Neonatal Sepsis: Clinical Guidelines

List of Abbreviations

CHD – congenital heart disease

GA – gestational age

RRT – renal replacement therapy

IMV – invasive mechanical ventilation

Med – medication

MIC – minimum inhibitory concentration

AKI – acute kidney injury

SVR – systemic vascular resistance

ARDS – acute respiratory distress syndrome

BV – blood volume

CVVHD – continuous venovenous hemodialysis

CVVHDF – continuous venovenous hemodiafiltration

CVVH – continuous venovenous hemofiltration

PCT – procalcitonin

MOD – multiple organ dysfunction

MOF – multiple organ failure

PN – parenteral nutrition

PT – prothrombin index

PCR – polymerase chain reaction

RCT – randomized controlled trial

SV – stroke volume

CI – cardiac index

CRP – C-reactive protein

SS – septic shock

SV – stroke volume

CVP – central venous pressure

CNS – central nervous system

RR – respiratory rate

EN – enteral nutrition

PD – peritoneal dialysis

nSOFA – Neonatal Sequential Organ Failure Assessment

PEEP – positive end-expiratory pressure – positive end-expiratory pressure

Terms and Definitions

Neonatal sepsis is a confirmed or suspected life-threatening condition caused by generalized infection and the progression of systemic inflammatory response syndrome against the background of immune dysregulation, leading to multiple organ dysfunction within the first 28 days of life.

Septic shock (SS) is an acute circulatory disorder characterized by a critical decrease in tissue blood flow, clinically manifested by signs of systemic hypoperfusion (arterial hypotension, oliguria, hyperlactatemia) in a patient with suspected or proven infection.

Infection (infectious process) is the interaction of a pathogen with the human or animal organism, manifesting as a disease or carriage.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Neonatal sepsis is a confirmed or suspected life-threatening condition caused by generalization of infection and progression of systemic inflammatory response syndrome against the background of immune response dysregulation, leading to multiple organ dysfunction in the first 28 days of life [1-3].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Neonatal sepsis can be caused by gram-positive and gram-negative aerobic and anaerobic microbes (Table 1), while the etiology of neonatal sepsis differs significantly depending on the timing of fetal and neonatal infection (antenatal, intranatal, and postnatal) and the portal of entry of the infection [1].

Table 1. Etiology of neonatal sepsis depending on the timing of manifestation

In ante- and intranatal infection, maternal flora plays a major role, whereas in postnatal infection, nosocomial microorganisms do.

It is known that gram-negative flora multiplies in aqueous and weak solutions of antiseptics and disinfectants (ATC code D08) (non-ethanol-based), gram-positive flora (especially staphylococci) colonizes the hands of personnel, and due to its hydrophobicity, Staphylococcus epidermidis is capable of adhering to plastic and polymeric materials (catheters, probes, etc.). Anaerobic flora can cause neonatal sepsis in cases of dust-borne, community-acquired "contamination", for example, in "home" births or with infected wounds, as well as in cases of pathogen entry (Clostridium difficile) onto the peritoneum and subsequently into the blood in necrotizing enterocolitis or intestinal perforation in newborns.

The diagnosis of "neonatal sepsis" is usually confirmed by a positive blood culture; however, a negative test result does not exclude it, since cultures are most often negative due to the use of systemic antibacterial drugs (ATC code J01) prior to blood sampling [2-5].

Fungi of the genus Candida (Candida albicans, Candida parapsilosis, Candida tropicalis, Candida glabrata, Candida krusei, Candida auris, etc.) can also cause generalized infection, but currently neonatal candidiasis is considered a separate nosological entity (invasive candidiasis) and has a different code in the International Classification of Diseases – P37.5 [6].

Infections specific to the perinatal period, such as urogenital and respiratory myco- or ureaplasmosis (Mycoplasma hominis, Mycoplasma pneumoniae, Mycoplasma genitalium, Ureaplasma urealyticum), chlamydial infection (Chlamydia trachomatis, Chlamydia psittaci, Chlamydophila pneumoniae), cytomegalovirus and herpesvirus infection, toxoplasmosis (Toxoplasma gondii), and others, are known as TORCH syndrome [1, 7, 8]

The most severe, life-threatening infections are caused by multidrug-resistant microorganisms designated by the Infectious Diseases Society of America (IDSA) as "ESCAPE" pathogens (from escape), because they effectively "escape" the action of systemic antibacterial drugs (ATC code J01) (Table 1) [9]. These include Enterococcus faecium, Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.

Pathogenesis

During the infectious process, there is an activation of pro- and anti-inflammatory cytokines, the synthesis control of which is significantly impaired under conditions of immune imbalance, leading to secondary damage to organ systems and the development of multiple organ dysfunction [2,10–14]. As a result of cytokine effects, a sepsis phenotype is formed involving non-immunological links of pathogenesis, including the cardiovascular and respiratory systems, as well as hormonal, neuronal, bioenergetic, metabolic, and coagulation pathways [12–15].

Features of the pathogenesis and course of early-onset neonatal sepsis

1. The causative agents of ascending infection are aerobic and anaerobic microbes living in the mother's birth canal.

2. Infection most often occurs during the first and second stages of labor, but can also occur during pregnancy.

3. The probability of developing chorioamnionitis and ascending infection correlates positively with the duration of the water-free period; as duration increases, the probability of developing sepsis increases significantly.

4. Risk factors for early neonatal infection include traumatic, difficult, and premature labor.

5. The most dangerous variant of ascending infection is the aspiration and swallowing of bacteria from amniotic fluid, leading to congenital pneumonia or systemic infection, the clinical manifestations of which may appear both before (tachycardia, symptoms of intrauterine fetal hypoxia) and after birth (perinatal asphyxia). In most cases, symptoms of infection appear a few hours or days after birth (respiratory distress, acute circulatory failure, shock).

Features of the pathogenesis of late-onset neonatal sepsis

1. Infection most commonly occurs in neonatal intensive care units or at home.

2. Invasive procedures (tracheal intubation, umbilical vessel catheterization) and resuscitation measures increase the risk of bacterial infection.

3. Main route of transmission: contact.

4. Central nervous system infections (meningitis) and generalized systemic reaction in most cases develop as a result of hematogenous dissemination.

1.3 Epidemiology of the Disease or Condition

Neonatal sepsis is one of the leading causes of morbidity and mortality in infants in the first month of life, resulting in significant socioeconomic burden and increasing pressure on the healthcare system [16, 17].

The incidence of sepsis in newborns depends on many factors, the main ones being climatic conditions, as well as the demographic and economic characteristics of the state [18]. The likelihood of fatal cases of neonatal sepsis in developing countries is significantly higher compared to developed ones [19].

Among childhood infectious diseases, sepsis and septic shock are the leading causes of mortality [20]. According to an international multicenter study in pediatric intensive care units, sepsis occurs in 8.2% of patients, and overall mortality ranges from 21 to 50% depending on the continent [21].

In the USA, the incidence of culture-proven early-onset neonatal sepsis is 0.3–2 per 1,000 live births. Sepsis will be confirmed by pathogen isolation in only 3–8% of newborns.

Based on a meta-analysis conducted in high-income countries, the incidence of pediatric sepsis was 22,000 to 48,000 cases per year [21,22]. The incidence of sepsis in newborns in the Russian Federation is not reported in accessible literature, most likely because neonatal sepsis is not classified as the primary condition, but rather as a complication of other pathological processes.

According to the Federal State Statistics Service (2021), the incidence of bacterial sepsis is 0.1% among all live births. Overall mortality reaches 24.4%, with early neonatal mortality accounting for 58.7% of these cases.

The incidence among full-term infants is extremely low (0.03%), whereas in preterm newborns it is 1.1%. Mortality is 15.8% in full-term infants and 31.6% in preterm infants with sepsis.

The incidence of sepsis in children with a birth weight of less than 1,000 g is at its maximum at 8.2%. Mortality is 42.5%, with early neonatal mortality accounting for 51% of these cases.

The incidence of sepsis among children with a birth weight greater than 1,000 g (including both full-term and preterm newborns) is 0.06%. Mortality is 19.5%, with early neonatal mortality accounting for 67.2% of these cases.

Perinatal hypoxia and birth asphyxia, meconium aspiration, maternal group B Streptococcus colonization, chorioamnionitis, premature rupture of membranes, low gestational age, maternal urogenital tract infections, perinatal fever, very low birth weight, and vitamin D deficiency in the blood of the mother and the newborn are risk factors for early-onset neonatal sepsis [24–26]. Risk factors for neonatal sepsis are presented in Table 2.

Table 2. Risk factors for neonatal sepsis

1.4 Features of Coding the Disease or Condition

In the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, the diagnosis "Neonatal sepsis" is coded in the following categories:

P36.0 – Group B streptococcal neonatal sepsis

P36.1 – Neonatal sepsis due to other and unspecified streptococci

P36.2 – Neonatal sepsis due to Staphylococcus aureus [Staphylococcus aureus]

P36.3 – Neonatal sepsis due to other and unspecified staphylococci

P36.4 – Neonatal sepsis due to Escherichia coli [Escherichia coli]

P36.5 – Neonatal sepsis due to anaerobes

P36.8 – Neonatal sepsis due to other bacterial agents

P36.9 – Bacterial sepsis of newborn, unspecified

If the patient has septic shock, an additional code is added to the primary code: R57.2

1.5 Classification of the disease or condition

According to the modern classification, early and late neonatal sepsis are distinguished [7, 8, 27].

Early neonatal sepsis (ENS) manifests within the first 72 hours of life, typically resulting from intrauterine (antenatal) or intranatal infection. In 85% of newborns, symptoms of ENS appear within the first twenty-four hours of life (most often 6-8 hours after birth), in 5% it develops within 24-48 hours, and in approximately 10% the signs appear on the second or third day of life. Most often, the initial manifestations of ENS are signs of acute respiratory failure.

Clinical manifestations of late neonatal sepsis may appear from 72 hours to 28 days of life, as postnatal infection occurs in the majority of cases.

1.6 Clinical presentation of the disease or condition

Specific clinical signs of neonatal sepsis do not exist [28,29].

Neonatal sepsis may manifest with the following non-specific symptoms and syndromes [1,7]: respiratory disorders (apnea), lethargy, temperature instability, jaundice, exanthema (including hemorrhagic), tachycardia or bradycardia, glycemic level instability, feeding difficulties, arterial hypotension (a late symptom).

When septic shock develops, the following symptoms are noted [21,28,30]: tachycardia, respiratory distress (tachypnea, use of accessory muscles in breathing, desaturation), refusal to feed, abnormal skin color, diarrhea, any signs of impaired tissue perfusion.

Arterial hypotension is not an absolute criterion for septic shock; however, its presence in a newborn with clinical manifestations of an infectious-inflammatory process may confirm the presence of this life-threatening condition.

A decrease in mean arterial pressure indicates pronounced perfusion disorders in the brain, heart, kidneys, and other organs and tissues [1, 21, 28, 30].

When diagnosing septic shock in newborns, it is necessary to exclude any conditions accompanied by severe circulatory disorders, primarily critical congenital heart diseases (hypoplastic left heart syndrome, transposition of the great arteries, valvular defects). Certain inborn errors of metabolism leading to hyperazotemia (e.g., transient hyperammonemia of the newborn) and hypoglycemia (disorders of fatty acid oxidation) can also mimic septic shock [31, 32].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria for neonatal sepsis

2.1 History and symptoms

The presence of risk factors for sepsis is a compelling basis for its verification in a newborn infant in the presence of clinical and laboratory signs of an ongoing infectious process.

