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sepsis and deth
{{For|the genus of flies of this name|Sepsis (genus)}}
{{Infobox medical condition
|Name = Sepsis
|Image = Bloodculturetubes.JPG
|Caption = ] bottles: orange label for ], green label for ], and yellow label for blood samples from children
|Field = ]
| pronounce = {{IPAc-en|ˈ|s|ɛ|p|s|ɨ|s}}
|DiseasesDB = 11960
|ICD10 = {{ICD10|A|40| |a|30}} – {{ICD10|A|41||a|30}}
|ICD9 = {{ICD9|995.91}}
|MedlinePlus = 000666
|eMedicineSubj =
|eMedicineTopic =
|MeshID = D018805
|
}}
<!-- Definition and symptoms -->
'''Sepsis''' is a life-threatening condition that arises when the body's response to ] injures its own tissues and organs.<ref>{{cite journal|title=The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)|date=February 23, 2016|doi=10.1001/jama.2016.0287}}</ref> Common signs and symptoms include ], ], ], and ].<ref name=CDC2014Q/> There may also be symptoms related to a specific infection, such as a cough with ], or ] with a ].<!-- <ref name=Tint2011/> --> In the very young, old, and people with a ], there may be no symptoms of a specific infection and the ] or normal rather than ].<ref name=Tint2011>{{cite book |last= Jui |first= Jonathan |chapter= Ch. 146: Septic Shock |editor-last1= Tintinalli |editor-first1= Judith E. |editor-last2= Stapczynski |editor-first2= J. Stephan |editor-last4= Cline |editor-first4= David M. |editor-last3= Ma |editor-first3= O. John |editor-last5= Cydulka |editor-first5= Rita K. |editor-last6= Meckler |editor-first6= Garth D. |editor7= American College of Emergency Physicians |display-editors= 4 |title= Tintinalli's Emergency Medicine: A Comprehensive Study Guide |edition= 7th |location= New York |publisher= ] |pages=1003–14|year= 2011 |chapterurl= http://www.accessmedicine.com/content.aspx?aID=6364928 |url= http://accessmedicine.mhmedical.com/book.aspx?bookid=348 |accessdate= December 11, 2012 |via= AccessMedicine |subscription= yes}}</ref> '''Severe sepsis''' is sepsis causing ] or insufficient blood flow.<!-- <ref name=Sepsis2012/> --> Insufficient blood flow may be evident by ], high ], or ].<!-- <ref name=Sepsis2012/> --> ] is low blood pressure due to sepsis that does not improve after reasonable amounts of intravenous fluids are given.<ref name=Sepsis2012>{{cite journal |last1= Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup |last2= Dellinger |first2= RP |last3= Levy |first3= MM |last4= Rhodes |first4= A |last5= Annane |first5= D |last6= Gerlach |first6= H |last7= Opal |first7= SM |last8= Sevransky |first8= JE |last9= Sprung |first9= CL |last10= Douglas |first10= IS |last11= Jaeschke |first11= R |last12= Osborn |first12= TM |last13= Nunnally |first13= ME |last14= Townsend |first14= SR |last15= Reinhart |first15= K |last16= Kleinpell |first16= RM |last17= Angus |first17= DC |last18= Deutschman |first18= CS |last19= Machado|first19= FR |last20= Rubenfeld |first20= GD |last21= Webb |first21= S |last22= Beale |first22= RJ |last23= Vincent |first23= J-L |last24= Moreno |first24= R |displayauthors= 4 |title= Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012 |journal= ] |volume= 41 |issue= 2 |year= 2013 |pages= 580–637 |pmid= 23353941 |doi= 10.1097/CCM.0b013e31827e83af |url= http://www.sccm.org/Documents/SSC-Guidelines.pdf |via= ]}}</ref>

<!-- Cause and diagnosis-->
Sepsis is caused by an ] triggered by an infection.<ref name=Tint2011/><ref name="Deutschman2014">{{cite journal|last=Deutschman|first=CS|last2=Tracey|first2=KJ|title=Sepsis: Current dogma and new perspectives|journal= ] |volume=40|issue=4|pages=463–75|date=April 2014|pmid=24745331|doi=10.1016/j.immuni.2014.04.001}}</ref> The infection is most commonly ]l, but it can be from ], ], or ].<ref name=Tint2011/> Common locations for the primary infection include lungs, brain, ], skin, and ].<!-- <ref name=Tint2011/> --> Risk factors include young or old age, a weakened immune system from conditions such as ] or ], and ] or ]s.<ref name=CDC2014Q>{{cite web |title= Sepsis Questions and Answers |url= http://www.cdc.gov/sepsis/basic/qa.html |website= cdc.gov |publisher= ] (CDC) |accessdate= 28 November 2014 |date= May 22, 2014}}</ref> Diagnosis was based on meeting at least two ] (SIRS) criteria due to a presumed infection.<ref name=Tint2011/> In 2016 screening by SIRS was replaced with ] which is two of the following three: increased breathing rate, change in level of consciousness, and low blood pressure.<ref name=Sepsis2016>{{cite journal|last1=Singer|first1=M|last2=Deutschman|first2=CS|last3=Seymour|first3=CW|last4=Shankar-Hari|first4=M|last5=Annane|first5=D|last6=Bauer|first6=M|last7=Bellomo|first7=R|last8=Bernard|first8=GR|last9=Chiche|first9=JD|last10=Coopersmith|first10=CM|last11=Hotchkiss|first11=RS|last12=Levy|first12=MM|last13=Marshall|first13=JC|last14=Martin|first14=GS|last15=Opal|first15=SM|last16=Rubenfeld|first16=GD|last17=van der Poll|first17=T|last18=Vincent|first18=JL|last19=Angus|first19=DC|title=The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).|journal=JAMA|date=23 February 2016|volume=315|issue=8|pages=801–10|pmid=26903338}}</ref> ] are recommended preferably before antibiotics are started; however, ] is not required for the diagnosis.<ref name=Tint2011/> ] should be done to look for the possible location of infection.<ref name=Sepsis2012/> Other potential causes of similar signs and symptoms include ], ], ], ], and ] among others.<ref name=Tint2011/>

<!-- Treatment -->
Sepsis is usually treated with ] and ].<!-- <ref name=CDC2014Q/> --> Antibiotics are typically given as soon as possible.<!-- <ref name=CDC2014Q/> --> This is often done in an ].<!-- <ref name=CDC2014Q/> --> If ] is not enough to maintain blood pressure, medications that ] can be used.<!-- <ref name=CDC2014Q/> --> ] and ] may be needed to support the function of the lungs and kidneys, respectively.<ref name=CDC2014Q/> To guide treatment, a ] and an ] may be placed for access to the bloodstream.<!-- <ref name=Sepsis2012/> --> Other measurements such as ] and ] ] may be used.<!-- <ref name=Sepsis2012/> --> People with sepsis need preventive measures for ], ]s and ]s, unless other conditions prevent such interventions.<!-- <ref name=Sepsis2012/> --> Some might benefit from tight control of ] levels with ].<ref name=Sepsis2012/> The use of ] is controversial.<ref name=Steroids2012>{{cite journal |last=Patel |first=GP |last2=Balk |first2= RA |title= Systemic steroids in severe sepsis and septic shock |journal= ] |date= January 15, 2012 |volume= 185 |issue= 2 |pages= 133–9 |pmid= 21680949 |doi= 10.1164/rccm.201011-1897CI |url= http://www.atsjournals.org/doi/full/10.1164/rccm.201011-1897CI#.VHVoJclZhsg}}</ref> ], originally marketed for severe sepsis, has not been found to be helpful and was withdrawn from sale in 2011.<ref name=APC2012>{{cite journal|last1=Martí-Carvajal|first1=AJ|last2=Solà|first2=I|last3=Gluud|first3=C|last4=Lathyris|first4=D|last5=Cardona|first5=AF|title=Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients.|journal=The Cochrane database of systematic reviews|date=12 December 2012|volume=12|pages=CD004388|pmid=23235609|doi=10.1002/14651858.CD004388.pub6}}</ref>

