|Classification and external resources|
|ICD-10||A40 – A41|
Sepsis (//) is whole-body inflammation caused by an infection. Common signs and symptoms include fever, increased heart rate, increased breathing rate, and confusion. There may also be symptoms related to a specific infection such as a cough with pneumonia or burning with urination with a kidney infection. In the very young, old, and people with a weakened immune system, there may be no symptoms of a specific infection and the body temperature may be low or normal rather than high. Severe sepsis is sepsis causing poor organ function or insufficient blood flow. Insufficient blood flow may be evident by low blood pressure, high blood lactate, or low urine output. Septic shock is low blood pressure due to sepsis that does not improve after reasonable amounts of intravenous fluids are given.
Sepsis is caused by an immune response triggered by an infection. The infection is most commonly by bacteria, but can also be by fungi, viruses, or parasites. Common locations for the primary infection include: lungs, brain, urinary tract, skin, and abdominal organs. Risk factors include: the young, the old, people with poor immune systems such as from cancer or diabetes, as well as major trauma and burns. Diagnosis is based on meeting at least two systemic inflammatory response syndrome (SIRS) criteria due to a presumed infection. Blood cultures are recommended preferably before antibiotics are started; however, infection of the blood is not required for the diagnosis. Medical imaging should be done looking for the possible location of infection. Other potential causes of similar signs and symptoms include: anaphylaxis, adrenal insufficiency, low blood volume, heart failure, and pulmonary embolism among others.
Sepsis is usually treated with intravenous fluids and antibiotics. This is often done in an intensive care unit. If fluid replacement is not enough to maintain blood pressure, medications that raise blood pressure can be used. Mechanical ventilation and dialysis may be needed to support the function of the lungs and kidneys, respectively. To guide treatment, a central venous catheter and an arterial catheter may be placed. Other measurement such as cardiac output and superior vena cava oxygenation saturation may also be used. People with sepsis need preventive measures for deep vein thrombosis, stress ulcers and pressure ulcers, unless other conditions prevent such interventions. Some might benefit from tight control of blood sugar levels with insulin. The use of corticosteroids is controversial. Activated drotrecogin alfa, originally marketed for severe sepsis, has not been found to be helpful, and was withdrawn from sale in 2011.
Outcomes depend on the severity of disease 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%. The total number of cases worldwide is unknown as there is little data from the developing world. Estimates suggest sepsis affects millions of people a year. In the developed world about 0.2 to 3 per 1000 people gets sepsis yearly or about a million cases per year in the United States. Rates of disease have been increasing. Sepsis is more common among males than females. The terms septicemia and blood poisoning referred to the microorganisms or their toxins in the blood and are no longer commonly used. The condition has been described at least since the time of Hippocrates.
- 1 Signs and symptoms
- 2 Cause
- 3 Diagnosis
- 4 Pathophysiology
- 5 Management
- 6 Prognosis
- 7 Epidemiology
- 8 History
- 9 Society and culture
- 10 Notes
- 11 References
- 12 External links
Signs and symptoms
In addition to symptoms related to the provoking cause, sepsis is frequently associated with either fever or low body temperature, rapid breathing, elevated heart rate, confusion, and edema. Early signs are a fast heart rate, decreased urination, and high blood sugar, while signs of established sepsis are confusion, metabolic acidosis, which may be accompanied by faster breathing leading to a respiratory alkalosis, low blood pressure, decreased systemic vascular resistance, higher cardiac output, and dysfunctions of blood coagulation (where clotting can lead to organ failure).
The most common primary sources of infection resulting in sepsis are the lungs, the abdomen, and the urinary tract. 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.
The infectious agents are usually bacteria but can also be fungi or viruses. While Gram-negative bacteria were previously the most common cause of sepsis, in the last decade, Gram-positive bacteria, most commonly staphylococci, are thought to cause more than 50% of cases of sepsis. Other commonly implicated bacteria include Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species. Fungal sepsis accounts for approximately 5% of severe sepsis and septic shock cases; the most common cause of fungal sepsis is infection by Candida species of yeast.
|Temperature||<36 °C (96.8 °F) or >38 °C (100.4 °F)|
|Respiratory rate||>20/min or PaCO2<32 mmHg (4.3 kPa)|
|WBC||<4x109/L (<4000/mm³), >12x109/L (>12,000/mm³), or 10% bands|
Within the first three hours of suspected sepsis, diagnostic studies should include WBCs, measuring serum lactate and obtaining appropriate cultures before starting antibiotics, so long as this does not delay their use by more than 45 minutes. To identify the causative organism(s), at least two sets of blood cultures using bottles with media for aerobic and anaerobic organisms should be obtained, with at least one drawn through the skin and one drawn through each vascular access device (such as an IV catheter) in place more than 48 hours. However, bacteria are present in the blood in only about 30% of cases.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, should also be obtained, as long as this does not delay the use of antibiotics.