2.2 Physical examination

General examination:

• temperature instability;

• core body temperature > 38.0⁰C or < 36.0⁰C

• pallor, icterus, mottling, and/or cyanosis of the skin

• hemorrhagic rash, sclerema

Nervous system alterations:

• marked agitation/crying or depressed level of consciousness

• muscle hypotonia, hyporeflexia

• seizures

Respiratory system manifestations:

• changes in respiratory rate and rhythm (apnea; RR < 35 or RR > 70)

• need for supplemental oxygen therapy (FiO₂ > 0.3)

• need for respiratory support (invasive or non-invasive)

• decompensated respiratory acidosis (pvCO₂ > 60 mmHg)

Cardiovascular system manifestations:

• marked tachycardia or bradycardia (HR < 110 or HR > 180 bpm)

• arterial hypotension

• capillary refill time > 3 s

• decreased hourly urine output (< 1 mL/kg/h)

Gastrointestinal manifestations:

• poor sucking, refusal to feed

• hepatosplenomegaly

• abdominal distention

• decreased or absent bowel sounds.

2.3 Laboratory diagnostic tests

• Leukocytosis (> 30 x 10⁹/L), neutrophilia inappropriate for gestational age and postconceptional age (1st–2nd day of life: > 20 x 10²/L; > 3 days of life: > 7.0 x 10³/L) [33].

• Leukopenia (< 5 x 10⁹/L), neutropenia (see Appendix A3.2)

• Thrombocytopenia (< 123 x 10⁹/L at gestational age ≥ 33 weeks; < 104 x 10⁹/L at gestational age ≤ 32 weeks in the first 72 hours of life, thereafter < 150 x 10⁹/L, regardless of gestational and postnatal age) [34].

• Blood procalcitonin: ≥ 2.5 ng/mL (early-onset neonatal sepsis); ≥ 2.0 ng/mL (late-onset neonatal sepsis) [35].

• C-reactive protein > 10 mg/L,

• Presepsin level > 800 pg/mL

• Ratio of immature forms to total neutrophils (immature-to-total neutrophil ratio > 0.2).

• Labile blood glucose levels: hypo- (< 2.6 mmol/L) or hyperglycemia (> 10 mmol/L).

• Metabolic acidosis, significant base deficit (BE < –4 mmol/L)

• Lactic acidosis (blood lactate level > 2 mmol/L).

• Positive results of blood microbiological (culture) testing for sterility (isolation of microorganism cultures).

2.4 Organ dysfunction: to assess the severity of organ dysfunction and the probability of mortality in neonatal sepsis, it is advisable to use the nSOFA (Neonatal Sequential Organ Failure Assessment) score, NEOMOD (Neonatal Multiple Organ Dysfunction Score), or its modified version (see Appendices G1–G3) [36, 37, 38, 39].

Evaluation using multiple organ dysfunction scores in newborns in the ICU is performed daily by summing the scores of individual organ systems (respiratory, cardiovascular, hematologic systems, etc.). For each system, the worst parameter recorded during the 24-hour period is used. As the score increases, the likelihood of an unfavorable clinical course and mortality rises.

To substantiate the diagnosis of "Neonatal sepsis", a standardized medical record template is provided (Appendix A.3.3).

2.1 Complaints and Anamnesis

• In cases of suspected sepsis in a newborn, it is recommended to carefully review the maternal medical history to identify risk factors for neonatal sepsis [1, 3, 7, 8].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Risk factors are listed in Section 1.3, Table 2.

2.2 Physical Examination

• In a newborn with suspected sepsis, it is recommended to perform a physical examination [1, 3, 7, 8].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment: All symptoms of sepsis and septic shock in newborns are non-specific and reflect the presence of multiorgan dysfunction (Section 1.6).

2.3 Laboratory Diagnostics

• In a newborn with suspected sepsis, to verify the systemic (generalized) infectious and inflammatory process and confirm the diagnosis, it is recommended to perform the following laboratory tests: complete blood count (CBC) with differential, urinalysis, general clinical biochemistry panel (levels of sodium, potassium, total and ionized calcium, total protein, urea, creatinine, total bilirubin, blood glucose, alanine aminotransferase, and aspartate aminotransferase), and serum C-reactive protein. All laboratory tests should be performed at least three times: at the time of diagnosis, 72 hours after starting antibiotic therapy, and after completion of the treatment course [1, 3, 7, 8, 40–48].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment: In the event of patient instability and/or sudden deterioration, the decision to perform additional laboratory tests is made on an individual basis, taking into account the clinical course of the disease.

A systematic review and meta-analysis published in 2024 evaluated the diagnostic value of early biomarkers of neonatal sepsis; the authors found that available literature data are highly contradictory, with the highest clinical and diagnostic significance demonstrated by procalcitonin (pooled sensitivity 79%, specificity 91%), presepsin (pooled sensitivity 82%, specificity 86%), and serum amyloid A (pooled sensitivity 92%, specificity 96%) in neonatal serum [40].

Similar results confirming the diagnostic value of C-reactive protein, procalcitonin, and presepsin in early-onset neonatal sepsis were reported by other authors [41–43].

Specifically, Poggi C. et al. (2022) demonstrated that the pooled sensitivity and specificity of presepsin were 0.93 (95% CI 0.86–0.95) and 0.91 (95% CI 0.85–0.95), respectively; the pooled diagnostic odds ratio was 131.69 (95% CI 54.93–310.94), and the accuracy of presepsin assessment was independent of gestational age [43].

It has been established that an increased mean platelet volume (> 9.28 fL) is a highly sensitive biomarker of sepsis in newborns [44].

There is evidence indicating that marked neutrophilia and thrombocytosis are highly sensitive markers of neonatal sepsis [45–48].

• In all newborns with sepsis and signs of septic shock, to rule out coagulopathy, determine management for its correction, and assess treatment efficacy, it is recommended to evaluate a coagulogram (screening hemostasis test) [1, 3, 7, 8].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Coagulopathy is a constant companion of severe infections, sepsis, and septic shock, which is especially true for premature infants who have functional characteristics of the hemostatic system. Pulmonary or gastrointestinal bleeding is often one of the first manifestations of sepsis and septic shock [1, 7, 8, 23, 28]. Evidence suggests that gram-positive sepsis in premature infants is associated with hypercoagulation and thrombocytopenia [49].

• In all premature newborns with sepsis, refractory septic shock, and severe hyperlactatemia, it is recommended to measure blood ammonia levels to rule out inborn errors of the urea cycle and organic acidurias [31, 32].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Inborn errors of metabolism accompanied by hyperammonemia, much like neonatal sepsis, lack specific clinical manifestations and most commonly present as gastrointestinal dysfunction (regurgitation, vomiting, diarrhea), leading to hypovolemia, hypoglycemia, secondary altered consciousness, and hyperlactatemia [31, 32].

In the absence of adequate differential diagnosis and exclusion of hyperammonemia, aggressive anti-shock and antibacterial therapy may lead to progressive clinical deterioration and death. This is particularly true for premature infants with very low and extremely low birth weight, in whom transient hyperammonemia can occur relatively frequently and, in most cases, has a favorable outcome.

• To assess the severity of hypoxia and the efficacy of intensive care measures in all newborns with sepsis and septic shock, it is recommended to evaluate acid-base balance, blood gases, and blood lactate levels in capillary and/or venous blood every 6–12 hours [50–52].

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Comment: A number of studies have demonstrated that in newborns with sepsis and septic shock, an increase in blood lactate concentration correlates with increased mortality, while its subsequent decrease correlates with decreased mortality in septic shock [51, 52]. A decrease in blood lactate concentration during intensive care measures is associated with a shorter duration of hemodynamic support and hospital stay [50, 51]. Thus, the normalization of lactate clearance indicates the success of intensive care, while a continuing increase in lactate levels indicates its ineffectiveness.

Microbiological diagnosis of sepsis in newborns

• All newborns with suspected sepsis who have risk factors are recommended to undergo microbiological (culture) blood testing for sterility and determination of antimicrobial susceptibility to identify the causative agent and determine the tactics of antibacterial therapy [53].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment: Blood culture is the main method for detecting bacteremia, allowing for the identification of the pathogen, determination of its susceptibility to systemic antibacterial drugs (ATX code J01), and selection of an adequate therapy regimen. The blood volume for culture should not exceed 4% of the circulating blood volume (CBV), with a minimum of at least 1 ml [54-56].

To ensure maximum sensitivity of the method, blood samples for culture should, if possible, be obtained before the initiation of antimicrobial therapy. If this is not possible, blood for culture should be drawn immediately before the administration of the next dose of a systemic antibacterial drug (ATX code J01), when the drug concentration in the blood is at its minimum.

It is preferable to use blood culture bottles containing antimicrobial adsorption resins. Several observational studies have demonstrated that the use of this tactic is associated with improved treatment outcomes [56–58].

Blood samples to detect bacteremia are obtained by peripheral venipuncture while observing asepsis and antisepsis rules. Sampling from a vascular catheter is allowed only in cases of suspected catheter-related bloodstream infection or, as a last resort, when venipuncture is technically impossible. The use of arterial blood for culture offers no advantages over venous blood. Cord blood obtained at delivery can be used as an alternative substrate for blood culture [59, 60].

Dierikx T.H. et al. (2022) performed a systematic evaluation of the accuracy of cord blood culture for diagnosing early-onset neonatal sepsis, based on which they state that cord blood culture has higher sensitivity and comparable specificity for diagnosing early-onset neonatal sepsis compared to peripheral blood culture, thereby avoiding the risk of iatrogenic anemia and, consequently, can be used as a diagnostic tool for early-onset sepsis [61].

Optimal diagnostic results for bacteremia are achieved by using standardized factory-produced bottles with an enriched culture medium intended for pediatric use. In all cases, except when anaerobic infection is suspected, aerobic blood culture bottles should be used [62].

If a sufficient volume of blood is obtained for culture, at least two bottles should be used, between which the collected sample is divided equally. Inoculating blood into only a single bottle should be avoided, as this practice leads to an insufficient blood volume being cultured, carries the risk of missing a significant number of bacteremia cases, and makes it impossible to rule out sample contamination.

A known limitation of the blood culture method is the duration of the test. Even in the best laboratories, at least 6–8 hours pass from the time samples are delivered for testing to obtaining information on microbial growth, which is required for microorganism multiplication; additional time is required to identify the pathogen and determine its susceptibility to systemic antibacterial drugs (ATX code J01). Given that microbiological laboratories often do not operate around the clock, the total test time can reach several days. At the same time, urgently informing the attending physician of a positive blood culture growth, as well as the results of Gram stain microscopy of the primary blood culture, provides exceptionally important information for refining antibiotic therapy.

The identification of the pathogen in the primary blood culture or pure culture can be significantly accelerated using MALDI-ToF mass spectrometry [62, 63].

In addition, molecular methods can be used to accelerate etiological diagnosis [64].

• All newborns, depending on the identified or suspected focus of infection, are recommended to undergo microbiological (culture) testing of the appropriate biological material (sputum, lavage fluid, cerebrospinal fluid, urine, pleural fluid, pericardial fluid, etc.) for aerobic and facultatively anaerobic microorganisms to verify the causative agent and determine antibacterial therapy tactics [65, 66].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Skin surface swabs should not be taken for culture in the absence of clinical signs of localized skin and soft tissue infection.

