|Classification and external resources|
Blood culture bottles: orange label for anaerobes, blue label for aerobes, and yellow label for pediatrics
|ICD-10||A40 – A41|
Sepsis (//; Greek: σῆψις, "putrefaction, decay") is a potentially fatal whole-body inflammation (a systemic inflammatory response syndrome or SIRS) caused by severe infection. Sepsis can continue even after the infection that caused it is gone. Severe sepsis is sepsis complicated by organ dysfunction. Septic shock is sepsis complicated by a high lactate level or by shock that does not improve after fluid resuscitation. Bacteremia is the presence of viable bacteria in the blood. The terms septicemia and blood poisoning, referring to the presence of microorganisms or their toxins in the blood, are no longer used by the consensus committee.
Sepsis causes millions of deaths globally each year.
Sepsis is caused by the immune system's response to a serious infection, most commonly bacteria, but also fungi, viruses, and parasites in the blood, urinary tract, lungs, skin, or other tissues. Sepsis can be thought of as falling within a continuum from infection to multiple organ dysfunction syndrome.
Common symptoms of sepsis include those related to a specific infection, but usually accompanied by high fevers, hot, flushed skin, elevated heart rate, hyperventilation, altered mental status, swelling, and low blood pressure. In the very young and elderly, or in people with weakened immune systems, the pattern of symptoms may be atypical, with hypothermia and without an easily localizable infection.
Sepsis is usually treated with intravenous fluids and antibiotics. If fluid replacement is not sufficient to maintain blood pressure, vasopressors can be used. Mechanical ventilation and dialysis may be needed to support the function of the lungs and kidneys, respectively. To guide therapy, a central venous catheter and an arterial catheter may be placed; measurement of other hemodynamic variables (such as cardiac output, mixed venous oxygen saturation or stroke volume variation) may also be used. Sepsis patients require preventive measures for deep vein thrombosis, stress ulcers and pressure ulcers, unless other conditions prevent this. Some might benefit from tight control of blood sugar levels with insulin (targeting stress hyperglycemia). The use of corticosteroids is controversial. Activated drotrecogin alfa (recombinant activated protein C), originally marketed for severe sepsis, has not been found to be helpful, and has recently been withdrawn from sale.
- 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 infection, sepsis is frequently associated with either fever or hypothermia, rapid breathing, elevated heart rate, confusion, and edema. Early signs are elevated heart rate, decreased urination, and elevated blood sugar, while signs of established sepsis are confusion, metabolic acidosis with compensatory respiratory alkalosis (which can manifest as faster breathing), low blood pressure, decreased systemic vascular resistance, higher cardiac output, and dysfunctions of blood coagulation.
Sepsis may also lead to a drop in blood pressure, resulting in shock. This may result in light-headedness. Bruising or intense bleeding may also occur.
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 source is found in one third of cases.
The infectious agents are usually bacteria but can also be fungi and 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.
|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|
Prompt diagnosis is crucial to the management of sepsis, as initiation of early-goal-directed therapy is key to reducing mortality from severe sepsis.
Within the first three hours of suspected sepsis, diagnostic studies should include measurement of serum lactate, obtaining appropriate cultures before initiation of antimicrobial treatment, so long as this does not delay antimicrobial treatment by more than 45 minutes. To identify the causative organism(s), at least two sets of blood cultures (aerobic and anaerobic bottles) should be obtained, with at least one drawn percutaneously and one drawn through each vascular access device (such as an IV catheter) in place more than 48 hours. If other sources are suspected, cultures of these sources, such as urine, cerebrospinal fluid, wounds, or respiratory secretions, should be obtained as well, so long as this does not delay antimicrobial treatment.
Within six hours, if there is persistent hypotension 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, peritonitis, cholangitis, intestinal infarction.
- 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 following the administration of intravenous fluids.
Infection can be suspected or proven (by culture, stain, or polymerase chain reaction (PCR)), or a clinical syndrome pathognomonic for infection. Specific evidence for infection includes WBCs in normally sterile fluid (such as urine or cerebrospinal fluid (CSF)); evidence of a perforated viscus (free air on abdominal x-ray or CT scan; signs of acute peritonitis); abnormal chest x-ray (CXR) consistent with pneumonia (with focal opacification); or petechiae, purpura, or purpura fulminans.
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, microthrombi, 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: oliguria and anuria, electrolyte abnormalities, volume overload
- Heart: systolic and diastolic heart failure, likely due to cytokines 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
- Renal dysfunction
- Hepatic 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.
