Systemic reactions in inflammation. "Systemic Inflammatory Response Syndrome"

SSVO - systemic reaction body for various severe tissue damage.

Initiating factor that triggers the release of neurotransmitters systemic inflammation, can be very different in origin - it is an infection, trauma, ischemia, blood loss, burns. The above effects transfer polymorphonuclear nuclei (neutrophils, basophils, granulocytes) and endotheliocytes into a state of "oxygen explosion", the result of this transformation is a powerful chaotic release by these cells into the bloodstream huge amount substances that have multidirectional effects and are PON mediators.

Currently, about 200 such mediators are known. The main ones are: cytokines, eicosanoids, nitric oxide (NO, interferons, platelet activating factor, fibronectin, oxygen radicals.

The cumulative effects of damage mediators form a generalized systemic inflammatory response or systemic inflammatory response syndrome– SIRS ( SSVO).

Stages of SIRS development (Table 9)

STAGE 1: Local production of cytokines in response to injury or infection. Cytokines are able to carry out a number of protective functions, participating in the processes of wound healing and protection of body cells from pathogenic microorganisms.

STAGE 2. Release of a small amount of cytokines into the systemic circulation. Even small amounts of mediators can activate macrophages, platelets, and growth hormone production. The developing acute phase reaction is controlled by pro-inflammatory mediators and their endogenous antagonists, such as interleukin-1, 10, 13 antagonists; tumor necrosis factor. Due to the balance between cytokines, mediator receptor antagonists and antibodies in normal conditions prerequisites are created for wound healing, destruction of pathogenic microorganisms, maintenance of homeostasis.

STAGE 3. Generalization inflammatory response . In the event that the regulatory systems are unable to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to impaired permeability and function of the capillary endothelium, the formation of distant foci of systemic inflammation, and the development of mono- and multiple organ dysfunction.

A number of studies have confirmed that the basis of the pathogenesis of PON is precisely a disseminated inflammatory reaction, accompanied by activation and release a large number biologically active compounds.

Syndrome of multiple organ failure
(MON) definition. Etiology. Pathogenesis

PON is commonly understood as a severe nonspecific stress reaction of the body, insufficiency of two or more functional systems, universal damage to all organs and tissues of the body by aggressive mediators of a critical state with a temporary predominance of symptoms of one or another organ failure - pulmonary, cardiac, renal, etc. it is necessary to state the inability of the body to function in the interests of maintaining vital important functions in general and the preservation of its structure in particular. The direct factors that determine the severity of multiple organ dysfunction are the different ability of organs to withstand hypoxia and reduce blood flow, the nature of the shock factor and the initial functional state the organ itself. According to the etiology, PON is divided into two main types:

1 PON, which has arisen in connection with the aggravation of any pathology, when one or more vital functions damaged to such an extent that artificial replacement is required.

2 Iatrogenic PON.

There are three main phases in the development of PON syndrome.

phases in the development of mon (Table 10)

Induction phase, the result of which is the synthesis of a whole series humoral factors triggering the systemic inflammatory response.

Cascade phase, accompanied by the development of acute pulmonary injury, activation of the cascades of the kallikrein-kinin system, the system arachidonic acid, blood coagulation system and others.

The phase of secondary auto-aggression, extremely pronounced organ dysfunction and stable hypermetabolism, in which the patient's body loses the ability to self-regulate homeostasis.

PON syndrome should be considered as the most severe degree SIRS is a generalized inflammation that causes damage to organ function.

In the light contemporary ideas about the systemic inflammatory response, the main pathways for the development of PON are distinguished.

the main ways of development of pon (Table 11)

Primary PON is a direct result of exposure to a certain damaging factor of any etiology. At the same time, signs of organ dysfunction appear early. An example of this type of PON can be multiple organ dysfunction in polytrauma, severe burns.

Secondary PON develops after the latent phase and is the result of a generalized systemic response of the organism to a damaging factor.

The septic variant of MOF can be considered as a classic secondary organ failure, a manifestation of an extremely severe systemic response to infectious invasion.

A fundamentally important prognostic sign is a timely assessment of the number of systemic dysfunctions. Thus, in case of insufficiency in one system, lethality is 25-40%, in two - 55-60%, in three - 75-98%, and with the development of dysfunction of four or more systems, lethality approaches 100%.

sequence of system involvement in pon (Table 12)

In most cases, in general view the sequence of systems involvement in PON looks like the following. way:

syndrome respiratory disorders → encephalopathy → renal dysfunction syndrome → hepatic dysfunction syndrome → stress ulcers gastrointestinal tract

Research recent years proved that the intestine plays a central role in the pathogenesis of the development of multiple organ failure in critical conditions. The intestine is not just an organ responsible for providing the body with essential nutrients. To maintain the integrity of the intestinal mucosa, it is necessary to have nutrients. The intestine performs endocrine, immune, metabolic and mechanical barrier functions. Many factors are involved in maintaining the integrity and regeneration of the mucosal layer of the gastrointestinal tract. These are gastrointestinal peptides, enteroglucagon, thyroxine, fatty acid, growth hormone, Peyer's patches, lymphocytes, macrophages, immunoglobulin A in the bile secretion. The intestinal wall is richly executed lymphoid tissue, which interacts with the bacterial flora of the intestine and nutritional factors; Normally, bacteria and toxins from the intestinal lumen in a small amount penetrate through the portal vein system into the liver, where they are cleared by Kupffer and reticuloendothelial cells.

The intestinal mucosa is constantly renewing, has a high degree of metabolic activity and is thus more vulnerable to ischemia and atrophy. If epitheliocytes are deprived of a nominal influx of nutrients, then there is a decrease in the activity of reproduction and cell migration, as well as DNA synthesis and intestinal barrier function.

For the first time, J. Meakins and J. Marshall in 1986 put forward the hypothesis of the development of PON as a result of changes in the permeability of the intestinal mucosa, which led to the translocation of bacteria and toxins into the circulation system. Also, these authors introduced two very figurative and common expressions: “Intestine is the engine of PON” (1986) and “Intestine is an undrained abscess of multiple organ failure” (1993).

It has been proven that hypoxic damage to the mucosa of the gastrointestinal tract leads to the movement of endotoxins and bacteria into the mesenteric The lymph nodes and then in blood vessels. Translocation of endotoxin can severely damage physiological processes which is manifested by the development of a septic condition. In the most severe form, this manifests itself in the form of PON syndrome.

In addition to bacteria and endotoxins, gut injury can lead to neutrophil activation and the release of powerful systemic inflammatory mediators—cytokines, eicosanoids, and others. This exacerbates organ perfusion disorders and dysfunction.

Since 1950, since the creation of the first enteral diet by D. Baron, studies have been conducted on the possibilities of early enteral nutrition as a factor that reduces the severity of the stress reaction and protects the intestinal mucosa in critical conditions. The development in the 70-80s of a new generation of enteral mixtures, consisting of di- and trimeric molecules of lipids, carbohydrates and proteins, gave impetus to multicenter trials to evaluate the effectiveness of nutrition with various diets.

PON treatment (Table 13)

It is customary to distinguish three pathogenetically determined areas of treatment:

First by significance and time direction - elimination of the trigger factor or a disease that triggered and maintains an aggressive effect on the patient's body (purulent destruction, severe hypovolemia, pulmonary hypoxia, highly invasive infection, etc.). With unresolved etiological factor any, the most intensive treatment of PON, to no avail.

