Sepsis

Sepsis (/ˈsɛpsɨs/) is a whole-body inflammation caused by an infection. Common signs and symptoms include fever, increased heart rate, increased breathing rate, and confusion. There may also be symptoms related to a specific infection such as a cough with pneumonia or painful urination, with a kidney infection. In the very young, old, and people with a weakened immune system, there may be no symptoms of a specific infection and the body temperature may be low or normal rather than high. Severe sepsis is sepsis causing poor organ function or insufficient blood flow. Insufficient blood flow may be evident by low blood pressure, high blood lactate, or low urine output. Septic shock is low blood pressure due to sepsis that does not improve after reasonable amounts of intravenous fluids are given.

Sepsis is caused by an immune response triggered by an infection. The infection is most commonly by bacteria, but can also be by fungi, viruses, or parasites. Common locations for the primary infection include: lungs, brain, urinary tract, skin, and abdominal organs. Risk factors include young or old age, a weakened immune system from conditions such as cancer or diabetes, and major trauma or burns. Diagnosis is based on meeting at least two systemic inflammatory response syndrome (SIRS) criteria due to a presumed infection. Blood cultures are recommended preferably before antibiotics are started; however, infection of the blood is not required for the diagnosis. Medical imaging should be done looking for the possible location of infection. Other potential causes of similar signs and symptoms include: anaphylaxis, adrenal insufficiency, low blood volume, heart failure, and pulmonary embolism among others.

Sepsis is usually treated with intravenous fluids and antibiotics. This is often done in an intensive care unit. If fluid replacement is not enough to maintain blood pressure, medications that raise blood pressure can be used. Mechanical ventilation and dialysis may be needed to support the function of the lungs and kidneys, respectively. To guide treatment, a central venous catheter and an arterial catheter may be placed. Other measurements such as cardiac output and superior vena cava oxygen saturation may also be used. People with sepsis need preventive measures for deep vein thrombosis, stress ulcers and pressure ulcers, unless other conditions prevent such interventions. Some might benefit from tight control of blood sugar levels with insulin. The use of corticosteroids is controversial. Activated drotrecogin alfa, originally marketed for severe sepsis, has not been found to be helpful, and was withdrawn from sale in 2011.

Disease severity partly determines the outcome with the risk of death from sepsis being as high as 30%, severe sepsis as high as 50%, and septic shock as high as 80%. The total number of cases worldwide is unknown as there is little data from the developing world. Estimates suggest sepsis affects millions of people a year. In the developed world about 0.2 to 3 per 1000 people gets sepsis yearly or about a million cases per year in the United States. Rates of disease have been increasing. Sepsis is more common among males than females. The terms septicemia and blood poisoning referred to the microorganisms or their toxins in the blood and are no longer commonly used. The condition has been described at least since the time of Hippocrates.

Signs and symptoms

In addition to symptoms related to the provoking cause, sepsis is frequently associated with either fever or low body temperature, rapid breathing, elevated heart rate, confusion, and edema. Early signs are a fast heart rate, decreased urination, and high blood sugar. Signs of established sepsis include confusion, metabolic acidosis (which may be accompanied by faster breathing leading to a respiratory alkalosis), low blood pressure, decreased systemic vascular resistance, higher cardiac output, and dysfunctions of blood coagulation (where clotting can lead to organ failure).

The drop in blood pressure seen in sepsis may lead to shock. This may result in light-headedness. Bruising or intense bleeding may also occur.

Cause

The most common primary sources of infection resulting in sepsis are the lungs, the abdomen, and the urinary tract. Typically, 50% of all sepsis cases start as an infection in the lungs. No definitive source is found in one third to one half of cases.

The infectious agents are usually bacteria but can also be fungi or viruses. While gram-negative bacteria were previously the most common cause of sepsis, in the last decade gram-positive bacteria, most commonly staphylococci, are thought to cause more than 50% of cases of sepsis. Other commonly implicated bacteria include Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species. Fungal sepsis accounts for approximately 5% of severe sepsis and septic shock cases; the most common cause of fungal sepsis is infection by Candida species of yeast.

Diagnosis

Early diagnosis is necessary to properly manage 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 WBCs, measuring serum lactate and obtaining appropriate cultures before starting antibiotics, so long as this does not delay their use by more than 45 minutes. To identify the causative organism(s), at least two sets of blood cultures using bottles with media for aerobic and anaerobic organisms should be obtained, with at least one drawn through the skin and one drawn through each vascular access device (such as an IV catheter) in place more than 48 hours. However, bacteria are present in the blood in only about 30% of cases. Another possible method of detection is by polymerase chain reaction. If other sources of infection are suspected, cultures of these sources, such as urine, cerebrospinal fluid, wounds, or respiratory secretions, should also be obtained, as long as this does not delay the use of antibiotics.

