Sepsis
Sepsis | |
---|---|
Prognosis | 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 to infection causes injury to its own tissues and organs.[4][7]
This initial stage of sepsis is followed by suppression of the
Sepsis is caused by many organisms including bacteria, viruses and fungi.
Sepsis requires immediate treatment with
Disease severity partly determines the outcome.
Signs and symptoms
In addition to symptoms related to the actual cause, people with sepsis may have a
The drop in blood pressure seen in sepsis can cause lightheadedness and is part of the criteria for septic shock.[21]
Oxidative stress is observed in septic shock, with circulating levels of copper and vitamin C being decreased.[22]
Cause
Infections leading to sepsis are usually
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]
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.[30] 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.[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 with burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis. However, sepsis also causes similar response to SIRS.[32]
Microbial factors
Bacterial
There are a number of microbial factors that may cause the typical septic
Host factors
Upon detection of microbial
Inflammatory responses cause
The low blood pressure seen in those with sepsis is the result of various processes, including excessive production of chemicals that
Diagnosis
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 from electronic health records to bring attention to potential cases as early as possible.[43]
Within the first three hours of suspected sepsis, diagnostic studies should include
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),
Within twelve hours, it is essential to diagnose or exclude any source of infection that would require emergent source control, such as a necrotizing soft tissue infection, an infection causing
Definitions
Finding | Value |
---|---|
Temperature |
<36 °C (96.8 °F) or >38 °C (100.4 °F) |
Heart rate | >90/min |
Respiratory rate | >20/min or PaCO2 <32 mmHg (4.3 kPa)
|
WBC |
<4x109/L (<4000/mm3), >12x109/L (>12,000/mm3), or ≥10% bands
|
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:
- SIRS is the presence of two or more of the following: abnormal blood gas, and white blood cellcount.
- Sepsis is defined as SIRS in response to an infectious process.[48]
- Severe sepsis is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (manifesting as hypotension, elevated lactate, or decreased urine output). Severe sepsis is an infectious disease state associated with multiple organ dysfunction syndrome (MODS)[9]
- Septic shock is severe sepsis plus persistently low blood pressure, despite the administration of intravenous fluids.[9]
In 2016 a new consensus was reached to replace screening by
End-organ dysfunction
Examples of end-organ dysfunction include the following:[52]
- Lungs: PaO2/FiO2 ratio < 300), different ratio in pediatric acute respiratory distress syndrome
- Brain: encephalopathy symptoms including agitation, confusion, coma; causes may include ischemia, bleeding, formation of blood clots in small blood vessels, microabscesses, multifocal necrotizing leukoencephalopathy
- Liver: disruption of protein synthetic function manifests acutely as progressive levels
- Kidney: electrolyte abnormalities, or volume overload
- Heart: systolic and diastolic chemical signals that depress myocyte function, cellular damage, manifest as a troponinleak (although not necessarily ischemic in nature)
More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.[53]
- 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
- vasopressorrequirement, or
- two of the following criteria:
- unexplained base deficit> 5 mEq/L
- lactic acidosis: serum lactate 2 times the upper limit of normal
- oliguria (urine output < 0.5 mL/kg/h)
- prolonged capillary refill > 5 seconds
- core to peripheral temperature difference > 3 °C
- unexplained
- Respiratory dysfunction (in the absence of a cyanotic heart defect or a known chronic respiratory disease)
- the ratio of the arterial partial-pressure of oxygen to the fraction of oxygen in the gases inspired (PaO2/FiO2) < 300 (the definition of acute lung injury), or
- arterial partial-pressure of carbon dioxide (PaCO2) > 65 torr (20 mmHg) over baseline PaCO2 (evidence of hypercapnic respiratory failure), or
- supplemental oxygen requirement of greater than FiO2 0.5 to maintain oxygen saturation ≥ 92%
- the ratio of the arterial partial-pressure of oxygen to the fraction of oxygen in the gases inspired (PaO2/FiO2) < 300 (the definition of
- Neurologic dysfunction
- Glasgow Coma Score(GCS) ≤ 11, or
- altered mental status with drop in GCS of 3 or more points in a person with developmental delay/intellectual disability
