sepsis sepsis sepsis (septicaemia in british english), or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. sepsisskin blotching and inflammation due to sepsispronunciation/ˈsɛpsɪs/ specialtyinfectious diseasesymptomsfeverincreased heart ratelow blood pressureincreased breathing ratelow urine outputabsent or near absent urine outputsevere painconfusioncomplicationsmultiple organ dysfunction syndrometemporary, transient, or permanent organ damageextra corporeal membrane oxygenationblood filtration or dialysisusual onsetmay be rapid (less than three hours) or prolonged (several days)causesimmune response triggered by an infectionrisk factorsyoung or old agecancerdiabetesmajor traumaasthma, chronic obstructive pulmonary diseasemultiple myelomaburnsdiagnostic methodsystemic inflammatory response syndrome (sirs), qsofapreventioninfluenza vaccination, vaccines, pneumonia vaccinationtreatmentintravenous fluids, antimicrobials, vasopressorsprognosis10 to 80% risk of death; these mortality rates (they are for a range of conditions along a spectrum: sepsis, severe sepsis, and septic shock) may be lower if treated aggressively and early, depending on the organism and disease, the patient's previous health, and the abilities of the treatment location and its stafffrequency0.2–3 per 1000 a year (developed world) this initial stage of sepsis is followed by suppression of the immune system. 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 painful urination with a kidney infection. the very young, old, and people with a weakened immune system may have no symptoms of a specific infection, and the body temperature may be low or normal instead of having a fever. severe sepsis causes poor organ function or blood flow. the presence of low blood pressure, high blood lactate, or low urine output may suggest poor blood flow. septic shock is low blood pressure due to sepsis that does not improve after fluid replacement. sepsis is caused by many organisms including bacteria, viruses and fungi. common locations for the primary infection include the lungs, brain, urinary tract, skin, and abdominal organs. risk factors include being very young or old, a weakened immune system from conditions such as cancer or diabetes, major trauma, and burns. previously, a sepsis diagnosis required the presence of at least two systemic inflammatory response syndrome (sirs) criteria in the setting of presumed infection. in 2016, a shortened sequential organ failure assessment score (sofa score), known as the quick sofa score (qsofa), replaced the sirs system of diagnosis. qsofa criteria for sepsis include at least two of the following three: increased breathing rate, change in the level of consciousness, and low blood pressure. sepsis guidelines recommend obtaining blood cultures before starting antibiotics; however, the diagnosis does not require the blood to be infected. medical imaging is helpful when looking for the possible location of the infection. other potential causes of similar signs and symptoms include anaphylaxis, adrenal insufficiency, low blood volume, heart failure, and pulmonary embolism. sepsis requires immediate treatment with intravenous fluids and antimicrobials. ongoing care often continues in an intensive care unit. if an adequate trial of fluid replacement is not enough to maintain blood pressure, then the use of medications that raise blood pressure becomes necessary. mechanical ventilation and dialysis may be needed to support the function of the lungs and kidneys, respectively. a central venous catheter and an arterial catheter may be placed for access to the bloodstream and to guide treatment. other helpful measurements include cardiac output and superior vena cava oxygen saturation. people with sepsis need preventive measures for deep vein thrombosis, stress ulcers, and pressure ulcers unless other conditions prevent such interventions. some people might benefit from tight control of blood sugar levels with insulin. the use of corticosteroids is controversial, with some reviews finding benefit, and others not. disease severity partly determines the outcome. the risk of death from sepsis is as high as 30%, while for severe sepsis it is as high as 50%, and septic shock 80%. sepsis affected about 49 million people in 2017, with 11 million deaths (1 in 5 deaths worldwide). in the developed world, approximately 0.2 to 3 people per 1000 are affected by sepsis yearly, resulting in about a million cases per year in the united states. rates of disease have been increasing. some data indicate that sepsis is more common among males than females, however, other data show a greater prevalence of the disease among women. descriptions of sepsis date back to the time of hippocrates. signs and symptoms in addition to symptoms related to the actual cause, people with sepsis may have a fever, low body temperature, rapid breathing, a fast heart rate, confusion, and edema. early signs include a rapid heart rate, decreased urination, and high blood sugar. signs of established sepsis include confusion, metabolic acidosis (which may be accompanied by a faster breathing rate that leads to respiratory alkalosis), low blood pressure due to decreased systemic vascular resistance, higher cardiac output, and disorders in blood-clotting that may lead to organ failure. fever is the most common presenting symptom in sepsis, but fever may be absent in some people such as the elderly or those who are immunocompromised. the drop in blood pressure seen in sepsis can cause lightheadedness and is part of the criteria for septic shock. oxidative stress is observed in septic shock, with circulating levels of copper and vitamin c being decreased. cause infections leading to sepsis are usually bacterial but may be fungal, parasitic or viral. gram-positive bacteria were the primary cause of sepsis