| Septic shock | |
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| Sepsis is one of the most common causes of death in critically ill patients inintensive care units. Oil byGabriël Metsu. | |
| Specialty | Infectious disease,critical care medicine,emergency medicine |
Septic shock is a potentially fatal medical condition that occurs whensepsis, which is organ injury or damage in response toinfection, leads to dangerouslylow blood pressure and abnormalities in cellular metabolism. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines septic shock as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by requiring avasopressor to maintain a mean arterial pressure of 65 mm Hg or greater and having serumlactate level greater than 2 mmol/L (>18 mg/dL) in the absence ofhypovolemia. This combination is associated with hospital mortality rates greater than 40%.[1]
The primary infection is most commonly caused bybacteria, but also may be caused byfungi,viruses, orparasites. It may be located in any part of the body, but most commonly in the lungs, brain,urinary tract, skin, orabdominal organs.[2] It can causemultiple organ dysfunction syndrome (formerly known as multiple organ failure) anddeath if not treated immediately.[3]
Frequently, people with septic shock are cared for inintensive care units. It most commonly affects children,immunocompromised individuals, and the elderly, as theirimmune systems cannot deal with infection as effectively as those of healthy adults. Themortality rate from septic shock is approximately 25–50%.[3]
Septic shock is a result of a systemic response to infection or multiple infectious causes. The precipitating infections that may lead to septic shock if severe enough include but are not limited toappendicitis,pneumonia,bacteremia,diverticulitis,pyelonephritis,meningitis,pancreatitis,necrotizing fasciitis,MRSA andmesenteric ischemia.[4][5]
According to the earlier definitions of sepsis updated in 2001,[6] sepsis is a constellation of symptoms secondary to an infection that manifests as disruptions in heart rate, respiratory rate, temperature, and white blood cell count. If sepsis worsens to the point of end-organ dysfunction (kidney failure, liver dysfunction, altered mental status, or heart damage), then the condition is called severe sepsis. In septic shock, events within tissue capillaries induce distributive shock in which the recovery of blood pressure is not achieved upon the administration of additional intravenous fluids, and requires a vasoconstrictive agent such as noradrenaline and/or vasopressin.[7]
The pathophysiology of septic shock is not entirely understood, but it is known that a key role in the development of severe sepsis is played by an immune andcoagulation response to an infection. Both pro-inflammatory and anti-inflammatory responses play a role in septic shock.[8] Septic shock involves a widespread inflammatory response that produces a hypermetabolic effect. This is manifested by increasedcellular respiration,protein catabolism, andmetabolic acidosis with a compensatoryrespiratory alkalosis.[9]
Most cases of septic shock are caused bygram-positive bacteria,[10] followed by endotoxin-producinggram-negative bacteria, although fungal infections are an increasingly prevalent cause of septic shock.[9] Toxins produced by pathogens cause an immune response; in gram-negative bacteria these areendotoxins, which are bacterial membranelipopolysaccharides (LPS).
In gram-positive bacteria, these areexotoxins orenterotoxins, which may vary depending on the species of bacteria. These are divided into three types. Type I, cell surface-active toxins, disrupt cells without entering, and includesuperantigens andheat-stable enterotoxins. Type II, membrane-damaging toxins, destroy cell membranes to enter and includehemolysins andphospholipases. Type III, intracellular toxins orA/B toxins interfere with internal cell function and includeshiga toxin,cholera toxin, andanthrax lethal toxin. (note thatShigella andVibrio cholerae are Gram negative organisms).[citation needed]
In gram-negative sepsis, a free LPS attaches to a circulatingLPS-binding protein, and the complex then binds to theCD14 receptor onmonocytes,macrophages, andneutrophils. Engagement of CD14 (even at doses as minute as 10 pg/mL) results in intracellular signaling via an associated "Toll-like receptor" protein 4 (TLR-4). This signaling results in the activation of nuclear factor kappaB (NF-κB), which leads to transcription of several genes that trigger a proinflammatory response. It was the result of significant activation of mononuclear cells and synthesis of effector cytokines. It also results in profound activation of mononuclear cells and the production of potent effector cytokines such asIL-1,IL-6, andTNF-α. TLR-mediated activation helps to trigger theinnate immune system to efficiently eradicate invading microbes, but the cytokines they produce also act on endothelial cells. There, they have a variety of effects, including reduced synthesis of anticoagulation factors such astissue factor pathway inhibitor andthrombomodulin. The effects of the cytokines may be amplified by TLR-4 engagement on endothelial cells.[citation needed]
In response to inflammation, a compensatory reaction of production of anti-inflammatory substances such asIL-4, IL-10 antagonists, IL-1 receptor, andcortisol occurs. This is called compensatory anti-inflammatory response syndrome (CARS).[11]Both the inflammatory and anti-inflammatory reactions are responsible for the course of sepsis and are described as MARS (Mixed Antagonist Response Syndrome). The aim of these processes is to keep inflammation at an appropriate level. CARS often leads to suppression of the immune system, which leaves patients vulnerable to secondary infection.[8] It was once thought that SIRS or CARS could predominate in a septic individual, and it was proposed that CARS follows SIRS in a two-wave process. It is now believed that the systemic inflammatory response and the compensatory anti-inflammatory response occur simultaneously.[11]
At high levels of LPS, the syndrome of septic shock supervenes; the same cytokine and secondary mediators, now at high levels, result in systemicvasodilation (hypotension), diminished myocardial contractility, widespread endothelial injury, activation causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung, and activation of the coagulation system culminating indisseminated intravascular coagulation (DIC).
