Syndrome of systemic inflammatory reaction and sepsis

Inflammation is a typical defensive reaction to local damage. Evolution of views on the nature of inflammation largely reflects the development of fundamental general biological concepts of the body's response to the effects of damaging factors. The generalization of new data made it possible to reach a qualitatively different level of understanding inflammation as a general pathological process underlying the pathogenesis of many critical conditions, including sepsis, severe burn and mechanical trauma, destructive pancreatitis, and others.

The main content of modern ideas about inflammation

Inflammation has an adaptive-adaptive character, caused by the reaction of the body's defense mechanisms to local damage. Classical signs of local inflammation - hyperemia, local fever, edema, pain - are associated with:

• morpho-functional rearrangement of endotheliocytes of postcapillary venules,
• coagulation of blood in postcapillar venules,
• adhesion and transendothelial migration of leukocytes,
• complement activation,
• kininogenesis,
• expansion of arterioles,
• degranulation of mast cells.

A special place among the mediators of inflammation is the cytokine network, which controls the processes of realization of immune and inflammatory reactivity. The main producers of cytokines are T-cells and activated macrophages, and also, to some extent, 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, performing as a result a number of protective functions.

Mediators in small quantities are able to activate macrophages and platelets, stimulate the release of adhesion molecules and the production of growth hormone from the endothelium. The developing acute phase reaction is controlled by pro-inflammatory mediators interleukins IL-1, IL-6, IL-8, TNF, and 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 healing wounds, destroying pathogenic microorganisms, maintaining homeostasis. Systemic adaptation changes in acute inflammation include:

• stressor reactivity of the neuroendocrine system,
• fever,
• the release of neutrophils into the circulatory channel from the vascular and bone marrow depot,
• an increase in leukocytopoiesis in the bone marrow,
• hyperproduction of acute phase proteins in the liver,
• development of generalized forms of immune response.

The normal concentration of key pro-inflammatory cytokines in the blood does not usually exceed 5-10 pg / ml. If the local inflammation or insufficiency of the mechanisms limiting its course is expressed, some of the cytokines - TNF-a, IL-1, IL-6, IL-10, TCP-beta, y-INF - can enter the systemic circulation, exerting long-range effects for limits of the primary focus. In these cases, their content in the blood can be tens or even hundreds of times higher than the normal values. With the failure of regulatory systems to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, leading to impaired permeability and function of the endothelium of the capillaries, triggering of the DIC syndrome, the formation of distant foci of systemic inflammation, and the development of organ dysfunction. Secondary humoral factors of systemic inflammation include almost all known endogenous biologically active substances enzymes, hormones, products and metabolism regulators (more than 200 biologically active substances).

The total effects of mediators form a syndrome of systemic inflammatory reaction (CBP).

In its development, three main stages

Stage 1. Local production of cytokines in response to infection

A special place among the mediators of inflammation is the cytokine network, which controls the processes of realization of immune and inflammatory reactivity. The main producers of cytokines are T-cells and activated macrophages, and also to some extent other types of leukocytes, endotheliocytes of postcapillary venules (PCV), platelets and various types of stromal cells. Cytokines act primarily in the center of inflammation and in the territory of reacting lymphoid organs, perform, in the final analysis, a number of protective functions, participating in the processes of wound healing and protection of body cells from pathogenic microorganisms.

Step 2. Throwing a small amount of cytokines into the systemic circulation

Small amounts of mediators are able to activate macrophages, platelets, release of adhesion molecules from the endothelium, production of growth hormone. The developing acute phase reaction is controlled by proinflammatory mediators (interleukins IL-1, IL-6, IL-8, tumor necrosis factor (TNF), etc.) and their endogenous antagonists, such as IL-4, IL-10, IL-13, soluble receptors to TNF, and others, called anti-inflammatory mediators. By maintaining balance and controlled relationships between pro- and anti-inflammatory mediators in normal conditions, prerequisites are created for healing wounds, destroying pathogenic microorganisms, maintaining homeostasis. Systemic adaptation changes in acute inflammation include stressor reactivity of the neuroendocrine system, fever, neutrophilic circulation into the circulation from the vascular and bone marrow depot, increased leukocytopoiesis in the bone marrow, hyperproduction of acute phase proteins in the liver, development of generalized forms of the immune response.

Stage 3. Generalization of the inflammatory reaction

In case of severe inflammation or its systemic insufficiency, certain types of cytokines TNF-a, IL-1, IL-6, IL-10, transforming growth factor ß, IFN-y (in viral infections) can enter the systemic circulation, accumulate there in amounts, sufficient to realize their long-range effects. In the case of inability of regulatory systems to maintain homeostasis, the destructive effects of cytokines and other mediators begin to dominate, which leads to impaired permeability and endothelial function of the capillaries, triggering of the DIC syndrome, the formation of distant foci of systemic inflammation, and the development of mono- and multi-organ dysfunction. As the factors of systemic damage, apparently, any disturbances of homeostasis, which can be perceived by the immune system as damaging or potentially damaging, can also act.