<!-- Prognosis, epidemiology and history -->
Disease severity partly determines the outcome with the risk of death from sepsis being as high as 30%, severe sepsis as high as 50%, and septic shock as high as 80%.<ref name=Jawad2012>{{cite journal |last1= Jawad |first1= I |last2= Lukšić |first2= I |last3= Rafnsson |first3= SB |title= Assessing available information on the burden of sepsis: Global estimates of incidence, prevalence and mortality |journal= Journal of Global Health |date= June 2012 |volume= 2 |issue= 1 |pages= 010404 |pmid= 23198133 |pmc= 3484761 |doi= 10.7189/jogh.02.010404 |doi-broken-date= 2015-02-02|url=http://www.jogh.org/documents/issue201201/12-Article%20Jawad.pdf}}</ref> The number of cases worldwide is unknown as there is little data from the ].<ref name=Jawad2012/> Estimates suggest sepsis affects millions of people a year.<ref name=Sepsis2012/> In the ] about 0.2 to 3 per 1000 people get sepsis yearly or about a million cases per year in the United States.<ref name=Jawad2012/><ref name=Martin2012>{{cite journal |last1= Martin |first1= GS |title= Sepsis, severe sepsis and septic shock: Changes in incidence, pathogens and outcomes |journal= ] |date= June 2012 |volume= 10 |issue= 6 |pages= 701–6 |pmid= 22734959 |pmc= 3488423 |doi= 10.1586/eri.12.50}}</ref> Rates of disease have been increasing.<ref name=Sepsis2012/> Sepsis is more common among males than females.<ref name=Tint2011/> The condition has been described at least since the time of ].<ref name=NEJM2013/> The terms septicemia and blood poisoning referred to the microorganisms or their toxins in the blood and are no longer commonly used.<ref name="1992consensus">{{cite journal |pages= 1644–55 |doi= 10.1378/chest.101.6.1644 |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 |year= 1992 |last1= Bone |first1=R |last2= Balk |first2= R |last3= Cerra |first3= F |last4= Dellinger |first4= R |last5= Fein |first5= A |last6= Knaus |first6= W |last7= Schein |first7= R |last8= Sibbald |first8= W |displayauthors= 4 |journal= ] |volume= 101 |issue= 6 |pmid= 1303622 |url= http://journal.publications.chestnet.org/data/Journals/CHEST/21647/1644.pdf}}</ref><ref name=NEJM2013>{{cite journal |title= Severe sepsis and septic shock |journal= ] |date= August 29, 2013 |volume= 369 |issue= 9 |pages= 840–51 |doi= 10.1056/NEJMra1208623 |pmid=23984731 |first1= DC |last1= Angus |first2= T |last2= van der Poll |layurl= http://blogs.nejm.org/now/index.php/severe-sepsis-and-septic-shock/2013/08/30/ |laydate= August 30, 2013 |url= http://www.nejm.org/doi/full/10.1056/NEJMra1208623}}</ref>

== Signs and symptoms ==
], with sepsis from a ].]]

In addition to symptoms related to the provoking cause, sepsis is frequently associated with either ] or ], ], ], ], and ].<ref name= "pmid12682500">{{cite journal |last2= Levy |first2= MM |title= 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference |journal= ] |volume= 31 |issue= 4 |pages= 1250–6 |date= April 2003 |pmid= 12682500 |doi= 10.1097/01.CCM.0000050454.01978.3B |last3= Fink |first3= MP |last4= Marshall |first4= JC |last5= Abraham |first5= E |last6= Angus |first6= D |last7= Cook |first7= D |last8= Cohen |first8= J |last9= Opal |first9= SM |last10= Vincent |first10= JL |last11= Ramsay |first11= G |last1= SCCM/ESICM/ACCP/ATS/SIS |displayauthors=4 |url= http://www.esicm.org/upload/file4.pdf |via= European Society of Intensive Care Medicine (ESICM)}}</ref> Early signs are a fast heart rate, ], and ]. Signs of established sepsis include confusion, ] (which may be accompanied by faster breathing leading to a ]), ] due to decreased systemic ], higher ], and dysfunctions of blood ] (where clotting can lead to organ failure).<ref name=Hospital2012>{{cite book |editor-first1= Sylvia |editor-last1= McKean |editor-first2= John J. |editor-last2= Ross |editor-first3= Daniel D. |editor-last3= Dressler |editor-first4= Daniel J. |editor-last4= Brotman |editor-first5= Jeffrey S. |editor-last5= Ginsberg |displayeditors= 4 |title= Principles and Practice of Hospital Medicine |year= 2012 |publisher= ] |location= New York |isbn= 0071603891 |chapter= Ch. 138: Sepsis |last1= Felner |first1= Kevin |last2= Smith |first2= Robert L. |pages= 1099–109}}</ref>

The drop in blood pressure seen in sepsis may lead to ]. This may result in light-headedness. Bruising or intense bleeding may occur.<ref>{{MedlinePlusEncyclopedia|000666|Sepsis}}{{Accessdate|November 29, 2014}}</ref>

== Cause ==
The most common primary sources of infection resulting in sepsis are the lungs, the abdomen, and the urinary tract.<ref name= "Mandell2014">{{cite book |editor-first1= John E. |editor-last1= Bennett |editor-first2= Raphael |editor-last2= Dolin |editor-first3= Martin J. |editor-last3= Blaser |editor3link=Martin J. Blaser |year= 2014 |title= Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases |location= Philadelphia |publisher= ] |isbn= 9780323263733 |first1= Robert S. |last1= Munford |first2= Anthony F. |last2= Suffredini |chapter= Ch. 75: Sepsis, Severe Sepsis and Septic Shock |chapterurl= https://books.google.com/books?id=73pYBAAAQBAJ&pg=PA914 |pages= 914–34 |edition= 8th}}</ref> Typically, 50% of all sepsis cases start as an infection in the lungs. No definitive source is found in one third to one half of cases.<ref name= "Mandell2014"/>

Infections leading to sepsis are usually bacterial but can be fungal or viral.<ref name= "Mandell2014"/> While ] were previously the most common cause of sepsis, in the last decade ], most commonly ], are thought to cause more than 50% of cases of sepsis.<ref>{{cite book |last= Bloch |first= KC |chapter= Ch. 4: Infectious Diseases |editor-last1= McPhee |editor-first1= Stephen J. |editor-last2= Hammer |editor-first2= Gary D. |title= Pathophysiology of Disease |edition= 6th |location= New York |publisher= ] |year= 2010 |chapterurl= http://www.accessmedicine.com/content.aspx?aID=5366994 |accessdate= January 10, 2013 |url= http://accessmedicine.mhmedical.com/book.aspx?bookid=339 |via= AccessMedicine |subscription= yes}}</ref> Other commonly implicated bacteria include '']'', '']'', '']'', and '']'' species.<ref name="Ramachandran2014">{{cite journal |last= Ramachandran |first= G |title= Gram-positive and gram-negative bacterial toxins in sepsis: A brief review |journal= ] |date= January 2014 |volume= 5 |issue= 1 |pages= 213–8 |pmid= 24193365 |pmc= 3916377 |doi= 10.4161/viru.27024}}</ref> ] accounts for approximately 5% of severe sepsis and septic shock cases; the most common cause of fungal sepsis is infection by '']'' species of ].<ref name="Delalove2014">{{cite journal |last= Delaloye|first=J|last2=Calandra|first2=T|title=Invasive candidiasis as a cause of sepsis in the critically ill patient|journal=]|date=January 2014|volume=5|issue= 1 |pages=161–9|pmid=24157707|pmc=3916370|doi=10.4161/viru.26187}}</ref>

== Diagnosis ==
Early diagnosis is necessary to properly manage sepsis, as initiation of ] is key to reducing mortality from severe sepsis.<ref name=Sepsis2012/>

Within the first three hours of suspected sepsis, diagnostic studies should include ], 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=Sepsis2012 /> To identify the causative organism(s), at least two sets of ]s using bottles with ] for ] and ]s should be obtained, with at least one drawn ] and one drawn through each vascular access device (such as an IV catheter) in place more than 48 hours.<ref name=Sepsis2012 /> However, bacteria are present in the blood in only about 30% of cases.<ref name="Wacker2013"/> Another possible method of detection is by ]. If other sources of infection are suspected, cultures of these sources, such as urine, cerebrospinal fluid, wounds, or respiratory secretions, should also be obtained, as long as this does not delay the use of antibiotics.<ref name=Sepsis2012 />

Within six hours, if blood pressure remains low despite initial fluid resuscitation of 30&nbsp;ml/kg, or if initial lactate is ≥ 4&nbsp;mmol/L (36&nbsp;mg/dL), ] and ] should be measured.<ref name=Sepsis2012 /> Lactate should be re-measured if the initial lactate was elevated.<ref name=Sepsis2012 /> Within twelve hours, it is essential to diagnose or exclude any source of infection that would require emergent source control, such as necrotizing soft tissue infection, infection causing ], ], or intestinal infarction.<ref name=Sepsis2012 /> A pierced ] (free air on abdominal x-ray or CT scan); an abnormal ] consistent with ] (with focal opacification); or ]e, ], or ] can be evident of infection.