Within six hours, if blood pressure remains low despite initial fluid resuscitation of 30 ml/kg, or if initial lactate is ≥ 4 mmol/L (36 mg/dL), central venous pressure and central venous oxygen saturation should be measured. Lactate should be re-measured if the initial lactate was elevated. Within twelve hours, it is essential to diagnose or exclude any source of infection that would require emergent source control, such as necrotizing soft tissue infection, infection causing inflammation of the abdominal cavity lining, infection of the bile duct, or intestinal infarction. A pierced internal organ (free air on abdominal x-ray or CT scan; an abnormal chest x-ray consistent with pneumonia (with focal opacification); or petechiae, purpura, or purpura fulminans can also be evident of infection.

If the SIRS criteria are negative it very unlikely the person has sepsis; however, if they are positive there is just a moderate probability that the person has sepsis.

Definitions

According to the American College of Chest Physicians and the Society of Critical Care Medicine, there are different levels of sepsis:

• Systemic inflammatory response syndrome (SIRS) is the presence of two or more of the following: abnormal body temperature, heart rate, respiratory rate or blood gas, and white blood cell count.
• Sepsis is defined as SIRS in response to an infectious process.
• Severe sepsis is defined as sepsis with sepsis-induced organ dysfunction or tissue hypoperfusion (manifesting as hypotension, elevated lactate, or decreased urine output).
• Septic shock is severe sepsis plus persistently low blood pressure despite the administration of intravenous fluids.

End-organ dysfunction

Examples of end-organ dysfunction include the following:

• Lungs: acute respiratory distress syndrome (ARDS) (PaO₂/FiO₂ < 300)
• Brain: encephalopathy symptoms including agitation, confusion, coma; causes may include ischemia, hemorrhage, formation of blood clots in small blood vessels, microabscesses, multifocal necrotizing leukoencephalopathy
• Liver: disruption of protein synthetic function manifests acutely as progressive disruption of blood clotting due to an inability to synthesize clotting factors and disruption of metabolic functions leads to impaired bilirubin metabolism, resulting in elevated unconjugated serum bilirubin levels
• Kidney: low urine output or no urine output, electrolyte abnormalities, or volume overload
• Heart: systolic and diastolic heart failure, likely due to chemical signals that depress myocyte function, cellular damage, manifest as a troponin leak (although not necessarily ischemic in nature)

More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.

• Cardiovascular dysfunction (after fluid resuscitation with at least 40 ml/kg of crystalloid)
  • hypotension with blood pressure < 5th percentile for age or systolic blood pressure < 2 standard deviations below normal for age, OR
  • vasopressor requirement, OR
  • two of the following criteria:
    • unexplained metabolic acidosis with 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
• 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
  • Glasgow Coma Score (GCS) ≤ 11, OR
  • altered mental status with drop in GCS of 3 or more points in a patient with developmental delay/intellectual disability
• Hematologic dysfunction
  • platelet count < 80,000/mm³ or 50% drop from maximum in chronically thrombocytopenic patients, 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 patients 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.

Biomarkers

A 2013 systematic review and meta-analysis concluded moderate-quality evidence exists to support use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS. The same review found the test's sensitivity to be 77% and the specificity to be 79%. The authors suggested procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone cannot definitively make the diagnosis. A 2012 systematic review found that soluble urokinase-type plasminogen activator receptor (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis. However, this same review concluded that SuPAR has prognostic value as higher SuPAR levels are associated with an increased rate of death in those with sepsis.

Differential diagnosis

The differential diagnosis for sepsis is broad and has to look at (to exclude) the noninfectious conditions that can cause the systemic signs of SIRS: alcohol withdrawal, acute pancreatitis, burns, pulmonary embolus, thyrotoxicosis, anaphylaxis, adrenal insufficiency, and neurogenic shock.

Neonatal sepsis

In common clinical usage, neonatal sepsis refers to a bacterial blood stream infection in the first month of life, such as meningitis, pneumonia, pyelonephritis, or gastroenteritis, but neonatal sepsis can also be due to infection with fungi, viruses, or parasites. Criteria with regard to hemodynamic compromise or respiratory failure are not useful because they present too late for intervention.

Pathophysiology

Sepsis is caused by a combination of factors related to the particular invading pathogen(s) and to the status of the host's immune system. The early phase of sepsis characterized by excessive inflammation (which can sometimes result in a cytokine storm) can be followed by a prolonged period of decreased functioning of the immune system. Either of these phases can prove fatal.

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 the host's response to the lipid A component of lipopolysaccharide, also called endotoxin. Sepsis caused by gram-positive bacteria can result from an immunological response to cell wall lipoteichoic acid. Bacterial exotoxins that act as superantigens can also cause sepsis. Superantigens simultaneously bind major histocompatibility complex and T-cell receptors in the absence of antigen presentation. This forced receptor interaction induces the production of pro-inflammatory chemical signals (cytokines) by T-cells.

