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Septic shock is a medical condition as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome (formerly known as multiple organ failure) and death. Its most common victims are children, immunocompromised individuals, and the elderly, as their immune systems cannot deal with infection as effectively as those of healthy adults. Frequently, patients suffering from septic shock are cared for in intensive care units. The mortality rate from septic shock is approximately 25–50%.
Septic shock is a subclass of distributive shock, a condition in which abnormal distribution of blood flow in the smallest blood vessels results in inadequate blood supply to the body's tissues, resulting in ischemia and organ dysfunction. Septic shock refers specifically to distributive shock due to sepsis as a result of infection.
Septic shock can be defined as sepsis-induced hypotension that persists despite treatment with intravenous fluids. Low blood pressure reduces tissue perfusion pressure, causing the tissue hypoxia that is characteristic of shock. Cytokines released in a large scale inflammatory response result in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction occur.
Septic shock can be regarded as a stage of SIRS (Systemic Inflammatory Response Syndrome), in which sepsis, severe sepsis and multiple 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.
According to current guidelines, requirements for diagnosis with sepsis are "the presence (probable or documented) of infection together with systemic manifestations of infection". These manifestations may include:
- Tachypnea (high respiratory rate), which is defined as more than 20 breaths per minute, or when testing blood gas, a PaCO
2 less than 32 mmHg, which signifies hyperventilation.
- White blood cell count either significantly low, (< 4000 cells/mm3) or elevated (> 12000 cells/mm3).
- Tachycardia (rapid heart rate), which in sepsis is defined as a rate greater than 90 beats per minute.
- Altered body temperature: Fever > 38.0 °C (100.4 °F) or hypothermia < 36.0 °C (96.8 °F)
Documented evidence of infection, may include positive blood culture, signs of pneumonia on chest x-ray, or other radiologic or laboratory evidence of infection. Signs of end-organ dysfunction are present in septic shock, including kidney failure, liver dysfunction, changes in mental status, or elevated serum lactate.
Septic shock is diagnosed if there is refractory hypotension (low blood pressure that does not respond to treatment). This means that intravenous fluid administration alone is not enough to maintain a patient's blood pressure. Diagnosis of sepsis-induced hypotension is made when systolic blood pressure is less than 90mm Hg, a mean arterial pressure (MAP) is less than 70 mm Hg, or a systolic blood pressure decreases 40 mm Hg or more without other causes for hypotension.
Septic shock is a result of a systemic response to infection, and can be a response to multiple infectious causes; septicemia may be present but septic shock can occur without septicemia. The precipitating infections which may lead to septic shock if severe enough include, but are not limited to, appendicitis, pneumonia, bacteremia, diverticulitis, pyelonephritis, meningitis, pancreatitis, necrotizing fasciitis, and mesenteric necrosis.
Sepsis is a constellation of symptoms secondary to infection that manifest as disruptions in heart rate, respiratory rate, temperature and white blood cell count. If sepsis worsens to the point of end-organ dysfunction (renal failure, liver dysfunction, altered mental status, or heart damage), then the condition is called severe sepsis. Once severe sepsis worsens to the point where blood pressure can no longer be maintained with intravenous fluids alone, then the criteria have been met for septic shock.
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 and coagulation response to an infection. Both pro-inflammatory and anti-inflammatory responses play a role in septic shock.
Most cases of septic shock are caused by gram-positive bacteria, followed by endotoxin-producing gram-negative bacteria, though fungal infections are an increasingly prevalent cause of septic shock. Toxins produced by pathogens cause an immune response; in gram-negative bacteria these are endotoxins, which are bacterial membrane lipopolysaccharides. In gram-positive bacteria, these are exotoxins or enterotoxins, 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 include superantigens and heat-stable enterotoxins. Type II, membrane-damaging toxins, destroy cell membranes in order to enter and include hemolysins and phospholipases. Type III, intracellular toxins or A/B toxins interfere with internal cell function and include shiga toxin, cholera toxin, and anthrax lethal toxin.
In gram-negative sepsis, free LPS attaches to a circulating LPS-binding protein, and the complex then binds to the CD14 receptor on monocytes, macrophages, and neutrophils. 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 a number of 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 as IL-1, IL-6, and TNF-α. TLR-mediated activation helps to trigger the innate 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 as tissue factor pathway inhibitor and thrombomodulin. The effects of the cytokines may be amplified by TLR-4 engagement on endothelial cells.
