10 to 80% risk of death;[4][6] 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 staff
Frequency
In 2017 there were 48.9 million cases and 11 million sepsis-related deaths worldwide (according to WHO)
Sepsis is a potentially life-threatening condition that arises when the body's response toinfection causes injury to its own tissues and organs.[4][7]
Disease severity partly determines the outcome.[6] The risk of death from sepsis is as high as 30%, while for severe sepsis it is as high as 50%, and the risk of death from septic shock is 80%.[14][15][6] Sepsis affected about 49 million people in 2017, with 11 million deaths (1 in 5 deaths worldwide).[16] In thedeveloped 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.[6][17] Rates of disease have been increasing.[9] Some data indicate that sepsis is more common among men than women,[2] however, other data show a greater prevalence of the disease among women.[16] Descriptions of sepsis date back to the time ofHippocrates.[7]
Oxidative stress is observed in septic shock, with circulating levels of copper and vitamin C being decreased.[22]
Diastolic blood pressure falls during the early stages of sepsis, causing a widening/increasing ofpulse pressure, which is the difference between the systolic and diastolic blood pressures. If sepsis becomes severe andhemodynamic compromise advances, thesystolic pressure also decreases, causing a narrowing/decreasing of pulse pressure.[23] A pulse pressure of over 70 mmHg in patients with sepsis is correlated with an increased chance of survival.[24] A widened pulse pressure is also correlated with an increased chance that someone with sepsis will benefit from and respond toIV fluids.[24]
The most common sites of infection resulting in severe sepsis are the lungs, the abdomen, and the urinary tract.[25] 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.[25]
Sepsis is caused by a combination of factors related to the particular invading pathogen(s) and the status of the immune system of the host.[30] The early phase of sepsis characterized by excessive inflammation (sometimes resulting in acytokine storm) may be followed by a prolonged period ofdecreased functioning of the immune system.[31][8] 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 withburns,polytrauma, or the initial state inpancreatitis andchemical pneumonitis. However, sepsis also causes similar response to SIRS.[32]
Other immunological responses related to microbial infections, such asNETs, can also play a role or be observed in sepsis. NET formation only occurs via neutrophil cell death, which occurs during microbial infections. Neutrophil extracellular traps called NETs eliminate bacteria from blood flow. These compounds are part of the innate immune system, which is activated initially during infections.[38]
Upon detection of microbialantigens, the host systemic immune system is activated. Immune cells not only recognise pathogen-associated molecular patterns but alsodamage-associated molecular patterns from damaged tissues. An uncontrolled immune response is then activated becauseleukocytes are not recruited to the specific site of infection, but instead, they are recruited all over the body. Then, animmunosuppression state ensues when the proinflammatoryT helper cell 1 (TH1) is shifted to TH2,[39] mediated byinterleukin 10, which is known as "compensatory anti-inflammatory response syndrome".[26] Theapoptosis (cell death) of lymphocytes further worsens the immunosuppression.Neutrophils,monocytes,macrophages,dendritic cells,CD4+ T cells, andB cells all undergo apoptosis, whereasregulatory T cells are more apoptosis-resistant.[8] Subsequently,multiple organ failure ensues because tissues are unable to use oxygen efficiently due to inhibition ofcytochrome c oxidase, possibly as part of a "cell hibernation" mechanism, in order to conserve oxygen.[39]
Early diagnosis is necessary to properly manage sepsis, as the initiation of rapid therapy is key to reducing deaths from severe sepsis.[9] Some hospitals use alerts generated fromelectronic health records to bring attention to potential cases as early as possible.[44]
Within the first three hours of suspected sepsis, diagnostic studies should includewhite 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.[9] To identify the causative organism(s), at least two sets ofblood cultures using bottles withmedia foraerobic andanaerobic organisms are necessary. At least one should be drawnthrough the skin and one through each vascular access device (such as an IV catheter) that has been in place for more than 48 hours.[9] Bacteria arepresent in the blood in only about 30% of cases.[46] Another possible method of detection is bypolymerase 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.[9]
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 andcentral venous oxygen saturation should be measured.[9] Lactate should be re-measured if the initial lactate was elevated.[9] Evidence forpoint of care lactate measurement over usual methods of measurement, however, is poor.[47]
<4x109/L (<4000/mm3), >12x109/L (>12,000/mm3), or ≥10%bands
Sepsis Steps. Training tool for teaching the progression of sepsis stages
Previously, SIRS criteria had been used to define sepsis. If the SIRS criteria are negative, it is very unlikely the person has sepsis; if it is positive, there is just a moderate probability that the person has sepsis. According to SIRS, there were different levels of sepsis: sepsis, severe sepsis, and septic shock.[32] The definition of SIRS is shown below:
Sepsis is defined as SIRS in response to an infectious process.[49]
