measurement over usual methods of measurement, however, is poor. 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 inflammation of the abdominal cavity lining, an infection of the bile duct, or an intestinal infarction. a pierced internal organ (free air on an abdominal x-ray or ct scan), an abnormal chest x-ray consistent with pneumonia (with focal opacification), or petechiae, purpura, or purpura fulminans may indicate the presence of an infection. definitions systemic inflammatory response syndrome findingvalue temperature<36 °c (96.8 °f) or >38 °c (100.4 °f) heart rate>90/min respiratory rate>20/min or paco2<32 mmhg (4.3 kpa) wbc<4x109/l (<4000/mm3), >12x109/l (>12,000/mm3), or ≥10% bands 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. 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. severe sepsis is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (manifesting as hypotension, elevated lactate, or decreased urine output). severe sepsis is an infectious disease state associated with multiple organ dysfunction syndrome (mods) septic shock is severe sepsis plus persistently low blood pressure, despite the administration of intravenous fluids. 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). 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. sepsis is suspected when 2 of the qsofa criteria are met. 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. some advantages of the qsofa score are that it can be administered quickly and does not require labs. 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. 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. 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 recommends "against using qsofa compared with sirs, news, or mews as a single screening tool for sepsis or septic shock". end-organ dysfunction main article: multiple organ dysfunction syndrome examples of end-organ dysfunction include the following: lungs: acute respiratory distress syndrome (ards) (pao2/fio2 ratio < 300), different ratio in pediatric acute respiratory distress syndrome brain: encephalopathy symptoms including agitation, confusion, 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 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: low urine output or no urine output, electrolyte abnormalities, or volume overload heart: systolic and diastolic heart failure, likely due to 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. cardiovascular dysfunction (after fluid resuscitation with at least 40 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 < 0.5 ml/kg/h) prolonged capillary refill > 5 seconds core to peripheral temperature difference > 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 (pao2/fio2) < 300 (the definition of acute lung injury), or arterial partial-pressure of carbon dioxide (paco2) > 65 torr (20 mmhg) over baseline paco2 (evidence of hypercapnic respiratory failure), or supplemental oxygen requirement of greater than fio2 0.5 to maintain oxygen saturation ≥ 92% neurologic dysfunction glasgow coma score (gcs) ≤ 11, or altered mental status with drop in gcs of 3 or more points in a person with developmental delay/intellectual disability hematologic dysfunction platelet count < 80,000/mm3 or 50% drop from 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 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. biomarkers biomarkers can help diagnosis because they can point to the presence or severity of sepsis, although their exact role in the management of sepsis remains undefined. 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. the same review found the 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. a 2012 systematic review found that soluble urokinase-type plasminogen activator receptor (supar) is a nonspecific marker of inflammation and does not accurately diagnose sepsis. 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. serial measurement of lactate levels (approximately every 4 to 6 hours) may guide treatment and is associated with lower mortality in sepsis. 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, burns, pulmonary embolism, thyrotoxicosis, anaphylaxis, adrenal insufficiency, and neurogenic shock. hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (hlh) may have similar symptoms and are on the differential diagnosis. neonatal sepsis in common clinical usage, neonatal sepsis refers to a bacterial blood stream infection in the first month of life, such as meningitis, pneumonia, pyelonephritis, or gastroenteritis, but neonatal sepsis also may be due to infection with fungi, viruses, or parasites. criteria with regard to hemodynamic compromise or respiratory failure are not useful because they present too late for intervention. management intravenous fluids being given early recognition and focused management may improve the outcomes in sepsis. current professional recommendations include a number of 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 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 initially it was raised. 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. apart from the timely administration of fluids and antibiotics, the management of sepsis also involves surgical drainage of infected fluid collections and appropriate support for organ dysfunction. this may include hemodialysis in kidney failure, mechanical ventilation in lung dysfunction, transfusion of 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. medication to prevent deep vein thrombosis and gastric ulcers also may be used. 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 more than 48 hours) are recommended if infections from these sites are suspected. in severe sepsis and septic shock, broad-spectrum antibiotics (usually two, a β-lactam antibiotic with broad coverage, or broad-spectrum carbapenem combined with fluoroquinolones, macrolides, or aminoglycosides) are recommended. the choice of antibiotics is important in determining the survival of the person. 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. others did not find a benefit with early administration. 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 or community-acquired infection, and which organ systems are thought to be infected. antibiotic regimens should be reassessed daily and narrowed if appropriate. treatment duration is typically 7–10 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 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 (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. prolonged antibiotic prophylaxis is not recommended in people who has sirs without any infectious origin such as acute pancreatitis and burns unless sepsis is suspected. 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 total daily dose would help to keep the antibiotics level above minimum inhibitory concentration (mic), thus providing a better clinical response. giving beta-lactam antibiotics continuously may be better than giving them intermittently. access to therapeutic drug monitoring is important to ensure adequate drug therapeutic level while at the same time preventing the drug from reaching toxic level. 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. in children an initial amount of 20 ml/kg is reasonable in shock. 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. 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,