The differential diagnosis for sepsis is broad and includes those conditions that can cause the systemic signs of SIRS: alcohol withdrawal, 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 (BSI), such as meningitis, pneumonia, pyelonephritis, or gastroenteritis, in the setting of fever. Criteria with regards to hemodynamic compromise or respiratory failure are not useful because these symptoms often do not arise in neonates until death is imminent and unpreventable.
Sepsis is caused by a combination of factors related to the invading organism(s) and the host (predisposing illnesses, genetics, and immune system).
A bacteria's capsule (for example, in certain strains of Streptococcus pneumoniae), can allow it to evade phagocytosis, while pili of some strains of E. Coli can allow this bacterium to adhere to the epithelium of the kidneys. Sepsis caused by gram negative bacteria is thought to be largely due to the host's response to lipopolysaccharides, also called LPS or endotoxin, in the cell wall, while gram positive bacteria are more likely to cause sepsis by their release of exotoxins. Some exotoxins can quickly lead to a rapid release of cytokines by acting as superantigens, which can simultaneously bind MHC and the T-cell receptor.
There are number of microbial factors which can cause the typical septic inflammatory cascade. An invading pathogen is recognised by its pathogen-associated molecular pattern (PAMP). Examples of PAMPs are lipopolysaccharides in Gram-negative bacteria, flagellin in Gram-negative bacteria, muramyl dipeptide in the peptidoglycan cell wall of a Gram-positive bacteria and CpG bacterial DNA. These PAMPs are recognised by the innate immune system's pattern recognition receptors (PRR). These receptors can be membrane-bound or cytosolic. There are four families of PRRs: the toll-like receptors, the C-type lectin receptors, the nucleotide oligemerization domain-like receptors and the RigI-helicases. 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 activating protein-1 will up regulate the expression of pro-inflammatory and anti-inflammatory cytokines.
Severe sepsis occurs when sepsis leads to organ dysfunction, such as pulmonary dysfunction, coagulation or other blood abnormalities, decreased urine production, or altered mental status. If the organ dysfunction of severe sepsis is associated with low blood pressure (hypotension), or insufficient blood flow (hypoperfusion) to one or more organs (causing, for example, lactic acidosis), this is septic shock.
Sepsis can lead to multiple organ dysfunction syndrome (MODS) (formerly known as multiple organ failure), and death. Organ dysfunction results from local changes in blood flow, from sepsis-induced hypotension (< 90 mmHg or a reduction of ≥ 40 mmHg from baseline) and from diffuse intravascular coagulation, among other things. One of the factors which appears to promote the development of MODS is the cytokine-induced abnormalities to microcirculation which has been observed as microvascular thrombosis within septic patients.
Endotoxins produced from bacteria and cytokines, particularly TNF, IL-1 and IL-6, can activate the procoagulation factors in the endothelium, leading to endothelial damage. This damaged endothelial surface inhibits anticoagulant properties as well as increases antifibrinolysis, which can lead to intravascular clotting, microvascular thrombosis and multiple organ failure.
Bacteremia is the presence of viable bacteria in the bloodstream. Likewise, the terms viremia and fungemia simply refer to viruses and fungi in the bloodstream. These terms say nothing about the consequences this has on the body. For example, bacteria can be introduced into the bloodstream during toothbrushing. This form of bacteremia almost never causes problems in normal individuals. However, bacteremia associated with certain dental procedures can cause bacterial infection of the heart valves (known as endocarditis) in high-risk patients. Conversely, a systemic inflammatory response syndrome can 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 therapy of sepsis rests on intravenous fluids, antibiotics, surgical drainage of infected fluid collections, and appropriate support for organ dysfunction. This may include hemodialysis in kidney failure, mechanical ventilation in pulmonary 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, 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.
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.
In EGDT, fluids are titrated in response to heart rate, blood pressure, and urine output; restoring large fluid deficits can require 6 to 10L of crystalloids. In cases where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure (CVP) reaches 8–12 cm of water (or 10–15 cm of water in mechanically ventilated patients). 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 is given to reach a hemoglobin of 10 g/dl and then inotropes are added until the SvO2 is optimized.
Balanced crystalloid solutions and albumin are better than other fluids (such as hydroxyethyl starch) in terms of mortality. 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.
Once the person has been sufficiently fluid resuscitated but the mean arterial pressure is not greater than 65 mmHg vasopressors are recommended. While current recommendations suggest either norepinephrine (noradrenaline) or dopamine, the former appears safer. If a single pressor is insufficient to raise the blood pressure, epinephrine (adrenaline) may be added.