before the introduction of antibiotics in the 1950s. after the introduction of antibiotics, gram-negative bacteria became the predominant cause of sepsis from the 1960s to the 1980s. after the 1980s, 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 an infection by candida species of yeast, a frequent hospital-acquired infection. the most common causes for parasitic sepsis are plasmodium (which leads to malaria), schistosoma and echinococcus. the most common sites of infection resulting in severe sepsis are the lungs, the abdomen, and the urinary tract. typically, 50% of all sepsis cases start as an infection in the lungs. in one-third to one-half of cases, the source of infection is unclear. pathophysiology sepsis is caused by a combination of factors related to the particular invading pathogen(s) and to the status of the immune system of the host. the early phase of sepsis characterized by excessive inflammation (sometimes resulting in a cytokine storm) may be followed by a prolonged period of decreased functioning of the immune system. either of these phases may prove fatal. on the other hand, systemic inflammatory response syndrome (sirs) occurs in people without the presence of infection, for example, in those with burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis. however, sepsis also causes similar response to sirs. microbial factors 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 a response by the host to the lipid a component of lipopolysaccharide, also called endotoxin. sepsis caused by gram-positive bacteria may result from an immunological response to cell wall lipoteichoic acid. bacterial exotoxins that act as superantigens also may 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 that may 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 pattern recognition receptors (prrs) of the innate immune system, which may 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. invariably, the association of a pamp and a prr will cause a series of intracellular signalling cascades. consequentially, transcription factors such as nuclear factor-kappa b and activator protein-1, will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines. host factors upon detection of microbial antigens, the host systemic immune system is activated. immune cells not only recognise pathogen-associated molecular patterns but also damage-associated molecular patterns from damaged tissues. an uncontrolled immune response is then activated because leukocytes are not recruited to the specific site of infection, but instead they are recruited all over the body. then, an immunosuppression state ensues when the proinflammatory t helper cell 1 (th1) is shifted to th2, mediated by interleukin 10, which is known as "compensatory anti-inflammatory response syndrome". the apoptosis (cell death) of lymphocytes further worsens the immunosuppression. neutrophils, monocytes, macrophages, dendritic cells, cd4+ t cells, and b cells all undergo apoptosis, whereas regulatory t cells are more apoptosis resistant. subsequently, multiple organ failure ensues because tissues are unable to use oxygen efficiently due to inhibition of cytochrome c oxidase. inflammatory responses cause multiple organ dysfunction syndrome through various mechanisms as described below. increased permeability of the lung vessels causes leaking of fluids into alveoli, which results in pulmonary edema and acute respiratory distress syndrome (ards). impaired utilization of oxygen in the liver impairs bile salt transport, causing jaundice (yellowish discoloration of the skin). in kidneys, inadequate oxygenation results in tubular epithelial cell injury (of the cells lining the kidney tubules), and thus causes acute kidney injury (aki). meanwhile, in the heart, impaired calcium transport, and low production of adenosine triphosphate (atp), can cause myocardial depression, reducing cardiac contractility and causing heart failure. in the gastrointestinal tract, increased permeability of the mucosa alters the microflora, causing mucosal bleeding and paralytic ileus. in the central nervous system, direct damage of the brain cells and disturbances of neurotransmissions causes altered mental status. cytokines such as tumor necrosis factor, interleukin 1, and interleukin 6 may 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 may lead to intravascular clotting, the formation of blood clots in small blood vessels, and multiple organ failure. 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. in those with severe sepsis and septic shock, this sequence of events leads to a type of circulatory shock known as distributive shock. diagnosis early diagnosis is necessary to properly manage sepsis, as the initiation of rapid therapy is key to reducing deaths from severe sepsis. some hospitals use alerts generated from electronic health records to bring attention to potential cases as early as possible. blood culture bottles: orange cap for anaerobes, green cap for aerobes, and yellow cap for blood samples from children within the first three hours of suspected sepsis, diagnostic studies should include white blood cell counts, measuring serum lactate, and obtaining appropriate cultures before starting antibiotics, so long as this does not delay their use by more than 45 minutes. to identify the causative organism(s), at least two sets of blood cultures using bottles with media for aerobic and anaerobic organisms are necessary. at least one should be drawn through the skin and one through each vascular access device (such as an iv catheter) that has been in place more than 48 hours. 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, also should 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 ≥ four 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. evidence for point of care lactate