Antibiotics (Properties, Application, Interaction) - M.P. Cherenko 1999

General surgical infection — Sepsis

General surgical infection (“Blood poisoning”), or Sepsis, is a generalized, non-specific inflammatory disease of an infectious and surgical nature that develops in patients with a local focus of surgical infection due to inadequate therapeutic management and impaired immunological defense. Less commonly, infectious agents enter the vascular bed during invasive examinations or therapeutic Procedures As a result of aseptic breaches. Reduced resistance to infection in patients is primarily a consequence of the toxic impact of the local infection site on the body and, less frequently, of congenital or acquired immunodeficiency.

Most often, sepsis develops in cases of delayed Diagnosis and ineffective Treatment of extensive local forms of purulent infection—such as untimely opening and drainage of purulent wounds, phlegmons, carbuncles, mastitis, felon, Arthritis, or delayed closure of burn wounds; or inadequate antibiotic and surgical management of specific infections (erysipelatous inflammation, Hematogenous Osteomyelitis, Pleurisy, Peritonitis, gynecological infections, Urinary Tract infections, etc.). In newborns, sepsis is caused by infection of the umbilicus (umbilical cord stump). Occasionally, sepsis develops following minor accidental injuries. The site of entry into the body (local infection focus, wound, burn, etc.) is referred to as the portal of entry. In rare cases where sepsis develops from an undetermined portal of entry, it is termed cryptogenic sepsis (derived from the Greek kryptos, meaning hidden).

Although there is no absolute direct correlation between the size of the portal of entry (local focus) and the frequency of sepsis, the probability of developing sepsis increases sharply in the presence of massive foci or when a large quantity of highly virulent microorganisms enters the body through the portal of entry. Especially dangerous are portals of entry (regardless of size) through which highly virulent microorganisms gain direct access to the bloodstream (via vascular punctures during the prolonged, non-aseptic Introduction of needles, tubes, or catheters), or when the source of infection is localized directly within the vessels (suppurative thrombophlebitis, lymphangitis, etc.). Sepsis can be triggered by A wide variety of microorganisms from the Class of pyogenic and putrefactive agents, most commonly gram-positive staphylococci, streptococci, and pneumococci, as well as gram-negative bacilli such as Escherichia coli, Neisseria meningitidis, Proteus, Pseudomonas aeruginosa, and Enterobacter. As a rule, sepsis is caused by a single microbial species (monoculture), and less frequently by an association of two or more microorganisms (e.g., staphylococcus and streptococcus; staphylococcus, E. coli, and Proteus; E. coli and non-clostridial anaerobes, etc.).

In most patients in our country, as in other former USSR states, staphylococcal sepsis is observed in 60% or more of cases (M.I. Kuzin, B.M. Kostyuchonok, 1981; M.N. Malynovsky et al., 1992). The most frequent sources and portals of entry for staphylococcal sepsis are purulent wounds, Burns, carbuncles, mastitis, osteomyelitis, felon, etc. Streptococcal sepsis, which held first place in the pre-antibiotic era, has become rare. It most commonly complicates infections of the Upper Respiratory Tract and ENT Organs (tonsillitis, sinusitis, etc.), the Middle ear (otitis), erysipelas, respiratory tract infections, bone infections, and umbilical infections. Pneumococcal sepsis, which is closely related to streptococcal sepsis, typically arises as a complication of Pneumonia, Bronchiectasis, Bronchitis, ENT diseases, pericarditis, etc. Over the past 30 years, gram-negative sepsis has become significantly more prevalent (accounting for up to 40% or more of sepsis cases), particularly coliform sepsis (colibacillary and others) and pseudomonal sepsis in Western Europe and the USA (W.A. Altemeir, 1976; S.G. Rabinowitz, 1980, et al.). Gram-negative coliform sepsis develops predominantly in infections of the digestive and urogenital systems, wounds, biliary tract, and ear, among others.

Pseudomonal sepsis occurs in cases of wound infections, respiratory tract infections, burns, urinary tract infections, invasive examinations, and prolonged intravenous therapy.

The source of anaerobic bacteroidal sepsis includes Disorders of the gastrointestinal tract, especially the colon and rectum, the biliary tract (cholangitis, etc.), wounds, and burns.

The sharp increase in cases of gram-negative sepsis is driven by A number of factors, including the high resistance of these microbes to the Antibiotics most frequently used to treat purulent surgical infections, their lower nutritional demands, hospitalism, and the widespread use of invasive diagnostic and therapeutic Methods and infusion therapy in clinical practice, which easily create favorable conditions for the vital activity of this microflora (angiogenic sepsis).

Sepsis is classified according to numerous criteria. First and foremost, based on its Clinical presentation, sepsis is divided into sepsis with metastases (the appearance of secondary infection foci beyond the primary source), which corresponds to the older term for this form—pyemia, and sepsis without metastases, which is identical to the former term—septicemia. Today, there is every reason to view these forms not as independent entities, but rather as phases or stages of a single pathological process, distinguishing among the toxemic phase (or initial stage of sepsis), septicemia, and septicopyemia.

Depending on the type of pathogen, sepsis is classified as staphylococcal, streptococcal, pneumococcal, meningococcal, coliform (Escherichia coli, Proteus vulgaris, Klebsiella, and other microbes of this group), pseudomonal (or pyocyanic), clostridial, or anaerobic non-clostridial (non-spore-forming) sepsis. Sepsis caused by Gram-positive microorganisms is termed gram-positive sepsis (staphylococcal, streptococcal, etc.), whereas that caused by Gram-negative microorganisms is termed gram-negative sepsis (coliform, pseudomonal, meningococcal, anaerobic, bacteroidal, etc.). Based on the presence or absence of a visible source of infection, sepsis is subdivided into primary or cryptogenic (rare) and secondary, complicating a visible (primary) source of infection.