At this stage of the syndrome of CBP from the standpoint of interaction between pro- and anti-inflammatory mediators, a conditional release of two periods is possible.

The first, the initial - the period of hyperinflammation, characterized by the release of ultrahigh concentrations of pro-inflammatory cytokines, nitric oxide, which is accompanied by the development of shock and early formation of the syndrome of multiple organ failure (PON). However, already at the moment there is a compensatory release of anti-inflammatory cytokines, the rate of their secretion, concentration in the blood and tissues gradually increases with a parallel decrease in the content of inflammatory mediators. Developing a compensatory anti-inflammatory response, combined with a decrease in the functional activity of immunocompetent cells - the period of "immune paralysis". In some patients, due to genetic determination or altered by the environmental factors of reactivity, the formation of a stable anti-inflammatory reaction is immediately recorded.

Principal differences of systemic inflammation from "classical" are expressed in the development of a systemic reaction to primary alteration. Proinflammatory mechanisms in this case lose their protective function of localization of damage factors and themselves become the main driving force of the pathological process.

The accumulation of proinflammatory mediators in the blood and the developing clinical changes are considered as SSRS. The formalization of the concept of the nature of inflammation in the form of SSRI was to a certain extent a random concept of sepsis syndrome introduced when trying to more accurately identify a group of patients with sepsis during clinical trials. The next step was decisive - working on the task of defining sepsis, the 1991 Consensus Conference of American College Chest Physicians / Society Critical Care Medicine, pushing away from fundamental research in the field of inflammation, formulated the concept of SSRM, emphasizing its nonspecificity.

Pathogenesis of sepsis

An abstract definition of the pathogenesis of sepsis was formulated by IV Davydovsky in the 1930s. "Infectious disease is a peculiar reflection of bilateral activity, it has nothing to do with either banal intoxication or with the attack of the" aggressor "that launches poisonous substances.

The causes of infection should be sought in the physiology of the body, and not in the physiology of the microbe. "

In the 21st century (2001) this definition was reflected in the concept of PIRO (PIRO), which involves 4 links of the pathogenesis of sepsis. Predisposition, including various genetic factors (genetic polymorphism of Tol-like receptors, polymorphism of the encoding of IL-1, TNF, CD14, etc.), the presence of co-morbidities, immunosuppression, age factor, Infection, pathogenicity factors, localization hearth, Response of the body to infection - syndrome of CBP and Organ dysfunction (Organ dysfunction).

The PIRO concept

Factor	Characteristic
Predisposition (predisposed to	Age, genetic factors, concomitant diseases, immunosuppressive treatment, etc.
Infection	Localization of the focus of infection is the causative agent of infection
Response	Clinical manifestations of the infectious process (such as body temperature, heart rate degree of leukocytosis, the concentration of procalcitonin C-reactive protein)
Organ dysfunction (organ dysfunction)	To assess the degree of organ dysfunction, use the scale S0FA

Experimental studies of the pathophysiological mechanisms of the development of sepsis at the end of the 20th century led to the conclusion that multiple organ dysfunction in the course of sepsis was a consequence of the early and excessive production of pro-inflammatory cytokines ("SSRM excess") in response to infection, but the failure of anticytokine therapy put this concept in doubt.

The "new" pathophysiological concept ("chaos theory", J Marshall, 2000) presupposes a variety of interacting pro- and anti-inflammatory mechanisms. "The basis of a systemic inflammatory response is not only and not so much the action of pro- and anti-inflammatory mediators, but the oscillatory multisystem interactions, the syndrome of the systemic inflammatory response with sepsis - not a monotonous reaction, but a symphony of chaos ", and" the determinant of the severity of sepsis is the imbalance of immunity and the depression of all endogenous mechanisms of anti-infective protection. "

Activation of systemic inflammation in sepsis begins with the activation of macrophages. The mediator between the macrophage and the microorganism (infection) is the so-called Toll-like receptors (TLR), each of which subtypes interact with the pathogenicity factors of a certain group of pathogens (for example, TLR type 2 interact with peptidoglycan, lipoteichoic acid, cell wall of fungi and t d, TLR type 4 - with lipopolysaccharide Gram-negative bacteria).

The most well studied pathogenesis of gram-negative sepsis. Lipopolysaccharide (LPS) of the cell wall of Gram-negative bacteria binds lipopolysaccharide-binding protein (LPS-SB), which transfers LPS to CD14 receptors of macrophages when it enters the systemic bloodstream, increasing the response of macrophages by LPS by 1000 times. The CD14 receptor in combination with TLR4 and MD2 protein through a series of mediators causes the activation of the synthesis of nuclear factor kappa B (NFKB), which enhances the transcription of genes responsible for the synthesis of pro-inflammatory cytokines - TNF and IL-1.

