Neonatal sepsis

Sepsis in newborns is a generalized form of purulent-inflammatory infection caused by opportunistic 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 (SIR) in response to the primary septic focus.

Systemic inflammatory reaction is a general biological non-specific immunocytological reaction of the body in response to the action of a damaging endogenous or exogenous factor. In the case of infection, SIR occurs in response to a primary purulent-inflammatory focus. SIR 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 SIR on the body.

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Epidemiology of neonatal sepsis

There is no reliable data on the frequency of infection among newborns in the domestic literature, which is largely due to the lack of generally accepted diagnostic criteria for diagnosis. According to foreign data, the frequency of septic conditions among newborns is 0.1-0.8%. A special contingent of patients are children in intensive care units (ICUs), as well as premature newborns, among whom the frequency of development of this disease is on average 14%.

In the structure of neonatal mortality, septic conditions make up an average of 4-5 per 1000 live births. The mortality rate from blood infections is also quite stable and amounts to 30-40%.

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What causes neonatal sepsis?

The septic condition is caused exclusively by opportunistic microflora. In some cases, for example, with immunodeficiency of a newborn, blood infection can be a component 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 newborn.

Early (congenital) neonatal septic condition is most often caused by gram-positive cocci S. agalacticae belonging to group B streptococci. This pathogen can be the cause of antenatal and intranasal infection of the fetus;

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

Time of infection	Probable causative agent
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 fetal infection much less frequently.

Late neonatal sepsis of the newborn usually occurs as a result of postnatal infection. The main pathogens are E. coli, S. aureus and Klebsiella pneumoniae; group B streptococci are rare. The importance of group A streptococci, pseudomonas and enterococci is increasing.

The structure of gram-negative pathogens of this disease, which make up about 40%, has undergone some changes over the past 10 years. The role of Pseudomonas spp., Klebsiella spp. and Enterobacter spp. has increased. As a rule, these pathogens cause blood infections in intensive care patients on artificial ventilation and parenteral nutrition, and surgical patients.

The etiologic structure of postnatal morbidity is significantly affected by the localization of the primary septic focus. For example, in the etiology of the umbilical type of infection, the leading role is played by staphylococci and E. coli, and in the etiology of cutaneous and rhinoconjunctival septic conditions - staphylococci and ß-hemolytic streptococci of group A. Also, the spectrum of pathogens of hospital infection depends on the entry portal of infection. For example, in catheterization septic condition, the predominant role is played by staphylococci or mixed generalized infection caused by the association of staphylococci with fungi of the genus Candida. In abdominal hospital infection, enterobacteria and anaerobes are often isolated.

The most likely pathogens of neonatal sepsis depending on the location of the primary source of infection

Localization of the primary lesion	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 region	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 using an intravenous catheter)	S. aureus et epidermidis

The etiology of generalized infections in immunocompromised patients (including deeply immature newborns) also has a number of features and depends on the nature of immunosuppression (acquired dysfunctions of the immune system, secondary immune deficiency, drug-induced immunosuppression, congenital, hereditary or acquired neutropenia, primary immunodeficiencies and HIV infection). Not always the infection developing against such a background is neonatal sepsis.

Pathogenesis of neonatal sepsis

The triggering moment 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 seeding, exceeding the capabilities of antimicrobial protection, leads to a breakthrough of the infectious agent into the patient's systemic bloodstream (bacteremia).

The most likely causative agents of generalized infections in immunodeficiencies in infants

Nature of immunodeficiency	Most likely pathogens
Secondary immune dysfunctions, including dysfunctions associated with gestational immaturity	Enterobacteriaceae spp. Staphylococcus spp. S. pyogenes Fungi of the genus Candida
Drug-induced immunosuppression	Cytomegalovirus Enterobacteriaceae spp. S. Aureus Fungi of the genus Aspergillus et Candida
Neutropenia	S. aureus E. coli Candida fungi
AIDS	Opportunistic microflora (fungi, mycobacteria, cytomegalovirus, etc.)
Primary immunodeficiencies	Enterobacterioceae spp. S. aureus et epidermidis Hemolytic streptococci group A

