Over the past decades, the treatment of sepsis has been one of the most pressing problems. The annual incidence of sepsis continues to grow and in the United States alone reaches over 700 thousand cases. First of all, this is associated with a change in the qualitative composition of sepsis pathogens, an increase in multi-resistant hospital strains, as well as with the emergence of a contingent of more severe patients, formed as a result of significant progress in the treatment of previously incurable diseases (optimization of surgical and resuscitation techniques, progress in transplantology, modern chemotherapeutic approaches in hematology and oncology, treatment of HIV infection). Despite the emergence of a large number of highly effective antibiotics, mortality associated with sepsis has decreased by only 20% over the past 50 years and today is about 40%, reaching 80-90% in multiple organ dysfunction syndrome and septic shock.

Classical concepts of bacteremia and distant pyemic foci do not reflect the full development of a generalized infectious process and are only possible clinical variants of the course of sepsis with a certain localization of the primary focus. The clinical interpretation of the modern view on the pathogenesis of sepsis was the diagnostic criteria and classification proposed at the consensus conference of the American College of Chest Physicians and the Society of Critical Care Medicine Specialists - ACCP/SCCM (R. Bone et. al., 1992). According to ACCP/SCCM, sepsis is defined as the body's systemic response to infection, characterized by a clearly identified infectious cause of illness and two or more features of systemic inflammatory response syndrome (SIRS). SIRS is a pathological condition caused by both infectious and non-infectious causes and characterized by the presence of two or more signs: 1) temperature > 38°C or< 36°С; 2) ЧСС >90/min; 3) RR > 20/min, PaCO2< 32 мм рт. ст.; лейкоциты >12000 or< 4000 в мл и/или палочко-ядерные >10%. Sepsis with organ dysfunction, hypoperfusion and/or hypotension is considered severe. Septic shock is defined as sepsis-induced hypotension that persists despite adequate fluid infusion; may be combined with impaired perfusion, which manifests itself in the form of lactic acidosis, oliguria, acute impairment of consciousness, but is not limited to these signs.

Pharmacological approaches to the treatment of sepsis

Numerous immune disorders that arise as a result of exposure to an infectious agent and manifest as a systemic inflammatory response are characterized by activation of the complement system, increased synthesis of cytokines, arachidonic acid metabolites and other vasoactive substances. With systemic inflammation, multi-stage cascades of immune reactions are triggered, dysregulation of the coagulation-anticoagulation systems occurs, dysfunction of the cardiovascular system occurs, and various variants of metabolic disorders are formed, including those that predetermine the development of shock.

The difficulty in determining pharmacological approaches for severe sepsis and septic shock lies in the complexity of this syndrome, which makes it difficult to choose treatment tactics. The need for combination therapy is dictated by the manifestation of the infectious nosology itself, which led to the development of septic shock, as well as the formation of numerous syndromes accompanying severe sepsis.

Medicines prescribed for sepsis and pathogenetically associated syndromes can be divided into three groups:

• drugs with a high degree of evidence that affect the prognosis of the disease;
• drugs that demonstrate a positive symptomatic effect without affecting survival;
• experimental means.

The only group of drugs that reliably influence the prognosis of the disease are antibacterial drugs. Non-pharmacological approaches to this category include surgical interventions aimed at fighting infection. From a practical point of view, with the exception of the use of the above groups of drugs, therapy for sepsis involves the use of drugs aimed at combating individual symptoms and maintaining the function of vital organs and systems (as, for example, in septic shock, adequate infusion therapy and the administration of vasopressors or artificial ventilation with respiratory failure). In turn, the experimental group may include drugs whose effectiveness in sepsis requires further study, for example, glucocorticosteroids, as well as medications undergoing clinical trials, but which have already demonstrated a certain clinical effectiveness (C1-esterase inhibitor, activated protein C, antibodies to tumor necrosis factor alpha, etc.).

Antibacterial agents

The effectiveness of antibacterial agents, observed in uncomplicated bacterial infections, is significantly limited in severe sepsis. Therefore, the task of the earliest and most adequate prescription of antimicrobial drugs is urgent. The rules for the empirical selection of antibiotics are based on the localization of the primary lesion, determining the severity of the condition, concomitant diseases, and determining the allergy history.

Identification of the primary localization of the process with a high degree of probability suggests a possible pathogen. At the same time, correct and timely collection of biological material (blood, urine, pleural fluid, biopsy, etc.) should be an indispensable attribute of diagnostic measures for sepsis. The effectiveness of treatment can be increased by prescribing antimicrobial agents as early as possible from the moment of verification of the bacterial process, which seems possible only with a quick and complete clinical and laboratory-instrumental analysis of the patient’s condition. Taking into account the pharmacokinetic and pharmacodynamic characteristics of the prescribed group of antibiotics ensures the creation of the required concentration of the drug at the primary site of infection with minimal adverse reactions, especially in patients with severe disease and multiple organ dysfunction syndrome ( ).

Medicines that affect the blood coagulation system

Multidirectional changes and various types of dysfunctions in the hemostatic system in sepsis make it difficult to create uniform algorithmic recommendations and require the most complete clinical, laboratory and instrumental assessment of the patient’s condition. As the pathology progresses, along with disturbances in the synthesis and consumption of coagulation factors, thrombocytopenia and signs of disseminated intravascular coagulation (DIC) occur. Suspicion of the development of DIC syndrome requires urgent initiation of therapeutic measures ( ).

Encouraging results were obtained from a study of the effectiveness of activated protein C (drotrecogin alfa), used to treat severe sepsis and septic shock. Synthetic activated protein C, like its endogenous analogue, demonstrates antithrombotic, profibrinolytic and anti-inflammatory effects. The PROWESS study showed a significant reduction in the absolute risk of mortality by 6.1% over a 28-day observation period in a group of patients with severe sepsis.

Medicines that affect the severity of the systemic inflammatory response

Data indicating the ability of glucocorticosteroids (GCS), on the one hand, to improve the function of the cardiovascular system by increasing the synthesis of β-adrenergic receptors and catecholamines, on the other hand, to modulate the immune response, inhibiting the aggregation and adhesion of leukocytes, as well as reducing the activation of the complement system, create theoretical prerequisites for their use in sepsis. In addition, any severe stress for the body (surgery, injury, severe infectious disease) activates the hypothalamic-pituitary system, thereby increasing the synthesis of cortisol. Therefore, in the case of even relative adrenal insufficiency, GCS are considered as a possible replacement therapy option. Based on the results of clinical studies, the use of GCS can be recommended for septic shock only in patients with signs of adrenal insufficiency according to the results of a corticotropin test (blood cortisol concentration > 9 mg/dL after corticotropin administration). The positive effect of prescribing GCS is described when using 50 mg of hydrocortisone every 6 hours in combination with fludrocortisone at a dose of 50 mg/day for 7 days.

One of the most promising areas today in the treatment of severe sepsis and septic shock is the effect on the complement system, since its excessive activation leads to severe systemic inflammation, increased capillary permeability and tissue destruction. The classic method of activation is through the C 1 factor of the complement system. C 1 -esterase inhibitor is the only known inhibitor of C 1 s and C 1 r - components of the classical method of complement activation and an inactivator of coagulation factors XII, XIa and kallikrein. Despite the fact that C1-esterase inhibitor is an acute phase protein, in patients with severe sepsis or septic shock there is an absolute and functional deficiency of C1-esterase inhibitor in sepsis, associated with its increased breakdown and consumption both in the systemic circulation and in site of inflammation. The administration of high doses of exogenous C1-esterase inhibitor involves inhibition of both local and systemic inflammation, as well as stabilization of hemodynamics due to a decrease in capillary permeability. The results of several blind, placebo-controlled clinical trials confirmed the safety of early administration of high doses of C1-esterase inhibitor (up to 12,000 units for 2 days), and also revealed a positive effect of the drug on the rate of recovery of renal function in patients with sepsis or septic shock, a decrease multiorgan manifestations, expressed in a decrease in severity indices of a number of scales (LOD, SOFA). In addition, in the course of observational studies, a positive trend was noted, expressed in a decrease in mortality in patients receiving a C 1-esterase inhibitor. Thus, early administration of a C1 inhibitor avoids the undesirable consequences of systemic inflammation and improves the prognosis in patients with sepsis or septic shock in whom traditional therapy has been ineffective.

Correction of hemodynamic disorders in sepsis and septic shock

Timely correction of arterial hypotension allows you to restore tissue perfusion, maintain homeostasis and improve the prognosis for shock of any origin. Therapy carried out using the principles of a strategy called EGRT (early-goal related therapy) has demonstrated that effective correction of perfusion disorders in severe sepsis is possible only with the early use of invasive hemodynamic monitoring (measurement of central venous pressure, pulmonary artery wedge pressure, central saturation venous blood). Among the key targets of therapy are central venous blood saturation and hematocrit level, the value of which already in the early stages of severe sepsis makes it possible to identify individuals with myocardial dysfunction and a high risk of perfusion disorders. The need to maintain central venous saturation above 70% requires inotropic dobutamine therapy (Dobutrex, Dobutamine Solvay, Dobutamine Lachem 250) and large volumes of infusion in patients at risk. This tactic promotes early withdrawal of vasopressors, reduces the duration of mechanical ventilation, optimizes pre- and afterload, improves cardiac contractility and significantly reduces mortality in patients with severe sepsis and septic shock.