With a large amount of lipopolysaccharide in the bloodstream, the "pro-inflammatory" mediators between LPS and macrophages play an anti-inflammatory role, modulating the immune response ("chaos theory"). Thus, LPS-SB binds the excess of LPS in the bloodstream, reducing the transmission of information to macrophages, and the soluble CD14 receptor enhances the transfer of monocyte-bound LPS to lipoproteins, reducing the inflammatory response.

The ways of modulation of systemic inflammation in sepsis are manifold and practically not studied, but each of the "pro-inflammatory" links in certain situations becomes an "anti-inflammatory" link in this "chaos".

The nonspecific factor of anti-infective protection is the activation of the complement system, besides the classical and alternative pathway of complement activation in recent years, a lectin pathway has been isolated in which the mannose-binding lectin (MBL) binds to a microbial cell in combination with serine proteases (MBL / MASP), directly splitting the SC, nonspecifically activates the complement system.

An increase in the concentration in the bloodstream of TNF and IL-1 becomes a starting point triggering the cascade of the main links in the pathogenesis of sepsis, activation of inducible NO synthase with an increase in nitric oxide synthesis, activation of the coagulation cascade and inhibition of fibrinolysis, damage to the collagen matrix of the lungs, increased permeability of the endothelium and .

An increase in the concentration of IL-1 in the blood, TNF activates inducible NO-synthase, which leads to an increase in the synthesis of nitric oxide (II). It is responsible for the development of organ dysfunction in sepsis due to the following effects: an increase in the release of free radicals, an increase in permeability and shunt, a change in the activity of enzymes , suppression of mitochondrial function, increased apoptosis, inhibition of adhesion of leukocytes, adhesion and aggregation of platelets.

TNF and IL-1, as well as the presence of chemoattractants in the source, leads to migration of leukocytes to the focus of inflammation, the synthesis of adhesion factors (integrins, selectins), secretion of proteases, free radicals, leukotrienes, endothelins, eicosanoids. This leads to damage to the endothelium, inflammation, hypercoagulability, and these effects, in turn, increase the migration of leukocytes, their adhesion and degranulation, closing the vicious circle.

For disorders of the lymphocyte germ of blood in SSRI are characterized by lymphopenia, "redifferentiation" of pro-inflammatory T-helpers 1 in anti-inflammatory T-helpers 2, intensification of apoptosis.

Violations of the hemostasis system during sepsis are also triggered by an increase in the concentration in the blood of TNF, IL-1.6, damage to the endothelium of capillaries with an increase in tissue factor IL-6 and tissue factor activate the external mezanizm of coagulation by activation of the VII factor, TNF depresses natural anticoagulants (protein C, antithrombin III, etc.) and violates fibrinolysis [(eg, due to the activation of the plasminogen activator-1 inhibitor (PAI-1)].

Thus, in the pathogenesis of sepsis, 3 key elements of microcirculatory disturbances are distinguished by an inflammatory response to infection (adhesion of neutrophils to the capillary endothelium, capillary leakage, endothelium damage), activation of the coagulation cascade, and inhibition of fibrinolysis.

Systemic inflammatory response and organ dysfunction

Local inflammation, sepsis, severe sepsis and PON are links of one chain during the body's reaction to inflammation due to bacterial, viral or fungal infection. Severe sepsis and septic shock constitute an essential part of the SVER of the body for infection and develop due to the progression of systemic inflammation with impaired functions of organs and their systems.

In general, from the perspective of modern knowledge, the pathogenesis of organ dysfunction involves 10 consecutive steps.

Activation of systemic inflammation

SSRM is formed against a background of bacterial, viral or fungal invasion, shock of any nature, phenomenon of ischemia / reperfusion, massive tissue damage, translocation of bacteria from the intestine.

[1], [2], [3], [4], [5], [6], [7], [8], [9],

Activation of initiating factors

As the system activating factors coagulative proteins, platelets, mast cells, contact activation systems (bradykinin production) and complement activation act.

[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]

Changes in the microcirculation system

Vasodilatation and increased vascular permeability. With local inflammation, the goal of these changes is to facilitate the penetration of phagocytes to the site of injury. In the case of CB activation, a decrease in the systemic vascular tone and damage to the vascular endothelium at a distance from the primary focus are observed.

[21], [22], [23], [24], [25], [26], [27]

Products of chemokines and chemoattractants

The main effects of chemokines and chemoattractants:

• marginalization of neutrophils,
• release of pro-inflammatory cytokines (TNF-a, IL-1, IL-6) from monocytes, lymphocytes and some other cellular populations,
• activation of an anti-inflammatory response (possible)

Margination ("sticking") of neutrophils to the endothelium

With local inflammation, the chemoattractant gradient focuses the neutrophils at the center of the lesion, whereas in the development of CB, the activated neutrophils diffuse infiltrate the perivascular spaces in various organs and tissues.