The hypoperfusion from the combined effects of widespread vasodilation, myocardial pump failure, and DIC causes multiorgan system failure that affects the liver, kidneys, and central nervous system, among other organ systems. Recently, severe damage to liver ultrastructure has been noticed from treatment with cell-free toxins ofSalmonella.[12] Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies.[citation needed]
The ability ofTLR4 to respond to a distinctLPS species is clinically important.Pathogenic bacteria may employ LPS with low biological activity to evade proper recognition by theTLR4/MD-2 system, dampening the hostimmune response and increasing the risk of bacterial dissemination. On the other hand, such LPS would not be able to induce septic shock in susceptible patients, rendering septic complications more manageable. Yet, defining and understanding how even the smallest structural differences between the very similar LPS species may affect the activation of theimmune response may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes.[13]
According to current guidelines, requirements for diagnosis with sepsis are "the presence (probable or documented) of infection together with systemic manifestations of infection".[9] These manifestations may include:
Documented evidence of infection may include positiveblood culture, signs ofpneumonia on chest x-ray, or other radiologic or laboratory evidence of infection. Signs ofend-organ dysfunction are present in septic shock, includingkidney failure, liver dysfunction, changes in mental status, or elevated serumlactate.
Septic shock is diagnosed if there is low blood pressure (BP) that does not respond to treatment. This means that intravenous fluid administration alone is not enough to maintain a patient's BP. Diagnosis of septic shock is made whensystolic blood pressure is less than 90 mm Hg, amean arterial pressure (MAP) is less than 70 mm Hg, or a systolic BP decrease of 40 mm Hg or more without other causes for low BP.[9]
Septic shock is a subclass ofdistributive shock, a condition in which abnormal distribution ofblood flow in thesmallest blood vessels results in inadequate blood supply to the bodytissues, resulting inischemia and organ dysfunction. Septic shock refers specifically to distributive shock due tosepsis as a result of infection.[14]
Septic shock may be defined as sepsis-inducedlow blood pressure that persists despite treatment withintravenous fluids.[9] Low blood pressure reduces tissueperfusion pressure, causing thetissue hypoxia that is characteristic of shock.Cytokines released in a large-scale inflammatory response result in massivevasodilation, increasedcapillary permeability, decreasedsystemic vascular resistance, and low blood pressure. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction occur.[citation needed]
Septic shock may be regarded as a stage ofSIRS (Systemic Inflammatory Response Syndrome), in which sepsis, severe sepsis, andmultiple organ dysfunction syndrome (MODS) represent different stages of a pathophysiological process. If an organism cannot cope with an infection, it may lead to a systemic response - sepsis, which may further progress to severe sepsis, septic shock, organ failure, and eventually, result in death.[citation needed]
Treatment primarily consists of the following:
Because lowered blood pressure in septic shock contributes to poor perfusion,fluid resuscitation is an initial treatment to increase blood volume. Patients demonstrating sepsis-induced hypoperfusion should be initially resuscitated with at least 30 ml/kg of intravenous crystalloid within the first three hours.[5]Crystalloids such asnormal saline andlactated Ringer's solution are recommended as the initial fluid of choice, while the use of colloid solutions such ashydroxyethyl starch have not shown any advantage or decrease in mortality. When large quantities of fluids are given, administeringalbumin has shown some benefit.[10] However, too high of a rate of fluid infusion can be more risky; the particular type of fluid's flow rate must be closely monitored, along with the patient's condition and vital signs.[16]