If the SIRS criteria are negative it is very unlikely the person has sepsis; if they are positive there is just a moderate probability that the person has sepsis.<ref name=1992consensus />

=== Definitions ===
{{SIRS}}
]
There are different levels of sepsis: sepsis, severe sepsis, and septic shock.<ref name="1992consensus" /> In 2016 screening by ] (SIRS) was replaced with ] which is two of the following three: increased breathing rate, change in level of consciousness, and low blood pressure.<ref name=Sepsis2016/>

* SIRS is the presence of two or more of the following: abnormal ], ], ] or ], and ] count.
*''Sepsis'' is defined as SIRS in response to an infectious process.<ref name=Soong2012>{{cite journal |last1= Soong |first= J |last2= Soni |first2= N |title= Sepsis: Recognition and treatment |journal= ] |date= June 2012 |volume= 12 |issue= 3 |pages= 276–80 |pmid= 22783783 |doi= 10.7861/clinmedicine.12-3-276 |url= http://www.clinmed.rcpjournal.org/content/12/3/276}}</ref>
*''Severe sepsis'' is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (manifesting as hypotension, elevated lactate, or ]).<ref name=Sepsis2012/>
*'']'' is severe sepsis plus persistently ] despite the administration of intravenous fluids.<ref name=Sepsis2012/>

=== End-organ dysfunction ===
Examples of end-organ dysfunction include the following:<ref name="pmid17948334">{{cite journal |pages= 2408–16 |doi= 10.1097/01.CCM.0000282072.56245.91 |title= Mechanisms of sepsis-induced organ dysfunction |year= 2007 |last1=Abraham |first1= E |last2= Singer |first2= M |journal= ] |volume= 35 |issue= 10 |pmid= 17948334 |url= http://www.sassit.co.za/journals/icu/sepsis/mechanisms%20of%20sepsis%20induced%20mods.pdf |via= South African Society of Surgeons in Training (SASSIT)}}</ref>
*Lungs: ] (ARDS) (PaO<sub>2</sub>/FiO<sub>2</sub> < 300){{refn|group=note| The term "ALI" appears to have fallen out of favor, based on the "Berlin definition"<ref>{{cite journal |last1= Ranieri |first1= VM |last2= Rubenfeld |first2= GD |last3= Thompson |first3= BT |last4= Ferguson |first4= ND |last5= Caldwell |first5= E |last6= Fan |first6= E |last7= Camporota |first7= L |last8= Slutsky |first8= AS |displayauthors= 4 |title= Acute respiratory distress syndrome: The Berlin definition |journal= ] |volume= 307 |issue= 23 |pages= 2526–33 |date= June 2012 |pmid=22797452 |doi= 10.1001/jama.2012.5669}}</ref><ref>{{cite web |title= Meet the new ARDS: Expert panel announces new definition, severity classes |url= http://pulmccm.org/main/2012/ards-review/consensus-panel-announces-new-definition-severity-classes-for-ards-jama/ |work= PulmCCM |publisher= Matthew Hoffman}}</ref>}}
*Brain: ] symptoms including agitation, confusion, coma; causes may include ischemia, hemorrhage, formation of blood clots in small blood vessels, microabscesses, multifocal necrotizing leukoencephalopathy
*Liver: disruption of protein synthetic function manifests acutely as progressive ] due to an inability to synthesize ] and disruption of metabolic functions leads to impaired ] metabolism, resulting in elevated unconjugated serum ] levels
*Kidney: ] or ], ], or ]
*Heart: systolic and diastolic ], likely due to ] that depress myocyte function, cellular damage, manifest as a ] leak (although not necessarily ischemic in nature)

More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.<ref name="pmid15636651">{{cite journal |last2= Goldstein |first2= B |last3= Giroir |first3= B |last4= Randolph |first4= A |title=International Pediatric Sepsis Consensus Conference: Definitions for sepsis and organ dysfunction in pediatrics |journal= ] |volume= 6 |issue= 1 |pages= 2–8 |year= 2005 |pmid= 15636651 |doi= 10.1097/01.PCC.0000149131.72248.E6 |last1= International Consensus Conference on Pediatric Sepsis}}</ref>
*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
**] requirement, OR
**two of the following criteria:
***unexplained ] with ] > 5 mEq/L
***]: serum lactate 2 times the upper limit of normal
***oliguria (urine output {{nowrap|< 0.5 ml/kg/h}})
***prolonged ] > 5 seconds
***core to peripheral temperature difference {{nowrap|> 3 °C}}
*Respiratory dysfunction (in the absence of ] or known ])
**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 ]), OR
**arterial partial-pressure of carbon dioxide (PaCO<sub>2</sub>) > 65 torr (20 ]) over baseline PaCO<sub>2</sub> (evidence of ] ]), OR
**supplemental oxygen requirement of greater than FiO<sub>2</sub> 0.5 to maintain oxygen saturation ≥ 92%
*Neurologic dysfunction
**] (GCS) ≤ 11, OR
**] with drop in GCS of 3 or more points in a patient with ]/]
*Hematologic dysfunction
**] count {{nowrap|< 80,000/mm<sup>3</sup>}} or 50% drop from maximum in chronically thrombocytopenic patients, OR
**] (INR) > 2
**]
*Kidney dysfunction
**serum ] ≥ 2 times the upper limit of normal for age or 2-fold increase in baseline ] in patients with ]
*Liver dysfunction (only applicable to infants > 1 month)
**total serum ] ≥ 4&nbsp;mg/dl, OR
**] (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===

A 2013 ] concluded moderate-quality evidence exists to support use of the ] level as a method to distinguish sepsis from non-infectious causes of SIRS.<ref name="Wacker2013">{{cite journal |last1= Wacker |first1= C |last2= Prkno |first2= A |last3= Brunkhorst |first3= FM |last4= Schlattmann |first4= P |title= Procalcitonin as a diagnostic marker for sepsis: A systematic review and meta-analysis |journal= ] |date= May 2013 |volume= 13 |issue= 5 |pages= 426–35 |pmid= 23375419 |doi= 10.1016/S1473-3099(12)70323-7 |url= http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0056874/}}</ref> The same review found the test's ] to be 77% and the specificity to be 79%. The authors suggested procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone cannot definitively make the diagnosis.<ref name="Wacker2013"/> A 2012 systematic review found that ] (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis.<ref name="Backes2012">{{cite journal|last1= Backes|first1=Y|last2=van der Sluijs|first2=KF|last3=Mackie|first3=DP|last4=Tacke|first4=F|last5=Koch|first5=A|last6=Tenhunen|first6=JJ|last7=Schultz|first7=MJ|title=Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review|journal= ]|date=September 2012|volume=38|issue=9|pages=1418–28|pmid=22706919|pmc=3423568|doi=10.1007/s00134-012-2613-1}}</ref> However, this same review concluded that SuPAR has prognostic value as higher SuPAR levels are associated with an increased rate of death in those with sepsis.<ref name="Backes2012"/>

=== Differential diagnosis ===

The ] for sepsis is broad and has to look at (to exclude) the noninfectious conditions that can cause the systemic signs of SIRS: ], ], ]s, ], ], ], ], and ].<ref name=Hospital2012 /><ref name="Mayr2014">{{cite journal |last= Mayr |first= FB |last2= Yende |first2= S |last3= Angus |first3= DC |title= Epidemiology of severe sepsis |journal= ] |date= January 2014 |volume= 5 |issue= 1 |pages= 4–11 |pmid= 24335434 |pmc= 3916382 |doi= 10.4161/viru.27372}}</ref>

=== Neonatal sepsis ===
In common clinical usage, ] refers to a bacterial ] in the first month of life, such as ], ], ], or ],<ref name="Satar2012">{{cite journal |last1= Satar|first=M|last2=Ozlu|first2=F|title=Neonatal sepsis: A continuing disease burden|journal= ] |date=September 2012|volume=54|issue=5|pages=449–57|pmid=23427506|url=http://www.turkishjournalpediatrics.org/pediatrics/pdf/pdf_TJP_1099.pdf}}</ref> but neonatal sepsis can also 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.