When central nervous system infection is suspected, it is advisable to perform blood and cerebrospinal fluid cultures [67, 68].

In critically ill neonates who exhibit a significant deterioration in circulatory or respiratory function in response to external stimuli, lumbar puncture may be delayed until their condition stabilizes [69, 70].

• All newborns with risk factors for sepsis, sepsis, and septic shock are recommended to undergo microbiological (culture) testing of mucus from the tonsils and posterior pharyngeal wall and feces for aerobic and facultatively anaerobic microorganisms for the purpose of screening for colonization by multidrug-resistant pathogens and identifying genetic markers of antimicrobial resistance [71-83].

GoR ALoE 2Grade of Recommendation A (Level of Evidence – 2).

Comment: The development of late-onset neonatal sepsis is primarily associated with hospital-acquired strains of microorganisms [71-75].

In the presence of risk factors such as prior hospital treatment, especially in the ICU, and prior antibacterial therapy, colonization of patients with multidrug-resistant flora is possible. When such antimicrobial-resistant microorganisms (ATX code J) are introduced into a hospital, conditions are created for hospital outbreaks and a deterioration of the hospital's microbiological landscape [76, 77].

Therefore, incoming screening for pathological colonization of non-sterile body niches should be carried out by taking throat and/or rectal swabs, targeting the following "problem" microorganisms: methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum β-lactamase and carbapenemase-producing Enterobacterales, multidrug-resistant non-fermenting Gram-negative bacteria (carbapenem-resistant isolates of P. aeruginosa, A. baumannii, and strains of Stenotrophomonas maltophilia resistant to sulfamethoxazole + trimethoprim** [ATX code J01EE01]).

It is also advisable to determine genetic markers of resistance to systemic antimicrobial drugs (ATX code J) [78–82].

Screening results should not guide the administration of antimicrobial therapy in the absence of clinical signs of an infectious process, but they may be taken into account when prescribing empirical therapy if an infection manifests. Furthermore, data obtained from screening are part of microbiological monitoring and determine the set of anti-epidemic measures that must be implemented upon admission of a patient colonized with multidrug-resistant flora [83].

2.4 Instrumental Diagnostics

• To optimize infusion, inotropic, and vasopressor support in a newborn with sepsis, it is recommended to perform echocardiography [84].

Level CLevel 3Level of recommendation evidence C (reliability level of evidence – 3).

Comment: Timely diagnosis of septic shock in newborns is complicated by the fact that sepsis occurs against the background of physiological or maladaptive changes in the cardiovascular system inherent in the early neonatal period. At the same time, the clinical manifestations of sepsis may overlap with those of hemodynamic disorders in congenital heart disease, the instrumental diagnosis of which may not always be possible at the initial stage of therapy. Therefore, misdiagnosing septic shock and administering massive fluid resuscitation in decompensated congenital heart disease can have catastrophic consequences for the patient.

Pugnaloni F. et al. (2024), in a systematic review, evaluated available echocardiographic findings in neonates with sepsis. The review covered 12 studies involving 438 neonates with sepsis and 232 healthy controls. Neonates with sepsis showed a high risk of pulmonary hypertension and/or left ventricular diastolic dysfunction. During the "warm" shock phase, a significant increase in cardiac output (CO) was observed. The analysis confirms that neonates with sepsis experience significant hemodynamic changes that can be detected by echocardiography. These findings highlight the need for a broader use of echocardiography to tailor hemodynamic-based strategies in this population [84].

Echocardiography prior to initiating hemodynamic support helps rule out ductus-dependent critical congenital heart disease, hemodynamically significant pericardial effusion, and verify hypovolemia, myocardial dysfunction, peripheral vasodilation, persistent pulmonary hypertension, intracardiac and extracardiac shunts, as well as the direction of the shunt [84, 85].

• In all newborns with sepsis and clinical signs of respiratory distress, chest X-ray and overview abdominal radiography are recommended to rule out infiltrative lung changes, pneumothorax, comorbidities, and congenital malformations [1, 21, 30].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Respiratory distress associated with pneumonia is the most frequent clinical manifestation of early-onset neonatal sepsis, which necessitates radiological examination to assess the severity of infiltrative changes and rule out potential complications [1, 21, 30].

• In all newborns with sepsis and septic shock, a comprehensive abdominal ultrasound and neurosonography are recommended to rule out internal organ pathology, ongoing bleeding, meningitis, intracranial hemorrhage, and hypoxic-ischemic brain injury [1, 30].

GoR BLoE 5Grade of Recommendation B (Level of Evidence – 5).

Comment: In premature newborns with very low and extremely low birth weight, the likelihood of early-onset neonatal sepsis and septic shock is highest, and the incidence of meningitis in this group is significantly higher than in term newborns [1]. In addition, against the backdrop of a progressing infectious-inflammatory process and aggressive anti-shock therapy, the risk of intraventricular and intracranial hemorrhage is extremely high, requiring timely detection since these conditions can also cause severe hemodynamic disturbances [30].

• In all newborns with sepsis, suspected sepsis, and septic shock, continuous bedside monitoring of vital functions and parameters (heart rate, respiratory rate, blood pressure, SpO₂, body temperature, urinary output) is recommended for the timely administration of symptomatic and pathogen-directed therapy [1, 3, 7, 8].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

2.5 Other Procedures

• When prescribing medications to newborns with sepsis and septic shock that are used in ways not specified in the approved product labeling (off-line/off-label), a clinical pharmacologist consultation is recommended to prevent adverse drug reactions [86, 87]. If drugs need to be prescribed in dosages or indications not registered in the Russian Federation, a medical commission (consilium) conclusion is required, provided informed consent is obtained from the patient's parents/legal representatives.

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comment: A prospective randomized double-blind study demonstrated that the involvement of a clinical pharmacologist in the management of patients in the neonatal ICU helps reduce the incidence of adverse drug reactions [86].

In accordance with Decree of the Government of the Russian Federation No. 1799 dated October 27, 2023, "On Approval of Requirements for a Medicinal Product Registered in the Territory of the Russian Federation Used in Accordance with Indicators (Characteristics) of the Medicinal Product Not Specified in its Instructions for Use, the Inclusion of Which is Permitted in Standards of Medical Care for Children and Clinical Guidelines," the following requirements apply:

– the efficacy and safety of using the medicinal product in accordance with indicators (characteristics) not specified in its instructions for use are confirmed by research data published in scientific publications and/or clinical case descriptions posted in the Russian Science Citation Index database and/or in "White List" journals for each departure from the instructions regarding indications for use, and/or dosing regimen, and/or route of administration, and/or drug-drug interactions and other types of interactions;

– indication of the efficacy and safety of the medicinal product's use is confirmed by its inclusion in recommendations adopted by international professional organizations.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Conservative management

3.1.1 Antimicrobial Therapy

• In all newborns with sepsis, septic shock, or suspected sepsis, antibacterial therapy is recommended for targeted treatment and should be initiated as early as possible. The optimal timeframe is within one hour of diagnosis [88, 89].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: Administration of systemic antibacterial drugs (ATC code J01) within the first 3 hours after sepsis diagnosis has been found to significantly improve survival rates and reduce the incidence of complications such as necrotizing enterocolitis and bronchopulmonary dysplasia [88, 89].

Despite the lack of robust evidence, the earliest possible initiation of antibacterial therapy may be considered a recommended measure in appropriate clinical conditions. Primary focus should be placed on identifying newborn infants at high risk for infection to justify empirical antibiotic therapy. A personalized approach exists with individualized risk prediction for neonatal sepsis based on gestational age [90]. Initially, empirical antibiotic therapy using drugs targeting the most likely pathogens is advisable. Following pathogen identification and determination of their susceptibility to systemic antibacterial drugs (ATC code J01), empirical antimicrobial therapy should be adjusted if necessary.

In clinical practice, it is often not feasible to quickly identify the causative agent, but the presence of signs of infection requires the physician to immediately prescribe antibacterial therapy, considering data on the probable increase in survival with early antibiotic initiation [88, 90]. Categorizing neonatal infections into early- and late-onset helps determine empirical therapy tactics, as they have different causes and etiologies. The main bacterial microorganisms causing early-onset neonatal sepsis are Streptococcus agalactiae, Escherichia coli, Staphylococcus aureus, and Listeria spp. [91–94].

These microorganisms frequently colonize the genital tract of pregnant women and are the primary pathogens of genital tract infections, leading to amniotic fluid infection via an ascending route. The empirical regimen of initial antibacterial therapy for suspected early-onset neonatal sepsis should aim to eliminate these microorganisms taking into account their expected susceptibility profile [91–94].

The initial antibacterial therapy regimen typically involves a combination of ampicillin** (ATC code J01CA01) with other aminoglycosides (ATC code J01GB) – #gentamicin**, amikacin**, which exhibit synergy against the specified pathogens [95]. Aminoglycosides (ATC code J01G) are effective against a range of bacterial isolates such as E. coli, Enterobacter, Klebsiella, Proteus spp., and P. aeruginosa [96].

As an alternative when meningitis is suspected, third-generation cephalosporins (ATC code J01DD) may be used due to better CNS penetration, though routine empirical use is inadvisable due to an increased risk of resistance. At the same time, third-generation cephalosporins (ATC code J01DD) lack significant efficacy in treating infections caused by L. monocytogenes [67].

Cefotaxime** (ATC code J01DD01) (intravenous solution) is used as the first-line cephalosporin, since ceftriaxone** (ATC code J01DD04) is contraindicated in neonates with hyperbilirubinemia, jaundice, acidosis, and hypoalbuminemia due to its high protein-binding affinity, which can displace bilirubin from albumin-binding sites, resulting in higher free bilirubin concentrations and subsequent tissue accumulation, thereby increasing the risk of jaundice [97].

It is important to emphasize the contraindication for administering ceftriaxone** (ATC code J01DD04) simultaneously with calcium-containing solutions, which leads to calcium precipitation and serious adverse events such as embolism [98].

Given the unfavorable trend of increasing prevalence of broad-spectrum penicillin-resistant (ATC code J01CA) E. coli and methicillin-resistant coagulase-negative staphylococci as pathogens in both early- and late-onset neonatal sepsis, treatment regimens may be modified using combinations of penicillins, including beta-lactamase inhibitor combinations (ATC code J01CR): ampicillin+sulbactam** (ATC code J01CR01), #piperacillin+tazobactam (ATC code J01CR05), and other beta-lactam antibacterial drugs (ATC code J01D): cefotaxime+sulbactam** (ATC code J01DD51) (intravenous solution), cefoperazone+sulbactam** (ATC code J01DD62) combined with vancomycin** (ATC code J01XA01), teicoplanin (ATC code J01XA02), or linezolid** (ATC code J01XX08) [63, 72, 99–101].

Late-onset neonatal sepsis typically develops in newborns who have required prolonged mechanical ventilation or invasive procedures. As a rule, it is caused by hospital-acquired pathogens characterized by multiple resistance to systemic antimicrobial drugs (ATC code J). According to several studies, late-onset neonatal sepsis in developing countries is predominantly caused by Gram-negative bacteria and coagulase-negative staphylococci [73, 74, 102, 103].

In the NeoOBS cohort multicenter study, the most common causative agents of late-onset neonatal sepsis were Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens, and Enterobacter cloacae [72]. The isolated strains frequently exhibit resistance to ampicillin** (ATC code J01CA01), #gentamicin** (ATC code J01GB03), cephalosporins (ATC codes J01DB, J01DC, J01DD, J01DE), and carbapenems (ATC code J01DH) [104].

