Sepsis: causes and pathogenesis

Causes of sepsis

The main pathogens in patients with sepsis are highly virulent gram-negative and anaerobic bacteria, less often gram-positive flora.

Especially in sepsis, E. Coli, S. Aureus, S. Pneumoniae and obligate anaerobes are isolated.

[1], [2], [3], [4]

Pathogenesis of sepsis

After the introduction to the clinical practice of terms and concepts proposed at the Conciliation Conference by R. Bon and co-authors in 1991, a new stage in the study of sepsis, its pathogenesis, the principles of diagnosis and treatment came. A single set of terms and concepts that focused on clinical signs was defined. Proceeding from them, now there are quite certain ideas about the pathogenesis of generalized inflammatory reactions. The leading concepts were "inflammation", "infection", "sepsis".

Development of the syndrome of a systemic inflammatory reaction is associated with a breakdown in the delimiting function of local inflammation and the ingestion of proinflammatory cytokines and inflammatory mediators in the systemic circulation. The clinical picture corresponding to these mechanisms is quite typical (temperature reaction, leukocytosis (leukopenia or shift of leukocyte formula to the left), tachycardia and tachypnoe). Such symptoms are similar to the symptoms inherent in the hyperergic type of sepsis in most patients. The treatment regimens developed according to the results of the experiments give very good results, as a rule, in the preclinical phase of the tests. At the same time, you can find a huge number of publications about the failures that seem to have been excellent in its idea of drugs (for example, anticytokine monoclonal antibodies) in conducting clinical trials. All this leads to the conclusion that hyperergic reaction is not the only way to realize systemic inflammation.

By now, quite a few groups of mediators, performing the function of stimulants of the inflammatory process and anti-inflammatory protection are known. In Table. 23-2 are some of them.

Hypothesis R. Bon et al. (1997) on the regularities of the development of the septic process, 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 counteragents-anti-inflammatory cytokines whose main function is to reduce the magnitude of the inflammatory response.

This process, which follows immediately after the activation of inducers of inflammation, was called "anti-inflammatory compensatory reaction", in the original transcription - "compensatory anti-inflammatory response syndrome (CARS)". By expression, the anti-inflammatory compensatory reaction can not only reach the degree of pro-inflammatory reaction, but also exceed it. Unfortunately, it is practically impossible to detect obvious clinical signs of one or another degree of activity of these systems. It is especially difficult to do this in the early stages of the process in connection with the ongoing neurohumoral consequences of a "pro-inflammatory mediator explosion" with typical signs of a systemic inflammatory response of the body. This condition is suggested to be called the syndrome of a mixed antagonistic reaction, in the original transcription - "mixed antagonists response syndrome (MARS)".

The lack of explicit clinical signs is argued by skeptics when they raise the question of whether it is advisable to single out such a reaction. However, studies of the dynamics of the activity of some pro-inflammatory and anti-inflammatory cytokines on the surface of circulating monocytes in the peripheral blood have made it possible to determine the sharp increase in IL-4 activity with reduced activity of interferon-y and IL-2. It has been shown that the important criteria for the anti-inflammatory compensatory response available for laboratory determination can be: a decrease in the expression level of HLA-DR on the surface of monocytes to 30% and lower, and a decrease in the ability of macrophages to synthesize the pro-inflammatory cytokines TNF-a and IL-6.

Proceeding from this, nowadays we offer as diagnostic criteria:

• for the syndrome of anti-inflammatory compensatory reaction - decrease in the level of HLA-DR expression on the surface of monocytes to 30% and lower, as well as a decrease in the ability to synthesize the pro-inflammatory cytokines TNF-a and IL-6;
• for the syndrome of mixed antagonistic reaction - clinical signs of a systemic inflammatory reaction in patients with immunological criteria of the syndrome of anti-inflammatory compensatory reaction.

It is known that in the determination of free circulating cytokines, the probability of error is so significant (without cytokines at the cell surface) that this criterion can not be used as a diagnostic criterion for the syndrome of anti-inflammatory compensatory reaction.

