Multiple organ dysfunction syndrome

Multiple organ dysfunction syndrome (MODS), previously known as multiple organ failure (MOF), total organ failure (TOF) 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 phrase was based upon physiological parameters to determine whether or not a particular organ was failing.^[1]

Definition

Multiple organ dysfunction syndrome is the presence of altered organ function in acutely ill patients such that homeostasis cannot be maintained without intervention. It usually involves two or more organ systems.^[1]

Cause

The condition usually results from infection, injury (accident, surgery), hypoperfusion and hypermetabolism. The primary cause triggers an uncontrolled inflammatory response. Sepsis is the most common cause in operative and non-operative patients. 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.^[1] Multiple organ dysfunction syndrome is well established as the final stage of a continuum: SIRS + 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 SIRS.^[2] 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).^[3] 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 (TNF-α) 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 TNF-α mRNA. The investigators concluded that increased IL-10 expression significantly reduced sepsis-induced Multiple organ injury.

Pathophysiology

A definite explanation has not been found. Local and systemic responses are initiated by tissue damage. Respiratory failure is common in the first 72 hours after the original insult. Subsequently, one might see liver failure (5–7 days), gastrointestinal bleeding (10–15 days) and kidney failure (11–17 days).^[1]

Gut hypothesis

The most popular hypothesis by Deitch to explain MODS in critically ill patients is the gut hypothesis.^[4] 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 bacteria. Liver dysfunction leads to toxins escaping into the systemic circulation and activating an immune response. This results in tissue injury and organ dysfunction.^[1]

Endotoxin macrophage hypothesis

Gram-negative infections in MODS patients are relatively common, hence endotoxins have been advanced as principal mediator in this disorder. It is thought that following the initial event cytokines 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.^[1]

Tissue hypoxia-microvascular hypothesis

As a result of macro- and microvascular changes insufficient supply of oxygen occurs. Hypoxemia causes cell death and organ dysfunction .^[1]

Mitochondrial DNA hypothesis

According to findings of Professor Zsolt Balohh and his team at University of Newcastle (Australia), Mitochondrial DNA is the leading cause of severe inflammation due to massive amount of Mitochondrial DNA that leaks into the blood stream due to cell death into the blood stream of patients that survived Major trauma.

Mitochondrial DNA is very similar-looking like bacterial DNA. And if bacteria is triggering leukocytes, maybe the mitochondrial DNA does the same. When confronted with bacteria, white blood cells, or Neutrophil granulocyte, behave like predatory spiders. They spit out a web, or net, to trap the invaders, then hit them with a deadly oxidative blast. Neutrophil extracellular traps (NETs)

This result in catastrophic immune response leading to multiple organ dysfunction syndrome.^[5][6]

Integrated hypothesis

Since in most cases no primary cause is found, the condition could be part of a compromised homeostasis involving the previous mechanisms.^[1]

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.^[1]

Four clinical phases have been suggested:

• Stage 1 the patient has increased volume requirements and mild respiratory alkalosis which is accompanied by oliguria, hyperglycemia and increased insulin requirements.
• Stage 2 the patient is tachypneic, hypocapnic and hypoxemic; develops moderate liver dysfunction and possible hematologic abnormalities.
• Stage 3 the patient develops shock with azotemia and acid-base disturbances; has significant coagulation abnormalities.
• Stage 4 the patient is vasopressor dependent and oliguric or anuric; subsequently develops ischemic colitis and lactic acidosis.

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 unit has reduced infectious complications.^[1]

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.^[1] In patients with sepsis, septic shock, or multiple organ dysfunction syndrome that is due to major trauma, the rs1800625 polymorphism is a functional single nucleotide polymorphism, a part of the receptor for advanced glycation end products (RAGE) transmembrane receptor gene (of the immunoglobulin superfamily) and confers host susceptibility to sepsis and MODS in these patients.^[7]

History

The historical origin of the concept of MODS is as follows. For many years, some patients were loosely classified as having sepsis 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 been developed: the SIRS and MODS.^[1]

References

Further reading

• The ICU Book by Marino
• Cecil Textbook of Medicine
• The Oxford Textbook of Medicine
• Harrison's Principles of Internal Medicine