If the causative agents of late-onset neonatal sepsis are Gram-negative microorganisms that do not produce extended-spectrum β-lactamases and retain antibiotic susceptibility to cephalosporins (ATC codes J01DB, J01DC, J01DD, J01DE), their use is most justified: ceftazidime** (ATC code J01DD02) for the treatment of infections caused by P. aeruginosa, and #cefepime** (ATC code J01DE01) [196].

A trend of recent years is a significant increase in the proportion of Gram-negative bacteria in the structure of nosocomial pathogens. According to the national antimicrobial resistance map (www.amrmap.ru), in the period 2020–2022, they accounted for 78% of the total structure of hospital infection pathogens in infants in their first year of life, while the proportion of enterobacteria in the structure of all pathogens was 46.7%, Pseudomonas aeruginosa – 16%, and Acinetobacter – 4.3%. These microorganisms are characterized by a variety of resistance mechanisms to systemic antibacterial drugs (ATC code J01), which, often acting in combination, are able to effectively resist most of the agents currently available in the clinical arsenal. The high frequency of extended-spectrum β-lactamase production in enterobacteria (especially Klebsiella pneumoniae) has shifted carbapenems (ATC code J01DH) from reserve drugs to first-line agents in the treatment of patients with infections caused by these pathogens [105].

The widespread and often irrational use of carbapenems (ATC code J01DH) has contributed to the emergence and spread of resistance to them. Infections caused by carbapenem-resistant (ATC code J01DH) non-fermenting Gram-negative bacteria, primarily Pseudomonas aeruginosa and Acinetobacter baumannii, also present a serious problem [106, 107].

Resistance of Gram-negative bacteria to carbapenems (ATC code J01DH) is caused by various mechanisms and their combinations, including impaired cell wall permeability, efflux, and enzymatic inactivation, in which the production of carbapenemases plays a key role. According to the Ambler classification, 4 molecular classes of β-lactamases are distinguished: serine (A, C, D) and metallo-enzymes having a zinc atom in the active center (B). AmpC-type enzymes (molecular class C), characteristic of enterobacteria and P. aeruginosa, predominantly demonstrate hydrolysis of cephalosporins (ATC codes J01DB, J01DC, J01DD, J01DE). Class A is represented by a number of enzymes with various substrate profiles, including ESBLs, which cause enterobacteria to be resistant to all other beta-lactam antibacterial drugs (ATC code J01D) except carbapenems (ATC code J01DH), as well as KPC and GES carbapenemases found in enterobacteria and P. aeruginosa. Class D includes OXA-type carbapenems characteristic of members of the order Enterobacterales and Acinetobacter. Metallo-beta-lactamases (IMP, VIM, NDM) are found predominantly in P. aeruginosa and enterobacteria, have a broad spectrum of hydrolytic activity, including carbapenems (ATC code J01DH), but are inactive against monobactams (ATC code J01DF). Detection of carbapenemase production makes carbapenem monotherapy inappropriate (ATC code J01DH), even if phenotypic susceptibility to them is present. At low MIC values (≤ 8 µg/mL) for #meropenem** (ATC code J01DH02), combination therapy regimens may be used in some cases, including #meropenem** (ATC code J01DH02) at maximum doses, amikacin** (ATC code J01GB06), fosfomycin** (ATC code J01XX01), #tigecycline** (ATC code J01AA12), and polymyxins (ATC code J01XB) in various combinations. At high MICs of #meropenem** (J01DH02), combination therapy based on polymyxins (ATC code J01XB) can be administered. If enterobacteria are resistant to carbapenems (ATC code J01DH) due to the production of serine carbapenemases, even with concomitant ESBL production, the new protected third-generation cephalosporin (ATC code J01DD) – #ceftazidime+[avibactam]** (ATC code J01DD52) – exhibits high efficacy [108].

When microbes produce metallo-enzymes that have high hydrolytic activity and are not inhibited by avibactam, as well as in the simultaneous production of multiple carbapenemases (the most frequent variant being OXA-48 + NDM), a combination of #ceftazidime+[avibactam]** (ATC code J01DD52) and #aztreonam (ATC code J01DF01) administered simultaneously can be used. This combination is active against ESBL producers and class B, C, and D carbapenemases. #Ceftazidime+[avibactam]** (ATC code J01DD52) also retains activity against a number of P. aeruginosa isolates, including those producing serine carbapenemases. Modern hospital isolates of A. baumannii are characterized by a high level of resistance to most classes of systemic antibacterial drugs (ATC code J01), including carbapenems (ATC code J01DH) and sulbactam (ATC code J01CG01; J01CG beta-lactamase inhibitors). Polymyxins (ATC code J01XB) exhibit high in vitro activity, and a number of isolates may be susceptible to #sulfamethoxazole+trimethoprim** (ATC code J01EE01) [196, 204].

For infections caused by Gram-positive microorganisms with preserved susceptibility to oxacillin** (ATC code J01CF04) (methicillin-susceptible strains), the optimal option is the use of #cefazolin** (ATC code J01DB04) and, in some cases, ceftaroline fosamil** (ATC code J01DI02). Recently, there has been an increase in the significance of methicillin-resistant staphylococci, as well as multidrug-resistant enterococci, which are resistant to all other beta-lactam antibacterial drugs (ATC code J01D). Such microorganisms are characterized by associated resistance to other systemic antibacterial drugs (ATC code J01) (macrolides (ATC code J01FA), aminoglycosides (ATC code J01G), etc.). Vancomycin** (ATC code J01XA01) remains the baseline systemic antibacterial drug (ATC code J01) for the treatment of problematic coccal infections; however, recently there is strong evidence of insufficient efficacy of this drug in severe infections caused by formally susceptible Staphylococcus aureus characterized by elevated vancomycin MICs** (ATC code J01XA01) (especially at MIC ≥ 2 µg/mL). In these cases, as well as in resistance of staphylococci and enterococci to standard therapy and in case of its intolerance, it is advisable to use alternative agents – oxazolidinones (other antibacterial drugs – ATC code J01XX) – #daptomycin** (ATC code J01XX09) and linezolid** (ATC code J01XX08).

If an anaerobic nature of the infection is suspected, metronidazole** (ATC code D06BX01) can be used as part of antimicrobial therapy.

Newborn infants, especially those with extremely low birth weight, are a risk group for the development of invasive candidiasis and candidemia.

For all high-risk patients (birth weight less than 1000 g and gestational age less than 27 weeks), to prevent invasive candidiasis, it is advisable to administer antifungal prophylaxis with fluconazole** (ATC code J02AC01) intravenously or orally in accordance with age-appropriate doses (see Appendix A3.4 Regimens of systemic antimicrobial drugs (ATC code J) for the treatment of sepsis in newborns) as long as intravenous access is required, starting from the 1st day of life and continuing up to 6 weeks of life.

In patients with higher body weight and older age, the issue of antifungal prophylaxis is decided individually based on data on the prevalence of invasive mycoses and candidemia in the hospital (department), colonization of mucous membranes by Candida fungi, and the presence or persistence of other risk factors.

Invasive fungal infections are characterized by an increasing clinical significance of non-albicans Candida species with reduced susceptibility to fluconazole** (ATC code J02AC01). The most effective drugs for the treatment of invasive candidiasis and candidemia are other systemic antifungals (ATC code J02AX): micafungin** (ATC code J02AX05), #anidulafungin (ATC code J02AX06), and #caspofungin** (ATC code J02AX04). Targeted antimycotic therapy should be prescribed taking into account the susceptibility of the identified pathogen to systemic antifungals (ATC code J02). Additionally, Malassezia furfur has recently been identified among nosocomial pathogens. Fungi of this species are extremely difficult to culture on conventional growth media and can cause severe fungal sepsis in extremely preterm infants [109]. Amphotericin B** (ATC code J02AA01) is used for M. furfur fungemia [110].

Thus, empirical antibiotic therapy for sepsis in neonates should include systemic antimicrobials (ATC code J) active against gram-negative and gram-positive pathogens, and, in the presence of risk factors, fungi as well. The choice of drugs is made in accordance with the localization of the infection focus and the susceptibility profile of the most likely pathogens, and in the case of empirical prescription, it is determined through microbiological monitoring of the predominant microflora of a specific ward and/or institution, combined with data on the colonization of the patient's non-sterile loci. Therapy adjustment is performed after receiving microbiological test results (blood and material from the focus).

The issue of rational antibiotic therapy, in addition to the adequate choice of drugs taking into account their spectrum of action and the localization of the infection focus, includes an important, yet not always properly considered aspect regarding the correct dosage regimen of systemic antimicrobials (ATC code J). Sepsis can lead to multidirectional changes in the pharmacokinetics and pharmacodynamics of systemic antimicrobials (ATC code J), especially in infancy, given the characteristics of the newborn's body. Suboptimal concentrations of systemic antimicrobials (ATC code J) in the blood and body tissues can lead to a decrease or complete lack of therapeutic effect, as well as the emergence of resistant pathogen strains [95].

Equally dangerous, especially in premature infants, is the overdose of certain systemic antimicrobials (ATC code J), which can lead to toxic side effects (in particular, due to nephro- or hepatotoxicity). The ultimate outcome in both cases will be worsened clinical treatment results and increased economic costs. The problem of adequate dosing of systemic antimicrobials (ATC code J) is of particular importance in patients with multiple organ dysfunction syndrome or a high risk of its development, as well as in patients undergoing various methods of extracorporeal detoxification. The current recommended rules and regimens of antibiotic therapy can be found in detail in the relevant manuals [111, 112].

The publication by Dekhnich A.V. et al. presents an algorithm for targeted therapy of infections caused by multidrug-resistant pathogens, depending on the resistance determinants produced by the pathogen [113].

An urgent problem in the treatment of severe infections in newborns is the scarcity of data on the possibility of using a number of systemic antimicrobials (ATC code J) in effective and safe dosage regimens, which may limit the availability of antimicrobial therapy. If it is necessary to prescribe systemic antimicrobials (ATC code J) used in accordance with indications (characteristics) of the medicinal product not specified in its instructions for use (off-label), a medical commission conclusion is required, provided that informed consent is obtained from the parents/legal representatives of the patient.

In accordance with the conclusions of large multicenter studies, the excessive use of systemic antimicrobials (ATC code J) in neonates contributes to the growth of pathogen resistance to systemic antibacterials (ATC code J01) [94, 96, 101].

3.1.2. Volume support

• In newborns with sepsis, routine fluid and electrolyte administration is recommended to be carried out based on body weight, gestational age, and postmenstrual age of the child, using the minimum necessary volumes (lower limit of age requirement) [114-118].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: see Appendix A.3.5

• In newborns with sepsis, it is not recommended to use the maximum allowable fluid volumes for routine infusion therapy to avoid the risk of volume overload and the development of multiple organ dysfunction [114-118].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Adequate volume loading and parenteral nutrition are a prerequisite for successful intensive care of sepsis and septic shock in newborns, while the fluid requirement for each specific patient may vary significantly based on gestational age and postmenstrual age [114–118]. All available guidelines for calculating fluid requirements indicate a very wide range of values, but it should be remembered that in sepsis, the risk of fluid overload is extremely high and is associated with an increased probability of a fatal outcome [119, 120].

