Polyorgan failure

Multiple organ failure was first described in surgical patients; it was subsequently identified as a separate syndrome (Baue A., 1975; 1980). According to V. A. Gologorsky et al. (1985), A. V. Konychev (1988), J. Zahringer et al. (1985), multiple organ failure can be considered as a breakdown of the organ adaptation response, and the nonspecific nature of the changes that arise in this case is manifested in the uniformity of disorders regardless of the etiological factor and pathological process that cause them.

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How does multiple organ failure develop?

Multiple organ failure is accompanied by significant metabolic disorders.

Muscle protein catabolism (or "autocannibalism") is especially pronounced in the terminal stage of the disease. This is due to the disruption of the utilization of normal energy substrates - carbohydrates and fats in patients in an extremely serious condition with the formation of an irreparable 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 and muscle tissue.

Substances secreted by activated microbial and viral toxins, macrophages, mastocytes, leukocytes (leukotrienes, lysosomal enzymes, oxygen radicals, various biologically active substances) are themselves capable of inducing cellular and tissue damage. A special place in the pathogenesis of multiple organ failure is given to free radical oxidation - one of the universal mechanisms of cell damage.

Material has been accumulated on the leading role of immune system disorders and septic processes in multiple organ failure, and among the causative agents of sepsis, the most important are gram-negative bacteria that penetrate from the gastrointestinal tract of patients into the blood and organs, in connection with which it has been suggested that the gastrointestinal tract is a kind of generator of multiple organ failure.

Features of the development of multiple organ failure

Common features of patients in critical condition are infection, trauma, inflammation, tissue hypoperfusion and hypermetabolism. The result is the development of multiple organ failure.

Any trauma leads to the development of multifocal pathophysiological processes. Mediators play a leading role in the origin of cellular damage in organs and tissues. Their release depends on the severity of the trauma and shock, activation of various mediator cascades during post-traumatic (post-operative) damage. The degree of damage occurring during the first day after the trauma affects the outcome of multiple organ failure. Inflammatory mediators - indicators of organ damage - serve to clarify this prognosis.

In case of multiple organ failure, the following are of primary importance:

• bacterial toxins,
• inflammatory mediators,
• endothelial damage,
• homeostasis disorders,
• damage to microcirculation.

As a result of hypoxia and reperfusion, aggregation and adhesion of neutrophils occurs, along with activation of the endothelium. Neutrophils use their mediators oxygen radicals, myeloperoxidase, hypochlorite, proteases. All of them destroy the cell membrane in organs and tissues and aggravate tissue hypoxia.

In the initial phase of trauma and shock, the complement system, coagulation, fibrinolysis, and the kallikrein-kinin system are activated. Tissue trauma activates complement via the alternative pathway, and bacteria via the classical and alternative pathways. Activated complement increases the production of proinflammatory cytokines [TNF, IL-1, platelet-activating factor (PAF)] by macrophages. The membrane-attack complex of complement (C5b-C9) causes the production of secondary inflammatory mediators PGE2, thromboxane, and leukotrienes. The concentration of C3a and C5b-C9 on the first day after trauma is higher in those patients who develop multiple organ failure. The release of free radicals, proteases, histamine, the C5b-C9 complex, and thrombin leads to an increase in the expression of P- and L-selectins and increased adhesion of neutrophils to the endothelium, which contributes to a further increase in tissue damage and aggravates the severity of multiple organ failure.

At the initial stage of severe trauma, a large number of cells are activated, which synthesize mediators that have a toxic effect on tissues. The result of the action of 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 enterocyte necrosis and increase intestinal wall permeability. In the small and large intestines (already at the early stages of shock), bacteria and their toxins are translocated from the intestinal lumen into the bloodstream. Hypoxia of the intestinal wall leads to activation of the lymphoid tissue associated with the intestine. A large number of inflammatory mediators (TNF, IL-1, IL-2, IL-4, IL-6, lysozyme, histamine, diphensins) enter the systemic bloodstream, causing vascular insufficiency. Its main cause is considered to be nitric oxide (NO). Increased NO production occurs during hypoxia due to induction of NO synthase in the lungs, liver, spleen and intestine. The renin-angiotensin system plays an important role in the regulation of organ blood flow. Angiotensin II is a mediator that increases total vascular resistance and reduces mesenteric blood flow. There is a positive correlation between the content of phospholipase A2 (PLA2), the development of ARDS and mortality. Ischemic damage to the intestinal mucosa during shock is accompanied by bacterial translocation and an increase in PLA2. The intestinal mucosa contains a large amount of PLA2, which is hyperactivated during organ hypoperfusion. Under the action of PLA2, proinflammatory lipids lysophospholipids (precursors of PAF) and arachidonic acid (a substrate for the synthesis of eicosanoids) are synthesized. The result is acceleration and intensification of tissue damage processes.