According to the localization of the primary source, obstetric-gynecological, otogenic, urological, odontogenic, surgical, and therapeutic sepsis are distinguished, among others.

Based on The Nature of the source, classifications include wound sepsis (including postoperative and injection-related angiogenic sepsis), burn sepsis, umbilical sepsis, and sepsis associated with INFECTIOUS DISEASES OF various organs and systems (osteomyelitis, arthritis, carbuncle, Pyelonephritis, lung abscess, etc.).

Depending on the time course of development, early sepsis (occurring within the first 2 weeks) and late sepsis (occurring after 2 weeks or more) are distinguished.

According to its clinical course, sepsis can be fulminant, acute, subacute, or chronic. Acute and chronic sepsis are observed most frequently, while other forms are less common. When sepsis is mentioned without further specification, an acute process is always implied.

Fulminant sepsis develops within a single day (sometimes just a few hours), occasionally following minor injuries. It typically results in death by the second or third day. This form is observed primarily in individuals with compromised General and Specific reactivity, and its causative agent is predominantly streptococcus.

Chronic sepsis is predominantly of odontogenic, tonsillogenic, or cardiogenic origin, and less frequently urological or cryptogenic. It is caused by staphylococci, streptococci, or their associations with non-clostridial anaerobes and fusospirochetes.

Some authors distinguish recurrent sepsis, which is essentially a chronic process punctuated by flare-ups. It should be noted that foreign researchers do not draw a sharp line between local infection and systemic infection (sepsis). They consider all forms of surgical purulent infection to be manifestations of sepsis, and purulent wound complications to be septic complications.

The Pathogenesis of sepsis is complex and not yet fully elucidated. It must be viewed as a process of intricate interaction between two main factors: pathogenic microbes and the macroorganism (taking into account the latter's characteristics, its resistance to microbial aggression, and its immunological reactivity). Furthermore, this interaction should be examined in terms of a balance disruption between these factors, primarily favoring the microbes. Such a balance disruption can result either from a massive and prolonged invasion of highly virulent microflora into a body with normal immunological reactivity, or from a minor microbial invasion into a body with profoundly altered acquired or congenital Immunity. Therefore, underestimating either of these factors, as well as overemphasizing one over the other, is detrimental to the treatment and Prevention of this dangerous disease. Naturally, today—when the causative agents of infections, including surgical ones, have long been known, effective antimicrobial drugs exist, and a high standard of sanitation and hygiene (both domestic and occupational) has been achieved, at least in industrialized nations—it would be logical to assume a decrease in the frequency of exogenous (from air, Water, soil, Skin, surrounding objects, etc.) massive invasions of pathogenic microorganisms into the human internal environment. Perhaps this reasoning was the reason why, not so long ago (particularly in the post-war years), The Role of microbes was somewhat underestimated, and the Organism's reactivity and immunity were assigned an exclusive role. However, all these assumptions proved incorrect for many reasons. Suffice it to name just the main ones, namely:

a) The Emergence of highly virulent strains of pathogenic microbes that are resistant to many modern antibiotics and other therapeutic agents;

b) the advancement of surgery with its cutting-edge complex methods—both invasive and non-invasive—of Diagnosis and treatment, which facilitate the direct penetration of pathogenic microflora into the vascular bed; along with an increase in the number of operations performed on elderly patients and the prolonged duration of surgical interventions;

c) the sharp deterioration of global ecology, with its negative impact on human health.

In the pathogenesis of sepsis, alongside the massiveness and virulence of the microflora, an important role is played by the anatomical and PHYSIOLOGICAL CHARACTERISTICS OF the primary focus (portal of entry), the Features of the organism's nonspecific and specific reactivity, and many other local and general factors (concomitant diseases, age, etc.). Evidence for the role of microbial invasion massiveness in the pathogenesis of sepsis is the fact that the latter predominantly develops in large and long-standing foci of local infection, during invasive examinations and intensive infusion therapy performed with breaches of asepsis, or when microbes gain direct entry into the vascular bed (bloodstream).

A major role in The Development of local INFECTION AND ITS complication by sepsis is played by the presence, within the portal of entry (primary source) zone, of a large amount of damaged (necrotic and semi-necrotic) tissues, impaired Blood Circulation in that area (tissue Hypoxia), delayed outflow of exudate, microbes, toxins, and Cell breakdown products, insufficient access of oxygen to the site of microbial invasion, and increased absorption of toxins and microbes by tissues. Under such conditions, local mechanisms of tissue and humoral defense cannot effectively counteract microorganism proliferation and infection development. The localization of the primary source is also of paramount importance. Infectious inflammatory processes in closed Bone and joint cavities, the Bone Marrow, the Pleura, the Peritoneum (due to the high absorptive capacity of these cavities), the maxillary sinuses, the urinary tract, the skin with its rich Lymphatic system, the subcutaneous tissue with its low resistance to infection and potential for horizontal spread, and the mammary gland—with its rich vascular, lymphatic, and ductal systems and frequent postpartum lactostasis—represent the most frequent anatomical primary sources of sepsis. When sepsis arises from the direct penetration of pathogenic microflora into Blood Vessels (angiogenic sepsis), especially when the portal of entry is long-standing, its Anatomical and physiological features are of no significant consequence, since the microflora immediately enters the systemic circulation; in this case, only the localization of secondary infection foci depends substantially on the anatomical and physiological properties of tissues and organs. Sepsis predominantly develops in accidental wounds with massive zones of tissue damage, frequently accompanied by injuries to major vessels and bones, as well as deep, extensive burns, and such common infectious diseases as hematogenous osteomyelitis, pyogenic arthritis, purulent pleurisy, peritonitis, pyelonephritis, phlegmons and abscesses of various localizations, erysipelas, mastitis, and suppurative thrombophlebitis (S. Popkirov, 1977).