• In newborns with sepsis during routine infusion therapy to maintain optimal cardiac output, it is recommended to maintain blood glucose levels in the range of 3.5–5.5 mmol/L, and the ionized calcium concentration should be at least 1.15 mmol/L [21, 30, 121, 122].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• In a newborn with sepsis and septic shock presenting with hypoglycemia (blood glucose level less than 2.6 mmol/L) and clinical symptoms, it is recommended to perform emergency correction by increasing the administration rate of #dextrose** (ATC code B05CX01) or its intravenous bolus administration – a 10% solution at a dose of 2 ml/kg (0.2 g/kg) at a rate not exceeding 1 ml/min [7, 8, 27, 122-123].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: One of the most prominent, early, and obvious manifestations of sepsis is calcium balance and carbohydrate metabolism disorders, and quite frequently both hypo- and hyperglycemia can occur [122, 123]. Hypocalcemia is an independent predictor of an unfavorable outcome in neonatal sepsis, which is undeniable proof of the need for its timely correction within the first minutes of septic shock therapy [21, 30, 124]. This is especially important given that in hypocalcemia, the efficacy of cardiotonic agents, except for cardiac glycosides (ATC code C01C), is significantly lower [124].

3.1.3. Hemodynamic support

• To eliminate hypovolemia in term neonates with septic shock in the first hour of therapy, it is recommended to use sodium chloride** (ATC code B05XA) – 0.9% solution or combination electrolyte solutions (ATC code B05XA30) in a maximum volume of 60 ml/kg – bolus administration of 10-20 ml/kg over 5-10 min [30, 125-128].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: The cause of hypovolemia in sepsis is fluid extravasation against the background of capillary leak syndrome, redistribution during vasodilation, inadequate intake due to intestinal insufficiency, or inadequate intake. Infusion therapy is performed to rapidly restore optimal tissue perfusion and blood pressure appropriate for gestational age [30].

The target endpoints of the first hour of anti-shock therapy are: normalization of mental status, appearance of pulse on peripheral arteries, capillary refill time < 3 s, heart rate and mean arterial pressure within age-specific reference ranges, diuresis > 1 ml/kg/h, decrease in lactate concentration, difference between preductal and postductal SpO₂ < 5%, ScVO₂ > 70%, SVCflow > 40 ml/kg/min, CI > 3.3 L/min/m² [30, 128]. If cardiac output measurement is not available, clinical manifestations of fluid overload indicating the need for its restriction include progression of respiratory failure, increased oxygen demand, appearance of moist rales during lung auscultation, presence of changes in lung parenchyma on ultrasound, and/or hepatomegaly [21, 129].

• In newborns with very low birth weight (VLBW), it is recommended not to exceed a volume load of 30 ml/kg during the first hour of septic shock therapy (bolus administration of 10 ml/kg over 20 min), and in infants with extremely low birth weight (ELBW) – 20 ml/kg (bolus administration of 10 ml/kg over 30 min) [30, 125-128].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Rapid administration of significant fluid volumes in preterm neonates can lead to intraventricular hemorrhage, whereas prolonged cerebral hypoperfusion due to untimely restoration of circulating blood volume is a risk factor for periventricular leukomalacia [30, 125–128].

• In newborns with sepsis presenting with low cardiac output syndrome and/or ineffectiveness of fluid therapy, the use of cardiotonic agents, excluding cardiac glycosides (ATC code C01C), is recommended to correct hemodynamic disturbances [130–132].

GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).

Comment: see Appendix A.3.6.

Evidence indicates that #dopamine** (5–20 mcg/kg/min) (ATC code C01CA04) and #epinephrine** (0.1–0.4 mcg/kg/min) (ATC code C01CA24) have comparable efficacy and allow achieving condition stabilization within the first hour of septic shock therapy [130, 131].

• In newborns with catecholamine-resistant and refractory septic shock, the administration of systemic corticosteroids (ATC code H02) — #dexamethasone** (0.5 mg/kg every 2–6 hours) (ATC code H02AB02) or #hydrocortisone** (1–2 mg/kg every 6 hours) (ATC code H02AB09) — is recommended to increase receptor sensitivity to catecholamines [133].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Children with fulminant purpura, Waterhouse-Friderichsen syndrome, prior systemic corticosteroid therapy (ATC code H02), and chronic endocrine pathology are at high risk for absolute adrenal insufficiency. However, it should be noted that indications for systemic corticosteroids (ATC code H02) in pediatric septic shock are highly controversial, as their use may increase mortality [134, 135]. In the absence of confirmed absolute adrenal insufficiency, stress-dose #hydrocortisone** (ATC code H02AB09) should be prescribed only in cases of catecholamine-resistant and refractory septic shock [136].

3.1.4. Respiratory support

• Oxygen therapy in newborns with sepsis is recommended as a first-line respiratory support method during the initial stabilization phase and as supportive therapy for mild respiratory distress [21, 30].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment: Oxygen therapy is justified in the presence of acute hypoxia of mixed genesis during the initial stabilization phase and as a method to correct mild-to-moderate hypoxemia in patients with mild respiratory distress [21, 30]. Oxygen therapy can be delivered using a wide variety of devices, the most effective of which are nasal cannulas for oxygen delivery during non-invasive continuous positive airway pressure (CPAP) ventilation.

Indications: 1) Hypoxemia (PaO₂ < 60 mmHg, SpO₂ < 93% on room air); 2) Severe anemia; 3) Low cardiac output syndrome (in the absence of cardiogenic shock)

Contraindications: 1) Depression of consciousness to the level of coma; 2) Progressive arterial hypotension; 3) Septic shock; 4) PaO₂/FiO₂ ratio < 300 mmHg; 5) Decompensated acidosis of any genesis (pH < 7.25); 6) Decompensated respiratory alkalosis

Starting parameters for high-flow nasal cannula oxygen therapy: a) temperature of the gas mixture: 34–37⁰C; b) FiO₂ = 0.4–0.6 to maintain SpO₂ = 92–95%; flow rate = 1 L/kg.

If respiratory failure progresses, the flow rate should be increased to 2 L/kg. As a last resort, increasing FiO₂ is possible. If ineffective with further progression of ARDS, non-invasive or invasive mechanical ventilation should be used.

• In newborns with sepsis, signs of septic shock, and severe acute respiratory distress syndrome, invasive mechanical ventilation is recommended to correct existing gas exchange disorders [21, 30].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: See Appendix A3.7.

Although there are currently no randomized controlled trials demonstrating the absolute necessity and undoubted efficacy of routine endotracheal intubation and mechanical ventilation, we believe that fluid-refractory septic shock is an absolute indication for invasive respiratory support. This is due to the high risk of progression to acute respiratory distress syndrome and multiple organ dysfunction syndrome in these patients against the background of hypoxia, high metabolic rate, lactic acidosis, and fluid overload, the negative effects of which can be mitigated by aggressive respiratory support [21, 30]. It should be noted that chest X-ray findings confirming ARDS very often "lag behind" the clinical picture of the pathological process, which may lead to delayed initiation of mechanical ventilation when the adverse course of ARDS is already nearly irreversible [30].

Indications for intubation and invasive mechanical ventilation:

1. Septic shock

2. Impaired consciousness due to progressive hypoxemia (severe agitation may be an equivalent).

3. Cyanosis and marked diaphoresis.

4. Grunting respiration

5. Marked tachypnea, areas of decreased breath sounds on lung auscultation.

6. Marked hypoxemia (PaO₂ < 60 mmHg)

7. Marked hypercapnia (PaCO₂ > 60 mmHg)

8. Marked hypocapnia (PvCO₂ < 45 mmHg)

9. Decrease in PvO₂ below 35 mmHg

10. Decrease in SvO₂ below 65%

• Midazolam** (ATC code N05CD08) and #fentanyl** (ATC code N01AH01) are recommended as the drugs of choice for sedation and analgesia during endotracheal intubation in newborns with sepsis and septic shock. #Fentanyl** (ATC code N01AH01) should be administered in small boluses at a dose of 1–2 mcg/kg over 60 seconds [30, 137].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment: Anesthesia induction for endotracheal intubation in newborns with septic shock is very frequently associated with arterial hypotension, hemodynamic instability, and pulmonary edema due to systolic-diastolic myocardial dysfunction; therefore, short-acting drugs (#fentanyl** (ATC code N01AH01), midazolam** (ATC code N05CD08)) are preferred. To prevent hemodynamic disturbances, the administration of cardiotonic agents other than cardiac glycosides (ATC code C01C) is justified prior to anesthesia induction. #Fentanyl** (ATC code N01AH01) is best used for analgesia, especially in younger children, as it has minimal impact on the patient's hemodynamic status [30, 137–139]. Appendices A.3.8, A.3.9. The use of long-acting anxiolytics (ATC code N05B), hypnotics, and sedatives (ATC code N05C) with pronounced cardiodepressive effects should be avoided [30, 138, 139].

• In newborns with septic shock requiring mechanical ventilation, it is recommended to use a tidal volume corresponding to the lower limit of age-specific reference values, equal to 5–8 mL/kg depending on the underlying disease and respiratory system compliance [140–142].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: When performing invasive mechanical ventilation in newborns with sepsis and septic shock, tidal volumes exceeding the upper limit of age-specific reference values should be avoided, as this may cause secondary lung injury, hyperventilation, hypocapnia, systemic vasospasm, and hemodynamic disturbances clinically and laboratory manifested by arterial hypotension and progressive lactic acidosis [140–142].

• In newborns with septic shock and severe ARDS, a step-by-step increase in the PEEP level up to 10 cm H₂O under the control of hemodynamic and oxygenation parameters is recommended [141].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: The use of positive end-expiratory pressure increases mean airway pressure, recruits collapsed alveoli, and improves oxygenation without increasing the fraction of inspired oxygen. However, currently, no study recommends an absolute value for positive end-expiratory pressure in children with acute respiratory distress syndrome. A starting PEEP level of 6–8 cm H₂O should be used [141, 142].

• During mechanical ventilation in newborns with sepsis and septic shock, target SpO₂ values are recommended to be maintained in the range of 92–97%, and central venous oxygen saturation within 65–75% [141, 142].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment: When performing mechanical ventilation in newborns with sepsis, septic shock (SS), and ARDS, one should strive to achieve target blood gas and oxygenation values. In patients with mild to moderate ARDS, when the applied PEEP level does not exceed 10 cm H₂O, pulse oximetry and central venous oxygen saturation values should be within reference ranges, although there is currently no convincing evidence that improving oxygenation contributes to a more favorable outcome [141, 142].

There is currently insufficient evidence to recommend the concept of permissive hypoxemia for routine clinical practice. All respiratory support strategies should aim to ensure adequate tissue oxygenation while minimizing the fraction of inspired oxygen and invasive mechanical ventilation parameters, since the long-term neurological outcomes of using permissive hypoxemia have not yet been studied, and clinicians must carefully weigh all potential risks in each specific clinical situation [141, 142].

• The use of permissive hypercapnia (pH = 7.25–7.35; pvCO₂ = 55–65 mm Hg) in newborns with sepsis and SS is recommended in severe ARDS to minimize ventilator-associated lung injury [143, 144].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: The use of permissive hypercapnia in routine clinical practice is a life-saving strategy aimed at minimizing invasive mechanical ventilation settings to prevent ventilator-induced lung injury, although a consensus on its efficacy and safety is currently lacking, which is especially true for premature newborns [143-144].

