View source for Sepsis

{{Short description|Life-threatening response to infection}}
{{For|the fly|Sepsis (fly){{!}}''Sepsis'' (fly)}}
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{{Use dmy dates|date=November 2025}}
{{Infobox medical condition (new)
| name = sepsis
| image = sepsis-Mikrothomben1.JPG
| caption = Skin blotching and inflammation caused by sepsis
| field = [[infectious disease (medical specialty)|infectious disease]], [[critical care medicine]], [[emergency medicine]]
| pronounce = {{IPAc-en|ˈ|s|ɛ|p|s|ᵻ|s}}
| symptoms = {{Hlist|[[Fever]]|[[tachycardia|increased heart rate]]|[[hypotension|low blood pressure]]|[[hyperventilation|increased breathing rate]]|[[oliguria|low urine output]]| [[anuria|absent or near absent urine output]]|[[pain|severe pain]]|[[mental confusion|confusion]]<ref name=CDC2014Q/>}}
| complications = {{Hlist|[[Multiple organ dysfunction syndrome]]|[[organ failure|temporary, transient, or permanent organ damage]]|[[ECMO|extra corporeal membrane oxygenation]]|[[hemodialysis|blood filtration or dialysis]]}}
| onset = May be rapid (less than three hours) or prolonged (several days)
| duration =
| causes = [[Immune system|Immune response]] triggered by an infection<ref name=Tint2011/><ref name=Deutschman2014/>
| risks = {{Hlist|Young or old age|[[cancer]]|[[diabetes mellitus|diabetes]]|[[major trauma]]|[[asthma]]|[[COPD|Chronic Obstructive Pulmonary Disease]]|[[multiple myeloma]]|[[burn]]s}}<ref name=CDC2014Q/>
| diagnosis = [[Systemic inflammatory response syndrome]] (SIRS),<ref name=Tint2011/> [[SOFA score#Quick SOFA score|qSOFA]]<ref name="Sepsis–3_2016"/>
| differential =
| prevention = [[Influenza vaccination]], [[Vaccinations|vaccines]], [[pneumococcal vaccination|pneumonia vaccination]]
| treatment = [[Intravenous fluids]], [[antimicrobial]]s, [[vasopressors]]<ref name=CDC2014Q/><ref name= "SSC–G2016"/>
| medication =
| prognosis = Mortality: sepsis ~30%, severe sepsis ~50%, septic shock ~80%.
The mortality may be lower if treated aggressively and early, depending on the organism and disease, the patient's previous health, and the abilities of the treatment location and its staff.
| frequency = In 2017, there were 48.9 million cases and 11 million sepsis-related deaths worldwide (according to WHO)
| deaths =
}}

'''Sepsis''' is a potentially life-threatening condition that arises when the body's dysregulated response to [[infection]] causes injury to its own tissues and organs.<ref name="Sepsis–3_2016"/><ref name=NEJM2013/>

This initial stage of sepsis is followed by dysregulation of the [[immune system]].<ref name="pmid31611560">{{cite journal | vauthors = Cao C, Yu M, Chai Y | title = Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis | journal = [[Cell Death & Disease]] | volume = 10 | issue = 10 | article-number = 782 | date = October 2019 | pmid = 31611560 | pmc = 6791888 | doi = 10.1038/s41419-019-2015-1 }}</ref> Common signs and symptoms include [[fever]], [[tachycardia|increased heart rate]], [[hyperventilation|increased breathing rate]], and [[mental confusion|confusion]].<ref name=CDC2014Q/> There may also be symptoms related to a specific infection, such as a cough with [[pneumonia]], or [[dysuria|painful urination]] with a [[pyelonephritis|kidney infection]].<ref name=Tint2011/> The very young, old, and people with a [[immunodeficiency|weakened immune system]] may not have any symptoms specific to their infection, and their [[hypothermia|body temperature]] may be low or normal instead of constituting a fever.<ref name=Tint2011/> Severe sepsis may cause [[organ dysfunction]] and significantly reduced blood flow.<ref name=SSCG2012>{{cite journal | vauthors = Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R | display-authors = 6 | title = Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012 | journal = Critical Care Medicine | volume = 41 | issue = 2 | pages = 580–637 | date = February 2013 | pmid = 23353941 | doi = 10.1097/CCM.0b013e31827e83af | doi-access = free }}</ref> The presence of [[Hypotension|low blood pressure]], high blood [[Lactic acid|lactate]], or [[Oliguria|low urine output]] may suggest poor blood flow.<ref name=SSCG2012/> [[Septic shock]] is low blood pressure due to sepsis that does not improve after [[fluid replacement]] or requires [[vasopressors|medications]] to raise the blood pressure.<ref name=SSCG2012/><ref name="Meyer 2024" />

Sepsis is caused by many organisms including bacteria, viruses, and fungi.<ref>{{cite journal | vauthors = Sehgal M, Ladd HJ, Totapally B | title = Trends in Epidemiology and Microbiology of Severe Sepsis and Septic Shock in Children | journal = [[American Academy of Pediatrics|Hospital Pediatrics]] | volume = 10 | issue = 12 | pages = 1021–1030 | date = December 2020 | pmid = 33208389 | doi = 10.1542/hpeds.2020-0174 | s2cid = 227067133 | doi-access = free }}</ref> [[Gram negative]] and [[gram positive]] bacteria are the most common causes of sepsis. Viral pathogens and diarrheal illnesses are common causes in children.<ref name="Meyer 2024" /> In 60–70% of cases an infectious pathogen is found.<ref name="Meyer 2024" /> Common locations for the primary infection include the lungs, brain, [[urinary tract]], skin, and [[abdominal organs]].<ref name="Tint2011" /> Risk factors include being very young or old, a weakened immune system from conditions such as [[cancer]] or [[diabetes mellitus|diabetes]], [[major trauma]], and [[burn]]s.<ref name="CDC2014Q" /> A shortened [[SOFA score|sequential organ failure assessment score]] (SOFA score), known as the [[SOFA score#Quick SOFA score|quick SOFA score]] (qSOFA), has replaced the [[systemic inflammatory response syndrome|SIRS]] system of diagnosis.<ref name="Sepsis–3_2016" /> qSOFA criteria for sepsis include at least two of the following three: increased breathing rate, change in the level of consciousness, and low blood pressure.<ref name="Sepsis–3_2016" /> Sepsis guidelines recommend obtaining [[blood culture]]s before starting antibiotics; however, the diagnosis does not require the [[Bacteremia|blood to be infected]].<ref name="Tint2011" /> [[Medical imaging]] is helpful when looking for the possible location of the infection.<ref name="SSCG2012" /> Other potential causes of similar signs and symptoms include [[anaphylaxis]], [[adrenal insufficiency]], [[hypovolemia|low blood volume]], [[heart failure]], and [[pulmonary embolism]].<ref name="Tint2011" />

Sepsis requires immediate treatment with [[intravenous fluids]] and [[antimicrobial]] medications.<ref name="CDC2014Q" /><ref name="SSC–G2016" /> Ongoing care and stabilization often continues in an [[intensive care unit]].<ref name=CDC2014Q/> If an adequate trial of fluid replacement is not enough to maintain blood pressure, then the use of medications that [[vasopressor|raise blood pressure]] becomes necessary.<ref name=CDC2014Q/> [[Mechanical ventilation]] and [[Kidney dialysis|dialysis]] may be needed to support the function of the lungs and kidneys, respectively.<ref name=CDC2014Q/> A [[central venous catheter]] and [[arterial line]] may be placed for access to the bloodstream and to guide treatment.<ref name=SSCG2012/> Other helpful measurements include [[cardiac output]] and [[superior vena cava]] [[oxygen saturation (medicine)|oxygen saturation]].<ref name=SSCG2012/> People with sepsis need preventive measures for [[deep vein thrombosis]], [[stress ulcer]]s, and [[pressure ulcer]]s unless other conditions prevent such interventions.<ref name=SSCG2012/> Some people might benefit from tight control of [[blood sugar level]]s with [[insulin]].<ref name=SSCG2012/> The use of [[corticosteroids]] is controversial, with some reviews finding benefit,<ref name=":1">{{Cite journal |last1=Annane |first1=Djillali |last2=Briegel |first2=Josef |last3=Granton |first3=David |last4=Bellissant |first4=Eric |last5=Bollaert |first5=Pierre Edouard |last6=Keh |first6=Didier |last7=Kupfer |first7=Yizhak |last8=Pirracchio |first8=Romain |last9=Rochwerg |first9=Bram |date=2025-06-05 |title=Corticosteroids for treating sepsis in children and adults |journal=[[The Cochrane Database of Systematic Reviews]] |volume=2025 |issue=6 |article-number=CD002243 |doi=10.1002/14651858.CD002243.pub5 |issn=1469-493X |pmc=12138977 |pmid=40470636 |pmc-embargo-date=5 June 2026 }}</ref><ref name=Fang2018/> others not.<ref name=Long2017/>

A person's age, immune system function, the virulence of the pathogen causing infection, the amount of microorganisms in the body causing infection (pathogen burden) all affect the incidence, severity and prognosis of sepsis.<ref name="Meyer 2024">{{cite journal |last1=Meyer |first1=Nuala J. |last2=Prescott |first2=Hallie C. |title=Sepsis and Septic Shock |journal=[[New England Journal of Medicine]] |date=5 December 2024 |volume=391 |issue=22 |pages=2133–2146 |doi=10.1056/NEJMra2403213}}</ref><ref name=Jawad2012/> The risk of death from sepsis is as high as 30%, while for severe sepsis it is as high as 50%, and the risk of death from septic shock is 80%.<ref>{{cite journal | vauthors = Epstein L, Dantes R, Magill S, Fiore A | title = Varying Estimates of Sepsis Mortality Using Death Certificates and Administrative Codes--United States, 1999-2014 | language = en-us | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 65 | issue = 13 | pages = 342–345 | date = April 2016 | pmid = 27054476 | doi = 10.15585/mmwr.mm6513a2 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Desale M, Thinkhamrop J, Lumbiganon P, Qazi S, Anderson J | title = Ending preventable maternal and newborn deaths due to infection | journal = Best Practice & Research. Clinical Obstetrics & Gynaecology | volume = 36 | pages = 116–130 | date = October 2016 | pmid = 27450868 | doi = 10.1016/j.bpobgyn.2016.05.008 }}</ref><ref name=Jawad2012>{{cite journal | vauthors = Jawad I, Lukšić I, Rafnsson SB | title = Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality | journal = Journal of Global Health | volume = 2 | issue = 1 | article-number = 010404 | date = June 2012 | pmid = 23198133 | pmc = 3484761 | doi = 10.7189/jogh.01.010404 }}</ref> Sepsis affected about 49 million people in 2017, with 11 million deaths (1 in 5 deaths worldwide).<ref name=":0"/> In the [[developed world]], approximately 0.2 to 3 people per 1000 are affected by sepsis yearly.<ref name=Jawad2012/><ref name=Martin2012/> Rates of disease have been increasing.<ref name=SSCG2012/> 85% of cases occurred in low or middle income countries with 40% of cases worldwide occurring in [[Sub-Saharan Africa]].<ref name="Meyer 2024"/> Some data indicate that sepsis is more common among men than women;<ref name=Tint2011/> however, other data show a greater prevalence of the disease among women.<ref name=":0">{{cite journal | vauthors = Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, Fleischmann-Struzek C, Machado FR, Reinhart KK, Rowan K, Seymour CW, Watson RS, West TE, Marinho F, Hay SI, Lozano R, Lopez AD, Angus DC, Murray CJ, Naghavi M | display-authors = 6 | title = Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study | language = English | journal = Lancet | volume = 395 | issue = 10219 | pages = 200–211 | date = January 2020 | pmid = 31954465 | pmc = 6970225 | doi = 10.1016/S0140-6736(19)32989-7 | hdl-access = free | hdl = 11343/273829 }}</ref>
[[File:En.Wikipedia-VideoWiki-Sepsis.webm|thumb|thumbtime=2:04|upright=1.4|Video summary ([[Wikipedia:VideoWiki/Sepsis|script]])]]

== Signs and symptoms ==
In addition to symptoms related to the actual cause, people with sepsis may have a [[fever]], [[hypothermia|low body temperature]], [[Tachypnea|rapid breathing]], [[tachycardia|a fast heart rate]], [[mental confusion|confusion]], and [[edema]].<ref name="pmid12682500"/> Early signs include a rapid heart rate, [[oliguria|decreased urination]], and high blood sugar. Signs of established sepsis include confusion, [[metabolic acidosis]] (which may be accompanied by a faster breathing rate that leads to [[respiratory alkalosis]]), low blood pressure due to decreased systemic [[vascular resistance]], higher [[cardiac output]], and [[disseminated intravascular coagulation|disorders in blood-clotting]] that may lead to organ failure.<ref name=Hospital2012/> Fever is the most common presenting symptom in sepsis, but fever may be absent in some people, such as the elderly or those who are immunocompromised.<ref name="Gauer et al" />

The drop in blood pressure seen in sepsis can cause [[lightheadedness]] and is part of the criteria for [[septic shock]].<ref name=MedLP/>