In addition to the aforementioned local infection foci, favorable conditions for the development of sepsis include the facilitation of direct, prolonged, or massive entry of pathogenic microbes into the vascular bed or sterile anatomical channels (urinary, biliary, etc.). This can occur due to traumatic or other disruptions in the integrity (permeability) of a vessel or duct wall. Today, this is observed with particular frequency due to the introduction into clinical practice of new diagnostic and intensive care technologies involving the long-term placement of catheters, guidewires, and needles into vessels and ducts. As a result of aseptic breaches, microflora enters the body's internal environment (the Circulatory system or duct cavities). Under normal immune conditions, microorganisms and toxins (exotoxins, endotoxins from microbial Cells, as well as tissue toxins from necrotic cells) are neutralized (phagocytized and inactivated), bacteremia may occur only episodically, and infection generalization is contained—although the body's overall systemic reaction to intoxication and microbes can be significant. This reaction was termed purulent-resorptive fever by the prominent pathologist I.V. Davydovsky (1960). With correct and timely Treatment of the local focus, this reaction is reversible, and toxemia phenomena disappear within an average of one week. If this does not occur (despite proper treatment), it indicates the onset of sepsis. The pathogenesis of sepsis is determined by the microbial factor, the characteristics and localization of the local focus (portal of entry), and the general reactivity, particularly immunological reactivity. The development of sepsis—specifically fulminant sepsis—following minor injuries (such as a puncture wound of a finger) is undeniable proof of The Significance of general reactivity and a manifestation of profound immune impairment. The latter may result either from congenital patient characteristics (immune system defects, e.g., agammaglobulinemia) or, more frequently, from acquired conditions caused by various illnesses—such as AIDS, Diabetes Mellitus, anemia, hypoproteinemia, malignant tumors, collagenoses, as well as advanced age, radiation sickness, post-splenectomy states, severe hypovitaminosis, and the administration of high doses of immunosuppressants, such as corticosteroids.

Numerous other systemic disturbances (such as dehydration, Shock, and atherosclerosis) also contribute to the development of sepsis. In other words, sepsis—like Other types of surgical infection (and infections in general)—is the outcome of a complex interaction between the infectious agent and the reactive Properties of the human body. The initial stage of sepsis (prolonged purulent-resorptive fever) is referred to by some authors as the toxemic stage. The sustained release of toxins, and less frequently microbes, into the BLOOD AND Lymph streams from the local focus—manifested by purulent-resorptive fever—suppresses and impairs humoral and tissue defense mechanisms, including chemotaxis, opsonization, The Complement System, phagocytosis, and the T- and B-lymphocyte systems (Yu.I. Zimin, 1988; M.N. Malynovsky et al., 1992, et al.), leading to generalized infection in the absence or insufficiency of therapeutic management. Microbes, by fixing and multiplying within the microcirculatory bed, saturate it with their toxins, causing septicemia (the Second Stage of sepsis), as well as The formation of new, secondary infection foci in organs and tissues via the deposition of microbial emboli in the form of small abscesses. This is the Third Stage of sepsis: sepsis with metastases, or septicopyemia. From these secondary foci of sepsis, an additional large quantity of toxins and microbes enters the bloodstream.

The reactivity of the organism, particularly immunological reactivity, is a highly complex phenomenon. Most often, the body's reaction to various stimuli, including toxic ones, can be of medium or normal intensity, which is defined as normergic. When the body's reaction is of high intensity and inadequate to the strength of the stimulus, it is termed a hyperergic reaction, and when it is of very low intensity, a hypergic reaction. Both hyperergic and hypergic reactivity are predominantly characteristic of patients with sepsis. Forms of so-called fulminant sepsis, which develops within extremely short timeframes following the invasion of an infectious agent, typically occur in individuals with a hyperergic reaction, whereas individuals with subacute and chronic sepsis more frequently exhibit a hypergic type of response.

Studies on the Pathophysiology of sepsis in recent years have demonstrated that sepsis is not merely a consequence of the direct action of microorganisms and their toxins on body cells. Its pathogenesis is largely driven by a combination of systemic reactions triggered by numerous anti-inflammatory mediators whose production is initiated by bacterial endo- and exotoxins. Since the primary cause of such a systemic inflammatory response can also be toxic products of necrotic tissues resulting from trauma, pancreatic necrosis, burns, and the like, sepsis is considered a specific form of the "systemic inflammatory response syndrome" (SIRS). If this syndrome develops as a result of a clearly defined infection, it is classified as sepsis.

It has been proven that a special role in triggering the body's systemic reactions during sepsis is played by the Polysaccharides of the gram-negative microbial envelope, as well as the capsular polysaccharides and peptidoglycans of gram-positive Bacteria. They activate macrophages and polymorphonuclear leukocytes, which leads to enhanced immunity through The production of numerous inflammatory mediators—cytokines—by these cells. Among the latter, tumor necrosis factor and interleukins are of particular importance. Cytokines stimulate the generation of many other inflammatory mediators (free oxygen radicals, nitric oxide, Proteolytic Enzymes, kinins, arachidonic acid metabolites such as Prostaglandins, Leukotrienes, biogenic amines, etc.).

