Multiple organ dysfunction syndrome
Encyclopedia
Multiple organ dysfunction syndrome (MODS), previously known as multiple organ failure (MOF) or multisystem organ failure (MSOF), is altered organ
function in an acutely ill patient requiring medical
intervention to achieve homeostasis
. The use of "multiple organ failure" or "multisystem organ failure" should be avoided since that term was based upon physiologic parameters to determine whether or not a particular organ was failing.
or the sepsis syndrome. In more recent years, these concepts have been refined, so that there are specific definitions of sepsis, and two new concepts have also been developed: the systemic inflammatory response syndrome
(SIRS) and multiple organ dysfunction syndrome (MODS).
cannot be maintained without intervention. It usually involves two or more organ systems.
. In operative and non-operative patients sepsis
is the most common cause. Sepsis may result in septic shock
. In the absence of infection a sepsis-like disorder is termed systemic inflammatory response syndrome
(SIRS). Both SIRS and sepsis could ultimately progress to multiple organ dysfunction syndrome. However, in one-third of the patients no primary focus can be found. Multiple organ dysfunction syndrome is well established as the final stage of a continuum Systemic inflammatory response syndrome
+ infection
sepsis
severe sepsis Multiple organ dysfunction syndrome. Currently, investigators are looking into genetic targets for possible gene therapy to prevent the progression to Multiple organ dysfunction syndrome. Some authors have conjectured that the inactivation of the transcription factors NF-κB and AP-1
would be appropriate targets in preventing sepsis
and Systemic inflammatory response syndrome
. These two genes
are pro-inflammatory. However, they are essential components of a normal healthy immune response, so there is risk of increasing vulnerability to infection, which can also cause clinical deterioration.
Some have developed a mouse
model sepsis via cecal ligation
and puncture (CLP). Male Balb/c
mice subjected to CLP were given an IL-10
-carrying vector or an empty control vector. Lung
, Liver
and kidney
tissue destruction were measured by assessing myeloperoxidase
and malonialdehyde activity. These last two are endogenous oxidizing compounds produced during tissue inflammation
. The authors assessed the level neutrophil infiltration in lung and liver tissue. IL-10
protein expression was measured using immunohistochemistry. The expression of Tumor necrosis factor-alpha mRNA was measured at 3,8, and 24 hours after CLP using reverse transcription polymerase chain reaction
. Their results show significantly reduced organ damage by IL-10
gene transfer, as quantified by reduced myeloperoxidase
activity in the lung
, liver
, and kidney
. The malonialdehyde level was not affected by the transfer into the liver
. The livers of the mice infected with the adenoviral vector showed reduced neutrophil activity. The lung
and kidney
samples in mice carrying the gene showed lower expression of Tumor necrosis factor-alpha mRNA. The investigators concluded that increased IL-10
expression significantly reduced sepsis
-induced Multiple organ injury.
is common in the first 72 hours after the original insult. Following this one might see hepatic failure (5–7 days), gastrointestinal bleeding
(10–15 days), and renal failure
(11–17 days)
. Hepatic dysfunction leads to toxins escaping into the systemic circulation and activating an immune response. This results in tissue injury and organ dysfunction.
infections in MODS patients are relatively common, hence endotoxin
s have been advanced as principal mediator in this disorder. It is thought that following the initial event cytokine
s are produced and released. The pro-inflammatory mediators are: tumor necrosis factor-alpha (TNF-α), interleukin
-1, interleukin-6, thromboxane
A2, prostacyclin
, platelet activating factor, and nitric oxide
.
causes organ dysfunction and cell death.
Four clinical phases have been suggested:
has reduced infectious complications.
Human recombinant activated protein C(activated drotrecogin alfa) can reduce 28-day mortality among patients with multiple organ dysfunction syndrome according to a randomized controlled trial
. The relative risk reduction
was 21.8%. For patients at similar risk to those in this study (33.9% had 28-day mortality), this leads to an absolute risk reduction
of 7.4%. 13.5 patients must be treated
for one to benefit.
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
function in an acutely ill patient requiring medical
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
intervention to achieve homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
. The use of "multiple organ failure" or "multisystem organ failure" should be avoided since that term was based upon physiologic parameters to determine whether or not a particular organ was failing.
History
The historical origin of the concept of MODS is as follows. For many years, some patients were loosely classified as having sepsisSepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
or the sepsis syndrome. In more recent years, these concepts have been refined, so that there are specific definitions of sepsis, and two new concepts have also been developed: the systemic inflammatory response syndrome
Systemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
(SIRS) and multiple organ dysfunction syndrome (MODS).
Definition
Multiple organ dysfunction syndrome is the presence of altered organ function in acutely ill patients such that homeostasisHomeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
cannot be maintained without intervention. It usually involves two or more organ systems.