== Pathophysiology ==
Sepsis is caused by a combination of factors related to the particular invading pathogen(s) and to the status of the host's immune system.<ref name=Critical2005 /> The early phase of sepsis characterized by excessive inflammation (which can sometimes result in a ]) can be followed by a prolonged period of ].<ref>{{cite journal |last1= Shukla |first1= P |last2= Rao |first2= GM |last3= Pandey |first3= G |last4= Sharma |first4= S |last5= Mittapally |first5= N |last6= Shegokar |first6= R |last7= Mishra |first7= PR |displayauthors= 4 |title= Therapeutic interventions in sepsis: Current and anticipated pharmacological agents |journal= ] |pages= 5011–31 |date= September 5, 2014 |doi= 10.1111/bph.12829 |pmid= 24977655 |url= http://onlinelibrary.wiley.com/doi/10.1111/bph.12829/full |volume= 171 |issue= 22}}</ref> Either of these phases can prove fatal.

=== Microbial factors ===
Bacterial ]s such as ] and various ] allow colonization, immune evasion, and establishment of disease in the host.<ref name=Critical2005>{{cite book |editor-first1= Jesse B. |editor-last1= Hall |editor-first2= Gregory A. |editor-last2= Schmidt |editor-first3= Lawrence D.H. |editor-last3= Wood |first1= E. Wesley |last1= Ely |first2= Richert E. |last2= Goyette |chapter= Ch. 46: Sepsis with Acute Organ Dysfunction |title= Principles of Critical Care |year= 2005 |publisher= ] |location= New York |isbn= 0071416404 |edition= 3rd |chapterurl= http://accessmedicine.mhmedical.com/content.aspx?bookid=361&sectionid=39866415 |url= http://accessmedicine.mhmedical.com/book.aspx?bookid=361 |subscription= yes |via= AccessMedicine}}</ref> Sepsis caused by ] bacteria is thought to be largely due to the host's response to the ] component of ], also called ].<ref name="Park2013">{{cite journal|last1=Park|first1=BS|last2=Lee|first2=JO|title=Recognition of lipopolysaccharide pattern by TLR4 complexes|journal= ] |date=December 2013|volume=45|issue=12|pages=e66|pmid= 24310172|pmc=3880462|doi=10.1038/emm.2013.97}}</ref><ref name="Cross2014">{{cite journal|last=Cross|first=AS|title=Anti-endotoxin vaccines: Back to the future|journal= ] |date=January 2014|volume=5|issue=1|pages=219–25|pmid=23974910|pmc=3916378 |doi=10.4161/viru.25965}}</ref> Sepsis caused by ] bacteria can result from an immunological response to cell wall ].<ref>{{cite journal|last1=Fournier|first1=B|last2=Philpott|first2=DJ|title=Recognition of Staphylococcus aureus by the innate immune system|journal= ]|date=July 2005|volume=18|issue=3|pages=521–40|pmid=16020688|pmc=1195972|doi=10.1128/CMR.18.3.521-540.2005}}</ref> Bacterial ]s that act as ] can also cause sepsis.<ref name=Critical2005 /> Superantigens simultaneously bind ] and ]s in the absence of ]. This forced receptor interaction induces the production of pro-inflammatory chemical signals (]) by T-cells.<ref name=Critical2005 />

There are a number of microbial factors which can cause the typical septic ]. An invading pathogen is recognized by its ]s (PAMPs). Examples of PAMPs include lipopolysaccharides and ] in gram-negative bacteria, ] in the ] of the gram-positive bacterial cell wall, and ]. These PAMPs are recognized by the innate immune system's ] (PRRs), which can be membrane-bound or cytosolic.<ref>{{cite journal |last1= Leentjens |first1= J |last2= Kox |first2= M |last3= van der Hoeven |first3= JG |last4= Netea |first4= MG |last5= Pickkers |first5= P |displayauthors= 4 |title= Immunotherapy for the adjunctive treatment of sepsis: From immunosuppression to immunostimulation. Time for a paradigm change? |journal= ] |date= June 15, 2013 |volume= 187 |issue= 12 |pages= 1287–93 |pmid= 23590272 |doi= 10.1164/rccm.201301-0036CP |url= http://www.atsjournals.org/doi/full/10.1164/rccm.201301-0036CP#.VHVwrclZhsg}}</ref> There are four families of PRRs: the ], the ] receptors, the ]s and the ]s. The association of a PAMP and a PRR will invariably cause a series of intracellular signalling cascades. Consequentially, transcription factors like ] and ] will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines.<ref>{{cite journal |last1= Antonopoulou |first1= A |last2= Giamarellos-Bourboulis |first2= EJ |title= Immunomodulation in sepsis: State of the art and future perspective |journal= ] |date= January 2011 |volume= 3 |issue= 1 |pages= 117–28 |pmid= 21174562 |doi= 10.2217/imt.10.82}}</ref>

=== Host factors ===
Cytokines such as ], ], and ] can activate ] factors in the ], leading to endothelial damage. The damaged endothelial surface inhibits anticoagulant properties as well as increases antifibrinolysis, which can lead to intravascular clotting, the formation of ] in small blood vessels, and multiple organ failure.<ref>{{cite journal |last= Nimah |first= M |first2= RJ |last2= Brilli |title= Coagulation dysfunction in sepsis and multiple organ system failure |journal= ] |year= 2003 |volume= 19 |pages= 441–58 |pmid= 12848314 |issue=3 |url= http://www.sassit.co.za/Journals/ICU/Coagulation/Coagulation%20dysfunction%20in%20sepsis%20&%20multiple%20otrgan%20failure%20Crit%20car%20eclin%202003.pdf |via= South African Society of Surgeons in Training (SASSIT) |doi=10.1016/s0749-0704(03)00008-3}}</ref>

A systemic inflammatory response syndrome can also occur in patients without the presence of infection, for example in those with ]s, ], or the initial state in ] and ].<ref name="1992consensus" /> The low blood pressure seen in those with sepsis is the result of various processes including excessive production of chemicals that ] such as ], a deficiency of chemicals that ] such as ], and activation of ]s.<ref name="Marik2014"/> In those with severe sepsis and septic shock, this sequence of events leads to a type of ] known as ].<ref name="Marik2014Chest">{{cite journal|last=Marik|first=PE|title=Early management of severe sepsis: concepts and controversies|journal=]|date=June 2014|volume=145|issue=6|pages=1407–18|pmid=24889440|doi=10.1378/chest.13-2104)}}</ref>

== Management ==
Early recognition and focused management can improve the outcomes in sepsis. Current professional recommendations include a number of actions ("bundles") to be taken 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 time 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 it was initially raised.<ref name=Sepsis2012/> A related bundle, the "sepsis six", is in widespread use in the ]; 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>{{cite journal|last1=Daniels|first1=R.|title=Surviving the first hours in sepsis: getting the basics right (an intensivist's perspective)|journal= ] |date=11 March 2011|volume=66|issue=Supplement 2|pages=ii11–ii23|doi=10.1093/jac/dkq515|pmid=21398303}}</ref><ref name=SIGN139>{{cite book | author=Scottish Intercollegiate Guidelines Network (SIGN) |authorlink= Scottish Intercollegiate Guidelines Network | title=Guideline 139: care of deteriorating patients | location=Edinburgh | publisher=SIGN | date=May 2014 | url=http://www.sign.ac.uk/guidelines/fulltext/139/ | isbn= 978-1-909103-26-9}}</ref>

Apart from the timely administration of fluids and ]s, the management of sepsis also involves surgical drainage of infected fluid collections, and appropriate support for organ dysfunction. This may include ] in ], ] in ] dysfunction, transfusion of ], and drug and fluid therapy for circulatory failure. Ensuring adequate nutrition—preferably by ], but if necessary by ]—is important during prolonged illness.<ref name=Sepsis2012/> In those with ] levels, ] 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>{{cite journal |last1= Hirasawa |first= H |last2=Oda |first2= S |last3=Nakamura |first3= M |title= Blood glucose control in patients with severe sepsis and septic shock |journal= ]|date= September 7, 2009 |volume= 15 |issue= 33 |pages= 4132–6 |pmid= 19725146 |doi= 10.3748/wjg.15.4132 |pmc= 2738808}}</ref> Medication to prevent ] and ] may also be used.<ref name=Sepsis2012 />