The chain of systemic reactions caused by microbes, their toxins, and anti-inflammatory mediators leads to the development of cardinal symptoms of sepsis and its late-stage complications—septic shock and multiple organ dysfunction syndrome (affecting the Lungs, Kidneys, Liver, bone marrow, intestines, etc.). Organ damage is largely associated with the translocation of a massive load of microorganisms and their toxins from the intestine into the vascular bed.

An uncontrolled cascade of systemic inflammatory reactions—many of which, in controlled and non-generalized forms, are Components of the body's physiological defense mechanism—transforms the purpose of these reactions from enhancing immunity to its opposite (immune paralysis). Given this effect, the cascade of systemic reactions in sepsis is often metaphorically compared to "autocannibalism" ("septic autocannibalism").

Advances in studying the pathogenesis of sepsis provide a foundation for expanding the arsenal of targeted treatments. In particular, clinicians administer inhibitors of various mediators, including tumor necrosis factor factors (pentoxifylline), free radicals, nitric oxide, prostaglandins, acetylsalicylic acid, monoclonal antileukocytic Antibodies, etc.

Pathomorphological changes in a sepsis patient are numerous but, unlike cyclic infections, non-specific. They manifest as inflammatory-dystrophic and necrotic phenomena in the patient's organs and tissues, with manifestations depending on the phase and nature of sepsis. The most pronounced changes are found in The Heart, organs rich in reticuloendothelial tissue (Spleen, liver, Lymph Nodes, etc.), and the kidneys. Fatty degeneration morphologically predominates. The heart resembles that in serous myocarditis, and rarely endocarditis (in streptococcal and colibacillary sepsis). The liver exhibits small focal areas of necrosis; the kidneys show inflammatory-dystrophic-necrotic Changes in the tubules, and occasionally pyelitis or nephritis. The spleen is significantly enlarged, soft, hyperemic, and dark red, revealing pulp hyperplasia, signs of cell necrosis and breakdown, a high number of leukocytes and hemolyzed erythrocytes, hemosiderin, and plasma cells.

The lymph nodes exhibit hyperplasia of the nodes themselves and their follicles, along with desquamation of the sinus endothelium.

Blood vessels, especially small ones, show signs of vasculitis, necrosis, and Hyalinosis of the cell walls.

Focal microhemorrhages occur in the skin, serous and mucous membranes, and parenchymatous organs.

The Nervous Tissue demonstrates glial edema, serous meningitis, and occasionally focal encephalitis.

The digestive tract displays mucosal edema, hemorrhages, and signs of exudation.

In septicopyemia, alongside the aforementioned changes, various organs and tissues predominantly exhibit numerous small abscesses—secondary foci (metastases) of infection. They are primarily localized in the liver, lungs, kidneys, Brain, skin, subcutaneous tissue, bones, and joints. Both the frequency and localization of metastases largely depend on the Nature of the causative pathogen. For instance, staphylococcal sepsis is accompanied by metastasis in 95% of cases, predominantly affecting the lungs, bones, joints, brain and its Meninges, subcutaneous tissue, and kidneys. In gram-negative sepsis, metastases are observed much less frequently (in 25%) and are more commonly localized in the liver, brain, meninges, kidneys, urinary tract, and bones.

Dystrophic, inflammatory, and necrotic processes in organs and tissues, as well as secondary foci of infection (metastases), severely impair the Functions (both specialized and defensive) of these organs and systems, frequently leading initially to metabolic, and later to respiratory and cardiac failure (A. Kazda, 1988). Multiple organ failure exacerbates the disorders caused by microbial intoxication, resulting in severe complications such as septic shock, thrombohemorrhagic phenomena, and severe Central Nervous system disorders.

The clinical picture of sepsis comprises signs and symptoms of the primary local infection focus, present in the majority of patients, alongside manifestations of a general infectious disease with symptoms of internal organ damage. Typically, regardless of the stage, the Clinical presentation of sepsis is dominated by symptoms of an acute generalized infectious disease. Its most prominent symptom complex is a high-grade fever accompanied by chills and sweating. This type of fever is particularly characteristic of septicemia. The Temperature curve in this stage of sepsis is hectic (febris hectica), with a diurnal fluctuation of 3 °C or more between morning and evening readings. It is believed that temperature spikes coincide with the release of toxins into the bloodstream.

In septicopyemia (sepsis with metastases), the temperature curve is predominantly of a continuously high type (febris continua) without sharp fluctuations between morning and evening.

The initial stage of sepsis—toxemia—is similar to septicemia in its fever pattern, though with somewhat less pronounced temperature spikes and chills. The patient's general condition at the onset of sepsis is severe and rapidly deteriorates.

Manifestations of intoxication in sepsis also include marked weakness, lethargy, loss of appetite, headache, dyspeptic disorders, and depression of the psycho-emotional sphere (more rarely euphoria and agitation), sometimes progressing to unconsciousness.