Second direction - correction of oxygen flow disorders, including the restoration of the oxygen transport function of the blood, the therapy of hypovolemia and hemoconcentration, the relief of hemorheological disorders.

Third direction - substitution, at least temporarily functions of the damaged organ or systems using medical and extracorporeal methods.

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In accordance with the decisions of the international conciliation conference of pulmonologists and intensive care specialists in 1991, the key concepts characterizing the body's response to any infectious inflammation ( infected wound, burn, perforation hollow organ abdominal cavity, inflammation appendix, pneumonia, endocarditis, etc.) characterizes systemic inflammatory response syndrome - SIRS (SIRS) (Bone R.C. et al., 1992). The systemic inflammatory response (reaction) is due to the release and uncontrolled spread of cytokines and pro-inflammatory mediators from the primary focus infectious inflammation into surrounding tissues and then into the bloodstream. Under their influence, with the participation of activators and macrophages, similar endogenous substances are formed and released in the tissues of other organs. Inflammatory mediators can be histamine, tumor necrosis factor, platelet activating factor, cell adhesion molecules, complement components, nitric oxide, toxic oxygen metabolites, lipid peroxidation products, etc.

Pathogenesis of SIRS

With inability immune system to extinguish the generalization of the spread of pro-inflammatory factors and the increase in their concentration in the blood, microcirculation is disturbed, the permeability of endothelial capillaries increases, the migration of toxic substances through the interendotheal "gaps" into the tissues of organs, the formation of distant foci of systemic inflammation, the development functional insufficiency organs and systems of the body. end result This multifactorial and multistage pathophysiological mechanism is the development of DIC, immune paralysis, multiple organ failure.

However, in the course of research it was found that the systemic inflammatory response syndrome occurs not only with the introduction of an infection, but also in response to trauma, stress, somatic diseases, drug allergy, tissue ischemia, etc., i.e. is the body's general response to pathological process. That's why talk about sepsis only when the systemic inflammatory response syndrome develops when infectious agents enter the pathological focus and with the development of dysfunctions of organs and systems, i.e. there are at least two signs: infectious focus , which determines the nature of the pathological process and USSR(criterion for the penetration of inflammatory mediators into the systemic circulation).

Accession signs of organ system dysfunction(a criterion for the spread of an infectious-inflammatory reaction beyond the primary focus) indicates severe forms sepsis (Table 2). It should be borne in mind that bacteremia may be transient and not result in generalization of the infection. But if it has become a trigger mechanism for SSVR and organ-system dysfunction, in this case we will talk about sepsis.

SIRS classification

SSVO	The diagnosis of SIRS is made when two or more of the following clinical signs are present: temperature > 38 °C or< 36 °С ЧСС>90 bpm respiratory rate >20/min or P CO2<32 кПа/мл (для больных, находящихся на ИВЛ) leukocytosis > 12×10 9 /l or leukopenia< 4х 10 9 /л >10% of young forms of leukocytes
Sepsis	A condition in which there are at least two signs of SIRS in the presence of an infectious focus, confirmed by the isolation of the pathogen from the blood
severe sepsis	Sepsis, accompanied by the appearance of multiple organ failure, perfusion disorders (including lactic acidosis, oliguria, acute disorder mental status) and development arterial hypotension, corrected by the use of intensive care methods
Septic shock	Severe sepsis, accompanied by persistent hypotension and perfusion disorders that cannot be corrected by adequate infusion, inotropic and vasopressor therapy. Sepsis/SIRS-induced hypotension refers to SBP<90 ммрт. ст. либо снижение САД более чем на40 ммрт. ст. от исходных показателей в отсутствии других причин гипотензии. Пациенты, получающие инотропные или вазопрессорные препараты, могут не иметь гипотензии, тем не менее, сохраняются признаки гипоперфузионных нарушений и дисфункции органов, которые относятся к проявлениям septic shock
Syndrome of multiple organ failure	Dysfunction of two or more vital organs in patients with severe SIRS who cannot maintain homeostasis without specific intensive care measures

The concept of two-phase flow of SSWO. The systemic inflammatory response is based on the launch of the cytokine cascade, which includes, on the one hand, pro-inflammatory cytokines, and, on the other hand, anti-inflammatory mediators. The balance between these two antagonistic groups largely determines the nature of the course and the outcome of the process.

There are five stages in the development of SIRS:

1) initial (induction) stage - represented by a local inflammatory response to the impact of a damaging factor;

2) cascade (mediator) stage - characterized by excessive production of inflammatory mediators and their release into the systemic circulation;

3) the stage of secondary autoaggression, which is characterized by the development of the clinical picture of SIRS, the formation of early signs of organ dysfunction;

4) the stage of immunological paralysis - the stage of deep immunosuppression and late organ disorders;

5) terminal stage.

The centuries-old study of sepsis has ended in recent decades with the understanding that this pathological process is based on the body's universal response to damage - a systemic inflammatory response. In other words, sepsis is a manifestation of a systemic inflammatory response in response to microbial aggression. However, sepsis is accompanied by more than just hyperproduction of pro- and anti-inflammatory mediators and activation of other regulatory systems, from apoptosis and coagulation to hormone release. In sepsis, a dysregulation of the systemic inflammatory response occurs, which made it possible to figuratively designate it as “malignant intravascular inflammation” or “mediator chaos”. This reaction can become autonomous, uncontrolled and independent of the action of the initiating factor. Coordination of efforts in the study of sepsis allowed to unify its diagnosis. Sepsis is evidenced by clinical signs of a systemic inflammatory response in the presence of a focus of infection. The clinical signs of a systemic inflammatory response are simple. These include: body temperature (core) more than 38°C or less than 36°C, tachycardia more than 90 beats per minute, tachypnea more than 20 beats per minute or PaCO2 less than 32 mm Hg. Art., leukocytosis more than 12,000/mm3 or leukopenia less than 4,000/mm3 or more than 10% of immature forms of white blood cells. However, these symptoms in sepsis are based on deep "behind the scenes" processes - the release of cytokines and other mediators, hyperdynamic shifts in blood circulation, endothelial damage, impaired capillary membrane permeability and lung function. The diagnostic information content of these signs is very high, and in the presence of a focus of infection, these symptoms should be alarming, since sepsis is a staged process that quickly leads to the development of multiple organ failure and profound hemodynamic and oxygen transport disorders in the form of septic shock. Local inflammation, sepsis, severe sepsis and multiple organ failure are links in the same chain in the body's response to inflammation due to microbial infection. (Saveliev V.S. (ed.) 80 lectures on surgery, 2008).

Concept of systemic inflammatory response and sepsis

August 2006 marked the 15th anniversary of the Sepsis Consensus Conference, which proposed the standardization of terminology relating to systemic inflammatory response syndrome (SIRS) and sepsis. Fifteen years of experience have shown that the concept of a systemic inflammatory response has not only clinical but also general biological significance.