Bacteremia, antigenemia and toxemia trigger a cascade of the body's defense systems - the SVR, which involves the immune system and mediators, acute phase proteins, the coagulation and anticoagulation systems of the blood, the kinin-kallekriin system, the complement system, etc. Neutrophilic granulocytes play an important role in the child's systemic response to an infection breaking through into the bloodstream, determining the adequacy of the functioning of other cells and systems of the body. Neutrophilic granulocytes have a high effector potential and react almost instantly 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 burst" and secretory degranulation with the release of bactericidal enzymes that generate toxic oxygen radicals. These cells synthesize not only inflammatory mediators, components of the coagulation and fibrinolysis systems, but also biologically active substances that stimulate cell growth. Neutrophilic granulocytes are capable of interacting with the 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 act as phagocytes. The importance of phagocytosis performed by neutrophils and macrophages differs significantly - true phagocytosis is performed by macrophages. Neutrophilic phagocytosis, although more intense than that of mononuclear cells, is due to other biochemical processes, because their task is different. The main function of neutrophils is to initiate an inflammatory reaction. Biologically active substances secreted by neutrophil granulocytes have a pro-inflammatory focus; among them, there are cytokines that work in foci of acute inflammation (IL-8, IL-1, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor) and those involved in the regulation of chronic inflammation (IL-6, y-interferon, transforming growth factor). Neutrophils synthesize a wide range of surface adhesive molecules, with the help of which they interact with the cells of the vascular endothelium, immune system, tissues and organs. As a result of adhesion, the sensitivity of neutrophils themselves to cytokines and other mediators changes, which allows them to adequately respond to changes in tissues and organs. The cytotoxicity of neutrophils is significantly higher than that of killer lymphoid cells (T-lymphocytes) and natural killers (NK-cells). Neutrophil cytotoxicity factors are aimed at the nuclear structures of target cells, structural elements of the genetic apparatus of the absorbed object, and the destruction of the genome using apoptosis-inducing factors (AIF). Cells undergoing apoptosis become objects of phagocytosis and are quickly destroyed.

Neutrophils actively phagocytize microorganisms, not caring about their true digestion, throw significant amounts of FIA into the intercellular space in order to cause damage to the genetic apparatus of pathogenic microorganisms as quickly as possible. The effect of the release of the contents of neutrophil granules on inflammation processes is enormous. The contents of neutrophil granules induce platelet aggregation, the release of histamine, serotonin, proteases, arachidonic acid derivatives, blood coagulation activators, the complement system, the kinin-kallekrein system, etc. FIA of neutrophils is destructive for any cells, as it causes the destruction of nucleoprotein complexes of the genome.

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

Excessive SVR underlies hyperactivation of the hypothalamic-pituitary-adrenal system, which normally ensures 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 this 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 slowdown in oxidative metabolism, limiting the adaptive capabilities of the newborn's body. In severe septic conditions (fulminant course, septic shock), the content of somatotropic hormone (STH) decreases in some patients. Low STH content in conditions of basal hypercortisolemia contributes to the rapid development of necrotic processes (STH inhibits the inflammatory process).

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

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

For mononuclear cells, neutrophils are helper cells. The main role of monocytes and macrophages is true phagocytosis with subsequent thorough digestion of the particles of target cells, neutrophils themselves, and the inflammatory cell dendrite, half-destroyed by neutrophils. Phagocytosis carried out by macrophages helps to calm down inflammation processes and heal damaged tissues.

The formation of a mediator response to a bacterial infection, which underlies the SVR syndrome, is a genetically controlled process involving cell receptors that recognize various structures of microbial origin and induce the expression of nonspecific resistance factors.

SVR syndrome underlies progressive organ dysfunction, in some cases reaching the level of organ failure. The pathogenesis of the septic condition is characterized by the rapid development of multiple organ failure and profound homeostasis disorders. One of the signs of homeostasis disorder in blood infection is pronounced proliferation of opportunistic microflora, creating prerequisites for the emergence of new infectious foci and additional translocation of the infectious agent into the systemic bloodstream. Currently, a popular concept is that homeostasis disorders are associated with the entry into the blood of endotoxin or lipopolysaccharide complex of endotoxin of gram-negative bacteria that vigorously colonize the upper parts of the small intestine under conditions of tissue hypoxia. Endotoxin significantly enhances SVR, provokes homeostasis disorders, and hypotension refractory to treatment. The entry of antigens into the bloodstream leads to disorganization of SVR - mediator chaos. Antigenic overload is the cause of pronounced immunosuppression in conditions of bacteremia and microcirculation disorders, contributing to the formation of metastatic purulent foci that support SVR, toxinemia and antigenemia. Disorganization of SVR is the basis for the development of septic shock.