Systemic activation of monocytes / macrophages.

Damage to the microvasculature

Running CB is accompanied by activation of free radical oxidation processes and damage to the endothelium with local activation of platelets at the site of injury.

[28], [29], [30], [31], [32], [33], [34], [35], [36], [37]

Impaired tissue perfusion

Due to endothelial damage, the occurrence of microthrombosis and the reduction of perfusion in some areas of microcirculation, the blood flow may completely stop.

Focal necrosis

Complete stop of blood flow in some parts of the microcirculatory bed is the cause of the appearance of local necrosis. The organs of the planknichnyi basin are especially vulnerable.

[38], [39], [40], [41], [42], [43]

Reactivation of the factors initiating inflammation

Tissue necrosis, caused by CB, in turn, stimulates its re-activation. The process becomes autocatalytic, supporting itself, even in conditions of a radical sanation of an infectious focus, or stopping bleeding, or eliminating another primary damaging factor.

Septic shock occurs as a result of excessive vasodilation, increased vascular permeability and myocardial dysfunction due to inhibition of myocardial beta and alpha-adrenoceptor activity (restriction of inotropic and chronotropic reaction), depressive effect of NO on cardiomyocytes, increase in the concentration of endogenous catecholamines, but decrease in their effectiveness due to oxidation with superoxidease , a decrease in beta-adrenergic receptor density, a violation of Ca2 + transport, a decrease in the sensitivity of myofibrils to Ca2 +, a progression septic shock, septic shock leads to hypoperfusion of organs and tissues, PON and death.

Imbalance of the mediator cascade during sepsis leads to damage to the endothelium and to significant disturbances in hemodynamics:

• increased cardiac output,
• reduction in OPSS,
• redistribution of organ blood flow,
• decrease myocardial contractility.

Septic shock occurs as a result of excessive vasodilation, increased vascular permeability and pronounced hypotension, progressing, it leads to hypoperfusion of organs and tissues, PON and death.

There are no generally accepted criteria for organ-system dysfunction to date. For routine clinical practice, the criteria A are most acceptable. Baue et al. And SOFA.

Criteria for organ dysfunction in sepsis (2000)

System, organ	Clinical and laboratory indicators
The cardiovascular system	Clinical and laboratory criteria Systolic BP <90 mmHg or mean BP <70 mmHg for 1 hour or more despite correction of hypovolemia
Urinary system	Urinary discharge <0 5 ml / kg / h for 1 hour with adequate volemic replenishment or increase in creatinine level by half from the normal value
Respiratory system	RD / TO, <250, or the presence of bilateral infiltrates on the radiograph or the need for ventilation
Liver	An increase in bilirubin content above 20 μmol / l for 2 days or an increase in the activity of transaminases is twice or more than normal
Convoluting system	The number of platelets <100 000 mm3 or their decrease by 50% of the highest value within 3 days
Metabolic dysfunction	PH <7.3, base deficiency> 5 0 mEq / L , lactate content in plasma is 1 5 times higher than normal
CNS	Less than 15 points on the Glasgow scale

The SOFA (Sepsis organ failure assessment) scale allows to determine in quantitative terms the severity of organ-system disorders. A zero value on the SOFA scale indicates the absence of organ dysfunction. Today, the information significance of the SOFA scale with the minimum of constituent parameters has the most valuable scientific confirmation, which makes it possible to use it in most domestic medical institutions.

Risk factors for organ-system dysfunction:

• elderly age,
• severe concomitant pathology,
• chronic alcoholism,
• the index of severity of general condition APACHE-II is above 15 points,
• genetic predisposition to rapid generalization of systemic inflammation.

The organ, which is at the very beginning of the chain of pathological lesions in sepsis, is usually light. In severe sepsis in the background of peritonitis, OPL occurs on average in 40-60% of cases, and its most severe form - ARDS - is diagnosed in 25-42% of cases. Functional failure of other organs / systems in 83.7% of cases is realized against the background of PLN. In this respect, the most vulnerable organ - kidneys renal dysfunction (PDD) acts as a component of MNP in 94.8% of patients with severe abdominal sepsis. If the oliguria is easily eliminated within 1-3 days, the disturbance of the renal nitrogen function persists for a longer time time.

The syndrome of acute hepatic dysfunction is recorded in a third of patients with abdominal sepsis, less often with other clinical forms of sepsis. Signs of liver failure almost always develop against the background of the already existing functional deficiency of other organs, most often joining the following combinations of a multi-organ syndrome of OPL + OPD or shock + OPL + OPD.

Violation of consciousness - the syndrome of encephalopathy - occurs on the average to the second day of the development of sepsis and is more common in elderly and elderly patients in the conditions of the existing PON syndrome. An important role in the development of encephalopathy is played by the severity of functional organ and homeostatic disorders, the cumulative effects of arterial hypotension and hypoxemia. Unlike ARDS, the duration of the resulting disorders of consciousness does not exceed 5-6 days.