Oxidative stress is observed in septic shock, with circulating levels of copper and vitamin&nbsp;C being decreased.<ref>{{cite journal | vauthors = Singer P, Blaser AR, Berger MM, Alhazzani W, Calder PC, Casaer MP, Hiesmayr M, Mayer K, Montejo JC, Pichard C, Preiser JC, van Zanten AR, Oczkowski S, Szczeklik W, Bischoff SC | display-authors = 6 | title = ESPEN guideline on clinical nutrition in the intensive care unit | journal = Clinical Nutrition | volume = 38 | issue = 1 | pages = 48–79 | date = February 2019 | pmid = 30348463 | doi = 10.1016/j.clnu.2018.08.037 | s2cid = 53036546 | doi-access = free }}</ref>

[[Diastolic blood pressure]] falls during the early stages of sepsis, causing a widening/increasing of [[pulse pressure]], which is the difference between the systolic and diastolic blood pressures. If sepsis becomes severe and [[hemodynamic]] compromise advances, the [[systolic pressure]] also decreases, causing a narrowing/decreasing of pulse pressure.<ref name=pedsepsis>{{cite journal |vauthors=Khilnani P, Singhi S, Lodha R, Santhanam I, Sachdev A, Chugh K, Jaishree M, Ranjit S, Ramachandran B, Ali U, Udani S, Uttam R, Deopujari S |date=January 2010 |title=Pediatric Sepsis Guidelines: Summary for resource-limited countries |journal=Indian J Crit Care Med |volume=14 |issue=1 |pages=41–52 |doi=10.4103/0972-5229.63029 |pmc=2888329 |pmid=20606908 |doi-access=free }}</ref> A pulse pressure of over 70&nbsp;mmHg in patients with sepsis is correlated with an increased chance of survival.<ref name=widesepsis/> A widened pulse pressure is also correlated with an increased chance that someone with sepsis will benefit from and respond to [[Fluid replacement#Intravenous|IV fluids]].<ref name=widesepsis>{{cite journal |vauthors=Al-Khalisy H, Nikiforov I, Jhajj M, Kodali N, Cheriyath P |date=11 December 2015 |title=A widened pulse pressure: a potential valuable prognostic indicator of mortality in patients with sepsis. J Community Hosp Intern Med Perspect |journal=J Community Hosp Intern Med Perspect |volume=5 |issue=6 |article-number=29426 |doi=10.3402/jchimp.v5.29426 |pmc=4677588 |pmid=26653692 }}</ref>

== Cause ==
[[File:Patient lying in bed in intensive care unit of hospital with apparatuses and hemodialysis machine.jpg|thumb|Patient of an [[intensive care unit]] of a German hospital (2015) with severe sepsis caused by a [[chain reaction]] of incidental negative events after a prior surgery of the [[abdomen]]. After an emergency surgery, he received [[antibiotics]], [[parenteral nutrition]], and [[pain killer]]s via automated injection employing [[infusion pump]]s (background right). [[Hemodialysis]] via the machine on the left became necessary due to [[kidney]] malfunction and [[multiple organ dysfunction syndrome]]. After three months in the hospital, the patient recovered within a month and has since then fully recovered (as of 2023).]]

Infections leading to sepsis are usually [[pathogenic bacteria|bacterial]] but may be [[mycosis|fungal]], [[Parasitic disease|parasitic]], or [[viral disease|viral]].<ref name= "Mandell2014"/> [[Gram-positive bacteria]] were the primary cause of sepsis before the introduction of antibiotics in the 1950s. After the introduction of antibiotics, [[gram-negative bacteria]] became the predominant cause of sepsis from the 1960s to the 1980s.<ref name="Polat"/> After the 1980s, gram-positive bacteria, most commonly [[staphylococci]], are thought to cause more than 50% of cases of sepsis.<ref name="Martin2012"/><ref name="BlochID"/> Other commonly implicated bacteria include ''[[Streptococcus pyogenes]]'', ''[[Escherichia coli]]'', ''[[Pseudomonas aeruginosa]]'', and ''[[Klebsiella]]'' species.<ref name="Ramachandran2014"/> [[Fungemia|Fungal sepsis]] accounts for approximately 5% of severe sepsis and septic shock cases; the most common cause of fungal sepsis is an infection by ''[[Candida (fungus)|Candida]]'' species of [[yeast]],<ref name="Delalove2014"/> a frequent [[hospital-acquired infection]]. The most common causes for parasitic sepsis are ''[[Plasmodium]]'' (which leads to [[malaria]]), ''[[Schistosoma]]'' and ''[[Echinococcus]]''.

The most common sites of infection resulting in severe sepsis are the lungs, the abdomen, and the urinary tract.<ref name= "Mandell2014"/> 40–60% of infections causing sepsis originate in the lungs, 15–30% are abdominal infections, and 15–30% are bladder, kidney, skin or soft tissue infections.<ref name="Meyer 2024" /> But the site of infection, as well as the causative infectious pathogen vary depending on geographic location and region.<ref name="Meyer 2024" />

== Pathophysiology ==
Sepsis is caused by a combination of factors related to the particular invading pathogen(s) and the status of the immune system of the host.<ref name=Critical2005 /> The early phase of sepsis, characterized by excessive inflammation (sometimes resulting in a [[cytokine storm]]), may be followed by a prolonged period of [[immunosuppression|decreased functioning of the immune system]].<ref name=Shukla2014/><ref name="pmid31611560" /> Either of these phases may prove fatal. On the other hand, systemic inflammatory response syndrome (SIRS) occurs in people without the presence of infection, for example, in those with [[burn]]s, [[polytrauma]], or the initial state in [[pancreatitis]] and [[chemical pneumonitis]]. However, sepsis also causes a similar response to SIRS.<ref name="1992consensus"/>

[[Platelet]]s have a potentially key role in immune modulation during sepsis.<ref name="xu">{{cite journal |vauthors=Xu X, Wang Y, Tao Y, Dang W, Yang B, Li Y |title=The role of platelets in sepsis: A review |journal=Biomolecules & Biomedicine |volume=24 |issue=4 |pages=741–752 |date=January 2024 |pmid=38236204 |pmc=11293227 |doi=10.17305/bb.2023.10135}}</ref> Systemic inflammation, endothelial injury, and dysregulated coagulation activate platelets in the early phases of the condition.<ref name=xu/> These activated platelets interact with [[leukocyte]]s and [[Endothelium|endothelial cells]], amplifying both inflammatory and [[Thrombosis|thrombotic]] responses.<ref name=xu/> This interaction contributes to microvascular thrombosis and progression to [[multiple organ dysfunction syndrome]].<ref name=xu/>

=== Microbial factors ===
Bacterial [[virulence factor]]s, such as [[glycocalyx]] and various [[adhesins]], allow colonization, immune evasion, and establishment of disease in the host.<ref name=Critical2005/> Sepsis caused by [[gram-negative]] bacteria is thought to be largely due to a response by the host to the [[lipid A]] component of [[lipopolysaccharide]], also called [[endotoxin]].<ref name="Park2013"/><ref name="Cross2014"/> Sepsis caused by [[gram-positive]] bacteria may result from an immunological response to cell wall [[lipoteichoic acid]].<ref name=Fournier2005/> Bacterial [[exotoxin]]s that act as [[superantigens]] also may cause sepsis.<ref name=Critical2005 /> Superantigens simultaneously bind [[major histocompatibility complex]] and [[T-cell receptor]]s in the absence of [[antigen presentation]]. This forced receptor interaction induces the production of pro-inflammatory chemical signals ([[cytokines]]) by T-cells.<ref name=Critical2005 />

There are several microbial factors that may cause the typical septic [[Inflammation|inflammatory cascade]]. An invading pathogen is recognized by its [[pathogen-associated molecular pattern]]s (PAMPs). Examples of PAMPs include lipopolysaccharides and [[flagellin]] in gram-negative bacteria, [[muramyl dipeptide]] in the [[peptidoglycan]] of the gram-positive bacterial cell wall, and [[CpG dinucleotide|CpG bacterial DNA]]. These PAMPs are recognized by the [[pattern recognition receptors]] (PRRs) of the innate immune system, which may be membrane-bound or cytosolic.<ref name=Leentjens2013/> There are four families of PRRs: the [[toll-like receptors]], the [[C-type lectin]] receptors, the [[NOD-like receptor]]s, and the [[RIG-I-like receptor]]s. Invariably, the association of a PAMP and a PRR will cause a series of intracellular signalling cascades. Consequently, transcription factors such as [[nuclear factor-kappa B]] and [[AP-1 transcription factor|activator protein-1]] will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines.<ref name=Antonopoulou2011/>

Other immunological responses related to microbial infections, such as [[Neutrophil extracellular traps|NETs]], can also play a role or be observed in sepsis. NET formation only occurs via neutrophil cell death, which occurs during microbial infections. Neutrophil extracellular traps, called NETs, eliminate bacteria from the blood flow. These compounds are part of the innate immune system, which is activated initially during infections.<ref>{{Cite journal |last1=Denning |first1=Naomi-Liza |last2=Aziz |first2=Monowar |last3=Gurien |first3=Steven D. |last4=Wang |first4=Ping |date=2019-10-30 |title=DAMPs and NETs in Sepsis |journal=Frontiers in Immunology |language=English |volume=10 |article-number=2536 |doi=10.3389/fimmu.2019.02536 |doi-access=free |pmid=31736963 |pmc=6831555 |issn=1664-3224}}</ref>

=== Host factors ===
Upon detection of microbial [[antigen]]s, the host systemic immune system is activated. Immune cells not only recognise pathogen-associated molecular patterns but also [[damage-associated molecular pattern]]s from damaged tissues. An uncontrolled immune response is then activated because leukocytes are not recruited to the specific site of infection, but instead, they are recruited all over the body. Then, an immunosuppression state ensues when the proinflammatory [[T helper cell]] 1 (TH1) is shifted to TH2,<ref name="Yuki"/> mediated by [[interleukin 10]], which is known as "compensatory anti-inflammatory response syndrome".<ref name="Polat"/> The [[apoptosis]] (cell death) of lymphocytes further worsens the immunosuppression. [[Neutrophil]]s, [[monocytes]], [[macrophages]], [[dendritic cell]]s, [[CD4|CD4+ T cells]], and [[B cell]]s all undergo apoptosis, whereas [[regulatory T cell]]s are more apoptosis-resistant.<ref name="pmid31611560" /> Subsequently, [[multiple organ dysfunction syndrome|multiple organ failure]] ensues because tissues are unable to use oxygen efficiently due to inhibition of [[cytochrome c oxidase]], possibly as part of a "cell hibernation" mechanism, to conserve oxygen.<ref name="Yuki"/>

Inflammatory responses cause [[multiple organ dysfunction syndrome]] through various mechanisms as described below. Increased permeability of the lung vessels causes leaking of fluids into alveoli, which results in [[pulmonary edema]] and [[acute respiratory distress syndrome]] (ARDS). Impaired utilization of oxygen in the liver impairs [[bile salt]] transport, causing [[jaundice]] (yellowish discoloration of the skin). In kidneys, inadequate oxygenation results in tubular epithelial cell injury (of the cells lining the kidney tubules), and thus causes [[acute kidney injury]] (AKI). Meanwhile, in the heart, impaired calcium transport and low production of [[adenosine triphosphate]] (ATP) can cause myocardial depression, reducing cardiac contractility and causing [[heart failure]]. In the [[gastrointestinal tract]], increased permeability of the mucosa alters the microflora, causing mucosal bleeding and [[paralytic ileus]]. In the [[central nervous system]], direct damage of the brain cells and disturbances of neurotransmissions causes altered mental status.<ref name=Fujishima2016/> Cytokines such as [[TNF-alpha|tumor necrosis factor]], [[Interleukin 1 family|interleukin 1]], and [[interleukin 6]] may activate [[coagulation|procoagulation]] factors in the [[endothelium|cells lining blood vessels]], leading to endothelial damage. The damaged endothelial surface inhibits anticoagulant properties as well as increases [[antifibrinolytic|antifibrinolysis]], which may lead to intravascular clotting, the formation of [[thrombus|blood clots]] in small blood vessels, and multiple organ failure.<ref name= Nimah2003/>

The low blood pressure seen in those with sepsis is the result of various processes, including excessive production of chemicals that [[Vasodilation|dilate blood vessels]] such as [[nitric oxide]], a deficiency of chemicals that [[vasoconstriction|constrict blood vessels]] such as [[vasopressin]], and activation of [[ATP-sensitive potassium channel]]s.<ref name="Marik2014"/> In those with severe sepsis and septic shock, this sequence of events leads to a type of [[circulatory shock]] known as [[distributive shock]].<ref name="Marik2014Chest"/>

== Diagnosis ==
Early diagnosis is necessary to properly manage sepsis, as the initiation of rapid therapy is key to reducing deaths from severe sepsis.<ref name=SSCG2012/> Some hospitals use alerts generated from [[electronic health record]]s to bring attention to potential cases as early as possible.<ref name=NPR/>

[[File:Bloodculturetubes.JPG|thumb |[[Blood culture]] bottles: orange cap for [[anaerobes]], green cap for [[aerobes]], and yellow cap for blood samples from children<ref>{{cite web |url=http://d2xk4h2me8pjt2.cloudfront.net/webjc/attachments/74/c6e3e84-blood-culture-and-isolator-collection-instructions.pdf |title=Blood Culture Collection |publisher=WVUH Laboratories |date=7 April 2012 |access-date=23 March 2020 }}</ref>]]