Symptoms of neonatal sepsis

Symptoms of neonatal sepsis, regardless of the form (septicemia or septicopyemia), are characterized by the severity of the general condition of the newborn. Thermoregulation disorders are expressed (in full-term morphofunctionally mature newborns - fever, in premature, low-birth-weight children, against an aggravated premorbid background - progressive hypothermia), the functional state of the central nervous system is impaired (progressive depression). A dirty-pale or grayish tint of the skin with jaundice and hemorrhages, areas of sclerema are characteristic. Marbling of the skin is expressed, acrocyanosis is possible. Jaundice appears early and increases rapidly. General edema syndrome often develops. A tendency to spontaneous bleeding is characteristic. Facial features are often sharpened.

Respiratory failure develops without inflammatory changes on the radiograph, often there is damage to the heart by the type of toxic cardiopathy, accompanied by the development of acute heart failure. Characteristic is an increase in the size of the spleen and liver, bloating, a pronounced venous network on the anterior abdominal wall, regurgitation, vomiting and anorexia, dysfunction of the gastrointestinal tract up to intestinal paresis are often observed. Typically, there is no weight gain, the formation of hypotrophy.

Premature infants typically have a subacute course of this disease in the form of respiratory distress syndrome (dyspnea with periods of bradypnea or apnea), bradycardia, impaired sucking reflex, and a tendency to hypothermia. The listed 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 characteristic of them, detected by laboratory and instrumental examination methods, are shown in the table.

Primary septic focus

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

After the introduction of primary surgical treatment of the umbilical cord stump, 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 conditions (at least 20%) has increased significantly. Other localizations of the primary focus are much less common and do not exceed 2-6%. In some cases, the entry point of infection cannot be determined. This is especially characteristic of children with a small gestational age, in whom alteration processes are weakly expressed.

Clinical and laboratory criteria of organ failure in septic conditions (Balk R. et al., 2001, as modified)

Localization of the lesion	Clinical criteria	Laboratory indicators
Respiratory system	Tachypnea, orthopnea, cyanosis, mechanical ventilation with or without positive end-expiratory pressure (PEEP)	PaO2 <70 mmHg SaO2 <90%. Changes in acid-base balance
Kidneys	Oliguria, anuria, edema syndrome	Increased creatinine and urea levels
Liver	Enlarged liver, jaundice	Hyperbilirubinemia (in newborns due to an increase in the indirect fraction). Increased AST, ALT, LDH. Hypoproteinemia
Cardiovascular system	Tachycardia, hypotension, enlargement of the cardiac borders, tendency to bradycardia, need for hemodynamic support	Change in central venous pressure, pulmonary artery wedge pressure. Decreased ejection fraction. Decreased cardiac output.
Hemostasis system	Bleeding, necrosis	Thrombocytopenia. Prolongation of prothrombin time or APTT. Signs of DIC syndrome
Gastrointestinal tract	Intestinal paresis, vomiting, regurgitation, abnormal bowel movements, inability to take enteral nutrition	Dysbiosis
Endocrine system	Adrenal insufficiency, hypothyroidism	Decreased cortisol levels. Decreased triiodothyronine and thyroxine levels with normal thyroid stimulating hormone levels.
Immune system	Splenomegaly, accidental thymus involution, nosocomial infection	Leukocytosis, leukopenia, lymphopenia. Neutrophil index (NI) >0.3. Increased C-reactive protein. Impaired lymphocyte subpopulation ratio. Impaired digestive function of phagocytes. Dysimmunoglobulinemia
Nervous system	Depression or excitation of CNS functions, convulsions	Increased protein levels in cerebrospinal fluid with normal cytosis. Increased cerebrospinal fluid pressure.

Septicemia

Septicemia is clinically characterized by the development of toxicosis and multiple organ failure against the background of a primary purulent inflammatory focus. 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.

Septicopyemia

Septicopyemia is characterized by the development of one or more foci that determine the characteristics of the clinical picture and course of the disease. Among the metastatic foci of neonatal sepsis, meningitis ranks first (more than half of the cases), osteomyelitis and abscessing pneumonia rank second and third. Other localizations of pyemic foci (liver and kidney abscesses, septic arthritis, mediastinitis, panophthalmitis, phlegmon of the stomach wall, intestines, etc.) are much less common, together accounting for no more than 10% of all cases of neonatal sepsis.

Septic shock

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

The clinical picture of septic shock in newborns is characterized by a rapid, sometimes catastrophic, increase in the severity of the condition, progressive hypothermia, pale skin, suppression 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 from mucous membranes, pastosity or edema of tissues. Exicosis is possible against the background of edema of tissues and organs, especially parenchymatous ones.

