Sepsis of newborns

Sepsis of newborns is a generalized form of purulent-inflammatory infection caused by a conditionally pathogenic bacterial microflora, the pathogenesis of which is associated with dysfunction of the immune system (mainly phagocytic) with the development of an inadequate systemic inflammatory response (SVP) in response to a primary septic focus.

Systemic inflammatory reaction is a general biological non-specific immunocytological reaction of an organism in response to the action of a damaging endogenous or exogenous factor. In the case of infection, CBP occurs in response to the primary purulent-inflammatory focus. For CBP is characterized by a rapid increase in the production of pro-inflammatory (to a greater extent) and anti-inflammatory (to a lesser extent) cytokines, inadequate to the action of the damaging factor, which induces apoptosis and necrosis, causing the damaging effect of CBP on the body.

[1], [2], [3], [4], [5], [6],

Epidemiology of neonatal sepsis

In the domestic literature there is no reliable data on the incidence of infection among newborns, which is largely due to the lack of generally accepted diagnostic criteria for diagnosis. According to foreign data, the frequency of septic states among newborns is 0.1-0.8%. A special contingent of patients is children residing in intensive care units (ICU), as well as premature newborns, among them the incidence of this disease on average is 14%.

In the structure of neonatal mortality, the septic state averages 4-5 per 1,000 live births. The mortality rates from a blood infection are also quite stable and are 30-40%.

[7], [8], [9], [10],

What causes sepsis of newborns?

The septic state is due exclusively to the conditionally pathogenic microflora. In a number of cases, for example, in the immunodeficiency of a newborn, a blood infection can be an integral part of a generalized mixed infection-viral-bacterial, bacterial-fungal, etc.

The cause of this disease in children can be more than 40 opportunistic microorganisms, but most often the blood infection is caused by streptococci, staphylococci, E. Coli, Klebsiella and other gram-negative bacteria and anaerobes.

The etiological structure of neonatal sepsis depends on the time of infection of the fetus and the newborn.

The early (congenital) neonatal septic state is most often due to gram-positive cocci of S. Agalacticae belonging to group B streptococci. This causative agent can cause antenatal and intranal infection of the fetus;

The most likely etiology of early neonatal sepsis, depending on the time of infection of the fetus and the newborn

Time of infection	Probable pathogen
Antenatal period	S. Agalacticae E. Coli (rare)
Intranatal period	S. Agalacticae E. Coli S. Aureus
Postnatal period	S. Aureus et epidermidis E. Coli Klebsiella spp. S. Pyogenes

E. Coli and other members of the family of intestinal gram-negative bacilli cause infection of the fetus significantly less.

Late neonatal neonatal sepsis usually occurs due to postnatal infection. The main pathogens are E. Coli, S. Aureus and Klebsiella pneumoniae; Group B streptococci are rare. Increases the importance of group A streptococci, pseudomonads and enterococci.

In the structure of gram-negative pathogens of this disease, amounting to about 40%, during the last 10 years there have been some changes. The role of Pseudomonas spp. Klebsiella spp. And Enterobacter spp. As a rule, these pathogens cause blood infection in ICU patients who are on artificial ventilation of lungs (IVL) and parenteral nutrition, surgical patients.

The etiology of postnatal morbidity is significantly influenced by the localization of the primary septic focus. For example, staphylococci and E. Coli play the leading role in the aetiology of the umbilical infection, and in the etiology of cutaneous and rhinoconjunctival septic states - staphylococci and ß-hemolytic group A streptococci. Also, the spectrum of causative agents of hospital infection depends on the entrance gate of the infection. For example, with a catheterized septic state, a predominant role is played by staphylococci or a mixed generalized infection caused by the association of staphylococci with the fungi of the genus Candida. With abdominal hospital infection, enterobacteria, anaerobes, are often isolated.

The most likely causative agents of neonatal sepsis, depending on the localization of the primary focus of infection

Localization of the primary focus	The most likely pathogens
Umbilical wound	S. Aureus et epidermidis E. Coli
Lungs	K. Pneumoniae S. Aureus et epidermidis Ps. Aeruginosa (with mechanical ventilation) Acinetobacter spp. (with mechanical ventilation)
Intestines	Enterobacteriaceae spp. Enterobacter spp.
Abdominal cavity (after surgical interventions)	Enterobacteriaceae spp. Enterococcus spp. Ps. Aeruginosa Anaerobes
Skin, rhinoconjunctival area	S. Epidermidis et aureus S. Pyogenes et viridans
Oropharynx and nasopharynx, middle ear	S. Epidermidis et aureus S. Pyogenes et viridans E. Coli
Urinary tract	E. Coli and other species of the Enterobacteriaceae family Enterococcus spp.
Venous bed (after intravenous catheter application)	S. Aureus et epidermidis

The etiology of generalized infections in immunocompromised patients (including those in deeply immature neonates) also has a number of characteristics and depends on the nature of immunosuppression (acquired immune system dysfunctions, secondary immune deficiency, drug immunosuppression, congenital, hereditary or acquired neutropenia, primary immunodeficiency and HIV infection ). It is not always an infection that develops against such a background, it is precisely the sepsis of newborns.

Pathogenesis of neonatal sepsis

The starting point of the disease is the presence of a primary purulent focus against the background of the initial failure of anti-infective protection. In this situation, massive microbial contamination, which exceeds the possibilities of antimicrobial protection, leads to the breakthrough of the infectious origin in the systemic blood flow of the patient (bacteremia).