Tracheal intubation and mechanical ventilation may be performed to reduce oxygen demand if the SvO2 remains low despite optimization of hemodynamics. Etomidate is 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 use of steroids in sepsis is controversial. 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 acute respiratory distress syndrome (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 cessation of glucocorticoid drugs is variable, and it is unclear whether they should be weaned or simply stopped abruptly.
Activated protein C
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 and did not decrease mortality. It was removed from sale in 2011.
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.
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 can 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. 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 septicemia 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 and elderly have the highest incidence of severe sepsis. Among U.S. patients who had multiple septicemia 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.
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.
- Levy, Mitchell M.; Fink, Mitchell P.; Marshall, John C.; Abraham, Edward; Angus, Derek; Cook, Deborah; Cohen, Jonathan; Opal, Steven M.; Vincent, Jean-Louis; Ramsay, Graham (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.
- Bone, R.; Balk, R.; Cerra, F.; Dellinger, R.; Fein, A.; Knaus, W.; Schein, R.; Sibbald, W. (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.
- Derek C. Angus and Tom van der Poll, (August 29, 2013). "Severe Sepsis and Septic Shock". N Engl J Med 369 (9): 840–851. doi:10.1056/NEJMra1208623. PMID 23984731. NOW@NEJM summary August 30th, 2013.
- Dellinger, RP; Levy, MM; Carlet, JM; Bion, J; Parker, MM; Jaeschke, R; Reinhart, K; Angus, DC; Brun-Buisson, C; Beale, R; Calandra, T; Dhainaut, JF; Gerlach, H; Harvey, M; Marini, JJ; Marshall, J; Ranieri, M; Ramsay, G; Sevransky, J; Thompson, BT; Townsend, S; Vender, JS; Zimmerman, JL; Vincent, JL (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.
- Annane D, Bellissant E, Cavaillon JM (2005). "Septic shock". Lancet 365 (9453): 63–78. doi:10.1016/S0140-6736(04)17667-8. PMID 15639681.
- Levy MM; Fink MP; Marshall JC et al. (April 2003). "2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference". Crit. Care Med. 31 (4): 1250–6. doi:10.1097/01.CCM.0000050454.01978.3B. PMID 12682500.
- Jui J. Chapter 146. Septic Shock. In: Tintinalli JE, Stapczynski JS, Cline DM, Ma OJ, Cydulka RK, Meckler GD, eds. Tintinalli's Emergency Medicine: A Comprehensive Study Guide. 7th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=6364928. Retrieved December 11, 2012.
- Patel, GP; Balk, RA (Jan 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 (Mar 14, 2012). "Human recombinant activated protein C for severe sepsis". In Martí-Carvajal, Arturo J. Cochrane database of systematic reviews (Online) 3: CD004388. doi:10.1002/14651858.CD004388.pub5. PMID 22419295.
- Levy, MM; Fink, MP; Marshall, JC; Abraham, E; Angus, D; Cook, D; Cohen, J; Opal, SM; Vincent, JL; Ramsay, G; SCCM/ESICM/ACCP/ATS/SIS, (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.
- al.], Sylvia McKean ... [et (2012). Principles and practice of hospital medicine. New York: McGraw-Hill. pp. Chapter 138. ISBN 0-07-160389-1.
- Dolin, [edited by] Gerald L. Mandell, John E. Bennett, Raphael (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases (7th ed.). Philadelphia, PA: Churchill Livingstone/Elsevier. pp. Chapter 70. ISBN 0-443-06839-9.
- Bloch KC. Chapter 4. Infectious Diseases. In: McPhee SJ, Hammer GD, eds. Pathophysiology of Disease. 6th ed. New York: McGraw-Hill; 2010. http://www.accessmedicine.com/content.aspx?aID=5366994. Retrieved January 10, 2013.
- "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". Crit. Care Med. 20 (6): 864–74. 1992. doi:10.1097/00003246-199206000-00025. PMID 1597042.
- Dellinger, RP; Levy, MM; Rhodes, A; Annane, D; Gerlach, H; Opal, SM; Sevransky, JE; Sprung, CL; Douglas, IS; Jaeschke, R; Osborn, TM; Nunnally, ME; Townsend, SR; Reinhart, K; Kleinpell, RM; Angus, DC; Deutschman, CS; Machado, FR; Rubenfeld, GD; Webb, SA; Beale, RJ; Vincent, JL; Moreno, R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric, Subgroup (February 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.