Already at the early stages, the coagulation system participates in the pathogenesis of multiple organ failure. Activation of external and internal thrombin formation occurs, which stimulates the expression of P-selectins on endothelial cells, converts fibrinogen into fibrin monomer and promotes thrombus formation from it. Fibrin deposition in the lumen of the alveoli, increased vascular permeability and transudation of plasma proteins into the interstitial space of the lung tissue lead to the development of ARDS. Activation of coagulation by the extrinsic pathway occurs with the participation of tissue and VII coagulation factor. Tissue factor is contained in many tissues, including the brain, endothelium, macrophages, and the interstitium of the pulmonary alveoli. Fibrin deposition, combined with inhibition of fibrinolytic activity (increased concentration of plasminogen activator inhibitor), is considered the cause of atelectasis, ventilation/perfusion imbalance, and morphological damage to the alveolar structure of the lungs. Hypercoagulation contributes to the development of DIC syndrome, fibrin deposition in the microvascular bed reduces tissue blood flow and accelerates the development of multiple organ failure. High procoagulant activity is typical for patients with trauma and sepsis, which causes organ dysfunction in the chain of mediator damage, especially in the lungs 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 anti-inflammatory, anticoagulant and profibrinolytic effects. Activated protein C degrades coagulation factors Va and VIlla, which reduces thrombus formation processes and inhibits thrombin synthesis. Fibrinolysis is activated as a result of suppression of the plasminogen activator inhibitor. The action of activated protein C leads to preservation of endothelial functions due to decreased interaction of leukocytes and selectins on the endothelium. Synthesis of cytokines (especially TNF) by monocytes decreases. 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), increased susceptibility to infection is noted. There is a relationship between the patient's severe condition and the development of generalized infectious complications. The patient's critical condition is always, for objective reasons, accompanied by a large number of infectious complications. Disturbances in the immune system in critical conditions contribute to the simultaneous occurrence of infection and multiple organ failure.

Currently, the issue of including immune system deficiency (secondary immunodeficiency) in the definition of multiple organ failure is being considered.

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Symptoms of multiple organ failure

Clinical symptoms of multiple organ failure and worsening prognosis of the disease are most often caused by combined disorders of the cardiovascular, respiratory systems, kidney and liver function.

There are several stages of multiple organ failure - latent, overt, decompensated and terminal. However, timely diagnosis of multiple organ failure presents significant difficulties: only with a special study or retrospective analysis it is revealed that already at an early stage of the disease, patients had latent failure of many organs. Late diagnosis of multiple organ failure is explained not only by the varying degrees of damage to individual organs and systems, but also by the insufficient sensitivity of the methods used to assess their functioning.

Does multiple organ failure syndrome develop in children with infectious diseases? It can be argued that it manifests itself in the most severe forms of diseases. In children with mild forms of infectious diseases, clinical symptoms of damage to individual organs are usually not determined. However, with the help of laboratory and instrumental tests, it is often possible to detect compensated or subcompensated multiple organ failure, which can be interpreted as a pre-stage of multiple organ failure, readiness for a total breakdown of the body's compensatory capabilities. Timely and detailed determination of the functional state of organs and systems in the pre-stage of multiple organ failure, as well as the availability of reserves for their compensation would allow choosing the optimal range of therapeutic interventions and the mode of their implementation, preventing the development of clinically obvious multiple organ failure.

As the severity of the toxic syndrome increases in children, hemodynamic disorders in the skin, kidneys, and liver progress, up to the development of their ischemia, circulatory blockade, found in patients with the most severe forms of toxicosis in the terminal stage of the disease. In parallel with hemodynamic disorders, various metabolites with toxic properties accumulate in the blood of children, which indicates a violation of the excretory function of the kidneys, liver, and gastrointestinal tract. A violation of the biochemical processes of detoxification in the liver is also indicated by the accumulation of ammonia in the blood of children with toxicosis, since the reaction of converting toxic ammonia into relatively harmless urea is one of the most stable in phylogenetic terms. The same can be said about the accumulation of free phenol in the blood, which binds to glucuronic or sulfuric acid in the liver and should be excreted in this form with urine. The accumulation of medium-weight peptides in the blood (normally 90% of them are excreted through the kidneys) is evidence of renal failure. In addition, we have established that the binding capacity of albumin, which is the main circulating sorbent of toxins in the blood, also decreases sharply in proportion to the severity of the toxic syndrome, the degree of toxemia.