The most likely pathogens of generalized infections in immunodeficiency in infants

The nature of immunodeficiency	The most likely pathogens
Secondary immune dysfunctions, including dysfunction in gestational immaturity	Enterobacteriaceae spp. Staphylococcus spp. S. Pyogenes Mushrooms of the genus Candida
Drug immunosuppression	Cytomegalovirus Enterobacteriaceae spp. S. Aureus Mushrooms of the genus Aspergillus and Candida
Neutropenia	S. Aureus E. Coli Fungi of the genus Candida
AIDS	Opportunistic microflora (fungi, mycobacteria, cytomegalovirus, etc.)
Primary immunodeficiencies	Enterobacterioceae spp. S. Aureus et epidermidis Hemolytic streptococci of group A

Bacteremia, antigenemia and toxemia trigger the cascade of the body's defense systems - CBP, which activates immunity and mediators, acute phase inflammation proteins, coagulating and anticoagulating blood systems, kinin-kaleriin system, complement system, etc. In the systemic reaction of the child's organism to the breakthrough of infection into the bloodstream, neutrophilic granulocytes play an important role, determining the adequacy of functioning of other cells and body systems. Neutrophilic granulocytes have a high effector potential and almost instantly react to changes in the tissues and cells of the body, are able to quickly change metabolism in response to any stimulating effect, up to the development of a "respiratory explosion" and secretory degranulation with the release of bactericidal enzymes that generate toxic oxygen radicals. These cells synthesize not only inflammatory mediators, components of clotting and fibrinolysis systems, but also biologically active substances that stimulate cell growth. Neutrophilic granulocytes are able to interact with cascade inflammatory humoral systems of the body. The degree of bactericidal activity and cytotoxicity also largely depend on the activity of neutrophilic granulocytes. Cationic peptides of these cells ("peptide antibiotics", defensins) have bactericidal, fungicidal and antiviral activity.

In addition to the above, neutrophils play the role of phagocytes. The importance of phagocytosis, carried out by neutrophils and macrophages, differs significantly - true phagocytosis is realized precisely by macrophages. Neutrophilic phagocytosis, although it proceeds more intensively than mononuclear cells, is caused by other biochemical processes, because they have a different problem. The main function of neutrophils is the initiation of an inflammatory reaction. Biologically active substances secreted by neutrophilic granulocytes have a pro-inflammatory orientation; among them, cytokines working in acute inflammatory foci (IL-8, IL-1, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor), and involved in the regulation of chronic inflammation (IL-6, γ-interferon, transforming factor growth). Neutrophils synthesize a wide range of surface adhesion molecules with which they interact with endothelial cells of the vessels, the immune system, tissues and organs. As a result of adhesion, the sensitivity of the neutrophils themselves to cytokines and other mediators changes, which allows them to respond adequately to changes in tissues and organs. Cytotoxicity of neutrophils is much higher than in killer lymphoid cells (T-lymphocytes) and natural killers (NK cells). The neutrophil cytotoxicity factors are aimed at the nuclear structures of target cells, the structural elements of the genetic apparatus of the absorbed object, the destruction of the genome using factors that induce apoptosis (FIA). Cells undergoing apoptosis become objects of phagocytosis and rapidly break down.

Neutrophils actively phagocytize microorganisms, not caring about their true digestion, throw considerable amounts of FIA into the intercellular space, so as to cause damage as soon as possible to the genetic apparatus of pathogenic microorganisms. The effect of the release of the contents of neutrophil granules on the processes of inflammation is enormous. The content of neutrophil granules induces platelet aggregation, the yield of histamine, serotonin, proteases, arachidonic acid derivatives, blood clotting activators, complement system, kinin-klelecrine system, etc. FIA neutrophils are harmful to any cells, as they cause the destruction of nucleoprotein complexes of the genome.

Thus, in the conditions of the infectious process, neutrophils initiate CBP, participate in the presentation of the pathogen antigen to activate a specific immune response of the organism. With excessive activation of neutrophils, their cytotoxic effect is not limited to foreign cells, realizing in relation to their own cells and body tissues.

Excessive SVR underlies the hyperactivation of the hypothalamic-pituitary-adrenal system, which normally provides an adequate response of the body to stress. Activation of this system leads to the release of ACTH and an increase in the content of cortisol in the blood. Excessive activation of the hypothalamic-pituitary-adrenal system in septic shock, the fulminant course of the disease leads to an inadequate response to the release of ACTH. Along with this, the functional activity of the thyroid gland is significantly reduced, which is associated with a slowing down of the oxidative metabolism, which limits the adaptive capabilities of the newborn's body. In severe septic state (fulminant course, septic shock), a number of patients have a content of somatotropic hormone (STH). Low content of STH in conditions of basal hypercortisolamia promotes rapid development of necrotic processes (STG inhibits the inflammatory process).

Another manifestation of inadequate SVR is uncontrolled activation of the coagulating system of blood, in conditions of increasing depression of fibrinolysis, which inevitably leads to thrombocytopathy and coagulopathy of consumption.

Thus, CBP, induced by excessive activation of peripheral blood neutrophils, activation of the hypothalamic-pituitary-adrenal system and hemostatic system, underlies the formation of multiple organ failure, leading to deep homeostasis disorders, sometimes incompatible with life.

For mononuclear cells, neutrophils are helper cells. The main role of monocytes and macrophages is true phagocytosis with further careful digestion of neutrophil-dilated particles of target cells, neutrophils themselves and inflammatory cell dendrites. Phagocytosis, carried out by macrophages, helps to stifle the processes of inflammation and the healing of damaged tissues.

The formation of a mediator response to a bacterial infection underlying the syndrome of CBP is a genetically controlled process in which cell receptors that recognize various structures of microbial origin and induce the expression of factors of nonspecific resistance participate.