Within the first three hours of suspected sepsis, diagnostic studies should include [[white blood cell counts]], measuring serum lactate, and obtaining appropriate cultures before starting antibiotics, so long as this does not delay their use by more than 45 minutes.<ref name=SSCG2012/> To identify the causative organism(s), at least two sets of [[blood culture]]s using bottles with [[growth medium|media]] for [[aerobic organism|aerobic]] and [[anaerobic organism]]s are necessary. At least one should be drawn [[percutaneously|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.<ref name=SSCG2012/> Bacteria are [[bacteremia|present in the blood]] in only about 30% of cases.<ref name="Wacker2013"/> Another possible method of detection is by [[polymerase chain reaction]]. If other sources of infection are suspected, cultures of these sources, such as urine, cerebrospinal fluid, wounds, or respiratory secretions, also should be obtained, as long as this does not delay the use of antibiotics.<ref name=SSCG2012/>

Within six hours, if blood pressure remains low despite initial fluid resuscitation of 30&nbsp;mL/kg, or if initial lactate is ≥ four&nbsp;mmol/L (36&nbsp;mg/dL), [[central venous pressure]] and [[central venous oxygen saturation]] should be measured.<ref name=SSCG2012/> Lactate should be re-measured if the initial lactate was elevated.<ref name=SSCG2012/> Evidence for [[point of care]] lactate measurement over usual methods of measurement, however, is poor.<ref name=Morris2017/>

Within twelve hours, it is essential to diagnose or exclude any source of infection that would require emergent source control, such as a necrotizing soft tissue infection, an infection causing [[Peritonitis#Infected peritonitis|inflammation of the abdominal cavity lining]], an [[cholangitis|infection of the bile duct]], or an intestinal infarction.<ref name=SSCG2012/> A pierced [[viscus|internal organ]] (free air on an abdominal X-ray or CT scan), an abnormal [[chest radiograph|chest X-ray]] consistent with [[pneumonia]] (with focal opacification), or [[petechia]]e, [[purpura]], or [[purpura fulminans]] may indicate the presence of an infection.{{citation needed|date=August 2021}}

=== Definitions ===
{{SIRS}}
[[File:Sepsis Steps.png|thumb|upright=1.25|Sepsis Steps. Training tool for teaching the progression of sepsis stages]]
Previously, SIRS criteria had been used to define sepsis. If the SIRS criteria are negative, it is very unlikely the person has sepsis; if it is positive, there is just a moderate probability that the person has sepsis. According to SIRS, there were different levels of sepsis: sepsis, severe sepsis, and septic shock.<ref name="1992consensus"/> The definition of SIRS is shown below:
* SIRS is the presence of two or more of the following: abnormal [[body temperature]], [[heart rate]], [[respiratory rate]], or [[blood gas]], and [[white blood cell]] count.
* ''Sepsis'' is defined as SIRS in response to an infectious process.<ref name=Soong2012/>
* ''Severe sepsis'' is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (manifesting as hypotension, elevated lactate, or [[oliguria|decreased urine output]]). Severe sepsis is an infectious disease state associated with multiple organ dysfunction syndrome (MODS)<ref name=SSCG2012/>
* ''[[Septic shock]]'' is severe sepsis plus persistently [[hypotension|low blood pressure]], despite the administration of intravenous fluids.<ref name=SSCG2012/>

In 2016, a new consensus was reached to replace screening by [[systemic inflammatory response syndrome]] (SIRS) with the sequential organ failure assessment ([[SOFA score]]) and the abbreviated version ([[qSOFA]]).<ref name="Sepsis–3_2016"/> The three criteria for the qSOFA score include a respiratory rate greater than or equal to 22 breaths per minute, systolic blood pressure 100&nbsp;mmHg or less, and altered mental status.<ref name="Sepsis–3_2016" /> Sepsis is suspected when 2 of the qSOFA criteria are met.<ref name="Sepsis–3_2016" /> The SOFA score was intended to be used in the intensive care unit (ICU) where it is administered upon admission to the ICU and then repeated every 48 hours, whereas the qSOFA could be used outside the ICU.<ref name="Gauer et al">{{cite journal | vauthors = Gauer RL | title = Early recognition and management of sepsis in adults: the first six hours | journal = [[American Family Physician]] | volume = 88 | issue = 1 | pages = 44–53 | date = July 2013 | pmid = 23939605 }}</ref> Some advantages of the qSOFA score are that it can be administered quickly and does not require labs.<ref name="Gauer et al" /> However, the [[American College of Chest Physicians]] (CHEST) raised concerns that qSOFA and SOFA criteria may lead to delayed diagnosis of serious infection, leading to delayed treatment.<ref name=Simpson2016/> Although SIRS criteria can be too sensitive and not specific enough in identifying sepsis, SOFA also has its limitations and is not intended to replace the SIRS definition.<ref name=Vincent2016/> qSOFA has also been found to be poorly sensitive though decently specific for the risk of death with SIRS possibly better for screening. NOTE - Surviving Sepsis Campaign 2021 Guidelines recommend "against using qSOFA compared with SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock".<ref name=Fernando2018/>

=== End-organ dysfunction ===
{{Main|Multiple organ dysfunction syndrome}}
Examples of [[end organ damage|end-organ dysfunction]] include the following:<ref name="pmid17948334"/>
* Lungs: [[acute respiratory distress syndrome]] (ARDS) ([[PaO2/FiO2 ratio|PaO<sub>2</sub>/FiO<sub>2</sub> ratio]] < 300), different ratio in [[Acute respiratory distress syndrome#Terminology|pediatric acute respiratory distress syndrome]]
* Brain: [[encephalopathy]] symptoms including agitation, confusion, and coma; causes may include ischemia, bleeding, formation of blood clots in small blood vessels, microabscesses, multifocal necrotizing leukoencephalopathy
* Liver: disruption of protein synthetic function manifests acutely as progressive [[coagulopathy|disruption of blood clotting]] due to an inability to synthesize [[clotting factors]] and disruption of metabolic functions leads to impaired [[bilirubin]] metabolism, resulting in elevated unconjugated serum [[bilirubin]] levels
* Kidney: [[oliguria|low urine output]] or [[anuria|no urine output]], [[electrolyte abnormalities]], or [[volume overload]]
* Heart: systolic and diastolic [[heart failure]], likely due to [[cytokines|chemical signals]] that depress myocyte function, cellular damage, manifest as a [[troponin]] leak (although not necessarily ischemic in nature)

More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.<ref name="pmid15636651"/>
* Cardiovascular dysfunction (after fluid resuscitation with at least 40&nbsp;mL/kg of crystalloid)
** hypotension with blood pressure < 5th percentile for age or systolic blood pressure < 2 standard deviations below normal for age, or
** [[vasopressor]] requirement, or
** Two of the following criteria:
*** unexplained [[metabolic acidosis]] with [[base deficit]] > 5 mEq/L
*** [[lactic acidosis]]: serum lactate 2 times the upper limit of normal
*** oliguria (urine output {{nowrap|< 0.5 mL/kg/h}})
*** prolonged [[capillary refill]] > 5 seconds
*** core to peripheral temperature difference {{nowrap|> 3 °C}}
* Respiratory dysfunction (in the absence of a [[cyanotic heart defect]] or a known chronic [[respiratory disease]])
** the ratio of the arterial partial pressure of oxygen to the fraction of oxygen in the gases inspired (PaO<sub>2</sub>/FiO<sub>2</sub>) < 300 (the definition of [[acute lung injury]]), or
** arterial partial pressure of carbon dioxide (PaCO<sub>2</sub>) > 65 torr (20 [[millimetre of mercury|mmHg]]) over baseline PaCO<sub>2</sub> (evidence of [[hypercapnia|hypercapnic]] [[respiratory failure]]), or
** supplemental oxygen requirement of greater than FiO<sub>2</sub> 0.5 to maintain oxygen saturation ≥ 92%
* Neurologic dysfunction
** [[Glasgow Coma Score]] (GCS) ≤ 11, or
** [[altered level of consciousness|altered mental status]] with a drop in GCS of 3 or more points in a person with [[Developmental disability|developmental delay]]/[[intellectual disability]]
* Hematologic dysfunction
** [[platelet]] count {{nowrap|< 80,000/mm<sup>3</sup>}} or 50% drop from the maximum in chronically thrombocytopenic, or
** [[international normalized ratio]] (INR) > 2
** [[Disseminated intravascular coagulation]]
* Kidney dysfunction
** serum [[creatinine]] ≥ 2 times the upper limit of normal for age or 2-fold increase in baseline [[creatinine]] in people with [[chronic kidney disease]]
* Liver dysfunction (only applicable to infants > 1 month)
** total serum [[bilirubin]] ≥ 4&nbsp;mg/dL, or
** [[alanine aminotransferase]] (ALT) ≥ 2 times the upper limit of normal

Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.<ref name="pmid12682500" />

=== Biomarkers ===
Biomarkers can help with diagnosis because they can point to the presence or severity of sepsis, although their exact role in the management of sepsis remains undefined.<ref>{{cite journal | vauthors = Pierrakos C, Vincent JL | title = Sepsis biomarkers: a review | journal = Critical Care | volume = 14 | issue = 1 | article-number = R15 | date = 2010 | pmid = 20144219 | pmc = 2875530 | doi = 10.1186/cc8872 | doi-access = free }}</ref> A 2013 [[review]] concluded moderate-quality evidence exists to support the use of the [[procalcitonin]] level as a method to distinguish sepsis from non-infectious causes of SIRS.<ref name="Wacker2013"/> The same review found the [[Sensitivity and specificity|sensitivity]] of the test to be 77% and the specificity to be 79%. The authors suggested that procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone does not definitively make the diagnosis.<ref name="Wacker2013"/> More current literature recommends utilizing the PCT to direct antibiotic therapy for improved antibiotic stewardship and better patient outcomes.<ref>{{cite journal | vauthors = Valencia L | title = PCT testing in sepsis protocols | journal = Frontiers in Analytical Science|  date = July 2023 | volume = 3 | article-number = 1229003 | doi = 10.3389/frans.2023.1229003 | doi-access = free }}</ref>

A 2012 systematic review found that [[SuPAR|soluble urokinase-type plasminogen activator receptor]] (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis.<ref name="Backes2012"/> This same review concluded, however, that SuPAR has prognostic value, as higher SuPAR levels are associated with an increased rate of death in those with sepsis.<ref name="Backes2012"/> Serial measurement of lactate levels (approximately every 4 to 6 hours) may guide treatment and is associated with lower mortality in sepsis.<ref name="Gauer et al" />

=== Differential diagnosis ===
The [[differential diagnosis]] for sepsis is broad and has to examine (to exclude) the non-infectious conditions that may cause the systemic signs of SIRS: [[alcohol withdrawal]], [[acute pancreatitis]], [[burn]]s, [[pulmonary embolism]], [[thyrotoxicosis]], [[anaphylaxis]], [[adrenal insufficiency]], and [[neurogenic shock]].<ref name=Hospital2012 /><ref name="Mayr2014"/> Hyperinflammatory syndromes such as [[hemophagocytic lymphohistiocytosis]] (HLH) may have similar symptoms and are on the differential diagnosis.<ref name=Machowicz2017/>

=== Neonatal sepsis ===
In common clinical usage, [[neonatal sepsis]] refers to a bacterial [[bacteremia|blood stream infection]] in the first month of life, such as [[meningitis]], [[pneumonia]], [[pyelonephritis]], or [[gastroenteritis]],<ref name="Satar2012"/> but neonatal sepsis also may be due to infection with fungi, viruses, or parasites.<ref name="Satar2012"/> Criteria with regard to hemodynamic compromise or respiratory failure are not useful because they present too late for intervention.<ref>{{Cite web |last=Wijekumara |first=Shanaka |date=6 October 2024 |title=Sepsis and Septic Shock: Definition, Symptoms, and Treatment |url=https://www.surgicaliq.com/sepsis-definition-symptoms-diagnosis-treatment/ |website=SurgicalIQ}}</ref>

== Treatment ==
[[File:Sepsis treatment.jpg|thumb|Intravenous fluids being given]]
{{See also|Antiseptic|Asepsis}}

Sepsis requires immediate treatment in a hospital as it can quickly worsen. Current professional recommendations include several actions ("bundles") to be followed as soon as possible after diagnosis. Within the first three hours, someone with sepsis should have received antibiotics and intravenous fluids if there is evidence of either low blood pressure or other evidence for inadequate blood supply to organs (as evidenced by a raised level of lactate); blood cultures should also be obtained within this period. After six hours, the blood pressure should be adequate, close monitoring of blood pressure and blood supply to organs should be in place, and the lactate should be measured again if initially it was raised.<ref name=SSCG2012/> A related bundle, the "[[Sepsis Six]]", is in widespread use in the [[United Kingdom]]; this requires the administration of antibiotics within an hour of recognition, blood cultures, lactate, and hemoglobin determination, urine output monitoring, high-flow oxygen, and intravenous fluids.<ref name=Daniels2011/><ref name=SIGN139/>

Apart from the timely administration of fluids and [[antibiotic]]s, the management of sepsis also involves surgical drainage of infected fluid collections and appropriate support for organ dysfunction. This may include [[Kidney dialysis|hemodialysis]] in [[kidney failure]], [[mechanical ventilation]] in [[lung]] dysfunction, transfusion of [[blood plasma|blood products]], and drug and fluid therapy for circulatory failure. Ensuring adequate nutrition—preferably by [[enteral feeding]], but if necessary, by [[parenteral nutrition]]—is important during prolonged illness.<ref name=SSCG2012/> Medication to prevent [[deep vein thrombosis]] and [[gastric ulcers]] also may be used.<ref name=SSCG2012/>