In the most common form, the sequence of the development of the NON looks like the following: OPL ± SHOCK - »SPD -» Encephalopathy - »Acute hepatic dysfunction syndrome.

The main feature of organ dysfunction in abdominal sepsis, unlike other localizations of the primary focus, is the severity of the multi-organ syndrome and the involvement of more systems in its structure. Risk factors for septic shock:

• elderly age,
• severe concomitant pathology of the cardiovascular system,
• chronic liver disease,
• the ARASNE-I index is 17,
• bacteremia caused by a gram-negative microorganism.

Refractory septic shock and progressive PON are the main causes of death of patients with sepsis in the acute period of the disease. An increase in the number of organs involved in the process of MES increases the risk of a lethal outcome of the disease, while the development of organ dysfunction is dominated by the infectious process. The development of organ dysfunction, complementary to the initially existing, increases the risk of death by 15-20%. The average level of mortality in sepsis with insufficiency in the two systems is 30-40%.

Bacteremia and septicemia

Bacteremia - the presence of a bacterial infectious agent in the systemic circulation is one of the possible but not necessary manifestations of sepsis. In the presence of criteria for sepsis, mentioned above, the absence of bacteremia should not influence the diagnosis. Even with the most scrupulous observance of blood sampling techniques and the use of modern technologies for detecting microorganisms in the most severe patients, the frequency of bacteremia detection usually does not exceed 45%. Detection of microorganisms in the bloodstream in the absence of clinical and laboratory confirmation of the syndrome of systemic inflammation should be regarded as transient bacteremia.

The clinical significance of bacteraemia registration may be:

• confirmation of the diagnosis and determination of the etiology of the infectious process,
• evidence of the mechanism of sepsis development (eg, catheter-related infection),
• assessment of the severity of the course of the pathological process (for some situations, for example, in the detection of K pneumoniae, P aeruginosa),
• substantiation of the choice of the scheme of antibacterial treatment,
• evaluation of treatment effectiveness.

[44], [45]

Kliiko-laboratory criteria of systemic inflammation

Clinical and laboratory signs of SSRM are non-specific, its manifestations are characterized by fairly simple diagnostic parameters:

• hyper- or hypothermia of the body,
• tachypnea,
• tachycardia,
• change in the number of leukocytes in the blood.

The diagnosis of SSRS syndrome is based on the registration of at least two of the four clinical and laboratory parameters listed in the table.

Criteria for diagnosis of sepsis and septic shock

Pathological process	Clinical and laboratory characteristics
SSSR - the systemic reaction of the body to the effect of various strong irritants (trauma surgery infection, etc.)	Characterized by two or more of the following symptoms : body temperature> 38 ° C or <36 ° C> 90 / min respiratory rate> 20 / min or hyperventilation (PaCO2 <32 mmHg) blood leukocytes> 12 × 10 9 / ml, or < 4 × 10 9 / ml or immature forms> 10%
Sepsis - SSRS for invasion of microorganisms	Presence of a foci of infection and 2 or more signs of a syndrome of systemic inflammatory reaction
Severe sepsis	Sepsis, combined with organ dysfunction of hypotension with disorders of tissue perfusion The manifestation of the latter in particular - increased concentration of lactate, oliguria acute impairment of consciousness
Septic shock	Severe sepsis with signs of tissue and organ hypoperfusion, arterial hypotension, which can not be eliminated with the help of infusion therapy
Syndrome of multiple organ dysfunction / insufficiency (NSP)	Dysfunction for 2 or more systems
Refractory septic shock	Arterial hypotension persists, despite the adequate infusion of inotropic and vasopressor support

Despite the imperfection of SSRS criteria (low specificity), their sensitivity reaches 100%. Therefore, the main practical significance of the diagnosis of SSRS syndrome is the allocation of a group of patients that cause anxiety in the clinician, which requires a rethinking of therapeutic tactics and proper diagnostic search necessary for timely and adequate therapy.

From general biological positions, sepsis is one of the clinical forms of SSRM, where the microorganism acts as a factor initiating damage. Thus, sepsis is a pathological process, which is based on the body's response in the form of generalized (systemic) inflammation to an infection of a different nature (bacterial, viral, fungal).

The result of the clinical interpretation of this view of the pathogenesis of sepsis was the classification and diagnostic criteria proposed by the conciliation conference of the American College of Pulmonology and the Society of Critical Medicine Specialists (ASSR / BSSM).

The low specificity of the SSRS criteria led to the development of approaches to differential diagnosis of the syndrome of infectious and non-infectious genesis. To date, the best diagnostic test for this purpose is to determine the content of procalcitonin in the blood with a direct measurement or a semi-quantitative rapid test. The concentration of procalcitonin in the blood increases with the bacterial or fungal nature of sepsis

Diagnosis of sepsis

Currently, it is possible to diagnose secondary immunodeficiency and its degree, as well as a dynamic assessment of the state of the immune system. However, there are no final criteria.