Treatment guidelines call for the administration ofbroad-spectrum antibiotics within the first hour following recognition of septic shock. Promptantimicrobial therapy is important, as the risk of dying increases by approximately 10% for every hour of delay in receiving antibiotics.[10] Time constraints do not allow the culture, identification, and testing for antibiotic sensitivity of the specific microorganism responsible for the infection. Therefore, combination antimicrobial therapy, which covers a wide range of potential causative organisms, is tied to better outcomes.[10] Antibiotics should be continued for 7–10 days in most patients, though treatment duration may be shorter or longer depending on clinical response.[11]
Among the choices forvasopressors,norepinephrine is superior todopamine in septic shock.[17] Norepinephrine is the preferred vasopressor, while epinephrine may be added to norepinephrine when needed. Low-dosevasopressin also may be used as an addition to norepinephrine, but is not recommended as a first-line treatment.Dopamine may causerapid heart rate andarrhythmias, and is only recommended in combination with norepinephrine in those withslow heart rate and low risk of arrhythmia. In the initial treatment of low blood pressure in septic shock, the goal of vasopressor treatment is amean arterial pressure (MAP) of 65 mm Hg.[10] In 2017, the FDA approvedangiotensin II injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock.[18]
Methylene blue is useful for this condition.[19][20][21][22] Although use of methylene blue has mostly been in adults it has also been shown to work in children.[23][24] Its mechanism of action is thought to be via the inhibition of thenitric oxide-cyclic guanosine monophosphate pathway.[25] This pathway is excessively activated in septic shock. Methylene blue has been found to work in cases resistant to the usual agents.[26] This effect was first reported in the early 1990s.[27][28]
While there is tentative evidence forβ-Blocker therapy to help controlheart rate, evidence is not significant enough for its routine use.[29][30] There is tentative evidence that steroids may be useful in improving outcomes.[31]
Tentative evidence exists thatPolymyxin B-immobilized fiber column hemoperfusion may be beneficial in the treatment of septic shock.[32] Trials are ongoing and it is currently being used in Japan and Western Europe.[33]
Recombinant activatedprotein C (drotrecogin alpha) in a 2011Cochrane review was found not to decrease mortality and to increase bleeding, and thus, was not recommended for use.[34] Drotrecogin alfa (Xigris) was withdrawn from the market in October 2011.
Sepsis has a worldwide incidence of more than 20 million cases a year, with mortality due to septic shock reaching up to 50 percent even in industrialized countries.[35]
According to the U.S.Centers for Disease Control, septic shock is the thirteenth leading cause of death in the United States and the most frequent cause of death in intensive care units. There has been an increase in the rate of septic shock deaths in recent decades, which is attributed to an increase in invasive medical devices and procedures, increases in immunocompromised patients, and an overall increase in elderly patients.[citation needed]
Tertiary care centers (such ashospice care facilities) have 2-4 times the rate of bacteremia than primary care centers, 75% of which arehospital-acquired infections.[citation needed]
The process of infection by bacteria or fungi may result in systemic signs and symptoms that are variously described. Approximately 70% of septic shock cases were once traceable togram-negative bacteria that produceendotoxins, however, with the emergence ofMRSA and the increased use of arterial and venous catheters,gram-positive bacteria are implicated approximately as commonly asbacilli. In rough order of increasing severity, these are bacteremia or fungemia, sepsis, severe sepsis or sepsis syndrome, septic shock, refractory septic shock, multiple organ dysfunction syndrome, and death.[citation needed]
35% of septic shock cases derive fromurinary tract infections, 15% from the respiratory tract, 15% from skin catheters (such asIVs), and more than 30% of all cases areidiopathic in origin.[citation needed]
The mortality rate from sepsis, especially if it is not treated rapidly with the needed medications in a hospital, is approximately 40% in adults and 25% in children. It is significantly greater when sepsis is left untreated for more than seven days.[36]