The most characteristic sign is increasing arterial hypotension, refractory to the administration of adrenomimetics. Shock is also characterized by the development of disseminated intravascular coagulation syndrome (DIC) with thrombocytopenia and consumption coagulopathy, and fibrinolysis depression. Along with bleeding, multiple necroses are rapidly formed, 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 somatotropic hormones of the pituitary gland, and hyperinsulinism. Shock causes pronounced disturbances in almost all cascade mechanisms of homeostasis regulation, including the body's systemic mediator response, which takes on the character of "mediator chaos."

Course and outcomes of neonatal sepsis

Neonatal sepsis is classified as an acyclic infectious disease; 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 course of the septic condition with a catastrophic deterioration of the condition, multiple organ failure and symptoms of DIC syndrome. A fatal outcome occurs within 3-5 days of the disease. Sepsis in newborns occurs lightning-fast in approximately 15% of cases, among surgical patients and with hospital blood infection, the incidence of this form reaches 20-25%.

In the blood formula, with the fulminant course of this disease, a tendency towards leukopenia is expressed, a shift in the leukocyte formula to the left, an increase in the neutrophil index (NI), absolute lymphopenia, thrombocytopenia, aneosinophilia, monocytosis are observed. The listed changes are typical for severe SVR.

If there is no septic shock at the onset of the disease or it was 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. A fatal outcome can occur in the 3rd-4th week of the disease from severe multiple organ failure incompatible with life.

The period of acute manifestations of the infectious process is up to 14 days, then comes the reparation period, which is characterized by the fading of toxicosis symptoms, gradual restoration of the functional activity of individual organs and systems, and the sanitation of metastatic foci. Splenomegaly, pale skin, lability of the functions of the central and autonomic nervous system, dysbacteriosis of the skin and mucous membranes, and body weight deficit up to grade I-III hypotrophy persist.

During this period, characterized by a decrease in the body's resistance, there is a high risk of superinfection of bacterial, fungal or viral etiology. Often the source of superinfection is the rapid proliferation of the child's intestinal microflora; nosocomial infection is also possible.

Hematological picture in the acute period of septic condition: pronounced leukocytosis (less often - normal values or leukopenia), shift of the leukocyte formula to the left, increase in NI. Thrombocytopenia, eosinopenia, lymphopenia, tendency to monocytosis are possible.

During the reparation period, redistribution anemia and moderate monocytosis develop. Neutrophilia in a third of cases is replaced by neutropenia. A tendency toward eosinophilia is characteristic. Basophils and plasma cells can be found in the peripheral blood.

Classification of neonatal sepsis

There is currently no generally accepted clinical classification of neonatal sepsis. The last clinical classification of this disease adopted in Russia was published more than 15 years ago and does not meet modern requirements. The International Classification of Diseases, 10th revision (ICD-10), which determines the diagnosis code for statistics, identifies "bacterial sepsis of the newborn", code P36.

Unlike the coding classification, when compiling a clinical classification of the disease, it is necessary to take into account the time and conditions of occurrence of blood infection - developed before the birth of the child, after birth; localization of the entry gate and / or primary septic focus, clinical features of the disease. These parameters characterize the etiological spectrum of the disease, the volume and nature of therapeutic, preventive and anti-epidemic measures. It is these parameters that are appropriate to use 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;
• nasopharyngeal;
• rhinoconjunctival;
• otogenic;
• urogenic;
• abdominal;
• catheterization;
• another.

By clinical form:

• septicemia; Septicopyemia.

By the presence of symptoms of multiple organ failure:

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

DIC syndrome.

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

When neonatal sepsis manifests clinically on the 6th-7th day of life and later, it is customary to speak of a late neonatal septic condition. Its peculiarity is postnatal infection. In this case, the primary source of infection is usually present, and the disease in 2/3 of cases proceeds as septicopyemia.

The above clinical classification of neonatal septic conditions is closely related to the spectrum of the most probable pathogens, knowledge of which is extremely important for a rational choice of primary antibacterial therapy. The spectrum of possible pathogens varies depending on the localization of the entry portal of infection, in connection with which it is advisable to indicate this parameter in the clinical diagnosis of blood infection. Localization of the entry portal has a certain epidemiological significance and is important for the development of anti-epidemic and preventive measures. There are umbilical, cutaneous, otogenic, nasopharyngeal, urogenital, catheter, pulmonary, abdominal and other, less common types of infection.

Septicemia is a clinical form of this disease, characterized by the presence of microbes and/or their toxins in the bloodstream against the background of pronounced symptoms of infectious toxicosis, but without the formation of pyemic foci. Morphologically and histologically, signs of microbial damage and myelosis of parenchymatous organs can be detected.