=== Antibiotics ===
Two sets of blood cultures (aerobic and anaerobic) are recommended without delaying the initiation of antibiotics. Cultures from other sites such as respiratory secretions, urine, wounds, cerebrospinal fluid, and catheter insertion sites are recommended if infections from these sites are suspected.<ref name= "SSC–G2016"/> In severe sepsis and septic shock, [[broad-spectrum antibiotic]]s (usually two, a [[β-lactam antibiotic]] with broad coverage, or broad-spectrum [[carbapenem]] combined with [[Quinolone antibiotic|fluoroquinolones]], [[macrolide]]s, or [[aminoglycoside]]s) are recommended. The choice of antibiotics is important in determining the survival of the person.<ref name="Marik2014Chest"/><ref name="SSC–G2016"/> Some recommend they be given within one hour of making the diagnosis, stating that for every hour of delay in the administration of antibiotics, there is an associated 6% rise in mortality.<ref name=Soong2012 /><ref name="Marik2014Chest"/> Others did not find a benefit with early administration.<ref name=Sterling2015/>

Several factors determine the most appropriate choice for the initial antibiotic regimen. These factors include local patterns of bacterial sensitivity to antibiotics, whether the infection is thought to be a [[Hospital-acquired infection|hospital]] or community-acquired infection, and which organ systems are thought to be infected.<ref name="Marik2014Chest"/><ref name="Gauer et al" /> Antibiotic regimens should be reassessed daily and narrowed if appropriate. Treatment duration is typically 7–10&nbsp;days with the type of antibiotic used directed by the results of cultures. If the culture result is negative, antibiotics should be de-escalated according to the person's clinical response or stopped altogether if an infection is not present to decrease the chances that the person is infected with [[multiple drug resistance]] organisms. In case of people having a high risk of being infected with [[multiple drug resistance|multiple drug resistant]] organisms such as ''[[Pseudomonas aeruginosa]]'', ''[[Acinetobacter baumannii]]'', the addition of an antibiotic specific to the organism is recommended. For [[Methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']] (MRSA), [[vancomycin]] or [[teicoplanin]] is recommended. For ''[[Legionella]]'' infection, addition of [[macrolide]] or [[fluoroquinolone]] is chosen. If fungal infection is suspected, an [[echinocandin]], such as [[caspofungin]] or [[micafungin]], is chosen for people with severe sepsis, followed by [[triazole]] ([[fluconazole]] and [[itraconazole]]) for less ill people.<ref name= "SSC–G2016"/> Prolonged antibiotic prophylaxis is not recommended in people who have SIRS without any infectious origin, such as [[acute pancreatitis]] and [[burn]]s unless sepsis is suspected.<ref name= "SSC–G2016"/>

Once-daily dosing of [[aminoglycoside]] is sufficient to achieve peak plasma concentration for a clinical response without kidney toxicity. Meanwhile, for antibiotics with low volume distribution (vancomycin, teicoplanin, colistin), a loading dose is required to achieve an adequate therapeutic level to fight infections. Frequent infusions of beta-lactam antibiotics without exceeding the total daily dose would help to keep the antibiotic level above [[minimum inhibitory concentration]] (MIC), thus providing a better clinical response.<ref name= "SSC–G2016"/> Giving beta-lactam antibiotics continuously may be better than giving them intermittently.<ref name=Roberts2016/> Access to [[therapeutic drug monitoring]] is important to ensure adequate drug therapeutic level while at the same time preventing the drug from reaching a toxic level.<ref name= "SSC–G2016"/>

=== Intravenous fluids ===
The [[Surviving Sepsis Campaign]] has recommended 30&nbsp;mL/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a target [[mean arterial pressure]] (MAP) of 65&nbsp;mmHg.<ref name= "SSC–G2016"/> In children, an initial amount of 20&nbsp;mL/kg is reasonable in shock.<ref name="de Caen2015"/> In cases of severe sepsis and septic shock where a [[central venous catheter]] is used to measure blood pressures dynamically, fluids should be administered until the [[central venous pressure]] reaches 8–12 mmHg.<ref name="Marik2014"/> Once these goals are met, the central venous oxygen saturation (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized.<ref name= "SSC–G2016"/> If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10&nbsp;g/dL and then [[inotrope]]s are added until the ScvO2 is optimized.<ref name=Critical2005 /> In those with [[acute respiratory distress syndrome]] (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully.<ref name=SSCG2012/>

[[Crystalloid solution]] is recommended as the fluid of choice for resuscitation.<ref name= "SSC–G2016"/> "Balanced" crystalloid solutions such as [[lactated ringers]] (which have levels of sodium, potassium and chloride closer to a person's extracellular levels) are associated with a lower mortality as compared to normal saline solutions in the treatment of sepsis.<ref name="Meyer 2024" /> [[Albumin]] can be used if a large amount of crystalloid is required for resuscitation.<ref name= "SSC–G2016"/> Crystalloid solutions shows little difference with [[hydroxyethyl starch]] in terms of risk of death.<ref name=Lew2018/> Starches also carry an increased risk of [[acute kidney injury]],<ref name=Lew2018 /><ref name= Zarychanski2013/> and need for blood transfusion.<ref name=Haase2013/><ref name=Serpa2014/> Various colloid solutions (such as modified gelatin) carry no advantage over crystalloid.<ref name=Lew2018 /> Albumin also appears to be of no benefit over crystalloids.<ref name=Patel2014/>

=== Blood products ===
The Surviving Sepsis Campaign recommended [[packed red blood cells]] transfusion for [[hemoglobin]] levels below 70&nbsp;g/L if there is no [[myocardial ischemia]], [[hypoxemia]], or acute bleeding.<ref name= "SSC–G2016"/> In a 2014 trial, blood transfusions to keep target hemoglobin above 70 or 90&nbsp;g/L did not make any difference to survival rates; meanwhile, those with a lower threshold of transfusion received fewer transfusions in total.<ref name=Holst2014/> [[Erythropoietin]] is not recommended in the treatment of anemia with septic shock because it may precipitate blood clotting events. [[Fresh frozen plasma]] transfusion usually does not correct the underlying clotting abnormalities before a planned surgical procedure. However, platelet transfusion is suggested for platelet counts below (10 billion/L) without any risk of bleeding, or (20 billion/L) with a high risk of bleeding, or (50 billion/L) with active bleeding, before planned surgery or an invasive procedure.<ref name= "SSC–G2016"/> IV immunoglobulin is not recommended because its beneficial effects are uncertain.<ref name= "SSC–G2016"/> Monoclonal and polyclonal preparations of [[intravenous immunoglobulin|intravenous immunoglobulin (IVIG)]] do not lower the rate of death in newborns and adults with sepsis.<ref name="Alejandria2013"/> Evidence for the use of [[immunoglobulin M|IgM]]-enriched polyclonal preparations of IVIG is inconsistent.<ref name="Alejandria2013"/> On the other hand, the use of [[antithrombin#Medical uses|antithrombin]] to treat [[disseminated intravascular coagulation]] is also not useful. Meanwhile, the blood purification technique (such as [[hemoperfusion]], plasma filtration, and coupled plasma filtration adsorption) to remove inflammatory mediators and bacterial toxins from the blood also does not demonstrate any survival benefit for septic shock.<ref name= "SSC–G2016"/>

=== Vasopressors ===
If the person has been sufficiently fluid resuscitated but the [[mean arterial pressure]] is not greater than 65&nbsp;mmHg, [[vasopressor]]s are recommended.<ref name= "SSC–G2016"/> [[Norepinephrine (medication)|Norepinephrine]] (noradrenaline) is recommended as the initial choice.<ref name= "SSC–G2016"/> Delaying initiation of vasopressor therapy during septic shock is associated with increased mortality.<ref>{{cite journal | vauthors = Bai X, Yu W, Ji W, Lin Z, Tan S, Duan K, Dong Y, Xu L, Li N | display-authors = 6 | title = Early versus delayed administration of norepinephrine in patients with septic shock | journal = Critical Care | volume = 18 | issue = 5 | article-number = 532 | date = October 2014 | pmid = 25277635 | pmc = 4194405 | doi = 10.1186/s13054-014-0532-y | doi-access = free }}</ref>

Norepinephrine is often used as a first-line treatment for hypotensive septic shock because evidence shows that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours.<ref name=Avni2015/> Norepinephrine raises blood pressure through a vasoconstriction effect, with little effect on [[stroke volume]] and heart rate.<ref name="SSC–G2016"/> In some people, the required dose of vasopressor needed to increase the mean arterial pressure can become exceedingly high, and it becomes toxic.<ref name=Hamzaoui2017/> To reduce the required dose of vasopressor, epinephrine may be added.<ref name=Hamzaoui2017/> Epinephrine is not often used as a first-line treatment for hypotensive shock because it reduces blood flow to the abdominal organs and increases lactate levels.<ref name= Avni2015/> Vasopressin can be used in septic shock because studies have shown that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. However, vasopressin reduces blood flow to the heart, fingers/toes, and abdominal organs, resulting in a lack of oxygen supply to these tissues.<ref name= "SSC–G2016"/> [[Dopamine]] is typically not recommended. Although dopamine is useful for increasing the stroke volume of the heart, it causes more [[Heart arrhythmia|abnormal heart rhythms]] than norepinephrine and also has an immunosuppressive effect. Dopamine is not proven to have protective properties on the kidneys.<ref name="SSC–G2016"/> [[Dobutamine]] can also be used in hypotensive septic shock to increase cardiac output and correct blood flow to the tissues.<ref name=Dubin2017/> Dobutamine is not used as often as epinephrine due to its associated side effects, which include reducing blood flow to the gut.<ref name=Dubin2017/> Additionally, dobutamine increases the cardiac output by abnormally increasing the heart rate.<ref name=Dubin2017/>

=== Steroids ===
The use of [[steroids]] in sepsis is controversial.<ref name=Patel2012/> Studies do not give a clear picture as to whether and when [[glucocorticoid]]s should be used.<ref name=Volbeda2015/> The 2016 Surviving Sepsis Campaign recommends low-dose [[hydrocortisone]] only if both intravenous fluids and vasopressors are not able to adequately treat septic shock.<ref name= "SSC–G2016"/> The 2021 Surviving Sepsis Campaign recommends IV corticosteroids for adults with septic shock who have an ongoing requirement for vasopressor therapy. A 2019 Cochrane (updated in 2025) review found moderate certainty evidence of benefit,<ref name=":1" /> as did two 2019 reviews.<ref name="Fang2018"/><ref name=Ni2019/>

During critical illness, a state of [[adrenal insufficiency]] and tissue resistance to [[corticosteroids]] may occur. This has been termed [[critical illness–related corticosteroid insufficiency]].<ref name="pmid18496365"/> Treatment with corticosteroids might be most beneficial in those with [[septic shock]] and early severe ARDS, whereas its role in others such as those with [[pancreatitis]] or severe [[pneumonia]] is unclear.<ref name="pmid18496365" /> However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. Neither [[Cort-stim test|ACTH stimulation testing]]<ref name="pmid18496365" /> nor random [[cortisol]] levels are recommended to confirm the diagnosis.<ref name= "SSC–G2016"/> The method of stopping glucocorticoid drugs is variable, and it is unclear whether they should be slowly decreased or simply abruptly stopped. However, the 2016 Surviving Sepsis Campaign recommended tapering steroids when vasopressors are no longer needed.<ref name= "SSC–G2016"/>

=== Anesthesia ===
A target [[tidal volume]] of 6&nbsp;mL/kg of predicted body weight (PBW) and a [[plateau pressure]] less than 30&nbsp;cm H<sub>2</sub>O is recommended for those who require [[mechanical ventilation|ventilation]] due to sepsis-induced severe ARDS. High [[positive end expiratory pressure]] (PEEP) is recommended for moderate to severe ARDS in sepsis as it opens more lung units for oxygen exchange. Predicted body weight is calculated based on sex and height, and tools for this are available.<ref name="Ardsnet"/> Recruitment maneuvers may be necessary for severe ARDS by briefly raising the transpulmonary pressure. It is recommended that the head of the bed be raised if possible to improve ventilation. However, [[beta2-adrenergic agonist|β2 adrenergic receptor agonists]] are not recommended to treat ARDS because they may reduce survival rates and precipitate [[Heart arrhythmia|abnormal heart rhythms]]. A [[spontaneous breathing trial]] using [[continuous positive airway pressure]] (CPAP), T piece, or inspiratory pressure augmentation can help reduce the duration of ventilation. Minimizing intermittent or continuous sedation helps reduce the duration of mechanical ventilation.<ref name="SSC–G2016"/>