[46], [47], [48]

Requirements for the indicators used for diagnosis

• be available in practice,
• objectively reflect the state of the various links of immunity,
• dynamically respond to changes in the clinical state of the patient during treatment.

Laboratory tests recommended for detection of immunodeficiency in patients in critical condition:

• determination of the absolute number of lymphocytes, HLA-DR monocytes and apoptotic lymphocytes,
• the content of immunoglobulins M, C, A in the blood,
• phagocytic activity of neutrophils.

Criteria for diagnosis of immunodeficiency ^

• the absolute number of lymphocytes in the peripheral blood is less than 1.4x10 ⁹ / l,
• the number of HLA-DR-positive monocytes is less than 20%, apoptotic lymphocytes - more than 10%,
• decrease in the blood content more than 1.5 times the normal (0.7-2.1 g / l) and - below the norm (9-15 g / l), the phagocytic index of neutrophils in the early stages of phagocytosis (FI 5 min - below 10%).

Counting the absolute number of lymphocytes with a general blood test is available in each clinic and is very informative. Reduction of lymphocytes below 1.0 × ^{10 9} / l indicates immunodeficiency. The definition of HLA-DR-positive monocytes and apoptotic lymphocytes (CD 95) is also informative, but the method is less available, since it is carried out by flow cytometry. The definition of the content of immunoglobulins (using test systems) and the phagocytic activity of neutrophils (latex test, microscopy) is quite simple. Thus, secondary immunodeficiency in the composition of the PON can be diagnosed on the basis of three criteria out of five available. A significant decrease in lymphocytes (less than 1.0x10 ⁹ / l) and immunoglobulins (IgM is 1.5 times lower than normal and IgG is below normal) is likely to indicate secondary immunodeficiency.

The determination of the concentration of cytokines in serum is not widespread in clinical practice, since none of the known mediators can be considered as universal. Numerous studies show that the release of pro-inflammatory mediators is differentiated. The content of TNF-a, IL-1, 6, 8 in blood in healthy donors averages from 0 to 100 pg / ml. The lethal concentration is considered to be 3000-4000 pg / ml. The content of TNF-a is associated with early events (shock), IL-8 - with later clinical manifestations (ICE, severe hypoxia, death). High concentration of IL-6 is characteristic for the rapid development of septic shock and correlates with mortality. Patients with septic shock are not considered a homogeneous group for the content of cytokines. There are reports of the existence of a link between a stably high concentration of TNF, IL-1, interferon-a and lethality. There may be no correlation between high levels of cytokines and shock. With gram-negative and fungal infections, the granulocyte colony-stimulating factor in the blood increases. Its high concentrations are found in patients with neutropenia, and they correlate with the degree of temperature increase.

The content of acute-phase proteins (procalcitonin and C-reactive protein) is related to the degree of inflammatory response and serves for monitoring during treatment. The concentration of C-reactive protein (more than 50 mg / l) with a sensitivity of 98.5% and a specificity of 45% indicates the development of sepsis. The content of procalcitonin 1.5 ng / ml and more allows to identify sepsis, with a sensitivity of 100% and a specificity of 72%. In patients with malignant neoplasm of the esophagus at 1-3 days after esophagectomy, an increase in the concentration of C-reactive protein (10-20 times, before operation - <10 mg / l) and procalcitonin (median 2.7 ng / ml, before operation - <0.5 ng / ml). No patients were diagnosed with sepsis, and an increase in the content of C-reactive protein and procalcitonin is considered a response to the surgical trauma. Despite the great diagnostic potential, procalcitonin is not used as a marker of sepsis in patients with SSER. This test is used to exclude the diagnosis of "sepsis" and monitor the effectiveness of the treatment.

A new diagnostic marker of inflammation may be a trigger receptor, expressed on myeloid cells (TREM-1). The content of soluble TREM-1 in BAL fluid in patients with bacterial or fungal pneumonia in IVL exceeds 5 pg / ml (sensitivity - 98%, specificity - 90%), and the concentrations of procalcitonin and C-reactive protein in patients with pneumonia and without it do not differ .

Immunotherapy for sepsis

The critical condition, severe infection and PON are inextricably linked. Data on pathophysiological mechanisms allow us to talk about the advisability of including in the complex therapy drugs that modulate and correct the systemic inflammatory response.

Post-traumatic disorders of immunity include hyperactivation of inflammatory processes and deep depression of cell-mediated immunity functions. Immunomodulation restores the depressed immune response, while not strengthening hyper-inflammation. The strategy of immunomodulation consists in preventing the development of MI with the help of blockade or weakening of SSRI manifestations. Immunomodulation should be performed as soon as possible after trauma. Its goal is to protect lymphocytes, macrophages, granulocytes, endothelial cells from hyperactivation and functional exhaustion. Immunological disorders in trauma and sepsis can not be caused by a change in the concentration of a single cytokine. The action of cytokines can be synergistic or antagonistic, and the effects repeatedly cross each other.