Septicopyemia is a clinical form of blood infection characterized by the presence of one or more pyemic, metastatic, purulent-inflammatory foci. The criterion for septicopyemia is the uniformity of the pathogen isolated from the foci of inflammation and the patient's blood.

Organ failure syndromes determine the severity and outcome of the disease, requiring specific treatment, and therefore it is also advisable to highlight them in the clinical diagnosis. Among them, due to the severity of the prognosis, the symptom complex of septic (infectious-toxic) shock deserves special attention.

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

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Diagnosis of neonatal sepsis

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

The first level of diagnostics is the most difficult - despite many years of studying blood infections, there are still no generally accepted clinical and laboratory diagnostic criteria in pediatric practice that meet the requirements of evidence-based medicine. One of the reasons for this is the absence of a primary infectious focus in the patient; it is localized in the mother's body or in the placenta. In addition, pronounced signs of SVR in children occur in many severe diseases of non-infectious (respiratory distress syndrome, hereditary aminoaciduria, etc.) and infectious (necrotic enterocolitis of the newborn, phlegmon, meningitis, etc.) nature.

Based on modern concepts of diagnostics of this disease, the disease should be assumed in a newborn in the first 6 days of life if he has severe infectious toxicosis and signs of SVR:

• prolonged (more than 3 days) fever (>37.5 °C) or progressive hypothermia (<36.2 °C);
• hyperleukocytosis in the first 1-2 days of life >30x10 ⁹, on the 3rd-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 <100x10 ⁹ /l;
• an increase in the content of C-reactive protein in the blood serum of more than 6 mg/l;
• increase in the content of procalcitonin in the blood serum by more than 2 ng/ml;
• increase in IL-8 content in blood serum by more than 100 pg/ml.

The presence of at least three of the above symptoms is a strong reason to assume a diagnosis of blood infection and immediately prescribe empirical antibacterial therapy and carry out the necessary treatment measures.

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

The diagnosis of a septic condition is confidently established in the presence of a primary infectious and inflammatory focus or metastatic purulent foci with the pathogen also isolated from the blood, provided that at least three signs of SVR are present.

Bacteremia is not considered a diagnostic sign of this disease; this condition can be observed in any infectious disease of bacterial origin. Establishing bacteremia is important for determining the etiology and justifying rational antibacterial treatment (the second stage of diagnostics). Along with the study of blood culture, the etiological diagnosis of neonatal sepsis includes a microbiological study of the discharge from the primary and metastatic foci.

Microbiological examination of the loci in contact with the environment (conjunctiva, mucous membrane of the nasal and oral cavity, skin, urine, feces) and not involved in the primary purulent-inflammatory focus cannot be used to establish the etiological diagnosis of a septic condition. At the same time, microbiological examination of these environments is indicated for assessing the degree and nature of dysbacteriosis - one of the constant companions of blood infection due to a decrease in the immunological reactivity of the patient's body (the third stage of diagnosis). The main clinical, laboratory and instrumental characteristics of multiple organ failure accompanying neonatal sepsis and determining its outcome are given above. Monitoring of these indicators is necessary for organizing adequate treatment of patients.

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

Differential diagnosis of neonatal sepsis

Differential diagnostics 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, necrotic enterocolitis of newborns), which also occur with signs of SVR. Unlike this disease, such diseases are characterized by a close relationship between the presence of a purulent focus and pronounced signs of SVR, as well as the relief of these signs soon after the focus is sanitized. Nevertheless, the main directions of treatment and principles of antibacterial therapy for blood infections and severe purulent-inflammatory diseases of bacterial origin are identical.

Sepsis in 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 scope of anti-epidemic measures, the appointment of specific antibacterial therapy. The basis of differential diagnosis is the epidemiological history and data from bacteriological and serological studies of materials taken from the patient.

When conducting differential diagnostics of this disease and congenital generalized forms of viral infections (cytomegalovirus, herpes, enterovirus, etc.), confirmation of the latter justifies specific antiviral and immunocorrective treatment, limiting the use of antibiotics. For this purpose, immunocytological research is carried out using the polymerase chain reaction (PCR) method of blood, cerebrospinal fluid and urine, serological tests.

Sepsis in newborns should be differentiated from generalized mycoses, primarily candidiasis, much less often - from aspergillosis, in order to justify the prescription of antimycotics, restriction or cancellation of antibiotics and to clarify the tactics of immunocorrective treatment. Differential diagnostics is based on the results of microscopic and mycological (sowing on Sabouraud's medium) examination of blood, cerebrospinal fluid, discharge from pyemic foci.