The basis for traditional intensive pharmacotherapy of septic shock is infusion solutions, drugs with inotropic and vasopressor activity. According to various recommendations, the initially required dosage regimen for crystalloids for patients with septic shock is 6-10 l in the first 24 hours, and for colloids it ranges from 2-4 l in the first day. The increase in cardiac index (CI) at a given infusion rate reaches 25-40%. If the previously carried out infusion did not lead to an increase in the contractile function of the left ventricle and CI is still less than 2.5 l/min/m2, it is advisable to use inotropic agents. The drug of choice in this situation is dobutamine ( ) . When using dobutamine in patients with septic shock, it is necessary to take into account its β 2 -agonist properties, while the combination with vasopressors, in particular with norepinephrine, avoids vasodilation.

The complexity of pathological reactions significantly complicates the treatment of sepsis. Undoubtedly, active study of the pathogenesis of the disease will contribute to the formation of a new strategy in modern pharmacotherapy of sepsis.

I. B. Lazareva, Candidate of Medical Sciences
A. A. Igonin, Candidate of Medical Sciences, Associate Professor
MMA im. I. M. Sechenova, Moscow

This is an insufficient or perverted reaction of the body in response to the introduction of various pathogens, accompanied by generalization of the infection, while the body’s independent ability to fight it is lost.

Unlike other infectious diseases, sepsis is not contagious and does not have a specific incubation period. Sepsis occurs in 1-2 out of 1000 surgical patients, in purulent surgery departments much more often - up to 20%.

Sepsis is 2 times more common in men, and at the age of 30-60 years. In older people and children, sepsis occurs more often and is more severe.

Mortality in sepsis reaches 60%, and in septic shock - 90%.

Theories of sepsis

1). Bacteriological theory(Davydovsky, 1928): all changes in the body are a consequence of microorganisms entering the blood.

2). Toxic theory(Savelyev, 1976): all changes are caused by exo- and endotoxins of microorganisms.

3). Allergic theory(Roix, 1983): Microbial toxins cause allergic reactions in the body.

4). Neurotrophic theory(Pavlov and his followers): the main importance is given to the role of the nervous system in the development of changes in the body.

5). Cytokine theory(Ertel, 1991) most fully reflects modern views: microorganisms cause an increased flow of cytokines into the blood (i.e., substances that regulate specific and nonspecific immunity). The process begins with the production of tumor necrosis factor (TNF) by macrophages, which causes the secretion of interleukins, which leads to damage and the development of systemic inflammatory response syndrome (SIRS). Soon, depression of the immune system develops and the secretion of interleukin-2, responsible for the formation of T- and B-lymphocytes and the synthesis of antibodies, sharply decreases.

Classification of sepsis

According to the majority of Yaroslavl scientists, in addition to sepsis, purulent-resorptive fever should be distinguished as a process that precedes it.

Purulent-resorptive fever persists for about a week after opening the purulent focus and is characterized by an undulating course, with negative blood cultures for flora.

Sepsis is a much more severe pathology. Sepsis is classified according to the following criteria:

1). By occurrence:

• Primary(cryptogenic) - occurs without an obvious purulent focus.
• Secondary- develops against the background of the existence of a purulent or inflammatory focus in the body.

2). According to the location of the primary purulent focus:

Surgical, gynecological, postpartum, neonatal sepsis, urological (urosepsis), therapeutic, otogenic, monotogenic, etc.

3). By type of pathogen:

Staphylococcal, streptococcal, coli-bacillary, Pseudomonas, anaerobic, mixed. There are also Gram-positive and Gram-negative sepsis.

4). By source:

Wound, postoperative, inflammatory (after abscesses, phlegmon).

5). By development time:

• Early- occurs within 2 weeks from the moment of the appearance of a purulent focus. It occurs like a violent allergic reaction in a sensitized body.
• Late- occurs 2 weeks or more after the appearance of the primary purulent focus. The reason for it is the occurrence of sensitization of the body during a long-term local purulent process.

6). According to the clinical course:

• Fulminant- lasts 1-2 days and usually ends in the death of the patient. More often, this form of sepsis occurs with boils and carbuncles of the face. It is clinically difficult to distinguish fulminant sepsis from septic shock. The latter is more characterized by severe hemodynamic disturbances.
• Spicy(the most common form: 70-80% of patients) - lasts up to 1-2 weeks and has a more favorable prognosis. However, the mortality rate is quite high.
• Subacute- lasts 1-2 months, usually ends with recovery or becomes chronic.
• Recurrent - lasts up to 6 months and is characterized by alternating periods of exacerbations and remissions. Blood cultures for flora during an exacerbation are usually positive.
• Chronic(chroniosepsis) - lasts for months, sometimes for years, gradually causing degeneration of internal organs. However, some authors believe that chronic sepsis does not exist.

7). According to the nature of the body's reactions:

• Hyperergic type - destructive and degenerative changes predominate in the body.
• Normergic type - inflammatory phenomena predominate.
• Hyperergic (anergic) type (occurs more often than others) - a sluggish reaction observed in weakened patients.

The normergic type of reaction is more common in septicopyemia, and the hyper- and hyperergic types are more common in septicemia.

8). By the presence of purulent screenings There are 2 forms (they occur with approximately the same frequency):

• Septicemia- proceeds without purulent screenings. This is a more severe form, characterized by a progressive course.
• Septicopyemia- occurs with secondary purulent metastases, which is expressed by periodic exacerbations, which is replaced by a subsidence of symptoms when secondary foci are opened.

9). By development phases(Yu.N. Belokurov et al., 1977):

• Voltage phase- sharp mobilization of the body's defenses as a result of stimulation of the pituitary-adrenal system.
• Catabolic phase- manifested by the catabolism of proteins, fats and carbohydrates; as well as violations of water-salt and acid-base balance.
• Anabolic phase - manifested by a transition of metabolism to the anabolic pathway. Structural proteins are restored first.
• Rehabilitation phase - there is a complete restoration of all metabolic processes.

Etiology

Sepsis can be caused by almost all known microorganisms - both pathogenic and opportunistic. Most often these are staphylococcus (50%), streptococcus, pneumococcus, Pseudomonas aeruginosa, Proteus, Escherichia coli, anaerobes (clostridial and non-clostridial), fungi (candida). In recent years, the frequency of mixed sepsis has increased (up to 10%).

Sepsis may occur:

1). For extensive wounds and open fractures, especially in weakened and bleeding patients. Microorganisms easily enter the bloodstream, because the tissue reaction (protective granulation shaft) does not have time to develop.

2). In case of local purulent infection, when the lesion was not opened and drained in time.

3). After medical procedures - vascular catheterization, prosthetics, etc. In this case, the causative agent is often Gram-negative nosocomial (nasocomial) microflora.

The development of one form or another of sepsis often depends on the type of pathogen:

• Staphylococcal sepsis usually occurs as septicopyemia (90-95%) and is complicated by septic pneumonia.
• Streptococcal sepsis most often occurs as septicemia (without purulent metastases). Metastases occur in only 35% of cases.
• Pseudomonas sepsis proceeds like lightning with frequent development of shock.
• Anaerobic sepsis is rarely accompanied by purulent metastases, but is characterized by severe intoxication and high mortality.

If the primary microflora that caused sepsis can be different, then starting from 2-3 weeks, the microflora usually changes to endogenous, which has a greater tropism for the body tissues and therefore displaces the exogenous flora in competition. The endogenous flora is dominated by non-clostridial anaerobes.

Pathogenesis

Predisposing factors are:

• Increased virulence of the microorganism, their resistance to antibiotics. Hospital strains of microorganisms are especially dangerous in this regard. Uncontrolled misuse of antibiotics and immunosuppressants.
• A weakened human body (exhaustion, hypovitaminosis, concomitant diseases), unable to limit the spread of infection. This also includes people with congenital or acquired immunodeficiency, as well as hormonal diseases (diabetes, adrenal insufficiency).
• A purulent focus that exists in the body for a long time, especially in cases where it is not subject to surgical treatment (long-term accumulation of pus). The spread of infection of their primary purulent focus can occur both hematogenously and lymphogenously.

The development of one or another form or type of clinical course of sepsis depends on the degree of interaction of these 3 factors.

Bacteria or their endotoxins activate the complement system, the coagulation system; as well as neutrophils, monocytes, macrophages and endothelial cells. These cells activate inflammatory mediators: cytokines, Hageman coagulation factor, kinins, leukotrienes, prostaglandins, proteolytic enzymes and free radicals. As a result, a systemic inflammatory reaction develops, leading to cell damage, disruption of microcirculation and the development of multiple organ failure.

Clinic

There are no pathognomonic symptoms of sepsis. Sepsis has many forms and clinical manifestations that are difficult to systematize.

The most common source of sepsis (i.e. primary focus) are severe injuries, carbuncles (especially on the face), phlegmon, abscesses, peritonitis, etc. With septicopyemia secondary purulent foci(usually abscesses) most often occur in the lungs, kidneys, bone marrow (with staphylococcal sepsis), in joints (with streptococcal sepsis), in the meninges (with pneumococcal sepsis), etc.

The most typical picture of acute sepsis is:

1). General symptoms:

• An increase in temperature to 40 o C or more, accompanied by chills - 2-7 times a day. With sepsis, there are 2 main types of fever: remitting (with septicemia) - the range of the temperature curve is usually no more than 2 o C; wavy (with septicopyemia) - an increase in temperature after the formation of secondary metastases is replaced by a drop after their opening and drainage. With chronic sepsis, the fever becomes irregular, and when the patient is exhausted, the temperature decreases.
• Cold, profuse, sticky sweat.
• Malaise, weakness.
• Loss of appetite, sometimes profuse diarrhea.
• Sometimes, in severe cases, mental disorders are observed: from complete apathy to psychosis, hallucinations and causeless euphoria.

