure of 100 mmHg or less, and altered mental status. Sepsis is suspected when two of the three are met. The SOFA score was meant for the intensive care unit, where it is taken at admission and repeated every 48 hours. The qSOFA can be used outside the unit, because it is quick and needs no lab tests.

  The American College of Chest Physicians, known as CHEST, raised a worry that SOFA and qSOFA could delay the diagnosis of serious infection. SIRS can be too sensitive and not specific enough, yet SOFA has limits of its own and was never meant to replace it. The qSOFA proved poorly sensitive, though decently specific, for the risk of death, and SIRS may screen better. The Surviving Sepsis Campaign, an international collaboration founded in 2002 to improve outcomes and publish guidelines, weighed in during 2021. It recommended "against using qSOFA compared with SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock."

  Children have their own thresholds. A capillary refill time longer than 5 seconds can count toward cardiovascular dysfunction after fluid resuscitation with at least 40 mL/kg of crystalloid. A Glasgow Coma Score of 11 or lower marks neurologic dysfunction. A platelet count below 80,000 per cubic millimetre signals hematologic dysfunction. Consensus definitions continue to change, and the latest expand the list of sepsis signs to reflect experience at the bedside.

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• 6. Treatment Under Debate

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  The Sepsis Six, a bundle in widespread use in the United Kingdom, shows how much treatment depends on speed. It calls for antibiotics within an hour of recognition, blood cultures, lactate and hemoglobin measurement, urine output monitoring, high-flow oxygen, and intravenous fluids. Other professional bundles set a three-hour target for antibiotics and fluids when blood pressure is low or lactate is raised. Sepsis needs immediate treatment in a hospital because it can worsen quickly. Care also includes surgical drainage of infected collections and support for failing organs through hemodialysis, mechanical ventilation, blood products, or drugs for the circulation.

  Ubi pus, ibi evacua is the Latin phrase behind source control, roughly meaning that where there is pus, it should be drained. Source control covers physical steps, such as draining an abscess, that reduce conditions favourable to microbes. It is one of the oldest procedures for controlling infection and remains important despite modern treatments.

  Some experts urge antibiotics within one hour of diagnosis, citing a 6% rise in mortality for every hour of delay, though others found no benefit from early administration. In severe sepsis and septic shock, guidelines recommend broad-spectrum antibiotics, usually two. The choice depends on local patterns of bacterial sensitivity, whether the infection came from hospital or community, and which organ systems are involved. Regimens are reassessed daily and narrowed where possible, and treatment typically lasts 7-10 days. For methicillin-resistant Staphylococcus aureus, vancomycin or teicoplanin is recommended. Legionella calls for an added macrolide or fluoroquinolone. Suspected fungal infection in severe sepsis calls for an echinocandin such as caspofungin or micafungin, followed by a triazole for less ill patients. If cultures are negative, antibiotics should be reduced or stopped, which lowers the chance of breeding multiple-drug-resistant organisms. Monitoring drug levels helps keep doses effective but below the toxic range.

  The Surviving Sepsis Campaign has recommended 30 mL/kg of fluid for adults in the first three hours. For children in shock, 20 mL/kg is a reasonable start. Crystalloid solutions are the fluid of choice. Balanced ones such as lactated Ringer's are associated with lower mortality than normal saline. Albumin can be used when large volumes of crystalloid are needed. Starches carry a higher risk of kidney injury and transfusion, and colloids such as modified gelatin offer no advantage.

  A 2014 trial found that keeping hemoglobin above 70 or above 90 g/L made no difference to survival, and the lower threshold meant fewer transfusions. Erythropoietin is not recommended for anemia in septic shock, because it may precipitate blood clotting events. Intravenous immunoglobulin and blood purification techniques such as hemoperfusion have not shown a survival benefit.