Severe sepsis is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (manifesting as hypotension, elevated lactate, ordecreased urine output). Severe sepsis is an infectious disease state associated with multiple organ dysfunction syndrome (MODS)[9]
In 2016 a new consensus was reached to replace screening bysystemic inflammatory response syndrome (SIRS) with the sequential organ failure assessment (SOFA score) and the abbreviated version (qSOFA).[4] The three criteria for the qSOFA score include a respiratory rate greater than or equal to 22 breaths per minute, systolic blood pressure 100 mmHg or less, and altered mental status.[4] Sepsis is suspected when 2 of the qSOFA criteria are met.[4] The SOFA score was intended to be used in the intensive care unit (ICU) where it is administered upon admission to the ICU and then repeated every 48 hours, whereas the qSOFA could be used outside the ICU.[20] Some advantages of the qSOFA score are that it can be administered quickly and does not require labs.[20] However, theAmerican College of Chest Physicians (CHEST) raised concerns that qSOFA and SOFA criteria may lead to delayed diagnosis of serious infection, leading to delayed treatment.[50] Although SIRS criteria can be too sensitive and not specific enough in identifying sepsis, SOFA also has its limitations and is not intended to replace the SIRS definition.[51] qSOFA has also been found to be poorly sensitive though decently specific for the risk of death with SIRS possibly better for screening. NOTE - Surviving Sepsis Campaign 2021 Guidelines recommend "against using qSOFA compared with SIRS, NEWS, or MEWS as a single screening tool for sepsis or septic shock".[52]
Brain:encephalopathy symptoms including agitation, confusion, and coma; causes may include ischemia, bleeding, formation of blood clots in small blood vessels, microabscesses, multifocal necrotizing leukoencephalopathy
Liver: disruption of protein synthetic function manifests acutely as progressivedisruption of blood clotting due to an inability to synthesizeclotting factors and disruption of metabolic functions leads to impairedbilirubin metabolism, resulting in elevated unconjugated serumbilirubin levels
Heart: systolic and diastolicheart failure, likely due tochemical signals that depress myocyte function, cellular damage, manifest as atroponin leak (although not necessarily ischemic in nature)
More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.[54]
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
the ratio of the arterial partial pressure of oxygen to the fraction of oxygen in the gases inspired (PaO2/FiO2) < 300 (the definition ofacute lung injury), or
arterial partial pressure of carbon dioxide (PaCO2) > 65 torr (20mmHg) over baseline PaCO2 (evidence ofhypercapnicrespiratory failure), or
supplemental oxygen requirement of greater than FiO2 0.5 to maintain oxygen saturation ≥ 92%
Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.[18]
Biomarkers can help with diagnosis because they can point to the presence or severity of sepsis, although their exact role in the management of sepsis remains undefined.[55] A 2013review concluded moderate-quality evidence exists to support the use of theprocalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS.[46] The same review found thesensitivity of the test to be 77% and the specificity to be 79%. The authors suggested that procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone does not definitively make the diagnosis.[46] More current literature recommends utilizing the PCT to direct antibiotic therapy for improved antibiotic stewardship and better patient outcomes.[56]
A 2012 systematic review found thatsoluble urokinase-type plasminogen activator receptor (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis.[57] This same review concluded, however, that SuPAR has prognostic value, as higher SuPAR levels are associated with an increased rate of death in those with sepsis.[57] Serial measurement of lactate levels (approximately every 4 to 6 hours) may guide treatment and is associated with lower mortality in sepsis.[20]
In common clinical usage,neonatal sepsis refers to a bacterialblood stream infection in the first month of life, such asmeningitis,pneumonia,pyelonephritis, orgastroenteritis,[60] but neonatal sepsis also may be due to infection with fungi, viruses, or parasites.[60] Criteria with regard to hemodynamic compromise or respiratory failure are not useful because they present too late for intervention.[61]
Early recognition and focused management may improve the outcomes of sepsis. Current professional recommendations include several actions ("bundles") to be followed as soon as possible after diagnosis. Within the first three hours, someone with sepsis should have received antibiotics, and intravenous fluids if there is evidence of either low blood pressure or other evidence for inadequate blood supply to organs (as evidenced by a raised level of lactate); blood cultures also should be obtained within this period. After six hours the blood pressure should be adequate, close monitoring of blood pressure and blood supply to organs should be in place, and the lactate should be measured again if initially it was raised.[9] A related bundle, the "Sepsis Six", is in widespread use in theUnited 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.[62][63]