Evaluating the clinical course of the septic process, four groups of patients can be distinguished:

1. Patients with severe injuries, burns, purulent diseases in which there are no clinical signs of the syndrome of systemic inflammatory reaction and the severity of the underlying pathology determines the course of the disease and the prognosis.
2. Patients with sepsis or severe diseases (trauma), who develop a moderate severity of the syndrome of systemic inflammatory reaction, there is a dysfunction of one or two organs, quickly restored with adequate therapy.
3. Patients who rapidly develop a severe form of the systemic inflammatory reaction syndrome, which is a severe sepsis or septic shock. Mortality in this group of patients is maximal.
4. Patients who have an inflammatory response to primary damage are less pronounced, but a few days after the appearance of signs of the infectious process, organ failure progresses (such dynamics of the inflammatory process, which has the form of two peaks (two-hit), was called the "two-humped curve"), . Mortality in this group of patients is also quite high.

Every doctor who has experience of working with patients with severe forms of surgical infection may consider such an idea of the types of sepsis flow reasonable. Any of these variants of the course of the infectious process is quite often encountered in clinical practice. However, is it possible to explain such significant differences in the variants of the clinical course of sepsis with the activity of proinflammatory mediators? The answer to this question is given by the hypothesis of the pathogenesis of the septic process, proposed by R. Bonn 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 proinflammatory mediators, which differ by multiple overlapping effects of interaction with each other. The main biological meaning of this answer is the objective definition of the volume of the lesion, its local limitation, the creation of conditions for a subsequent favorable outcome.

The biological significance of the anti-inflammatory response that develops shortly after the onset of activation of the compensatory response is to provide mechanisms for limiting inflammation so that the inflammatory response is of a constructive, not destructive nature. Anti-inflammatory mediators include IL-4, IL-10, IL-11, IL-13, soluble receptor for TNF-a, receptor antagonist IL-1 and other substances. They reduce the expression of monocytic major histocompatibility complex class II, stop antigen presenting activity, reduce the ability of cells to produce pro-inflammatory cytokines.

2. Primary systemic reaction. At a severe degree of primary damage, proinflammatory, and later anti-inflammatory mediators fall into the systemic circulation. The biological meaning of getting proinflammatory mediators in the systemic circulation is to mobilize the body's defense systems no longer at the local, but at the systemic level. It should be noted that this process is part of the normal inflammatory response of the body. Proinflammatory mediators ensure the participation of polymorphonuclear leukocytes, T- and B-lymphocytes, platelets, coagulation factors in the inflammatory cascade for the localization of lesions. Compensatory anti-inflammatory response reduces the severity of the inflammatory reaction quickly enough. The organ disturbances that occurred during this period because of the influx of proinflammatory mediators into the systemic bloodstream are usually temporary and are quickly eliminated.
3. Massive systemic inflammation. Decrease in the effectiveness of regulation of the proinflammatory response leads to a pronounced systemic response, clinically manifested as signs of a syndrome of systemic inflammatory response. The basis of these manifestations can be the following pathophysiological changes:
   • progressive endothelial dysfunction leading to an increase in microvascular permeability;
   • stasis and aggregation of platelets, leading to blockage of the microcirculatory bed, redistribution of blood flow and after ischemia - postperfusion disorders;
   • activation of the coagulation system;
   • deep vasodilation, transudation of fluid into the intercellular space, accompanied by redistribution of blood flow and development of shock. The initial consequence of this is organ dysfunction, which grows into an organ failure.
4. Excess immunosuppression. Excessive activation of the anti-inflammatory system is not uncommon. In domestic publications, it is known as hypoergia or anergy. In foreign literature this condition was called immunoparality or "window in immunodeficiency." R. Bon and his co-authors suggested calling this condition a syndrome of anti-inflammatory compensatory reaction, putting a wider meaning in its meaning than immunoparality. The predominance of anti-inflammatory cytokines does not allow the development of excessive, pathological inflammation, as well as the normal inflammatory process, which is necessary to complete the wound process. It is such a reaction of the body - the cause of long-term healing wounds with a large number of pathological granulations. In this case, it seems that the process of reparative regeneration has stopped.