Signs of SIRS appear to be sensitive criteria for identifying a population at risk of infectious complications and serve as the basis for a leading principle in the diagnosis of sepsis and other critical conditions. With an adequate clinical interpretation, the symptoms of SIRS have significant differential diagnostic value. The frequency of detection of signs of SIRS in intensive care units is very high - up to 75%. Only in 25-50% of patients with signs of SIRS, its infectious etiology is confirmed. At the same time, the probability of its infectious cause clearly correlates with the number of detected signs.

Given the new amount of knowledge about systemic inflammation of an infectious nature, the need to develop the PIR0 concept was recognized, which characterizes the predisposition to infection (P), describes the features of the etiology and localization of the primary focus (I), the systemic reaction of the body (R) and the presence of organ dysfunction (0) .

In recent years, there have been certain changes in the microbiological structure of sepsis. If 15-20 years ago, gram-negative bacteria and Staphylococcus aureus dominated in the etiology of surgical sepsis, now the role of saprophytic staphylococci, enterococci and fungi has significantly increased. To date, in most large multidisciplinary medical centers, the frequency of gram-positive (Gr+) and gram-negative (Gr-) sepsis has been approximately equal. This happened as a result of the increasing role in the pathology of such gram-positive bacteria as Streptococcus spp., Staphylococcus and Enterococcus spp. The frequency of isolation of microbes, the names of which were previously generally unknown to clinicians, has increased. The reason for this is the selection of resistant microbes under the influence of antibiotics, the widespread use of invasive diagnostic and treatment methods, and the influence of various factors that cause immunosuppression. ( Saveliev V.S. (ed.) 80 lectures on surgery, 2008, Datsenko B.M., Shapoval S.D., Kirilov A.V. Criteria for the diagnosis and prognosis of surgical sepsis Med journal. - 2005)

Among surgical diseases, a significant place is occupied by acute inflammatory diseases of the abdominal and thoracic cavities, soft tissues of the body. Achievements in molecular biology have provided a basis for revising previous ideas about the essence of inflammation and the regulation of the immune response to it. It has been established that intercellular relationships are a universal mechanism that determines the physiological and pathological processes in the body.

The main role in the regulation of intercellular relationships is played by a group of protein molecules called the cytokine system. In this regard, we considered it appropriate before presenting particular issues of inflammatory diseases to give brief information about modern ideas about the essence of inflammation and the regulation of the immune response to it.

The body's response to inflammation, regardless of the location of the inflammatory process, develops in accordance with the general patterns inherent in any acute inflammation. The inflammatory process and the response to it develop with the participation of numerous inflammatory mediators, including the cytokine system, according to the same patterns, both during the introduction of an infection and under the influence of trauma, foci of tissue necrosis, burns and some other factors.

Clinical manifestations of acute inflammatory diseases, along with symptoms common to inflammation, have specific symptoms due to damage to one or another organ, its localization: for example, in acute appendicitis and acute cholecystitis, common symptoms characteristic of inflammation are pain, fever, leukocytosis, increased pulse rate. During the physical examination, symptoms specific to each disease are revealed, allowing to differentiate one disease from another. The body's response to inflammation the functions of the vital systems of the body are not disturbed, called local.

With phlegmon or gangrene of the affected organ, the symptoms characteristic of inflammation become more pronounced, usually begin to appear signs of impaired function of vital body systems in the form of significant tachycardia, tachypnea, hyperthermia, high leukocytosis. The response to severe inflammation becomes systemic and proceeds as a serious general illness inflammatory nature, involving in the response almost all body systems. This type of reaction, at the suggestion of the conciliation commission of American surgeons (1992), is called syndrome of the body's systemic response to inflammation (Sys temic Inflammatory Response Syndrome - SIRS).

Inflammation is an adaptive reaction of the body aimed at destroying the agent that caused the inflammatory process and restoring damaged tissue.

The inflammatory process, developing with the obligatory participation of inflammatory mediators, may be accompanied by a predominantly local reaction with typical local manifestations of the disease and a moderate, subtle general reaction of the organs and systems of the body. The local reaction protects the body, frees it from pathogenic factors, delimits "foreign" from "own", which contributes to recovery.

mediators of inflammation. IN this group includes many active chemical compounds: 1) cytokines (pro-inflammatory and anti-inflammatory); 2) interferons; 3) eicosanoids; 4) active oxygen radicals; 5) blood plasma complement; 6) biologically active substances and stress hormones (histamine, serotonin, catecholamine, cortisol, vasopressin, prostaglandins, growth hormone); 7) platelet activating factor; 8) nitrogen monoxide (N0), etc.

Inflammation and immunity function in close interaction, they cleanse the internal environment of the body both from foreign elements and from damaged, altered tissues with their subsequent rejection. And elimination of the consequences of damage. Normally functioning control mechanisms of the immune system prevent the uncontrolled release of cytokines and other mediators of inflammation, provide an adequate local response to the process (see diagram).

Local reaction of the body to inflammation. The penetration of infection and the impact of other damaging factors cause complement activation, which in turn promotes the synthesis of C-reactive proteins (C-3, C-5), stimulates the production of platelet activating factor, the formation of opsonins involved in the process of phagocytosis and chemotaxis. The main task of the inflammatory phagocytic reaction is to remove microorganisms and limit inflammation. During this period, transient bacteremia may appear. Microorganisms that have penetrated into the blood are destroyed by neutrophilic leukocytes, macrophages, freely circulating in the blood, and Kupffer cells, which act as macrophages. The most important role in the removal of microorganisms and other foreign substances, as well as in the production of cytokines and various inflammatory mediators, belongs to activated macrophages, both freely circulating in the blood and resident, fixed in the liver, spleen, lungs, and other organs. It should be emphasized that Kupffer cells, which are resident macrophages, make up more than 70% of all macrophages in the body. They play the main role in the removal of microorganisms in the event of the appearance of transient or persistent bacteremia, degradation products of proteins, xenogeneic substances, neutralization of endotoxins.

Simultaneously with the activation of complement, activation of neutrophils and macrophages occurs. Neutrophils are the first phagocytic cells that appear in the focus of inflammation, they release active oxygen radicals, which lead to damage and at the same time to the activation of endothelial cells. Neutrophils begin to secrete pro-inflammatory and anti-inflammatory interleukins (IL) related to the cytokine system. At the same time, anti-inflammatory drugs are able to weaken the action of pro-inflammatory interleukins. Thanks to this, their balance and a decrease in the severity of inflammation are achieved.

macrophage activation. Macrophages appear in the lesion within 24 hours from the onset of the inflammatory response. Activated macrophages carry out the transcription of antigens (bacteria, endotoxins, etc.). Through this mechanism, they present antigens to lymphocytes, promote their activation and proliferation. Activated T-lymphocytes acquire significantly greater cytotoxic and cytolytic properties, sharply increase the production of cytokines. B-lymphocytes begin to produce specific antibodies. In connection with the activation of lymphocytes, the production of cytokines and other mediators of inflammation increases sharply, hypercytokinemia occurs. Inclusion of activated macrophages in developing inflammation is the line between local and systemic response to inflammation.

