Septic shock is a potentially fatal

medical Medicine is the science and practice of caring for a patient, managing the diagnosis, prognosis, prevention, treatment, palliation of their injury or disease, and promoting their health. Medicine encompasses a variety of health care practic ...

condition that occurs when

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

, which is organ injury or damage in response to

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

, leads to dangerously

low blood pressure Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

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 a vasopressor to maintain a mean arterial pressure of 65 mm Hg or greater and having serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. The primary infection is most commonly caused by

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

, but also may be by

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...

viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...

parasites Parasitism is a Symbiosis, close relationship between species, where one organism, the parasite, lives on or inside another organism, the Host (biology), host, causing it some harm, and is Adaptation, adapted structurally to this way of lif ...

. It may be located in any part of the body, but most commonly in the lungs, brain,

urinary tract The urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressure, c ...

, skin or abdominal organs. It can cause

multiple organ dysfunction syndrome Multiple organ dysfunction syndrome (MODS) is altered organ (anatomy), organ function in an acutely ill patient requiring medicine, medical intervention to achieve homeostasis. Although Irwin and Rippe cautioned in 2005 that the use of "multiple ...

(formerly known as multiple organ failure) and

death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

. Frequently, people with septic shock are cared for in

intensive care units 220px, Intensive care unit An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensiv ...

. It most commonly affects children,

immunocompromised Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...

individuals, and the elderly, as their

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

s cannot deal with infection as effectively as those of healthy adults. The

mortality rate Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. Mortality rate is typically expressed in units of de ...

from septic shock is approximately 25–50%.

Causes

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 to

appendicitis Appendicitis is inflammation of the appendix. Symptoms commonly include right lower abdominal pain, nausea, vomiting, and decreased appetite. However, approximately 40% of people do not have these typical symptoms. Severe complications of a rup ...

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity ...

bacteremia Bloodstream infections (BSIs), which include bacteremias when the infections are bacterial and fungemias when the infections are fungal, are infections present in the blood. Blood is normally a sterile environment, so the detection of microb ...

, diverticulitis,

pyelonephritis Pyelonephritis is inflammation of the kidney, typically due to a bacterial infection. Symptoms most often include fever and flank tenderness. Other symptoms may include nausea, burning with urination, and frequent urination. Complications may ...

meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...

necrotizing fasciitis Necrotizing fasciitis (NF), also known as flesh-eating disease, is a bacterial infection that results in the death of parts of the body's soft tissue. It is a severe disease of sudden onset that spreads rapidly. Symptoms usually include red or p ...

MRSA Methicillin-resistant ''Staphylococcus aureus'' (MRSA) is a group of Gram-positive bacteria that are genetically distinct from other strains of ''Staphylococcus aureus''. MRSA is responsible for several difficult-to-treat infections in humans. ...

and

mesenteric ischemia Intestinal ischemia is a medical condition in which injury to the large or small intestine occurs due to not enough blood supply. It can come on suddenly, known as acute intestinal ischemia, or gradually, known as chronic intestinal ischemia. The ...

. According to the earlier definitions of sepsis updated in 2001, 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. Once severe sepsis worsens to the point where blood pressure can no longer be maintained with intravenous fluids alone, then the criterion has been met for septic shock.

Pathophysiology

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 Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

response to an infection. Both pro-inflammatory and anti-inflammatory responses play a role in septic shock. Septic shock involves a widespread inflammatory response that produces a hypermetabolic effect. This is manifested by increased cellular respiration, protein catabolism, and metabolic acidosis with a compensatory respiratory alkalosis. Most cases of septic shock are caused by

gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

, followed by endotoxin-producing

gram-negative bacteria Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

, although fungal infections are an increasingly prevalent cause of septic shock. Toxins produced by pathogens cause an immune response; in gram-negative bacteria these are

endotoxin Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...

s, which are bacterial membrane

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...

s (LPS).

Gram-positive

In gram-positive bacteria, these are

exotoxins An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, simi ...

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 Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are ...

and heat-stable enterotoxins. Type II, membrane-damaging toxins, destroy cell membranes in order to enter and include

hemolysin Hemolysins or haemolysins are lipids and proteins that cause lysis of red blood cells by disrupting the cell membrane. Although the lytic activity of some microbe-derived hemolysins on red blood cells may be of great importance for nutrient acqu ...

s and

phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...

s. Type III, intracellular toxins or A/B toxins interfere with internal cell function and include

shiga toxin Shiga toxins are a family of related toxins with two major groups, Stx1 and Stx2, expressed by genes considered to be part of the genome of lambdoid prophages. The toxins are named after Kiyoshi Shiga, who first described the bacterial or ...

cholera toxin Cholera toxin (also known as choleragen and sometimes abbreviated to CTX, Ctx or CT) is AB5 multimeric protein complex secreted by the bacterium ''Vibrio cholerae''. CTX is responsible for the massive, watery diarrhea characteristic of cholera i ...