In newborns, sepsis should be differentiated from hereditary pathology of amino acid metabolism, accompanied by all the signs of SVR, but not requiring antibacterial therapy. In case of hereditary defects of amino acid metabolism, the condition of the newborn quickly deteriorates soon after birth, dyspnea, pulmonary-cardiac insufficiency, depression of the central nervous system, hypothermia, leukopenia, thrombocytopenia, anemia progress. A distinctive sign of a defect of amino acid metabolism is persistent intense metabolic acidosis, the appearance of a pronounced odor from the patient is possible. Bacteremia cannot be ruled out, demonstrating severe dysbacteriosis and decreased resistance of the body. The main method of differential diagnosis is a biochemical blood test (detection of pathological acidemia) in combination with intractable metabolic acidosis.

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

Treatment of neonatal sepsis

Treatment of neonatal sepsis should include the following simultaneous measures:

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

Etiological treatment of neonatal sepsis

Antibacterial treatment is a cardinal method of etiological treatment of a septic condition. When neonatal sepsis is suspected, in the vast majority of cases antibiotics are prescribed empirically, based on the assumption of the most probable spectrum of possible infectious agents in a given patient.

General provisions for the choice of antibacterial therapy:

1. The choice of drugs at the beginning of treatment (before the etiology of the disease is clarified) is carried out depending on the time of occurrence (congenital, postnatal), conditions of occurrence (outpatient, hospital - in a therapeutic or surgical department, intensive care unit), localization of the primary septic focus.
2. Antibiotics in the form of a combination of antibacterial drugs with a bactericidal type of action, active against potential pathogens of this disease (de-escalation principle) are considered the drugs of choice in empirical therapy. When the nature of the microflora and its sensitivity are clarified, antibacterial treatment is adjusted by changing the drug, switching to monotherapy or narrow-spectrum drugs.
3. When choosing antibiotics, preference should be given to systemic drugs that penetrate the body's biological barriers and create a sufficient therapeutic concentration in the cerebrospinal fluid, brain matter and other tissues (bone, lung, etc.).
4. In all cases, it is advisable to prescribe the least toxic antibiotics, taking into account the nature of organ disorders, avoiding a sharp increase in the concentration of endotoxin in the blood, which reduces the risk of shock.
5. Drugs that can be administered intravenously are preferred.

Empirical Antibacterial Treatment Program for Neonatal Sepsis

Characteristics of a septic condition	Drugs of choice	Alternative drugs
Early	Ampicillin + aminoglycosides	Third generation cephalosporins + aminoglycosides
Umbilical	Aminopenicillins or oxacillin + aminoglycosides. III generation cephalosporins (ceftriaxone, cefotaxime) + aminoglycosides	Carbapenems. Glycopeptides. Linezolid
Cutaneous, nasopharyngeal	Aminopenicillins + aminoglycosides. II generation cephalosporins + aminoglycosides	Glycopeptides. Linezolid
Rhinopharyngeal, otogenic	III generation cephalosporins (ceftriaxone, cefotaxime) + aminoglycosides	Glycopeptides. Linezolid
Intestinal	III and IV generation cephalosporins + aminoglycosides. Inhibitor-protected aminopenicillins + aminoglycosides	Carbapenems. Aminoglycosides
Urogenic	Cephalosporins III and IV generation. Aminoglycosides	Carbapenems
Iatrogenic abdominal	Third generation cephalosporins (ceftazidime, cefoperazone/sulbactam) + aminoglycosides. Inhibitor-protected carboxycins + aminoglycosides	Carbapenems. Metronidazole
Against the background of neutropenia	Cephalosporins of the third generation + aminoglycosides. Glycopeptides	Carbapenems. Glycopeptides
Against the background of drug-induced immunosuppression	Cephalosporins III or IV generation + aminoglycosides. Glycopeptides	Carbapenems. Linezolid. Inhibitor-protected carboxapenicillins
Iatrogenic catheterization, pulmonary (associated with artificial ventilation)	Third-generation cephalosporins with antipseudomonal effect + aminoglycosides. Inhibitor-protected carboxocillins + aminoglycosides. Glycopeptides + aminoglycosamides. Third-generation cephalosporins (ceftazidime, cefoperazone/sulbactam) + aminoglycosides. Inhibitor-protected carboxocillins + aminoglycosides	Carbapenems. Linezolid. Glycopeptides. Metronidazole. Lincosamides

To date, there is no universal antimicrobial drug, drug combination or treatment regimen that cures any newborn with equal efficiency. There are only recommended schemes for choosing antibacterial drugs. The rational choice of drugs in each specific case depends on the individual characteristics of the patient, regional data on the most likely pathogens, and their sensitivity to antibiotics.