Within six hours, if blood pressure remains low despite initial fluid resuscitation of 30 ml/kg, or if initial lactate is ≥ 4 mmol/L (36 mg/dL), central venous pressure and central venous oxygen saturation should be measured. Lactate should be re-measured if the initial lactate was elevated. 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 inflammation of the abdominal cavity lining, infection of the bile duct, or intestinal infarction. A pierced internal organ (free air on abdominal x-ray or CT scan; an abnormal chest x-ray consistent with pneumonia (with focal opacification); or petechiae, purpura, or purpura fulminans can also be evident of infection.
- Systemic inflammatory response syndrome (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).
- Septic shock is severe sepsis plus persistently low blood pressure despite the administration of intravenous fluids.
Examples of end-organ dysfunction include the following:
- Lungs: acute respiratory distress syndrome (ARDS) (PaO2/FiO2 < 300)[note 1]
- Brain: encephalopathy symptoms: agitation, confusion, coma; cause: ischemia, hemorrhage, formation of blood clots in small blood vessels, microabscesses, multifocal necrotizing leukoencephalopathy
- Liver: disruption of protein synthetic function: manifests acutely as progressive coagulopathy due to inability to synthesize clotting factors, disruption of metabolic functions: manifests as cessation of 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:
- Respiratory dysfunction (in the absence of cyanotic heart disease or known chronic lung 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
- Hematologic dysfunction
- Kidney dysfunction
- Liver dysfunction (only applicable to infants > 1 month)
Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.
A 2013 systematic review and meta-analysis concluded moderate-quality evidence exists to support use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS. The same review found the test's sensitivity 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. 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. 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.
The differential diagnosis for sepsis is broad and has to look at (to exclude) the noninfectious conditions that can cause the systemic signs of SIRS: alcohol withdrawal, acute pancreatitis, burns, pulmonary embolus, thyrotoxicosis, anaphylaxis, adrenal insufficiency, and neurogenic shock.
In common clinical usage, neonatal sepsis specifically refers to the presence of a bacterial blood stream infection in the first month of life, such as meningitis, pneumonia, pyelonephritis, or gastroenteritis. Neonatal sepsis is most commonly due to bacterial infection, but it can also be due to infection with fungi, viruses, or parasites. Criteria with regards to hemodynamic compromise or respiratory failure are not useful because they present too late for intervention.
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. The early hyperinflammatory phase of sepsis (which can sometimes result in a cytokine storm) can be followed by a prolonged period of immunosuppression. Either of these phases can prove fatal.
Bacterial virulence factors such as glycocalyx and various adhesins allow colonization, immune evasion, and establishment of disease in the host. Sepsis caused by Gram-negative bacteria is thought to be largely due to the host's response to the lipid A component of lipopolysaccharide, also called endotoxin. Sepsis caused by Gram-positive bacteria can result from an immunological response to cell wall lipoteichoic acid. Bacterial exotoxins that act as superantigens can also cause sepsis. Superantigens simultaneously bind major histocompatibility complex and T-cell receptors in the absence of antigen presentation. This forced receptor interaction induces the production of pro-inflammatory chemical signals (cytokines) by T-cells.
There are a number of microbial factors which can cause the typical septic inflammatory cascade. An invading pathogen is recognized by its pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include lipopolysaccharides and flagellin in Gram-negative bacteria, muramyl dipeptide in the peptidoglycan of the Gram-positive bacterial cell wall, and CpG bacterial DNA. These PAMPs are recognized by the innate immune system's pattern recognition receptors (PRRs), which can be membrane-bound or cytosolic. There are four families of PRRs: the toll-like receptors, the C-type lectin receptors, the NOD-like receptors and the RIG-I-like receptors. The association of a PAMP and a PRR will invariably cause a series of intracellular signalling cascades. Consequentially, transcription factors like nuclear factor-kappa B and activator protein-1 will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines.
Cytokines such as tumor necrosis factor, interleukin 1, and interleukin 6 can activate procoagulation factors in the cells lining blood vessels, 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 blood clots in small blood vessels, and multiple organ failure.