The interaction of macrophages with T-lymphocytes and "natural killer" cells, mediated by cytokines, provides the necessary conditions for the destruction of bacteria and the neutralization of endotoxins, the localization of inflammation, and the prevention of infection generalization. An important role in protecting the body from infection is played by natural (natural) killer cells (Natural Killer - NK cells). They originate from the bone marrow and are a subpopulation of large granular lymphocytes that, unlike killer T-cells, are capable of lysing bacteria and target cells without prior sensitization. These cells, like macrophages, remove particles and microorganisms alien to the body from the blood, provide adequate production of inflammatory mediators and local protection against infection, maintain a balance between pro-inflammatory and anti-inflammatory inflammatory mediators. Thus, they prevent disruption of microcirculation and damage to parenchymal organs by an excessive amount of produced cytokines, localize inflammation, prevent the development of a severe general (systemic) reaction of vital organs in response to inflammation, and prevent the development of dysfunction of parenchymal organs.

Of great importance for the regulation of acute inflammation through tumor necrosis factor are protein molecules known as nuclear factor kappa B (Nuclear factor k-kappa B), which play an important role in the development of systemic inflammation response syndrome and multiple organ dysfunction syndrome. For therapeutic purposes, it is possible to limit the activation of this factor, which will lead to a decrease in the production of inflammatory mediators and may have a beneficial effect in reducing tissue damage by inflammatory mediators and reducing the risk of developing organ dysfunction.

The role of endothelial cells in the development of inflammation. Endothelial cells are a link between the cells of parenchymal organs and platelets, macrophages, neutrophils, cytokines and their soluble receptors circulating in the bloodstream, therefore the endothelium of the microvasculature reacts subtly both to changes in the concentration of inflammatory mediators in the blood and to their content outside the vascular bed.

In response to injury, endothelial cells produce nitric monoxide (NO), endothelium, platelet activating factor, cytokines, and other mediators. Endothelial cells are at the center of all reactions that develop during inflammation. It is these cells, after being stimulated by their cytokines, that acquire the ability to "direct" leukocytes to the site of injury.

Activated leukocytes located in the vascular bed make rotational movements along the surface of the endothelium of the microvasculature; there is a marginal standing of leukocytes. Adhesive molecules are formed on the surface of leukocytes, platelets and endothelial cells. Blood cells begin to adhere to the walls of the venules, their movement stops. In the capillaries, microthrombi are formed, consisting of platelets, neutrophils and fibrin. As a result, first, in the area of the focus of inflammation, blood circulation in the microcirculatory bed is disturbed, capillary permeability increases sharply, edema appears, leukocyte migration outside the capillaries is facilitated, and typical signs of local inflammation appear.

In severe aggression, hyperactivation of cells producing cytokines and other inflammatory mediators occurs. The amount of cytokines and nitric monoxide increases not only in the focus of inflammation, but also outside it in the circulating blood. Due to the excess of cytokines and other mediators in the blood, the microcirculatory system of organs and tissues outside the primary focus of inflammation is damaged to some extent. Violated the function of vital systems and organs, the syndrome begins to develop systemic response to inflammation (SIRS).

At the same time, against the background of pronounced local signs of inflammation, there is a violation of the function of the respiratory and cardiovascular systems, kidneys, liver, and inflammation proceeds as a severe general disease involving all functional systems of the body.

Cytokines are relatively large protein molecules with a molecular weight of 10,000 to 45,000 daltons. In terms of chemical structure, they are close to each other, but they have different functional properties. They provide interaction between cells that are actively involved in the development of local and systemic responses to inflammation by enhancing or inhibiting the ability of cells to produce cytokines and other inflammatory mediators.

Cytokines can affect target cells - endocrine, paracrine, autocrine and intercrine action. The endocrine factor is secreted by the cell and affects the target cell located at a considerable distance from it. It is delivered to the target cell by the blood stream. The paracrine factor is secreted by the cell and affects only nearby cells. An autocrine factor is secreted by a cell and affects the same cell. The intercrine factor acts inside the cell without leaving it. Many authors consider these relationships as "microendocrine system".

Cytokines are produced by neutrophils, lymphocytes, endothelial cells, fibroblasts, and other cells.

Cytokine system includes 5 broad classes of compounds, grouped according to their dominant effect on other cells.

1. Cytokines produced by leukocytes and lymphocytes are called interleukins (IL, IL), because, on the one hand, they are produced by leukocytes, on the other hand, leukocytes are target cells for IL and other cytokines.

Interleukins are subdivided into inflammatory(IL-1,6,8,12); anti-inflammatory (IL-4,10,11,13, etc.).

Tumor necrosis factor [TNF].

Factors of growth and differentiation of lymphocytes.

Factors stimulating the growth of macrophage and granulocyte populations.

5. Factors causing the growth of mesenchymal cells. Most cytokines belong to IL (see table).

Table

	Place of synthesis	target cells
GM-CSF (identical in effect to IL-3) Interferons-al-fa, beta, gamma	fibroblasts, monocytes Endothelium, fibroblasts, Bone marrow, T-lymphocytes Epithelial cells, fibroblasts, lymphocytes, macrophages, neutrophils Endothelial cells, keratin cells, lymphocytes, macrophages	Predecessor of CFU-G Cell precursors of granulocytes, erythrocytes, monocytes CFU-GEMM, MEG, GM Lymphocytes, macrophages, infected and cancerous cells Monocytes, macrophages, T and B cells	Supports neutrophil production Supports the proliferation of macrophages, neutrophils, eosinophils and colonies containing monocytes, supports long-term bone marrow stimulation Inhibits the proliferation of viruses. Activates defective phagocytes, inhibits the reproduction of cancer cells, activates T-killers, inhibits the synthesis of collagenase Stimulates T-, B-, NK- and LAK-cells. Induces the activity and production of cytokines that can destroy the tumor, stimulates the production of endogenous pyrogen (through the release of prostaglandin PGE 2). Induces the release of steroids, proteins of the early phase of inflammation, hypotension, neutrophil chemotaxis. Stimulates respiratory burst
	Monocytes	Blocks IL-1 receptors on T cells fibroblasts, chondrocytes, endothelial cells	Blocks IL-1 type receptors on T-cells, fibroblasts, chondrocytes, endothelial cells. Improves experimental model of septic shock, arthritis and intestinal inflammation
	Lymphocytes	T, NK, B-activated monocytes	Stimulates the growth of T-, B- and NK-cells
	T-, N K-cells	All hematopoietic cells and many others, express receptors	Stimulates the growth of T- and B-cells, the production of HLA-class 11 molecules
	Cells endo- telium, fibro- blasts, lim- phocytes, some tumors	T-, B- and plasma cells, keratinocytes, hepatocytes, stem cells	Differentiation of B cells, stimulation of growth of T cells and hematopoietic stem cells. Stimulates the production of proteins of the early phase of inflammation, the growth of keratinocytes
	Cells endo- telium, fibro- blasts, lim- phocytes, mono-	basophils, neutrophils,	Causes the expression of LECAM-1 receptors by endothelial cells, beta-2-integrins and transmigration of neutrophils. Stimulates respiratory burst
	Cells endo- telium, fibro- blasts, mono-	Monocyte precursor CFU-M Monocytes	Supports the proliferation of monocytoforming colonies. Activates macrophages
	Monocytes. Some tumors secrete similar peptides Macrophages	Non-activated monocytes	Only specific monocyte chemoattractants are known
	NK-, T-cell- ki, B cells	Endothelial cells, monocytes, neutrophils	Stimulates the growth of T-lymphocytes. Directs cytokine to certain tumor cells. A pronounced pro-inflammatory effect by stimulating IL-1 and prostaglandin E-2. When administered to experimental animals, it causes numerous symptoms of sepsis. Stimulates respiratory burst and phagocytosis

List of term abbreviations in the table

English		English
	colony forming unit		Monocyte chemotaxis and activating factor
	Granulocyte colony stimulating factor		macrophage colony stimulating factor
	Granulocyte-macrophage colony-stimulating factor		monocytic chemotaxis peptide- 1
	Interferon		natural killer
	Interleukin
	receptor antagonist Torah IL-1		Transform- growth factor beta
	Lipopolysaccharides		Transform- growth factor alpha
	lymphotoxin

Normally, cytokine production is negligible and is designed to maintain interaction between cells producing cytokines and cells releasing other inflammatory mediators. But it increases dramatically during inflammation due to the activation of the cells that produce them.