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

• assessment of the overall effectiveness of the antibacterial therapy;
• assessment of the effectiveness of the treatment of primary and metastatic foci, search for newly emerging purulent foci;
• monitoring the impact 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 if it results in stabilization or improvement of the patient’s condition within 48 hours.

Treatment is considered ineffective if it results in an increase in the severity of the condition and organ failure within 48 hours; ineffectiveness of therapy is the basis for switching to an alternative treatment regimen.

In neonatal sepsis caused by gram-negative microflora, effective antibiotic therapy may cause the patient's condition to worsen due to the release of endotoxin from dying bacteria. In this regard, when choosing antibiotics, preference should be given to drugs that do not cause significant endotoxin release into the bloodstream. Antibacterial treatment is carried out against the background of adequate detoxification, including infusion therapy and intravenous administration of immunoglobulin enriched (pentaglobin).

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

The basis for discontinuing antibacterial drugs should be considered the sanitation of the primary and pyemic foci, the absence of new metastatic foci, relief of signs of acute SVR, persistent weight gain, normalization of the leukocyte formula of peripheral blood and the number of platelets.

Full restoration of organ and system functions, disappearance of pallor, splenomegaly and anemia occurs much later (not earlier than 4-6 weeks from the start of treatment). These clinical symptoms themselves do not require the prescription of antibacterial drugs, only restorative treatment is necessary.

Considering the need for long-term intensive antibacterial therapy, the significant role of dysbacteriosis in the pathogenesis of neonatal sepsis, it is advisable to combine antibacterial treatment with "accompaniment therapy". This includes the simultaneous administration of probiotics (bifidumbacterin, lactobacterin, linex) and the antimycotic fluconazole (diflucan, forcan) at a dose of 5-7 mg / (kg x day) in 1 dose. Low therapeutic and prophylactic efficacy of nystatin, its extremely low bioavailability does not allow recommending it for the prevention of candidiasis in newborns. Ketoconazole (nizoral) is not recommended for children under 7 years of age.

Along with probiotics and antifungals, it is important to organize hygienic measures (hygienic treatment of the skin and visible mucous membranes, bathing) and proper feeding to prevent dysbacteriosis. Feeding with native mother's milk is absolutely indicated (breastfeeding, native milk from a bottle or introducing milk through a tube, depending on the baby's condition). In the absence of mother's milk, adapted formulas for feeding the child, enriched with bifidobacteria (fermented milk formula "Agusha", "NAN fermented milk", acidophilic formula "Malutka") are used. It should be remembered that in children with severe acidosis, fermented milk formulas often provoke regurgitation. In this case, it is advisable to use fresh adapted formulas enriched with prebiotics, with a low lactose content, prepared on whey (Nutrilon Comfort, Nutrilon Low-Lactose, AL-110, etc.). In premature babies with agalactia in the mother, special adapted formulas for premature babies are used (Alprem, Nenatal, Fresopre, etc.).

Sanitation of primary septic and pyemic foci, even by surgical intervention, is a mandatory component of etiotropic treatment of neonatal sepsis.

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

Pathogenetic treatment of neonatal sepsis

Pathogenetic therapy of neonatal sepsis includes the following main areas:

• immunocorrection;
• detoxification;
• restoration of water and electrolyte balance, acid-base balance;
• 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 currently used to treat neonatal sepsis is quite extensive. "Aggressive" methods include partial exchange transfusion, hemosorption and plasmapheresis. They are used only in extremely severe cases of fulminant neonatal sepsis, with a full-blown clinical picture of septic shock and an immediate threat of death. The listed methods allow to reduce the degree of endotoxinemia, reduce the antigen load on immunocompetent and phagocytic blood cells, and replenish the content of opsonins and immunoglobulins in the blood.

In neonatal sepsis accompanied by absolute neutropenia, as well as with an increase in the neutrophil index above 0.5, transfusion of leukocyte suspension or leukocyte concentrate is used for the purpose of immunocorrection at a rate of 20 ml/kg of the child's body weight every 12 hours until the leukocyte concentration in the peripheral blood reaches 4-5x10 ⁹ /l. This treatment method is justified by the key importance of neutrophils in the pathogenesis of SVR in neonatal sepsis.