Consequently, the retention of metabolites in the blood of children at the height of clinical manifestations of toxicosis is caused not only by mechanical reasons associated with the deterioration of the intake (delivery) of toxins to the organs that excrete them, but also by the disruption of the entire detoxifying complex, including the stage of preliminary biochemical transformation of metabolites and the processes of their elimination from the body. At the same time, we believe that the trigger for the development of endotoxemia in children with toxicosis is the reaction of centralization of the systemic circulation, which is the main cause of circulatory hypoxia of the organs and tissues of the child's body. Undoubtedly, a number of organs directly involved in the regulation of the adaptation syndrome described by G. Selye (1955) have a direct impact on the implementation and maintenance of hemodynamic centralization. These include, in particular, hormones of the renin-angiotensin system, adrenal glands (catecholamines, GCS, aldosterone), pituitary gland (vasopressin), as well as a number of biologically active substances involved in the regulation of blood circulation and affecting the permeability of the vascular wall: histamine, serotonin, kinins, etc., released from depot cells as a result of a stress reaction in children with severe forms of infectious diseases.

Their long presence in the circulating blood predetermines an equally long preservation of the centralization of blood circulation, and therefore, the circulatory "stealing" of the body's organs and tissues. Apparently, at an early age, the stress (essentially, protective) reaction of the body under certain circumstances (this includes the anatomical and physiological characteristics of children, and the characteristics of the infection - its virulence) turns into distress - a self-deepening pathological process, which is extremely dangerous for the child in prognostic terms.

Normally, the utilization of most hormones, biologically active substances and metabolites occurs in the liver. In infectious pathology, increased production of these substances, combined with suppression of liver function, leads to their accumulation and long-term maintenance of high concentrations in the blood. Their pathological effect in the body is enhanced due to the fact that with the development of toxic syndromes in children, inactivation of their specific inhibitors and inactivators circulating in the blood occurs.

Consequently, in the pathogenesis of multiple organ failure, which naturally develops in children with toxicosis, the main factors are infectious stress, disruption of systemic circulation with the development of ischemia of most organs and tissues of the child's body, increasing hypoxia and progressive metabolic disorder with the accumulation of metabolic products, suppression of immunity and the protective capabilities of biological barriers for microflora and its toxic substances, an increase in the concentration of all kinds of toxins in the blood, including microbes and their toxins, as well as hormones and biologically active substances. Moreover, the retention of toxic substances in the body of a sick child is caused not only by the deterioration of the ability to deliver toxins to the excretory organs, but also by a disruption of the entire detoxifying complex, including the stages of their preliminary neutralization, biochemical transformation and elimination.

The third link in the pathogenesis of multiple organ failure is apparently the formation of multiple vicious circles, the mutual aggravation of which leads to an inevitable fatal outcome. As a rule, vicious circles are based on adaptive reactions that eventually turn into pathological ones. Decompensation of the cardiovascular system, kidneys and (or) liver is also the cause of the strongest long-term stimulation of the vegetative centers of the brain and the pituitary-adrenal system. We discovered the depletion of this system when studying the pathogenesis of acute adrenal insufficiency in children with severe forms of acute intestinal infections and meningococcal infection. A relationship was found between the severity of toxic syndrome and intestinal paresis, as well as the level of toxic substances (for example, PSM, accumulating during toxicosis) and functional insufficiency of the kidneys and liver. This means that with the appearance of functional decompensation of even one organ of the detoxification and elimination system, a vicious circle of endotoxin formation and further deepening of the pathological process is formed. To a certain extent, the development of multiple organ failure resembles an avalanche, involving in its movement everything that is in its path. The same is true for a child's body: a failure in the work of one organ during a severe infectious disease affects the work of others, like an avalanche.

Treatment of multiple organ failure

Thus, multiple organ failure in children with toxicosis is a self-deepening process, a variant of a vicious circle, the trigger of which is most often acute cardiovascular and renal-hepatic failure. With the occurrence of multiple organ failure, the probability of an unfavorable outcome of the disease increases significantly. At the same time, timely diagnosis and correctly chosen treatment tactics can reduce the adverse effects of multiple organ failure and prevent the death of the patient.

Multiple organ failure in children with toxicosis requires immediate inclusion in the treatment complex of methods of functional support of life-support organs (artificial ventilation, pacemaker, cardiotonic drugs and vasopressors), extracorporeal elimination of toxic substances (plasmapheresis, dialysis, hemofiltration, hemosorption, etc.) until the functions of the body's own detoxification and elimination organs are restored, which will allow the body to independently maintain homeostasis.