• The use of inhaled nitric oxide (iNO) in newborns with sepsis and SS is recommended in the presence of persistent refractory hypoxemia and pulmonary hypertension. Routine use is not recommended [145, 146].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: The use of inhaled nitric oxide (iNO) in newborns with sepsis and SS is unjustified because sepsis is not characterized by primary pulmonary artery involvement leading to pulmonary hypertension. At the same time, it should be noted that sepsis very frequently occurs in premature infants, children with congenital heart disease, and bronchopulmonary dysplasia, in whom inhaled nitric oxide (iNO) may be justified to reverse secondary pulmonary hypertension. Thus, the use of inhaled nitric oxide (iNO) is advisable only in children with confirmed pulmonary hypertension, severe right ventricular dysfunction, and a high risk of developing bronchopulmonary dysplasia [145, 146].

3.1.5. Nutritional support

Nutritional support in newborns with sepsis and SS is an essential component of intensive care, alongside antibiotic therapy, infusion therapy, respiratory support, etc.

• Calculating the requirement for energy substrates in newborns with sepsis and septic shock is recommended based on the phase of the pathological process [147, 148].

GoR BLoE 5Grade of Recommendation B (Level of Evidence – 5).

Comment: In the acute phase of the disease (critical condition), the provision of energy substrates should cover resting energy expenditure. In the stabilization phase, their amount gradually increases and reaches twice the requirement or more during the recovery phase to ensure the child's growth and development [147, 148].

• Early enteral nutrition is recommended in newborns with sepsis and SS [149, 150].

GCR BLEL 4Grade of Recommendation B (Level of Evidence – 4).

Comment: Randomized clinical trials on nutrition in newborns with sepsis and septic shock are currently lacking; however, a considerable body of work indicates that early enteral nutrition—in infants older than one month and adults as well as in newborns, especially preterm infants with low and extremely low birth weight—offers several advantages, including a reduced probability of sepsis and shorter lengths of stay in the ICU and hospital [149, 150].

• Expressed breast milk is recommended as the optimal method of nutritional support in newborns with sepsis and septic shock, provided there are no contraindications [151-153].

GOM ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment: Early administration of breast milk helps reduce the duration of parenteral nutrition in preterm newborns with VLBW and ELBW with growth restriction during late-onset sepsis, which can significantly impact neonatal outcomes [151, 153]. Breast milk is administered via a nasogastric/orogastric tube every 3 hours [154]. If maternal milk is unavailable, it can be replaced by pasteurized donor milk from a human milk bank or infant formula. Initially, the volume of enteral nutrition is 20–35 ml/kg/day, with gradual advancement up to 120 ml/kg/day. Transitioning to full enteral nutrition is desirable by days 12–13 [154].

• In newborns with sepsis and septic shock, enteral nutrition is recommended even during continuous infusion of cardiotonic drugs (excluding cardiac glycosides, ATC code C01C), provided hemodynamics are stable and there is no risk of gastrointestinal ischemia secondary to systemic hypoperfusion [21, 30, 154, 155].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: A number of studies in children with septic shock receiving cardiotonic therapy have demonstrated the feasibility of enteral nutrition without an increase in adverse effects or gastrointestinal complications [21]. The use of breast milk as a component of nutritional support in newborns with sepsis helps reduce the doses of cardiotonic drugs (except cardiac glycosides, ATC code C01C) and the duration of hemodynamic support [154]. At the same time, it should be noted that early enteral nutrition using high doses of cardiotonic drugs (other than cardiac glycosides, ATC code C01C) is invariably associated with intestinal ischemia and the development of necrotizing enterocolitis [155].

• During the initial stage of treatment for sepsis and septic shock in newborns, it is recommended to administer trophic enteral nutrition with its gradual increase to full volume [155-158].

GoR ALoE 2Grade of Recommendation A (Level of Evidence – 2).

Comment: Trophic nutrition aims to maintain the physiological state of the intestine rather than meet the overall metabolic needs of the patient [156]. Its purpose is to prevent mucosal atrophy and maintain motility. Trophic nutrition continuously stimulates the intestine and reduces the risk of bacterial translocation, which is particularly important in sepsis. A stepwise approach to advancing enteral nutrition shortens the time required to achieve treatment goals and reduces the risk of intestinal ischemia [154, 155–158].

• In newborns with sepsis and septic shock, parenteral nutrition for the provision of essential energy substrates is recommended in all cases where adequate enteral nutrition is not feasible [157-159].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Studies on this aspect of nutritional support in newborns with sepsis and septic shock are lacking. Parenteral nutrition should be prescribed when enteral nutrition is impossible or contraindicated. The timing of initiating parenteral nutrition must be individualized. During parenteral nutrition, enteral milk administration should be maintained even if the tolerated volume is minimal, as early enteral feeding with breast milk can reduce the severity of intestinal mucosal atrophy, prevent bacterial translocation, and shorten the duration of parenteral nutrition [157–159]. Parenteral nutrition is administered using solutions for parenteral nutrition (ATC code B05BA) when it is impossible to deliver the gestational age-appropriate requirements for proteins, fats, carbohydrates, electrolytes, and fluid volume via enteral nutrition. Parenteral nutrition utilizes: amino acids for parenteral nutrition**, lipid emulsions for parenteral nutrition**, carbohydrates (ATC code B05BA solutions for parenteral nutrition), electrolyte solutions (ATC code B05XA), and calcium preparations (ATC code A12AA).

• Routine measurement of gastric residual volume in newborns with sepsis and septic shock is not recommended [160].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: Randomized clinical trials evaluating the necessity of measuring gastric residual volume in newborns with sepsis and septic shock are currently lacking. There is only a single similar study in older children, where the authors concluded that this procedure is not mandatory as it does not significantly affect the incidence of aspiration, nausea, and vomiting [160]. Based on our clinical experience, when a newborn is stable and lacks overt clinical signs of gastrointestinal dysfunction, measuring gastric residual volume before each feeding is unjustified.

• The use of lipid emulsions (ATC code B05BA solutions for parenteral nutrition) in newborns with sepsis is recommended against the background of condition stabilization, regression of septic shock, and acceptable hemodynamic parameters under minimal inotropic support [147, 154, 155, 158].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Currently, there is insufficient data to definitively state the safety and efficacy of lipid emulsions (ATC code B05BA solutions for parenteral nutrition) in newborns with sepsis and septic shock (SS); however, the necessity of their use during condition stabilization and the recovery phase is unquestionable, as it provides the infant's body with essential energy resources, ensuring development, recovery, and a favorable long-term outcome [147, 148, 151].

3.1.6. Extra- and intracorporeal therapy

The main methods of extracorporeal therapy in newborns with sepsis and septic shock are renal replacement therapy (RRT): peritoneal dialysis, continuous renal replacement therapies (continuous veno-venous hemodialysis (CVVHD) / hemofiltration (CVVHF) / hemodiafiltration (CVVHDF)), and extracorporeal blood purification sorption methods, plasma exchange/plasmapheresis.

The use of these methods makes it possible to achieve stabilization of the patient's condition by normalizing homeostasis parameters, correcting water and electrolyte disorders (renal replacement therapy), and reducing the concentration of endotoxins and cytokines (mostly via sorption techniques), which trigger and maintain the cascade of septic reactions. The targets of such extracorporeal blood purification methods as hemoperfusion using a polymyxin-based hemosorbent and hemoperfusion using an extracorporeal blood purification device are elements of the septic reaction cascade.

• The use of RRT in newborns with sepsis and septic shock is recommended in the presence of fluid overload or the risk of its development refractory to conservative therapy [161-165].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: More than 50% of children with septic shock have severe acute kidney injury (AKI), of whom 21.6% require renal replacement therapy [161, 162]. Dialysis may be used in the presence of renal and extrarenal indications to improve treatment outcomes in pediatric intensive care unit patients [161, 162]. These include persistent oliguria, fluid overload, hyperkalemia, metabolic acidosis, hyperlactatemia, and hyperammonemia [31, 165]. In many cases, RRT allows not only correction of fluid status, but also elimination of hyperkalemia and decompensated metabolic acidosis refractory to conservative therapy. Most clinical guidelines for the management of sepsis and septic shock in children contain data confirming the efficacy of RRT when dialysis indications are present [21, 166, 167]. Guidelines for the management of neonatal sepsis currently lack instructions on performing RRT, which is primarily due to the relatively rare use of extracorporeal blood purification therapies in neonatology and the lack of large randomized trials [168]. The available literature contains a fairly large number of small studies and case reports on the successful use of RRT in newborns with sepsis and septic shock [169–173]. Based on the literature analysis, pathophysiological mechanisms, and our clinical experience, it is advisable to consider the possibility of using RRT in neonatal sepsis and septic shock.

The choice of renal replacement therapy method in newborns with sepsis and septic shock depends on the technical feasibility of performing dialysis and the presence/absence of contraindications to a specific method [168-176].

Classic contraindications to peritoneal dialysis are unmanaged peritonitis; early postoperative period after laparotomy (less than two days); and inflammatory changes of the anterior abdominal wall that preclude the placement of a peritoneal dialysis catheter due to a high risk of infection. In the absence of the possibility of performing CVVHD due to the infant's small weight, these contraindications are relative. Contraindications to CVVHDF/CVVHF/CVVHD include hemostasis disorders (bleeding, hemorrhage, coagulopathy) and the inability to establish central venous access.

Most protocols for the management of sepsis and septic shock in adults contain recommendations for various modifications of hemodialysis and hemofiltration (intermittent and continuous/prolonged), whereas peritoneal dialysis is extremely rarely used in the treatment of sepsis-associated AKI in adults. At the same time, in pediatric practice, the lower the patient's weight, the more frequently peritoneal dialysis is used, although with technological advancements and the advent of not only universal machines but also special devices for CVVHDF/CVVHD in children weighing less than 10 kg, hemodialysis technologies are being used increasingly often [165, 168, 174, 175]. In neonatal practice, the choice of RRT method primarily depends on the technical feasibility of using the technique in a specific patient and the presence of contraindications—specifically, the difficulty and often impossibility of securing the vascular access required to maintain the extracorporeal circuit during CVVHDF/CVVHF/CVVHD in children with a body weight of less than 1.5–2 kg [176]. The same applies to various dialysis modes, which in this age group are determined primarily by body and vessel size, and consequently, the technical feasibility of providing RRT in the prescribed mode [162].

• The use of plasma exchange, plasmapheresis, and exchange blood transfusion in newborns with sepsis and septic shock is not recommended [177].

GoR ALoE 2Grade of Recommendation A (Level of Evidence – 2).

Comment: All available sources indicate insufficient data to recommend plasma exchange, plasmapheresis, and exchange blood transfusion in sepsis and septic shock in patients of all age groups, including newborns. Mathias S. et al. (2022) found that exchange blood transfusion is associated with thrombocytopenia and increased mortality in newborns with sepsis and septic shock [177].

• In newborns with sepsis and septic shock, the use of selective lipopolysaccharide hemadsorption is recommended if technically feasible [178, 179].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: Current guidelines for patients of other age groups do not contain recommendations for or against the use of sorption treatment methods, largely due to an insufficient number of studies, as well as the heterogeneity of sorbents and the lack of large studies comparing sorbents with different properties. In our literature analysis, we encountered publications dedicated to complications during hemadsorption (direct hemoperfusion) using a polymyxin-based hemosorbent in newborns [178–180]. At the same time, taking into account the data of other authors and our own clinical experience, we consider the use of sorption technologies feasible in the event of septic shock in a newborn [181, 182].