Two sets of blood cultures (aerobic and anaerobic) are recommended without delaying the initiation of antibiotics. Cultures from other sites such as respiratory secretions, urine, wounds, cerebrospinal fluid, and catheter insertion sites (in situ for more than 48 hours) are recommended if infections from these sites are suspected.[5] In severe sepsis and septic shock,broad-spectrum antibiotics (usually two, aβ-lactam antibiotic with broad coverage, or broad-spectrumcarbapenem combined withfluoroquinolones,macrolides, oraminoglycosides) are recommended. The choice of antibiotics is important in determining the survival of the person.[43][5] Some recommend they be given within one hour of making the diagnosis, stating that for every hour of delay in the administration of antibiotics, there is an associated 6% rise in mortality.[49][43] Others did not find a benefit with early administration.[64]
Several factors determine the most appropriate choice for the initial antibiotic regimen. These factors include local patterns of bacterial sensitivity to antibiotics, whether the infection is thought to be ahospital or community-acquired infection, and which organ systems are thought to be infected.[43][20] Antibiotic regimens should be reassessed daily and narrowed if appropriate. Treatment duration is typically 7–10 days with the type of antibiotic used directed by the results of cultures. If the culture result is negative, antibiotics should be de-escalated according to the person's clinical response or stopped altogether if an infection is not present to decrease the chances that the person is infected withmultiple drug resistance organisms. In case of people having a high risk of being infected withmultiple drug resistant organisms such asPseudomonas aeruginosa,Acinetobacter baumannii, the addition of an antibiotic specific to the gram-negative organism is recommended. Formethicillin-resistantStaphylococcus aureus (MRSA),vancomycin orteicoplanin is recommended. ForLegionella infection, addition ofmacrolide orfluoroquinolone is chosen. If fungal infection is suspected, anechinocandin, such ascaspofungin ormicafungin, is chosen for people with severe sepsis, followed bytriazole (fluconazole anditraconazole) for less ill people.[5] Prolonged antibiotic prophylaxis is not recommended in people who has SIRS without any infectious origin such asacute pancreatitis andburns unless sepsis is suspected.[5]
Once-daily dosing ofaminoglycoside is sufficient to achieve peak plasma concentration for a clinical response without kidney toxicity. Meanwhile, for antibiotics with low volume distribution (vancomycin, teicoplanin, colistin), a loading dose is required to achieve an adequate therapeutic level to fight infections. Frequent infusions of beta-lactam antibiotics without exceeding the total daily dose would help to keep the antibiotics level aboveminimum inhibitory concentration (MIC), thus providing a better clinical response.[5] Giving beta-lactam antibiotics continuously may be better than giving them intermittently.[65] Access totherapeutic drug monitoring is important to ensure adequate drug therapeutic level while at the same time preventing the drug from reaching a toxic level.[5]
TheSurviving Sepsis Campaign has recommended 30 mL/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a targetmean arterial pressure (MAP) of 65 mmHg.[5] In children an initial amount of 20 mL/kg is reasonable in shock.[66] In cases of severe sepsis and septic shock where acentral venous catheter is used to measure blood pressures dynamically, fluids should be administered until thecentral venous pressure reaches 8–12 mmHg.[42] Once these goals are met, the central venous oxygen saturation (ScvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized.[5] If the ScvO2 is less than 70%, blood may be given to reach a hemoglobin of 10 g/dL and theninotropes are added until the ScvO2 is optimized.[30] In those withacute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully.[9]
Crystalloid solution is recommended as the fluid of choice for resuscitation.[5]Albumin can be used if a large amount of crystalloid is required for resuscitation.[5] Crystalloid solutions shows little difference withhydroxyethyl starch in terms of risk of death.[67] Starches also carry an increased risk ofacute kidney injury,[67][68] and need for blood transfusion.[69][70] Various colloid solutions (such as modified gelatin) carry no advantage over crystalloid.[67] Albumin also appears to be of no benefit over crystalloids.[71]
The Surviving Sepsis Campaign recommendedpacked red blood cells transfusion forhemoglobin levels below 70 g/L if there is nomyocardial ischemia,hypoxemia, or acute bleeding.[5] In a 2014 trial, blood transfusions to keep target hemoglobin above 70 or 90 g/L did not make any difference to survival rates; meanwhile, those with a lower threshold of transfusion received fewer transfusions in total.[72]Erythropoietin is not recommended in the treatment of anemia with septic shock because it may precipitateblood clotting events.Fresh frozen plasma transfusion usually does not correct the underlying clotting abnormalities before a planned surgical procedure. However, platelet transfusion is suggested for platelet counts below (10 × 109/L) without any risk of bleeding, or (20 × 109/L) with a high risk of bleeding, or (50 × 109/L) with active bleeding, before planned surgery or an invasive procedure.[5] IV immunoglobulin is not recommended because its beneficial effects are uncertain.[5] Monoclonal and polyclonal preparations ofintravenous immunoglobulin (IVIG) do not lower the rate of death in newborns and adults with sepsis.[73] Evidence for the use ofIgM-enriched polyclonal preparations of IVIG is inconsistent.[73] On the other hand, the use ofantithrombin to treatdisseminated intravascular coagulation is also not useful. Meanwhile, the blood purification technique (such ashemoperfusion, plasma filtration, and coupled plasma filtration adsorption) to remove inflammatory mediators and bacterial toxins from the blood also does not demonstrate any survival benefit for septic shock.[5]