Syndrome CBP underlies progressive organ dysfunction, in some cases reaching the degree of organ failure. For the pathogenesis of the septic state, the rapid development of polyorganic insufficiency and deep homeostatic disorders are characteristic. One of the signs of disturbance of homeostasis in blood infection is a marked proliferation of opportunistic microflora, creating prerequisites for the emergence of new infectious foci and additional translocation of the infectious onset into the systemic bloodstream. Currently, the concept is popular, according to which violations of homeostasis are associated with the ingestion of endotoxin or a lipopolysaccharide endotoxin complex of gram-negative bacteria that rapidly colonize the upper parts of the small intestine under conditions of tissue hypoxia. Endotoxin significantly strengthens CBP, provokes disturbances of homeostasis, refractory to the treatment of hypotension. The entry of antigens into the bloodstream leads to disorganization of CBP - mediator chaos. Antigenic overload is the cause of pronounced immunosuppression in conditions of bacteremia and microcirculation disorders, which contributes to the formation of metastatic purulent foci that support CBP, toxemia and antigenemia. Disruption of SVR is the basis for the development of septic shock.

Symptoms of neonatal sepsis

Symptoms of neonatal sepsis, regardless of form (septicemia or septicopyemia), characterize the severity of the general condition of the newborn. Disturbances in thermoregulation were expressed (in mature, morfofunctional mature newborns, fever, in preterm, low-born children, progressive hypothermia with aggravated premorbid background), the functional state of the central nervous system (progressive depression) was disrupted. Characterized by a dirty-pale or grayish shade of skin with icterus and hemorrhages, areas of sclera. The marbling of the skin is expressed, acrocyanosis is possible. Early there is and jaundice quickly builds up. Often develops a common edema syndrome. A tendency to spontaneous bleeding is characteristic. The facial features are often pointed.

Respiratory failure develops without inflammatory changes on the roentgenogram, heart damage often occurs as a type of toxic cardiopathy, accompanied by the development of acute heart failure. Characteristic increase in the size of the spleen and liver, bloating, expressed by the venous network in the anterior abdominal wall, often observed regurgitation, vomiting and anorexia, dysfunction of the gastrointestinal tract up to the intestinal paresis. Typically, the lack of weight gain, the formation of hypotrophy.

For premature infants, the subacute course of this disease in the form of respiratory distress syndrome (dyspnea with periods of bradypnoea or apnea), bradycardia, disturbances of the sucking reflex, and tendency to hypothermia. The above symptoms of neonatal sepsis reflect different degrees of development of multiple organ failure. The most typical syndromes of multiple organ failure in blood infections, as well as the changes that are typical for them, found in laboratory and instrumental survey methods, are shown in the table.

Primary septic hearth

As it was noted above, in studying the clinical picture of the disease with late neonatal sepsis, in most cases it is possible to detect a primary septic focus.

After the introduction of the primary surgical treatment of the umbilical cord, the incidence of omphalitis decreased; Currently, these diseases occur in no more than a third of cases. Against this background, the incidence of pulmonary (up to 20-25%) and intestinal septic state (not less than 20%) increased significantly. Other localizations of the primary focus are much less common and do not exceed 2-6%. In some cases, the entrance gate of the infection can not be established. This is especially true for children with a small gestational age, in whom the processes of alteration are poorly expressed.

Clinical and laboratory criteria of organ failure in the septic state (Balk R. Et al., 2001, in modification)

Localization of lesions	Clinical criteria	Laboratory indicators
Respiratory system	Tachypnea, orthopnea, cyanosis, IVL with or without positive end-expiratory pressure (PEP)	PaO2 <70 mmHg. SaO2 <90%. Changes in the acid-base state
Kidneys	Oliguria, anuria, edema syndrome	Increase in creatinine and urea levels
Liver	Increased liver size, jaundice	Hyperbilirubinemia (in newborns due to an increase in the indirect fraction). Increased ACT, ALT, LDH. Hypoproteinemia
Cardio vascular system	Tachycardia, hypotension, expansion of the heart boundaries, a tendency to bradycardia, the need for hemodynamic support	Change in central venous pressure, pulmonary artery wedge pressure. Reduction of the ejection fraction. Decreased cardiac output
Hemostasis system	Bleeding, necrosis	Thrombocytopenia. Prothrombin time extension or APTT. Signs of DIC syndrome
Gastro intestinal tract	Intestinal paresis, vomiting, regurgitation, stool disruption, impossibility of enteral feeding	Dysbiosis
Endocrine system	Adrenal insufficiency, hypothyroidism of the thyroid gland	Reduction of cortisol. Reduction of the content of triiodothyronine and thyroxine at a normal concentration of thyroid-stimulating hormone
The immune system	Splenomegaly, accidental involution of the thymus, nosocomial infection	Leukocytosis, leukopenia, lymphopenia. The neutrophil index (NI)> 0.3. Increase the content of C-reactive protein. Violation of the ratio of subpopulations of lymphocytes. Violation of the digestive function of phagocytes. Dysimmunoglobulinemia
Nervous System	Inhibition or excitation of CNS functions, convulsions	Increase in the level of protein in the cerebrospinal fluid with normal cytosis. Increase in CSF pressure

Septicemia

Septicemia is clinically characterized by the development of toxicosis and multiple organ failure in the background of the primary purulent inflammatory focus. For congenital early septicemia is characterized by the presence of isolated symptoms of infectious toxicosis and organ failure in the absence of a primary purulent focus.

Septiccopymia

Septicopyemia is characterized by the development of one or more foci that determine the features of the clinical picture and course of the disease. Among the metastatic foci of neonatal sepsis, meningitis (more than half the cases) takes the first place, the second and third - osteomyelitis and abscessed pneumonia. Other localization of piemic foci (abscesses of the liver and kidneys, septic arthritis, mediastinitis, panophthalmitis, phlegmon of the stomach wall, intestine, etc.) are much less common, amounting together to no more than 10% of all cases of sepsis of newborns.

Septic shock

Septic shock, according to various authors, is observed in 10-15% of neonatal sepsis, with the same frequency with septicemia and septicopyemia. In 80-85% of cases, septic shock develops in a septic state caused by gram-negative bacilli. Kokkov etiology of the disease less often leads to the development of shock. The exception is streptococcus group B and enterococci (70-80%). Mortality in the development of septic shock is more than 40%.