2). Appearance :

• The face is initially hyperemic, but as sepsis progresses it becomes haggard, sallow in color, and sometimes icterus of the sclera and skin is observed (in 25% of patients).
• The skin may acquire a marbled tint due to impaired microcirculation.
• The tongue is dry, cracked, coated.
• On the body, petechiae are often detected on the skin and oral mucosa; herpes can be observed on the lips.
• With septicopyemia, small abscesses (secondary purulent metastases) may appear under the skin.
• Bedsores often develop.

3). Symptoms of damage to the cardiovascular system:

• Tachycardia.
• Blood pressure is normal or slightly reduced. In septic shock, blood pressure may drop to critical levels, in which case urine filtration will stop.
• During auscultation of the heart, a diastolic murmur may be heard over the aorta.
• Septicopyemia can be complicated by endocarditis and embolism of the systemic circulation.

4). Symptoms of gastrointestinal tract damage:

• Paralytic intestinal obstruction.
• Increased size of the liver and spleen. Symptoms of hepatic renal failure are usually detected by laboratory methods (see below).

5). Symptoms of respiratory failure:

• Obstructive DN is manifested by tachypnea, cyanosis, tachycardia, and increased blood pressure.
• In septic shock, DN occurs as a respiratory distress syndrome with subsequent development of pulmonary edema.
• Secondary purulent screenings are often found in the lungs.

6). Condition of the primary purulent focus with sepsis has some features. The purulent focus in sepsis is the first to react, even before the development of a severe general condition:

• Granulations are flaccid, pale, and bleed easily when touched.
• Rapid progression of necrotic changes.
• Necrotic tissue is rejected extremely slowly.
• The wound discharge is scanty and becomes hemorrhagic or putrefactive.
• The tissues around the lesion are swollen and have a pale bluish tint.

If in aerobic sepsis the boundaries of the purulent focus are clearly visible, then in anaerobic sepsis the lesion may look good externally, but in fact the infection has already spread far through the fatty tissue and interfascial spaces.

Additional research methods for sepsis:

1). General blood analysis:

• Leukocytosis (up to 15-20 x 10 9 /l) with a shift to the left, toxic granularity of leukocytes, increased leukocyte intoxication index (LII), relative lymphopenia.
• A sharp acceleration of ESR - up to 60-80 mm/h (which does not correspond to leukocytosis).
• Progressive anemia (decrease in hemoglobin to 70-80 g/l).
• Progressive thrombocytopenia.

2). Blood chemistry

Reveals signs of hepatic-renal failure:

• Reducing inorganic phosphate levels.
• Increased level and activity of proteolytic enzymes (trypsin, chymotrypsin).
• Increased lactate levels (especially in anaerobic sepsis).
• Increasing the level of “medium molecules” (peptides with a mass of 300-500 Daltons).
• Increased creatinine levels.
• Increased levels of bilirubin, AST and ALT.
• Protein deficiency (since protein losses during sepsis can reach 0.5 g per day).
• Measuring the level of cytokines allows us to assess the severity of the process and its stage.

3). General urine analysis: 20% of patients develop renal failure: oliguria, proteinuria are determined; as well as erythrocyturia, leukocyturia, cylindruria.

4). Blood culture for the presence of microorganisms(= culture for flora, culture for sterility) - take 3 days in a row (at the height of the chill or immediately after it). The result of the sowing becomes known only after about a week. A negative result does not contradict the diagnosis of sepsis (since this is often observed during antibacterial therapy). At the same time, the presence of microorganisms in the blood does not indicate sepsis; an appropriate clinic is required to make such a diagnosis. And bacteremia can occur without sepsis (for example, with typhoid fever, erysipelas, acute osteomyelitis).

Urine, sputum and wound discharge from a purulent focus are also subjected to bacteriological examination.

5). Coagulogram: increased blood clotting time.

6). Immunogram: decrease in the number of T-lymphocytes - especially characteristic of anaerobic sepsis. The production of antibodies (especially classes M and G) decreases.

7). Special methods an increase in blood concentration can be detected:

• Immune complexes.
• Free radical oxidation products (butyraldehyde, isovaleric aldehyde, etc.).

Complications of sepsis

1). Septic (infectious-toxic) shock.

2). Septic bleeding - develops as a result of:

• Purulent melting of a vessel in a purulent focus (arrosive bleeding).
• Violations of the permeability of the vascular wall (diapedetic bleeding).
• Pressure ulcer of the vessel wall with drainage.

Promotes bleeding and disturbances in the hemostatic system during sepsis.

3). Septic endocarditis (most often the mitral valve is affected). Septic thrombi often occur on the valves, which can cause thromboembolism of the arteries of the limbs or internal organs and lead to gangrene of the limbs or infarction of the internal organs.

4). Septic pneumonia, often abscessing.

5). Bedsores.

Septic shock

This is the body’s reaction to a massive breakthrough of microorganisms or their toxins into the blood, which is manifested by acute vascular insufficiency:

• A sharp drop in blood pressure to critical.
• Frequent weak arrhythmic pulse.
• The skin is pale.
• Severe acrocyanosis, shortness of breath (up to 40 breaths per minute).
• Due to a drop in pressure, oliguria progresses to anuria.

During septic shock, phases of compensation, subcompensation and decompensation are distinguished.

Gram-negative sepsis is complicated by septic shock in 20-25%, gram-positive - only in 5% of cases.

The occurrence of shock during sepsis significantly worsens the patient's condition and worsens the prognosis of the disease - mortality up to 90%.

The most common causes of death in sepsis:

1). Septic pneumonia.

2). Progressive intoxication.

3). Progressive hepatic-renal failure.

4). Development of purulent metastases in vital organs (heart, lungs, liver, kidneys).

5). Acute heart failure (as a result of damage to the heart valves).

Criteria for diagnosing sepsis

The diagnostic criteria for sepsis were developed in 1991 at a “consensus conference” with the participation of the world's leading septologists.

1). Symptoms of systemic inflammatory response (SIRR):

• Temperature above 38 o C or below 36 o C.
• Tachycardia more than 90 per minute.
• The respiratory rate is more than 20 per minute (or a decrease in the partial pressure of carbon dioxide in the blood is less than 32 mmHg).
• In the blood test - leukocytosis more than 12 x 10 9 / l or less than 4 x 10 9 / l (or the number of immature forms exceeds 10%).

2). Symptoms of organ failure:

• Lungs: the need for mechanical ventilation or oxygen therapy to maintain the partial pressure of oxygen above 60 mm Hg.
• Liver: bilirubin level above 34 µmol/l; or the level of AST and ALT is 2 times higher than normal.
• Kidneys: increase in creatinine more than 0.18 mmol/l (or oliguria less than 30 ml/hour).
• The cardiovascular system: a drop in blood pressure below 90 mm Hg, requiring drug therapy.
• Hemostasis system: decrease in platelet level less than 100 x 10 9 /l.
• Gastrointestinal tract: paralytic ileus unresponsive to drug therapy for more than 8 hours.
• CNS: lethargy or stupor (in the absence of head injury or cerebrovascular accident).

The diagnosis of sepsis is made based on:

1). The presence of a primary purulent focus.

2). Presence of at least 3 signs of SIRS.

3). The presence of at least one sign of organ failure.

A comprehensive diagnosis of sepsis should include:

• The primary source of sepsis (purulent focus).
• The course of sepsis (fulminant, acute, etc.), its form (septicemia, etc.), phase (tension, etc.).
• Complications.

Differential diagnosis

should be carried out with typhoid and typhus, miliary tuberculosis, brucellosis, malaria, as well as purulent-resorptive fever.

Purulent-resorptive fever is a syndrome caused by the absorption into the blood of products of purulent tissue decay and bacterial toxins from the focus of acute purulent infection, and manifested by a prolonged temperature reaction. The main differences between purulent-resorptive fever and sepsis are the following symptoms:

• The severity of purulent-resorptive fever corresponds to local changes in the purulent focus, while with sepsis a severe general condition can be observed with unexpressed local changes.
• After opening and eliminating the purulent focus, the symptoms of purulent-resorptive fever disappear (no more than a week), which is not observed with sepsis, in which only some improvement in the condition occurs.
• Blood cultures are sterile, and bacteremia is common in sepsis.

Treatment of sepsis

Treatment of sepsis should be both general and local (elimination of a purulent focus). Be sure to replenish the increased energy consumption of the body through adequate nutrition - both enteral and parenteral (4000-5000 kcal/day).

1). Antibiotic therapy sepsis has its own characteristics:

• First, broad-spectrum bactericidal antibiotics (ampiox, gentamicin, lincomycin, cephalosporins) are prescribed. It is better to use a combination of 2-3 antibiotics with different mechanisms and spectrum of action, and 1 of them must be administered intravenously. If ineffective (i.e., if there is no improvement within 3-5 days), reserve antibiotics (tsiprobay, tienam) are used. After identifying the pathogen, I prescribe an antibiotic according to its sensitivity.
• Antibiotics for sepsis are administered only parenterally (intramuscular, intravenous, intra-arterial, endolymphatic) and locally.
• Antibiotics are administered in maximum dosages.
• It is better to combine antibiotics with sulfonamides, nitrofurans, dioxidine and metrogil.
• Antibiotics are discontinued at least 2 weeks after clinical recovery and 2-3 consecutive negative blood cultures for sterility.

