Editing Sepsis (section)

== Management ==
[[File:Sepsis treatment.jpg|thumb|Intravenous fluids being given]]
Early recognition and focused management may improve the outcomes of sepsis. 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 also should 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 (in situ for more than 48 hours) 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 gram-negative 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 has 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 antibiotics 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 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 mmHg.<ref name= "SSC–G2016"/> In children an initial amount of 20 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"/> [[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 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 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 × 10<sup>9</sup>/L) without any risk of bleeding, or (20 × 10<sup>9</sup>/L) with a high risk of bleeding, or (50 × 10<sup>9</sup>/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 | pages = 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 review found low-quality evidence of benefit,<ref name=Ann2019 /> 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 to taper steroids when vasopressors are no longer needed.<ref name= "SSC–G2016"/>

=== Anesthesia ===
A target [[tidal volume]] of 6 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 it 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 infective 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 | pages = 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 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"/> 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]] 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]] are 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 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 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 |pages=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>