, and anthrax lethal toxin. (note that ''Shigella'' and ''Vibrio cholerae'' are Gram negative organisms).

Gram-negative

In gram-negative sepsis, free LPS attaches to a circulating LPS-binding protein, and the complex then binds to the

CD14 CD14 (cluster of differentiation 14) is a human protein made mostly by macrophages as part of the innate immune system. It helps to detect bacteria in the body by binding lipopolysaccharide (LPS), a pathogen-associated molecular pattern (PAMP). ...

receptor on

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s, and

neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...

s. 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 Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

), 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 Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

. TLR-mediated activation helps to trigger the

innate immune system The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...

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 Tissue factor pathway inhibitor (or TFPI) is a single-chain polypeptide which can reversibly inhibit Factor Xa (Xa). While Xa is inhibited, the Xa-TFPI complex can subsequently also inhibit the FVIIa-tissue factor complex. TFPI contributes signif ...

and

thrombomodulin Thrombomodulin (TM), CD141 or BDCA-3 is an integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme from a procoag ...

. 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 Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...

(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 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 other organ systems. Recently, severe damage to liver ultrastructure has been noticed from treatment with cell-free toxins of

Salmonella ''Salmonella'' is a genus of rod-shaped (bacillus) Gram-negative bacteria of the family Enterobacteriaceae. The two species of ''Salmonella'' are ''Salmonella enterica'' and ''Salmonella bongori''. ''S. enterica'' is the type species and is fur ...

. Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies. The ability of

TLR4 Toll-like receptor 4 is a protein that in humans is encoded by the ''TLR4'' gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an ...

to respond to a distinct LPS species are clinically important.

Pathogenic bacteria Pathogenic bacteria are bacteria that can cause disease. This article focuses on the bacteria that are pathogenic to humans. Most species of bacteria are harmless and are often Probiotic, beneficial but others can cause infectious diseases. The n ...

may employ LPS with low biological activity to evade proper recognition by the

/ MD-2 system, dampening the host

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

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 the

may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes.

Diagnosis

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 Tachypnea, also spelt tachypnoea, is a respiratory rate greater than normal, resulting in abnormally rapid and shallow breathing. In adult humans at rest, any respiratory rate of 1220 per minute is considered clinically normal, with tachypnea b ...

(fast rate of breathing), which is defined as more than 20 breaths per minute, or when testing

blood gas A blood gas test or blood gas analysis tests blood to measure blood gas tension values, it also measures blood pH, and the level and base excess of bicarbonate. The source of the blood is reflected in the name of each test; arterial blood gase ...

, a less than 32 mm Hg, which signifies hyperventilation *

White blood cell White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...

count either significantly low (< 4000 cells/mm³), or elevated (> 12000 cells/mm³) *

Tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...

(rapid

heart rate Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). The heart rate can vary according to the body's physical needs, including the need to absorb oxygen and excr ...

), which in sepsis is defined as a rate greater than 90 beats per minute * Altered body

temperature Temperature is a physical quantity that expresses quantitatively the perceptions of hotness and coldness. Temperature is measured with a thermometer. Thermometers are calibrated in various temperature scales that historically have relied o ...

Fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...

> or hypothermia < Documented evidence of infection, may include positive

blood culture A blood culture is a medical laboratory test used to detect bacteria or fungi in a person's blood. Under normal conditions, the blood does not contain microorganisms: their presence can indicate a bloodstream infection such as bacteremia or f ...

, signs of

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 Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

, liver dysfunction, changes in mental status, or elevated serum lactate. 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 when

systolic blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

is less than 90 mm Hg, a

mean arterial pressure In medicine, the mean arterial pressure (MAP) is an average blood pressure in an individual during a single cardiac cycle. MAP is altered by cardiac output and systemic vascular resistance. Testing Mean arterial pressure can be measured dire ...

(MAP) is less than 70 mm Hg, or a systolic BP decrease of 40 mm Hg or more without other causes for low BP.

Definition

Septic shock is a subclass of

distributive shock Distributive shock is a medical condition in which abnormal distribution of blood flow in the smallest blood vessels results in inadequate supply of blood to the body's tissues and organs. It is one of four categories of shock, a condition wher ...