A systemic inflammatory response syndrome can also occur in patients without the presence of infection, for example in those with burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis. The low blood pressure seen in those with sepsis is the result of various processes including excessive production of chemicals that dilate blood vessels such as nitric oxide, a deficiency of chemicals that constrict blood vessels such as vasopressin, and activation of ATP-sensitive potassium channels.
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. 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. In those with high blood sugar levels, insulin to bring it down to 7.8-10 mmol/L (140–180 mg/dL) is recommended with lower levels potentially worsening outcomes. Medication to prevent deep vein thrombosis and gastric ulcers may also be used.
In severe sepsis and septic shock, broad-spectrum antibiotics are recommended within 1 hour of making the diagnosis. For every hour delay in the administration, there is an associated 6% rise in mortality. Antibiotic regimens should be reassessed daily and narrowed if appropriate. Duration of treatment is typically 7–10 days with the type of antibiotic used directed by the results of cultures.
Intravenous fluids are titrated in response to heart rate, blood pressure, and urine output; restoring large fluid deficits can require 6 to 10 liters of crystalloids. 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 (CVP) reaches 8–12mmHg. Once these goals are met, the mixed venous oxygen saturation (SvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the SvO2 is less than 70%, blood maybe given to reach a hemoglobin of 10 g/dL and then inotropes are added until the SvO2 is optimized. In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully.
Crystalloid solutions are recommended initially. Crystalloid solutions and albumin are better than other fluids (such as hydroxyethyl starch) in terms of risk of death. Starches also carry an increased risk of acute kidney injury, and need for blood transfusion. Various colloid solutions (such as modified gelatin) carry no advantage over crystalloid. Albumin also appears to be of no benefit over crystalloids. Packed red blood cells are recommended to keep the hemoglobin levels between 70 and 90 g/L. A 2014 trial; however, found no difference between a target hemoglobin of 70 or 90 g/L.
If the person has been sufficiently fluid resuscitated but the mean arterial pressure is not greater than 65 mmHg, vasopressors are recommended. Norepinephrine (noradrenaline) is recommended as the initial choice. If a single vasopressor is not enough to raise the blood pressure, epinephrine (adrenaline) or vasopressin may be added. Dopamine is typically not recommended. Dobutamine may be used if heart function is poor or blood flow is insufficient despite sufficient fluid volumes and blood pressure.
Tracheal intubation and mechanical ventilation may be performed to reduce oxygen demand if the SvO2 remains low despite optimization of hemodynamics. Etomidate is often not recommended as a medication to help with intubation in this situation due to concerns it may lead to poor adrenal function and an increased risk of death. The small amount of evidence there is, however, has not found a change in the risk of death with etomidate.
The use of steroids in sepsis is controversial. 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. During critical illness, a state of adrenal insufficiency and tissue resistance to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency. 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. However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. ACTH stimulation testing is not recommended to confirm the diagnosis. 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
Early goal directed therapy (EGDT) is an approach to the management of severe sepsis during the initial 6 hours after diagnosis. A step-wise approach should be used, with the physiologic goal of optimizing cardiac preload, afterload, and contractility. It has been found to reduce mortality in those with sepsis.
Urine output is also monitored, with a minimum goal of 0.5 ml/kg/h. In the original trial, mortality was cut from 46.5% to 30.5%. An appropriate decrease in serum lactate however may be equivalent to SvO2 and easier to obtain.
Neonatal sepsis is difficult to diagnose. Newborns may be relatively asymptomatic until hemodynamic and respiratory collapse is imminent. If there is even a remote suspicion of sepsis, they are frequently treated with antibiotics empirically until cultures are sufficiently proven to be negative.
Monoclonal and polyclonal preparations of intravenous immunoglobulin (IVIG) do not lower the rate of death in newborns and adults with sepsis. Evidence for the use of IgM-enriched polyclonal preparations of IVIG is inconsistent.
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. However, subsequent studies showed that it increased adverse events—bleeding risk in particular—and did not decrease mortality. It was removed from sale in 2011.
Approximately 20–35% of people with severe sepsis and 30–70% of people with septic shock die. Lactate is a useful method of determining prognosis with those who have a level greater than 4 mmol/L having a mortality of 40% and those with a level of less than 2 mmol/L have a mortality of less than 15%.
There are a number of prognostic stratification systems such as APACHE II and Mortality in Emergency Department Sepsis. APACHE II factors in the person's age, underlying condition, and various physiologic variables to yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of 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.
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.