- Hematologic dysfunction
- platelet count < 80,000/mm3 or 50% drop from maximum in chronically thrombocytopenic, or
- international normalized ratio(INR) > 2
- Disseminated intravascular coagulation
- Kidney dysfunction
- serum creatinine ≥ 2 times the upper limit of normal for age or 2-fold increase in baseline creatinine in people with chronic kidney disease
- Liver dysfunction (only applicable to infants > 1 month)
- total serum bilirubin ≥ 4 mg/dL, or
- alanine aminotransferase(ALT) ≥ 2 times the upper limit of normal
Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.[18]
Biomarkers
Biomarkers can help diagnosis because they can point to the presence or severity of sepsis, although their exact role in the management of sepsis remains undefined.[54] A 2013 review concluded moderate-quality evidence exists to support the use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS.[45] The same review found the sensitivity of the test to be 77% and the specificity to be 79%. The authors suggested that procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone does not definitively make the diagnosis.[45] More current literature recommends utilizing the PCT to direct antibiotic therapy for improved antibiotic stewardship and better patient outcomes.[55]
A 2012 systematic review found that
Differential diagnosis
The
Neonatal sepsis
In common clinical usage,
Management
Early recognition and focused management may improve the outcomes in sepsis. Current professional recommendations include a number of actions ("bundles") to be followed as soon as possible after diagnosis. Within the first three hours, someone with sepsis should have received antibiotics and, intravenous fluids if there is evidence of either low blood pressure or other evidence for inadequate blood supply to organs (as evidenced by a raised level of lactate); blood cultures also should be obtained within this time period. After six hours the blood pressure should be adequate, close monitoring of blood pressure and blood supply to organs should be in place, and the lactate should be measured again if initially it was raised.[9] A related bundle, the "Sepsis Six", is in widespread use in the United Kingdom; this requires the administration of antibiotics within an hour of recognition, blood cultures, lactate, and hemoglobin determination, urine output monitoring, high-flow oxygen, and intravenous fluids.[60][61]
Apart from the timely administration of fluids and
Antibiotics
Two sets of blood cultures (aerobic and anaerobic) are recommended without delaying the initiation of antibiotics. Cultures from other sites such as respiratory secretions, urine, wounds, cerebrospinal fluid, and catheter insertion sites (in-situ more than 48 hours) are recommended if infections from these sites are suspected.
Several factors determine the most appropriate choice for the initial antibiotic regimen. These factors include local patterns of bacterial sensitivity to antibiotics, whether the infection is thought to be a
Once-daily dosing of aminoglycoside is sufficient to achieve peak plasma concentration for a clinical response without kidney toxicity. Meanwhile, for antibiotics with low volume distribution (vancomycin, teicoplanin, colistin), a loading dose is required to achieve an adequate therapeutic level to fight infections. Frequent infusions of beta-lactam antibiotics without exceeding total daily dose would help to keep the antibiotics level above minimum inhibitory concentration (MIC), thus providing a better clinical response.[5] Giving beta-lactam antibiotics continuously may be better than giving them intermittently.[63] Access to therapeutic drug monitoring is important to ensure adequate drug therapeutic level while at the same time preventing the drug from reaching toxic level.[5]
Intravenous fluids
The Surviving Sepsis Campaign has recommended 30 mL/kg of fluid to be given in adults in the first three hours followed by fluid titration according to blood pressure, urine output, respiratory rate, and oxygen saturation with a target mean arterial pressure (MAP) of 65 mmHg.[5] In children an initial amount of 20 mL/kg is reasonable in shock.[64] In cases of severe sepsis and septic shock where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure reaches 8–12 mmHg.[41] 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 then inotropes are added until the ScvO2 is optimized.[30] In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully.[9]
Blood products
The Surviving Sepsis Campaign recommended
Vasopressors
If the person has been sufficiently fluid resuscitated but the
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.
Steroids
The use of
During critical illness, a state of
Anesthesia
A target
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.