As a systemic inflammatory response, sepsis is accompanied by damage to all systems and organs. Functions are impaired to varying degrees, depending on the baseline condition of the organs, the CHARACTERISTICS OF THE pathogen, and the patient's reactivity. However, regardless of the initial status, organs rich in reticuloendothelial tissue—namely the liver, lymph nodes, bone marrow, spleen, kidneys, lungs, and The Cardiovascular system—sustain the most severe damage. This is primarily due to the vital role these organs and systems play in maintaining Homeostasis and detoxifying harmful substances. The damage to these organs is accompanied by numerous clinical signs and complications.

The general appearance of patients indicates an unsatisfactory condition; they lose their vitality and vigor, becoming indifferent to their surroundings. The patient's skin has a pale cyanotic or pale yellowish tint with focal microhemorrhages (petechiae and larger spots) and is covered in sweat. The mucous membrane of the Lips is cyanotic, and the lingual mucosa is dry with a brownish-gray coating. The voice is muffled and low-pitched due to dehydration, particularly of the mucous membranes.

Cardiovascular disorders manifest as tachycardia, decreased blood pressure, reduced Cardiac Output, and muffled heart sounds. Myocarditis develops more frequently, and endocarditis less frequently. Respiration is rapid and shallow. Pneumonia is frequently detected and requires differentiation from metastatic abscesses.

Regarding the Digestive System, alongside dyspeptic phenomena (nausea, less frequently vomiting), enterocolitis—especially in staphylococcal sepsis—and toxic hepatitis are frequently observed. The latter conditions, along with erythrocyte hemolysis, cause jaundice of the sclera and skin, which is particularly common in gram-negative sepsis.

Blood tests reveal high leukocytosis with a left shift in the leukocyte formula (appearance of immature neutrophil forms, such as band cells and metamyelocytes). Eosinophils disappear, and the lymphocyte count decreases sharply. Anemia progresses catastrophically due to bone marrow impairment and disrupted hematopoiesis. Alongside quantitative hemogram changes, biochemical alterations occur, particularly in protein and vitamin profiles (primarily due to toxic liver damage). The concentration of low-molecular-weight Proteins (albumins) drops sharply, while globulin and fibrinogen levels increase. The blood enzyme spectrum changes, marked by rising concentrations of proteolytic enzymes and kinins (G.A. Ivashkevich et al., 1979). The production of Vitamins A, D, K, B₁₂, and others declines. Coagulation disorders ensue. Initially, biochemical blood changes lead to enhanced coagulativity (which can trigger thromboembolic complications). Subsequently, due to escalating proteolysis (Fibrinolysis), suppression of hepatic clotting factor synthesis, and consumption of these factors in microcirculatory thrombus formation, blood coagulativity decreases while bleeding tendencies increase. The latter results in neurotrophic hemorrhages of various types in the skin—predominantly petechiae or streak-like ecchymoses—and in the mucous membranes, especially of the digestive tract.

Urinalysis reveals protein, leukocytes, and casts. Urine specific gravity and diuresis are reduced. Clinical (physical) signs of pyelitis (pyelonephritis), such as lower back pain, are frequently observed.

In septicopyemia, secondary foci of infection (metastases) are detected in various tissues and organs (skin, subcutaneous tissue, joints, periosteum, meninges, lungs, etc.). Infectious metastases are particularly characteristic of staphylococcal sepsis (95%). This is explained by the ability of staphylococci to coagulate fibrin, which helps microbes and toxins entering the bloodstream from a wound or another source settle in organs. Streptococci and coliform microbes do not coagulate fibrin, and therefore their likelihood of fixation in organs is much lower. Infectious metastases in these forms of sepsis account for 25–35%, respectively.

Metastases are detected using radiological, sonographic methods, computed tomography, Magnetic Resonance imaging, and other diagnostic tools.

All METABOLISM/4.html">Types of Metabolism are disrupted. The general pattern of metabolism is characterized by a sharp predominance of catabolic processes over anabolic ones. A dramatic increase in Catabolism leads to heightened basal metabolism, rapid weight loss (due to high Energy Expenditure by the body at the expense of fats and proteins), fluid loss (dehydration and electrolyte imbalance), decreased concentrations of sodium and chlorides, as well as calcium, elevated potassium levels, and acidosis. Acidosis can frequently develop secondary to respiratory disorders; in other words, metabolic acidosis is compounded by respiratory acidosis. However, in many cases of sepsis, predominantly gram-negative, alkalosis is observed (associated with frequent, deep breathing), which disrupts the acid-base balance. Metabolic Disorders are closely linked to dysfunctions of their regulatory centers—the hypothalamic-pituitary complex and peripheral Endocrine glands, such as the Adrenal Glands, the endocrine Pancreas, and others.

The body's small Glycogen reserves, concentrated primarily in The Liver and to a lesser extent in the Muscles, are rapidly depleted during sepsis (within the first 12 hours). Through anaerobic Glycogenolysis, the body cannot fully meet its energy demands, prompting a shift toward utilizing energy derived from fats and proteins. Their entry into Catabolic pathways is stimulated by activation of the sympathetic nervous system, catecholamines, corticosteroids, and Glucagon. Supplying the body with energy via fats and proteins is accompanied by rapid and significant weight loss in the patient. Fat mass loss can reach 200–500 g per day, while protein loss can amount to 200–300 g. Catecholamines and glucagon (the primary second messengers of lipolysis) activate adenylate cyclase, which catalyzes the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). cAMP subsequently activates triglyceride lipase, which breaks down triglycerides in fat cells into glycerol and Fatty acids. The latter are oxidized in the Krebs cycle (Tricarboxylic Acid Cycle or Citric Acid Cycle) to supply energy to the body. Cortisol and somatotropin act in a similar manner, albeit less intensively. The second source of energy is Muscle Proteins, whose Amino Acids are utilized by the liver for Gluconeogenesis. Cortisol plays an even more crucial role in this process than in lipolysis. Insulin secretion in sepsis patients is generally depressed and is only stimulated by hyperglycemia, which occurs in the Cytology/cytology/16.html">Early stages of sepsis as a consequence of hypercatecholaminemia.