A study of the study of the expression of HLA-DR on the surface of monocytes in patients with severe burn injury showed that in the group of patients where the HLA-DR expression level was below 30% and interferon-y was used for treatment, encouraging results were obtained: of patients was significantly improved, and immunological tests showed the restoration of HLA-DR expression level and the ability of monocytes to express TNF-α and IL-6. The obtained data testify to the restoration of the immunological balance between the syndrome of the systemic inflammatory reaction and the syndrome of the anti-inflammatory compensatory reaction.

5. Immunological dissonance. The final stage of multi-organ insolvency was called the "phase of immunological dissonance". In this period, there may be a progressive inflammation, and the opposite state - a deep syndrome of anti-inflammatory compensatory reaction.

The absence of a stable balance is the most characteristic feature of this phase. You can observe a fairly rapid change of leading syndromes (inflammatory and compensatory) literally within 24 hours, which indicates the depletion of mechanisms responsible for the parity of these systems. This undoubtedly leads to an imbalance not only of proinflammatory and anti-inflammatory mechanisms, but also of the participatory functions of the organs and systems of the body.

In the opinion of the authors of the above hypothesis, the balance between proinflammatory and anti-inflammatory systems can be violated in one of three cases:

• when infection, severe trauma, bleeding, etc. So strong that it is quite enough for a massive generalization of the process, a syndrome of systemic inflammatory reaction, multiple organ failure;
• when due to previous severe illness or trauma patients are already "prepared" for the development of the syndrome of systemic inflammatory reaction and multiple organ failure;
• when the pre-existing (background) condition of the patient is closely related to the pathological level of cytokines.

At the same time, "readiness" for the development of the syndrome of a systemic inflammatory reaction or multi-organ failure means that the patient is at the time of trauma, bleeding, acute pancreatitis, etc. Already has a significant pathological component in its "anamnesis" and therefore it can not be regarded as an initially healthy patient.

Summing up the discussion of modern ideas about the pathogenesis of sepsis, it is necessary to return to the basic concepts of the problem again, in order to avoid the often encountered ambiguous interpretations and to more clearly define the role and place of each of the concepts in the theoretical concept of generalized forms of infection and in the clinical practice of their treatment.

First of all, we are talking about a systemic inflammatory reaction. In publications, it is referred to as a systemic inflammatory response or a syndrome of a systemic inflammatory response. Depending on the purposes of use and the context of the discussion, different meanings are put into these notations. Systemic inflammatory reaction syndrome, or SIRS, is a screening category that allows to select from a population a group of individuals who have three or four known signs that have the status of determining criteria (SIRSIII or SIRSIV, respectively). It is a mistake to supplement the screening criteria with different laboratory, functional or other indicators. It is also incorrect to oppose the two concepts proposed by R. Bon and co-authors, the syndrome of the systemic inflammatory reaction (SIRS) and the anti-inflammatory compensatory reaction syndrome (CARS). The latter has a more capacious and complex semantic content. As a natural "counterweight", this reaction controls the excessive expression of the systemic inflammatory response, being in its deepest essence as multifactorial as the latter. It can not be expressed concisely and clearly as a syndrome, and therefore it should not be used as an alternative to the syndrome of a systemic inflammatory reaction (SIRS). The anti-inflammatory compensatory reaction (CARS) syndrome manifests itself indirectly, through the relationship with the multifactorial mechanisms of the systemic inflammatory response, and through one of the isolated phases (forms) of the generalized inflammatory response of the body to infection.

According to the authors' conception, the pathogenesis of clinical manifestations depends on the pro-inflammatory cascade ratio (for systemic inflammatory reaction) and anti-inflammatory mediators (for anti-inflammatory compensatory reaction). The form of clinical manifestation of this multifactorial interaction is the degree of severity of multiorgan 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.

Thus, each of the notations proposed for the systematization of modern concepts of sepsis has a specific purpose in the overall concept.