For the clinical picture of septic shock in neonates characterized by rapid, sometimes catastrophic, increasing severity of the condition, progressive hypothermia, skin pallor, oppression of unconditioned reflexes, tachycardia and bradycardia, increasing dyspnea in the absence of infiltrative changes on chest radiographs, bleeding from injection sites, petechial rash or bleeding with mucous membranes, pastovnost or puffiness of tissues. Possible an excoxic effect on the background of swelling of tissues and organs, especially parenchymal.

The most characteristic sign is the increasing arterial hypotension, refractory to the introduction of adrenomimetics. The shock is also characterized by the development of the syndrome of disseminated intravascular coagulation (DVS) with thrombocytopenia and consumption coagulopathy, depression of fibrinolysis. Along with hemorrhage, multiple necrosis is rapidly forming, including the walls of the small intestine, cortical parts of the kidneys, myocardium, brain and other organs, which determines the severity of the patient's condition.

Shock is accompanied by severe hormonal dysfunction in the form of hypercortisolemia, a drop in the concentration of thyroid hormones, thyroid-stimulating and growth hormones of the pituitary gland, hyperinsulinism. With shock, there are pronounced violations of almost all cascade mechanisms of homeostasis regulation, including systemic mediator response of the organism, acquiring the character of "mediator chaos".

The course and outcome of neonatal sepsis

Sepsis of newborns is attributed to acyclic infectious diseases; without treatment or with inadequate therapy, the condition almost always leads to death.

The development of septic shock at the onset of the disease can lead to a lightning-fast septic state with catastrophic deterioration of the condition, multiple organ failure and symptoms of DIC syndrome. The lethal outcome occurs within 3-5 days of the disease. Sepsis of newborns occurs lightning fast in about 15% of cases, among surgical patients and with hospital blood infection the frequency of development of this form reaches 20-25%.

In the blood formula, with a lightning-fast course of the disease, a tendency to leukopenia is expressed, a shift of the leukocyte formula to the left, an increase in the neutrophil index, absolute lymphopenia, thrombocytopenia, aneosinophilia, monocytosis. The listed changes are typical for heavy SVR.

If at the beginning of the disease there is no septic shock or it was managed to be stopped, there is an acute course of the disease, the duration of which is up to 8 weeks. This variant of the course of this disease is observed in 80% of cases. Lethal outcome can occur at the 3-4th week of the disease from severe multi-organ failure, incompatible with life.

The period of acute manifestations of the infectious process is up to 14 days, then the repair period begins, characterized by the extinction of symptoms of toxicosis, the gradual restoration of the functional activity of individual organs and systems, and the reorganization of metastatic foci. Splenomegaly, pallor of the skin, lability of central and autonomic nervous system functions, dysbacteriosis of the skin and mucous membranes, deficiency of body weight up to grade I-III hypotrophy are preserved.

During this period, characterized by a decrease in the resistance of the body, there is a high risk of superinfection of bacterial, fungal or viral etiology. Often, the source of superinfection - the rapid proliferation of the microflora of the baby's intestines; and possibly nosocomial infection.

Hematologic picture in the acute period of the septic state: marked leukocytosis (less often - normal indices or leukopenia), shift of the leukocyte formula to the left, increase of HI. Possible thrombocytopenia, eosinopenia, lymphopenia, the tendency to monocytosis.

In the reparation period, anemia of a redistributive nature develops, mild monocytosis. Neutrophilia in a third of cases is replaced by neutropenia. The tendency to eosinophilia is characteristic. In the peripheral blood, basophils and plasma cells can be detected.

Classification of neonatal sepsis

The generally accepted clinical classification of neonatal sepsis is currently not available. The latest clinical classification of this disease in Russia was published more than 15 years ago and does not meet modern requirements. In the International Classification of Diseases X revision (ICD-10), which defines the diagnosis code for statistics, the "bacterial sepsis of the newborn", code P36, has been identified.

In contrast to the coding classification, when compiling a clinical classification of the disease, it is necessary to take into account the time and conditions of the occurrence of a blood infection - developed before the birth of the child, after birth; localization of the entrance gates and / or primary septic focus, clinical features of the disease. These parameters characterize the etiological spectrum of the disease, the extent and nature of therapeutic, preventive and anti-epidemic measures. It is these parameters that are useful in the classification of neonatal sepsis.

By development time:

• early neonatal;
• late neonatal.

By localization of the entrance gate (primary septic focus):

• umbilical;
• pulmonary;
• cutaneous;
• rhinopharyngeal;
• rhinoconjunctival;
• otogenic;
• urogenous;
• abdominal;
• catheterization;
• other. 

According to the clinical form:

• septicemia; septicopyemia.

By the presence of symptoms of multiple organ failure:

• septic shock;
• acute pulmonary insufficiency;
• acute heart failure;
• acute renal insufficiency;
• acute intestinal obstruction;
• acute adrenal insufficiency;
• edema of the brain;
• secondary immune dysfunction;

DIC-syndrome.

When antenatal or intranatal infection of the fetus with a clinical manifestation of the disease in the first 6 days of the child's life, it is customary to talk about early sepsis of newborns. Its features: intrauterine infection, the absence of a primary infectious focus and the predominance of the clinical form without metastatic piemic foci (septicemia).

In the clinical manifestation of neonatal sepsis on the 6th-7th day of life and later it is customary to talk about the late neonatal septic state. Its feature is postnatal infection. In this case, the primary focus of infection is usually present, and the disease in two-thirds of cases occurs in the form of septicopyemia.

The above clinical classification of the neonatal septic state is closely interrelated with the spectrum of the most probable pathogens, knowledge of which is extremely important for the rational choice of primary antibiotic therapy. The spectrum of possible pathogens varies depending on the localization of the entrance gate of the infection, and therefore this parameter should be indicated in the clinical diagnosis of a blood infection. The localization of the entrance gate has a certain epidemiological significance and is important for the development of antiepidemic and preventive measures. There are umbilical, cutaneous, otogenic, rhinopharyngeal, urogenital, catheter, pulmonary, abdominal and other, less common types of infection.