2). Detoxification therapy:

• Drink plenty of fluids and infusion therapy - saline solution, 5% glucose with insulin (1 unit of insulin per 5 g of dry glucose), hemodez (no more than 400 ml/day), rheopolyglucin. The daily volume of administered fluid can reach 3-6 liters. The method of forced diuresis is often used (the administration of infusion solutions is combined with diuretics). For septic shock, the rule of 3 catheters is used (in the subclavian vein for infusions, in the bladder to control diuresis, in the nose for oxygen therapy).
  Monitoring diuresis is mandatory: the amount of fluid administered should not exceed the amount of urine by more than 1 liter, because this is dangerous for the development of pulmonary edema and shock lung syndrome. To prevent these complications, infusion of albumin solutions is used.
• In case of sepsis, extracorporeal detoxification methods are widely used: hemosorption, plasmasorption, plasmapheresis, ultraviolet irradiation of blood, intravascular laser blood cavitation (ILBI), electrochemical oxidation of blood (intravenous administration of sodium hypochlorite), hemosplenoperfusion (perfusion of blood through the xenospleen).
• HBO therapy - increases the intensity of neutralization of toxic substances.

3). Immunocorrective therapy:

• In the catabolic phase Passive immunization is indicated: blood transfusion, leukomass, plasma (including hyperimmune), gamma globulin, bacteriphages, interleukin-2 derivatives (roncoleukin).
• In the anabolic phase stimulate the immune system: staphylococcal toxoid, pentoxyl, levamisole, prodigiosan, splenin, thymus preparations (thymalin, T-activin).

4). Anti-inflammatory and analgesic therapy:

Analgin is used for pain relief; if ineffective, narcotic analgesics (promedol, omnopon) are used. Among anti-inflammatory drugs, strong NSAIDs (Voltaren, ibuprofen) are most often used.

For septic shock, NSAIDs are usually ineffective. In this case, glucocorticoids are used (short course - 2-3 days), which also have an antiallergic effect and increase blood pressure. Dosage: on the first day - 500-800 mg; on days 2-3 - 100-150. However, hormones can only be used under hormonal control.

5). Symptomatic therapy:

• For heart failure- cardiac glycosides (strophanthin), cocarboxylase, vitamin C.
• For peripheral circulatory disorders- no-spa, reopolyglucin, nicotinic acid, trental, complamin.
• For respiratory failure- oxygen therapy, if ineffective - in combination with mechanical ventilation. Medications that thin sputum (trypsin, acetylcysteine) and relieve bronchospasm (aminophylline) are used.
• For hypokalemia- solutions with potassium ions are administered intravenously.
• With metabolic acidosis- sodium bicarbonate intravenously; for alkalosis - potassium chloride, vitamin C, diamox.
• For gastrointestinal paresis- simultaneously with intestinal stimulation, parenteral nutrition is administered (concentrated glucose solutions, fat emulsions, protein hydrolysates and mixtures of amino acids, vitamins).
• For hepatic-renal failure- hepatoprotectors (Carsil, Legalon), albumin, vitamins B and C in large doses.
• For bleeding disorders- contrical, calcium preparations, sodium thiosulfate, heparin.
• When exhausted- in the anabolic phase, anabolic hormones (retabolil) are used and the amount of protein in food is increased.

Features of local treatment (opening a purulent focus) for sepsis:

1). A wide opening of the lesion is necessary.

2). Removal of all necrotic tissue, up to amputation of a limb or removal of an entire organ. In case of anaerobic sepsis, the widest possible opening of the lesion and excision of all necrotic tissues is recommended; in aerobic sepsis - less wide (to avoid wound exhaustion).

3). After surgery, immobilization is required.

4). In the postoperative period, ultrasonic cavitation, laser irradiation of the wound, and treatment of the wound with a pulsating jet of antiseptic are used.

5). Wide adequate drainage.

Currently, there are 2 tactics for treating postoperative wounds with sepsis:

• Open method (most common)- the wound is drained, but not sutured. Subsequently, it heals by secondary intention under bandages. The advantage of this method is the possibility of further dynamic monitoring of the condition of the wound, the disadvantage is the traumatic nature of dressings and the possibility of reinfection of the wound or the spread of infection throughout the hospital. Local treatment is carried out in accordance with the principles of therapy for purulent wounds. It is better to treat wounds using the open method in rooms with a controlled abacterial environment (gnotobiological protection).
• Private method- closed suturing of the wound is used, leaving tubular drainages for flow-wash and vacuum drainage. The advantages of the method are the prevention of wound exhaustion and the reduction of contact of the wound with the external environment. However, it is impossible to observe such a wound.

Prevention of sepsis

consists of early, full-fledged primary surgical treatment of wounds, followed by local and general treatment, as well as timely surgical treatment of local purulent infection.

RCHR (Republican Center for Health Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical protocols of the Ministry of Health of the Republic of Kazakhstan - 2015

Bacterial infection of unspecified site (A49), Other septicemia (A41), Other bacterial diseases not elsewhere classified (A48), Other types of shock (R57.8), Candidal septicemia (B37.7), Complications of surgical and therapeutic interventions, not elsewhere classified (T80-T88), Complications caused by abortion, ectopic or molar pregnancy (O08), Puerperal sepsis (O85), Systemic inflammatory response syndrome of infectious origin with multiple organ failure (R65.1), Systemic inflammatory response syndrome of non-infectious origin origin without organ failure (R65.2), Streptococcal septicemia (A40)

Short description

Recommended
Expert advice
RSE at PVC "Republican Center for Health Development"
Ministry of Health
and social development
dated September 30, 2015
Protocol No. 10

Protocol name: Sepsis

Sepsisis a systemic inflammatory response syndrome in response to infection.

Protocol code:

ICD-10 code(s):
A40 Streptococcal septicemia
A41 Other septicemia
A48 Other bacterial diseases not elsewhere classified
A49 Bacterial infection of unspecified localization
R65.10 CCVO for non-infectious origin without organic dysfunction
R65.20 Severe sepsis without septic shock
R65.21 Severe sepsis with septic shock
B37.7 Candidal septicemia
T80-T88 Complications of surgical and therapeutic interventions not classified elsewhere
O85 Puerperal sepsis
O08 Complications caused by abortion, ectopic or molar pregnancy
R57.8 Other types of shock. Endotoxic shock

Abbreviations used in the protocol:
D-dimer is a fibrin breakdown product;
FiO 2 - oxygen content in the inhaled air-oxygen mixture;
Hb - hemoglobin;
Ht - hematocrit;
PaO 2 - partial oxygen tension in arterial blood;
PaCO 2 - partial tension of carbon dioxide in arterial blood;
PvO 2 - partial tension of oxygen in venous blood;
PvСO 2 - partial tension of carbon dioxide in venous blood;
ScvO 2 - central venous blood saturation;
SvO 2 - saturation of mixed venous blood;
BP - blood pressure;
BP avg. - average blood pressure;
ALT - alanine aminotransferase;
APTT - activated partial thromboplastin time;
AST - aspartate aminotransferase.
DIC - disseminated intravascular coagulation;
Gastrointestinal tract - gastrointestinal tract;
RRT - renal replacement therapy;
IVL - artificial lung ventilation;
IT - infusion therapy;
ITT - infusion-transfusion therapy;
AOS - acid-base state;
CT - computed tomography;
LII - leukocyte intoxication index;
INR - international normalized ratio;
TPR - total peripheral vascular resistance;
ARDS - acute respiratory distress syndrome;
BCC - circulating blood volume;
PT - prothrombin time;
FDP - fibrinogen degradation products;
PCT - procalcitonin;
MON - multiple organ failure;
PTI - prothrombin index;
SA - spinal anesthesia;
SBP - systolic blood pressure;
FFP - fresh frozen plasma
SI - cardiac index;
MODS - multiple organ failure syndrome;
SIRS - systemic inflammatory response syndrome;
SS - septic shock;
TV - thrombin time;
TM - platelet mass
EL - level of evidence;
Ultrasound - ultrasound examination;
SV - stroke volume of the heart;
FA - fibrinolytic activity;
CVP - central venous pressure;
CNS - central nervous system;
RR - respiratory rate;
HR - heart rate;
EDA - epidural anesthesia;
ECG - electrocardiography;

Date of protocol development/revision: 2015

Protocol users: therapists, general practitioners, surgeons, urologists, traumatologists, vascular surgeons, anesthesiologist-resuscitator, ambulance and emergency doctors, obstetrician-gynecologists, neurosurgeons, infectious disease specialists, paramedics.

Recommendation level designation :
Recommendations are assigned Level 1, if, based on current evidence, experts are convinced that, if used, the benefit to the patient would outweigh the potential risk. Recommendations are assigned Level 2 in the absence of specific data on the balance of benefit and risk.

Level of evidence designation:
If the evidence is based on sufficiently large, prospective randomized trials, the evidence is graded A. Good randomized controlled trials with clear evidence - level IN. Where multiple prospective studies have been conducted with conflicting results or methodological shortcomings, the evidence is graded WITH. Case reports and non-randomized studies are classified as D.

