How does multi-organ failure develop?
Multiple organ failure is accompanied by significant metabolic disturbances.
The catabolism of muscle proteins (or "autocannibalism") is especially pronounced in the terminal stage of the disease. This is due to the disruption of the utilization of conventional energy substrates - carbohydrates and fats in patients in extremely serious condition with the formation of an irreplaceable energy deficit and the development of protein-dependent energy metabolism, which is based on the activation of proteolysis and the breakdown of structural proteins of vital organs, muscle tissue.
The substances released by activated microbial and viral toxins, macrophages, mastocytes, leukocytes (leukotrienes, lysosomal enzymes, oxygen radicals, various BAS) can themselves induce cell and tissue damage. A special place in the pathogenesis of polyorganic insufficiency is given to free radical oxidation, one of the universal mechanisms of cell damage.
The material on the leading role of immune system disorders and septic processes in multiorgan insufficiency has been accumulated. Gram-negative bacteria penetrating from the gastrointestinal tract of patients into the blood and organs are of primary importance, therefore it is suggested that the gastrointestinal tract is a kind of generator of multi-organ failure.
Features of the development of multiple organ failure
General features of patients in critical condition - infection, trauma, inflammation, tissue hypoperfusion and hypermetabolism. Summary - development of multi-organ failure.
Any trauma leads to the development of multifocal pathophysiological processes. Mediators occupy a leading place in the origin of cellular damage in organs and tissues. Their release depends on the severity of injury and shock, the activation of various mediator cascades during post-traumatic (post-operative) injuries. The degree of damage that occurs during the first 24 hours after trauma affects the outcome of multiple organ failure. Inflammatory mediators - indicators of organ damage - serve to refine this prognosis.
In the case of multiple organ failure, the main importance is:
- bacterial toxins,
- mediators of inflammation,
- damage to the endothelium,
- disturbance of homeostasis,
- damage to microcirculation.
As a result of hypoxia and reperfusion, neutrophil aggregation and adhesion occur, together with activation of the endothelium. Neutrophils use their mediators oxygen radicals, myeloperoxidase, hypochlorite, proteases. They all destroy the cell membrane in the organs and tissues and exacerbate tissue hypoxia.
In the initial phase of trauma and shock, the complement system, coagulation, fibrinolysis, kallikrein-kinin system is activated. Tissue trauma activates complement on an alternative pathway, and bacteria - according to the classical and alternative. Activated complement increases the production of pro-inflammatory cytokines [TNF, IL-1, platelet activating factor (PAF)] by macrophages. Membrane-attacking complement complex (C5b-C9) causes the production of secondary mediators of inflammation of PGE2, thromboxane and leukotrienes. The concentration of SZa and C5b-C9 on the first day after injury is higher in those patients who develop multiple organ failure. The release of free radicals, proteases, histamine, C5b-C9 complex, thrombin leads to an increase in P- and L-selectin expression and enhanced adhesion of neutrophils to the endothelium, which contributes to the further increase of tissue damage and aggravates the severity of multiple organ failure.
In the initial stage of severe trauma, a large number of cells are activated which synthesize neurotransmitters that act toxicly on tissues. The result of the action of the mediators is a systemic inflammatory reaction. In many cases, systemic inflammation leads to hypoxia and damage to organ function with the development of multiple organ failure. Hypoxia and reperfusion damage cause necrosis of enterocytes and increase the permeability of the intestinal wall. In the small and large intestine (already in the early stages of shock), there is a translocation of bacteria and their toxins from the lumen of the gut into the bloodstream. Hypoxia of the intestinal wall leads to the activation of lymphoid tissue associated with the intestine. A large number of inflammatory mediators (TNF, IL-1, IL-2, IL-4, IL-6, lysozyme, histamine, diphenesin), causing vascular insufficiency, enters the systemic bloodstream. Its main reason is considered nitrogen oxide (NO). The increase in NO production occurs with hypoxia due to the induction of NO synthase in the lungs, liver, spleen and intestines. An important place in the regulation of organ blood flow is occupied by the renin-angiotensin system. Angiotensin II is a mediator that increases the overall vascular resistance and decreases mesenteric blood flow. There is a positive correlation between the content of phospholipase A2 (PLA2), the development of ARDS and lethality. Ischemic damage to the intestinal mucosa in shock is accompanied by translocation of bacteria and increased PLA2. The intestinal mucosa contains a large amount of PLA2, which is hyperactivated by organ hypoperfusion. Under the action of PLA2, proinflammatory lipids are synthesized, lysifospholipids (precursors of PAF) and arachidonic acid (a substrate for the synthesis of eicosanoids). The result is the acceleration and enhancement of tissue damage processes.
Already in the early stages of the coagulation system involved in the pathogenesis of multiple organ failure. There is activation of external and internal formation of thrombin, which stimulates the expression of P-selectins on endothelial cells, converts fibrinogen into fibrin monomer and promotes the formation of thrombi. Fibrin deposition in the lumen of the alveoli, increased vascular permeability and transudation of plasma proteins into the interstitial space of lung tissue lead to development of ARDS. The activation of coagulation along the external pathway occurs with the participation of the tissue and VII clotting factors. The tissue factor is found in many tissues, including the brain, endothelium, macrophages, interstitial pulmonary alveoli. The deposition of fibrin, combined with inhibition of fibrinolytic activity (increase in the concentration of the inhibitor of the plasminogen activator), is considered the cause of atelectasis, violation of the ratio of ventilation (perfusion), morphological damage to the alveolar structure of the lungs. Hypercoagulation promotes the development of DIC syndrome, the deposition of fibrin in the microvascular channel reduces tissue blood flow and accelerates the development of multiple organ failure. High procoagulant activity is characteristic for patients with trauma and sepsis, which causes organ dysfunction in the chain of mediator damage, especially in the lungs, the PAF is a toxic mediator leading to the development of multiple organ failure due to increased vascular permeability.
Activation of the coagulation system and inhibition of fibrinolysis cause severe organ hypoperfusion. The negative aspects of this phenomenon are corrected with the help of activated protein C. It has an anti-inflammatory, anticoagulant and abribrinolytic effect. Activated protein C degrades Va and VIlla clotting factors, which leads to a reduction in thrombogenesis and inhibition of thrombin synthesis. As a result of inhibition of the plasminogen activator inhibitor, fibrinolysis is activated. The action of activated protein C leads to the preservation of endothelial functions due to a decrease in the interaction of leukocytes and selectins on the endothelium. The synthesis of cytokines (especially TNF) by monocytes decreases. The endothelium is protected from apoptosis. Activated protein C has an anti-inflammatory effect on neutrophils and endothelial cells.
In patients in critical condition (due to severe secondary immunodeficiency), an increased susceptibility to infection is noted. There is a correlation between the patient's severe condition and the development of generalized infectious complications. The critical state of the patient is always, for objective reasons, accompanied by a large number of infectious complications. Disturbances in the immunity system in critical conditions contribute simultaneously to the onset of infection and multiple organ failure.
At the moment, the question of inclusion in the multiorgan insufficiency of the immune system deficiency (secondary immunodeficiency) is being considered.
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