Sepsis causes millions of deaths globally each year and is the most common cause of death in people who have been hospitalized. In the United States sepsis affects approximately 3 in 1,000 people, and severe sepsis contributes to more than 200,000 deaths per year.
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. A study by the Agency for Healthcare Research and Quality (AHRQ) of selected States found that there were approximately 651 hospital stays per 100,000 population with a sepsis diagnosis in 2010. It is the second-leading cause of death in non-coronary intensive care unit (ICU) patients, and the tenth-most-common cause of death overall (the first being heart disease). Children under 12 months of age and elderly people have the highest incidence of severe sepsis. 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. 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.
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 cancer, diabetes, or the absence of a spleen; and major trauma and burns.
The term Σήψις (sepsis) was introduced by Hippocrates in the fourth century BC, and it meant the process of decay or decomposition of organic matter. In the eleventh century, Avicenna used the term "blood rot" for diseases linked to severe purulent process. Though severe systemic toxicity was observed prior, it was only in the 19th century that a specific term – sepsis – was coined for this condition.
By the end of the 19th century, it was widely believed that microbes produced substances that could injure the mammalian host and that soluble toxins released during infection caused the fever and shock that were commonplace during severe infections. Pfeiffer coined the term endotoxin at the beginning of the 20th century to denote the pyrogenic principle associated with Vibrio cholerae. It was soon realised that endotoxins were expressed by most and perhaps all Gram-negative organisms. The lipopolysaccharide character of enteric endotoxins was elucidated in 1944 by Shear. The molecular character of this material was determined by Luderitz et al. in 1973.
It was discovered in 1965 that a strain of C3H/HeJ mice were immune to the endotoxin-induced shock. The genetic locus for this effect was dubbed Lps. These mice were also found to be hypersusceptible to infection by Gram-negative bacteria. These observations were finally linked in 1998 by the discovery of the Toll-like receptor gene 4 (TLR 4). 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 cytoplasmic domain.
Society and culture
Septicemia was the most expensive condition seen in U.S. hospital stays in 2011, at an aggregate cost of $20.3 billion for nearly 1.1 million hospitalizations. Costs for septicemia stays more than quadrupled since 1997 with an 11.5 percent annual increase. 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.
A large international collaboration entitled the "Surviving Sepsis Campaign" was established in 2002 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.
- Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup; Dellinger, RP; Levy, MM; Rhodes, A et al. (2013). "Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012". Critical Care Medicine 41 (2): 580–637. doi:10.1097/CCM.0b013e31827e83af. PMID 23353941 – via Surviving Sepsis Campaign.
- "Sepsis Questions and Answers". cdc.gov. Centers for Disease Control and Prevention (CDC). May 22, 2014. Retrieved 28 November 2014.
- Jui, Jonathan (2011). "Ch. 146: Septic Shock". In Tintinalli, Judith E.; Stapczynski, J. Stephan; Ma, O. John; Cline, David M. et al. Tintinalli's Emergency Medicine: A Comprehensive Study Guide (7th ed.). New York: McGraw-Hill. pp. 1003–14. Retrieved December 11, 2012 – via AccessMedicine. (subscription required (. ))
- Deutschman, CS; Tracey, KJ (April 2014). "Sepsis: Current dogma and new perspectives". Immunity 40 (4): 463–75. doi:10.1016/j.immuni.2014.04.001. PMID 24745331.
- Patel, GP; Balk, RA (January 15, 2012). "Systemic steroids in severe sepsis and septic shock". American Journal of Respiratory and Critical Care Medicine 185 (2): 133–9. doi:10.1164/rccm.201011-1897CI. PMID 21680949.
- Martí-Carvajal, AJ; Solà, I; Lathyris, D; Cardona, AF (March 14, 2012). Martí-Carvajal, Arturo J., ed. "Human recombinant activated protein C for severe sepsis". Cochrane Database of Systematic Reviews 3: CD004388. doi:10.1002/14651858.CD004388.pub5. PMID 22419295.[needs update]
- Jawad, I; Lukšić, I; Rafnsson, SB (June 2012). "Assessing available information on the burden of sepsis: Global estimates of incidence, prevalence and mortality". Journal of Global Health 2 (1): 010404. doi:10.7189/jogh.02.010404 (inactive 2014-11-28). PMC 3484761. PMID 23198133.
- Martin, GS (June 2012). "Sepsis, severe sepsis and septic shock: Changes in incidence, pathogens and outcomes". Expert Review of Anti-infective Therapy 10 (6): 701–6. doi:10.1586/eri.12.50. PMC 3488423. PMID 22734959.