Septicemia is a clinical form of the disease, characterized by the presence of microbes and / or their toxins in the bloodstream on the background of severe symptoms of infectious toxicosis, but without the formation of piemic foci. Morphologically and histologically, it is possible to detect signs of microbial involvement and myelosis of parenchymal organs.

Septicopaemia is a clinical form of a blood infection characterized by the presence of one or more piemic, metastatic, purulent-inflammatory foci. Criterion septikopieemii - the same type of pathogen, isolated from the foci of inflammation and blood of the patient.

Syndrome of organ failure determine the severity and outcome of the disease, requiring certain treatment, and therefore it is also advisable to isolate them in a clinical diagnosis. Among them, due to the severity of the prognosis, special attention deserves a symptomatic complex of septic (infectious-toxic) shock.

By septic shock is understood the development of progressive arterial hypotension, not associated with hypovolemia, in conditions of an infectious disease. Despite the name, septic shock is not considered a predictor of a blood infection - the condition can occur in other severe infectious diseases (peritonitis, meningitis, pneumonia, enterocolitis).

[11], [12], [13], [14], [15]

Diagnosis of neonatal sepsis

Diagnosis of neonatal sepsis consists of several stages. First of all, it is necessary to establish or presume a diagnosis of the septic state. The second stage is the etiologic diagnosis of the disease. The third stage is the assessment of violations of organs and systems, shifts in homeostasis.

The first level of diagnosis is the most difficult - despite the long-term study of a blood infection, in pediatric practice there are still no generally accepted clinical and laboratory diagnostic criteria that meet the requirements of evidence-based medicine. One of the reasons for this is that the patient has no primary infectious focus; it is located in the body of the mother or in the placenta. In addition, severe signs of SVR in children occur in many severe non-infectious diseases (respiratory distress syndrome, hereditary aminoaciduria, etc.) and infectious (necrotizing enterocolitis of the newborn, phlegmon, meningitis, etc.) of nature.

Based on the current understanding of the diagnosis of this disease, the disease must be assumed in the newborn for the first 6 days of life in the presence of severe infectious toxicosis and signs of CBP:

• prolonged (more than 3 days) fever (> 37.5 ° С) or progressive hypothermia (<36,2 ° С);
• hyperleukocytosis in the first 1-2 days of life> 30x10 ⁹, on the 3rd to 6th day of life -> 20x10 ⁹, in children older than 7 days of life -> 15x10 ⁹ / l OR leukopenia <4x10 ⁹ / l, NI> 0.2 -0.3, thrombocytopenia <100х10 ⁹ / l;
• increase in the content of C-reactive protein in the serum of more than 6 mg / l;
• increase in the content of procalcitonin in the blood serum more than 2 ng / ml;
• an increase in the content of IL-8 in the serum of more than 100 pg / ml.

The presence of at least three of the signs listed above is a good reason for assuming a diagnosis of a blood infection and immediate appointment of empirical antibacterial therapy, and the necessary therapeutic measures.

In newborns older than 6 days of age, the diagnosis of a septic condition should be assumed in the presence of a primary infectious inflammatory focus (associated with the environment) and at least three of the listed signs of CBP. Given that the diagnosis of a blood infection to date has a clinical status, it is advisable, within a period of 5 to 7 days, to retrospectively confirm it or reject it. The absence of a link between the clinical symptoms of SVP and the infection speaks against the diagnosis of "neonatal sepsis" and requires further diagnostic search.

Diagnosis of a septic condition is established with confidence in the presence of a primary infectious inflammatory focus or metastatic purulent foci with an exciter, also isolated from the blood, provided that there are at least three signs of CBP.

Bacteremia is not considered a diagnostic sign of the disease; this condition can be observed with any infectious disease of a bacterial nature. The establishment of bacteremia is important for determining the etiology and rationale for rational antibacterial treatment (the second stage of diagnosis). Along with the study of hemoculture, etiologic diagnosis of neonatal sepsis includes a microbiological study of the primary and metastatic foci.

Microbiological examination of loci that come into contact with the environment (conjunctiva, mucous membrane of the nasal cavity and mouth, skin, urine, feces) and not involved in the primary purulent-inflammatory focus can not be used to establish an etiological diagnosis of the septic state. At the same time, a microbiological study of these media is shown to assess the extent and nature of dysbiosis - one of the constant satellites of blood infection due to a decrease in the immunological reactivity of the patient's body (the third stage of diagnosis). Above are the main clinical, laboratory and instrumental characteristics of multiple organ failure, accompanying sepsis of newborns and determining its outcome. Monitoring of these indicators is necessary for the organization of adequate treatment of patients.

[16], [17], [18], [19],

Differential diagnosis of neonatal sepsis

Differential diagnosis of neonatal sepsis should be carried out with severe purulent-inflammatory localized diseases (purulent peritonitis, purulent mediastinitis, purulent-destructive pneumonia, purulent meningitis, purulent hematogenous osteomyelitis, necrotizing enterocolitis of newborns), also taking place with signs of CBP. In contrast to this disease, such a disease characterizes the close relationship between the presence of a purulent focus and the expressed signs of CBP, as well as the cessation of these symptoms soon after the sanation of the focus. Nevertheless, the main directions of treatment and the principles of antibiotic therapy for blood infection and severe purulent-inflammatory diseases of bacterial nature are identical.

Sepsis of newborns must be differentiated from generalized (septic) forms of bacterial infections caused by pathogenic agents (salmonella septicemia and septicopyemia, disseminated tuberculosis, etc.). The correct diagnosis of these diseases determines the nature and extent of anti-epidemic measures, the appointment of specific antibiotic therapy. The basis of differential diagnosis is the epidemiological anamnesis and the data of bacteriological and serological examination of the materials taken from the patient.