In response to inflammation, a compensatory reaction of production of anti-inflammatory substances such as IL-4, IL-10 antagonists, IL-1 receptor and cortisol occurs. This is called Compensatory Anti-inflammatory Response Syndrome (CARS). 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. 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.
At high levels of LPS, the syndrome of septic shock supervenes; the same cytokine and secondary mediators, now at high levels, result in systemic vasodilation (hypotension), diminished myocardial contractility, widespread endothelial injury and activation, causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung activation of the coagulation system, culminating in disseminated 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 others. Severe damage to liver ultrastructure has been recently noticed by treatment with cell-free toxins of Salmonella. Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies.
Treatment primarily consists of the following:
- Volume resuscitation
- Early antibiotic administration
- Early goal directed therapy
- Rapid source identification and control
- Support of major organ dysfunction
- Sequestration of lipopolysaccharides
Treatment guidelines call for the administration of broad-spectrum antibiotics within the first hour following recognition of septic shock. Prompt antimicrobial therapy is critically important, as risk of dying increases by approximately 10% for every hour of delay in receiving antibiotics. Time constraints do not allow the culture, identification and testing for antibiotic sensitivity of the specific microorganism responsible for infection. Therefore, combination antimicrobial therapy, which covers a wide range of potential causative organisms, is tied to better outcomes.
Because lowered blood pressure, in septic shock contributes to poor perfusion, fluid resuscitation is an initial treatment to increase blood volume. Crystalloids such as normal saline and lactated Ringer's solution are recommended as the initial fluid of choice, while the use of colloid solutions such as hydroxyethyl starch have not shown any advantage or decrease in mortality. When large quantities of fluids are given, administering albumin has shown some benefit.
Among the choices for vasopressors, norepinephrine is superior to dopamine in septic shock. Norepinephrine is the preferred vasopressor, while epinephrine can be added to norepinephrine when needed. Low-dose vasopressin may also be used as an addition to norepinephrine, but is not recommended as a first-line treatment. Dopamine can cause rapid heart rate and arrhythmias, and is only recommended in combination with norepinephrine in those with slow heart rate and low risk of arrhythmia. In the initial treatment of hypotension in septic shock, the goal of vasopressor treatment is a mean arterial pressure (MAP) of 65 mm Hg.
A controversial approach is to use β-Blocker therapy. It may attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. Microvascular blood flow alterations are frequent in patients with sepsis and are more severe in patients with a worse outcome. Heart rate control by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume and a preserved microvascular blood flow. It has also shown a trend toward an improvement of the microcirculation on a piglet model of septic shock. A study has shown that the use of esmolol versus standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. An improvement in mortality was observed, but as it was a secondary clinical outcomes, it warrants further investigation.
Antimediator agents may be of some limited use in severe clinical situations however are controversial:
- Low dose steroids (hydrocortisone) for 5 – 7 days led to improved outcomes.
- Recombinant activated protein C (drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality and thus was not recommended for use. Other reviews however comment that it may be effective in those with very severe disease. The first and only activated protein C drug, drotrecogin alfa (Xigris), was voluntarily withdrawn in October 2011 after it failed to show a benefit in patients with septic shock, including the more severe disease subgroups.
A technique that has shown success and is currently used in Japan, if not elsewhere[where?] , involves sequestering the lipopolysacharides that effectively cause septic shock. The antibiotic toraymyxin coincidentally does this, but is also too toxic to be administered. The Japanese technique binds this toraymixin to an immobile material like polystyrene, and pass the blood over it, but this isn't always practical. Recent peer-reviewed research has found a substance derived from the very same spermine found in semen, to bind to lipopolysaccharids which, so far, seems to be non-toxic as well.
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.
According to the US CDC, septic shock is the 13th leading cause of death in the United States, and the #1 cause of deaths 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. Tertiary care centers (such as hospice care facilities) have 2-4 times the rate of bacteremia than primary care centers, 75% of which are hospital-acquired infections.
The process of infection by bacteria or fungi can result in systemic signs and symptoms that are variously described. Approximately 70% of septic shock cases were once traceable to gram-negative bacteria that produce endotoxins; however, with the emergence of MRSA and the increased use of arterial and venous catheters, gram-positive bacteria are implicated approximately as commonly as bacilli. In rough order of increasing severity, these are bacteremia or fungemic; septicemia; sepsis, severe sepsis or sepsis syndrome; septic shock; refractory septic shock; multiple organ dysfunction syndrome, and death.
The mortality rate from sepsis is approximately 40% in adults, and 25% in children, and is significantly greater when left untreated for more than 7 days.
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