- Bone, R; Balk, R; Cerra, F; Dellinger, R et al. (1992). "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". Chest 101 (6): 1644–55. doi:10.1378/chest.101.6.1644. PMID 1303622.
- Angus, DC; van der Poll, T (August 29, 2013). "Severe sepsis and septic shock". The New England Journal of Medicine 369 (9): 840–51. doi:10.1056/NEJMra1208623. PMID 23984731. Lay summary (August 30, 2013).
- SCCM/ESICM/ACCP/ATS/SIS; Levy, MM; Fink, MP; Marshall, JC et al. (April 2003). "2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference". Critical Care Medicine 31 (4): 1250–6. doi:10.1097/01.CCM.0000050454.01978.3B. PMID 12682500 – via European Society of Intensive Care Medicine (ESICM).
- Felner, Kevin; Smith, Robert L. (2012). "Ch. 138: Sepsis". In McKean, Sylvia; Ross, John J.; Dressler, Daniel D.; Brotman, Daniel J. et al. Principles and Practice of Hospital Medicine. New York: McGraw-Hill. pp. 1099–109. ISBN 0071603891.
- MedlinePlus Encyclopedia Sepsis. Retrieved November 29, 2014.
- Munford, Robert S.; Suffredini, Anthony F. (2014). "Ch. 75: Sepsis, Severe Sepsis and Septic Shock". In Bennett, John E.; Dolin, Raphael; Blaser, Martin J. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (8th ed.). Philadelphia: Elsevier Health Sciences. pp. 914–34. ISBN 9780323263733.
- Bloch, KC (2010). "Ch. 4: Infectious Diseases". In McPhee, Stephen J.; Hammer, Gary D. Pathophysiology of Disease (6th ed.). New York: McGraw-Hill. Retrieved January 10, 2013 – via AccessMedicine. (subscription required (. ))
- Ramachandran, G (January 2014). "Gram-positive and gram-negative bacterial toxins in sepsis: A brief review". Virulence 5 (1): 213–8. doi:10.4161/viru.27024. PMC 3916377. PMID 24193365.
- Delaloye, J; Calandra, T (January 2014). "Invasive candidiasis as a cause of sepsis in the critically ill patient". Virulence 5 (1): 161–9. doi:10.4161/viru.26187. PMC 3916370. PMID 24157707.
- "American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis". Critical Care Medicine 20 (6): 864–74. 1992. doi:10.1097/00003246-199206000-00025. PMID 1597042.
- Wacker, C; Prkno, A; Brunkhorst, FM; Schlattmann, P (May 2013). "Procalcitonin as a diagnostic marker for sepsis: A systematic review and meta-analysis". The Lancet Infectious Diseases 13 (5): 426–35. doi:10.1016/S1473-3099(12)70323-7. PMID 23375419.
- Soong, J; Soni, N (June 2012). "Sepsis: Recognition and treatment". Clinical Medicine 12 (3): 276–80. doi:10.7861/clinmedicine.12-3-276. PMID 22783783.
- Abraham, E; Singer, M (2007). "Mechanisms of sepsis-induced organ dysfunction". Critical Care Medicine 35 (10): 2408–16. doi:10.1097/01.CCM.0000282072.56245.91. PMID 17948334 – via South African Society of Surgeons in Training (SASSIT).
- Ranieri, VM; Rubenfeld, GD; Thompson, BT; Ferguson, ND et al. (June 2012). "Acute respiratory distress syndrome: The Berlin definition". JAMA 307 (23): 2526–33. doi:10.1001/jama.2012.5669. PMID 22797452.
- "Meet the new ARDS: Expert panel announces new definition, severity classes". PulmCCM. Matthew Hoffman.
- International Consensus Conference on Pediatric Sepsis; Goldstein, B; Giroir, B; Randolph, A (2005). "International Pediatric Sepsis Consensus Conference: Definitions for sepsis and organ dysfunction in pediatrics". Pediatric Critical Care Medicine 6 (1): 2–8. doi:10.1097/01.PCC.0000149131.72248.E6. PMID 15636651.
- Backes, Y; van der Sluijs, KF; Mackie, DP; Tacke, F; Koch, A; Tenhunen, JJ; Schultz, MJ (September 2012). "Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review". Intensive Care Medicine 38 (9): 1418–28. doi:10.1007/s00134-012-2613-1. PMC 3423568. PMID 22706919.
- Mayr, FB; Yende, S; Angus, DC (January 2014). "Epidemiology of severe sepsis". Virulence 5 (1): 4–11. doi:10.4161/viru.27372. PMC 3916382. PMID 24335434.