Etiology
The condition usually results from infection, injury (accident, surgery), hypoperfusion and hypermetabolism. The primary cause triggers an uncontrolled inflammatory responseInflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. In operative and non-operative patients sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
is the most common cause. Sepsis may result in septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery 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 and death...
. In the absence of infection a sepsis-like disorder is termed systemic inflammatory response syndrome
Systemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
(SIRS). Both SIRS and sepsis could ultimately progress to multiple organ dysfunction syndrome. However, in one-third of the patients no primary focus can be found. Multiple organ dysfunction syndrome is well established as the final stage of a continuum Systemic inflammatory response syndrome
Systemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
+ infection
sepsisSepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
severe sepsis Multiple organ dysfunction syndrome. Currently, investigators are looking into genetic targets for possible gene therapy to prevent the progression to Multiple organ dysfunction syndrome. Some authors have conjectured that the inactivation of the transcription factors NF-κB and AP-1AP-1
AP1 or AP-1 can refer to:* AP-1 * Autopista AP-1, a Spanish motorway* Caproni AP.1, a 1934 Italian attack aircraft monoplane* USS Henderson...
would be appropriate targets in preventing sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
and Systemic inflammatory response syndrome
Systemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
. These two genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
are pro-inflammatory. However, they are essential components of a normal healthy immune response, so there is risk of increasing vulnerability to infection, which can also cause clinical deterioration.
Some have developed a mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
model sepsis via cecal ligation
Ligature (medicine)
In surgery or medical procedure, a ligature consists of a piece of thread tied around an anatomical structure, usually a blood vessel or another hollow structure to shut it off. With a blood vessel the surgeon will clamp the vessel perpendicular to the axis of the artery or vein with a hemostat,...
and puncture (CLP). Male Balb/c
BALB/c
BALB/c is an albino, laboratory-bred strain of the House Mouse from which a number of common substrains are derived. Now over 200 generations from their origin in New York in 1920, BALB/c mice are distributed globally, and are among the most widely used inbred strains used in animal...
mice subjected to CLP were given an IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
-carrying vector or an empty control vector. Lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
, Liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
tissue destruction were measured by assessing myeloperoxidase
Myeloperoxidase
Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO gene. Myeloperoxidase is most abundantly expressed in neutrophil granulocytes . It is a lysosomal protein stored in azurophilic granules of the neutrophil...
and malonialdehyde activity. These last two are endogenous oxidizing compounds produced during tissue inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. The authors assessed the level neutrophil infiltration in lung and liver tissue. IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
protein expression was measured using immunohistochemistry. The expression of Tumor necrosis factor-alpha mRNA was measured at 3,8, and 24 hours after CLP using reverse transcription polymerase chain reaction
Reverse transcription polymerase chain reaction
Reverse transcription polymerase chain reaction is a variant of polymerase chain reaction , a laboratory technique commonly used in molecular biology to generate many copies of a DNA sequence, a process termed "amplification"...
. Their results show significantly reduced organ damage by IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
gene transfer, as quantified by reduced myeloperoxidase
Myeloperoxidase
Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO gene. Myeloperoxidase is most abundantly expressed in neutrophil granulocytes . It is a lysosomal protein stored in azurophilic granules of the neutrophil...
activity in the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
. The malonialdehyde level was not affected by the transfer into the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. The livers of the mice infected with the adenoviral vector showed reduced neutrophil activity. The lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
samples in mice carrying the gene showed lower expression of Tumor necrosis factor-alpha mRNA. The investigators concluded that increased IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
expression significantly reduced sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
-induced Multiple organ injury.
Pathophysiology
A definite explanation has not been found. Local and systemic responses are initiated by tissue damage. Respiratory failureRespiratory failure
The term respiratory failure, in medicine, is used to describe inadequate gas exchange by the respiratory system, with the result that arterial oxygen and/or carbon dioxide levels cannot be maintained within their normal ranges. A drop in blood oxygenation is known as hypoxemia; a rise in arterial...
is common in the first 72 hours after the original insult. Following this one might see hepatic failure (5–7 days), gastrointestinal bleeding
Gastrointestinal bleeding
Gastrointestinal bleeding or gastrointestinal hemorrhage describes every form of hemorrhage in the gastrointestinal tract, from the pharynx to the rectum. It has diverse causes, and a medical history, as well as physical examination, generally distinguishes between the main forms...
(10–15 days), and renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
(11–17 days)
Gut hypothesis
The most popular hypothesis by Deitch to explain MODS in critically ill patients is the gut hypothesis. Due to splanchnic hypoperfusion and the subsequent mucosal ischaemia there are structural changes and alterations in cellular function. This results in increased gut permeability, changed immune function of the gut and increased translocation of bacteriaBacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. Hepatic dysfunction leads to toxins escaping into the systemic circulation and activating an immune response. This results in tissue injury and organ dysfunction.