Paralytic agents are not suggested for use in sepsis cases in the absence of ARDS, as a growing body of evidence points to reduced durations of mechanical ventilation, ICU and hospital stays.[9] However, paralytic use in ARDS 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
Source control refers to physical interventions to control a focus of infection and reduce conditions favorable to microorganism growth or host defense impairment, such as drainage of pus from an abscess. It is one of the oldest procedures for control of infections, giving rise to the Latin phrase Ubi pus, ibi evacua, and remains important despite the emergence of more modern treatments.[84][85]
Early goal directed therapy
In the original trial, early goal-directed therapy was found to reduce mortality from 46.5% to 30.5% in those with sepsis,[87] 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.[89] It is likely that some parts of EGDT are more important than others.[89] Following these trials the use of EGDT is still considered reasonable.[90]
Newborns
Neonatal sepsis can be difficult to diagnose as newborns may be asymptomatic.[91] 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.[92] 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.[93]
Other
Treating fever in sepsis, including people in septic shock, has not been associated with any improvement in mortality over a period of 28 days.[94] Treatment of fever still occurs for other reasons.[95][96]
A 2012
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.[100] 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 continuous
People in sepsis may have micronutrient deficiencies, including low levels of vitamin C.[101] Reviews mention that an intake of 3.0 g/day, which requires intravenous administration, may needed to maintain normal plasma concentrations in people with sepsis or severe burn injury.[102][103] Sepsis mortality is reduced with administration of intravenous vitamin C.[104]
Prognosis
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).[105] 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%.[48]
There are a number of prognostic stratification systems, such as APACHE II and Mortality in Emergency Department Sepsis. APACHE II factors in the person's age, underlying condition, and various physiologic variables to yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of 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.[106]
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 to study.[107]
Epidemiology
Sepsis causes millions of deaths globally each year and is the most common cause of death in people who have been hospitalized.[3][86] The number of new cases worldwide of sepsis is estimated to be 18 million cases per year.[108] In the United States sepsis affects approximately 3 in 1,000 people,[48] and severe sepsis contributes to more than 200,000 deaths per year.[109]
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 of U.S. states found approximately 651 hospital stays per 100,000 population with a sepsis diagnosis in 2010.[110] It is the second-leading cause of death in non-coronary intensive care unit (ICU) and the tenth-most-common cause of death overall (the first being heart disease).[111] 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.[110] A study of 18 U.S. states found that, amongst people with Medicare in 2011, sepsis was the second most common principal reason for readmission within 30 days.[112]
Several medical conditions increase a person's susceptibility to infection and developing sepsis. Common sepsis risk factors include age (especially the very young and old); conditions that weaken the immune system such as
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 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 on immunosuppressive medications, and also the increase in the number of invasive procedures being performed, has led to an increased rate of sepsis.[26]
History
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.[115][116][117] In the eleventh century, Avicenna used the term "blood rot" for diseases linked to severe purulent 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. The
The current terms are dependent on the microorganism that is present:
By the end of the 19th century, it was widely believed that
It was discovered in 1965 that a strain of C3H/HeJ mouse was immune to the endotoxin-induced shock.[122] The genetic locus for this effect was dubbed Lps. These mice were also found to be hyper susceptible to infection by gram-negative bacteria.[123] These observations were finally linked in 1998 by the discovery of the toll-like receptor gene 4 (TLR 4).[124] 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 cytoplasm.[125]
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,
Society and culture
Economics
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.[132] Costs for sepsis hospital stays more than quadrupled since 1997 with an 11.5 percent annual increase.[133] By payer, it was the most costly condition billed to Medicare and the uninsured, the second-most costly billed to Medicaid, and the fourth-most costly billed to private insurance.[132]
Education
A large international collaboration entitled the "Surviving Sepsis Campaign" was established in 2002[134] 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.[86] The guidelines were updated in 2016[135] and again in 2021.[136]
Sepsis Alliance is a charitable organization that was created to raise sepsis awareness among both the general public and healthcare professionals.[137]
Research
Some authors suggest that initiating sepsis by the normally mutualistic (or neutral) members of the microbiome may not always be an accidental side effect of the deteriorating host immune system. Rather it is often an adaptive 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 as decomposers, and then transmitted through soil or water to establish mutualistic relations with new individuals. The bacteria Streptococcus pneumoniae, Escherichia coli, Proteus spp., Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella spp., Clostridium spp., Lactobacillus spp., Bacteroides spp. and the fungi Candida spp. are all capable of such a high level of phenotypic plasticity. Evidently, not all cases of sepsis arise through such adaptive microbial strategy switches.[138]
Overall, the evidence for any role for vitamin C in the treatment of sepsis remains unclear as of 2021[update].[142]
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External links
- Sepsis at Curlie
- SIRS, Sepsis, and Septic Shock Criteria Archived 17 February 2015 at the Wayback Machine
- "Sepsis". MedlinePlus. U.S. National Library of Medicine.