Striking changes occur at the local site of infection. Granulation tissue development is inhibited; granulations become pale gray, flabby, lose their luster and moisture, and subsequently undergo necrosis. Exudate becomes sparse, watery, seropurulent, or serohemorrhagic (forming a "dry wound"). Tissue necrosis progresses within the local inflammatory foci. Thrombophlebitis, lymphadenitis, and lymphangitis are frequently detected around the source of infection. The general appearance of the wound (or focus) indicates a complete halt in regenerative and reparative processes.

Clinical symptoms, particularly physical signs, are the most critical indicators of sepsis and form the cornerstone of its diagnosis. At the same time, by definition, confirming a diagnosis of sepsis requires blood test results demonstrating bacteremia. Although bacteremia as an episodic, transient phenomenon can occur with various local infection sites in the absence of clinical signs of sepsis (some researchers even classify bacteremia as a distinct form of infection development), it is far from always detected in sepsis patients, even with repeated testing. This circumstance explains why the term "septic state," alongside others, is frequently used instead of "sepsis" (G.A. Ivashkevych, 1976, et al.). Presumably for this reason, many Western researchers, particularly in the USA, refer to any purulent wound infection or postoperative infection accompanied by a drainage-requiring abscess as sepsis. However, reports indicate that bacteremia was successfully detected in 99% of sepsis patients within the first three blood samples drawn over a 24-hour period (S.G. Rabinowitz, 1980). Naturally, in every case of a septic state, one should strive to confirm the diagnosis with blood culture results (bacteremia); however, given current understandings of sepsis pathogenesis, its developmental phases (toxemia, septicemia, and septicopyemia), and the limitations of microbiological testing technology, such confirmation is not always obtainable. Therefore, the absence of bacteremia in the presence of clinical signs of sepsis does not rule out the diagnosis. To increase the detection rate of bacteremia when sepsis is suspected—and all the more so when undeniable clinical signs are present—blood cultures should be drawn repeatedly (up to 3 times a day if no growth is found in the initial samples), particularly during fever spikes, and microbiological analysis should be performed under both aerobic and anaerobic conditions. To microbiologically confirm the diagnosis of gram-negative sepsis—when identifying Microorganisms in the blood During the first 48 hours is difficult—attempts were made in the USA to test for the presence of gram-negative endotoxins in the blood, which consist of outer membrane Lipoproteins from these microbes. The test utilized amoebocyte lysates from the horseshoe crab *Limulus polyphemis*. When mixed with endotoxin *in vitro*, the prepared lysate transformed into a gel. In practice, however, this test proved to have low efficacy.

MICROBIOLOGICAL EXAMINATION OF blood and material (pus) from a wound (or other site of infection) may yield non-identical species of microorganisms. Wounds are frequently contaminated with microorganisms other than those that caused the sepsis. Consequently, in the absence of bacteremia, the microflora of a wound (or local purulent process) cannot be assumed to be the CAUSATIVE AGENT OF sepsis. The absence of Microbial growth on culture media inoculated with discharge from a purulent wound or blood indicates the anaerobic nature of the microbes rather than their absence.

Sepsis is frequently complicated by numerous general and local pathological conditions, which are predominantly what leads to the patient's death. Among these complications, the most frequent are pneumonia, Hemorrhage resulting from vessel erosion within a wound or purulent focus (erosive, mechanical hemorrhage, or neurotrophic hemorrhage due to coagulation system disorders), thromboembolism of major vessels (pulmonary artery, cerebral vessels, and extremities, especially the lower ones), toxic or septic shock, pressure ulcers, and others. Toxic shock is the most dangerous, particularly frequently accompanying gram-negative sepsis. Against the Background of sepsis, shock is accompanied by a sharp drop in cardiac output—rapid, thready pulse, low blood pressure, respiratory failure manifested by tachypnea and cyanosis (with flushed Cheeks in the hyperdynamic phase of shock), cold sweat, oliguria progressing to anuria, disseminated intravascular coagulation (DIC syndrome), and other symptoms.

Septic shock is predominantly observed in severe damage to The Heart and other Internal Organs, particularly when multiple organs are affected (multiple organ failure). It is accompanied by a high mortality rate of 50–70% or more.

Recently, the development of septic shock has been linked to the hyperproduction of nitric oxide (NO) in the body of a sepsis patient. As an intermediate product of L-Arginine metabolism, NO is produced in large quantities by peripheral monocytes, alveolar macrophages, Kupffer cells, non-profile leukocytes, and the vascular endothelium when stimulated by bacterial lipopolysaccharides and cytokines. Nitric oxide, which plays a major physiological role in vascular relaxation—particularly in coronary vessels (its deficiency can lead to coronary artery disease, Hypertension, etc.)—causes vascular relaxation, tissue edema formation, and modulates nerve ending sensitivity when its production is elevated. By reacting with free radicals, it also forms sodium peroxynitrite, which is a cytotoxic agent. The effects of NO on the vasculature and nervous system contribute to the development of shock. Nitric oxide production is inhibited by corticosteroids such as hydrocortisone (cortisol) and prednisolone.