If the person has been sufficiently fluid resuscitated but themean arterial pressure is not greater than 65 mmHg,vasopressors are recommended.[5]Norepinephrine (noradrenaline) is recommended as the initial choice.[5] Delaying initiation of vasopressor therapy during septic shock is associated with increased mortality.[74]
Norepinephrine is often used as a first-line treatment for hypotensive septic shock because evidence shows that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours.[75] Norepinephrine raises blood pressure through a vasoconstriction effect, with little effect onstroke volume and heart rate.[5] In some people, the required dose of vasopressor needed to increase the mean arterial pressure can become exceedingly high and it becomes toxic.[76] To reduce the required dose of vasopressor, epinephrine may be added.[76] Epinephrine is not often used as a first-line treatment for hypotensive shock because it reduces blood flow to the abdominal organs and increases lactate levels.[75] Vasopressin can be used in septic shock because studies have shown that there is a relative deficiency of vasopressin when shock continues for 24 to 48 hours. However, vasopressin reduces blood flow to the heart, fingers/toes, and abdominal organs, resulting in a lack of oxygen supply to these tissues.[5]Dopamine is typically not recommended. Although dopamine is useful for increasing the stroke volume of the heart, it causes moreabnormal heart rhythms than norepinephrine and also has an immunosuppressive effect. Dopamine is not proven to have protective properties on the kidneys.[5]Dobutamine can also be used in hypotensive septic shock to increase cardiac output and correct blood flow to the tissues.[77] Dobutamine is not used as often as epinephrine due to its associated side effects, which include reducing blood flow to the gut.[77] Additionally, dobutamine increases the cardiac output by abnormally increasing the heart rate.[77]
The use ofsteroids in sepsis is controversial.[78] Studies do not give a clear picture as to whether and whenglucocorticoids should be used.[79] The 2016 Surviving Sepsis Campaign recommends low dosehydrocortisone only if both intravenous fluids and vasopressors are not able to adequately treat septic shock.[5] The 2021 Surviving Sepsis Campaign recommends IV corticosteroids for adults with septic shock who have an ongoing requirement for vasopressor therapy. A 2019 Cochrane review found low-quality evidence of benefit,[11] as did two 2019 reviews.[12][80]
During critical illness, a state ofadrenal insufficiency and tissue resistance tocorticosteroids may occur. This has been termedcritical illness–related corticosteroid insufficiency.[81] Treatment with corticosteroids might be most beneficial in those withseptic shock and early severe ARDS, whereas its role in others such as those withpancreatitis or severepneumonia is unclear.[81] However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. NeitherACTH stimulation testing[81] nor randomcortisol levels are recommended to confirm the diagnosis.[5] The method of stopping glucocorticoid drugs is variable, and it is unclear whether they should be slowly decreased or simply abruptly stopped. However, the 2016 Surviving Sepsis Campaign recommended to taper steroids when vasopressors are no longer needed.[5]
A targettidal volume of 6 mL/kg of predicted body weight (PBW) and aplateau pressure less than 30 cm H2O is recommended for those who requireventilation due to sepsis-induced severe ARDS. Highpositive end expiratory pressure (PEEP) is recommended for moderate to severe ARDS in sepsis as it opens more lung units for oxygen exchange. Predicted body weight is calculated based on sex and height, and tools for this are available.[82] Recruitment maneuvers may be necessary for severe ARDS by briefly raising the transpulmonary pressure. It is recommended that the head of the bed be raised if possible to improve ventilation. However,β2 adrenergic receptor agonists are not recommended to treat ARDS because it may reduce survival rates and precipitateabnormal heart rhythms. Aspontaneous breathing trial usingcontinuous positive airway pressure (CPAP), T piece, or inspiratory pressure augmentation can help reduce the duration of ventilation. Minimizing intermittent or continuous sedation helps reduce the duration of mechanical ventilation.[5]
General anesthesia is recommended for people with sepsis who require surgical procedures to remove the infective source. Usually, inhalational and intravenous anesthetics are used. Requirements for anesthetics may be reduced in sepsis.Inhalational anesthetics can reduce the level of proinflammatory cytokines, altering leukocyte adhesion and proliferation, inducingapoptosis (cell death) of the lymphocytes, possibly with a toxic effect onmitochondrial function.[39] Althoughetomidate has a minimal effect on the cardiovascular system, it is often not recommended as a medication to help withintubation in this situation due to concerns it may lead topoor adrenal function and an increased risk of death.[83][84] The small amount of evidence there is, however, has not found a change in the risk of death with etomidate.[85]
Paralytic agents are not suggested for use in sepsis cases in the absence ofARDS, as a growing body of evidence points to reduced durations ofmechanical ventilation, ICU and hospital stays.[9] However, paralytic use inARDS cases remains controversial. When appropriately used, paralytics may aid successful mechanical ventilation, however, evidence has also suggested that mechanical ventilation in severe sepsis does not improve oxygen consumption and delivery.[9]