Currently, instead of leukocyte suspension transfusions, recombinant granulocyte or granulocyte-macrophage colony-stimulating factors are increasingly prescribed. The drugs are prescribed at a rate of 5 μg/kg of the patient's body weight 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 unfolds by the 3rd-4th day of treatment, and therefore, with a fulminant course of this disease, leukocyte suspension transfusion is preferable. Combined use of these methods is possible. 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, immunoglobulins for intravenous administration occupy a leading position. 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 premature babies, hypogammaglobulinemia is even more pronounced.

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

For maximum effectiveness of anti-infective therapy in septic conditions, it is most appropriate to combine antibacterial therapy with intravenous immunoglobulin. In infants, especially premature infants, it is advisable to administer the drug until the blood level reaches 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 early as possible, immediately after the infectious diagnosis is established, in sufficient volume. Prescribing intravenous immunoglobulin in the 3rd-5th week of the disease is ineffective.

For intravenous administration, standard immunoglobulins (preparations of normal donor Ig) are used: sandoglobin, alphaglobin, endobulin C/D4, intraglobin, octagam, domestic immunoglobulin for intravenous administration, etc. Their mechanism of action and clinical effect are approximately the same.

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

Detoxification therapy, correction of electrolyte disturbances and acid-base balance

Detoxification is a mandatory component of pathogenetic treatment of the acute period of neonatal sepsis. Most often, intravenous drip infusion of fresh frozen plasma and glucose-salt solutions is performed. Fresh frozen plasma supplies the child's body with antithrombin III, the concentration of which drops significantly in neonatal sepsis, which underlies the depression of fibrinolysis and the development of DIC syndrome. When calculating the volume of infusate, standard recommendations are used that take into account the gestational maturity of the child, his age, body weight, the presence of dehydration or edema syndrome, fever, vomiting, diarrhea, and the volume of enteral nutrition.

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

Infusion therapy allows to replenish the volume of circulating blood, correct electrolyte disorders and improve hemorheological characteristics of blood. For this purpose, rheopolyglucin, dopamine, complamine, potassium, calcium and magnesium solutions are used.

To correct the acid-base balance, adequate oxygen therapy is indicated, the intensity and method of which depend on the patient's condition (from the supply of humidified and warmed oxygen through a mask or nasal catheters to mechanical ventilation).

In some cases (inability to feed), infusion therapy is combined with parenteral nutrition of the infant, including amino acid solutions in the infusion.

For maximum energy conservation during the acute period of clinical manifestations of toxicosis in a septic condition, septic shock, it is advisable to keep the child in an incubator at a temperature of at least 30 °C and humidity of at least 60%.

Correction of vital functions is carried out under monitoring control, including:

• assessment of acid-base balance parameters, pO2;
• determination of hemoglobin concentration, hematocrit;
• assessment of the content of glucose, creatinine (urea), potassium, sodium, calcium, magnesium, and, if indicated, bilirubin, transaminase activity and other indicators;
• blood pressure assessment, electrocardiogram.

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

Anti-shock therapy

Septic shock is the most formidable symptom of neonatal sepsis, with a mortality rate exceeding 50%. The main pathogenetic components of shock are intense proinflammatory SVR, which in the late phase of shock turns into the stage of "mediator chaos"; extreme tension of the adaptive reaction of the hypothalamic-pituitary-adrenal system with subsequent failure of adaptive mechanisms, symptoms of latent or overt adrenal insufficiency, thyroid hypofunction, pituitary dysregulation and the development of DIC syndrome up to blood coagulability due to thrombocytopathy and consumption coagulopathy. Severe multiple organ failure always accompanies septic shock. Shock treatment includes three main areas:

• intravenous administration of immunoglobulins (preferably immunoglobulin enriched with IgM), which reduces the concentration in the blood and the synthesis of proinflammatory cytokines by cells;
• the introduction of low doses of glucocorticoids, which allows for the relief of latent adrenal insufficiency and the activation of the reserve capacity of the hypothalamic-pituitary-adrenal system;
• correction of hemostasis, including daily transfusions of fresh frozen plasma, administration of sodium heparin at a dose of 50-100 mg/kg of body weight.

In addition to the above-mentioned areas, the treatment regimen for septic shock 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, there is a high risk of activation of intestinal microflora and the development of intense dysbacteriosis. In this regard, much attention is paid to the correctness of the hygienic regime and the rationality of feeding the child.

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

If neonatal sepsis is accompanied by severe immune disorders confirmed by laboratory tests, immunotherapy is indicated. During the recovery period, depending on the nature of the immune disorders, likopid, azoximer, and interferons may be prescribed. Particular attention is paid to restoring the functional activity of individual organs and systems.