General anesthesia is recommended for people with sepsis who require surgical procedures to remove the infectious source. Usually, inhalational and intravenous anesthetics are used. Requirements for anesthetics may be reduced in sepsis. [[Inhalational anaesthetic|Inhalational anesthetics]] can reduce the level of proinflammatory cytokines, altering leukocyte adhesion and proliferation, inducing [[apoptosis]] (cell death) of the lymphocytes, possibly with a toxic effect on [[mitochondria]]l function.<ref name="Yuki"/> Although [[etomidate]] has a minimal effect on the cardiovascular system, it is often not recommended as a medication to help with [[intubation]] in this situation due to concerns it may lead to [[adrenal insufficiency|poor adrenal function]] and an increased risk of death.<ref name=Cherfan2012/><ref name=Chan2012/> The small amount of evidence there is, however, has not found a change in the risk of death with etomidate.<ref name=Gu2015/>

[[Neuromuscular-blocking drug|Paralytic agents]] are not suggested for use in sepsis cases in the absence of [[Acute respiratory distress syndrome|ARDS]], as a growing body of evidence points to reduced durations of [[mechanical ventilation]], ICU, and hospital stays.<ref name=SSCG2012/> However, paralytic use in [[Acute respiratory distress syndrome|ARDS]] cases remains controversial. When appropriately used, paralytics may aid successful mechanical ventilation; however, evidence has also suggested that mechanical ventilation in severe sepsis does not improve oxygen consumption and delivery.<ref name=SSCG2012/>

=== Source control ===
Source control refers to physical interventions to control a [[focus of infection]] and reduce conditions favorable to microorganism growth or host defense impairment, such as [[Incision and drainage|drainage of pus]] from an [[abscess]]. It is one of the oldest procedures for the control of infections, giving rise to the Latin phrase ''[[Ubi pus, ibi evacua]]'', and remains important despite the emergence of more modern treatments.<ref>{{cite journal | vauthors = Lagunes L, Encina B, Ramirez-Estrada S | title = Current understanding in source control management in septic shock patients: a review | journal = Annals of Translational Medicine | volume = 4 | issue = 17 | page = 330 | date = September 2016 | pmid = 27713888 | pmc = 5050189 | doi = 10.21037/atm.2016.09.02 | doi-access = free }}</ref><ref>{{cite book | vauthors = De Waele JJ | chapter = Source Control in the ICU|date=2009| title = Yearbook of Intensive Care and Emergency Medicine|pages=93–101| veditors = Vincent JL, Malbrain MM, De Laet IE |publisher=Springer Berlin Heidelberg|language=en|doi=10.1007/978-3-540-92276-6_9|isbn=978-3-540-92275-9}}</ref>

=== Early goal-directed therapy ===
[[Early goal directed therapy]] (EGDT) is an approach to the management of severe sepsis during the initial 6&nbsp;hours after diagnosis.<ref name=Campaign2008 /> It is a step-wise approach, with the physiologic goal of optimizing cardiac preload, afterload, and contractility.<ref name="EGDT"/> It includes giving early antibiotics.<ref name="EGDT"/> EGDT also involves monitoring of hemodynamic parameters and specific interventions to achieve key resuscitation targets which include maintaining a central venous pressure between 8–12 mmHg, a mean arterial pressure of between 65 and 90&nbsp;mmHg, a central venous oxygen saturation (ScvO<sub>2</sub>) greater than 70% and a urine output of greater than 0.5&nbsp;mL/kg/hour. The goal is to optimize oxygen delivery to tissues and achieve a balance between systemic oxygen delivery and demand.<ref name="EGDT"/> An appropriate decrease in serum [[Lactic acid|lactate]] may be equivalent to ScvO<sub>2</sub> and easier to obtain.<ref name=Fuller2012/>

In the original trial, early goal-directed therapy was found to reduce mortality from 46.5% to 30.5% in those with sepsis,<ref name="EGDT"/> and the Surviving Sepsis Campaign has been recommending its use.<ref name=SSCG2012/> However, three more recent large randomized control trials (ProCESS, ARISE, and ProMISe), did not demonstrate a 90-day mortality benefit of early goal-directed therapy when compared to standard therapy in severe sepsis.<ref name=Dell2015/> It is likely that some parts of EGDT are more important than others.<ref name=Dell2015/> Following these trials, the use of EGDT is still considered reasonable.<ref name=Rusconi2015/>

=== Newborns ===
[[Neonatal sepsis]] can be difficult to diagnose as newborns may be asymptomatic.<ref name="Shane2014"/> If a newborn shows signs and symptoms suggestive of sepsis, antibiotics are immediately started and are either changed to target a specific organism identified by diagnostic testing or discontinued after an infectious cause for the symptoms has been ruled out.<ref name=Camacho2013/> Despite early intervention, death occurs in 13% of children who develop septic shock, with the risk partly based on other health problems. For those without multiple organ system failures or who require only one inotropic agent, mortality is low.<ref name="pmid12831416"/>

=== Other ===
Treating fever in sepsis, including people in septic shock, has not been associated with any improvement in mortality over a period of 28 days.<ref name=Drewry2017/> Treatment of fever still occurs for other reasons.<ref name=Niven2013/><ref name=Launey2011/>

A 2012 [[Cochrane Database of Systematic Reviews|Cochrane review]] concluded that [[N-acetylcysteine]] does not reduce mortality in those with SIRS or sepsis and may even be harmful.<ref name="Szakmany2012"/>

[[Recombinant DNA|Recombinant]] activated [[protein C]] ([[drotrecogin alpha]]) was originally introduced for severe sepsis (as identified by a high [[APACHE II]] score), where it was thought to confer a survival benefit.<ref name=Campaign2008 /> However, subsequent studies showed that it increased adverse events—bleeding risk in particular—and did not decrease mortality.<ref name=APC2012/> It was removed from sale in 2011.<ref name=APC2012 /> Another medication known as [[eritoran]] also has not shown benefit.<ref name=Fink2014/>

In those with [[hyperglycemia|high blood sugar]] levels, [[insulin]] to bring it down to 7.8–10&nbsp;mmol/L (140–180&nbsp;mg/dL) is recommended, with lower levels potentially worsening outcomes.<ref name=Hirasawa2009/> Glucose levels taken from capillary blood should be interpreted with care because such measurements may not be accurate. If a person has an arterial catheter, arterial blood is recommended for blood glucose testing.<ref name= "SSC–G2016"/>

Intermittent or continuous [[renal replacement therapy]] may be used if indicated. However, [[sodium bicarbonate]] is not recommended for a person with lactic acidosis secondary to hypoperfusion. [[Low-molecular-weight heparin]] (LMWH), [[unfractionated heparin]] (UFH), and mechanical prophylaxis with [[intermittent pneumatic compression]] devices are recommended for any person with sepsis at moderate to high risk of [[venous thromboembolism]].<ref name= "SSC–G2016"/> Stress ulcer prevention with [[proton-pump inhibitor]] (PPI) and [[H2 antagonist|H<sub>2</sub> antagonist]] are useful in a person with risk factors of developing [[upper gastrointestinal bleeding]] (UGIB) such as on mechanical ventilation for more than 48 hours, coagulation disorders, liver disease, and renal replacement therapy.<ref name= "SSC–G2016"/> Achieving partial or full enteral feeding (delivery of nutrients through a [[feeding tube]]) is chosen as the best approach to provide nutrition for a person who is contraindicated for oral intake or unable to tolerate orally in the first seven days of sepsis when compared to [[parenteral nutrition|intravenous nutrition]]. However, [[omega-3 fatty acid]]s are not recommended as immune supplements for a person with sepsis or septic shock. The usage of [[prokinetic agent]]s such as [[metoclopramide]], [[domperidone]], and [[erythromycin]] is recommended for those who are septic and unable to tolerate enteral feeding. However, these agents may precipitate prolongation of the [[QT interval]] and consequently provoke a [[ventricular arrhythmia]] such as [[torsades de pointes]]. The usage of prokinetic agents should be reassessed daily and stopped if no longer indicated.<ref name= "SSC–G2016"/>

People in sepsis may have micronutrient deficiencies, including low levels of vitamin&nbsp;C.<ref>{{cite journal | vauthors = Belsky JB, Wira CR, Jacob V, Sather JE, Lee PJ | title = A review of micronutrients in sepsis: the role of thiamine, L-carnitine, vitamin C, selenium and vitamin D | journal = Nutrition Research Reviews | volume = 31 | issue = 2 | pages = 281–90 | date = December 2018 | pmid = 29984680 | doi = 10.1017/S0954422418000124 | s2cid = 51599526 }}</ref> Reviews mention that an intake of 3.0&nbsp;g/day, which requires intravenous administration, may be needed to maintain normal plasma concentrations in people with sepsis or severe burn injury.<ref name=Liang2023>{{cite journal |vauthors=Liang B, Su J, Shao H, Chen H, Xie B |title=The outcome of IV vitamin C therapy in patients with sepsis or septic shock: a meta-analysis of randomized controlled trials |journal=Crit Care |volume=27 |issue=1 |article-number=109 |date=March 2023 |pmid=36915173 |pmc=10012592 |doi=10.1186/s13054-023-04392-y |url= | doi-access = free | title-link = doi }}</ref><ref>{{cite journal |vauthors=Berger MM, Oudemans-van Straaten HM |title=Vitamin C supplementation in the critically ill patient |journal=Curr Opin Clin Nutr Metab Care |volume=18 |issue=2 |pages=193–201 |date=March 2015 |pmid=25635594 |doi=10.1097/MCO.0000000000000148 |s2cid=37895257 |url=}}</ref>

== Prognosis ==
Sepsis proves fatal for approximately 24.4% of people, and septic shock proves fatal for 34.7% of people within 30 days (with fatality rates for sepsis and septic shock being 32.2% and 38.5% after 90 days, respectively).<ref name="pmid32430052"/>
Lactate is a useful method of determining prognosis, with those who have a level greater than 4&nbsp;mmol/L having a mortality of 40% and those with a level of less than 2&nbsp;mmol/L having a mortality of less than 15%.<ref name=Soong2012 />

There are several prognostic stratification systems, such as [[APACHE II]] and Mortality in Emergency Department Sepsis. APACHE II factors in the person's age, underlying condition, and various physiologic variables to yield estimates of the risk of dying of severe sepsis. Of the individual covariates, 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 (MEDS) score is simpler and useful in the emergency department environment.<ref name=Carpenter2009/>

Some people may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most people with sepsis makes the incidence of this difficult to quantify or study.<ref name=Jackson2009/> Other complications in those who survive sepsis include functional decline, being unable to return to work, or in pediatrics being unable to regain baseline health status.<ref name="Meyer 2024" /> Immune dysfunction and hyperinflammation may persist long after sepsis has resolved.<ref name="Meyer 2024" />

The global mortality rate from sepsis declined from 50% in 1990 to 35% in 2017. However, the incidence and mortality of sepsis is difficult to quantify due to changing definitions of sepsis and increased recognition of the complication over time.<ref name="Meyer 2024" /><ref name="Rudd 2020">{{cite journal |last1=Rudd |first1=Kristina E. |last2=Johnson |first2=Sarah Charlotte |last3=Agesa |first3=Kareha M. |last4=Shackelford |first4=Katya Anne |last5=Tsoi |first5=Derrick |last6=Kievlan |first6=Daniel Rhodes |last7=Colombara |first7=Danny V. |last8=Ikuta |first8=Kevin S. |last9=Kissoon |first9=Niranjan |last10=Finfer |first10=Simon |last11=Fleischmann-Struzek |first11=Carolin |last12=Machado |first12=Flavia R. |last13=Reinhart |first13=Konrad K. |last14=Rowan |first14=Kathryn |last15=Seymour |first15=Christopher W. |last16=Watson |first16=R Scott |last17=West |first17=T Eoin |last18=Marinho |first18=Fatima |last19=Hay |first19=Simon I. |last20=Lozano |first20=Rafael |last21=Lopez |first21=Alan D. |last22=Angus |first22=Derek C. |last23=Murray |first23=Christopher J L. |last24=Naghavi |first24=Mohsen |title=Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study |journal=The Lancet |date=January 2020 |volume=395 |issue=10219 |pages=200–211 |doi=10.1016/S0140-6736(19)32989-7 |pmid=31954465 |pmc=6970225 }}</ref>

== Epidemiology ==
Sepsis causes millions of deaths globally each year and is the most common cause of death in people who have been hospitalized.<ref name="Deutschman2014"/><ref name=Campaign2008 /> The [[Incidence (epidemiology)|number of new cases]] of sepsis worldwide is estimated to be 18 million cases per year.<ref name="Lyle2014"/> In the [[United States]], sepsis affects approximately 3 in 1,000 people,<ref name=Soong2012 /> and severe sepsis contributes to more than 200,000 deaths per year.<ref name=Munford2011/>

Sepsis occurs in 1–2% of all hospitalizations and accounts for as much as 25% of ICU bed utilization. As it is rarely reported as a primary diagnosis (often being a complication of cancer or other illness), the incidence, mortality, and morbidity rates of sepsis are probably underestimated.<ref name=Critical2005 /> A study of [[U.S. state]]s found approximately 651 hospital stays per 100,000 population with a sepsis diagnosis in 2010.<ref name="hcup-us.ahrq.gov"/> It is the second-leading cause of death in non-coronary [[intensive care unit]] (ICU) and the tenth-most-common cause of death overall (the first being heart disease).<ref name=Martin2003/> Children under 12 months of age and elderly people have the highest incidence of severe sepsis.<ref name=Critical2005 /> Among people from the U.S. who had multiple sepsis hospital admissions in 2010, those who were discharged to a skilled nursing facility or long-term care following the initial hospitalization were more likely to be readmitted than those discharged to another form of care.<ref name="hcup-us.ahrq.gov" /> A study of 18 U.S. states found that amongst people with [[Medicare (United States)|Medicare]] in 2011, sepsis was the second most common principal reason for readmission within 30 days.<ref name=Hines2014/>