  Norepinephrine, also called noradrenaline, is the first-choice drug when fluids leave mean arterial pressure at or below 65 mmHg. Starting it late is associated with higher mortality. It raises pressure by narrowing blood vessels, with little effect on stroke volume and heart rate. Vasopressin is useful because shock lasting 24 to 48 hours brings a relative deficiency of it, though it reduces blood flow to the heart, fingers and toes, and abdominal organs. When the norepinephrine dose becomes exceedingly high and toxic, epinephrine may be added, but it cuts blood flow to abdominal organs and raises lactate. Dopamine is typically not recommended, because it causes more abnormal heart rhythms and has an immunosuppressive effect. Dobutamine can raise cardiac output but reduces blood flow to the gut.

  In 2016, the Surviving Sepsis Campaign recommended low-dose hydrocortisone only when fluids and vasopressors could not adequately treat septic shock. The 2021 version recommends intravenous corticosteroids for adults with septic shock who still need vasopressors. A 2019 Cochrane review, updated in 2025, found moderate certainty evidence of benefit, as did two other reviews from 2019. Critical illness-related corticosteroid insufficiency, a state of adrenal insufficiency and tissue resistance to corticosteroids, may be at work. Neither ACTH stimulation testing nor random cortisol levels are recommended to confirm it.

  A tidal volume of 6 mL/kg of predicted body weight and a plateau pressure under 30 cm H2O are recommended for ventilated patients with severe ARDS. Predicted body weight comes from sex and height. High positive end expiratory pressure is advised for moderate to severe ARDS because it opens more lung units for oxygen exchange. Insulin is recommended to bring high blood sugar down to 7.8-10 mmol/L (140-180 mg/dL), since lower levels may worsen outcomes. Patients also need measures against deep vein thrombosis, stress ulcers, and pressure ulcers.

  General anesthesia is recommended when a patient needs surgery to remove the source of infection. Etomidate has a minimal effect on the cardiovascular system, yet it is often avoided for intubation in sepsis over concern that it harms adrenal function and raises the risk of death. The small amount of evidence available has found no change in the risk of death.

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• 7. Promises That Failed

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  Pfeiffer coined the term endotoxin at the beginning of the 20th century for the fever-causing principle associated with Vibrio cholerae. Researchers soon realized that most, and perhaps all, gram-negative bacteria make endotoxins. Shear worked out the lipopolysaccharide character of enteric endotoxins in 1944. Luderitz and colleagues determined its molecular character in 1973.

  In 1965, a strain of C3H/HeJ mouse was found to be immune to endotoxin-induced shock. The genetic locus behind the effect was named Lps. These mice were also unusually susceptible to infection by gram-negative bacteria. The two observations were finally linked in 1998 by the discovery of the toll-like receptor gene TLR4. Genetic mapping over five years showed that TLR4 was the only candidate in the Lps critical region, strongly implying that a mutation there explained the resistance.

  By 2013, mice had become a source of doubt. Scientists that year published a review comparing the mouse immune system with the human one and found that the two work very differently at a systems level. They noted that over 150 clinical trials of sepsis had been run in humans, almost all backed by promising mouse data, and that all had failed. The authors called for abandoning mouse models. Others rejected that but urged more caution with mouse results and more careful design of preclinical studies. One approach is to study biopsies and clinical data from people who have had sepsis, searching for biomarkers and drug targets.

  In the original trial of early goal-directed therapy, mortality fell from 46.5% to 30.5%. The approach is a step-wise program for the first 6 hours after diagnosis, aimed at optimizing cardiac preload, afterload, and contractility, and it includes early antibiotics. Its targets are a central venous pressure of 8-12 mmHg, a mean arterial pressure of 65-90 mmHg, central venous oxygen saturation above 70%, and urine output above 0.5 mL/kg/hour. Three later large randomized trials, ProCESS, ARISE, and ProMISe, found no 90-day mortality benefit over standard therapy. Some parts of the program probably matter more than others, and its use is still considered reasonable. A suitable fall in serum lactate may serve in place of oxygen saturation and is easier to obtain.