Source control refers to physical interventions to control afocus of infection and reduce conditions favorable to microorganism growth or host defense impairment, such asdrainage of pus from anabscess. It is one of the oldest procedures for the control of infections, giving rise to the Latin phraseUbi pus, ibi evacua, and remains important despite the emergence of more modern treatments.[86][87]
Early goal directed therapy (EGDT) is an approach to the management of severe sepsis during the initial 6 hours after diagnosis.[88] It is a step-wise approach, with the physiologic goal of optimizing cardiac preload, afterload, and contractility.[89] It includes giving early antibiotics.[89] EGDT also involves monitoring of hemodynamic parameters and specific interventions to achieve key resuscitation targets which include maintaining a central venous pressure between 8–12 mmHg, a mean arterial pressure of between 65 and 90 mmHg, a central venous oxygen saturation (ScvO2) greater than 70% and a urine output of greater than 0.5 mL/kg/hour. The goal is to optimize oxygen delivery to tissues and achieve a balance between systemic oxygen delivery and demand.[89] An appropriate decrease in serumlactate may be equivalent to ScvO2 and easier to obtain.[90]
In the original trial, early goal-directed therapy was found to reduce mortality from 46.5% to 30.5% in those with sepsis,[89] and the Surviving Sepsis Campaign has been recommending its use.[9] However, three more recent large randomized control trials (ProCESS, ARISE, and ProMISe), did not demonstrate a 90-day mortality benefit of early goal-directed therapy when compared to standard therapy in severe sepsis.[91] It is likely that some parts of EGDT are more important than others.[91] Following these trials the use of EGDT is still considered reasonable.[92]
Neonatal sepsis can be difficult to diagnose as newborns may be asymptomatic.[93] If a newborn shows signs and symptoms suggestive of sepsis, antibiotics are immediately started and are either changed to target a specific organism identified by diagnostic testing or discontinued after an infectious cause for the symptoms has been ruled out.[94] Despite early intervention, death occurs in 13% of children who develop septic shock, with the risk partly based on other health problems. For those without multiple organ system failures or who require only one inotropic agent, mortality is low.[95]
Treating fever in sepsis, including people in septic shock, has not been associated with any improvement in mortality over a period of 28 days.[96] Treatment of fever still occurs for other reasons.[97][98]
Recombinant activatedprotein C (drotrecogin alpha) was originally introduced for severe sepsis (as identified by a highAPACHE II score), where it was thought to confer a survival benefit.[88] However, subsequent studies showed that it increased adverse events—bleeding risk in particular—and did not decrease mortality.[100] It was removed from sale in 2011.[100] Another medication known aseritoran also has not shown benefit.[101]
In those withhigh 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.[102] Glucose levels taken from capillary blood should be interpreted with care because such measurements may not be accurate. If a person has an arterial catheter, arterial blood is recommended for blood glucose testing.[5]
Intermittent or continuousrenal replacement therapy may be used if indicated. However,sodium bicarbonate is not recommended for a person with lactic acidosis secondary to hypoperfusion.Low-molecular-weight heparin (LMWH),unfractionated heparin (UFH), and mechanical prophylaxis withintermittent pneumatic compression devices are recommended for any person with sepsis at moderate to high risk ofvenous thromboembolism.[5] Stress ulcer prevention withproton-pump inhibitor (PPI) andH2 antagonist are useful in a person with risk factors of developingupper gastrointestinal bleeding (UGIB) such as on mechanical ventilation for more than 48 hours, coagulation disorders, liver disease, and renal replacement therapy.[5] Achieving partial or full enteral feeding (delivery of nutrients through afeeding tube) is chosen as the best approach to provide nutrition for a person who is contraindicated for oral intake or unable to tolerate orally in the first seven days of sepsis when compared tointravenous nutrition. However,omega-3 fatty acids are not recommended as immune supplements for a person with sepsis or septic shock. The usage ofprokinetic agents such asmetoclopramide,domperidone, anderythromycin are recommended for those who are septic and unable to tolerate enteral feeding. However, these agents may precipitate prolongation of theQT interval and consequently provoke aventricular arrhythmia such astorsades de pointes. The usage of prokinetic agents should be reassessed daily and stopped if no longer indicated.[5]
People in sepsis may have micronutrient deficiencies, including low levels of vitamin C.[103] Reviews mention that an intake of 3.0 g/day, which requires intravenous administration, may be needed to maintain normal plasma concentrations in people with sepsis or severe burn injury.[104][105]
Sepsis will prove fatal in approximately 24.4% of people, and septic shock will prove fatal in 34.7% of people within 30 days (32.2% and 38.5% after 90 days).[106]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 having a mortality of less than 15%.[49]