Several medical conditions increase a person's susceptibility to infection and the development of sepsis. Common sepsis risk factors include age (especially the very young and old); conditions that weaken the immune system such as [[cancer]], [[diabetes mellitus|diabetes]], or the [[asplenia|absence of a spleen]]; and [[major trauma]] and [[burn]]s.<ref name="CDC2014Q"/><ref name="Koh2012"/><ref name="Rubin2014"/>

From 1979 to 2000, data from the United States National Hospital Discharge Survey showed that the incidence of sepsis increased fourfold, to 240 cases per 100,000 population, with a higher incidence in men when compared to women. However, the global prevalence of sepsis has been estimated to be higher in women.<ref name=":0" /> During the same time frame, the in-hospital case fatality rate was reduced from 28% to 18%. However, according to the nationwide inpatient sample from the United States, the incidence of severe sepsis increased from 200 per 10,000 population in 2003 to 300 cases in 2007 for a population aged more than 18 years. The incidence rate is particularly high among infants, with an incidence of 500 cases per 100,000 population. Mortality related to sepsis increases with age, from less than 10% in the age group of 3 to 5 years to 60% by the sixth decade of life.<ref name= "Mandell2014"/> The increase in the average age of the population, alongside the presence of more people with chronic diseases or on [[immunosuppressive drug|immunosuppressive medications]], and also the increase in the number of invasive procedures being performed, has led to an increased rate of sepsis.<ref name="Polat"/>

== History ==
[[File:'ware Hitler's Greatest Ally Art.IWMPST14196.jpg|thumb|upright|Personification of ''septicemia'', carrying a spray can marked "[[Poison]]"]]

The term "σήψις" (sepsis) was introduced by Hippocrates in the fourth century BC, and it meant the process of [[putrefaction|decay or decomposition]] of organic matter.<ref name=Geroulanos2006/><ref name="CavaillonAdrie2008"/><ref name="pmid18171697"/> In the eleventh century, [[Avicenna]] used the term "blood rot" for diseases linked to severe [[Pus|purulent]] process. Though severe systemic toxicity had already been observed, it was only in the 19th century that the specific term&nbsp;– sepsis&nbsp;– was used for this condition.

The terms "septicemia", also spelled "septicaemia", and "blood poisoning" referred to the microorganisms or their toxins in the blood. The [[International Statistical Classification of Diseases and Related Health Problems]] (ICD) version 9, which was in use in the US until 2013, used the term septicemia with numerous modifiers for different diagnoses, such as "Streptococcal septicemia".<ref name="aapc"/> All those diagnoses have been converted to sepsis, again with modifiers, in [[ICD-10]], such as "Sepsis due to streptococcus".<ref name="aapc">{{Cite web |url=https://www.aapc.com/blog/11406-understand-how-icd-10-expands-sepsis-coding/ |title=Understand How ICD-10 Expands Sepsis Coding – AAPC Knowledge Center | vauthors = Stewart C |website=AAPC |date=8 April 2011 |language=en-US |access-date=2020-02-06}}</ref>

The current terms are dependent on the microorganism that is present: [[bacteremia]] if [[bacteria]] are present in the blood at abnormal levels and are the causative issue, [[viremia]] for [[viruses]], and [[fungemia]] for a [[fungus]].<ref name=Merck/>

By the end of the 19th century, it was widely believed that [[microbes]] produced substances that could injure the [[mammalian]] host and that soluble [[toxins]] released during infection caused the fever and shock that were commonplace during severe infections. [[Richard Friedrich Johannes Pfeiffer|Pfeiffer]] coined the term [[endotoxin]] at the beginning of the 20th century to denote the pyrogenic principle associated with ''[[Vibrio cholerae]]''. It was soon realized that endotoxins were expressed by most and perhaps all [[gram-negative bacteria]]. The [[lipopolysaccharide]] character of enteric endotoxins was elucidated in 1944 by Shear.<ref name=Shear1944/> The molecular character of this material was determined by Luderitz et al. in 1973.<ref name=Luderitz1973/>

It was discovered in 1965 that a strain of [[C3H/HeJ]] [[mouse]] was immune to the endotoxin-induced shock.<ref name=Heppner1965/> The genetic locus for this effect was dubbed ''Lps''. These mice were also found to be hyper-susceptible to infection by gram-negative bacteria.<ref name=Obrien1980/> These observations were finally linked in 1998 by the discovery of the [[toll-like receptor]] gene 4 (TLR 4).<ref name=Poltorak1998/> Genetic mapping work, performed over five years, showed that TLR4 was the sole candidate locus within the Lps critical region; this strongly implied that a mutation within TLR4 must account for the lipopolysaccharide resistance phenotype. The defect in the TLR4 gene that led to the endotoxin-resistant phenotype was discovered to be due to a mutation in the [[cytoplasm]].<ref name=Poltorak1998B/>

Controversy occurred in the scientific community over the use of mouse models in research into sepsis in 2013 when scientists published a review of the mouse immune system compared to the human immune system and showed that on a systems level, the two worked very differently; the authors noted that as of the date of their article over 150 clinical trials of sepsis had been conducted in humans, almost all of them supported by promising data in mice and that all of them had failed. The authors called for abandoning the use of mouse models in sepsis research; others rejected that but called for more caution in interpreting the results of mouse studies,<ref>{{cite journal | vauthors = Korneev KV | title = [Mouse Models of Sepsis and Septic Shock] | journal = Molekuliarnaia Biologiia | volume = 53 | issue = 5 | pages = 799–814 | date = 18 October 2019 | pmid = 31661479 | doi = 10.1134/S0026893319050108 | s2cid = 204758015 | doi-access = free }}</ref> and more careful design of preclinical studies.<ref name=Lewis2016/><ref name=Mills2016/><ref name=Engber2013/><ref name="pmid23401516"/> One approach is to rely more on studying biopsies and clinical data from people who have had sepsis, to try to identify [[biomarkers]] and [[drug target]]s for intervention.<ref name=Haseldine2016/>

== Society and culture ==
=== Economics ===
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.<ref name=Torio2006/> Costs for sepsis hospital stays more than quadrupled since 1997 with an 11.5 percent annual increase.<ref name=Pfuntner2013/> By payer, it was the most costly condition billed to Medicare and the uninsured, the second-most costly billed to [[Medicaid]], and the fourth-most costly billed to [[health insurance in the United States|private insurance]].<ref name=Torio2006/>

=== Education ===
A large international collaboration entitled the "[[Surviving Sepsis Campaign]]" was established in 2002<ref name=SSCHistory/> to educate people about sepsis and to improve outcomes with sepsis. The Campaign has published an evidence-based review of management strategies for severe sepsis, with the aim of publishing a complete set of guidelines in subsequent years.<ref name=Campaign2008/> The guidelines were updated in 2016<ref>{{cite journal | vauthors = Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP | display-authors = 6 | title = Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 | journal = Critical Care Medicine | volume = 45 | issue = 3 | pages = 486–552 | date = March 2017 | pmid = 28098591 | doi = 10.1097/CCM.0000000000002255 | s2cid = 52827184 | url = https://archive.lstmed.ac.uk/19349/1/0.%20SSC%202020%20main%20paper%20ICM%20Revisions%20FINAL%20CLEAN%20copy.docx }}</ref> and again in 2021.<ref>{{cite journal | vauthors = Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, Mcintyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Hylander Møller M, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M | display-authors = 6 | title = Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021 | journal = Critical Care Medicine | volume = 49 | issue = 11 | pages = e1063–e1143 | date = November 2021 | pmid = 34605781 | doi = 10.1097/CCM.0000000000005337 | s2cid = 238257608 | doi-access = free }}</ref>

=== Awareness ===
[[Sepsis Alliance]] is a charitable organization based in the United States that was created to raise sepsis awareness among both the general public and healthcare professionals.<ref name="SepsisAlliance" /> In 2011, September was declared [[Sepsis Alliance#Sepsis Awareness Month|Sepsis Awareness Month]]. One year later, the Global Sepsis Alliance declared September 13 World Sepsis Day.<ref>{{Cite web |date=2025-02-06 |title=World Sepsis Day - September 13 |url=https://www.worldsepsisday.org/ |access-date=2025-02-11 |website=World Sepsis Day - September 13 |language=en-US}}</ref>

==Research==
[[File:Sepsis fig.png|thumb|Phenotypic strategy switches of microbes capable of provoking sepsis]]
Some authors suggest that initiating sepsis by the normally [[Mutualism (biology)|mutualistic]] (or neutral) members of the [[microbiome]] may not always be an accidental side effect of the deteriorating host immune system. Rather, it is often an [[Adaptive behavior|adaptive]] microbial response to a sudden decline of host survival chances. Under this scenario, the microbe species provoking sepsis benefit from monopolizing the future cadaver, utilizing its biomass as [[decomposer]]s, and then transmitting through soil or water to establish mutualistic relations with new individuals. The bacteria ''[[Streptococcus pneumoniae]]'', ''[[Escherichia coli]]'', ''[[Proteus (bacterium)|Proteus]]'' spp., ''[[Pseudomonas aeruginosa]]'', ''[[Staphylococcus aureus]]'', ''[[Klebsiella]]'' spp., ''[[Clostridium]]'' spp., ''[[Lactobacillus]]'' spp., ''[[Bacteroides]]'' spp. and the fungi ''[[Candida (fungus)|Candida]]'' spp. are all capable of such a high level of [[phenotypic plasticity]]. Not all cases of sepsis arise through such adaptive microbial strategy switches.<ref name=Rozsa2017/>

[[Paul E. Marik]]'s "Marik protocol", also known as the "HAT" protocol, proposed a combination of [[hydrocortisone]], [[vitamin C|vitamin&nbsp;C]], and [[thiamine]] as a treatment for preventing sepsis for people in [[intensive care]]. Marik's initial research, published in 2017, showed dramatic evidence of benefit, leading to the protocol becoming popular among intensive care physicians, especially after the protocol received attention on social media and [[National Public Radio]], leading to criticism of [[science by press conference]] from the wider medical community. Subsequent independent research failed to replicate Marik's positive results, indicating the possibility that they had been compromised by bias.<ref name=jama>{{cite journal | vauthors = Rubin R | title = Wide Interest in a Vitamin C Drug Cocktail for Sepsis Despite Lagging Evidence | journal = JAMA | volume = 322 | issue = 4 | pages = 291–293 | date = July 2019 | pmid = 31268477 | doi = 10.1001/jama.2019.7936 | s2cid = 195788169 }}</ref> A [[systematic review]] of trials in 2021 found that the claimed benefits of the protocol could not be confirmed.<ref>{{cite journal | vauthors = Lee YR, Vo K, Varughese JT | title = Benefits of combination therapy of hydrocortisone, ascorbic acid and thiamine in sepsis and septic shock: A systematic review | journal = Nutrition and Health | volume = 28 | issue = 1 | pages = 77–93 | date = March 2022 | pmid = 34039089 | doi = 10.1177/02601060211018371 | s2cid = 235215735 }}</ref>

Overall, the evidence for any role of vitamin&nbsp;C in the treatment of sepsis remains unclear {{as of|lc=yes|2021}}.<ref>{{cite journal | vauthors = Li YR, Zhu H | title = Vitamin C for sepsis intervention: from redox biochemistry to clinical medicine | journal = Molecular and Cellular Biochemistry | volume = 476 | issue = 12 | pages = 4449–4460 | date = December 2021 | pmid = 34478032 | pmc = 8413356 | doi = 10.1007/s11010-021-04240-z }}</ref>

== See also ==
* ''[[Capnocytophaga canimorsus]]'' – bacteria that can lead to [[purpura fulminans]] and severe acute sepsis after a dog bite

{{Clear}}

== References ==
{{Reflist |refs=

<ref name=CDC2014Q>{{cite web |title= Sepsis Questions and Answers |url= https://www.cdc.gov/sepsis/basic/qa.html |website= cdc.gov |publisher= [[Centers for Disease Control and Prevention]] (CDC) |access-date= 28 November 2014 |date= 22 May 2014 |url-status=live |archive-url= https://web.archive.org/web/20141204083832/http://www.cdc.gov/sepsis/basic/qa.html |archive-date= 4 December 2014 }}</ref>

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<ref name="Deutschman2014">{{cite journal | vauthors = Deutschman CS, Tracey KJ | title = Sepsis: current dogma and new perspectives | journal = Immunity | volume = 40 | issue = 4 | pages = 463–475 | date = April 2014 | pmid = 24745331 | doi = 10.1016/j.immuni.2014.04.001 | name-list-style = vanc | doi-access = free }}</ref>

<ref name= "Sepsis–3_2016">{{cite journal | vauthors = Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC | display-authors = 6 | title = The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) | journal = JAMA | volume = 315 | issue = 8 | pages = 801–810 | date = February 2016 | pmid = 26903338 | pmc = 4968574 | doi = 10.1001/jama.2016.0287 }}</ref>

<ref name= "SSC–G2016">{{cite journal | vauthors = Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP | display-authors = 6 | title = Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 | journal = Intensive Care Medicine | volume = 43 | issue = 3 | pages = 304–377 | date = March 2017 | pmid = 28101605 | doi = 10.1007/s00134-017-4683-6 | doi-access = free }}</ref>