In the differential diagnosis of this disease and congenital generalized forms of viral infections (cytomegalovirus, herpetic, enterovirus, etc.), the confirmation of the latter justifies specific antiviral and immunocorrective treatment, limiting the use of antibiotics. For this purpose, an immunocytological study is carried out by the method of polymerase chain reaction (PCR) of blood, liquor and urine, serological tests.

Sepsis of newborns should be differentiated from generalized mycoses, primarily candidiasis, much less often - with aspergillosis, to justify the appointment of antimycotics, restrict or eliminate antibiotics and clarify the tactics of immunocorrective treatment. Differential diagnosis is based on the results of a microscopic and mycological (sowing on the Saburou environment) studies of blood, liquor, and separated piemic foci.

In newborns, sepsis must be differentiated with a hereditary pathology of amino acid metabolism, accompanied by all signs of CBP, but not requiring antibiotic therapy. With hereditary defects in amino acid metabolism, a rapidly deteriorating condition of the newborn occurs soon after birth, shortness of breath, pulmonary heart failure, oppression of the central nervous system, hypothermia, leukopenia, thrombocytopenia, anemia progress. A distinctive feature of the defect exchange amino acids - persistent intensive metabolic acidosis, it is possible the appearance of a pronounced odor from the patient. It is not excluded bacteremia, showing a severe dysbiosis and a decrease in resistance of the body. The main method of differential diagnosis is a biochemical blood test (detection of pathological acidemia) in combination with non-curable metabolic acidosis.

[20], [21], [22], [23], [24], [25]

Treatment of neonatal sepsis

Treatment of neonatal sepsis should include the following concurrent activities:

1. etiological therapy - influence on the causative agent of the disease, including local treatment aimed at sanation of primary and metastatic foci, systemic antibacterial treatment and correction of disorders of the biocenosis of the skin and mucous membranes;
2. pathogenetic therapy - the impact on the patient's body, including treatment aimed at correcting the violations of homeostasis, including immune reactions.

Etiological treatment of neonatal sepsis

Antibacterial treatment is the cardinal method of etiologic treatment of the septic state. If there is a suspicion of sepsis of newborns, in the vast majority of cases, antibiotics are prescribed empirically, based on the assumption of the most probable spectrum of possible causative agents of infection in this patient.

General provisions for the selection of antibacterial therapy:

1. The choice of drugs at the beginning of treatment (before the specification of the etiology of the disease) is performed depending on the time of onset (congenital, postnatal), conditions of origin (community-based, hospital - in the conditions of therapeutic or surgical department, ICU), localization of the primary septic focus.
2. Drugs of choice in empirical therapy are considered antibiotics in the form of a combination of antibacterial drugs with a bactericidal type of action, active against potentially possible causative agents of this disease (de-escalation principle). When clarifying the nature of microflora, its sensitivity, antibacterial treatment is corrected by changing the drug, switching to monotherapy or preparations of a narrow spectrum of action.
3. When choosing antibiotics, preference should be given to systemic drugs that penetrate the biological barriers of the body and create a sufficient therapeutic concentration in cerebrospinal fluid, brain substance and other tissues (bone, pulmonary, etc.).
4. In all cases, it is desirable to prescribe the least toxic antibiotics, given the nature of organ damage, avoiding a sharp increase in endotoxin concentration in the blood, which reduces the risk of shock.
5. Preferred preparations with the possibility of intravenous administration.

The program of empirical antibacterial treatment of neonatal sepsis

Characteristics of the septic state	Drugs of choice	Alternative drugs
Early	Ampicillin + aminoglycosides	Third generation cephalosporins + aminoglycosides
Umbilical	Aminopenicillins or oxacillin + aminoglycosides. Third-generation cephalosporins (ceftriaxone, cefotaxime) + aminoglycosides	Carbapenems. Glycopeptides. Linezolid
Cutaneous, rhinopharyngeal	Aminopenicillins + aminoglycosides. Second-generation cephalosporins + aminoglycosides	Glycopeptides. Linezolid
Rhinopharyngeal, otogenic	Third-generation cephalosporins (ceftriaxone, cefotaxime) + aminoglycosides	Glycopeptides. Linezolid
Intestinal	Cephalosporins III and IV generation + aminoglycosides. Inhibitor-protected aminopenicillins + aminoglycosides	Carbapenems. Aminoglycosides
Urogenic	Cephalosporins III and IV generations. Aminoglycosides	Carbapenems
Iatrogenic abdominal	Third-generation cephalosporins (ceftazidime, cefoperazone / sulbactam) + aminoglycosides. Inhibitor-protected carboxylic acids + aminoglycosides	Carbapenems. Metronidazole
Against neutropenia	Third-generation cephalosporins + aminoglycosides. Glycopeptides	Carbapenems. Glycopeptides
Against the background of drug-induced immunosuppression	Cephalosporins III or IV generation + aminoglycosides. Glycopeptides	Carbapenems. Linezolid. Inhibitor-protected carboxypepenicillins
Iatrogenic catheterization, pulmonary (IVL-associated)	Cephalosporins of the third generation with antisignogenic effect + aminoglycosides. Inhibitor-protected carboxylic acids + aminoglycosides. Glycopeptides + aminoglycosamide. Third-generation cephalosporins (ceftazidime, cefoperazone / sulbactam) + aminoglycosides. Inhibitor-protected carboxylic acids + aminoglycosides	Carbapenems. Linezolid. Glycopeptides. Metronidazole. Lincosamides

To date, there is no universal antimicrobial drug, a combination of drugs or a regimen of therapy, with the same efficacy curing any newborn. There are only recommended schemes for selecting antibacterial drugs. Rational choice of drugs in each case depends on the individual characteristics of the patient, regional data on the most likely pathogens, their sensitivity to antibiotics.