There are a number of prognostic stratification systems, such asAPACHE 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 the 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.[107]
Some people may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most people with sepsis makes the incidence of this difficult to quantify or study.[108]
Sepsis causes millions of deaths globally each year and is the most common cause of death in people who have been hospitalized.[3][88] Thenumber of new cases worldwide of sepsis is estimated to be 18 million cases per year.[109] In theUnited States sepsis affects approximately 3 in 1,000 people,[49] and severe sepsis contributes to more than 200,000 deaths per year.[110]
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.[30] A study ofU.S. states found approximately 651 hospital stays per 100,000 population with a sepsis diagnosis in 2010.[111] It is the second-leading cause of death in non-coronaryintensive care unit (ICU) and the tenth-most-common cause of death overall (the first being heart disease).[112] Children under 12 months of age and elderly people have the highest incidence of severe sepsis.[30] Among people from the U.S. 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.[111] A study of 18 U.S. states found that amongst people withMedicare in 2011, sepsis was the second most common principal reason for readmission within 30 days.[113]
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 ascancer,diabetes, or theabsence of a spleen; andmajor trauma andburns.[1][114][115]
From 1979 to 2000, data from the United States National Hospital Discharge Survey showed that the incidence of sepsis increased fourfold, to 240 cases per 100,000 population, with a higher incidence in men when compared to women. However, the global prevalence of sepsis has been estimated to be higher in women.[16] During the same time frame, the in-hospital case fatality rate was reduced from 28% to 18%. However, according to the nationwide inpatient sample from the United States, the incidence of severe sepsis increased from 200 per 10,000 population in 2003 to 300 cases in 2007 for a population aged more than 18 years. The incidence rate is particularly high among infants, with an incidence of 500 cases per 100,000 population. Mortality related to sepsis increases with age, from less than 10% in the age group of 3 to 5 years to 60% by sixth decade of life.[25] The increase in the average age of the population, alongside the presence of more people with chronic diseases or onimmunosuppressive medications, and also the increase in the number of invasive procedures being performed, has led to an increased rate of sepsis.[26]
Personification ofsepticemia, carrying a spray can marked "Poison"
The term "σήψις" (sepsis) was introduced by Hippocrates in the fourth century BC, and it meant the process ofdecay or decomposition of organic matter.[116][117][118] In the eleventh century,Avicenna used the term "blood rot" for diseases linked to severepurulent process. Though severe systemic toxicity had already been observed, it was only in the 19th century that the specific term – sepsis – was used for this condition.
The terms "septicemia", also spelled "septicaemia", and "blood poisoning" referred to the microorganisms or their toxins in the blood. TheInternational Statistical Classification of Diseases and Related Health Problems (ICD) version 9, which was in use in the US until 2013, used the term septicemia with numerous modifiers for different diagnoses, such as "Streptococcal septicemia".[119] All those diagnoses have been converted to sepsis, again with modifiers, inICD-10, such as "Sepsis due to streptococcus".[119]
The current terms are dependent on the microorganism that is present:bacteremia ifbacteria are present in the blood at abnormal levels and are the causative issue,viremia forviruses, andfungemia for afungus.[120]
By the end of the 19th century, it was widely believed thatmicrobes produced substances that could injure themammalian host and that solubletoxins released during infection caused the fever and shock that were commonplace during severe infections.Pfeiffer coined the termendotoxin at the beginning of the 20th century to denote the pyrogenic principle associated withVibrio cholerae. It was soon realized that endotoxins were expressed by most and perhaps allgram-negative bacteria. Thelipopolysaccharide character of enteric endotoxins was elucidated in 1944 by Shear.[121] The molecular character of this material was determined by Luderitz et al. in 1973.[122]
It was discovered in 1965 that a strain of C3H/HeJmouse was immune to the endotoxin-induced shock.[123] The genetic locus for this effect was dubbedLps. These mice were also found to be hyper-susceptible to infection by gram-negative bacteria.[124] These observations were finally linked in 1998 by the discovery of thetoll-like receptor gene 4 (TLR 4).[125] Genetic mapping work, performed over 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 thecytoplasm.[126]
Controversy occurred in the scientific community over the use of mouse models in research into sepsis in 2013 when scientists published a review of the mouse immune system compared to the human immune system and showed that on a systems level, the two worked very differently; the authors noted that as of the date of their article over 150 clinical trials of sepsis had been conducted in humans, almost all of them supported by promising data in mice and that all of them had failed. The authors called for abandoning the use of mouse models in sepsis research; others rejected that but called for more caution in interpreting the results of mouse studies,[127] and more careful design of preclinical studies.[128][129][130][131] One approach is to rely more on studying biopsies and clinical data from people who have had sepsis, to try to identifybiomarkers anddrug targets for intervention.[132]