- Satar, M; Ozlu, F (September 2012). "Neonatal sepsis: A continuing disease burden". The Turkish Journal of Pediatrics 54 (5): 449–57. PMID 23427506.
- Ely, E. Wesley; Goyette, Richert E. (2005). "Ch. 46: Sepsis with Acute Organ Dysfunction". In Hall, Jesse B.; Schmidt, Gregory A.; Wood, Lawrence D.H. Principles of Critical Care (3rd ed.). New York: McGraw-Hill Medical. ISBN 0071416404 – via AccessMedicine. (subscription required (. ))
- Shukla, P; Rao, GM; Pandey, G; Sharma, S et al. (September 5, 2014). "Therapeutic interventions in sepsis: Current and anticipated pharmacological agents". British Journal of Pharmacology 171 (22): 5011–31. doi:10.1111/bph.12829. PMID 24977655.
- Park, BS; Lee, JO (December 2013). "Recognition of lipopolysaccharide pattern by TLR4 complexes". Experimental & Molecular Medicine 45 (12): e66. doi:10.1038/emm.2013.97. PMC 3880462. PMID 24310172.
- Cross, AS (January 2014). "Anti-endotoxin vaccines: Back to the future". Virulence 5 (1): 219–25. doi:10.4161/viru.25965. PMC 3916378. PMID 23974910.
- Fournier, B; Philpott, DJ (July 2005). "Recognition of Staphylococcus aureus by the innate immune system". Clinical Microbiology Reviews 18 (3): 521–40. doi:10.1128/CMR.18.3.521-540.2005. PMC 1195972. PMID 16020688.
- Leentjens, J; Kox, M; van der Hoeven, JG; Netea, MG et al. (June 15, 2013). "Immunotherapy for the adjunctive treatment of sepsis: From immunosuppression to immunostimulation. Time for a paradigm change?". American Journal of Respiratory and Critical Care Medicine 187 (12): 1287–93. doi:10.1164/rccm.201301-0036CP. PMID 23590272.
- Antonopoulou, A; Giamarellos-Bourboulis, EJ (January 2011). "Immunomodulation in sepsis: State of the art and future perspective". Immunotherapy 3 (1): 117–28. doi:10.2217/imt.10.82. PMID 21174562.
- Nimah, M; Brilli, RJ (2003). "Coagulation dysfunction in sepsis and multiple organ system failure". Critical Care Clinics 19 (3): 441–58. doi:10.1016/S0749-0704(03)00008-3 (inactive November 26, 2014). PMID 12848314 – via South African Society of Surgeons in Training (SASSIT).
- Marik, PE (June 2014). "Iatrogenic salt water drowning and the hazards of a high central venous pressure". Annals of Intensive Care 2014 (4): 21. doi:10.1186/s13613-014-0021-0. PMC 4122823. PMID 25110606.
- Daniels, R. (11 March 2011). "Surviving the first hours in sepsis: getting the basics right (an intensivist's perspective)". Journal of Antimicrobial Chemotherapy 66 (Supplement 2): ii11–ii23. doi:10.1093/jac/dkq515. PMID 21398303.
- Scottish Intercollegiate Guidelines Network (SIGN) (May 2014). Guideline 139: care of deteriorating patients. Edinburgh: SIGN. ISBN 978-1-909103-26-9.
- Hirasawa, H; Oda, S; Nakamura, M (September 7, 2009). "Blood glucose control in patients with severe sepsis and septic shock". World Journal of Gastroenterology 15 (33): 4132–6. doi:10.3748/wjg.15.4132. PMC 2738808. PMID 19725146.
- Dellinger, RP; Levy, MM; Carlet, JM; Bion, J et al. (January 2008). "Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008". Intensive Care Medicine 34 (1): 17–60. doi:10.1007/s00134-007-0934-2. PMC 2249616. PMID 18058085.
- Fluids in Sepsis and Septic Shock Group; Rochwerg, B; Alhazzani, W; Sindi, A et al. (September 2014). "Fluid resuscitation in sepsis: A systematic review and network meta-analysis". Annals of Internal Medicine 161 (5): 347–55. doi:10.7326/M14-0178. PMID 25047428.
- Perel, P; Roberts, I; Ker, K (2013). "Colloids versus crystalloids for fluid resuscitation in critically ill patients". Cochrane Database of Systematic Reviews (2): CD000567. doi:10.1002/14651858.CD000567.pub6. PMID 23450531.