In the initial stage of the development of inflammation, pro-inflammatory and anti-inflammatory interleukins are simultaneously released. The damaging effect of pro-inflammatory interleukins is largely neutralized by anti-inflammatory ones, and balance is maintained in their production. Anti-inflammatory cytokines have a beneficial effect, they help limit inflammation, reduce the overall response to inflammation, and heal the wound.

Most reactions during the development of inflammation are mediated by cytokines. For example, IL-1 activates T- and B-lymphocytes, stimulates the formation of C-reactive proteins of the early phase of inflammation, the production of pro-inflammatory mediators (IL-6, IL-8, TNF) and platelet activating factor. It increases the procoagulant activity of the endothelium and the activity of adhesive molecules on the surface of endothelial cells, leukocytes and platelets, causes the formation of microthrombi in the vessels of the microvasculature, and causes an increase in body temperature.

IL-2 stimulates T- and B-lymphocytes, growth of NK-cells, production of TNF and interferon, increases the proliferation and cytotoxic properties of T-lymphocytes.

TNF has the strongest pro-inflammatory effect: it stimulates the secretion of pro-inflammatory interleukins (IL-1, IL-6), the release of prostaglandins, enhances the activation of neutrophils, eosinophils, monocytes; activates complement and coagulation, increases the molecular adhesion of the endothelium of leukocytes and platelets, resulting in the formation of microthrombi in the vessels of the microvasculature. At the same time, the permeability of the vascular wall increases, the blood supply to vital organs is disturbed, in which foci of ischemia occur, which is manifested by various signs of dysfunction of internal organs.

Excessive production of cytokines and other mediators of inflammation causes a violation of the regulatory function of the immune system, leads to their uncontrolled release, imbalance between pro-inflammatory and anti-inflammatory cytokines in favor of pro-inflammatory ones. In this regard, mediators of inflammation from the factors that protect the body become damaging.

Nitrogen monoxide (N0) - potentially toxic gas. It is synthesized from a-arginine and predominantly acts as an inhibitory neurotransmitter. Nitric oxide is synthesized not only by leukocytes, but also by the vascular endothelium.

The small size of this particle, the absence of an electric charge and lipophilicity allow it to easily penetrate cell membranes, take part in many reactions, and change the properties of some protein molecules. NO is the most active of the inflammatory mediators.

The optimal level of NO in the blood is necessary to maintain normal venous tone and permeability of the vascular wall. in the microcirculation. NO protects the vascular endothelium (including the liver) from the damaging effects of endotoxins and tumor necrosis factor.

Nitric oxide inhibits excessive activation of macrophages, thereby helping to limit the synthesis of excess cytokines. This weakens the degree of violation of the regulatory role of the immune system in the production of cytokines, helps to maintain a balance between pro-inflammatory and anti-inflammatory cytokines, limits the ability of inflammatory mediators to cause dysfunction of parenchymal organs and the development of a systemic response to inflammation syndrome.

Nitrogen monoxide relaxes muscle cells in the walls of blood vessels, is involved in the regulation of vascular tone, relaxation of sphincters and permeability of the vascular wall.

Excessive production of NO under the influence of cytokines contributes to a decrease in venous tone, impaired tissue perfusion, the occurrence of ischemia foci in various organs, which favors further activation of cells that produce cytokines and other inflammatory mediators. This increases the severity of the dysfunction of the immune system, impairs its ability to regulate the production of inflammatory mediators, leads to an increase in their content in the blood, progression of the systemic reaction to inflammation syndrome, a decrease in venous tone, a decrease in peripheral vascular resistance, the development of hypotension, blood deposition, and the development of edema. , the occurrence of multiple organ dysfunction, often ending in irreversible multiple organ failure.

Thus, the action of NO can be both damaging and protective in relation to tissues and organs.

Clinical manifestationssystemic reaction syndrome for inflammation include signs characteristic of it: 1) an increase in body temperature above 38 ° C or a decrease below 36 ° C with anergy; 2) tachycardia - an increase in the number of heartbeats over 90 in 1 min; 3) tachypnea - an increase in respiratory rate over 20 in 1 min or a decrease in PaCO 2 less than 32 mm Hg; 4) leukocytosis over 12 10 3 in 1 mm 3, or a decrease in the number of leukocytes below 4 10 3 in 1 mm 3, or a stab shift of more than 10%

The severity of the syndrome is determined by the number of signs of organ dysfunction in a given patient. In the presence of two of the four signs described above, the syndrome is assessed as moderate (mild) severity, with three signs - as moderate, with four - as severe. When three and four signs of the systemic response syndrome to inflammation are identified, the risk of disease progression, the development of multiple organ failure, which requires special measures for correction, increases dramatically.

Microorganisms, endotoxins and local mediators of aseptic inflammation usually come from the primary site of infection or foci of aseptic inflammation.

In the absence of a primary focus of infection, microorganisms and endotoxins can enter the bloodstream from the intestine due to tran slocation and through the intestinal wall into the blood or from primary sterile foci of necrosis in acute pancreatitis. This is usually observed with severe dynamic or mechanical intestinal obstruction due to acute inflammatory diseases of the abdominal organs.

Mild systemic inflammatory response syndrome is primarily a signal of excessive production of cytokines by overly activated macrophages and other cytokine-producing cells.

If preventive measures and treatment of the underlying disease are not taken in time, the syndrome of the systemic response to inflammation will continuously progress, and the incipient multiple organ dysfunction can turn into multiple organ failure, which, as a rule, is a manifestation of a generalized infection - sepsis.

Thus, the syndrome of a systemic response to inflammation is the beginning of a continuously developing pathological process, which is a reflection of excessive secretion of cytokines and other inflammatory mediators, insufficiently controlled by the immune system, due to a violation of intercellular relationships in response to severe antigenic stimuli of both bacterial and non-bacterial nature.

The syndrome of a systemic reaction to inflammation resulting from a severe infection is indistinguishable from the reaction that occurs in response to aseptic inflammation in massive trauma, acute pancreatitis, traumatic surgery, organ transplantation, and extensive burns. This is due to the fact that the same pathophysiological mechanisms and mediators of inflammation are involved in the development of this syndrome.

Diagnosis and treatment. The definition and assessment of the severity of the systemic inflammation response syndrome is available to any medical institution. This term is accepted by the international community of doctors of various specialties in most countries of the world.