=== Antibiotics ===
In severe sepsis and septic shock, ]s (usually two or a ] with broad coverage) are recommended.<ref name=Sepsis2012/><ref name="Marik2014Chest"/> Some recommend they be given within 1 hour of making the diagnosis stating that for every hour 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>{{cite journal|last1=Sterling|first1=SA|last2=Miller|first2=WR|last3=Pryor|first3=J|last4=Puskarich|first4=MA|last5=Jones|first5=AE|title=The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis.|journal=Critical Care Medicine|date=26 June 2015|pmid=26121073|doi=10.1097/CCM.0000000000001142|volume=43|pages=1907–15}}</ref> Two sets of blood cultures should be obtained before starting antibiotics if this can be done without delaying the administration of antibiotics.<ref>{{cite book|last1=Sabatine|first1= Marc S.|title=Pocket medicine|date=2014|publisher=Aspen Publishers, Inc|location=|isbn=1451193785|edition=Fifth edition.}}</ref>

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 ] or community-acquired infection, and which organ systems are thought to be infected.<ref name="Marik2014Chest"/> Antibiotic regimens should be reassessed daily and narrowed if appropriate.<ref name=Sepsis2012/> Treatment duration is typically 7–10&nbsp;days with the type of antibiotic used directed by the results of cultures.<ref name=Campaign2008>{{cite journal |last1=Dellinger |first1=RP |last2=Levy |first2= MM |last3= Carlet |first3= JM |last4= Bion |first4= J |last5= Parker |first5= MM |last6= Jaeschke |first6= R |last7= Reinhart |first7= K |last8= Angus |first8= DC |last9= Brun-Buisson |first9= C |last10= Beale |first10= R |last11= Calandra |first11= T |last12= Dhainaut |first12= JF |last13= Gerlach |first13= H |last14= Harvey |first14= M |last15= Marini |first15= JJ |last16= Marshall |first16= J |last17= Ranieri |first17= M |last18= Ramsay |first18= G |last19= Sevransky |first19= J |last20= Thompson |first20= BT |last21= Townsend |first21= S |last22= Vender |first22= JS |last23= Zimmerman |first23= JL |last24= Vincent |first24= JL |displayauthors= 4 |title= Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 |journal= ] |date= January 2008 |volume= 34 |issue= 1 |pages= 17–60 |pmid= 18058085 |doi= 10.1007/s00134-007-0934-2 |pmc= 2249616}}</ref>

=== Intravenous fluids ===
Intravenous fluids are titrated (measured and adjusted) in response to ], ], and urine output; restoring large fluid deficits can require 6 to 10 liters of ] in adults.<ref name=Critical2005 /> In children an initial amount of 20mL/Kg is reasonable in shock.<ref>{{cite journal|last1=de Caen|first1=AR|last2=Berg|first2=MD|last3=Chameides|first3=L|last4=Gooden|first4=CK|last5=Hickey|first5=RW|last6=Scott|first6=HF|last7=Sutton|first7=RM|last8=Tijssen|first8=JA|last9=Topjian|first9=A|last10=van der Jagt|first10=ÉW|last11=Schexnayder|first11=SM|last12=Samson|first12=RA|title=Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.|journal=Circulation|date=3 November 2015|volume=132|issue=18 Suppl 2|pages=S526-42|pmid=26473000}}</ref> In cases of severe sepsis and septic shock where a ] is used to measure blood pressures dynamically, fluids should be administered until the ] (CVP) reaches 8–12mmHg.<ref name="Marik2014">{{cite journal|last=Marik|first=PE|title=Iatrogenic salt water drowning and the hazards of a high central venous pressure|journal=]|volume=2014|issue= 4|pages=21|date=June 2014|pmid=25110606|pmc=4122823|doi=10.1186/s13613-014-0021-0}}</ref> Once these goals are met, the ] (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10&nbsp;g/dL and then ]s are added until the ScvO2 is optimized.<ref name=Critical2005 /> In those with ] (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully.<ref name=Sepsis2012/>

Crystalloid solutions are recommended initially.<ref name=Sepsis2012/> Crystalloid solutions and ] are better than other fluids (such as ]) in terms of risk of death.<ref>{{cite journal |last2= Rochwerg |first2= B |last3= Alhazzani |first3= W |last4= Sindi |first4= A |last5= Heels-Ansdell |first5= D |last6= Thabane |first6= L |last7= Fox-Robichaud |first7= A |last8= Mbuagbaw |first8= L |last9= Szczeklik |first9= W |last10= Alshamsi |first10= F |last11= Altayyar |first11= S |last12= Ip |first12= WC |last13= Li |first13= G |last14= Wang |first14= M |last15= Wludarczyk |first15= A |last16= Zhou |first16= Q |last17= Guyatt |first17= GH |last18= Cook |first18= DJ |last19= Jaeschke |first19= R |last20= Annane |first20= D |last1= Fluids in Sepsis and Septic Shock Group |displayauthors= 4 |title=Fluid resuscitation in sepsis: A systematic review and network meta-analysis |journal= ] |volume= 161 |issue= 5 |pages= 347–55 |date= September 2014 |pmid= 25047428 |doi=10.7326/M14-0178}}</ref> Starches also carry an increased risk of ],<ref name=CochraneFluids/><ref>{{cite journal |last1= Zarychanski |first1= R |last2= Abou-Setta |first2= AM |last3= Turgeon |first3= AF |last4= Houston |first4= BL |last5= McIntyre |first5= L |last6= Marshall |first6= JC |last7= Fergusson |first7= DA |displayauthors= 4 |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= ] |volume= 309 |issue= 7 |pages= 678–88 |date= February 2013 |pmid= 23423413 |doi= 10.1001/jama.2013.430 |url= http://jama.jamanetwork.com/article.aspx?articleid=1653505}}</ref> and need for blood transfusion.<ref>{{cite journal |last1= Haase |first1= N |last2= Perner |first2= A |last3= Hennings |first3= LI |title= Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: Systematic review with meta-analysis and trial sequential analysis |journal= ] |volume=346 |issue= |pages=f839 |year=2013 |pmid=23418281 |pmc=3573769 |doi=10.1136/bmj.f839 |displayauthors= 4 |last4=Siegemund |first4= M |last5=Lauridsen |first5= B |last6= Wetterslev |first6= M |last7=Wetterslev |first7= J }}</ref><ref>{{cite journal |last1= Serpa Neto |first1= A |last2= Veelo |first2= DP |last3= Peireira |first3= VG |last4= de Assunção |first4= MS |last5= Manetta |first5= JA |last6= Espósito |first6= DC |last7= Schultz |first7= MJ |displayauthors= 4 |title= Fluid resuscitation with hydroxyethyl starches in patients with sepsis is associated with an increased incidence of acute kidney injury and use of renal replacement therapy: A systematic review and meta-analysis of the literature |journal= ] |volume= 29 |issue= 1 |pages= 185.e1–7 |date= February 2014 |pmid= 24262273 |doi= 10.1016/j.jcrc.2013.09.031 |url= http://www.jccjournal.org/article/S0883-9441%2813%2900387-0/fulltext}}</ref> Various colloid solutions (such as modified gelatin) carry no advantage over crystalloid.<ref name=CochraneFluids>{{cite journal |last1=Perel |first1= P |last2= Roberts |first2= I |last3= Ker |first3= K |title= Colloids versus crystalloids for fluid resuscitation in critically ill patients |journal= ] |volume= 2|issue= 2 |pages= CD000567 |year= 2013 |pmid= 23450531 |doi= 10.1002/14651858.CD000567.pub6 |url= http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000567.pub6/full}}</ref> Albumin also appears to be of no benefit over crystalloids.<ref>{{cite journal|last1=Patel|first1=A|last2=Laffan|first2=MA|last3=Waheed|first3=U|last4=Brett|first4=SJ|title=Randomised trials of human albumin for adults with sepsis: A systematic review and meta-analysis with trial sequential analysis of all-cause mortality|journal= ] |date= July 22, 2014 |volume= 349 |pages= g4561 |pmid= 25099709 |doi= 10.1136/bmj.g4561 |url= http://www.bmj.com/content/349/bmj.g4561}}</ref> ] are recommended to keep the ] levels between 70 and 90 g/L.<ref name=Sepsis2012/> A 2014 trial; however, found no difference between a target hemoglobin of 70 or 90 g/L.<ref>{{cite journal |last3= Holst |first3=LB |last4=Haase |first4=N |last5=Wetterslev |first5=J |last6=Wernerman |first6=J |last7=Guttormsen |first7=AB |last8=Karlsson |first8=S |last9=Johansson |first9=PI |last10=Aneman |first10=A |last11=Vang |first11=ML |last12=Winding |first12=R |last13=Nebrich |first13=L |last14=Nibro |first14=HL |last15=Rasmussen |first15=BS |last16=Lauridsen |first16=JR |last17=Nielsen |first17=JS |last18=Oldner |first18=A |last19=Pettilä |first19=V |last20=Cronhjort |first20=MB |last21=Andersen |first21=LH |last22=Pedersen |first22=UG |last23=Reiter |first23=N |last24=Wiis |first24=J |last25=White |first25=JO |last26=Russell |first26=L |last27=Thornberg |first27=KJ |last28=Hjortrup |first28=PB |last29=Müller |first29=RG |last30=Møller |first30=MH |last31=Steensen |first31=M |last32=Tjäder |first32=I |last33=Kilsand |first33=K |last34=Odeberg-Wernerman |first34=S |last35=Sjøbø |first35=B |last36=Bundgaard |first36=H |last37=Thyø |first37=MA |last38=Lodahl |first38=D |last39=Mærkedahl |first39=R |last40=Albeck |first40=C |last41=Illum |first41=D |last42=Kruse |first42=M |last43=Winkel |first43=P |last44=Perner |first44=A |author1= TRISS Trial Group |author2= Scandinavian Critical Care Trials Group |displayauthors= 4 |title=Lower versus higher hemoglobin threshold for transfusion in septic shock |journal= ] |date= October 9, 2014 |volume= 371 |issue= 15 |pages= 1381–91 |pmid= 25270275 |doi= 10.1056/NEJMoa1406617}}</ref>