- Soong, J; Soni, N (June 2012). "Sepsis: recognition and treatment". Clinical medicine (London, England) 12 (3): 276–80. doi:10.7861/clinmedicine.12-3-276. PMID 22783783.
- Dellinger, RP; Levy, MM; Rhodes, A; Annane, D; Gerlach, H; Opal, SM; Sevransky, JE; Sprung, CL; Douglas, IS; Jaeschke, R; Osborn, TM; Nunnally, ME; Townsend, SR; Reinhart, K; Kleinpell, RM; Angus, DC; Deutschman, CS; Machado, FR; Rubenfeld, GD; Webb, SA; Beale, RJ; Vincent, JL; Moreno, R; Surviving Sepsis Campaign Guidelines, Committee; Pediatric, Subgroup (February 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.
- Abraham, Edward; Singer, Mervyn (2007). "Mechanisms of sepsis-induced organ dysfunction". Critical Care Medicine 35 (10): 2408–16. doi:10.1097/01.CCM.0000282072.56245.91. PMID 17948334.
- Goldstein B, Giroir B, Randolph A (2005). "International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics". Pediatr Crit Care Med 6 (1): 2–8. doi:10.1097/01.PCC.0000149131.72248.E6. PMID 15636651.
- Principles of critical care (3rd ed.). New York: McGraw-Hill, Medical Pub. Division. 2005. ISBN 0-07-141640-4.
- Leentjens, J; Kox, M; van der Hoeven, JG; Netea, MG; Pickkers, P (Jun 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, Marianne; Richard J. Brilli (2003). "Coagulation dysfunction in sepsis and multiple organ system failure". Critical Care Clinics 19 (3): 441–458. doi:10.1016/S0749-0704(03)00008-3. PMID 12848314.
- Lockhart, P. B.; Brennan, M. T.; Sasser, H. C.; Fox, P. C.; Paster, B. J.; Bahrani-Mougeot, F. K. (2008). "Bacteremia Associated with Tooth Brushing and Dental Extraction". Circulation 117 (24): 3118–25. doi:10.1161/CIRCULATIONAHA.107.758524. PMC 2746717. PMID 18541739.
- Wilson, W.; Taubert, K. A.; Gewitz, M.; Lockhart, P. B.; Baddour, L. M.; Levison, M.; Bolger, A.; Cabell, C. H.; Takahashi, M.; Baltimore, R. S.; Newburger, J. W.; Strom, B. L.; Tani, L. Y.; Gerber, M.; Bonow, R. O.; Pallasch, T.; Shulman, S. T.; Rowley, A. H.; Burns, J. C.; Ferrieri, P.; Gardner, T.; Goff, D.; Durack, D. T.; American Heart Association Rheumatic Fever (2007). "Prevention of Infective Endocarditis: Guidelines from the American Heart Association: A Guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group". Circulation 116 (15): 1736–54. doi:10.1161/CIRCULATIONAHA.106.183095. PMID 17446442.
- Hirasawa, H; Oda, S; Nakamura, M (Sep 7, 2009). "Blood glucose control in patients with severe sepsis and septic shock". World journal of gastroenterology : WJG 15 (33): 4132–6. doi:10.3748/wjg.15.4132. PMC 2738808. PMID 19725146.
- Rivers, Emanuel; Nguyen, Bryant; Havstad, Suzanne; Ressler, Julie; Muzzin, Alexandria; Knoblich, Bernhard; Peterson, Edward; Tomlanovich, Michael; Early Goal-Directed Therapy Collaborative Group (2001). "Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock". New England Journal of Medicine 345 (19): 1368–77. doi:10.1056/NEJMoa010307. PMID 11794169.
- Jones, Alan E.; Brown, Michael D.; Trzeciak, Stephen; Shapiro, Nathan I.; Garrett, John S.; Heffner, Alan C.; Kline, Jeffrey A.; Emergency Medicine Shock Research Network investigators (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.
- Jones, AE; Shapiro, NI, Trzeciak, S, Arnold, RC, Claremont, HA, Kline, JA, Emergency Medicine Shock Research Network (EMShockNet), Investigators (Feb 24, 2010). "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial". JAMA: the Journal of the American Medical Association 303 (8): 739–46. doi:10.1001/jama.2010.158. PMC 2918907. PMID 20179283.
- Hall, Jesse (2005). Principles of critical care (3rd ed.). New York: McGraw-Hill, Medical Pub. Division. pp. Chapter 46. ISBN 0-07-141640-4.