Knowledge of the pathogenesis of the syndrome of systemic reaction to inflammation allows the development of anticytokine therapy, prevention and treatment of complications. For these purposes, monoclonal antibodies against cytokines, antibodies against the most active pro-inflammatory cytokines (IL-1, IL-6, tumor necrosis factor) are used. There are reports on the good efficiency of plasma filtration through special columns that allow the removal of excess cytokines from the blood. To inhibit the cytokine-producing function of leukocytes and reduce the concentration of cytokines in the blood, large doses of steroid hormones are used (though not always successfully). The most important role in the treatment of patients belongs to the timely and adequate treatment of the underlying disease, comprehensive prevention and treatment of dysfunction of vital organs.

The frequency of systemic response syndrome to inflammation in patients in intensive care units in surgical clinics reaches 50%. At the same time, in patients with high body temperature (this is one of the signs of the syndrome) who are in the intensive care unit, the syndrome of a systemic response to inflammation is observed in 95% of patients. A collaborative study covering several medical centers in the United States showed that of the total number of patients with systemic inflammation reaction syndrome, only 26% developed sepsis and 4% - septic shock. Mortality increased depending on the severity of the syndrome. In severe systemic response syndrome to inflammation, it was 7%, in sepsis - 16%, in septic shock - 46%.

The systemic inflammatory response syndrome may last only a few days, but it can exist for a longer period of time, until the level of cytokines and nitric monoxide (NO) in the blood decreases, until the balance between pro-inflammatory and anti-inflammatory cytokines is restored, the function of the immune system is restored to control production cytokines.

With a decrease in hypercytokinemia, the symptoms may gradually subside, in these cases the risk of complications is sharply reduced, and recovery can be expected in the coming days.

In severe form of the syndrome, there is a direct correlation between the content of cytokines in the blood and the severity of the patient's condition. Pro- and anti-inflammatory mediators may eventually mutually reinforce their pathophysiological effects, creating a growing immunological dissonance. It is under these conditions that inflammatory mediators begin to have a damaging effect on the cells and tissues of the body.

A complex complex interaction of cytokines and cytokine-neutralizing molecules probably determines the clinical manifestations and course of sepsis. Even a severe systemic response syndrome to inflammation cannot be considered as sepsis if the patient does not have a primary focus of infection (gate of entry), bacteremia, confirmed by the isolation of bacteria from the blood during multiple cultures.

Sepsis as a clinical syndrome is difficult to define. The Conciliation Commission of American Physicians defines sepsis as a very severe form of a systemic response to inflammation syndrome in patients with a primary focus of infection, confirmed by blood cultures, with signs of CNS depression and multiple organ failure.

We should not forget about the possibility of developing sepsis in the absence of a primary focus of infection. In such cases, microorganisms and endotoxins may appear in the blood due to the translocation of intestinal bacteria and endotoxins into the blood.

Then the intestine becomes a source of infection, which was not taken into account when searching for the causes of bacteremia. Translocation of bacteria and endotoxins from the intestine into the bloodstream becomes possible when the barrier function of the intestinal mucosa is impaired due to ischemia of its walls in peritonitis, acute intestinal obstruction, shock, and other factors. Under these conditions, the intestine becomes like an "undrained purulent cavity."

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Essay

WITHsystemic inflammatory response.Sepsis

Introduction

The term "sepsis" in a meaning close to the current understanding was first used by Hippoktas more than two thousand years ago. This term originally meant the process of tissue breakdown, inevitably accompanied by decay, disease and death.

The discoveries of Louis Pasteur, one of the founders of microbiology and immunology, played a decisive role in the transition from empirical experience to a scientific approach in the study of surgical infections. Since that time, the problem of the etiology and pathogenesis of surgical infections and sepsis has been considered from the point of view of the relationship between macro- and microorganisms.

In the works of the outstanding Russian pathologist I.V. Davydovsky, the idea of the leading role of macroorganism reactivity in the pathogenesis of sepsis was clearly formulated. It was certainly a progressive step, orienting clinicians to rational therapy, aimed, on the one hand, at the eradication of the pathogen, and on the other hand, at correcting the dysfunction of organs and systems of the macroorganism.

1. ModernThese ideas about inflammation

Inflammation should be understood as a universal, phylogenetically determined reaction of the body to damage.

Inflammation has an adaptive nature, due to the reaction of the body's defense mechanisms to local damage. The classic signs of local inflammation - hyperemia, local fever, swelling, pain - are associated with:

morphological and functional rearrangement of endotheliocytes of postcapillary venules,

coagulation of blood in postcapillary venules,

adhesion and transendothelial migration of leukocytes,

complement activation,

kininogenesis,

expansion of arterioles

Degranulation of mast cells.

The cytokine network occupies a special place among inflammatory mediators.

Controlling the processes of implementation of immune and inflammatory reactivity

The main producers of cytokines are T-cells and activated macrophages, as well as, to varying degrees, other types of leukocytes, endotheliocytes of postcapillary venules, platelets and various types of stromal cells. Cytokines act primarily in the focus of inflammation and in the reacting lymphoid organs, ultimately performing a number of protective functions.

Mediators in small amounts are able to activate macrophages and platelets, stimulate the release of adhesion molecules from the endothelium and the production of growth hormone.

The developing acute phase reaction is controlled by pro-inflammatory mediators interleukins IL-1, IL-6, IL-8, TNF, as well as their endogenous antagonists, such as IL-4, IL-10, IL-13, soluble TNF receptors, called anti-inflammatory mediators. . Under normal conditions, by maintaining a balance of relationships between pro- and anti-inflammatory mediators, prerequisites are created for wound healing, the destruction of pathogenic microorganisms, and the maintenance of homeostasis. Systemic adaptive changes in acute inflammation include:

stress reactivity of the neuroendocrine system,

a fever

The release of neutrophils into the circulatory bed from the vascular and bone marrow

increased leukocytopoiesis in the bone marrow,

hyperproduction of acute phase proteins in the liver,

development of generalized forms of the immune response.

When the regulatory systems are unable to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to impaired permeability and function of the capillary endothelium, triggering DIC, the formation of distant foci of systemic inflammation, and the development of organ dysfunction. The cumulative effects of mediators form the systemic inflammatory response syndrome (SIR).

As criteria for a systemic inflammatory reaction that characterizes the body's response to local tissue destruction, the following are used: ESR, C-reactive protein, systemic temperature, leukocyte index of intoxication, and other indicators that have different sensitivity and specificity.

At the Consensus Conference of the American College of Pulmonologists and the Society for Critical Care Medicine, held in 1991 in Chicago, under the leadership of Roger Bone (R. Bone), it was proposed to consider at least three of the four unified signs as criteria for a systemic inflammatory response of the body:

* heart rate over 90 per minute;

* the frequency of respiratory movements is more than 20 in 1 minute;

* body temperature more than 38°C or less than 36°C;

* the number of leukocytes in the peripheral blood is more than 12x106 or less

4x106 or the number of immature forms is more than 10%.

The approach proposed by R. Bon to determine the systemic inflammatory response caused ambiguous responses among clinicians - from complete approval to categorical denial. The years that have passed since the publication of the decisions of the Conciliation Conference have shown that, despite numerous criticisms of this approach to the concept of systemic inflammation, it remains today the only one generally recognized and commonly used.