Classification

Clinical classification:
Depending on the primary focus, the following forms of surgical sepsis are distinguished:
Post-traumatic:
· wounded;
· burn;
pulmonary
· angiogenic;
· cardiogenic;
Abdominal:
· biliary;
· pancreatogenic;
· intestinogenic;
· peritoneal;
· appendicular.
· inflammatory diseases of soft tissues;
· urological.

· By the nature of the primary focus: wound, postpartum, burn, sepsis in diseases of internal organs;
· According to the localization of the primary focus: tonsilogenic, odontogenic, rhinootogenic, urosepsis. umbilical sepsis in children, cardiogenic, gynecological, abdominal, angiogenic;
· According to the clinical course: fulminant (1-2 days), acute (5-10 days without remission), subacute (2-12 weeks), chronic, recurrent sepsis (more than 3 months);
· By the presence or absence of a primary focus: primary (there is no focus) and secondary (there is a primary focus or an entrance gate);
· According to the characteristics of the development of the clinical picture: early (up to 3 weeks from the introduction of the infection) and late (later than 3 weeks from the introduction of the infection);
· By type and nature of the pathogen: aerobic sepsis, anaerobic, mixed, fungal, nosocomial;
· By the nature of generalization of infection: septicemia, septicopyemia;

Clinical picture

Symptoms, course

Diagnostic criteria for diagnosis:

Diagnostic criteria sepsis ( International Guidelines for Management of Severe Sepsis and Septic Shock: 2012) :

Against the background of an existing or suspected infection:
General changes:
· fever (body temperature >38.3°C);
Hypothermia (body temperature<36°C);
· Heart rate is more than 90 per minute or more than the age norm;
· tachypnea (more than age norm);
· disturbances of consciousness;
Visible swelling or positive water balance (fluid retention) more than 20 ml/kg/day;
· hyperglycemia (plasma glucose >7.7 mmol/l) in the absence of diabetes mellitus.
Inflammatory changes:
leukocytosis (>12*109/l) or leukopenia (<4*109/л);
· normal number of leukocytes with the presence of 10% immature forms;
· C - reactive protein more than 2 standard deviations above the normal value;
· plasma procalcitonin is more than 2 standard deviations above the normal value.
Hemodynamic disorders:
arterial hypotension (SBP)<90 мм. рт. ст., АДcр< 70 мм. рт.ст., или снижение САД более чем на 30 мм.рт.ст от возрастной нормы)
Organ function disorders*:
arterial hypoxemia (PaO2/FiO2<300)
Acute oliguria (diuresis rate< 0.5 мл/кг/час в течение не менее 2 часов, несмотря на адекватную регидратацию);
· increase in creatinine > 176 µmol/l;
· coagulopathy (INR>1.5 or APTT>60 sec);
thrombocytopenia (<100*109/л);
· intestinal paresis (lack of peristalsis);
· hyperbilirubinemia > 70 µmol/l.
Tissue perfusion disorders:
· increased lactate (> 2mmol/l);
· signs of microcirculation disorders.
*Note:
· The severity of organ-system disorders is determined using the SOFA scale (Appendix 2);
· The overall severity of the condition is determined using the APACHE II (Acute Physiology And Chronic Health Evaluation) scale (Appendix 3).

Complaints and anamnesis:
Complaints:
· general weakness;
· increase in body temperature ( heat, fever, chills);
· sweating;
· thirst;
· heartbeat;
· pain in the area of ​​inflammation.
Complaints/signs of intoxication:
· severe headaches;
· dizziness;
· insomnia;
· prostration.
Complaints/signs of gastroenteritis:
· nausea, vomiting;
· loss of appetite;
· bloating;
· failure to pass gas and stool (paralytic ileus).
Complaints/signs of gastrointestinal bleeding (stress ulcers):
· pallor of the skin;
· weakness;
Dizziness, vomiting blood;
· black chair.
Complaints/signs of dysfunction of the central nervous system:
· euphoria, excitement, delirium, lethargy (signs of encephalopathy);
· disturbance of consciousness up to coma.

Anamnesis:
· presence of an inflammatory or purulent focus.

Physical examination:
General examination of the skin and mucous membranes:
· hot skin;
· pallor, marbling of the skin;
· facial hyperemia, acrocyanosis;
· yellowness of the sclera and skin (cholestatic jaundice due to damage to hepatocytes);
· hemorrhagic rash (from punctate ecchymosis to confluent erythema and large hemorrhagic and necrotic foci, appears in the early stages, localized on the anterior surface of the chest, on the abdomen and arms).
· increased size of lymph nodes, polyadenitis.
Respiratory assessment:
· change in the frequency and rhythm of breathing;
· change in percussion pattern:
· shortening of percussion sound;
· decreased vocal breathing;
· change in auscultation pattern in the lungs:
· weakened/hard breathing;
· appearance of moist wheezing;
· crepitation.
Functional assessment of the heart:
· weakening of the sonority of heart sounds;
· tachycardia, tachyarrhythmia.
When examining the oral cavity:
· dry tongue with a brown coating, sometimes raspberry in color;
· bleeding gums.
Percussion and auscultation of the abdomen:
Splenomegaly and hepatomegaly;
· bloating (high tympanitis);
· weakening or absence of intestinal motility.

Diagnostics

List of basic and additional diagnostic measures:

Basic (mandatory) diagnostic examinations performed on an outpatient basis:
· physical examination (measurement of blood pressure, temperature, pulse count, respiratory rate calculation).

Additional diagnostic examinations performed on an outpatient basis: No.

Basic (mandatory) diagnostic examinations carried out at the hospital levelin case of emergency hospitalizationand after a period of more than 10 days has passed from the date of testing in accordance with the order of the Ministry of Defense:
· physical examination (measurement of temperature, saturation, blood pressure, heart rate, respiratory rate);
· general blood analysis;
· general urine analysis;
· clotting time and duration of bleeding;
· Leukocyte index of intoxication;
Determination of glucose in urine;
· determination of ketone bodies in urine;
· biochemical tests (bilirubin, AST, ALT, alkaline phosphatase, total protein, albumin and its fractions, urea, creatinine, residual nitrogen);
· indicators of the acid-base state of the blood (pH, BE, HCO3, lactate);
· blood electrolytes (potassium, sodium, calcium);
· coagulogram (PT, TV, PTI, APTT, fibrinogen, INR, D-dimer, PDF);
· determination of blood group according to the ABO system;
Determination of the Rh factor of blood.
· ECG;
chest x-ray;
· Ultrasound of the abdominal cavity and kidneys.

Additional diagnostic examinations carried out at the hospital level during emergency hospitalization and after more than 10 days have passed from the date of testing in accordance with the order of the Ministry of Defense:
· measurement of central venous pressure;
· measurement of central hemodynamics (invasive/non-invasive) - SV, CI, OPSS;
· determination of blood gases (PaCO 2, PaO 2, PvCO 2, PvO 2, ScvO 2, SvO 2);
· determination of procalcitonin in blood serum;
· determination of “C” reactive protein semi-quantitatively/qualitatively in blood serum;
· blood for sterility;
· test for malaria (“thick drop”, blood smear);
· RNGA testing for listeriosis in blood serum;
· RNGA testing for pasteurellosis in blood serum;
· RNGA testing for typhus in blood serum;
· RNGA testing for tularemia in blood serum;
· collection of exudate for bacteriological examination and sensitivity to antibiotics;
· bacteriological culture of urine;
· bacteriological culture of sputum;
· CT, MRI of the abdominal cavity/other organs.
· determination of blood gases and electrolytes with additional tests (lactate, glucose, blood carboxyhemoglobin)

Diagnostic measures carried out at the stage of emergency care:
· physical examination (measurement of blood pressure, temperature, pulse count, respiratory rate calculation);
· ECG.

Instrumental studies
Chest X-ray- accumulation of fluid in the pleural cavities, the presence of infiltrates in the lung tissue, pulmonary edema;
ECG- rhythm disturbances, cardiac conduction, signs of myocarditis;
Ultrasound of the abdominal organs- presence of free fluid, hepato-splenomegaly, detection of a primary or secondary source of infection;
Ultrasound of the kidneys and retroperitoneum- an increase in the size of the kidney, detection of various lesions of the kidneys and retroperitoneal space;

Indications for specialist consultations:
· consultation with a rheumatologist - if symptoms of a systemic disease appear;
· consultation with a hematologist - to exclude blood diseases;
· consultation with an otolaryngologist - when a source of infection is identified with subsequent sanitation;
· consultation with a traumatologist - if there is an injury;
· consultation with a dentist - when identifying foci of infection with subsequent sanitation;
· consultation with an obstetrician-gynecologist - in case of pregnancy/if pathology of the reproductive organs is detected;
· consultation with a cardiologist - in the presence of ECG abnormalities or heart pathology;
· consultation with a neurologist - in the presence of neurological symptoms;
· consultation with an infectious disease specialist - in the presence of viral hepatitis, zoonotic and other infections;
· consultation with a gastroenterologist - in the presence of pathology of the gastrointestinal tract;
· consultation with a clinical pharmacologist - to adjust the dosage and combination of medications.