With the help of immunotherapy solve two problems:

1. Removal of pathogens and their toxic products. This reduces the role of the infectious agent in maintaining a systemic inflammatory response.
2. Reduction of the manifestation of the systemic inflammatory reaction caused by trauma and severe infection, for the prevention of hemodynamic disorders and the functioning of organs, the development of PON.

The main criteria of immunomodulatory therapy (according to BaM E, 1996)

• prevention of excessive stimulation of macrophages by neutralization of circulating exo- and endotoxins with high doses of polyvalent immunoglobulins and soluble receptors to complement,
• global short-term (<72 h) suppression of inflammatory activity of macrophages and neutrophils - granulocyte colony-stimulating factor, pentoxifylline, IL-13,
• restoration of cell-mediated immunity to prevent posttraumatic functional paralysis - indomethacin, interferon-y.

Immunocorrection application areas:

• humoral, cellular, nonspecific immunity,
• cytokine network,
• coagulation system.

With humoral immunity, the priority is to increase the content of immunoglobulins of class M and C (in the processes of opsonization and killing of infectious agents, activation of phagocytosis and neutralization of complement), as well as stimulation of B lymphocytes.

For cellular immunity, it is necessary to restore the normal relationship between T-helpers and T-suppressors (characterized by a predominance of suppressors) and activate NK cells.

Nonspecific immunity is the first barrier to infection. Its tasks are to restore the phagocytic activity of neutrophils and macrophages, to reduce the hyperproduction by macrophages of pro-inflammatory cytokines (TNF and IL-1), to neutralize the activated membrane-depleting components of complement (C5-9).

Features specific to cytokines

• a small role in normal homeostasis,
• are produced in response to exogenous stimuli,
• are synthesized by many types of cells (lymphocytes, neutrophils, macrophages, endotheliocytes, etc.)
• damage the immunoregulatory and metabolic function of the body,
• Suppression of excessive release of cytokines is necessary, but no more.

Hyperproduction of such pro-inflammatory cytokines as TNF and IL-1 leads to an increase in vascular permeability, hyperactivation of lymphocytes, and the formation of hypercatabolism. IL-8 promotes the migration of granulocytes from the vascular bed to the interstitial space. An increase in the concentration of anti-inflammatory cytokines (IL-4, 10, soluble TNF receptor, IL-1 receptor antagonist) leads to the development of anergy to infection, or so-called immune paralysis. To restore the optimal balance between pro- and anti-inflammatory cytokines, and also to prevent the persistence of high concentrations of TNF and IL-6 in the area of cytokine network correction is very difficult.

In the coagulation system, thrombus formation must be suppressed and fibrinolysis activated. In parallel, the processes of apoptosis in endothelial cells are reduced.

On the mechanism of action, treatment can be immunosuperbative (replacement of immunodeficiency) or immunocorrecting (modulation of immunity units - stimulation or suppression).

The critical condition of the patient leads to the development of an acute form of immunodeficiency (pronounced shifts in the immune system quickly replace each other). The cases studied in the Russian literature are referred to chronic immunodeficiencies (shifts in the immune system are not so significant and do not affect the patient's general condition, which can not be called critical). However, not all the immunocorrecting drugs used are considered effective, and the studies are correctly carried out.

Criteria for drugs used for immunocorrection

• proven effectiveness,
• security,
• purposeful action (the presence of a target),
• speed of action,
• dose-dependent effect,
• clear control parameters.

Appointment of the drug to a patient in serious condition receiving powerful medicines should have reasoned evidence and evidence of its effectiveness. The main requirement is the absence of side effects. Immunocorrecting drug can not act immediately on all links of immunity. Its effectiveness is achieved through targeted action on a specific target in pathogenesis. The speed of action and the dose-dependent effect are universal requirements for drugs used in intensive care. The effect of the treatment is needed in a few days, and not after 2-3 weeks after its end. The indicator of the effectiveness of the therapy, in addition to the general clinical evaluation of the severity of the condition (APACHE, SOFA, etc.), is considered a change in the pathogenetic link to which the main effect of immunocorrection is directed. These changes are diagnosed with the help of available laboratory research methods.

Possible directions of correction of the main pathophysiological aspects of systemic inflammation in critical conditions and sepsis are presented in the table.