Diagnosing sepsis in typical cases presents no difficulty when the primary, characteristic syndromes and symptoms are present—namely, a significant local infection site, chills, hypotension, a fever that fails to regress or disappear within an average of one week following radical surgical intervention, and bacteremia. However, this constellation of signs, particularly the presence of bacteremia, occurs in no more than 50–85% of cases.

Consequently, diagnosing sepsis is frequently challenging, and diagnostic errors occur quite often—in up to 37% of patients, it goes undiagnosed (V.I. Petrov, N.A. Lopatkin, 1986).

Clinical observation of the relationship between the local site of infection and the body's general reaction—specifically the dependence of the latter on the state of the focus—plays a major role in diagnosing sepsis. A direct correlation exists between the condition of the local focus and the severity of the general reaction, particularly fever. Following an intervention at the infection site—its removal or opening, if unopened or inadequately drained, and clearing it of purulent exudate and necrotic masses—the systemic toxic reaction is rapidly eliminated (within 3–5 days, and no later than 7 days). However, if toxic manifestations persist after radical intervention at the infection site, or if they appear in the absence of local source complications, sepsis should be suspected regardless of the presence or absence of bacteremia. Such a clinical course should be considered the onset of sepsis, its initial phase—toxemia (M.N. Zubkov et al., 1989).

Alongside escalating systemic intoxication, impaired function of multiple organs (appearance of scleral and skin jaundice, respiratory failure), progressive anemia, and a left shift in the leukocyte differential, a critical indicator is the cessation of reparative and regenerative processes within the local focus itself—the wound, burn surface, etc. The appearance of infection metastases or the development of heart failure and septic shock are late manifestations of sepsis.

Septic shock develops particularly frequently in gram-negative sepsis, in which bacteremia is less commonly detected. Instrumental, immunological, and biochemical Research Methods (determining the levels of active lymphocytes, lactic acid in blood and other fluids, blood coagulativity indices, etc.) are of great importance for the timely diagnosis of sepsis and infection metastases.

Blood cultures for bacteremia should be performed 5–8 times over a 48–72 hour period from the onset of sepsis signs, drawing blood for bacteriological seeding during peak BODY TEMPERATURE AND chills. In the absence of bacterial growth on the nutrient medium inoculated with wound discharge, one should always consider the presence of anaerobic microflora rather than the absence of microorganisms. Only early diagnosis of sepsis and intensive, comprehensive treatment significantly impact the final therapeutic outcome of this life-threatening condition.

Treatment for sepsis must be aggressive, comprehensive, etiopathogenetic, and individualized. The individualization of sepsis treatment is based on criteria such as the portal of entry (the source of the infectious agent), the nature of the pathogen, the clinical form of sepsis, and the patient's pathophysiological profile. Sepsis treatment is multimodal, encompassing both surgical intervention and conservative therapy. Because nearly all cases of sepsis are linked to a local infection site, primary control of this focus is mandatory—including wide opening (in cases of inadequate drainage), removal of devitalized tissues, and, whenever possible, complete excision. Although during the established sepsis stage there is no longer the same direct dependence between the state of the local focus and systemic pathological manifestations as seen in purulent resorptive fever (where systemic febrile phenomena rapidly and reversibly resolve following radical intervention and sanitation of the local infection source), neglecting the debridement of the local focus is unacceptable.

Surgical intervention is performed on both the primary source of infection and secondary metastatic abscesses, provided they are surgically accessible (removal, opening, or aspiration via puncture of, for example, superficial abscesses, deep purulent collections, infected cavities, etc.). It is generally impossible to surgically eliminate numerous small abscesses in the lungs, liver, bone marrow, etc. In such cases, success depends entirely on therapeutic measures, primarily antibiotic and detoxification therapy. Nevertheless, even with such metastatic abscesses, punctures and pus aspiration under ultrasound or computed tomography guidance can be employed.

Antimicrobial and detoxification therapy play a decisive role in overcoming generalized infection. Antimicrobial therapy for sepsis is primarily carried out using antibiotics (antibiotic therapy). It is conducted using antibiotics to which the sepsis pathogen is sensitive. This is established through prior identification of the microflora and its antibiotic sensitivities in the local infection site that precipitated the sepsis, or *a priori* based on the broad-spectrum coverage of the prescribed antibiotic if microflora and sensitivity cannot be determined due to the rapid progression of sepsis. In the latter scenario, the initially prescribed antibiotic therapy must subsequently be adjusted following microbiological identification of the microflora (from blood cultures) and determination of its antibiotic sensitivities.

The most effective agents in treating staphylococcal sepsis are Aminoglycosides (such as gentamicin) and 3rd- to 4th-generation Cephalosporins, whereas penicillin-group drugs and erythromycin are most effective for streptococcal sepsis. For gram-negative sepsis, effective agents include gentamicin, chloramphenicol, metronidazole, clindamycin, ciprofloxacin and its derivatives, as well as sulfonamides (particularly trimethoprim-sulfamethoxazole/bactrim), tienam, and others. Antibiotic therapy—specifically penicillin-group drugs, including semisynthetic forms—is prescribed in high doses according to appropriate regimens. Antibiotics are administered intramuscularly, intravenously, and endolymphatically (using appropriate preparations and formulations), or orally if the digestive tract is not compromised (e.g., ciprofloxacin preparations and sulfonamides). Tienam exhibits high antimicrobial activity.