Laboratory diagnostics

Laboratory research :

In the blood test: leukocytosis/leukopenia (>12x10 9 or<4х10 9 или количество незрелых форм превышает 10%), токсическая зернистость нейтрофилов, нейтрофилия, лимфопения (<1,2х10 9), повышенное СОЭ, повышение ЛИИ, снижение Hb, эритроцитов, Ht, тромбоцитопения (тромбоциты <100х10 9);

In biochemical analysis: an increase in bilirubin above 70 µmol/l, an increase in the level of transaminases (ALT, AST) and alkaline phosphatase by 1.5 times or more, an increase in creatinine > 176 µmol/l or an increase by 50 mmol/l per day, urea - an increase by 5 .0 mmol/l per day, residual nitrogen - increase by 6.0 mmol/l, decrease in total protein<60 г/л, альбумина < 35 г/л.
In the coagulogram: increased PDP, D-dimers. Decrease in PTI<70% или МНО>1.5, fibrinogen<1,5 г/л, удлинение АПТВ>60 sec.
CBS: pH<7,3, дефицит оснований ≥5 ммоль/л, повышение уровня лактата >2 mmol/l. Blood electrolytes: changes in potassium levels, increased C-reactive protein and PCT (procalcitonin).

Differential diagnosis

Differential diagnosis:

Table - 1. Differential diagnosis of sepsis

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Treatment

Treatment goals:

· early diagnosis and sanitation of the source of inflammation;
· stop the activity of SIRS;
· prevent the development of MODS;
· prevent/correct violations of vital functions in severe sepsis/SS - damage to the central nervous system, circulatory disorders, damage to the lungs and kidneys.

Treatment tactics**:

Non-drug treatment:

Choosing a food method:
· natural enteral nutrition - predominantly;
· tube feeding (through a nasogastric or nasointestinal tube) if independent nutrition is impossible;
· parenteral nutrition (intravenous administration of nutrients) - if oral or tube nutrition is impossible or insufficient.
Contraindications for enteral/tube feeding:
· mechanical intestinal obstruction;
· ongoing gastrointestinal bleeding;
· acute destructive pancreatitis (severe course) - only fluid administration.
Contraindications (indications for limitation) of enteral, tube/parenteral nutrition:
Uncorrectable hypoxemia due to ARDS.

In patients with severe sepsis and septic shock, daily calorie intake in the first 7 days from diagnosis should not exceed 500 kcal/day (LE 2B). In this case, preference is given to a combination of enteral nutrition and intravenous glucose rather than parenteral alone (LE 2B) (International Guidelines for Management of Severe Sepsis and Septic Shock: 2012).

Drug treatment:

Infusion-transfusion therapy:
· starting solution for severe sepsis/septic shock: crystalloids (Ringer's lactate, saline (NaCl 0.9%), balanced electrolyte solutions - sterofundin) up to 30 ml/kg during the first 6 hours of starting IT with initial hypotension (LE 1B) ;
· albumin showed safety and effectiveness as well as crystalloids (LE 2C). Used for hypoproteinemia or hypoalbuminemia;
· the use of sodium bicarbonate (soda) solution is not recommended for the correction of metabolic lactic acidosis at a pH of more than 7.15 (LE 2B);
· synthetic colloids are contraindicated (UD - 1B).
Safety criteria for infusion therapy:
· in the presence of tachycardia, CVP should not exceed 10-20 mm water column;
· with an increase in tachycardia and (or) a sharp increase in central venous pressure, infusion-transfusion therapy is stopped or its rate is reduced;
· in the absence of hypotension and the possibility of enteral nutrition, the infusion should be carried out strictly according to indications. The total volume of fluid received by the patient (enterally and parenterally) is 40 ml/kg per day.
· in the absence of hypotension and the impossibility of enteral or tube feeding, parenteral nutrition and infusion of the necessary medications and corrective solutions are carried out. The total volume of fluid received parenterally by the patient is 40 ml/kg per day.
· daily diuresis in combination with other fluid losses (wound losses, ascites, stool, ultrafiltration volume, etc.) should be at least 80% of the sum of the volumes of enterally and parenterally administered fluid.

Vasopressors:
· prescribed for blood pressure averaging less than 65 mmHg, without expecting the effect of infusion therapy (LE 1C);
· vasopressors are prescribed for proven or suspected vascular insufficiency - reduced peripheral vascular resistance (invasive or non-invasive), warm skin for hypotension;
norepinephrine (norepinephrine (NA) is the main drug (LE 1B);
· epinephrine (adrenaline) is added to enhance the effect of NA (LE 2B);
· dopamine up to 10-15 mcg/kg/min IV - an alternative to NA in patients without the risk of tachyarrhythmia and relative or absolute bradycardia;
· phenylephrine (Mezatone) can be used in patients with septic shock, in the absence of NA or an ineffective inotrope/vasopressor combination, indicated in patients with high cardiac output, low peripheral resistance and low blood pressure; excluding patients with severe arrhythmia;
· the effectiveness of the use of vasopressors is determined by the increase in blood pressure, decrease in heart rate, and normalization of peripheral vascular resistance.

Inotropic drugs:
· dobutamine in a dose of up to 20 mcg/kg/min (possibly in combination with vasopressors) is used when myocardial contractility decreases, especially with tachycardia, when signs of hypoperfusion increase despite adequate volume and blood pressure mean (LE 1C);
· dopamine (dopamine) can replace dobutamine;
· there is no need to strive to increase the cardiac index above normal values.

Corticosteroids:
· IV hydrocortisone is not used in patients with septic shock, if adequate fluid therapy and vasopressors stabilize hemodynamics, if hemodynamic instability persists, prescribe 200 mg/day IV (LE 2C), in the absence of hydrocortisone, 8 mg/day dexamethasone is recommended;
· if hydrocortisone is prescribed, then a long course is carried out;
Corticosteroids are not prescribed in patients with sepsis without septic shock (LE: 1D);

Blood components:
· transfusion of red blood cell-containing blood components should be prescribed when hemoglobin level<70 г/л. Повышать уровень гемоглобина у взрослых следует до 70-90 г/л (УД 1В);
· higher hemoglobin levels may be required under certain circumstances and increased oxygen extraction;
Erythropoietin should not be used to treat anemia caused by sepsis (LE: 1B);
· FFP transfusions should be prescribed to correct reduced levels of coagulation factors only in the case of hemorrhagic syndrome, bleeding or during planned invasive interventions (LE 2D).
A transfusion of platelet concentrate should be given (LE 2D) when:
The platelet count is<10х109/л;
· the platelet count is less than 30x109/l and there are signs of hemorrhagic syndrome.
· for surgical/other invasive interventions when a high platelet count is required - at least 50x109/l;
· albumin is used during infusion therapy with crystalloids to prevent a decrease in colloid-oncotic pressure during hypoproteinemia (less than 60 g/l) or hypoalbuminemia (less than 35 g/l);
All transfusions are carried out in accordance with Rules for storage, transfusion of blood, its components and preparations .

Correction of hyperglycemia:
· It is recommended to begin dosed insulin administration when 2 consecutive blood glucose levels are >10 mmol/L (180 mg/dL). The goal of insulin therapy is to maintain blood glucose levels below 10 mmol/L (180 mg/dL) (LE: 1A);
· insulin is administered intravenously using a dosing syringe or infusion pump;
· monitor the intake of glucose into the body and the level of glucose in the blood every 1-2 hours (4 hours in a stable condition) in patients who are receiving insulin intravenously (LE 1C);
· interpret the level of glucose in capillary blood with caution, more accurately determining glucose in arterial or venous blood (LE 1B).
Target indicators of intensive care for hypoperfusion due to severe sepsis, septic shock in the first 6 hours:
· central venous pressure 100-150 mmH2O (in the absence of tachycardia);
· mean arterial pressure ≥ 65 mm Hg;
· diuresis rate ≥ 0.5 ml/kg per hour;
· normalization of oxygenation and saturation of central or mixed venous blood (UD 1C);
· normalization of lactate levels (LE 2C).

Antibacterial therapy:
· empirical prescription of intravenous antibiotics within 1 hour after diagnosis of sepsis, severe sepsis (UD-1C), septic shock (UD-1B) is the goal that determines the effectiveness of therapy;
· initial empirical therapy should include antibacterial drugs and/or an antifungal drug and/or an antiviral drug, depending on what kind of infection is suspected;
· the concentration and bioavailability of drugs must be sufficient to penetrate and suppress the intended source of infection (UD - 1B);
· the daily dose should be the maximum permitted, with minimal administration intervals or in the form of a continuous infusion (in accordance with the instructions for use of the drug);
· the effectiveness of antibacterial therapy should be examined daily for possible de-escalation (LE - 1C);
· it is necessary to monitor the effectiveness of antibacterial therapy by the level of body temperature, the number of leukocytes and the leukocyte formula, examine the level of procalcitonin and other markers of inflammation to monitor the effectiveness of empirical antibacterial therapy, and the possibility of continuing the latter, in patients with signs of sepsis, but without an obvious source of infection (LE - 2C);
· empirical therapy should include a combination of antibiotics (at least 2), especially in patients with neutropenia (UD - 2B), resistant forms of Acinetobacter Pseuodomonas spp. (UD - 2B);
· in the presence of Streptococcus pneumoniae bacteremia with septic shock, a combination of beta-lactam antibiotic and macrolide drugs is required (LE - 2B);
· metronidazole can be used in combination with antibiotics;
Empirical therapy should not last more than 3-5 days. De-escalation therapy or antibacterial therapy appropriate to the infection profile should begin immediately after bacteriological identification of the infection profile and sensitivity determination (LE - 2B);
· the duration of therapy is on average 7-10 days, longer - in patients with immunodeficiency and a slow clinical response, with a non-drainable source of infection, S. aureus bacteremia; some fungal and viral infections with immunodeficiency, including neutropenia (LE - 2C);
· antiviral therapy should be carried out as early as possible in patients with sepsis and septic shock of viral etiology (LE - 2C). Antiviral therapy is prescribed on the recommendation of an infectious disease specialist;
· in patients with a systemic inflammatory response of a non-bacterial nature, antibacterial drugs should not be used.
Criteria for the effectiveness of antimicrobial therapy for sepsis:
· stable normalization of body temperature (maximum temperature less than 38 0 C);
· positive dynamics of the main symptoms of infection;
· absence of signs of a systemic inflammatory reaction;
· normalization of gastrointestinal function;
· persistent decrease in leukocytes in the blood, improvement of the leukocyte formula;
· negative bacteriological studies;
· normal concentrations of C-reactive protein and PCT.