<ref name=Martin2012>{{cite journal | vauthors = Martin GS | title = Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes | journal = Expert Review of Anti-Infective Therapy | volume = 10 | issue = 6 | pages = 701–706 | date = June 2012 | pmid = 22734959 | pmc = 3488423 | doi = 10.1586/eri.12.50 }}</ref>

<ref name=Fang2018>{{cite journal | vauthors = Fang F, Zhang Y, Tang J, Lunsford LD, Li T, Tang R, He J, Xu P, Faramand A, Xu J, You C | display-authors = 6 | title = Association of Corticosteroid Treatment With Outcomes in Adult Patients With Sepsis: A Systematic Review and Meta-analysis | journal = JAMA Internal Medicine | volume = 179 | issue = 2 | pages = 213–223 | date = February 2019 | pmid = 30575845 | pmc = 6439648 | doi = 10.1001/jamainternmed.2018.5849 }}</ref>

<ref name=Long2017>{{cite journal | vauthors = Long B, Koyfman A | title = Controversies in Corticosteroid use for Sepsis | journal = The Journal of Emergency Medicine | volume = 53 | issue = 5 | pages = 653–661 | date = November 2017 | pmid = 28916121 | doi = 10.1016/j.jemermed.2017.05.024 }}</ref>

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<ref name="1992consensus">{{cite journal | vauthors = Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ | display-authors = 6 | title = Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine | journal = Chest | volume = 101 | issue = 6 | pages = 1644–1655 | date = June 1992 | pmid = 1303622 | doi = 10.1378/chest.101.6.1644 | url = http://www.reanimatology.com/rmt/article/view/1584 | quote = Septicemia... has been used... in a variety of ways... We therefore suggest that this term be eliminated from current usage. | collaboration = The ACCP/SCCM Consensus Conference Committee. [[American College of Chest Physicians]]/[[Society of Critical Care Medicine]] | url-access = subscription }}</ref>

<ref name="pmid12682500">{{cite journal | vauthors = Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G | display-authors = 6 | title = 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference | journal = Critical Care Medicine | volume = 31 | issue = 4 | pages = 1250–1256 | date = April 2003 | pmid = 12682500 | doi = 10.1097/01.CCM.0000050454.01978.3B | url = http://www.esicm.org/upload/file4.pdf | url-status = live | s2cid = 19605781 | archive-url = https://web.archive.org/web/20150924002142/http://www.esicm.org/upload/file4.pdf | archive-date = 24 September 2015 }}</ref>

<ref name=Hospital2012>{{cite book | veditors = McKean S, Ross JJ, Dressler DD, Brotman DJ, Ginsberg JS  |title= Principles and Practice of Hospital Medicine |year= 2012 |publisher= [[McGraw-Hill Education|McGraw-Hill]] |location= New York |isbn= 978-0-07-160389-8 |chapter= Ch. 138: Sepsis | vauthors = Felner K, Smith RL |pages= 1099–109}}</ref>

<ref name=MedLP>{{MedlinePlusEncyclopedia|000666|Sepsis}}. Retrieved 29 November 2014.</ref>

<ref name= "Mandell2014">{{cite book | veditors = Bennett JE, Dolin R, Blaser MJ |editor3-link=Martin J. Blaser  |year= 2014 |title= Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases |location= Philadelphia |publisher= [[Elsevier|Elsevier Health Sciences]] |isbn= 978-0-323-26373-3 | vauthors = Munford RS, Suffredini AF |chapter= Ch. 75: Sepsis, Severe Sepsis and Septic Shock |chapter-url= https://books.google.com/books?id=73pYBAAAQBAJ&pg=PA914 |pages= 914–34 |edition= 8th}}</ref>

<ref name="Polat">{{cite journal | vauthors = Polat G, Ugan RA, Cadirci E, Halici Z | title = Sepsis and Septic Shock: Current Treatment Strategies and New Approaches | journal = The Eurasian Journal of Medicine | volume = 49 | issue = 1 | pages = 53–58 | date = February 2017 | pmid = 28416934 | pmc = 5389495 | doi = 10.5152/eurasianjmed.2017.17062 }}</ref>

<ref name="BlochID">{{cite book | vauthors = Bloch KC |chapter= Ch. 4: Infectious Diseases | veditors = McPhee SJ, Hammer GD |title= Pathophysiology of Disease |edition= 6th |location= New York |publisher= [[McGraw-Hill Education|McGraw-Hill]] |year= 2009 |isbn= 978-0-07-162167-0 }}</ref>

<ref name="Ramachandran2014">{{cite journal | vauthors = Ramachandran G | title = Gram-positive and gram-negative bacterial toxins in sepsis: a brief review | journal = Virulence | volume = 5 | issue = 1 | pages = 213–218 | date = January 2014 | pmid = 24193365 | pmc = 3916377 | doi = 10.4161/viru.27024 }}</ref>

<ref name="Delalove2014">{{cite journal | vauthors = Delaloye J, Calandra T | title = Invasive candidiasis as a cause of sepsis in the critically ill patient | journal = Virulence | volume = 5 | issue = 1 | pages = 161–169 | date = January 2014 | pmid = 24157707 | pmc = 3916370 | doi = 10.4161/viru.26187 }}</ref>

<ref name=NPR>{{cite web|title=Synergy Between Nurses And Automation Could Be Key To Finding Sepsis Early|url=https://www.npr.org/sections/health-shots/2018/02/22/583846656/synergy-between-nurses-and-automation-could-be-key-to-finding-sepsis-early|publisher= [[NPR]] |series= [[All Things Considered]] | vauthors = Harris R |date= 22 February 2018 |access-date=26 February 2018 |archive-url=https://web.archive.org/web/20180227201532/https://www.npr.org/sections/health-shots/2018/02/22/583846656/synergy-between-nurses-and-automation-could-be-key-to-finding-sepsis-early |archive-date= 27 February 2018 |url-status=live}}</ref>

<ref name="Wacker2013">{{cite journal | vauthors = Wacker C, Prkno A, Brunkhorst FM, Schlattmann P | title = Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis | journal = The Lancet. Infectious Diseases | volume = 13 | issue = 5 | pages = 426–435 | date = May 2013 | pmid = 23375419 | doi = 10.1016/S1473-3099(12)70323-7 | url = https://nbn-resolving.org/urn:nbn:de:gbv:27-dbt-20160830-1116291 }}</ref>

<ref name=Morris2017>{{cite journal | vauthors = Morris E, McCartney D, Lasserson D, Van den Bruel A, Fisher R, Hayward G | title = Point-of-care lactate testing for sepsis at presentation to health care: a systematic review of patient outcomes | journal = The British Journal of General Practice | volume = 67 | issue = 665 | pages = e859–e870 | date = December 2017 | pmid = 29158243 | pmc = 5697556 | doi = 10.3399/bjgp17X693665 }}</ref>

<ref name=Soong2012>{{cite journal | vauthors = Soong J, Soni N | title = Sepsis: recognition and treatment | journal = Clinical Medicine | volume = 12 | issue = 3 | pages = 276–280 | date = June 2012 | pmid = 22783783 | pmc = 4953494 | doi = 10.7861/clinmedicine.12-3-276 }}</ref>

<ref name=Simpson2016>{{cite journal | vauthors = Simpson SQ | title = New Sepsis Criteria: A Change We Should Not Make | journal = Chest | volume = 149 | issue = 5 | pages = 1117–1118 | date = May 2016 | pmid = 26927525 | doi = 10.1016/j.chest.2016.02.653 | quote = We believe that adopting a more restrictive definition that requires further progression along the sepsis pathway may delay intervention in this highly time-dependent condition, with additional risk to patients. | doi-access = free }}</ref>

<ref name=Vincent2016>{{cite journal | vauthors = Vincent JL, Martin GS, Levy MM | title = qSOFA does not replace SIRS in the definition of sepsis | journal = Critical Care | volume = 20 | issue = 1 | article-number = 210 | date = July 2016 | pmid = 27423462 | pmc = 4947518 | doi = 10.1186/s13054-016-1389-z | quote = We hope this editorial will clarify that the qSOFA is meant to be used to raise suspicion of sepsis and prompt further action—it is not a replacement for SIRS and is not part of the definition of sepsis. | doi-access = free }}</ref>

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<ref name=Antonopoulou2011>{{cite journal | vauthors = Antonopoulou A, Giamarellos-Bourboulis EJ | title = Immunomodulation in sepsis: state of the art and future perspective | journal = Immunotherapy | volume = 3 | issue = 1 | pages = 117–128 | date = January 2011 | pmid = 21174562 | doi = 10.2217/imt.10.82 }}</ref>

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<ref name= Zarychanski2013>{{cite journal | vauthors = Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, Fergusson DA | title = Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis | journal = JAMA | volume = 309 | issue = 7 | pages = 678–688 | date = February 2013 | pmid = 23423413 | doi = 10.1001/jama.2013.430 | doi-access = free }}</ref>

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<ref name=Hamzaoui2017>{{cite journal | vauthors = Hamzaoui O, Scheeren TW, Teboul JL | title = Norepinephrine in septic shock: when and how much? | journal = Current Opinion in Critical Care | volume = 23 | issue = 4 | pages = 342–347 | date = August 2017 | pmid = 28509668 | doi = 10.1097/mcc.0000000000000418 | s2cid = 2078670 }}</ref>

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<ref name=Launey2011>{{cite journal | vauthors = Launey Y, Nesseler N, Mallédant Y, Seguin P | title = Clinical review: fever in septic ICU patients--friend or foe? | journal = Critical Care | volume = 15 | issue = 3 | page = 222 | date = 2011 | pmid = 21672276 | pmc = 3218963 | doi = 10.1186/cc10097 | doi-access = free }}</ref>

<ref name="Szakmany2012">{{cite journal | vauthors = Szakmany T, Hauser B, Radermacher P | title = N-acetylcysteine for sepsis and systemic inflammatory response in adults | journal = The Cochrane Database of Systematic Reviews | volume = 9 | issue = 9 | article-number = CD006616 | date = September 2012 | pmid = 22972094 | pmc = 6517277 | doi = 10.1002/14651858.CD006616.pub2 }}</ref>

<ref name=APC2012>{{cite journal | vauthors = Martí-Carvajal AJ, Solà I, Gluud C, Lathyris D, Cardona AF | title = Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | article-number = CD004388 | date = December 2012 | issue = 12 | pmid = 23235609 | pmc = 6464614 | doi = 10.1002/14651858.CD004388.pub6 }}</ref>

<ref name=Fink2014>{{cite journal | vauthors = Fink MP, Warren HS | title = Strategies to improve drug development for sepsis | journal = Nature Reviews. Drug Discovery | volume = 13 | issue = 10 | pages = 741–758 | date = October 2014 | pmid = 25190187 | doi = 10.1038/nrd4368 | s2cid = 20904332 }}</ref>

<ref name=Hirasawa2009>{{cite journal | vauthors = Hirasawa H, Oda S, Nakamura M | title = Blood glucose control in patients with severe sepsis and septic shock | journal = World Journal of Gastroenterology | volume = 15 | issue = 33 | pages = 4132–4136 | date = September 2009 | pmid = 19725146 | pmc = 2738808 | doi = 10.3748/wjg.15.4132 | doi-access = free }}</ref>

<ref name="pmid32430052">{{cite journal | vauthors = Bauer M, Gerlach H, Vogelmann T, Preissing F, Stiefel J, Adam D | title = Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019- results from a systematic review and meta-analysis | journal = Critical Care | volume = 24 | issue = 1 | article-number = 239 | date = May 2020 | pmid = 32430052 | pmc = 7236499 | doi = 10.1186/s13054-020-02950-2 | doi-access = free }}</ref>

<ref name=Carpenter2009>{{cite journal | vauthors = Carpenter CR, Keim SM, Upadhye S, Nguyen HB | title = Risk stratification of the potentially septic patient in the emergency department: the Mortality in the Emergency Department Sepsis (MEDS) score | journal = The Journal of Emergency Medicine | volume = 37 | issue = 3 | pages = 319–327 | date = October 2009 | pmid = 19427752 | doi = 10.1016/j.jemermed.2009.03.016 }}</ref>

<ref name=Jackson2009>{{cite journal | vauthors = Jackson JC, Hopkins RO, Miller RR, Gordon SM, Wheeler AP, Ely EW | title = Acute respiratory distress syndrome, sepsis, and cognitive decline: a review and case study | journal = Southern Medical Journal | volume = 102 | issue = 11 | pages = 1150–1157 | date = November 2009 | pmid = 19864995 | pmc = 3776422 | doi = 10.1097/SMJ.0b013e3181b6a592 }}</ref>

<ref name="Lyle2014">{{cite journal | vauthors = Lyle NH, Pena OM, Boyd JH, Hancock RE | title = Barriers to the effective treatment of sepsis: antimicrobial agents, sepsis definitions, and host-directed therapies | journal = Annals of the New York Academy of Sciences | volume = 1323 | issue = 2014 | pages = 101–114 | date = September 2014 | pmid = 24797961 | doi = 10.1111/nyas.12444 | s2cid = 5089865 | bibcode = 2014NYASA1323..101L }}</ref>