Antimicrobial therapy also includes laser and ultraviolet blood irradiation, among other methods. Detoxification therapy (intoxication being caused by microbial exo- and endotoxins as well as metabolic products—various peptide compounds, middle molecules, antigen-antibody complexes, biogenic amines, etc.) is accomplished by diluting toxic substances in the blood, binding (neutralizing) them, and eliminating them from the body. Detoxification is performed using substances (solutions) of diverse chemical composition alongside physicochemical procedures (hemo- and lymphosorption, plasmapheresis, peritoneal dialysis, Forced diuresis, renal dialysis, etc.). Reduction of concentration, inactivation, and elimination of toxins are carried out using specialized agents: solutions of various compositions—isotonic solutions (0.9% sodium lactate and sodium chloride solution), Ringer-Locke solution, disol, trisol, polisol, 5% glucose solution (10–20%), protein solution (10%), albumin, native and dry plasma, fresh blood, gelatin (for inactivation and binding), polyvinylpyrrolidone, macrodex (for binding and elimination), and others. When sepsis is complicated by toxic shock, hemodynamic monitoring (ECG, arterial and central venous pressure, pulse), treatment with specialized anti-shock solutions (reopolyglucukin, polyvinylpyrrolidone), protein solutions (albumin, protein), and native plasma are employed. To support cardiac function and pulmonary ventilation, cardiac Glycosides, Oxygen therapy (including Hyperbaric Oxygenation), and mechanical ventilation are prescribed.

Elimination of toxic products in sepsis is also achieved through artificial hemodialysis and forced diuresis, gastrointestinal and peritoneal dialysis, hemo- and lymphosorption, and the connection of animal xenogenous organs (pig liver and spleen).

Alongside detoxification, infusion-Transfusion Therapy is used to correct metabolic disorders and provide parenteral nutritional support to the body.

The primary energy source in parenteral Nutrition is a 10% glucose solution (not exceeding 3 g of glucose per kg of body weight). Fat emulsions also serve as an energy source, though they are still underutilized due to scarcity and a high incidence of pyrogenic reactions. Protein metabolism disorders are compensated for by administering amino acid solutions—which must include all Essential Amino Acids—along with protein preparations.

The volume of infusion therapy is determined based on the volume of lost water, electrolytes, and nitrogen (via urine, feces, sweat, and exhaled air). To this end, the fluid-electrolyte balance in the body's fluid compartments is assessed.

In the absence of severe digestive tract disorders, a high-calorie, vitamin-fortified enteral nutrition regimen is prescribed (unconcentrated broth from lean meats and ground meat, vegetable and dairy soups, cottage cheese and kefir, fruit juices and kissels, etc.). Enteral nutrition and its composition are tailored to account for dysfunctions of internal organs, particularly the liver and kidneys. The Use of vitamin supplements—foremost ascorbic acid, B-group vitamins, and others—is mandatory. Immunostimulating and immunocorrective therapy play a major role (administration of native blood, plasma, leukocyte mass containing neutrophils, IMMUNOGLOBULINS, antitoxic sera, thymic preparations such as thymalin, tactividin, thymogen, as well as corticosteroids). Immunization with Vaccines targeting gram-negative microbes (*Escherichia coli*, *Pseudomonas aeruginosa*) holds promise in the treatment of gram-negative sepsis.

An important measure is the use of inhibitors targeting various mediators of the septic inflammatory process, specifically proteolytic Enzyme Inhibitors—such as kontrikal, trasylol, and others (A.V. Grigoryan, 1970; K.M. Veremeenko, 1971; V.K. Gostishchev, 1987)—inhibitors of tumor necrosis factor production (trental), prostaglandin inhibitors (acetylsalicylic acid), free radical and nitric oxide inhibitors (cortisol, prednisolone), as well as desensitizing agents.

Oxygen therapy, breathing exercises, and distraction therapy play an important role in preventing Pulmonary Atelectasis and pneumonia. Digitalization (cardiac glycosides such as strophanthine and corglycon), liver-protecting agents (Essentiale, Heptral), and renal function enhancers (spironolactone and osmotic Diuretics) are also utilized. Thromboembolic complications are prevented and managed using anticoagulants and antiplatelet agents (persantine, etc.), as well as blood-flow improvers (polyvinylpyrrolidone, Rheopolyglucukin, etc.).

Patient care is of paramount importance. Proper hygiene, fresh air, a quiet environment, compassionate care, continuous functional monitoring, and the meticulous execution of all therapeutic procedures ensure maximum treatment efficacy. However, despite all these measures, mortality rates in sepsis remain high, ranging from 20% to 50% depending on the specific form and type of the disease. Mortality is particularly high in Gram-negative sepsis. Unlike cyclic infections, which are typically caused by specific pathogens, feature a distinct incubation period, cause characteristic morphological changes in organs and systems, and are highly contagious (thus posing a risk of widespread outbreaks), sepsis lacks these features. Consequently, sepsis patients do not require anti-epidemic measures in the conventional sense. Preventive measures during patient care are limited to standard Sanitary and hygienic protocols.

The foundation of sepsis prevention lies in measures aimed at preventing infectious complications in wounds—including microtraumas—and treating surgical infections. Strict adherence to aseptic techniques, both organizational and technical, is critically important. This includes organizing the workflow in surgical departments and outpatient clinics in compliance with asepsis rules, controlling nosocomial (hospital-acquired) infections, handling tissues with care during surgeries, and preventing microbial contamination of Body Cavities during operational procedures.

Vaccination with monovaccines and the development of novel therapeutic approaches for surgical infections can play a significant role in preventing infections, particularly those caused by Gram-negative pathogens.