Drug treatment provided at the emergency stage:
· NaCl solution 0.9% 400-800 IV drip for initial hypotension;
· solution of norepinephrine (norepinephrine) 1 ml intravenously in a dilution of sodium chloride solution 0.9% 200-400 for initial hypotension;
· or a solution of phenylephrine (mesatone) 1% 1 ml intravenously in a dilution of sodium chloride solution 0.9% 200-400 for initial hypotension.

Other types of treatment:
Other types of treatment provided on an outpatient basis:
· oxygen therapy.

Other types of services provided at the stationary level:
Immunomodulators, immunoglobulins:
· the use of oral and parenteral immunomodulators, immunoglobulins in severe sepsis and septic shock is not recommended (LE - 2B);

Artificial ventilation:
Indications for transfer to mechanical ventilation:
· lack of consciousness (less than 10 points on the Glasgow scale), tachypnea more than 25 per minute, bradypnea less than 10 per minute, decrease in saturation below 90% with inhalation of humidified oxygen, decrease in PaO 2 below 80 mmHg, increase in PaO 2 above 60 mmHg or decrease below 30 mmHg;
General principles of mechanical ventilation:
· Mechanical ventilation is indicated for patients with acute respiratory distress syndrome (ARDS). The severity of ARDS and the dynamics of the lung condition are determined by the oxygenation index (IO) - PaO 2 /FiO 2: light - IO< 300, средне тяжелый - ИО < 200 и тяжелый - ИО < 100;
· Some patients with ARDS may benefit from non-invasive ventilation for moderate respiratory failure. Such patients should be hemodynamically stable, conscious, in comfortable conditions, with regular sanitation of the respiratory tract (LE 2B);
· in patients with ARDS, tidal volume is 6 ml/kg (correct body weight) (LE: 1B). Proper body weight: for men - (height - 100 kg), for women - (height - 110 kg);
· the preferred ventilation mode is pressure ventilation with support for spontaneous breathing (SIMV(P). The upper pressure limit should be< 30 см вод. ст. (УД 1В);
· it is possible to increase the partial pressure of CO 2 to reduce the plateau pressure or the volume of the oxygen mixture (UD 1C);
· the value of positive expiratory pressure (PEEP) should be adjusted depending on the AI ​​- the lower the AI, the higher the PEEP (from 7 to 15 cm water column);
· use the alveolar opening maneuver (recruitment) in patients with difficult-to-treat acute hypoxemia (LE 2C);
· Patients with severe ARDS can lie on their stomach (prone position) unless this poses a risk (LE: 2C);
· patients undergoing mechanical ventilation should be in a reclining position (unless this is contraindicated) (LE 1B), the head end of the bed should be raised by 30-45° (LE 2C);
· when the severity of ARDS decreases, one should strive to transfer the patient from mechanical ventilation to support spontaneous breathing;
· Long-term drug sedation is not recommended in patients with sepsis and ARDS (LE: 1B);
· the use of muscle relaxation is not recommended in patients with sepsis (LE 1C), only for a short time (less than 48 hours) in early ARDS and with AI less than 150 (LE 2C).

Detoxification methods: RRT (ultrafiltration, hemodiafiltration, hemodialysis).
Indications:
· to maintain the life of a patient with irreversible loss of kidney function.
Contraindications:
· presence of a clinic for ongoing bleeding;
· hemorrhagic syndrome of any origin;
· tuberculosis of internal organs;
· decompensated heart failure.
Detoxification regimen:
· for the purpose of detoxification in sepsis with multiple organ failure, therapeutic plasma exchange can be carried out with the removal and replacement of up to 1-1.5 of the total plasma volume (LE 2B);
Diuretics should be used to correct fluid overload (> 10% of total body weight) after recovery from shock. If diuretics are ineffective, renal replacement therapy may be used to prevent fluid overload (LE: 2B);
· with the development of renal failure with oligoanuria, or with high rates of azotemia, electrolyte disturbances, renal replacement therapy is carried out;
There is no benefit to the use of intermittent hemodialysis or continuous venovenous hemofiltration (CVVH) (LE: 2B);
· CVVH is more convenient for patients with unstable hemodynamics (LE 2B). Failure of vasopressors and fluid resuscitation are nonrenal indications for initiating CVVH;
· CVVH or intermittent dialysis may be used in patients with underlying acute brain injury or other causes of increased intracranial pressure or generalized cerebral edema (LE: 2B).
· the rules for the use of renal replacement therapy are specified in the CP “Acute renal failure” recommended by the expert council of the RCHR dated December 12, 2014.

Other types of treatment provided at the emergency stage
Peripheral vein catheterization;
· transfer to mechanical ventilation for health reasons.

Surgical intervention:

Surgical intervention provided on an outpatient basis: no.

Surgical intervention provided in an inpatient setting:

Surgical treatment for sepsis:
Types of operations for sepsis:
· drainage of purulent cavities;
· removal of foci of infectious necrosis;
· removal of internal sources of contamination.

Removing internal sources of contamination.
· colonized implants;
· artificial heart valves;
· vascular/articular prostheses;
· foreign bodies temporarily introduced into tissues or internal environments of the body for therapeutic purposes (tubular drainages and catheters);
· removal/proximal shutdown (diversion) of the flow of contents from defects of hollow organs considered as sources of infection.

Abscess drainage:
· creation of a constant outflow of liquid contents from a limited purulent cavity.

Removal of foci of infectious necrosis:
· removal of necrotically altered tissues must be performed after a complete opening of the site of destruction and assessment of the condition of the tissues;
· if there are obvious signs of necrosis, it is necessary to perform excision (necrectomy);
· if there are no obvious signs of infection before surgery, then it is necessary to adhere to a wait-and-see approach with constant dynamic monitoring;
· if local and general signs of infection increase, it is necessary to adopt active surgical tactics;
· in the presence of a thin layer of necrotic tissue, it is possible to use hydrophilic dressings or preparations containing enzymes;

Removal of foreign bodies:
· foreign bodies that support the infectious process must be removed;
· When perforation of a hollow organ occurs, constant contamination by microbes of the abdominal cavity occurs, this requires control and elimination of the source of peritonitis (appendectomy, cholecystectomy, bowel resection, suturing of perforation, etc.), careful sanitation of the abdominal cavity with antiseptics, drainage of the abdominal cavity;
· in the absence of conditions for radical elimination of the source of peritonitis (serious condition of the patient, general contraindications for performing an extensive operation), the option of applying a fistula or bypass anastomosis is possible, which is a less dangerous intervention at this time;
Completing the operation:
· one-step treatment method;
· staged treatment method.
The staged treatment method involves programmed laparotomy to control the source of peritonitis and its regression.

Programmed laparosanation:
Indications:
widespread fibrinous-purulent/fecal peritonitis;
· signs of anaerobic infection of the abdominal cavity;
· impossibility of immediate elimination/reliable localization of the source of peritonitis;
· stage of peritonitis corresponding to severe sepsis/septic shock;
· the condition of the surgical wound does not allow closing the defect of the anterior abdominal wall;
· intra-abdominal hypertension syndrome;
· infected pancreatic necrosis with symptoms of sepsis (UD-B);
· the timing of surgical intervention for pancreatic necrosis is no earlier than 14 days, with the exception of patients with severe sepsis, MODS (UD-V).

Necrectomy is indicated:
· for purulent-inflammatory diseases of soft tissues;
· infected post-traumatic wounds;
· with infected pancreatic necrosis (UD-A). If local conditions for performing transcutaneous drainage are ineffective or lacking, as well as the impossibility of removing necrotic masses and effective drainage of purulent cavities, laparotomy is performed when another focus of infection is formed.
· a contraindication for repeated interventions is MODS refractory to drug treatment. The exception is intra-abdominal or ongoing gastrointestinal bleeding.

Preparation for surgery and pain relief:
· surgical intervention is necessarily preceded by active resuscitation measures to improve the vital functions of the patient’s organs and systems, which will reduce the risk of deaths during anesthesia;
· preoperative preparation is carried out within 2-4 hours in order to stabilize the condition: normalize hemodynamics, correct existing violations of biochemical parameters, the coagulation system;
· during preparation, the necessary additional examination is carried out;
· ineffective preparation within 2-4 hours is not a contraindication for emergency surgery;
· during operations, type of anesthesia: local anesthesia, general anesthesia;
· Regional anesthesia (EDA, SA) is contraindicated for sepsis;
· in the postoperative period, pain relief is carried out by preventive administration of NSAIDs (in the absence of contraindications) in combination with an antispasmodic (drotaverine). Narcotic analgesics are prescribed when NSAIDs are ineffective;
· epidural analgesia can be carried out only after complete sanitation of the source of infection and if antibacterial therapy is effective, in the absence of other contraindications.