3.1.7. Additional methods of therapy

• Routine administration of systemic corticosteroids (ATC code H02) in septic shock in newborns is not recommended. The administration of dexamethasone** (0.5 mg/kg every 2–6 hours) (ATC code H02AB02) via intravenous drug administration or hydrocortisone** (1–2 mg/kg every 6 hours) (ATC code H02AB09) via intravenous drug administration is justified only in refractory septic shock and the presence of clinical and laboratory signs of adrenal insufficiency [133, 135].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Recent guidelines for the diagnosis and management of septic shock in children and newborns contain no indications for prescribing systemic corticosteroids (ATC code H02); however, some studies have revealed minor benefits of hydrocortisone** (ATC code H02AB09) in treating septic shock in patients requiring high doses of inotropic drugs other than cardiac glycosides (ATC code C01C) [136, 183].

• The use of short-acting insulins and their injectable analogues (ATC code A10AB) is recommended to maintain the target blood glucose level at or below 7.8 mmol/L. An absolute indication is a blood glucose level greater than 10 mmol/L when assessed dynamically and in the absence of an effect from reducing the carbohydrate infusion rate [21].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Numerous studies have proven that hyperglycemia is associated with poor outcomes; however, three prospective multicenter randomized controlled trials failed to demonstrate the clinical efficacy of maintaining blood glucose at a low target range in children [21].

• Red blood cell transfusions in hemodynamically stable newborns with sepsis and septic shock are not recommended if the blood hemoglobin concentration is greater than 100 g/L [184, 185].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: Currently, there are no randomized controlled trials and meta-analyses investigating the transfusion of red blood cell components of donor blood in newborns with sepsis and septic shock. In newborns with septic shock requiring invasive mechanical ventilation and hemodynamic drug support, transfusion of leukoreduced red blood cell components of donor blood is indicated if the hemoglobin concentration is below 120 g/L and there is no risk-benefit predominance regarding concomitant organ damage [184, 185, 186].

• Prophylactic fresh frozen plasma transfusion in newborns with sepsis and coagulopathy without bleeding is not recommended [185, 186, 187].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: There are international guidelines on the transfusion of fresh frozen plasma and platelet concentrate in critically ill children, the authors of which consider that fresh frozen plasma transfusion in children with sepsis is not indicated in the absence of hemorrhagic syndrome if the INR is less than 1.5 [185, 187]. Observational studies in critically ill children have shown that fresh frozen plasma transfusion is associated with worse clinical outcomes [184].

• In newborns with sepsis, septic shock, and/or disseminated intravascular coagulation syndrome without signs of bleeding, platelet concentrate transfusion is recommended when the blood platelet count is < 25 x 10⁹/L. In ongoing bleeding, platelet concentrate transfusion is recommended when the blood platelet count is less than 50 x 10⁹/L [185-188].

GCR ALoE 2Grade of Recommendation A (Level of Evidence – 2).

Comment: An association has been demonstrated between platelet transfusions in preterm infants and adverse treatment outcomes – increased incidence of sepsis, necrotizing enterocolitis, intraventricular hemorrhage, longer ICU stay, progression of multiple organ dysfunction, and increased mortality [188]. We believe that in critically ill newborns with sepsis, septic shock, and/or disseminated intravascular coagulation syndrome, platelet concentrate transfusion in the absence of bleeding may be justified only when their count is < 25 × 10⁹/L [185]. In septic shock and bleeding, platelet transfusion is indicated when their count is < 50 × 10⁹/L [187-189].

• In newborns with sepsis and septic shock in the early stages of the disease, to reduce the risk of death, it is recommended to intravenously administer normal human immunoglobulin [IgG+IgM+IgA]** (ATX code J06BA02) [190-193].

GoR ALoE 2Grade of Recommendation A (Level of Evidence – 2).

Comment: Intravenous administration of immunoglobulins (ATX code J06B) in patients with sepsis can reduce mortality and the duration of hospital treatment. Immunoglobulin preparations (ATX code J06B) enriched with IgM were more effective, although this therapy did not have a significant effect on mortality rates in neonatal sepsis [191]. Similar data were obtained by Dinleyici E.C. et al. (2023), who found that mortality rates were significantly lower in patients treated with IgM-enriched immunoglobulin (ATX code J06B) compared to the control group. When evaluating the efficacy of therapy in neonatal studies alone, a significant advantage of prolonged treatment exceeding 3 days was established [192]. There is evidence indicating that prolonged administration (for 7 days) of normal human immunoglobulin [IgG+IgM+IgA]** (ATX code J06BA02) in newborns with very low birth weight diagnosed with sepsis is a safe and effective treatment method and can be considered as adjuvant therapy [190, 191].

3.2 Surgical Treatment

Not applicable

3.3 Other Treatment

Not applicable

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation and sanatorium-resort treatment of newborns with sepsis are carried out taking into account the severity and course characteristics of the underlying disease against which neonatal sepsis developed.

The goal of rehabilitation of newborns with sepsis is the restoration and preservation of health.

Main tasks of rehabilitation of newborns with sepsis:

1. prevention or reduction of the severity of dysfunctions of organs and body systems

2. prevention or reduction of the degree of limitations in life activity, disease progression, and development of complications

3. elimination and correction of emotional and psychological disorders

4. reduction of the severity of disabling consequences of the disease, adaptation to daily household physical loads

5. Prevention and Dispensary Observation

There are currently no effective specific methods for preventing sepsis in newborns.

The single and most effective method for preventing early-onset neonatal sepsis is the treatment of acute and chronic infections of the maternal urogenital tract both before and during pregnancy.

For the prevention of late-onset neonatal sepsis, strict compliance with all sanitary and epidemiological norms and rules is necessary for medical organizations and intensive care units providing care to newborns.

• To reduce the risk of late-onset neonatal sepsis and decrease the duration of parenteral nutrition, early initiation of enteral nutrition with breast milk is recommended for all premature newborns with extremely low birth weight [194].

GRC ALEL 3Grade of Recommendation A (Level of Evidence – 3).

Comment: Breastfeeding helps reduce the duration of parenteral nutrition and is associated with a lower probability of developing late-onset neonatal sepsis in premature newborns with very low and extremely low birth weight [194].

Clinical dispensary observation of newborns with sepsis

Dispensary observation represents an examination of newborns who have undergone sepsis, suffering from any complications or consequences of this disease that have transformed into chronic diseases or functional disorders, carried out with a certain periodicity for the purpose of timely detection, prevention of complications, exacerbations of diseases, their prevention, and implementation of medical rehabilitation of these individuals, carried out in the manner established by the relevant orders.

Dispensary observation of newborns who have undergone sepsis is carried out by medical workers of a medical organization or a structural unit of another organization carrying out medical activities where the child receives primary health care.

6. Organization of Medical Care

Medical care for newborns with sepsis and septic shock aimed at primary stabilization of the condition should be carried out at all stages, starting from the maternity hospital and ending with a specialized Level III hospital.

Indications for inpatient hospitalization:

All newborns with confirmed or suspected sepsis require emergency hospitalization in a specialized Level III hospital with capabilities for emergency diagnosis of the infection focus and treatment of various pathologies. Septic shock is an absolute indication for hospitalization.

A newborn in a hospital lacking such capabilities should be transferred as soon as possible to a medical organization equipped with all modern technologies used in the treatment of sepsis, including the sanitation of the infection focus.

Medical evacuation of newborns with sepsis and septic shock to a medical organization capable of providing the necessary specialized medical care is carried out by specialized emergency transport teams of anesthesiology-resuscitation, air-medical emergency teams, or emergency consultative teams of the ambulance service. In each region, regional rules for emergency transfer and a routing protocol for newborns with sepsis and septic shock must be developed, taking into account available features.

A newborn with clear signs of sepsis or suspicion thereof must be transferred to the intensive care unit.

When providing care to a newborn in the ICU of an adult multidisciplinary hospital, telemedicine consultations with specialists from national medical research centers are justified. If necessary, the possibility of an on-site face-to-face consultation with the performance of necessary diagnostic and therapeutic interventions by staff of national medical research centers should be considered.

Indications for ICU transfer

Since the diagnosis of sepsis in newborns implies the mandatory presence of organ dysfunction, all patients with suspected sepsis must be hospitalized in the ICU, which leads to a decrease in in-hospital mortality.

Indications for transferring a patient from the ICU

After stabilization of the condition, normalization of hemodynamic parameters, and elimination of life-threatening conditions, the earliest possible transfer of the newborn to a specialized pediatric department with experience in treating this category of patients is indicated.

Indications for discharge from the hospital

Discharge of the patient from the hospital is carried out after the normalization of all clinical and laboratory parameters and negative results of bacteriological testing from all sterile biological sites.

7. Additional Information

Not applicable

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Aleksandrovich Yuriy Stanislavovich – Doctor of Medical Sciences, Professor, Chief freelance pediatric specialist anesthesiologist-resuscitologist of the Northwestern Federal District of the Russian Ministry of Health, Head of the Department of Anesthesiology, Intensive Care and Emergency Pediatrics of the Faculty of Postgraduate and Additional Professional Education of the St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, member of the Association of Pediatric Anesthesiologists-Resuscitologists of Russia

2. Balashova Ekaterina Nikolaevna – Candidate of Medical Sciences, Leading Researcher at the Prof. A.G. Antonov ICU of the Neonatology and Pediatrics Institute of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Associate Professor at the Department of Neonatology of the Institute of Professional Education of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, member of the Council of the Russian Society of Neonatologists

3. Boronina Irina Vladimirovna – Candidate of Medical Sciences, Associate Professor, Head of the Department of Anesthesiology and Intensive Care at Voronezh State Medical University named after N.N. Burdenko of the Russian Ministry of Health, Deputy Chief Physician for Neonatology at the Voronezh Regional Clinical Hospital No. 1

4. Zavyalova Anna Nikitichna – Doctor of Medical Sciences, Associate Professor at the Department of Propaedeutics of Children's Diseases with a Course of General Childcare at the St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Dietitian at the Clinic of the St. Petersburg State Pediatric Medical University of the Russian Ministry of Health

5. Zolotareva Lyubov Svyatoslavovna – Candidate of Medical Sciences, Anesthesiologist-Resuscitologist, Senior Researcher at the Department of Pediatric Reconstructive and Plastic Surgery of the Research Institute of Clinical Surgery of the Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation, Medical Methodologist at the Moscow Regional Hospice for Children

6. Ivanov Dmitry Olegovich – Doctor of Medical Sciences, Professor, Rector of the St. Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation, Head of the Department of Neonatology with Courses in Neurology and Obstetrics and Gynecology of the Faculty of Postgraduate and Additional Professional Education of the St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Chief freelance Neonatologist of the Ministry of Health of the Russian Federation.

7. Kirilochev Oleg Konstantinovich – Doctor of Medical Sciences, Associate Professor, Head of the Department of Anesthesiology and Intensive Care at the Astrakhan State Medical University of the Russian Ministry of Health.

8. Lisitsa Ivan Aleksandrovich – Assistant Professor at the Department of General Medical Practice of the St. Petersburg State Pediatric Medical University of the Russian Ministry of Health

9. Makulova Anastasia Ivanovna – Candidate of Medical Sciences, Anesthesiologist-Resuscitologist, Head of the Center for Neonatal Nephrology and Dialysis at the Children's City Clinical Hospital No. 9 named after G.N. Speransky of the Moscow Healthcare Department, Associate Professor at the Department of Pediatrics named after Academician M.Ya. Studenikin of the Faculty of General Medicine at the Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation

10. Mironov Petr Ivanovich – Doctor of Medical Sciences, Professor at the Department of Pediatric Surgery with a Course of the Institute of Additional Professional Education of the Bashkir State Medical University of the Ministry of Health of the Russian Federation.