- Zarychanski, R; Abou-Setta, AM; Turgeon, AF; Houston, BL et al. (February 2013). "Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: A systematic review and meta-analysis". JAMA 309 (7): 678–88. doi:10.1001/jama.2013.430. PMID 23423413.
- Haase, N; Perner, A; Hennings, LI; Siegemund, M et al. (2013). "Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: Systematic review with meta-analysis and trial sequential analysis". BMJ 346: f839. doi:10.1136/bmj.f839. PMC 3573769. PMID 23418281.
- Serpa Neto, A; Veelo, DP; Peireira, VG; de Assunção, MS et al. (February 2014). "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 of Critical Care 29 (1): 185.e1–7. doi:10.1016/j.jcrc.2013.09.031. PMID 24262273.
- Patel, A; Laffan, MA; Waheed, U; Brett, SJ (July 22, 2014). "Randomised trials of human albumin for adults with sepsis: A systematic review and meta-analysis with trial sequential analysis of all-cause mortality". BMJ 349: g4561. doi:10.1136/bmj.g4561. PMID 25099709.
- TRISS Trial Group; Scandinavian Critical Care Trials Group; Holst, LB; Haase, N et al. (October 9, 2014). "Lower versus higher hemoglobin threshold for transfusion in septic shock". The New England Journal of Medicine 371 (15): 1381–91. doi:10.1056/NEJMoa1406617. PMID 25270275.
- Cherfan, AJ; Arabi, YM; Al-Dorzi, HM; Kenny, LP (May 2012). "Advantages and disadvantages of etomidate use for intubation of patients with sepsis". Pharmacotherapy 32 (5): 475–82. doi:10.1002/j.1875-9114.2012.01027.x. PMID 22488264.
- Chan, CM; Mitchell, AL; Shorr, AF (November 2012). "Etomidate is associated with mortality and adrenal insufficiency in sepsis: A meta-analysis". Critical Care Medicine 40 (11): 2945–53. doi:10.1097/CCM.0b013e31825fec26. PMID 22971586.
- Gu, WJ; Wang, F; Tang, L; Liu, JC (September 25, 2014). "Single-dose etomidate does not increase mortality in patients with sepsis: A systematic review and meta-analysis of randomized controlled trials and observational studies". Chest. doi:10.1378/chest.14-1012. PMID 25255427.
- American College of Critical Care Medicine; Marik, PE; Pastores, SM; Annane, D et al. (2008). "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". Critical Care Medicine 36 (6): 1937–49. doi:10.1097/CCM.0b013e31817603ba. PMID 18496365 – via University of Chicago.
- Early Goal-Directed Therapy Collaborative Group; Rivers, E; Nguyen, B; Havstad, S et al. (2001). "Early goal-directed therapy in the treatment of severe sepsis and septic shock". The New England Journal of Medicine 345 (19): 1368–77. doi:10.1056/NEJMoa010307. PMID 11794169.
- Emergency Medicine Shock Research Network (EMShockNet), investigators; Jones, AE; Brown, MD; Trzeciak, S et al. (2008). "The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: A meta-analysis". Critical Care Medicine 36 (10): 2734–9. doi:10.1097/CCM.0b013e318186f839. PMC 2737059. PMID 18766093.
- Emergency Medicine Shock Research Network (EMShockNet), investigators; Jones, AE; Shapiro, NI; Trzeciak, S et al. (February 24, 2010). "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: A randomized clinical trial". JAMA 303 (8): 739–46. doi:10.1001/jama.2010.158. PMC 2918907. PMID 20179283.
- Alejandria, MM; Lansang, MA; Dans, LF; Mantaring, JB 3rd (September 2013). "Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock". Cochrane Database of Systematic Reviews 9 (CD001090). doi:10.1002/14651858.CD001090.pub2. PMID 24043371.
- Russel, JA (October 2008). "The current management of septic shock". Minerva Medica 99 (5): 431–58. PMID 18971911.
- Best Evidence in Emergency Medicine Investigator, Group; Carpenter, CR; Keim, SM; Upadhye, S et al. (October 2009). "Risk stratification of the potentially septic patient in the emergency department: The mortality in the emergency department sepsis (MEDS) score". The Journal of Emergency Medicine 37 (3): 319–27. doi:10.1016/j.jemermed.2009.03.016. PMID 19427752.
- Jackson, JC; Hopkins, RO; Miller, RR; Gordon, SM et al. (November 2009). "Acute respiratory distress syndrome, sepsis, and cognitive decline: A review and case study". Southern Medical Journal 102 (11): 1150–7. doi:10.1097/SMJ.0b013e3181b6a592. PMC 3776422. PMID 19864995.