Sepsis was the most expensive condition treated in United States' hospital stays in 2013, at an aggregate cost of $23.6 billion for nearly 1.3 million hospitalizations.[133] Costs for sepsis hospital stays more than quadrupled since 1997 with an 11.5 percent annual increase.[134] By payer, it was the most costly condition billed to Medicare and the uninsured, the second-most costly billed toMedicaid, and the fourth-most costly billed toprivate insurance.[133]
A large international collaboration entitled the "Surviving Sepsis Campaign" was established in 2002[135] to educate people about sepsis and to improve 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.[88] The guidelines were updated in 2016[136] and again in 2021.[137]
Sepsis Alliance is a charitable organization based in the United States that was created to raise sepsis awareness among both the general public and healthcare professionals.[138] In 2011, September was declaredSepsis Awareness Month. One year later, the Global Sepsis Alliance declared September 13 World Sepsis Day.[139]
Phenotypic strategy switches of microbes capable of provoking sepsis
Some authors suggest that initiating sepsis by the normallymutualistic (or neutral) members of themicrobiome may not always be an accidental side effect of the deteriorating host immune system. Rather it is often anadaptive microbial response to a sudden decline of host survival chances. Under this scenario, the microbe species provoking sepsis benefit from monopolizing the future cadaver, utilizing its biomass asdecomposers, and then transmitting through soil or water to establish mutualistic relations with new individuals. The bacteriaStreptococcus pneumoniae,Escherichia coli,Proteus spp.,Pseudomonas aeruginosa,Staphylococcus aureus,Klebsiella spp.,Clostridium spp.,Lactobacillus spp.,Bacteroides spp. and the fungiCandida spp. are all capable of such a high level ofphenotypic plasticity. Not all cases of sepsis arise through such adaptive microbial strategy switches.[140]
Paul E. Marik's "Marik protocol", also known as the "HAT" protocol, proposed a combination ofhydrocortisone,vitamin C, andthiamine as a treatment for preventing sepsis for people inintensive care. Marik's initial research, published in 2017, showed dramatic evidence of benefit, leading to the protocol becoming popular among intensive care physicians, especially after the protocol received attention on social media andNational Public Radio, leading to criticism ofscience by press conference from the wider medical community. Subsequent independent research failed to replicate Marik's positive results, indicating the possibility that they had been compromised by bias.[141] Asystematic review of trials in 2021 found that the claimed benefits of the protocol could not be confirmed.[142]
Overall, the evidence for any role of vitamin C in the treatment of sepsis remains unclear as of 2021[update].[143]
^Desale M, Thinkhamrop J, Lumbiganon P, Qazi S, Anderson J (October 2016). "Ending preventable maternal and newborn deaths due to infection".Best Practice & Research. Clinical Obstetrics & Gynaecology.36:116–130.doi:10.1016/j.bpobgyn.2016.05.008.PMID27450868.
^abFelner K, Smith RL (2012). "Ch. 138: Sepsis". In McKean S, Ross JJ, Dressler DD, Brotman DJ, Ginsberg JS (eds.).Principles and Practice of Hospital Medicine. New York:McGraw-Hill. pp. 1099–109.ISBN978-0071603898.
^abcdeGauer RL (July 2013). "Early recognition and management of sepsis in adults: the first six hours".American Family Physician.88 (1):44–53.PMID23939605.
^abcdefgEly EW, Goyette RE (2005). "Ch. 46: Sepsis with Acute Organ Dysfunction". In Hall JB, Schmidt GA, Wood LD (eds.).Principles of Critical Care (3rd ed.). New York:McGraw-Hill Medical.ISBN978-0071416405.
^Leentjens J, Kox M, van der Hoeven JG, Netea MG, Pickkers P (June 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):1287–1293.doi:10.1164/rccm.201301-0036CP.PMID23590272.
^Antonopoulou A, Giamarellos-Bourboulis EJ (January 2011). "Immunomodulation in sepsis: state of the art and future perspective".Immunotherapy.3 (1):117–128.doi:10.2217/imt.10.82.PMID21174562.
^Nimah M, Brilli RJ (July 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.PMID12848314.
^Fernando SM, Tran A, Taljaard M, Cheng W, Rochwerg B, Seely AJ, Perry JJ (February 2018). "Prognostic Accuracy of the Quick Sequential Organ Failure Assessment for Mortality in Patients With Suspected Infection: A Systematic Review and Meta-analysis".Annals of Internal Medicine.168 (4):266–275.doi:10.7326/M17-2820.PMID29404582.S2CID3441582.
^Goldstein B, Giroir B, Randolph A (January 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.PMID15636651.S2CID8190072.
^Machowicz R, Janka G, Wiktor-Jedrzejczak W (June 2017). "Similar but not the same: Differential diagnosis of HLH and sepsis".Critical Reviews in Oncology/Hematology.114:1–12.doi:10.1016/j.critrevonc.2017.03.023.PMID28477737.
^Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, et al. (September 2016). "Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. A Meta-analysis of Individual Patient Data from Randomized Trials".American Journal of Respiratory and Critical Care Medicine.194 (6):681–691.doi:10.1164/rccm.201601-0024oc.PMID26974879.
^Serpa Neto A, Veelo DP, Peireira VG, de Assunção MS, Manetta JA, Espósito DC, Schultz MJ (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.e1–185.e7.doi:10.1016/j.jcrc.2013.09.031.PMID24262273.