, a condition in which abnormal distribution of

blood flow Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuously m ...

in the smallest blood vessels results in inadequate blood supply to the body tissues, resulting in

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

and organ dysfunction. Septic shock refers specifically to distributive shock due to

as a result of infection. Septic shock may be defined as sepsis-induced

that persists despite treatment with

intravenous fluid Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

s. Low blood pressure reduces tissue perfusion pressure, causing the tissue hypoxia that is characteristic of shock.

Cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

released in a large scale inflammatory response result in massive

, increased

capillary permeability Vascular permeability, often in the form of capillary permeability or microvascular permeability, characterizes the capacity of a blood vessel wall to allow for the flow of small molecules (drugs, nutrients, water, ions) or even whole cells (lymph ...

, decreased systemic vascular resistance, and low blood pressure. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction occur. Septic shock may be regarded as a stage of SIRS (Systemic Inflammatory Response Syndrome), in which sepsis, severe sepsis and

(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.

Treatment

Treatment primarily consists of the following: # Giving intravenous fluids # Early antibiotic administration #

Early goal directed therapy Early goal-directed therapy (GDT) was introduced by Emanuel P. Rivers in ''The New England Journal of Medicine'' in 2001 and is a technique used in critical care medicine involving intensive monitoring and aggressive management of perioperative h ...

# Rapid source identification and control # Support of major organ dysfunction

Fluids

Because lowered blood pressure in septic shock contributes to poor perfusion,

fluid resuscitation Fluid replacement or fluid resuscitation is the medical practice of replenishing bodily fluid lost through sweating, bleeding, fluid shifts or other pathologic processes. Fluids can be replaced with oral rehydration therapy (drinking), intravenous ...

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.

Crystalloids A volume expander is a type of intravenous therapy that has the function of providing volume for the circulatory system. It may be used for fluid replacement or during surgery to prevent nausea and vomiting after surgery. Physiology When blood is ...

such as

normal saline Saline (also known as saline solution) is a mixture of sodium chloride (salt) and water. It has a number of uses in medicine including cleaning wounds, removal and storage of contact lenses, and help with dry eyes. By injection into a vein i ...

and

lactated Ringer's solution Ringer's lactate solution (RL), also known as sodium lactate solution, Lactated Ringer’s, and Hartmann's solution, is a mixture of sodium chloride, sodium lactate, potassium chloride, and calcium chloride in water. It is used for replacing ...

are recommended as the initial fluid of choice, while the use of colloid solutions such as

hydroxyethyl starch Hydroxyethyl starch (HES/HAES), sold under the brand name Voluven among others, is a nonionic starch derivative, used as a volume expander in intravenous therapy. The use of HES on critically ill patients is associated with an increased risk of ...

have not shown any advantage or decrease in mortality. When large quantities of fluids are given, administering

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

has shown some benefit. 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.

Antibiotics

Treatment guidelines call for the administration of

broad-spectrum antibiotics A broad-spectrum antibiotic is an antibiotic that acts on the two major bacterial groups, Gram-positive and Gram-negative, or any antibiotic that acts against a wide range of disease-causing bacteria. These medications are used when a bacterial i ...

within the first hour following recognition of septic shock. Prompt antimicrobial therapy is 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 the infection. Therefore, combination antimicrobial therapy, which covers a wide range of potential causative organisms, is tied to better outcomes. Antibiotics should be continued for 7–10 days in most patients, though treatment duration may be shorter or longer depending on clinical response.

Vasopressors

Among the choices for

vasopressors An antihypotensive agent, also known as a vasopressor agent or simply vasopressor, or pressor, is any substance, whether endogenous or a medication, that tends to raise low blood pressure. Some antihypotensive drugs act as vasoconstrictors to in ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

is superior to

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

in septic shock. Norepinephrine is the preferred vasopressor, while epinephrine may be added to norepinephrine when needed. Low-dose

vasopressin Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travel ...

also may be used as an addition to norepinephrine, but is not recommended as a first-line treatment.

Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

may cause rapid heart rate and

arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

s, and is only recommended in combination with norepinephrine in those with

slow heart rate Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

and low risk of arrhythmia. In the initial treatment of low blood pressure in septic shock, the goal of vasopressor treatment is a

(MAP) of 65 mm Hg. In 2017, the FDA approved

angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adre ...

injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock.