There are a number of microbial factors which can cause the typical septic inflammatory cascade. An invading pathogen is recognized by its pathogen-associated molecular patterns (PAMPs). Examples of PAMPs include lipopolysaccharides and flagellin in gram-negative bacteria, muramyl dipeptide in the peptidoglycan of the gram-positive bacterial cell wall, and CpG bacterial DNA. These PAMPs are recognized by the innate immune system's pattern recognition receptors (PRRs), which can be membrane-bound or cytosolic. There are four families of PRRs: the toll-like receptors, the C-type lectin receptors, the NOD-like receptors and the RIG-I-like receptors. The association of a PAMP and a PRR will invariably cause a series of intracellular signalling cascades. Consequentially, transcription factors like nuclear factor-kappa B and activator protein-1 will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines.

Host factors

Cytokines such as tumor necrosis factor, interleukin 1, and interleukin 6 can activate procoagulation factors in the cells lining blood vessels, leading to endothelial damage. The damaged endothelial surface inhibits anticoagulant properties as well as increases antifibrinolysis, which can lead to intravascular clotting, the formation of blood clots in small blood vessels, and multiple organ failure.

A systemic inflammatory response syndrome can also occur in patients without the presence of infection, for example in those with burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis. The low blood pressure seen in those with sepsis is the result of various processes including excessive production of chemicals that dilate blood vessels such as nitric oxide, a deficiency of chemicals that constrict blood vessels such as vasopressin, and activation of ATP-sensitive potassium channels. In those with severe sepsis and septic shock, this sequence of events leads to a type of circulatory shock known as distributive shock.

Management

Early recognition and focused management can improve the outcomes in sepsis. Current professional recommendations include a number of actions ("bundles") to be taken as soon as possible after diagnosis. Within the first three hours someone with sepsis should have received antibiotics, and intravenous fluids if there is evidence of either low blood pressure or other evidence for inadequate blood supply to organs (as evidenced by a raised level of lactate); blood cultures should also be obtained within this time period. After six hours the blood pressure should be adequate, close monitoring of blood pressure and blood supply to organs should be in place, and the lactate should be measured again if it was initially raised. A related bundle, the "sepsis six", is in widespread use in the United Kingdom; this requires the administration of antibiotics within an hour of recognition, blood cultures, lactate and hemoglobin determination, urine output monitoring, high-flow oxygen, and intravenous fluids.

Apart from the timely administration of fluids and antibiotics, the management of sepsis also involves surgical drainage of infected fluid collections, and appropriate support for organ dysfunction. This may include hemodialysis in kidney failure, mechanical ventilation in lung dysfunction, transfusion of blood products, and drug and fluid therapy for circulatory failure. Ensuring adequate nutritionâ€"preferably by enteral feeding, but if necessary by parenteral nutritionâ€"is important during prolonged illness. In those with high blood sugar levels, insulin to bring it down to 7.8-10 mmol/L (140â€"180 mg/dL) is recommended with lower levels potentially worsening outcomes. Medication to prevent deep vein thrombosis and gastric ulcers may also be used.

Antibiotics

In severe sepsis and septic shock, broad-spectrum antibiotics (usually two or a β-lactam antibiotic with broad coverage) are recommended within 1 hour of making the diagnosis. For every hour delay in the administration of antibiotics, there is an associated 6% rise in mortality. 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 hospital or community-acquired infection, and which organ systems are thought to be infected. Antibiotic regimens should be reassessed daily and narrowed if appropriate. Treatment duration is typically 7â€"10 days with the type of antibiotic used directed by the results of cultures.

Intravenous fluids

Intravenous fluids are titrated (measured and adjusted) in response to heart rate, blood pressure, and urine output; restoring large fluid deficits can require 6 to 10 liters of crystalloids. In cases of severe sepsis and septic shock where a central venous catheter is used to measure blood pressures dynamically, fluids should be administered until the central venous pressure (CVP) reaches 8â€"12mmHg. 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. 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. In those with acute respiratory distress syndrome (ARDS) and sufficient tissue blood fluid, more fluids should be given carefully.

Crystalloid solutions are recommended initially. Crystalloid solutions and albumin are better than other fluids (such as hydroxyethyl starch) in terms of risk of death. Starches also carry an increased risk of acute kidney injury, and need for blood transfusion. Various colloid solutions (such as modified gelatin) carry no advantage over crystalloid. Albumin also appears to be of no benefit over crystalloids. Packed red blood cells are recommended to keep the hemoglobin levels between 70 and 90 g/L. A 2014 trial; however, found no difference between a target hemoglobin of 70 or 90 g/L.