=== Vasopressors ===
If the person has been sufficiently fluid resuscitated but the ] is not greater than 65&nbsp;mmHg, ]s are recommended.<!-- <ref name=Sepsis2012/> --> ] (noradrenaline) is recommended as the initial choice.<!-- <ref name=Sepsis2012/> --> If a single vasopressor is not enough to raise the blood pressure, ] (adrenaline) or ] may be added.<!-- <ref name=Sepsis2012 /> --> ] is typically not recommended.<!-- <ref name=Sepsis2012/> --> ] may be used if heart function is poor or blood flow is insufficient despite sufficient fluid volumes and blood pressure.<ref name=Sepsis2012/>

=== Ventilation ===
] is often not recommended as a medication to help with ] in this situation due to concerns it may lead to ] and an increased risk of death.<ref>{{cite journal |last1= Cherfan |first1= AJ |last2= Arabi |first2= YM |last3= Al-Dorzi |first3= HM |last4= Kenny |first4= LP |title= Advantages and disadvantages of etomidate use for intubation of patients with sepsis |journal= ] |date= May 2012 |volume= 32 |issue= 5 |pages= 475–82 |pmid= 22488264 |doi= 10.1002/j.1875-9114.2012.01027.x}}</ref><ref>{{cite journal |last1= Chan |first1= CM |last2= Mitchell |first2= AL |last3= Shorr |first3= AF |title= Etomidate is associated with mortality and adrenal insufficiency in sepsis: A meta-analysis |journal= ] |date= November 2012 |volume= 40 |issue= 11 |pages= 2945–53 |pmid= 22971586 |doi= 10.1097/CCM.0b013e31825fec26}}</ref> The small amount of evidence there is, however, has not found a change in the risk of death with etomidate.<ref>{{cite journal |last1= Gu |first1= WJ |last2= Wang |first2= F|last3= Tang |first3= L |last4= Liu |first4= JC |title= Single-dose etomidate does not increase mortality in patients with sepsis: A systematic review and meta-analysis of randomized controlled trials and observational studies |journal= ] |date= September 25, 2014 |pmid= 25255427 |doi= 10.1378/chest.14-1012 |volume=147 |issue=2 |pages=335}}</ref>

It is recommended that the head of the bed be raised if possible to improve ventilation.<ref name=Sepsis2012/> ] should be avoided unless ARDS is suspected.<ref name=Sepsis2012/>

=== Steroids ===
The use of ] in sepsis is controversial.<ref name=Steroids2012 /> Studies do not give a clear picture as to whether and when ]s should be used.<ref>{{cite journal |vauthors=Volbeda M, Wetterslev J, Gluud C, Zijlstra JG, van der Horst IC, Keus F | title=Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis | journal=Intensive Care Med |date=July 2015 |volume=41 | issue=7| pages=1220–34| pmid=26100123|doi=10.1007/s00134-015-3899-6}}</ref> The 2012 Surviving Sepsis Campaign recommends against their use in those with septic shock if intravenous fluids and vasopressors stabilize the person's cardiovascular function.<ref name=Sepsis2012/> While a 2015 Cochrane review found low quality evidence of benefit.<ref>{{cite journal|last1=Annane|first1=D|last2=Bellissant|first2=E|last3=Bollaert|first3=PE|last4=Briegel|first4=J|last5=Keh|first5=D|last6=Kupfer|first6=Y|title=Corticosteroids for treating sepsis.|journal=The Cochrane database of systematic reviews|date=4 December 2015|volume=12|pages=CD002243|pmid=26633262|doi=10.1002/14651858.CD002243.pub3}}</ref>

During critical illness, a state of ] and tissue resistance to ] may occur. This has been termed ].<ref name="pmid18496365">{{cite journal |pages= 1937–49 |doi= 10.1097/CCM.0b013e31817603ba |title= Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine |year= 2008 |last2= Marik |first2= PE |last3= Pastores |first3= SM |last4= Annane |first4= D |last5= Meduri |first5= GU |last6= Sprung |first6= CL |last7= Arlt |first7= W |last8= Keh |first8= D |last9= Briegel |first9= J |last10= Beishuizen |first10= A |journal= ] |volume= 36 |issue= 6 |pmid= 18496365 |last11= Dimopoulou |first11= I |last12= Tsagarakis |first12= S |last13= Singer |first13= M |last14= Chrousos |first14= GP |last15= Zaloga |first15= G |last16= Bokhari |first16= F |last17= Vogeser |first17= M |last1= American College of Critical Care Medicine |displayauthors= 4 |url= http://pediatrics.uchicago.edu/chiefs/picu/documents/guidelines.pdf |via= ]}}</ref> Treatment with corticosteroids might be most beneficial in those with ] and early severe ARDS, whereas its role in others such as those with ] or severe ] 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. ] is not recommended to confirm the diagnosis.<ref name="pmid18496365" /> The method of stopping glucocorticoid drugs is variable, and it is unclear whether they should be slowly decreased or simply abruptly stopped.

=== 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"/> It 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 65-90 mmHg, a central venous oxygen saturation (ScvO<sub>2</sub>) greater than 70% and a urine output of greater than 0.5 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">{{cite journal |pages= 1368–77 |doi= 10.1056/NEJMoa010307 |title= Early goal-directed therapy in the treatment of severe sepsis and septic shock |year= 2001 |last2= Rivers |first2= E |last3= Nguyen |first3= B |last4= Havstad |first4= S |last5= Ressler |first5= J |last6= Muzzin |first6= A |last7= Knoblich |first7= B |last8= Peterson |first8= E |last9= Tomlanovich |first9= M |journal= ] |volume= 345 |issue= 19 |pmid= 11794169 |author1= Early Goal-Directed Therapy Collaborative Group |display-authors= 4 |authorlink2= Emanuel Rivers |url= http://www.nejm.org/doi/full/10.1056/NEJMoa010307}}</ref> An appropriate decrease in serum ] may be equivalent to ScvO<sub>2</sub> and easier to obtain.<ref>{{cite journal|last1=Fuller|first1=BM|last2=Dellinger|first2=RP|title=Lactate as a hemodynamic marker in the critically ill.|journal=Current opinion in critical care|date=June 2012|volume=18|issue=3|pages=267–72|pmid=22517402|doi=10.1097/MCC.0b013e3283532b8a|pmc=3608508}}</ref>

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=Sepsis2012/> 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 versus the standard therapy in severe sepsis.<ref name=Dell2015>{{cite journal|last1=Dell'anna|first1=AM|last2=Taccone|first2=FS|title=Early-goal directed therapy for septic shock: is it the end?|journal=Minerva anestesiologica|date=19 June 2015|pmid=26091011|volume=81|pages=1138–43}}</ref> 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>{{cite journal|last1=Rusconi|first1=AM|last2=Bossi|first2=I|last3=Lampard|first3=JG|last4=Szava-Kovats|first4=M|last5=Bellone|first5=A|last6=Lang|first6=E|title=Early goal-directed therapy vs usual care in the treatment of severe sepsis and septic shock: a systematic review and meta-analysis.|journal=Internal and emergency medicine|date=16 May 2015|pmid=25982917|doi=10.1007/s11739-015-1248-y|volume=10|pages=731–43}}</ref>