- Rochwerg B, Alhazzani W, Sindi A, et al. (September 2014). "Fluid resuscitation in sepsis: a systematic review and network meta-analysis". Ann. Intern. Med. 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 Syst Rev 2: CD000567. doi:10.1002/14651858.CD000567.pub6. PMID 23450531.
- Zarychanski R, Abou-Setta AM, Turgeon AF, 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, 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, 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". J Crit Care 29 (1): 185.e1–7. doi:10.1016/j.jcrc.2013.09.031. PMID 24262273.
- Patel, A; Laffan, MA; Waheed, U; Brett, SJ (Jul 22, 2014). "Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality.". BMJ (Clinical research ed.) 349: g4561. PMID 25099709.
- De Backer, D; Aldecoa, C; Njimi, H; Vincent, JL (March 2012). "Dopamine versus norepinephrine in the treatment of septic shock: A meta-analysis". Critical Care Medicine 40 (3): 725–30. doi:10.1097/CCM.0b013e31823778ee. PMID 22036860.
- Vasu TS, Cavallazzi R, Hirani A, Kaplan G, Leiby B, Marik PE (2012). "Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials". J Intensive Care Med 27 (3): 172–8. doi:10.1177/0885066610396312. PMID 21436167.
- 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.
- Marik, Paul E.; Pastores, Stephen M.; Annane, Djillali; Meduri, G Umberto; Sprung, Charles L.; Arlt, Wiebke; Keh, Didier; Briegel, Josef; Beishuizen, Albertus; Dimopoulou, Ioanna; Tsagarakis, Stylianos; Singer, Mervyn; Chrousos, George P.; Zaloga, Gary; Bokhari, Faran; Vogeser, Michael; American College of Critical Care Medicine (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.
- Russel, JA (October 2008). "The current management of septic shock". Minerva medica 99 (5): 431–58. PMID 18971911.
- Carpenter, CR; Keim, SM; Upadhye, S; Nguyen, HB; Best Evidence in Emergency Medicine Investigator, Group (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; Wheeler, AP; Ely, EW (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.
- Longo, Dan (2011). Harrison's principles of internal medicine. (18th ed.). New York: McGraw-Hill. p. Chapter 271. ISBN 978-0-07-174889-6.
- Sutton, JP; Friedman, B (September 2013). Trends in Septicemia Hospitalizations and Readmissions in Selected HCUP States, 2005 and 2010: Statistical Brief #161. PMID 24228290.
- Martin, Greg S.; Mannino, David M.; Eaton, Stephanie; Moss, Marc (2003). "The Epidemiology of Sepsis in the United States from 1979 through 2000". New England Journal of Medicine 348 (16): 1546–54. doi:10.1056/NEJMoa022139. PMID 12700374.
- Hines AL, Barrett ML, Jiang HJ, and Steiner CA. (April 2014). "Conditions With the Largest Number of Adult Hospital Readmissions by Payer, 2011.". HCUP Statistical Brief #172. Rockville, MD: Agency for Healthcare Research and Quality.
- Jean-Marc Cavaillon; Christophe Adrie (24 November 2008). Sepsis and Non-infectious Systemic Inflammation. John Wiley & Sons. pp. 3–. ISBN 978-3-527-31935-0. Retrieved 13 July 2013.
- Marshall, John C. (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. J Natl Canc Inst 4: 461-476
- Luderitz O, Galanos C, Lehmann V, Nurminen, M., Rietschel, E. T., Rosenfelder, G., Simon, M., Westphal, O. (1973). "Lipid A: chemical structure and biologic activity". J Infect Dis 128: 29. doi:10.1093/infdis/128.Supplement_1.S17.
- Heppner G, Weiss DW (1965). "High susceptibility of strain A mice to endotoxin and endotoxin-red blood cell mixtures". J Bacteriol 90 (3): 696–703. PMC 315712. PMID 16562068.
- O'Brien AD, Rosenstreich DL, Scher I et al. (1980). "Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene". J Immunol 124 (1): 20–24. PMID 6985638.
- Poltorak A, Smirnova I, He XL 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 Mol Dis 24: 340-355
- Torio, CM; Andrews, RM (Aug 2013). National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2011: Statistical Brief #160. PMID 24199255.
- Pfuntner, A; Wier, LM; Steiner, C (December 2013). Costs for Hospital Stays in the United States, 2011: Statistical Brief #168. PMID 24455786.
- "History". Surviving Sepsis Campaign. Society of Critical Care Medicine. Retrieved 24 February 2014.