<ref name=Munford2011>{{cite book | veditors = Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J | vauthors = Munford RS |title= Harrison's Principles of Internal Medicine |year= 2011 |publisher= [[McGraw-Hill Education|McGraw-Hill]] |location= New York |isbn= 978-0-07-174889-6 |edition= 18th |chapter= Ch. 271: Severe Sepsis and Septic Shock |pages= 2223–31}}</ref>

<ref name="hcup-us.ahrq.gov">{{cite book | title = Healthcare Cost and Utilization Project |chapter= Trends in Septicemia Hospitalizations and Readmissions in Selected HCUP States, 2005 and 2010 |series = Statistical Brief #161 | date = September 2013 | pmid = 24228290 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK169246/ | vauthors = Sutton JP, Friedman B |url-status=live |archive-url= https://web.archive.org/web/20170906203715/https://www.ncbi.nlm.nih.gov/books/NBK169246/ |archive-date= 6 September 2017 |publisher= [[United States National Library of Medicine]]|title-link= Healthcare Cost and Utilization Project }}</ref>

<ref name=Martin2003>{{cite journal | vauthors = Martin GS, Mannino DM, Eaton S, Moss M | title = The epidemiology of sepsis in the United States from 1979 through 2000 | journal = The New England Journal of Medicine | volume = 348 | issue = 16 | pages = 1546–1554 | date = April 2003 | pmid = 12700374 | doi = 10.1056/NEJMoa022139 | url = https://works.bepress.com/cgi/viewcontent.cgi?article=1295&context=david_mannino | doi-access = free }}</ref>

<ref name=Hines2014>{{cite book |chapter = Conditions with the Largest Number of Adult Hospital Readmissions by Payer, 2011 |series = Statistical Brief #172 | date = April 2014 | pmid = 24901179 |chapter-url = http://hcup-us.ahrq.gov/reports/statbriefs/sb172-Conditions-Readmissions-Payer.jsp |title = Healthcare Cost and Utilization Project | publisher = [[Agency for Healthcare Research and Quality]]: [[United States National Library of Medicine]] | archive-url = https://web.archive.org/web/20160304052719/http://hcup-us.ahrq.gov/reports/statbriefs/sb172-Conditions-Readmissions-Payer.jsp | url-status=live | archive-date = 4 March 2016 | vauthors = Hines AL, Barrett ML, Jiang HJ, Steiner CA |display-authors=2|title-link = Healthcare Cost and Utilization Project }}</ref>

<ref name="Koh2012">{{cite journal | vauthors = Koh GC, Peacock SJ, van der Poll T, Wiersinga WJ | title = The impact of diabetes on the pathogenesis of sepsis | journal = European Journal of Clinical Microbiology & Infectious Diseases | volume = 31 | issue = 4 | pages = 379–388 | date = April 2012 | pmid = 21805196 | pmc = 3303037 | doi = 10.1007/s10096-011-1337-4 }}</ref>

<ref name="Rubin2014">{{cite journal | vauthors = Rubin LG, Schaffner W | title = Clinical practice. Care of the asplenic patient | journal = The New England Journal of Medicine | volume = 371 | issue = 4 | pages = 349–356 | date = July 2014 | pmid = 25054718 | doi = 10.1056/NEJMcp1314291 }}</ref>

<ref name=Geroulanos2006>{{cite journal | vauthors = Geroulanos S, Douka ET | title = Historical perspective of the word "sepsis" | journal = Intensive Care Medicine | volume = 32 | issue = 12 | page = 2077 | date = December 2006 | pmid = 17131165 | doi = 10.1007/s00134-006-0392-2 | s2cid = 37084190 }}</ref>

<ref name="CavaillonAdrie2008">{{cite book | veditors = Cavaillon JM, Christophe A  |title= Sepsis and Non-infectious Systemic Inflammation: From Biology to Critical Care |year= 2008 |publisher= [[John Wiley & Sons]] |isbn= 978-3-527-31935-0 |page= 3 |chapter-url=https://books.google.com/books?id=wZDWjuFGsIcC&pg=PA3 | vauthors = Vincent JL |chapter= Ch. 1: Definition of Sepsis and Non-infectious SIRS}}</ref>

<ref name="pmid18171697">{{cite journal | vauthors = Marshall JC | title = Sepsis: rethinking the approach to clinical research | journal = Journal of Leukocyte Biology | volume = 83 | issue = 3 | pages = 471–482 | date = March 2008 | pmid = 18171697 | doi = 10.1189/jlb.0607380 | s2cid = 24332955 | citeseerx = 10.1.1.492.7774 }}</ref>

<ref name=Merck>{{cite web|title=Bacteremia|url=http://www.merckmanuals.com/home/infections/bacteremia-sepsis-and-septic-shock/bacteremia/|work= [[The Merck Manuals|The Merck Manual—Home Health Handbook]] |access-date=25 November 2017|url-status=live|archive-url=https://web.archive.org/web/20170728011557/http://www.merckmanuals.com/home/infections/bacteremia-sepsis-and-septic-shock/bacteremia/|archive-date=28 July 2017|publisher=[[Merck & Co.]]}}</ref>

<ref name=Shear1944>{{cite journal | vauthors = Shear MJ |year= 1944 |title= Chemical treatment of tumors, IX: Reactions of mice with primary subcutaneous tumors to injection of a hemorrhage-producing bacterial polysaccharide |journal= [[Journal of the National Cancer Institute]] |volume= 4 |issue= 5 |pages= 461–76 |doi= 10.1093/jnci/4.5.461}}</ref>

<ref name=Luderitz1973>{{cite journal | vauthors = Lüderitz O, Galanos C, Lehmann V, Nurminen M, Rietschel ET, Rosenfelder G, Simon M, Westphal O | display-authors = 6 | title = Lipid A: chemical structure and biological activity | journal = The Journal of Infectious Diseases | volume = 128 | pages = Suppl:17–Suppl:29 | date = July 1973 | pmid = 4352586 | doi = 10.1093/infdis/128.Supplement_1.S17 | jstor = 30106029 }}</ref>

<ref name=Heppner1965>{{cite journal | vauthors = Heppner G, Weiss DW | title = High Susceptibility of Strain A Mice to Endotoxin and Endotoxin-Red Blood Cell Mixtures | journal = Journal of Bacteriology | volume = 90 | issue = 3 | pages = 696–703 | date = September 1965 | pmid = 16562068 | pmc = 315712 | doi = 10.1128/JB.90.3.696-703.1965 }}</ref>

<ref name=Obrien1980>{{cite journal | vauthors = O'Brien AD, Rosenstreich DL, Scher I, Campbell GH, MacDermott RP, Formal SB | title = Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene | journal = Journal of Immunology | volume = 124 | issue = 1 | pages = 20–24 | date = January 1980 | doi = 10.4049/jimmunol.124.1.20 | pmid = 6985638 | s2cid = 34569641 | doi-access = free }}</ref>

<ref name=Poltorak1998>{{cite journal | vauthors = Poltorak A, Smirnova I, He X, Liu MY, Van Huffel C, McNally O, Birdwell D, Alejos E, Silva M, Du X, Thompson P, Chan EK, Ledesma J, Roe B, Clifton S, Vogel SN, Beutler B | display-authors = 6 | title = Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region | journal = Blood Cells, Molecules & Diseases | volume = 24 | issue = 3 | pages = 340–355 | date = September 1998 | pmid = 10087992 | doi = 10.1006/bcmd.1998.0201 }}</ref>

<ref name=Poltorak1998B>{{cite journal | vauthors = Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B | display-authors = 6 | title = Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene | journal = Science | volume = 282 | issue = 5396 | pages = 2085–2088 | date = December 1998 | pmid = 9851930 | doi = 10.1126/science.282.5396.2085 | bibcode = 1998Sci...282.2085P }}</ref>

<ref name=Lewis2016>{{cite journal | vauthors = Lewis AJ, Seymour CW, Rosengart MR | title = Current Murine Models of Sepsis | journal = Surgical Infections | volume = 17 | issue = 4 | pages = 385–393 | date = August 2016 | pmid = 27305321 | pmc = 4960474 | doi = 10.1089/sur.2016.021 }}</ref>

<ref name=Mills2016>{{cite journal | vauthors = Mills M, Estes MK | title = Physiologically relevant human tissue models for infectious diseases | journal = Drug Discovery Today | volume = 21 | issue = 9 | pages = 1540–1552 | date = September 2016 | pmid = 27352632 | pmc = 5365153 | doi = 10.1016/j.drudis.2016.06.020 }}</ref>

<ref name=Engber2013>{{cite news| vauthors = Engber D |title=Septic Shock |url=http://www.slate.com/articles/health_and_science/the_mouse_trap/2013/02/lab_mouse_models_of_inflammation_for_burns_sepsis_trauma_animal_testing.html |work=Slate|date=13 February 2013|url-status=live|archive-url=https://web.archive.org/web/20170409203438/http://www.slate.com/articles/health_and_science/the_mouse_trap/2013/02/lab_mouse_models_of_inflammation_for_burns_sepsis_trauma_animal_testing.html |archive-date=9 April 2017}}</ref>

<ref name="pmid23401516">{{cite journal | vauthors = Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, López CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG | display-authors = 6 | title = Genomic responses in mouse models poorly mimic human inflammatory diseases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 9 | pages = 3507–3512 | date = February 2013 | pmid = 23401516 | pmc = 3587220 | doi = 10.1073/pnas.1222878110 | doi-access = free | bibcode = 2013PNAS..110.3507S }}</ref>

<ref name=Haseldine2016>{{cite journal | vauthors = Hazeldine J, Hampson P, Lord JM | title = The diagnostic and prognostic value of systems biology research in major traumatic and thermal injury: a review | journal = Burns & Trauma | volume = 4 | page = 33 | date = 2016 | article-number = s41038-016-0059-3 | pmid = 27672669 | pmc = 5030723 | doi = 10.1186/s41038-016-0059-3 | doi-access = free }}</ref>

<ref name=Torio2006>{{cite book | title = Healthcare Cost and Utilization Project  | date = 1 January 2006 | pmid = 27359025 | chapter = National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2013 |series= Statistical Brief #204 | publisher = [[Agency for Healthcare Research and Quality]], [[National Library of Medicine]] | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK368492/ | url-status=live | archive-url = https://web.archive.org/web/20170906203715/https://www.ncbi.nlm.nih.gov/books/NBK368492/ | archive-date = 6 September 2017 | vauthors = Torio CM, Moore BJ | title-link = Healthcare Cost and Utilization Project }}</ref>

<ref name=Pfuntner2013>{{cite book |chapter = Costs for Hospital Stays in the United States, 2011 |title = Healthcare Cost and Utilization Project |series = Statistical Brief #168 | date = December 2013 | pmid = 24455786 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK179289/ | vauthors = Pfuntner A, Wier LM, Steiner C |publisher=[[National Library of Medicine]]|title-link = Healthcare Cost and Utilization Project }}</ref>

<ref name=SSCHistory>{{cite web |title= History |url= http://www.survivingsepsis.org/About-SSC/Pages/History.aspx |website= [[Surviving Sepsis Campaign]] |publisher= [[Society of Critical Care Medicine]] |access-date= 24 February 2014 |url-status=live |archive-url= https://web.archive.org/web/20140304091645/http://www.survivingsepsis.org/About-SSC/Pages/History.aspx |archive-date= 4 March 2014 }}</ref>

<ref name=SepsisAlliance>{{cite web |title= About Us |author= Sepsis Alliance |url= http://www.sepsis.org/about/ |website= sepsis.org|access-date=8 October 2015 |url-status=live |archive-url= https://web.archive.org/web/20150908101815/http://www.sepsis.org/about |archive-date=8 September 2015 }}</ref>

<ref name=Rozsa2017>{{cite journal | vauthors = Rózsa L, Apari P, Sulyok M, Tappe D, Bodó I, Hardi R, Müller V | title = The evolutionary logic of sepsis | journal = Infection, Genetics and Evolution | volume = 55 | pages = 135–141 | date = November 2017 | pmid = 28899789 | doi = 10.1016/j.meegid.2017.09.006 | name-list-style = vanc | doi-access = free | bibcode = 2017InfGE..55..135R | hdl = 10831/67370 | hdl-access = free }}</ref>

}}

== External links ==
{{commons category}}
{{offline|med}}
* [http://www.mdcalc.com/sirs-sepsis-and-septic-shock-criteria/ SIRS, Sepsis, and Septic Shock Criteria] {{Webarchive|url=https://web.archive.org/web/20150217001620/http://www.mdcalc.com/sirs-sepsis-and-septic-shock-criteria/ |date=17 February 2015 }}
* {{cite web | url = https://medlineplus.gov/sepsis.html | publisher = U.S. National Library of Medicine | work = MedlinePlus | title = Sepsis }}

{{Medical condition classification and resources
|DiseasesDB     = 11960
 |ICD11          = {{ICD11| 1G40}}, {{ICD11| 1G41}}
 |ICD10          = {{ICD10|A|40| |a|30}}, {{ICD10|A|41||a|30}}, {{ICD10|T81.4}}, {{ICD10|T|88.0||a|30}}
 |ICD9           = {{ICD9|995.91}}
 |MedlinePlus    = 000666
 |eMedicineSubj  =
 |eMedicineTopic =
 |MeshID         = D018805
 |Scholia        = Q183134
}}
{{Intensive care medicine}}
{{Abnormal clinical and laboratory findings}}
{{Authority control}}

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