=== Newborns ===
] can be difficult to diagnose as newborns may be asymptomatic.<ref name="Shane2014">{{cite journal|last1=Shane|first1=AL|last2=Stoll|first2=BJ|title=Neonatal sepsis: progress towards improved outcomes|journal=]|volume=68|issue=Supplement 1|pages=S24–32|date=January 2014|pmid=24140138|doi=10.1016/j.jinf.2013.09.011}}</ref> 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>{{cite journal|last1=Camacho-Gonzalez|first1=A|last2=Spearman|first2=PW|last3=Stoll|first3=BJ|title=Neonatal infectious diseases: evaluation of neonatal sepsis|journal=]|volume=60|issue=2|pages=367–89|date=April 2013|pmid=23481106|doi=10.1016/j.pcl.2012.12.003}}</ref>

=== Other ===
Monoclonal and polyclonal preparations of ] do not lower the rate of death in newborns and adults with sepsis.<ref name="Alejandria2013">{{cite journal|last1=Alejandria|first=MM|last2=Lansang|first2=MA|last3=Dans|first3=LF|last4=Mantaring|first4=JB 3rd|title=Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock|journal= ]|date=September 2013|volume=9|issue=CD001090|pages=CD001090|pmid=24043371|url=http://onlinelibrary.wiley.com/enhanced/doi/10.1002/14651858.CD001090.pub2?regionCode=US-NV&identityKey=acb5a1f3-78ad-4fe6-8764-b96243f1c9e3&isReportingDone=true|doi=10.1002/14651858.CD001090.pub2}}</ref> Evidence for the use of ]-enriched polyclonal preparations of IVIG is inconsistent.<ref name="Alejandria2013"/> A 2012 ] concluded that ] does not reduce mortality in those with SIRS or sepsis and may even be harmful.<ref name="Szakmany2012">{{cite journal|last1=Szakmany|first=T|last2= Hauser|first2=B|last3=Radermacher|first3=P|title=N-acetylcysteine for sepsis and systemic inflammatory response in adults|journal=]|date=September 2012|volume=9|issue=CD006616|pages=CD006616|pmid=22972094|doi=10.1002/14651858.CD006616.pub2}}</ref>

] activated ] (]) was originally introduced for severe sepsis (as identified by a high ] 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 ] also has not shown benefit.<ref>{{cite journal|last1=Fink|first1=MP|last2=Warren|first2=HS|title=Strategies to improve drug development for sepsis.|journal=Nature reviews. Drug discovery|date=October 2014|volume=13|issue=10|pages=741–58|pmid=25190187|doi=10.1038/nrd4368}}</ref>

== Prognosis ==
Approximately 20–35% of people with severe sepsis and 30–70% of people with septic shock die.<ref>{{cite journal |last= Russel |first= JA |title= The current management of septic shock |journal= ] |date= October 2008 |volume= 99 |issue= 5 |pages= 431–58 |pmid= 18971911}}</ref> 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 have a mortality of less than 15%.<ref name=Soong2012 />

There are a number of prognostic stratification systems such as ] 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 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>{{cite journal |last2=Carpenter |first2=CR |last3=Keim |first3= SM |last4= Upadhye |first4= S |last5=Nguyen |first5= HB |last1= Best Evidence in Emergency Medicine Investigator, Group |displayauthors= 4 |title= Risk stratification of the potentially septic patient in the emergency department: The mortality in the emergency department sepsis (MEDS) score |journal= ] |date= October 2009 |volume= 37 |issue= 3 |pages= 319–27 |pmid= 19427752 |doi= 10.1016/j.jemermed.2009.03.016}}</ref>

Some people may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most sepsis patients makes the incidence of this difficult to quantify or to study.<ref>{{cite journal |last1= Jackson |first= JC |last2= Hopkins |first2= RO |last3= Miller |first3= RR |last4= Gordon |first4= SM |last5= Wheeler |first5= AP |last6= Ely |first6= EW |displayauthors= 4 |title= Acute respiratory distress syndrome, sepsis, and cognitive decline: A review and case study |journal= ] |date= November 2009 |volume= 102 |issue= 11 |pages= 1150–7 |pmid= 19864995 |doi= 10.1097/SMJ.0b013e3181b6a592 |pmc= 3776422}}</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 worldwide ] of sepsis is estimated to be 18 million cases per year.<ref name="Lyle2014">{{cite journal|last=Lyle|first=NH|last2=Pena|first2=OM|last3=Boyd|first3=JH|last4=Hancock|first4=RE|title=Barriers to the effective treatment of sepsis: antimicrobial agents, sepsis definitions, and host-directed therapies|journal=]|volume=1323|issue=2014|pages=101–14|date=September 2014|pmid= 24797961|doi=10.1111/nyas.12444}}</ref> In the ] sepsis affects approximately 3 in 1,000 people,<ref name=Soong2012 /> and severe sepsis contributes to more than 200,000 deaths per year.<ref>{{cite book |editor-last1= Longo |editor-first1= Dan L. |editor-first2= Anthony S. |editor-last2= Fauci |editor-first3= Dennis L. |editor-last3= Kasper |editor-first4= Stephen L. |editor-last4= Hauser |editor-first5= J. Larry |editor-last5= Jameson |editor-first6= Joseph |editor-last6= Loscalzo |display-editors= 4 |first1= Robert S. |last1= Munford |title= Harrison's Principles of Internal Medicine |year= 2011 |publisher= ] |location= New York |isbn= 9780071748896 |edition= 18th |chapter= Ch. 271: Severe Sepsis and Septic Shock |pages= 2223–231}}</ref>

Sepsis occurs in 1-2% of all hospitalizations and accounts for as much as 25% of ICU bed utilization. Due to it rarely being reported as a primary diagnosis (often being a complication of cancer or other illness), the incidence, mortality, and morbidity rates of sepsis are likely underestimated.<ref name=Critical2005 /> A study by the ] (AHRQ) of selected States found that there were approximately 651 hospital stays per 100,000 population with a sepsis diagnosis in 2010.<ref name="hcup-us.ahrq.gov">{{cite web |last= Sutton |first= JP |last2= Friedman |first2= B |title= Trends in Septicemia Hospitalizations and Readmissions in Selected HCUP States, 2005 and 2010 |issue= Statistical Brief #161 |date= September 2013 |pmid= 24228290 | publisher = ] | location = Rockville, MD |url= http://www.ncbi.nlm.nih.gov/books/NBK169246/ |work= ]}}</ref> It is the second-leading cause of death in non-coronary ] (ICU) patients and the tenth-most-common cause of death overall (the first being heart disease).<ref>{{cite journal |pages= 1546–54 |doi= 10.1056/NEJMoa022139 |title= The epidemiology of sepsis in the United States from 1979 through 2000 |year= 2003 |last1= Martin |first1= GS |last2= Mannino |first2= DM |last3= Eaton |first3= S |last4= Moss |first4= M |journal= ] |volume= 348 |issue= 16 |pmid= 12700374 |url= http://www.nejm.org/doi/full/10.1056/NEJMoa022139#t=article}}</ref> Children under 12 months of age and elderly people have the highest incidence of severe sepsis.<ref name=Critical2005 /> Among U.S. patients 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 Medicare patients in 2011, septicemia was the second most common principal reason for readmission within 30 days.<ref>{{cite web |last1= Hines |first1= AL |last2= Barrett |first2= ML |last3= Jiang |first3= HJ |last4= Steiner |first4= CA | title = Conditions with the Largest Number of Adult Hospital Readmissions by Payer, 2011. |issue= Statistical Brief #172 |work= ] | publisher = ] | location = Rockville, MD | date = April 2014 | url = http://hcup-us.ahrq.gov/reports/statbriefs/sb172-Conditions-Readmissions-Payer.jsp |pmid= 24901179}}</ref>

Several medical conditions increase a person's susceptibility to infection and developing sepsis. Common sepsis risk factors include age (especially the very young and old); conditions that weaken the immune system such as ], ], or the ]; and ] and ]s.<ref name="CDC2014Q"/><ref name="Koh2012">{{cite journal|last=Koh|first=GC|last2=Peacock|first2=SJ|last3=van der Poll|first3=T|last4=Wiersinga|first4=WJ|title=The impact of diabetes on the pathogenesis of sepsis|journal= ] |volume= 31|issue=4|pages=379–88|date=April 2012|pmid=21805196|pmc=3303037|doi=10.1007/s10096-011-1337-4}}</ref><ref name="Rubin2014">{{cite journal|last=Rubin|first=LG|last2=Schaffner|first2=W|title=Clinical practice. Care of the asplenic patient|journal= ] |volume=371|issue=4|pages=349–56|date=July 2014|pmid=25054718|doi=10.1056/NEJMcp1314291}}</ref>

== History ==
]'.]]