Methylene blue

Methylene blue Methylthioninium chloride, commonly called methylene blue, is a salt used as a dye and as a medication. Methylene blue is a thiazine dye. As a medication, it is mainly used to treat methemoglobinemia by converting the ferric iron in hemoglobin ...

has been found to be useful for this condition.Jang DH, Nelson LS, Hoffman RS (2013) Methylene blue for distributive shock: a potential new use of an old antidote. J Med Toxicol 9(3):242-249Baldo CF, Silva LM, Arcencio L, Albuquerque AAS, Celotto AC, Basile-Filho A, Evora PRB (2018) Why Methylene Blue have to be always present in the tocking of emergency antidotes. Curr Drug Targets 19(13):1550-1559McCartney SL, Duce L, Ghadimi K (2018) Intraoperative vasoplegia: methylene blue to the rescue! Curr Opin Anaesthesiol. 31(1):43-49Booth AT, Melmer PD, Tribble B, Mehaffey JH, Tribble C (2017) Methylene blue for vasoplegic syndrome. Heart Surg Forum 20(5):E234-E238 Although use of methylene blue has mostly been in adults it has also been shown to work in children.Rutledge C, Brown B, Benner K, Prabhakaran P, Hayes L (2015) A novel use of methylene blue in the pediatric ICU. Pediatrics 136(4):e1030-4Volpon LC, Evora PRB, Teixeira GD, Godinho M, Scarpelini S, Carmona F, Carlotti APCP (2018) Methylene blue for refractory shock in polytraumatized patient: A case report. J Emerg Med 55(4):553-558 Its mechanism of action is thought to be via the inhibition of the

nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

cyclic guanosine monophosphate Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in r ...

pathway.Da Silva PS, Furtado P (2018) Methylene blue to treat refractory latex-induced anaphylactic shock: a case report. A A Pract 10(3):57-60 This pathway is excessively activated in septic shock. Methylene blue has been found to work in cases resistant to the usual agents.Lo JC, Darracq MA, Clark RF (2014) A review of methylene blue treatment for cardiovascular collapse. J Emerg Med 46(5):670-679 This effect was first reported in the early 1990s.Schneider F, Lutun P, Hasselmann M, Stoclet JC, Tempé JD (1992) Methylene blue increases systemic vascular resistance in human septic shock. Preliminary observations. Intensive Care Med 18(5):309-11Preiser JC, Lejeune P, Roman A, Carlier E, De Backer D, Leeman M, Kahn RJ, Vincent JL (1995) Methylene blue administration in septic shock: a clinical trial. Crit Care Med 23(2):259-264

Other

While there is tentative evidence for β-Blocker therapy to help control

, evidence is not significant enough for its routine use. There is tentative evidence that steroids may be useful in improving outcomes. Tentative evidence exists that Polymyxin B-immobilized fiber column hemoperfusion may be beneficial in treatment of septic shock. Trials are ongoing and it is currently being used in Japan and Western Europe. Recombinant activated

protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIX, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintainin ...

(

drotrecogin alpha Drotrecogin alfa (activated) (Xigris, marketed by Eli Lilly and Company) is a recombinant form of human activated protein C that has anti-thrombotic, anti-inflammatory, and profibrinolytic properties. Drotrecogin alpha (activated) belongs to th ...

) in a 2011

Cochrane review Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health profes ...

was found not to decrease mortality and to increase bleeding, and thus, was not recommended for use. Drotrecogin alfa (Xigris), was withdrawn from the market in October 2011.

Epidemiology

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 U.S.

Centers for Disease Control The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...

, 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. Tertiary care centers (such as

hospice Hospice care is a type of health care that focuses on the palliation of a terminally ill patient's pain and symptoms and attending to their emotional and spiritual needs at the end of life. Hospice care prioritizes comfort and quality of life by ...

care facilities) have 2-4 times the rate of bacteremia than primary care centers, 75% of which are

hospital-acquired infections A hospital-acquired infection, also known as a nosocomial infection (from the Greek , meaning "hospital"), is an infection that is acquired in a hospital or other health care facility. To emphasize both hospital and nonhospital settings, it is ...

. 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 to

that produce

endotoxins Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer me ...

, however, with the emergence of

and the increased use of arterial and venous catheters,

are implicated approximately as commonly as

bacilli Bacilli is a taxonomic class of bacteria that includes two orders, Bacillales and Lactobacillales, which contain several well-known pathogens such as ''Bacillus anthracis'' (the cause of anthrax). ''Bacilli'' are almost exclusively gram-positi ...

. 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. 35% of septic shock cases derive from

urinary tract infections A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...

, 15% from the respiratory tract, 15% from skin catheters (such as IVs), and more than 30% of all cases are

idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent wikt:spontaneous, spontaneous origin. From Ancient Greek, Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approxi ...

in origin. 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.

References

External links

{{DEFAULTSORT:Septic Shock Medical emergencies Intensive care medicine Causes of death Sepsis