  Drotrecogin alpha, a recombinant activated protein C, was introduced for severe sepsis identified by a high APACHE II score, in the hope of improving survival. Later studies showed more adverse events, bleeding in particular, and no drop in mortality. It was removed from sale in 2011. Another drug, eritoran, has not shown benefit either. A 2012 Cochrane review concluded that N-acetylcysteine does not reduce mortality and may even be harmful. Treating fever has not been linked to better survival over 28 days.

  Paul E. Marik's protocol, also known as the HAT protocol, combined hydrocortisone, vitamin C, and thiamine for intensive care patients. His initial research, published in 2017, showed dramatic benefit, and the protocol grew popular among intensive care physicians after attention on social media and National Public Radio. The wider medical community criticized it as science by press conference. Independent research failed to replicate the positive results, suggesting bias may have compromised them, and a systematic review of trials in 2021 could not confirm the claimed benefits. People with sepsis may have low vitamin C, and reviews mention that 3.0 g/day, given intravenously, may be needed to maintain normal levels in sepsis or severe burn injury. Whether vitamin C has any role in treatment remains unclear.

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• 8. Counting the Toll

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  Within 30 days, sepsis proves fatal for approximately 24.4% of people and septic shock for 34.7%. At 90 days the figures rise to 32.2% and 38.5%. The global mortality rate from sepsis declined from 50% in 1990 to 35% in 2017. Changing definitions and growing recognition of the condition make both incidence and mortality hard to measure.

  APACHE II estimates the risk of dying of severe sepsis from a person's age, underlying condition, and various physiologic variables. Of these, the severity of the underlying disease most strongly influences the risk of death. Septic shock is also a strong predictor of short- and long-term mortality. Case-fatality rates are similar for culture-positive and culture-negative severe sepsis. The Mortality in Emergency Department Sepsis score, known as MEDS, is simpler and suits the emergency department.

  Some survivors face severe long-term cognitive decline. Most people with sepsis lack baseline neuropsychological data, so the true incidence is difficult to study. Other complications include functional decline, an inability to return to work, and, in children, a failure to regain baseline health. Immune dysfunction and hyperinflammation may persist long after sepsis has resolved.

  Sub-Saharan Africa accounts for 40% of cases worldwide, and 85% of all cases occur in low or middle income countries. In the developed world, approximately 0.2 to 3 people per 1000 are affected each year. In the United States the figure is approximately 3 in 1,000, and severe sepsis contributes to more than 200,000 deaths per year. Sepsis occurs in 1-2% of all hospitalizations and accounts for as much as 25% of intensive care bed use. It is the tenth-most-common cause of death overall and the second-leading cause in non-coronary intensive care units. Children under 12 months and elderly people have the highest incidence of severe sepsis.

  From 1979 to 2000, data from the United States National Hospital Discharge Survey showed incidence rising fourfold, to 240 cases per 100,000 population. Over the same period, in-hospital case fatality fell from 28% to 18%. Mortality climbs with age, from less than 10% in the age group of 3 to 5 years to 60% by the sixth decade of life. Among Medicare patients in a study of 18 states, sepsis was the second most common principal reason for readmission within 30 days in 2011. An aging population, more people on immunosuppressive medications, and more invasive procedures have all pushed the rate up. Data conflict on sex, with some showing more cases in men and other estimates higher in women.

  Sepsis was the most expensive condition treated in United States hospital stays in 2013, at an aggregate cost of $23.6 billion for nearly 1.3 million hospitalizations. Costs for sepsis stays more than quadrupled after 1997, rising 11.5 percent a year. It was the most costly condition billed to Medicare and to the uninsured, and the second-most costly billed to Medicaid.

  Sepsis Alliance, a charitable organization based in the United States, was created to raise sepsis awareness among the public and healthcare professionals. In 2011, September was declared Sepsis Awareness Month. A year later, the Global Sepsis Alliance declared the 13th of September World Sepsis Day.

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