2. Furanism and structure of inflammation

sepsis pasteur inflammatory surgical

Inflammation can be imagined by taking a basic model in which five main links involved in the development of the inflammatory response can be distinguished:

· Clotting system activation- according to some opinions, the leading link in inflammation. With it, local hemostasis is achieved, and the Hegeman factor activated in its process (factor 12) becomes the central link in the subsequent development of the inflammatory response.

· Platelet link of hemostasis- performs the same biological function as clotting factors - stops bleeding. However, products released during platelet activation, such as thromboxane A2, prostaglandins, due to their vasoactive properties, play a crucial role in the subsequent development of inflammation.

· mast cells activated by factor XII and platelet activation products stimulate the release of histamine and other vasoactive elements. Histamine, acting directly on smooth muscles, relaxes the latter and provides vasodilation of the microvascular bed, which leads to an increase in the permeability of the vascular wall, an increase in total blood flow through this zone, while reducing blood flow velocity.

· Activation of kallikrein-kinin The system also becomes possible due to factor XII, which ensures the conversion of prekallikrein to kallikrenin, a catalyst for the synthesis of bradykinin, the action of which is also accompanied by vasodilation and an increase in the permeability of the vascular wall.

· Activation of the complement system proceeds both along the classical and alternative paths. This leads to the creation of conditions for the lysis of cellular structures of microorganisms, in addition, activated complement elements have important vasoactive and chemoattractant properties.

The most important common property of these five different inducers of the inflammatory response is their interactivity and mutual reinforcement of the effect. This means that when any of them appear in the damage zone, all the others are activated.

Phases of inflammation.

The first phase of inflammation is the induction phase. The biological meaning of the action of inflammation activators at this stage is to prepare the transition to the second phase of inflammation - the phase of active phagocytosis. For this purpose, leukocytes, monocytes, and macrophages accumulate in the intercellular space of the lesion. The most important role in this process is played by endothelial cells.

When the endothelium is damaged, endothelial cells are activated and the maximum synthesis of NO-synthetase occurs, which, as a result, leads to the production of nitric oxide and the maximum dilatation of intact vessels, and the rapid movement of leukocytes and platelets to the damaged area.

The second phase of inflammation (the phase of phagocytosis) begins from the moment when the concentration of chemokines reaches the critical level necessary to create an appropriate concentration of leukocytes. when the concentration of chemokines (a protein that promotes the selective accumulation of leukocytes in the focus) reaches a critical level necessary to create an appropriate concentration of leukocytes.

The essence of this phase is the migration of leukocytes to the site of injury, as well as monocytes. monocytes reach the site of injury, where they differentiate into two distinct subpopulations, one dedicated to killing microorganisms and the other to phagocytosis of necrotic tissue. Tissue macrophages process antigens and deliver them to T and B cells, which are involved in the destruction of microorganisms.

Along with this, anti-inflammatory mechanisms are launched simultaneously with the onset of the act of inflammation. They include cytokines with a direct anti-inflammatory effect: IL-4, IL-10 and IL-13. There is also expression of receptor antagonists, such as the IL-1 receptor antagonist. However, the mechanisms of termination of the inflammatory response are still not fully understood. There is an opinion that it is most likely that a decrease in the activity of the processes that caused it plays a key role in stopping the inflammatory reaction.

3. Systemic inflammatory response syndrome (SIRS)

After the introduction into clinical practice of the terms and concepts proposed at the Conciliation Conference by R. Bonom et al. in 1991, a new stage began in the study of sepsis, its pathogenesis, principles of diagnosis and treatment. A single set of terms and concepts focused on clinical signs was defined. Based on them, at present, there are quite definite ideas about the pathogenesis of generalized inflammatory reactions. The leading concepts were "inflammation", "infection", "sepsis".

The development of the systemic inflammatory response syndrome is associated with a disruption (breakthrough) of the restrictive function of local inflammation and the entry of pro-inflammatory cytokines and inflammatory mediators into the systemic circulation.

To date, quite numerous groups of mediators are known that act as stimulators of the inflammatory process and anti-inflammatory protection. The table shows some of them.

The hypothesis of R. Bon et al. (1997) on the patterns of development of the septic process, which is currently accepted as the leading one, is based on the results of studies confirming that the activation of chemoattractants and pro-inflammatory cytokines as inducers of inflammation stimulates the release of contractors - anti-inflammatory cytokines, the main function of which is to reduce the severity of the inflammatory response.

This process, which immediately follows the activation of inflammatory inducers, is called the "anti-inflammatory compensatory response", in the original transcription - "compensatory anti-inflammatory response syndrome (CARS)". In terms of severity, the anti-inflammatory compensatory reaction can not only reach the degree of the pro-inflammatory reaction, but also exceed it.

It is known that when determining freely circulating cytokines, the error probability is so significant (without taking into account cytokines on the cell surface-2) that this criterion cannot be used as a diagnostic criterion.

°~ for the syndrome of anti-inflammatory compensatory reaction.

Assessing the options for the clinical course of the septic process, four groups of patients can be distinguished:

1. Patients with severe injuries, burns, purulent diseases, who do not have clinical signs of systemic inflammatory response syndrome and the severity of the underlying pathology determines the course of the disease and prognosis.

2. Patients with sepsis or severe illness (trauma) who develop a moderate systemic inflammatory response syndrome, dysfunction of one or two organs occurs, which recovers quickly enough with adequate therapy.

3. Patients who rapidly develop a severe form of systemic inflammatory response syndrome, which is severe sepsis or septic shock. Mortality in this group of patients is maximum.

4. Patients in whom the inflammatory response to the primary injury is not so pronounced, but already a few days after the onset of signs of the infectious process, organ failure progresses (such dynamics of the inflammatory process, which has the form of two peaks, is called the “double-humped curve”). Mortality in this group of patients is also quite high.

However, can such significant differences in the variants of the clinical course of sepsis be explained by the activity of pro-inflammatory mediators? The answer to this question is given by the hypothesis of the pathogenesis of the septic process, proposed by R. Bon et al. In accordance with it, five phases of sepsis are distinguished:

1. Local reaction to injury or infection. Primary mechanical damage leads to the activation of pro-inflammatory mediators, which are characterized by multiple overlapping effects of interaction with each other. The main biological meaning of such a response is to objectively determine the volume of the lesion, its local limitation, and create conditions for a subsequent favorable outcome. The composition of anti-inflammatory mediators includes: IL-4,10,11,13, IL-1 receptor antagonist.

They reduce the expression of the monocytic histocompatibility complex and reduce the ability of cells to produce anti-inflammatory cytokines.

2. Primary systemic reaction. With a severe degree of primary damage, pro-inflammatory, and later anti-inflammatory mediators enter the systemic circulation. The organ disorders that occurred during this period due to the entry of pro-inflammatory mediators into the systemic circulation, as a rule, are transient and are quickly leveled.

3. Massive systemic inflammation. A decrease in the effectiveness of the regulation of the pro-inflammatory response leads to a pronounced systemic reaction, clinically manifested by signs of a systemic inflammatory response syndrome. The basis of these manifestations may be the following pathophysiological changes:

* progressive dysfunction of the endothelium, leading to an increase in microvascular permeability;

* stasis and platelet aggregation, leading to blockage of the microvasculature, redistribution of blood flow and, following ischemia, postperfusion disorders;

* activation of the coagulation system;

* deep vasodilation, extravasation of fluid into the intercellular space, accompanied by a redistribution of blood flow and the development of shock. The initial consequence of this is organ dysfunction, which develops into organ failure.