Endotoxin macrophage hypothesis
Gram-negativeGram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
infections in MODS patients are relatively common, hence endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
s have been advanced as principal mediator in this disorder. It is thought that following the initial event cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s are produced and released. The pro-inflammatory mediators are: tumor necrosis factor-alpha (TNF-α), interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
-1, interleukin-6, thromboxane
Thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring....
A2, prostacyclin
Prostacyclin
Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...
, platelet activating factor, and nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
.
Tissue hypoxia-microvascular hypothesis
As a result of macro- and microvascular changes insufficient supply of oxygen occurs. HypoxemiaHypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
causes organ dysfunction and cell death.
Integrated hypothesis
Since in most cases no primary cause is found, the condition could be part of a compromised homeostasis involving the previous mechanisms.Diagnosis
The European Society of Intensive Care organized a consensus meeting in 1994 to create the "Sepsis-Related Organ Failure Assessment (SOFA)" score to describe and quantitate the degree of organ dysfunction in six organ systems. Using similar physiologic variables the Multiple Organ Dysfunction Score was developed.Four clinical phases have been suggested:
- Stage 1 the patient has increased volume requirements and mild respiratory alkalosisAlkalosisAlkalosis refers to a condition reducing hydrogen ion concentration of arterial blood plasma . Generally, alkalosis is said to occur when pH of the blood exceeds 7.45. The opposite condition is acidosis .-Causes:...
which is accompanied by oliguriaOliguriaOliguria is the low output of urine, It is clinically classified as an output below 300-500ml/day. The decreased output of urine may be a sign of dehydration, renal failure, hypovolemic shock, HHNS Hyperosmolar Hyperglycemic Nonketotic Syndrome, multiple organ dysfunction syndrome, urinary...
, hyperglycemiaHyperglycemiaHyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
and increased insulinInsulinInsulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
requirements. - Stage 2 the patient is tachypneic, hypocapnicHypocapniaHypocapnia or hypocapnea also known as hypocarbia, sometimes incorrectly called acapnia, is a state of reduced carbon dioxide in the blood. Hypocapnia usually results from deep or rapid breathing, known as hyperventilation....
and hypoxemic. Moderate liver dysfunction and possible hematologic abnormalities. - Stage 3 the patient develops shock with azotemiaAzotemiaAzotemia is a medical condition characterized by abnormally high levels of nitrogen-containing compounds, such as urea, creatinine, various body waste compounds, and other nitrogen-rich compounds in the blood...
and acid-base disturbances. Significant coagulation abnormalities. - Stage 4 the patient is vasopressor dependent and oliguric or anuric. Ischemic colitisIschemic colitisIschemic colitis is a medical condition in which inflammation and injury of the large intestine result from inadequate blood supply. Although uncommon in the general population, ischemic colitis occurs with greater frequency in the elderly, and is the most common form of bowel ischemia...
and lactic acidosisLactic acidosisLactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
follow.
Management
At present there is no agent that can reverse the established organ failure. Therapy therefore is limited to supportive care, i.e. safeguarding hemodynamics, and respiration. Maintaining adequate tissue oxygenation is a principal target. Starting enteral nutrition within 36 hours of admission to an Intensive care unitIntensive Care Unit
thumb|220px|ICU roomAn intensive-care unit , critical-care unit , intensive-therapy unit/intensive-treatment unit is a specialized department in a hospital that provides intensive-care medicine...
has reduced infectious complications.
Human recombinant activated protein C(activated drotrecogin alfa) can reduce 28-day mortality among patients with multiple organ dysfunction syndrome according to a randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
. The relative risk reduction
Relative risk reduction
In epidemiology, the relative risk reduction is a measure calculated by dividing the absolute risk reduction by the control event rate.The relative risk reduction can be more useful than the absolute risk reduction in determining an appropriate treatment plan, because it accounts not only for the...
was 21.8%. For patients at similar risk to those in this study (33.9% had 28-day mortality), this leads to an absolute risk reduction
Absolute risk reduction
In epidemiology, the absolute risk reduction or risk difference is the decrease in risk of a given activity or treatment in relation to a control activity or treatment. It is the inverse of the number needed to treat....
of 7.4%. 13.5 patients must be treated
Number needed to treat
The number needed to treat is an epidemiological measure used in assessing the effectiveness of a health-care intervention, typically a treatment with medication. The NNT is the average number of patients who need to be treated to prevent one additional bad outcome...
for one to benefit.
Prognosis
Mortality varies from 30% to 100% where the chance of survival is diminished as the number of organs involved increases. Since the 1980s the mortality rate has not changed.See also
- Acute renal failureAcute renal failureAcute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...
- Acute respiratory distress syndromeAcute respiratory distress syndromeAcute respiratory distress syndrome , also known as respiratory distress syndrome or adult respiratory distress syndrome is a serious reaction to various forms of injuries to the lung....
- Heart failure
- Intensive care
- Liver failureLiver failureAcute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
- Respiratory insufficiency
- Shock
- systemic inflammatory response syndromeSystemic inflammatory response syndromeSystemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...