11. Osokina Regina Agzamovna – Clinical Pharmacologist at the Bakulev National Medical Research Center for Cardiovascular Surgery of the Russian Ministry of Health.

12. Pavlova Ekaterina Yurievna – Assistant, Department of Anesthesiology, Critical Care and Emergency Pediatrics, Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Anesthesiologist-Intensivist, St. Nicholas the Wonderworker Children's City Hospital No. 17

13. Popov Dmitry Alexandrovich – Professor of the Russian Academy of Sciences, Doctor of Medical Sciences, Head of the Microbiological (Bacteriological) Laboratory, A.N. Bakulev National Medical Research Center for Cardiovascular Surgery of the Russian Ministry of Health, Chief Freelance Specialist in Medical Microbiology of the Russian Ministry of Health in the Central Federal District

14. Pshenisnov Konstantin Viktorovich – Doctor of Medical Sciences, Associate Professor, Professor of the Department of Anesthesiology, Critical Care and Emergency Pediatrics, Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Member of the Association of Pediatric Anesthesiologists and Intensivists of Russia

15. Sergeeva Vera Alekseevna – Doctor of Medical Sciences, Associate Professor, Professor of the Department of Anesthesiology, Critical Care and Intensive Therapy, Institute of Continuing Education, Kursk State Medical University of the Russian Ministry of Health

16. Serednyakov Konstantin Vladimirovich – Candidate of Medical Sciences, Associate Professor, Department of Anesthesiology, Critical Care and Emergency Pediatrics, Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Head of the Anesthesiology and Intensive Care Unit, Pediatric Research and Clinical Center for Infectious Diseases of the Federal Medical-Biological Agency

17. Fedorova Larisa Arzumanovna – Candidate of Medical Sciences, Associate Professor, Department of Neonatology with Courses of Neurology and Obstetrics and Gynecology, Faculty of Postgraduate and Additional Professional Education, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used for evidence collection/selection: the evidence base for the recommendations included publications from the Cochrane Library, PubMed, EMBASE, MEDLINE, Scopus, Web of Science, eLibrary, clinicaltrials.gov, electronic libraries, and clinical guidelines hosted by The National Institute for Health and Care Excellence, The European Association of Perinatal Medicine, The European Society for Pediatric Research, The European Foundation for the Care of Newborn Infants, and the European Society for Neonatology. The search depth was 5 years.

During the preparation of the clinical guidelines, key questions were formulated using the PIPOH formula:

– P (population) – patient population and disease characteristics (neonates with sepsis and septic shock)

– I (interventions) – interventions (intensive care measures)

– P (professionals) – target audience of the clinical guidelines (anesthesiologists-intensivists, neonatologists, pediatricians, surgeons, infectious disease specialists)

– O (outcomes) – expected outcomes that can be improved (patient outcomes, healthcare system indicators, epidemiological indicators, etc.);

– H (health care setting) – healthcare setting (outpatient clinic, inpatient facility, ICU)

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

Scales for assessing levels of evidence (LE) (Tables 1, 2) for diagnostic, preventive, therapeutic, and rehabilitation methods (diagnostic, preventive, therapeutic, rehabilitation interventions) with definitions, and the scale for assessing grades of recommendation (GR) (Table 3) for preventive, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions).

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for analysis of evidence.

When selecting publications as potential sources of evidence, the methodology used in each study was examined to ensure its validity. Methodological review was based on questions focusing on study design features that significantly impact the validity of results and conclusions.

To minimize potential subjective errors, each study was evaluated independently by at least two members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not evaluated.

Method of guidelines validation:

• external expert review;

• internal expert review.

Description of the guidelines validation method:

The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.

Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.

The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultation and peer review:

The draft guidelines were reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Target audience for these clinical guidelines:

1. Anesthesiologists-intensivists

2. Neonatologists

3. Pediatricians

4. Infectious disease specialists

5. Clinical pharmacologists

6. Medical students;

7. Residents and interns.

Table 1 – Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2 – Scale for assessing levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural healing factors (preventive, therapeutic, and rehabilitative interventions)

Table 3 – Scale for assessing grades of recommendation (GR) for prevention, diagnosis, treatment, and medical rehabilitation methods, including those based on natural healing factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1. Related Documents

1. Federal Law No. 323-FZ of November 21, 2011 "On the Fundamentals of Public Health Protection in the Russian Federation"

2. Order of the Russian Ministry of Health No. 909n of November 12, 2012, "On Approval of the Rules for the Provision of Medical Care to Children in the Profile 'Anesthesiology and Critical Care'"

3. Order of the Russian Ministry of Health No. 388n of June 20, 2013 (as amended on February 21, 2020) "On Approval of the Rules for the Provision of Ambulance, Including Specialized Ambulance, Medical Care" (Registered with the Ministry of Justice of Russia on August 16, 2013, No. 29422)

4. Order of the Russian Ministry of Health No. 1170n of October 28, 2020, "On Approval of the Rules for the Provision of Medical Care to the Population in the Profile 'Transfusiology'"

5. Order of the Russian Ministry of Health No. 921n of November 15, 2012, "On Approval of the Rules for the Provision of Medical Care in the Profile 'Neonatology'"

6. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."

7. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (World Health Organization), 2019 version.

8. Nomenclature of Medical Services (Order of the Russian Ministry of Health No. 804n of October 13, 2017).

9. List of Vital and Essential Medicines for Medical Use and Minimum Assortment of Medicinal Products Required for Medical Care (Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019).

Appendix A3.2. Indicators of neutropenia in neonates according to birth weight and postconceptional age

Diagnostic criteria for neonatal neutropenia [195]

Appendix A.3.3. Template for justifying the diagnosis of "Neonatal sepsis" for medical record documentation

Justification of the diagnosis of "Neonatal sepsis"

1. Infectious focus: PNEUMONIA, NEC, CONJUNCTIVITIS, OMPHALITIS, MENINGITIS, URINARY TRACT INFECTION (underline as appropriate)

2. Multiple organ dysfunction syndrome (at least 3 systems) (underline the system and signs)

3.Systemic inflammatory response (documented upon detection of2 SIRS signs provided thatoneof them ishematological, or at least3 anysigns) (Underline as appropriate and insert values)

• neutropenia (Manroe et al., 1979., Mouzinho, 1994., Funke A., 2000., Schmutz et al., 2008.,)

Conclusion:

Appendix A3.4. Regimens for systemic antimicrobials (ATC code J) for the treatment of neonatal sepsis

Appendix A3.5. Daily fluid requirement in newborns depending on gestational age and postmenstrual age (ml/g) [118]

Appendix A3.6. Doses of cardiotonic support drugs [132, 201]

Appendix A3.7. Initial parameters of invasive mechanical ventilation depending on the clinical course of the disease [202]

Appendix A3.8. Mean arterial pressure in newborns depending on gestational age and postmenstrual age [203]

Appendix A3.9. Medications used for premedication for endotracheal intubation [30, 137-139]

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Neonatal sepsis is one of the most severe conditions in the neonatal period, with numerous diverse causes. Most often, sepsis develops as a result of intrauterine infection, although in premature infants requiring prolonged treatment in the intensive care unit, the infection may be acquired at a later stage.

Sepsis is diagnosed if a newborn shows signs of a severe infection involving various organ systems. The most common initial symptoms of sepsis include grunting, marked pallor, jaundice, gray or cyanotic skin discoloration, refusal to feed, and extreme lethargy.

The highest risk of severe sepsis is characteristic of premature newborns with low and extremely low birth weight.

If sepsis is diagnosed, your baby will most likely require prolonged treatment in an intensive care unit, where they will be prescribed medications targeting the infectious agent and correcting existing organ dysfunctions.

In severe cases, mechanical ventilation may be required, whereby a special tube connected to a ventilator is inserted into the child's trachea.

If there are no gastrointestinal issues, the baby will be able to receive expressed breast milk through a special tube (feeding tube) inserted into the stomach. Therefore, it is very important for the mother to maintain breast milk supply for as long as possible, as this is the most important and valuable contribution a mother can make to help her baby.

If this is not possible, all nutrition and vitamins will be administered to the infant as liquid medications given intravenously.

Until recently, the mortality rate from neonatal sepsis was extremely high. Today, neonatologists and neonatal intensivists have a powerful arsenal of equipment and medications allowing them to save even the most hopeless patients; however, the prognosis for this disease remains extremely guarded even with the advances of modern neonatology.

Following stabilization in the intensive care unit, prolonged treatment and rehabilitation may be required, both in the hospital and in the coming months after discharge home.

It is very important to understand that sepsis is an extremely serious illness that cannot be cured in a single day; it can be marked by periods of improvement and worsening. Therefore, it is vital to have patience and resilience, maintain calm, show love for your child, retain faith in their recovery, and trust the doctors who will do everything possible to restore their little patient's health.

Remember that your mood directly affects your baby's condition!

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. nSOFA severity score

Russian title: Assessment of the severity of multiple organ dysfunction in newborns

Original title: Neonatal sequential organ failure (nSOFA)

Source (official developer website, validation publication):

Wynn J.L., Polin R.A. A neonatal sequential organ failure assessment score predicts mortality to late-onset sepsis in preterm very low birth weight infants // Pediatr Res. 2020. Vol. 88, № 1.

Type: rating scale

Purpose: assessment of the severity of multiple organ dysfunction in newborns

Content (template)

nSOFA score

1. The nSOFA score in newborns admitted to the ICU is assessed daily

2. The score is calculated by summing the scores of three organ systems (respiratory, cardiovascular, and blood systems).

3. For each system, the worst value recorded during the 24-hour period is used for scoring.

Interpretation: Higher scores are associated with an increased risk of adverse outcomes and mortality.

Appendix G2. Multiple Organ Dysfunction Scoring System for Low Birth Weight Neonates

Russian title: Assessment of the severity of multiple organ dysfunction in low birth weight neonates

Original title: Neonatal Multiple Organ Dysfunction Score (NEOMOD)

Source (official developers' website, validation study): Janota J, Stranák Z, Statecná B, Dohnalová A, Sípek A, Simák J. Characterization of multiple organ dysfunction syndrome in very low birthweight infants: a new sequential scoring system. Shock. 2001 May;15(5):348-52.

Type: rating scale

Purpose: assessment of the severity of multiple organ dysfunction in newborns

Content (template)

NEOMOD score

Interpretation: Higher scores are associated with an increased risk of adverse outcomes and mortality.

Appendix G3. Modified score for assessing the severity of multiple organ dysfunction in newborns

Russian title: Assessment of the severity of multiple organ dysfunction in newborns

Original title: Neonatal Multiple Organ Dysfunction Score (NEOMOD)

Source (official developers' website, validation study): Cetinkaya M., Köksal N., Özkan H. A new scoring system for evaluation of multiple organ dysfunction syndrome in premature infants. Am J Crit Care. 2012 Sep;21(5):328-37.

Type: rating scale

Purpose: assessment of the severity of multiple organ dysfunction in newborns

Content (template)

NEOMOD score

Interpretation: Higher scores are associated with an increased risk of adverse outcomes and mortality.