Editing Sepsis (section)

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

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

Within the first three hours of suspected sepsis, diagnostic studies should include [[white blood cell counts]], measuring serum lactate, and obtaining appropriate cultures before starting antibiotics, so long as this does not delay their use by more than 45 minutes.<ref name=SSCG2012/> To identify the causative organism(s), at least two sets of [[blood culture]]s using bottles with [[growth medium|media]] for [[aerobic organism|aerobic]] and [[anaerobic organism]]s are necessary. At least one should be drawn [[percutaneously|through the skin]] and one through each vascular access device (such as an IV catheter) that has been in place for more than 48 hours.<ref name=SSCG2012/> Bacteria are [[bacteremia|present in the blood]] in only about 30% of cases.<ref name="Wacker2013"/> Another possible method of detection is by [[polymerase chain reaction]]. If other sources of infection are suspected, cultures of these sources, such as urine, cerebrospinal fluid, wounds, or respiratory secretions, also should be obtained, as long as this does not delay the use of antibiotics.<ref name=SSCG2012/>

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

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

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

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

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

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

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

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

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

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

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