Bronchopulmonary Dysplasia: Clinical Guidelines

List of Abbreviations

BP – blood pressure

ALT – alanine aminotransferase

AST - aspartate aminotransferase

BPD - bronchopulmonary dysplasia

OBS - obstructive bronchial syndrome

PEM – protein-energy malnutrition

GA – gestational age

PAP – pulmonary artery pressure

VSD – ventricular septal defect

RF - respiratory failure

TV – tidal volume

GI - gastrointestinal tract

MV - mechanical ventilation

ABDS – acid-base balance status

CT – computed tomography

PA – pulmonary artery

PH - pulmonary hypertension

HC – healthcare organization

PDA – patent ductus arteriosus

VLBW - very low birth weight

ARI - acute respiratory infection

PEEP – positive end-expiratory pressure

Pressure)

RV – right ventricle

PEEP – positive end-expiratory pressure

PPHN – persistent pulmonary hypertension of the newborn

PMA – postmenstrual (postconceptual) age

RDS - respiratory distress syndrome

RCT – randomized controlled trial

RSV - respiratory syncytial virus infection

RVSP – right ventricular systolic pressure

sPAP - systolic pulmonary artery pressure

TR - tricuspid regurgitation

CRF - chronic respiratory failure

CNS – central nervous system

RR – respiratory rate

HR – heart rate

ECG - electrocardiography

ELBW - extremely low birth weight

EchoCG – echocardiography

FiO₂ - Fraction of inspired oxygen

INSURE - INtubation – SURfactant – Extubation

IPPV - intermittent positive pressure ventilation

LISA – Less Invasive Surfactant Administration

LUS – Lung ultrasonography score

eLUS – extended version Lung ultrasonography score

MAP – Mean airway pressure

MIST – Minimally Invasive Surfactant Therapy

NCPAP (nCPAP) – Nasal Continuous Positive Airway Pressure (non-invasive mechanical ventilation)

NIPPV – Non-invasive positive pressure ventilation (non-invasive mechanical ventilation)

NT-proBNP – N-terminal pro-brain natriuretic peptide

PaO2 - partial pressure of oxygen

PaCO2 – partial pressure of carbon dioxide

PIP – Peak inspiratory pressure

PPV – Positive pressure ventilation (invasive mechanical ventilation)

SNIPPV – Synchronized non-invasive positive pressure ventilation (non-invasive mechanical ventilation)

CPAP – Continuous Positive Airway Pressure (non-invasive mechanical ventilation)

SpO₂ (peripheral saturation O₂) – peripheral blood oxygen saturation

Terms and Definitions

Prematurity – birth of a child before 37 completed weeks of gestation. Depending on gestational age, preterm newborns are classified as extremely preterm (<28 weeks of gestation), very preterm (28–31 weeks of gestation), moderate preterm (32–33 weeks of gestation), and late preterm (34–36 weeks of gestation).

Very low birth weight (VLBW) – birth weight of 1499 g or less.

Extremely low birth weight (ELBW) – birth weight of 999 g or less.

Postmenstrual age (PMA) or postconceptual age (PCA) – is a measure of a preterm infant's age that combines gestational and postnatal age in weeks, generally used up to 40 weeks. For example, an infant with a gestational age of 23 weeks, 9 weeks after birth, has a postconceptual age of 32 weeks.

Corrected age – a measure of a preterm infant's age used after reaching 40 weeks PCA. Defined as the difference between chronological (actual) age in weeks and the number of weeks missing to reach term gestation. For example, a 6-month-old infant born at 28 weeks of gestation has a corrected age of 24 weeks (6 months) minus 12 weeks = 12 weeks.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Bronchopulmonary dysplasia (BPD) is a chronic diffuse parenchymal (interstitial) lung disease developing in preterm newborns as an outcome of respiratory distress syndrome and/or lung immaturity, diagnosed on the basis of oxygen dependency at 28 days of life and/or 36 weeks of postconceptual age (PCA), persistent parenchymal lung injury confirmed by blood gas analysis and chest radiography (see Section 2 "Criteria for Diagnosing BPD"). It is dangerous due to the development of complications (chronic respiratory failure, acute respiratory failure, protein-energy malnutrition, pulmonary hypertension, cor pulmonale, arterial hypertension), characterized by the regression of clinical manifestations as the child grows, with persistence of morphological changes in lung tissue and impaired external respiration function [1–7].