4. Excessive immunosuppression. Overactivation of the anti-inflammatory system is not uncommon. In domestic publications, it is known as hypoergy or anergy. In foreign literature, this condition is called immunoparalysis or “window to immunodeficiency”. R. Bon with co-authors proposed to call this condition the syndrome of anti-inflammatory compensatory reaction, investing in its meaning a broader meaning than immunoparalysis. The predominance of anti-inflammatory cytokines does not allow the development of excessive, pathological inflammation, as well as the normal inflammatory process that is necessary to complete the wound process. It is this reaction of the body that is the cause of long-term non-healing wounds with a large number of pathological granulations. In this case, it seems that the process of reparative regeneration has stopped.

5. Immunological dissonance. The final stage of multiple organ failure is called the “phase of immunological dissonance”. During this period, both progressive inflammation and its opposite state, a deep syndrome of anti-inflammatory compensatory reaction, can occur. The lack of a stable balance is the most characteristic feature of this phase.

According to acad. RAS and RAMS V.S. Saveliev and Corresponding Member. RAMS A.I. Kiriyenko's hypothesis above, the balance between pro-inflammatory and anti-inflammatory systems can be disturbed in one of three cases:

*when infection, severe injury, bleeding, etc. so strong that this is quite enough for a massive generalization of the process, systemic inflammatory response syndrome, multiple organ failure;

* when, due to a previous serious illness or injury, patients are already “prepared” for the development of a systemic inflammatory response syndrome and multiple organ failure;

* when the pre-existing (background) state of the patient is closely related precisely to the pathological level of cytokines.

According to the concept of acad. RAS and RAMS V.S. Saveliev and Corresponding Member. RAMS A.I. Kirienko, pathogenesis clinical manifestations depends on the ratio of the cascade of pro-inflammatory (for a systemic inflammatory response) and anti-inflammatory mediators (for an anti-inflammatory compensatory response). The form of clinical manifestation of this multifactorial interaction is the severity of multiple organ failure, determined on the basis of one of the internationally agreed scales (APACHE, SOFA, etc.). In accordance with this, three gradations of severity of sepsis are distinguished: sepsis, severe sepsis, septic shock.

Diagnostics

According to the decisions of the Conciliation Conference, the severity of systemic violations is determined based on the following settings.

The diagnosis of "sepsis" is proposed to be established in the presence of two or more symptoms of a systemic inflammatory reaction with a proven infectious process (this includes verified bacteremia).

The diagnosis of "severe sepsis" is proposed to be established in the presence of organ failure in a patient with sepsis.

The diagnosis of organ failure is made on the basis of agreed criteria that formed the basis of the SOFA scale (Sepsis oriented failure assessment)

Treatment

A decisive shift in treatment methodology occurred after the agreed definitions of sepsis, severe sepsis, and septic shock were adopted.

This allowed different researchers to speak the same language using the same concepts and terms. The second most important factor was the introduction of the principles of evidence-based medicine into clinical practice. These two circumstances led to the development of evidence-based recommendations for the treatment of sepsis, published in 2003 and called the "Barcelona Declaration". It announced the creation of an international program known as the "Movement for effective treatment sepsis” (Surviving sepsis campaign).

Primary intensive care measures. Aimed at achieving in the first 6 hours of intensive care (activities begin immediately after diagnosis) the following parameter values:

* CVP 8-12 mm Hg. Art.;

* Mean BP >65 mmHg Art.;

* the amount of urine excreted> 0.5 mlDkghh);

* saturation mixed venous blood >70%.

If the transfusion of various infusion media fails to achieve an increase in CVP and the level of saturation of mixed venous blood to the indicated figures, then it is recommended:

* transfusion of erythromass to achieve a hematocrit level of 30%;

* infusion of dobutamine at a dose of 20 mcg/kg per minute.

Carrying out the specified complex of measures allows to reduce mortality from 49.2 to 33.3%.

Antibiotic therapy

* All samples for microbiological studies are taken immediately upon admission of the patient, before the start of antibiotic therapy.

*Treatment with antibiotics a wide range actions begin within the first hour after diagnosis.

*Depending on the results obtained microbiological research after 48-72 h regimen used antibacterial drugs reviewed to select a more narrow and targeted therapy.

Control of the source of the infectious process. Each patient with signs of severe sepsis should be carefully examined to identify the source of the infectious process and carry out appropriate source control measures, which include three groups of surgical interventions:

1. Drainage of the abscess cavity. An abscess is formed as a result of triggering an inflammatory cascade and the formation of a fibrin capsule surrounding a fluid substrate consisting of necrotic tissue, polymorphonuclear leukocytes and microorganisms and well known to clinicians as pus.

Drainage of an abscess is a mandatory procedure.

2. Secondary debridement(necrectomy). Removal of necrotic tissue involved in infectious process, is one of the main challenges in achieving source control.

3. Removal foreign bodies supporting (initiating) the infectious process.

To the main directions of treatment of severe sepsis and septic shock, received evidence base and reflected in the documents of the "Movement for effective treatment of sepsis", include:

Algorithm infusion therapy;

The use of vasopressors;

Inotropic therapy algorithm;

Use of low doses of steroids;

Use of recombinant activated protein C;

Transfusion therapy algorithm;

Algorithm of mechanical ventilation in the syndrome acute injury lungs / respiratory - adult distress syndrome (ADS / ARDS);

Protocol for sedation and analgesia in patients with severe sepsis;

Glycemic control protocol;

Protocol for the treatment of acute renal failure;

Bicarbonate protocol;

Prevention of deep vein thrombosis;

Prevention of stress ulcers.

Conclusion

Inflammation is a necessary component of reparative regeneration, without which the healing process is impossible. However, according to all the canons of the modern interpretation of sepsis, it must be considered as a pathological process that must be fought. This conflict is well understood by all leading experts in sepsis, so in 2001 an attempt was made to develop a new approach to sepsis, essentially continuing and developing the theory of R. Bohn. This approach is called the PIRO concept (PIRO - predisposition infection response outcome). The letter P stands for predisposition ( genetic factors, preceding chronic diseases etc.), I - infection (type of microorganisms, localization of the process, etc.), P - result (outcome of the process) and O - response (nature of the response various systems body for infection). Such an interpretation seems to be very promising, however, the complexity, heterogeneity of the process and the extreme breadth of clinical manifestations have not made it possible to unify and formalize these signs so far. Understanding the limitations of the interpretation proposed by R. Bon, it is widely used on the basis of two ideas.

First, there is no doubt that severe sepsis is the result of the interaction of microorganisms and a macroorganism, which entailed a disruption in the functions of one or several leading life support systems, which is recognized by all scientists involved in this problem.

Secondly, the simplicity and convenience of the approach used in the diagnosis of severe sepsis (criteria for a systemic inflammatory response, infectious process, criteria for diagnosing organ disorders) make it possible to single out more or less homogeneous groups of patients. The use of this approach has made it possible today to get rid of such ambiguously defined concepts as "septicemia", "septicopyemia", "chroniosepsis", "refractory septic shock".

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