Vasopressors

If the person has been sufficiently fluid resuscitated but the mean arterial pressure is not greater than 65 mmHg, vasopressors are recommended. Norepinephrine (noradrenaline) is recommended as the initial choice. If a single vasopressor is not enough to raise the blood pressure, epinephrine (adrenaline) or vasopressin may be added. Dopamine is typically not recommended. Dobutamine may be used if heart function is poor or blood flow is insufficient despite sufficient fluid volumes and blood pressure.

Ventilation

Etomidate is often not recommended as a medication to help with intubation in this situation due to concerns it may lead to poor adrenal function and an increased risk of death. The small amount of evidence there is, however, has not found a change in the risk of death with etomidate.

It is recommended that the head of the bed be raised if possible to improve ventilation. Paralytic agents should be avoided unless ARDS is suspected.

Steroids

The use of steroids in sepsis is controversial. The 2012 Surviving Sepsis Campaign recommends against their use in those with septic shock if intravenous fluids and vasopressors stabilize the person's cardiovascular function. During critical illness, a state of adrenal insufficiency and tissue resistance to corticosteroids may occur. This has been termed critical illnessâ€"related corticosteroid insufficiency. Treatment with corticosteroids might be most beneficial in those with septic shock and early severe ARDS, whereas its role in others such as those with pancreatitis or severe pneumonia is unclear. However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. ACTH stimulation testing is not recommended to confirm the diagnosis. The method of stopping glucocorticoid drugs is variable, and it is unclear whether they should be slowly decreased or simply abruptly stopped.

Early goal directed therapy

Early goal directed therapy (EGDT) is an approach to the management of severe sepsis during the initial 6 hours after diagnosis. A step-wise approach should be used, with the physiologic goal of optimizing cardiac preload, afterload, and contractility. It has been found to reduce mortality in those with sepsis.

Urine output is also monitored, with a minimum goal of 0.5 ml/kg/hour. 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.

Newborns

Neonatal sepsis can be difficult to diagnose as newborns may be asymptomatic. 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.

Other

Monoclonal and polyclonal preparations of intravenous immunoglobulin (IVIG) do not lower the rate of death in newborns and adults with sepsis. Evidence for the use of IgM-enriched polyclonal preparations of IVIG is inconsistent. A 2012 Cochrane review concluded that N-acetylcysteine does not reduce mortality in those with SIRS or sepsis and may even be harmful.

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 eventsâ€"bleeding risk in particularâ€"and did not decrease mortality. It was removed from sale in 2011.

Prognosis

Approximately 20â€"35% of people with severe sepsis and 30â€"70% of people with septic shock die. Lactate is a useful method of determining prognosis with those who have a level greater than 4 mmol/L having a mortality of 40% and those with a level of less than 2 mmol/L have a mortality of less than 15%.

There are a number of prognostic stratification systems such as APACHE II and Mortality in Emergency Department Sepsis. APACHE II factors in the person's age, underlying condition, and various physiologic variables to yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of underlying disease most strongly influences the risk of death. Septic shock is also a strong predictor of short- and long-term mortality. Case-fatality rates are similar for culture-positive and culture-negative severe sepsis. The Mortality in Emergency Department Sepsis (MEDS) score is simpler and useful in the emergency department environment.

Some people may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most sepsis patients makes the incidence of this difficult to quantify or to study.

Epidemiology

Sepsis causes millions of deaths globally each year and is the most common cause of death in people who have been hospitalized. The worldwide incidence of sepsis is estimated to be 18 million cases per 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 sepsis diagnosis in 2010. It is the second-leading cause of death in non-coronary intensive care unit (ICU) patients, and the tenth-most-common cause of death overall (the first being heart disease). Children under 12 months of age and elderly people have the highest incidence of severe sepsis. Among U.S. patients who had multiple sepsis hospital admissions in 2010, those who were discharged to a skilled nursing facility or long term care following the initial hospitalization were more likely to be readmitted than those discharged to another form of care. A study of 18 U.S. States found that, amongst Medicare patients in 2011, septicemia was the second most common principal reason for readmission within 30 days.

Several medical conditions increase a person's susceptibility to infection and developing sepsis. Common sepsis risk factors include age (especially the very young and old); conditions that weaken the immune system such as cancer, diabetes, or the absence of a spleen; and major trauma and burns.

History

The term "σeψις" (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 had already been observed, it was only in the 19th century that the specific term â€" sepsis â€" was used 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 bacteria. 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 cytoplasm.

Society and culture

Economics

Septicemia was the most expensive condition treated 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.

Education

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.

Notes

References

External links

• Sepsis at DMOZ
• SIRS, Sepsis, and Septic Shock Criteria

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