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

BPD is a multi-etiological disease whose etiology typically involves a combination of multiple causative factors. Among these factors, one can distinguish conditionally manageable (modifiable) and conditionally unmanageable (non-modifiable), exogenous and endogenous factors (Table 1).

The most significant risk factors for BPD are prematurity and very low birth weight [8–14].

Nearly 80% of infants born at 22–24 weeks of gestation are diagnosed with BPD [15], whereas among those born at 28 weeks of gestation, only 20% develop BPD. Among infants with BPD, 95% have VLBW at birth [16]. Other perinatal risk factors include fetal growth restriction [17], male sex, chorioamnionitis, race or ethnicity [9,12,17], as well as smoking [18,19].

Exogenous risk factors for the development of BPD include the use of aggressive respiratory therapy in the early neonatal period, infectious agents, and other factors. Predictive significance for BPD is associated with mechanical ventilation for more than 3 days requiring high settings — FiO2>0.5 and PIP >30 mm H2O [20].

Genetic risk factors may also contribute to the development of BPD, as shown by twin studies [21,22]; the search for genetic markers of BPD is actively ongoing [23–27].

Table 1 – Risk factors for the development of BPD [3,28–30].

The pathogenesis of BPD involves multiple "vicious circles," combining: the damaging effect of the primary disease (RDS and/or pneumonia); the impact of mechanical damaging factors during respiratory therapy (volutrauma, barotrauma, rheotrauma, etc.); exposure to supplemental oxygen; systemic inflammation; and immaturity of the lung tissue [3].

Pathomorphological studies in BPD in children requiring respiratory therapy from birth, especially invasive mechanical ventilation, demonstrate damage to all parts of the respiratory system, including bronchioles, alveoli, interstitial tissue, and blood vessels. The central mechanisms of respiratory regulation, respiratory muscles, and the chest cage framework (including due to osteopenia of prematurity) of the immature infant also suffer [31].

The acute phase of lung injury in BPD (epithelial necrosis of the airways, inflammatory changes) is gradually replaced by fibrotic processes (obliterative bronchiolitis, peribronchial, and intra-alveolar fibrosis) with reactive hypertrophy of the glandular epithelium, proliferation of bronchial muscle tissue, and the development of bronchial hyperreactivity [32]. All of this contributes to impaired air exchange in the lungs due to the formation of atelectasis, emphysema, and "air traps" – thus creating the basis for reduced lung compliance, increased airway resistance and work of breathing, and respiratory failure.

The histological picture of the lungs characteristic of BPD is characterized by decreased alveolar septation and a reduced gas exchange surface area [33–38]. Along with impaired alveolar growth and development, dysmorphic growth of pulmonary capillaries with their remodeling and expansion of lymphatic vessels are observed – these vascular disorders contribute to interstitial pulmonary edema and pulmonary hypertension with subsequent development of right ventricular hypertrophy and dilation (cor pulmonale) [39–41].

Remodeling of bronchopulmonary structures against the background of BPD creates a favorable ground for the child's increased sensitivity to both toxins, inhaled allergens, and irritants (passive smoking, other environmental pollutants) and respiratory infections, especially RSV and rhinovirus, with children with BPD being characterized by a severe course of these infections accompanied by marked bronchial obstruction leading to severe RF [36].