The term "σήψις"<ref name="CavaillonAdrie2008">{{cite book |editor-first1=Jean-Marc |editor-last1= Cavaillon |editor-first2=Christophe |editor-last2= Adrie |title= Sepsis and Non-infectious Systemic Inflammation: From Biology to Critical Care |year= 2008 |publisher= ] |isbn= 9783527319350 |page= |first= Jean-Louis |last= Vincent |chapter= Ch. 1: Definition of Sepsis and Non-infectious SIRS}}</ref> (sepsis) was introduced by Hippocrates in the fourth century BC, and it meant the process of ] of organic matter.<ref name="pmid18171697">{{cite journal |last= Marshall |first= JC |title= Sepsis: Rethinking the approach to clinical research |journal= ] |date= July 2013 |volume= 94 |issue= 1 |doi= 10.1189/jlb.0607380 |pmid= 18171697 |pages= 471–82 |url= http://www.jleukbio.org/content/83/3/471.full}}</ref> In the eleventh century, ] used the term "blood rot" for diseases linked to severe ] 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.

By the end of the 19th century, it was widely believed that ] produced substances that could injure the ] host and that soluble ] released during infection caused the fever and shock that were commonplace during severe infections. ] coined the term ] at the beginning of the 20th century to denote the pyrogenic principle associated with '']''. It was soon realised that endotoxins were expressed by most and perhaps all ]. The ] character of enteric endotoxins was elucidated in 1944 by Shear.<ref name=Shear1944>{{cite journal |last= Shear |first= 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= ] |volume= 4 |issue= 5 |pages= 461–76 |doi= 10.1093/jnci/4.5.461|doi_brokendate= 2015-02-02 }}</ref> The molecular character of this material was determined by Luderitz et al. in 1973.<ref name=Luderitz1973>{{cite journal |last1= Luderitz |first1= O |year= 1973 |title=Lipid A: Chemical structure and biologic activity |journal= ] |volume= 128 |page= 29 |last2=Galanos |first2= C |last3=Lehmann |first3= V |doi= 10.1093/infdis/128.Supplement_1.S17 |first4= M |first5= ET |first6= G |first7= M |first8= O |last4=Nurminen |last5=Rietschel |last6=Rosenfelder |last7=Simon |last8=Westphal |displayauthors= 4 |jstor= 30106029}}</ref>

It was discovered in 1965 that a strain of C3H/HeJ ] were immune to the endotoxin-induced shock.<ref name=Heppner1965>{{cite journal |last1= Heppner |first1= G |last2= Weiss |first2= DW |year= 1965 |title= High susceptibility of strain A mice to endotoxin and endotoxin-red blood cell mixtures |journal= ] |volume= 90 |issue= 3 |pages= 696–703 |pmid= 16562068 |pmc= 315712}}</ref> The genetic locus for this effect was dubbed ''Lps''. These mice were also found to be hypersusceptible to infection by gram-negative bacteria.<ref name=O>{{cite journal |last1= O'Brien |first1= AD |year= 1980 |title= Genetic control of susceptibility to ''Salmonella typhimurium'' in mice: Role of the LPS gene |journal= ] |volume= 124 |issue= 1 |pages= 20–4 |last2= Rosenstreich |first2= DL |last3= Scher |first3= I |displayauthors= 4 |pmid=6985638 |last4= Campbell |first4= GH |last5= MacDermott |first5= RP |last6= Formal |first6= SB}}</ref> These observations were finally linked in 1998 by the discovery of the ] gene 4 (TLR 4).<ref name=Poltorak1998>{{cite journal |last1= Poltorak |first1= A |last2= Smirnova |first2=I |last3= He |first3= X |last4= Liu |first4= M-Y |last5= Van Huffel |first5= C |last6= Birdwell |first6= D |last7= Alejos |first7= E |last8= Silva |first8=M |last9= Du |first9= X |last10= Thompson |first10= P |last11= Chan |first11= EKL |last12= Ledesma |first12= J |last13= Roe |first13= B |last14= Clifton |first14= S |last15= Vogel |first15= SN |last16= Beutler |first16= B |displayauthors= 4 |title= Genetic and physical mapping of the Lps locus: Identification of the toll-4 receptor as a candidate gene in the critical region |journal= ] |volume= 24 |issue= 3 |year= 1998 |pages= 340–55 |pmid= 10087992 |doi= 10.1006/bcmd.1998.0201}}</ref> Genetic mapping work, performed over a period of 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 ].<ref name=Poltorak1998B>{{cite journal |last1= Poltorak |first1= A |year= 1998 |title= Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene |journal= ] |volume= 282 |issue= 5396 |pages= 2085–8 |last2= He |first2= X |last3= Smirnova |first3= I |displayauthors= 4 |doi= 10.1126/science.282.5396.2085 |pmid= 9851930 |last4=Liu |first4= MY |last5= Van Huffel |first5= C |last6= Du |first6= X |last7= Birdwell |first7= D |last8= Alejos |first8= E |last9= Silva |first9= M |last10= Galanos |first10= C |last11= Freudenberg |first11= M |last12= Ricciardi-Castagnoli |first12= P |last13= Layton |first13= B |last14= Beutler |first14= B |bibcode=1998Sci...282.2085P}}</ref>

== Society and culture ==

=== Economics ===
Sepsis was the most expensive condition treated in U.S. hospital stays in 2011, at an aggregate cost of $20.3 billion for nearly 1.1 million hospitalizations.<ref name=Tor2013>{{cite web |last1= Torio |first1=CM |last2=Andrews |first2= RM |title= National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2011 |work= ] |publisher= ] |location= Rockville, MD |issue= Statistical Brief #160 |date= August 2013 |pmid= 24199255 |url= https://www.ncbi.nlm.nih.gov/books/NBK169005/ |postscript= .}}</ref> Costs for sepsis hospital stays more than quadrupled since 1997 with an 11.5 percent annual increase.<ref>{{cite web |last1= Pfuntner |first= A |last2= Wier |first2= LM |last3=Steiner |first3= C |title= Costs for Hospital Stays in the United States, 2011 |issue= Statistical Brief #168 |date= December 2013 |pmid= 24455786 |url= https://www.ncbi.nlm.nih.gov/books/NBK179289/ |work= ] |publisher= ] |location= Rockville, MD}}</ref> By payer, it was the most costly condition billed to Medicare, the second-most costly billed to Medicaid and the uninsured, and the fourth-most costly billed to private insurance.<ref name=Tor2013 />

=== Education ===
A large international collaboration entitled the "]" was established in 2002<ref>{{cite web |title= History |url= http://www.survivingsepsis.org/About-SSC/Pages/History.aspx |work= ] |publisher= ] |accessdate= February 24, 2014}}</ref> to educate people about sepsis and to improve patient outcomes with sepsis. The Campaign has published an evidence-based review of management strategies for severe sepsis, with the aim to publish a complete set of guidelines in subsequent years.<ref name=Campaign2008 />

] is a charitable organization run by a team of dedicated laypeople and healthcare professionals who share a strong commitment to battling sepsis. The organization was created to raise sepsis awareness among both the general public and healthcare professionals.<ref>{{cite web|title=About Us - About the Sepsis Alliance|url=http://www.sepsis.org/about/|website=www.sepsis.org|accessdate=8 October 2015}}</ref>

== Notes ==
{{Reflist|group=note}}

== References ==
{{Reflist|2}}

== External links ==
{{commonscatinline}}
* {{dmoz|Health/Conditions_and_Diseases/Infectious_Diseases/Sepsis/}}
*

{{Intensive care medicine}}
{{Abnormal clinical and laboratory findings}}

{{Authority control}}

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Revision as of 21:45, 26 July 2016

sepsis and deth