Observation of a sick child during the period of antibacterial treatment includes the following parameters:

• Assessment of the overall effectiveness of antibiotic therapy;
• assessment of the effectiveness of sanation of primary and metastatic foci, the search for newly emerging purulent foci;
• control of the effect of antibiotic therapy on the biocenosis of the most important loci of the body and its correction;
• control of possible toxic and undesirable effects, their prevention and treatment.

Antibacterial therapy is considered effective, against which the stabilization or improvement of the patient's condition occurs within 48 hours.

Ineffective treatment is considered, against the background of which within 48 hours there is an increase in the severity of the condition and organ failure; Inefficiency of therapy is the basis for switching to an alternative treatment regimen.

In sepsis of newborns caused by a gram-negative microflora, effective antibiotic therapy can be the cause of worsening of the patient's condition due to the release of endotoxin from the dying bacteria. In this regard, when choosing antibiotics should be preferred drugs that do not cause significant intake of endotoxin in the bloodstream. Antibacterial treatment is performed against the background of adequate detoxification, including infusion therapy and intravenous immunoglobulin, enriched (pentaglobin).

The duration of successful antibacterial therapy is at least 3-4 weeks with the exception of aminoglycosides, the duration of treatment which should not exceed 10 days. The course of treatment with the same drug with its sufficient effectiveness can reach 3 weeks.

The basis for the abolition of antibacterial drugs should be considered the sanation of primary and piemic foci, the absence of new metastatic foci, the relief of acute SWR symptoms, persistent weight gain, the normalization of the leukocyte formula of peripheral blood and the number of platelets.

Complete restoration of the functions of organs and systems, the disappearance of pallor, splenomegaly and anemia occurs much later (no earlier than 4-6 weeks from the start of treatment). These clinical symptoms by themselves do not require the appointment of antibacterial drugs, only restorative treatment is necessary.

Given the need for prolonged intensive antibiotic therapy, a significant role of dysbiosis in the pathogenesis of neonatal sepsis, it is advisable to combine antibacterial treatment with "maintenance therapy". It includes the simultaneous administration of probiotics (bifidumbacterin, lactobacterin, linex) and antimycotics fluconazole (diflucan, forkan) in a dose of 5-7 mg / (kghsut) in 1 dose. Low therapeutic and preventive effectiveness of nystatin, its extremely low bioavailability does not allow to recommend it for the prevention of candidiasis in newborns. Ketoconazole (Nizoral) for children under 7 years is not recommended.

Along with probiotics and antimycotics for the prevention of dysbacteriosis, it is important to organize hygienic measures (hygienic treatment of the skin and visible mucous membranes, bathing) and proper feeding. Absolute feeding of native mother's milk (breast-feeding, native milk from a bottle or introduction of milk through a probe depending on the condition of the baby) is absolutely shown. In the absence of mother's milk, adapted infant formula is used, enriched with bifidobacteria ("Agusha" fermented milk mix, "Sour milk acid", acidophilic mixture "Malyutka"). It should be remembered that in children with severe acidosis, fermented milk mixtures often provoke regurgitation. In this case, it is advisable to use fresh, prebiotic-adapted, low-lactose-supplemented mixtures prepared with milk whey (Nutrilon Comfort, Nutrilon Low Lactose, AL-110, etc.). In preterm infants with agalactia, the mother uses special adapted mixtures for prematurity ("Alprem", "Nenatal", "Fresopre", etc.).

The sanation of primary septic and pyemic foci even by surgical intervention is an obligatory component of etiotropic treatment of neonatal sepsis.

[26], [27], [28], [29], [30],

Pathogenetic treatment of neonatal sepsis

Pathogenetic therapy for neonatal sepsis includes the following main areas:

• immunocorrection;
• detoxification;
• restoration of water and electrolyte balance, acid-base state;
• anti-shock therapy;
• restoration of the functions of the main organs and systems of the body.

Immunocorrective therapy

The arsenal of methods and means of immunocorrection, used at present for the treatment of neonatal sepsis, is very extensive. "Aggressive" methods include partial exchange blood transfusion, hemosorption and plasmapheresis. They are used only in extremely severe cases of fulminant neonatal sepsis, with the unfolded clinical picture of septic shock and the immediate threat of death. These methods can reduce the degree of endotoxinemia, reduce the antigenic load on immunocompetent and phagocytic blood cells, make up the content of opsonins and immunoglobulins in the blood.

In neonatal sepsis, accompanied by absolute neutropenia, and with an increase in the neutrophil index of more than 0.5, the immunocorrection is used to use a transfusion of a leukocyte suspension or leuco concentrate from the calculation of 20 ml / kg of the body weight of the baby every 12 hours until the leukocyte concentration is 4-5x10 ⁹ / l in peripheral blood. This method of treatment is justified by the key value of neutrophils in the pathogenesis of CBP in the sepsis of newborns.

Currently, instead of transfusions of a suspension of leukocytes, recombinant granulocyte or granulocyte-macrophage colony-stimulating factors are increasingly prescribed. The drugs are prescribed from the calculation of 5 μg / kg body weight of the patient for 5-7 days. It should be remembered that the therapeutic effect caused by an increase in the number of leukocytes in the peripheral blood is unfolding by the 3rd-4th day of treatment, so that with the lightning-fast course of this disease, transfusion of the leukocyte suspension is preferable. Perhaps the combined use of these methods. The use of recombinant granulocyte colony-stimulating factor significantly increases the survival rate of patients.

Great hopes are placed on the use of polyclonal antibody preparations. In this area, the leading place is occupied by immunoglobulins for intravenous administration. The use of immunoglobulins in children is pathogenetically justified. The concentration of IgM and IgA in the neonatal period is low and increases only after 3 weeks of life. This condition is called physiological hypogammaglobulinemia of newborns; in preterm infants, hypogammaglobulinemia is even more pronounced.

In the conditions of a serious infectious process of bacterial etiology, the physiological hypogammaglobulinemia of the infant is sharply aggravated, which can lead to the development of a severe generalized infectious process. Simultaneous effects of bacterial antigenemia and toxemia exacerbate intoxication and lead to disruption of normal intercellular interactions in the immune response aggravated by multiple organ failure.