Indicators of treatment effectiveness.
· reduction in the degree of intoxication (clinically and laboratory);
· normalization of blood circulation parameters;
· normalization of external respiration;
· normalization of kidney function.

Drugs (active ingredients) used in treatment

Groups of drugs according to ATC used in treatment

Hospitalization

Indications for hospitalization indicating the type of hospitalization:

Indications for planned hospitalization: No.

Indications for emergency hospitalization: presence of a SIRS clinic.

Prevention

Preventive actions:

Prevention of deep vein thrombosis:
If there are no contraindications, low doses of unfractionated or low molecular weight heparin should be used (LE 1A). Prophylactic products (compression tights, etc.) should be used if heparin administration is contraindicated (LE 1A);
A combination of medical and mechanical treatment should be used in patients at high risk of developing deep vein thrombosis (LE 2C).

Prevention of stress ulcers :
Stress ulcers should be prevented using H2-histamine receptor blockers or proton pump inhibitors (LE 1B);
· when preventing stress ulcers, it is better to use proton pump inhibitors (LE 2C);
· if there is no risk of developing stress lesions of the gastrointestinal tract - enteral or tube feeding is restored - prophylaxis is stopped (LE 2B).

Further management:
· psycho-emotional rehabilitation;
· correction of diet and composition of food;
· Spa treatment.

Information

Sources and literature

1. Minutes of meetings of the Expert Council of the RCHR of the Ministry of Health of the Republic of Kazakhstan, 2015
   1. List of used literature: 1) Grinev M.V., Gromov M.I., Komrakov V.E. Surgical sepsis. - St. Petersburg. – M., 2001.- 315 p.; 2) Kozlov V.K. Sepsis: etiology, immunopathogenesis, concept of modern immunotherapy. – St. Petersburg: Dialect, 2006. – 304 p.; 3) Surgical infections: a guide, ed. I.A. Eryukhina, B.R. Gelfanda, S.A. Shlyapnikov. – St. Petersburg: Peter, 2003.- 864 p.; 4) Surgical infections: a practical guide / Ed. I.A. Eryukhina, B.R. Gelfanda, S.A. Shlyapnikov. – 2nd ed. reworked and additional – M.: Litterra, 2006. – 736 p.; 5) Sepsis at the beginning of the 21st century: classification, clinical diagnostic concept and treatment. Pathological and anatomical diagnosis: A practical guide. – M.: Litterra, 2006. – 176 p.; 6) Abdominal surgical infection: clinical picture, diagnosis, antimicrobial therapy: A practical guide / Ed. V.S. Savelyeva, B.R. Gelfand. – M.: Litterra, 2006. – 168 p.; 7) International Guidelines for Management of Severe Sepsis and Septic Shock: 2012; 8) Bone R.C., Balk R.A., Cerra F.B. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis the ACCP/SCCM consensus conference committee // Chest. 1992; 101: 1644-1655; 9) Perzilli P.A., Zerbi V., Di Carbo C., Bassi G.F. , Delle Fave G.F. Practical Guidelines for Acute Pancreatitis. Pancreatology 2010; 10: 523-535; 10) Barkhatova N.A., Privalov V.A. Sepsis in surgery. – 2010. – ChMGA, textbook. – 334 pp.; 11) Schwartz, Joseph, et al. "Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Sixth Special Issue." Journal of clinical apheresis 28.3 (2013): 145-284.; 12) A National Clinical Guideline No. 6. Sepsis Management http://www.hse.ie/eng/about/Who/clinical/natclinprog/sepsis/sepsis management.pdf; 13) Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter., Suppl. 2012; 2:1–138. 14) Savelyev V.S., Gelfand B.R. Sepsis at the beginning of the 21st century. Classification, clinical diagnostic concept and treatment. Pathological diagnosis. – M.: Litterra, 2012. – 176 p.; 15) Order of the Ministry of Health of the Republic of Kazakhstan No. 666 dated November 6, 2009 No. 666 “On approval of the Nomenclature, Rules for the procurement, processing, storage, sale of blood and its components, as well as Rules for the storage, transfusion of blood, its components and preparations” as amended by the Order of the Ministry of Health of the Republic of Kazakhstan No. 501 dated July 26, 2012; 16) Peritonitis. Practical guide /Ed. Savelyeva V.S., Gelfanda B.R., Filimonova. – M.: Litterra, 2006. – 208 p.; 17) Kozlov S.N. Modern antimicrobial therapy. Medical Information Agency. – 2009; 18) Savelyev V.S., Gelfand B.R. Sepsis. Classification, clinical diagnostic concept and treatment. Practical guide. Medical information agency. – 2013. – 368 p.

Information

List of protocol developers with qualification information:
1) Zhantalinova Nurzhamal Asenovna - Doctor of Medical Sciences Professor of the Department of Internship and Residency in Surgery at the Russian State University at the KazNMU named after. S.D. Asfendiyarov".
2) Chursin Vadim Vladimirovich - candidate of medical sciences, associate professor, head of the department of anesthesiology and resuscitation of JSC KazMUNO.
3) Zhakupova Gulzhan Akhmedzhanovna - State Public Enterprise at the Burabay Central Regional Hospital. Deputy Chief Physician for Audit, anesthesiologist-resuscitator of the highest category.
4) Mazhitov Talgat Mansurovich - Doctor of Medical Sciences, Professor of Astana Medical University JSC, clinical pharmacologist of the highest category, general practitioner of the highest category.

Indication of no conflict of interest: No

Reviewers: Turgunov Ermek Meiramovich - Doctor of Medical Sciences, Professor, surgeon of the highest qualification category, RSE at the Karaganda State Medical University of the Ministry of Health of the Republic of Kazakhstan, head of the Department of Surgical Diseases No. 2, independent accredited expert of the Ministry of Health of the Republic of Kazakhstan.

Indication of the conditions for reviewing the protocol: Review of the protocol 3 years after its publication and from the date of its entry into force or if new methods with a level of evidence are available.

Annex 1

Attached files

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In contrast to blood loss in sepsis and AGP, hypovolemia and loss of NOC occur secondary to two main reasons. One is plasma leakage, which occurs against the background of endothelial damage due to endotoxicosis and disseminated intravascular coagulation syndrome, characteristic of a general inflammatory reaction of the body, the other is a violation of the recirculation of digestive juices and the formation of the so-called “third space”, which is explained by endotoxicosis and abdominal ischemia, in turn turn, leads to an increase in intestinal translocation. Therefore, the anti-inflammatory ITM complex begins with crystalloid solutions. The use of protein blood products due to leakage from the vascular bed will increase the blockade of the interstitium, since water associated with them accumulates along with the proteins. Protein and “bound” water can be removed from the interstitium only by lymphatic drainage of the tissues, and this process is slow, and it is disrupted when interstitial pressure increases. “Free” water in crystalloid solutions is able to leave the interstitial space much faster, since it is easily reabsorbed into the vascular bed. In addition, from the Starling equation, which describes transcapillary fluid exchange, it follows:

SKD = ​​CODE pl + R tk – CODE tk,

where SBP is the average capillary blood pressure, COD pl is the colloid-oncotic plasma pressure, P tk is the hydrostatic interstitial pressure, COD tk is the colloid-oncotic interstitial pressure.

This means that an increase in Htc can contribute to an increase in SBP (along with it, the venous return of blood to the heart and blood pressure) only if the SODtc does not increase. Therefore, the basis of infusion therapy until the restoration of NOC, the elimination of disseminated intravascular coagulation syndrome and oxygen debt should be crystalloid solutions, and the use of protein drugs turns out to be dangerous. After stabilization of NOC and with residual hypoproteinemia, it is advisable to use dosed infusion of HES (10%) at a rate of 80–100 ml/hour to correct COD pl. After surgical debridement, which reduces endotoxemia, the use of protein drugs is less dangerous.

Treatment program:

1. Urgent hospitalization in the ICU.

2. Catheterization of the central vein.

3. Administration of crystalloids or colloids to target values:

CVP 8 – 12 mm Hg. (12 – 15 mmHg with mechanical ventilation);

SBP > 65 mm Hg;

Diuresis 0.5 ml/kg/h;

Mixed venous blood saturation ≥ 65%.

4. Transfusion of red blood mass to a level of Ht > 30% to achieve mixed venous blood saturation ≥ 65%.

5. Maintain SBP > 65 mmHg. dopamine or norepinephrine.

6. Immediate initiation of initial antibiotic therapy with preliminary collection of materials for bacteriological examination:

Obtain a blood culture from peripheral blood;

One culture from each vascular catheter inserted >48 hours ago;

Cultures from other sites as clinically indicated.

7. Start intravenous antibiotics as early as possible, in the first hour after recognition of severe sepsis.

8. Perform appropriate interventions to eliminate the source of infection, remove potentially infected vascular catheters.

9. Providing ventilation of the lungs (monitoring the patency of the airways, using oxygen 4-6 l/min through nasal catheters or an oronasal mask, mechanical ventilation for sepsis-induced nostrils/ARDS).

10. Corticosteroids – hydrocortisone up to 300 mg/day. with persistent hypotension.

11. Extracorporeal detoxification methods.

12. Enteral and parenteral nutrition with glycemic levels<8,3 мМоль/л.

13. Prevention of stress ulcers with H2 blockers or proton pump inhibitors (H2 receptor inhibitors are the preferred agents).