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. Tissue hypoxia-microvascular hypothesis
As a result of macro- and microvascular changes insufficient supply of oxygen occurs. Hypoxemia causes cell death and organ dysfunction. Mitochondrial DNA hypothesis
According to findings of Professor Zsolt Balogh and his team at the University of Newcastle (Australia), mitochondrial DNA is the leading cause of severe inflammation due to a massive amount of mitochondrial DNA that leaks into the bloodstream due to cell death of patients who survived major trauma.Mitochondrial DNA resembles bacterial DNA. If bacteria triggers leukocytes, mitochondrial DNA may do the same. When confronted with bacteria, white blood cells, or neutrophil granulocytes, behave like predatory spiders. They spit out a web, or net, to trap the invaders, then hit them with a deadly oxidative blast, forming neutrophil extracellular traps (NETs).This results in catastrophic immune response leading to multiple organ dysfunction syndrome. 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.
Signs and symptoms
Mild or early cases of Pagets are asymptomatic, and so most people are diagnosed with Pagets disease incidentally during medical evaluation for another problem. Approximately 35% of patients with Pagets have symptoms related to the disease when they are first diagnosed. Overall, the most common symptom is bone pain. When symptoms do occur, they may be confused with those of arthritis or other disorders, and so diagnosis may be delayed. Pagets may first be noticed as an increasing deformity of a persons bones.Pagets disease affecting the skull may cause frontal bossing, increased hat size, and headaches. Often patients may develop loss of hearing in one or both ears due to auditory foramen narrowing and resultant compression of the nerves in the inner ear. Rarely, skull involvement may lead to compression of the nerves that supply the eye, leading to vision loss. Associated conditions
Pagets disease is a frequent component of multisystem proteinopathy. Advanced Pagets disease may lead to other medical conditions, including:

Osteoarthritis may result from changes in bone shape that alter normal skeletal mechanics. For example, bowing of a femur affected by Pagets may distort overall leg alignment, subjecting the knee to abnormal mechanical forces and accelerating degenerative wear. Heart failure is a rare, reported consequence of severe Pagets disease (i.e. more than 40% skeletal involvement). The abnormal bone formation is associated with recruitment of abnormal blood vessels, forcing the cardiovascular system to work harder (pump more blood) to ensure adequate circulation. Kidney stones are somewhat more common in patients with Pagets disease.