To maximize the effectiveness of anti-infective therapy in septic conditions, the combination of antibacterial therapy with intravenous immunoglobulin is most appropriate. In infants, especially prematurity, it is advisable to administer the drug to a blood level of at least 500-800 mg%. The recommended daily dose is 500-800 mg / kg of body weight, and the duration of the course of administration is 3-6 days. Immunoglobulin should be administered as soon as possible, immediately after an infectious diagnosis is established, in sufficient volume. The appointment of intravenous immunoglobulin in the 3-5th week of the disease is ineffective.

For intravenous administration, standard immunoglobulins (preparations of normal donor Ig) are used: sandhoglobin, algoglobin, C / D4 endobulin, intraglobin, octagums, domestic immunoglobulin for intravenous administration, etc. The mechanism of their action and the clinical effect are approximately the same.

Especially effective are preparations of immunoglobulins enriched with IgM. In Russia they are represented by a single drug - pentaglobin (Biotest Pharma, Germany). It contains 12% IgM (6 mg). The presence in the pentaglobin of IgM (the first immunoglobulin formed in response to antigenic stimulation and carrying antibodies to endotoxin and capsular antigens of gram-negative bacteria) makes the drug extremely effective. In addition, IgM is better than other Ig classes, fix complement, improve opsonization (preparation of bacteria for phagocytosis). Intravenous administration of pentaglobin is accompanied by a significant increase in IgM levels on the 3-5th day after administration.

Detoxication therapy, correction of electrolyte disorders and acid-base state

Detoxification is an obligatory component of the pathogenetic treatment of acute neonatal sepsis. Most often, intravenous drip infusion of freshly frozen plasma and glucose-salt solutions is carried out. Freshly frozen plasma supplies the child with antithrombin III, the concentration of which falls significantly during neonatal sepsis, which is the basis for the depression of fibrinolysis and the development of DIC syndrome. When calculating the volume of infusate, standard recommendations that take into account the gestational maturity of the child, its age, body weight, the presence of dehydration or edematous syndrome, fever, vomiting, diarrhea, the volume of enteral nutrition are used.

Other methods of detoxification (hemosorption, partial exchange blood transfusion, plasmapheresis) are used strictly according to special indications (lightning current) with appropriate technical support.

Infusion therapy allows replenishing the volume of circulating blood, correcting electrolyte disorders and improving hemorheological characteristics of the blood. For this purpose, use rheopolyglucin, dopamine, komplamin, solutions of potassium, calcium, magnesium.

To correct the acid-base state, adequate oxygen therapy has been shown, the intensity and technique of which depends on the patient's condition (from the supply of moistened and warmed oxygen through the mask or nasal catheters to the ventilator).

In a number of cases (impossibility of feeding), infusion therapy is combined with parenteral nutrition of the infant, including amino acid solutions in the infusate.

For maximum energy conservation in the acute period of clinical manifestations of toxicosis in the septic state, septic shock, it is advisable that the child stay in the kuveze at a temperature of at least 30 ° C and a humidity of at least 60%.

Correction of vital functions is performed under the monitor control, which includes:

• assessment of the parameters of the acid-base state, pO2;
• determination of hemoglobin concentration, hematocrit;
• assessment of glucose, creatinine (urea), potassium, sodium, calcium, magnesium, according to indications - bilirubin, activity of transaminases and other indicators;
• evaluation of blood pressure, removal of the electrocardiogram.

[31], [32], [33], [34], [35]

Anti-shock therapy

Septic shock is the most formidable symptom of newborn sepsis, the lethality in which exceeds 50%. The main pathogenetic components of the shock are intense CBP with a pro-inflammatory orientation, passing in the late phase of shock into the stage of "mediator chaos"; the extreme tension of the adaptive reaction of the hypothalamic-pituitary-adrenal system with subsequent disruption of adaptive mechanisms, symptoms of latent or apparent adrenal insufficiency, hypothyroidism, pituitary dysregulation, and the development of DIC syndrome up to blood incontinence due to thrombocytopathy and consumption coagulopathy. Severe multiorgan failure always accompanies septic shock. Treatment of shock includes three main areas:

• intravenous immunoglobulins (preferably immunoglobulin, enriched with IgM), which allows to reduce the concentration in the blood and the synthesis of pro-inflammatory cytokines;
• the introduction of low doses of glucocorticoids, which allows to stop the latent adrenal insufficiency and activate the reserve capabilities of the hypothalamic-pituitary-adrenal system;
• correction of hemostasis, including daily transfusion of fresh frozen plasma, administration of heparin sodium at a dose of 50-100 mg / kg body weight.

In the treatment of septic shock, in addition to the above directions, includes support for the functions of vital organs and systems.

[36], [37], [38], [39], [40], [41],

Restorative treatment of neonatal sepsis

Restorative therapy begins as the symptoms of infectious toxicosis disappear. During this period, children are extremely vulnerable to superinfection, the risk of activation of intestinal microflora and development of intensive dysbiosis is high. In this regard, much attention is paid to the correctness of the hygienic regime and the rationality of feeding the baby.

In the recovery period, it is advisable to organize a joint stay of the child with the mother, isolating him from other patients of the department, ensuring strict adherence to the hygiene regime, correction of the intestinal biocenosis, prescribing antimycotic drugs (if necessary) and allowing breastfeeding. It is advisable to carry out metabolic therapy aimed at restoring oxidative intracellular processes, maintaining anabolic metabolism. For this purpose, vitamin complexes, essential amino acids, enzymes are used.

If sepsis of newborns is accompanied by severe impairment of immunity, confirmed by laboratory tests, immunotherapy is indicated. In the recovery period, depending on the nature of immune disorders, can be prescribed lycopide, azoxime, interferons. Particular attention is paid to the restoration of the functional activity of individual organs and systems.