Possible directions of correction of the main pathophysiological aspects of systemic inflammation in critical conditions and sepsis

Target	Agent	Mechanism of action
Endotoxin	Monoclonal antibodies to endotoxin	Opsonization
Complex LPS-LPS-binding protein	Antibodies to L PS	Reduced activation of macrophages caused by LPS
TNF	Monoclonal antibodies to TNF soluble receptor for TNF	The binding and inactivation of TNF
IL-1	A receptor antagonist for IL-1	Competing with the receptor to IL-1
Cytokines	Glucocorticoids, pentoxifylline	Blockade of cytokine synthesis
Factor of platelet activation	Thrombocyte activation factor antagonist, phospholipase A2 inhibitor, platelet activation factor acetylhydrolase	Competition with the receptor for PAP decreases the content of PAA and leukotrienes
Thromboxane	Ketoconazole	Inhibition of thromboxane synthesis
NO	The synthesis inhibitor NO	Inhibition of NO synthesis
Free Radicals	Acetylcysteine, sodium selenite vitamins C and E catalase, superoxide dismutase	Inactivation and reduction of the release of free radicals
Metabolites of arachidonic acid	Indomethacin, ibuprofen, a leukotriene receptor antagonist	Inhibition of the cyclo- and lipoxygenase pathway, prostaglandin receptor blockade
Coagulation system	Antithrombin III, activated protein C	Anticoagulation, decrease in platelet activation, decrease in pro-inflammatory cytokines, effect on neutrophils
The cytokine network of humoral immuno-	Interferon-y, granulocyte colony-stimulating factor, immunoglobulin	Recovery of antibody deficiency recovery of neutrophil activity, decrease in the concentration of pro-inflammatory cytokines

Currently, clinical trials are being conducted on the use of immunotherapy in severe infections and critical conditions. The effectiveness of preparations of enriched immunoglobulin (a preparation of pentaglobin) and activated protein C [drotrekogin-alpha activated (zygris)] is considered to be proved. Their action is associated with the replacement of immunodeficiency in the area of humoral immunity (pentaglobin) and the coagulation system [drotrekogin-alpha activated (zygris)] - a direct immunotherapeutic effect. These drugs also have an immunomodulatory effect on the cytokine network, nonspecific and cellular immunity. Clinical studies have proven the effectiveness of enriched immunoglobulin (5 ml / kg, 28 ml / h, 3 consecutive consecutive days) for neutropenia, immunological anergy, neonatal sepsis, in the prevention of polyneuropathy of critical conditions. Activated protein C [24 μg / (kghh), as a continuous infusion, for 96 h] is effective in severe sepsis.

Interferon-y restores expression of macrophages HLA-DR and TNF production. The use of activated complement antibodies (C5a) reduces the incidence of bacteremia, prevents apoptosis and increases survival. The use of antibodies to a factor that inhibits the migration of macrophages protects rats from peritonitis. Nitric oxide is an endogenous vasodilator synthesized by CGO synthetase from L-arginine. Its hyperproduction causes hypotension and myocardial depression in septic shock, and the use of inhibitors (KT-methyl-L-arginine) restores blood pressure. In the process of activation and degranulation of neutrophils, a large number of free radicals are formed, causing tissue damage in systemic inflammation. They study the possibilities of endogenous antioxidants (catalase and superoxide dismutase) to neutralize free radicals in sepsis.

The table summarizes the results of multicenter, double-blind, placebo-controlled randomized trials to study the efficacy of immunocorrective therapy for sepsis and PON.

Results of multicenter, double-blind, placebo-controlled randomized trials to study the efficacy of immunocorrective therapy for sepsis and PON

A drug	Result of research	Author, date
Granulocyte colony-stimulating factor (filgrastim)	Does not reduce the 28-day lethality	Rott R.K., 2003
Antibodies to endotoxin (E 5)	Do not reduce mortality in patients without shock	Bone R.S., 1995
Antibodies to the common endotoxin of enterobacteria	Do not reduce the lethality	Albertson TE, 2003
Pentoxifylline	Reduction of mortality - 100 newborns	Lauterbach R., 1999
Glucocorticoids	Use "small doses" Stabilization of hemodynamics	Appape D, 2002, Keh D 2003
Il-1 receptor antagonist	Does not reduce lethality	Opal SM 1997
Antibodies to TNF	Do not reduce the 28-day lethality	Abraham E. 1997, 1998
The antagonist of the PAF receptor	Does not reduce lethality	Dhamaut JF 1998
COX Inhibitors	Do not reduce the lethality	Zen IF, 1997
Antithrombin III	Does not reduce lethality	Warren BL 2001
Ketoconazole	Does not reduce lethality	The ARDS network, 2000
Immunoglobulins (G + M)	Significantly reduce the lethality	Alejandria MM 2002
Activated Protein C	Reduces lethality	Bernard GR, 2004
Interferon-y Antibody to C5a Antibodies to FUM Inhibitors N0 Antioxidants	Effective in experimental animal models	Hotchkiss RS 2003

When studying the pathogenesis of critical states and understanding the role of the immune system in these processes, the criteria for the diagnosis of immunodeficiency in the composition of the PNS will be developed and effective drugs will be developed to correct it.