Inflammation may result in organ damage. Blood clotting during sepsis reduces blood flow to limbs and internal organs, depriving them ofnutrients and oxygen. In severe cases, one or more organs fail. In the worst cases, infection leads to a life-threatening drop in blood pressure, called septic shock. This can quickly lead to the failure of several organs -- lungs, kidneys, and liver -- causing death.
Severe sepsis affects more than a million Americans each year. Up to half of these people will die from this condition.
Bacterial infections are the most common cause of sepsis. However, sepsis can also be caused by other infections. The infection can begin anywhere bacteria or other infectious agents can enter the body. It can result from something as seemingly harmless as a scraped knee or nicked cuticle or from a more serious medical problem such asappendicitis, pneumonia, meningitis, or a urinary tract infection.
Sepsis may accompany infection of the bone, called osteomyelitis. In hospitalized patients, common sites of initial infection include IV lines, surgical incisions, urinary catheters, and bed sores.
Although anyone can get sepsis, certain groups of people are at greater risk. They include:
Because sepsis can begin in different parts of the body, it can have many different symptoms. Rapid breathing and a change in mental status, such as reduced alertness or confusion, may be the first signs that sepsis is starting. Other common symptoms include:
Sepsis is a life-threatening condition that arises when the body's response to infection injures its own tissues and organs. 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 thanhigh. 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 bacterial, but it can also be from 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 canceror diabetes, and major trauma or burns. Diagnosis was based on meeting at least twosystemic inflammatory response syndrome (SIRS) criteria due to a presumed infection. In 2016 screening by SIRS was replaced with qSOFA which is two of the following three: increased breathing rate, change in level of consciousness, and low blood pressure. 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 to look 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 embolismamong others.
Sepsis is usually treated with intravenous fluids and antibiotics. Antibiotics are typically given as soon as possible. This is often done in anintensive 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, acentral venous catheter and an arterial catheter may be placed for access to the bloodstream. Other measurements such as cardiac outputand 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.
In addition to symptoms related to the provoking cause, sepsis is frequently associated with either feveror 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 due to decreased systemic vascular resistance, higher cardiac output, and dysfunctions of blood coagulation (where clotting can lead to organ failure).
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.
Infections leading to sepsis are usually bacterial but can also be fungal or viral. 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.
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 bypolymerase 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 is very unlikely the person has sepsis; if they are positive there is just a moderate probability that the person has sepsis.
|Temperature||<36 °C (96.8 °F) or >38 °C (100.4 °F)|
|Respiratory rate||>20/min or PaCO2<32 mmHg (4.3 kPa)|
|WBC||<4x109/L (<4000/mm³), >12x109/L (>12,000/mm³), or 10% bands|
There are different levels of sepsis: sepsis, severe sepsis, and septic shock. In 2016 screening bysystemic inflammatory response syndrome (SIRS) was replaced with qSOFA which is two of the following three: increased breathing rate, change in level of consciousness, and low blood pressure.
Examples of end-organ dysfunction include the following:
More specific definitions of end-organ dysfunction exist for SIRS in pediatrics.
Consensus definitions, however, continue to evolve, with the latest expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience.
The differential diagnosis for sepsis is broad and 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, andneurogenic shock.
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.
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.
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 oflipopolysaccharide, 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 bindmajor 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.
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.
In severe sepsis and septic shock, broad-spectrum antibiotics (usually two or a ?-lactam antibiotic with broad coverage) are recommended. Some recommend they be given within 1 hour of making the diagnosis stating that for every hour delay in the administration of antibiotics, there is an associated 6% rise in mortality. Others did not find a benefit with early administration.Two sets of blood cultures should be obtained before starting antibiotics if this can be done without delaying the administration of antibiotics.
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 7–10 days with the type of antibiotic used directed by the results of cultures.
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 adults. In children an initial amount of 20mL/Kg is reasonable in shock. 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 8–12mmHg. 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.
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.
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.
The use of steroids in sepsis is controversial. Studies do not give a clear picture as to whether and when glucocorticoids should be used. 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. While a 2015 Cochrane review found low quality evidence of benefit.
During critical illness, a state of adrenal insufficiency and tissue resistance to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency. Treatment with corticosteroids might be most beneficial in those with septic shock and early severe 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 (EGDT) is an approach to the management of severe sepsis during the initial 6 hours after diagnosis. It is a step-wise approach, with the physiologic goal of optimizing cardiac preload, afterload, and contractility. It includes giving early antibiotics. It 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 65-90 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. An appropriate decrease in serum lactate may be equivalent to ScvO2 and easier to obtain.
In the original trial, early goal directed therapy was found to reduce mortality from 46.5% to 30.5% in those with sepsis, and the Surviving Sepsis Campaign has been recommending its use. 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 versus the standard therapy in severe sepsis. It is likely that some parts of EGDT are more important than others. Following these trials the use of EGDT is still considered reasonable.
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.
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 thatN-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 events—bleeding risk in particular—and did not decrease mortality. It was removed from sale in 2011. Another medication known as eritoran also has not shown benefit.