^Patel GP, Balk RA (January 2012). "Systemic steroids in severe sepsis and septic shock".American Journal of Respiratory and Critical Care Medicine.185 (2):133–139.doi:10.1164/rccm.201011-1897CI.PMID21680949.
^Ni YN, Liu YM, Wang YW, Liang BM, Liang ZA (September 2019). "Can corticosteroids reduce the mortality of patients with severe sepsis? A systematic review and meta-analysis".The American Journal of Emergency Medicine.37 (9):1657–1664.doi:10.1016/j.ajem.2018.11.040.PMID30522935.S2CID54537066.
^abcMarik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, et al. (June 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):1937–1949.doi:10.1097/CCM.0b013e31817603ba.PMID18496365.S2CID7861625.
^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):2945–2953.doi:10.1097/CCM.0b013e31825fec26.PMID22971586.S2CID916535.
^Gu WJ, Wang F, Tang L, Liu JC (February 2015). "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.147 (2):335–346.doi:10.1378/chest.14-1012.PMID25255427.S2CID22739840.
^De Waele JJ (2009). "Source Control in the ICU". In Vincent JL, Malbrain MM, De Laet IE (eds.).Yearbook of Intensive Care and Emergency Medicine. Springer Berlin Heidelberg. pp. 93–101.doi:10.1007/978-3-540-92276-6_9.ISBN978-3-540-92275-9.
^abDell'Anna AM, Taccone FS (October 2015). "Early-goal directed therapy for septic shock: is it the end?".Minerva Anestesiologica.81 (10):1138–1143.PMID26091011.
^Rusconi AM, Bossi I, Lampard JG, Szava-Kovats M, Bellone A, Lang E (September 2015). "Early goal-directed therapy vs usual care in the treatment of severe sepsis and septic shock: a systematic review and meta-analysis".Internal and Emergency Medicine.10 (6):731–743.doi:10.1007/s11739-015-1248-y.PMID25982917.S2CID207311061.
^Shane AL, Stoll BJ (January 2014). "Neonatal sepsis: progress towards improved outcomes".The Journal of Infection.68 (Suppl 1):S24 –S32.doi:10.1016/j.jinf.2013.09.011.PMID24140138.
^Kutko MC, Calarco MP, Flaherty MB, Helmrich RF, Ushay HM, Pon S, Greenwald BM (July 2003). "Mortality rates in pediatric septic shock with and without multiple organ system failure".Pediatric Critical Care Medicine.4 (3):333–337.doi:10.1097/01.PCC.0000074266.10576.9B.PMID12831416.S2CID18089789.
^Fink MP, Warren HS (October 2014). "Strategies to improve drug development for sepsis".Nature Reviews. Drug Discovery.13 (10):741–758.doi:10.1038/nrd4368.PMID25190187.S2CID20904332.
^Belsky JB, Wira CR, Jacob V, Sather JE, Lee PJ (December 2018). "A review of micronutrients in sepsis: the role of thiamine, L-carnitine, vitamin C, selenium and vitamin D".Nutrition Research Reviews.31 (2):281–90.doi:10.1017/S0954422418000124.PMID29984680.S2CID51599526.
^Carpenter CR, Keim SM, Upadhye S, Nguyen HB (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):319–327.doi:10.1016/j.jemermed.2009.03.016.PMID19427752.
^Lyle NH, Pena OM, Boyd JH, Hancock RE (September 2014). "Barriers to the effective treatment of sepsis: antimicrobial agents, sepsis definitions, and host-directed therapies".Annals of the New York Academy of Sciences.1323 (2014):101–114.Bibcode:2014NYASA1323..101L.doi:10.1111/nyas.12444.PMID24797961.S2CID5089865.
^Munford RS (2011). "Ch. 271: Severe Sepsis and Septic Shock". In Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (eds.).Harrison's Principles of Internal Medicine (18th ed.). New York:McGraw-Hill. pp. 2223–31.ISBN9780071748896.
^Rubin LG, Schaffner W (July 2014). "Clinical practice. Care of the asplenic patient".The New England Journal of Medicine.371 (4):349–356.doi:10.1056/NEJMcp1314291.PMID25054718.
^Lüderitz O, Galanos C, Lehmann V, Nurminen M, Rietschel ET, Rosenfelder G, et al. (July 1973). "Lipid A: chemical structure and biological activity".The Journal of Infectious Diseases.128: Suppl:17–Suppl:29.doi:10.1093/infdis/128.Supplement_1.S17.JSTOR30106029.PMID4352586.
^Poltorak A, Smirnova I, He X, Liu MY, Van Huffel C, McNally O, et al. (September 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 & Diseases.24 (3):340–355.doi:10.1006/bcmd.1998.0201.PMID10087992.
^Lee YR, Vo K, Varughese JT (March 2022). "Benefits of combination therapy of hydrocortisone, ascorbic acid and thiamine in sepsis and septic shock: A systematic review".Nutrition and Health.28 (1):77–93.doi:10.1177/02601060211018371.PMID34039089.S2CID235215735.