- Munford, Robert S. (2011). "Ch. 271: Severe Sepsis and Septic Shock". In Longo, Dan L.; Fauci, Anthony S.; Kasper, Dennis L.; Hauser, Stephen L. et al. Harrison's Principles of Internal Medicine (18th ed.). New York: McGraw-Hill. pp. 2223–231. ISBN 9780071748896.
- Sutton, JP; Friedman, B (September 2013). "Trends in Septicemia Hospitalizations and Readmissions in Selected HCUP States, 2005 and 2010". Healthcare Cost and Utilization Project (Statistical Brief #161). Rockville, MD: Agency for Healthcare Research and Quality. PMID 24228290.
- Martin, GS; Mannino, DM; Eaton, S; Moss, M (2003). "The epidemiology of sepsis in the United States from 1979 through 2000". The New England Journal of Medicine 348 (16): 1546–54. doi:10.1056/NEJMoa022139. PMID 12700374.
- Hines, AL; Barrett, ML; Jiang, HJ; Steiner, CA (April 2014). "Conditions with the Largest Number of Adult Hospital Readmissions by Payer, 2011.". Healthcare Cost and Utilization Project (Statistical Brief #172). Rockville, MD: Agency for Healthcare Research and Quality. PMID 24901179.
- Koh, GC; Peacock, SJ; van der Poll, T; Wiersinga, WJ (April 2012). "The impact of diabetes on the pathogenesis of sepsis". European Journal of Clinical Microbiology & Infectious Diseases 31 (4): 379–88. doi:10.1007/s10096-011-1337-4. PMC 3303037. PMID 21805196.
- Rubin, LG; Schaffner, W (July 2014). "Clinical practice. Care of the asplenic patient". The New England Journal of Medicine 371 (4): 349–56. doi:10.1056/NEJMcp1314291. PMID 25054718.
- Vincent, Jean-Louis (2008). "Ch. 1: Definition of Sepsis and Non-infectious SIRS". In Cavaillon, Jean-Marc; Adrie, Christophe. Sepsis and Non-infectious Systemic Inflammation: From Biology to Critical Care. John Wiley & Sons. p. 3. ISBN 9783527319350.
- Marshall, JC (July 2013). "Sepsis: Rethinking the approach to clinical research". Journal of Leukocyte Biology 94 (1): 471–82. doi:10.1189/jlb.0607380. PMID 18171697.
- Shear, MJ (1944). "Chemical treatment of tumors, IX: Reactions of mice with primary subcutaneous tumors to injection of a hemorrhage-producing bacterial polysaccharide". Journal of the National Cancer Institute 4 (5): 461–76. doi:10.1093/jnci/4.5.461.
- Luderitz, O; Galanos, C; Lehmann, V; Nurminen, M et al. (1973). "Lipid A: Chemical structure and biologic activity". The Journal of Infectious Diseases 128: 29. doi:10.1093/infdis/128.Supplement_1.S17. JSTOR 30106029.
- Heppner, G; Weiss, DW (1965). "High susceptibility of strain A mice to endotoxin and endotoxin-red blood cell mixtures". Journal of Bacteriology 90 (3): 696–703. PMC 315712. PMID 16562068.
- O'Brien, AD; Rosenstreich, DL; Scher, I; Campbell, GH et al. (1980). "Genetic control of susceptibility to Salmonella typhimurium in mice: Role of the LPS gene". Journal of Immunology 124 (1): 20–4. PMID 6985638.
- Poltorak, A; Smirnova, I; He, X; Liu, M-Y et al. (1998). "Genetic and physical mapping of the Lps locus: Identification of the toll-4 receptor as a candidate gene in the critical region". Blood Cells, Molecules, and Diseases 24 (3): 340–55. doi:10.1006/bcmd.1998.0201. PMID 6985638.
- Torio, CM; Andrews, RM (August 2013). "National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2011". Healthcare Cost and Utilization Project (Statistical Brief #160). Rockville, MD: Agency for Healthcare Research and Quality. PMID 24199255.
- Pfuntner, A; Wier, LM; Steiner, C (December 2013). "Costs for Hospital Stays in the United States, 2011". Healthcare Cost and Utilization Project (Statistical Brief #168). Rockville, MD: Agency for Healthcare Research and Quality. PMID 24455786.
- "History". Surviving Sepsis Campaign. Society of Critical Care Medicine. Retrieved February 24, 2014.