In recent decades, the molecular and genetic mechanisms contributing to the development of BPD have been elucidated. A large number of candidate genes for BPD development have been described, including genes for cytokines and their receptors, Toll-like receptors, proteinases and their inhibitors, antioxidants, surfactant proteins, and the major histocompatibility complex. Associations between mutations in these genes and both the development of various severity forms of the disease and individual resistance to BPD etiological factors have been established [37–41].

In the pathogenesis of BPD complicated by the development of pulmonary hypertension (PH), the significance of biologically active substances associated with effects on the pulmonary vessels has been established. Thus, in the development of this complication, patients showed an increased level of endogenous nitric oxide inhibitor, asymmetric dimethylarginine, which is regarded both as a marker of PH and as a potential therapeutic target in preterm infants with BPD complicated by PH [42,43].

1.3 Epidemiology of the Disease or Condition

The population incidence of BPD in the Russian Federation as a whole is unknown; in individual regions, its incidence ranges from 0.13 to 0.28% among all live-born infants. According to domestic and foreign publications, among preterm infants with a gestational age (GA) < 30 weeks and a birth weight < 1500 g, who constitute the risk group for the disease, the incidence of BPD reaches 20%; with decreasing GA and birth weight, the risk of developing BPD increases [4]. According to the Effective Perinatal Intensive Care in Europe (EPICE) registry, the incidence of BPD in very preterm infants in European countries averages 26.5% (ranging from 12.1% to 47.3% depending on the region), and severe BPD accounts for 42.6% of all newborns with BPD [44]. Over the past few decades, there has been a significant improvement in perinatal outcomes due to the introduction of surfactant and gentle respiratory therapy to reduce lung injury, while the survival rate of extremely preterm infants has increased. Thus, the incidence of BPD has not changed, and it remains a frequent cause of late morbidity in preterm infants. It is estimated that approximately 10,000 infants are diagnosed with BPD annually in the United States [45]. The overall incidence of BPD in infants born at a GA < 28 weeks ranges from 48 to 68%, with the incidence being inversely proportional to GA [46].

1.4 Features of Coding the Disease or Condition

ICD-10 code – P27.1 – Chronic respiratory disease originating in the perinatal period.

Notes: In children with BPD, it is permissible to use the code for respiratory failure (RF) if it persists for more than several weeks or months – J96.1 – Chronic respiratory failure. In case of persistent respiratory symptoms in children with BPD after discharge, the code J44.9 – Chronic obstructive pulmonary disease, unspecified (chronic obstructive airway disease without further specification) may be used. At the age older than 2 years, when bronchiolitis obliterans is verified as an outcome of BPD, the ICD-10 code J44.8 – Other specified chronic obstructive pulmonary disease (corresponding to the diagnosis of "bronchiolitis obliterans") should be used.

1.5 Classification of the disease or condition

According to the criteria of the working group on BPD of the National Institute of Child Health and Human Development (NICHD), the National Heart, Lung, and Blood Institute (NHLBI), and the Office of Rare Diseases (ORD) of the USA (2001), the severity and further course of BPD are determined by the degree of oxygen dependency assessed at 36 weeks postmenstrual age (PMA) (in infants born at a gestational age of less than 32 weeks), on the 56th day of life (in infants with a gestational age of more than 32 weeks), or at discharge, whichever comes first (Table 2).

Table 2. Classification of BPD severity [47].

¹One day of treatment is defined as oxygen therapy lasting at least 12 hours.

²This classification includes infants with a GA ≥ 32 weeks; currently, the development of BPD in infants with a GA ≥ 33 weeks is extremely rare.

In 2016, NICHD (USA) proposed a new classification of BPD that takes into account new non-invasive mechanical ventilation methods not included in previous definitions. It is proposed to use new terms: "severity grade I, II, III", with grade III referring to the most severe form of BPD (Table 3).

Table 3. Proposed refinements for defining BPD severity (at 36 weeks PMA) [1].

^{1 -} excluding newborns who undergo mechanical ventilation for a primary airway disease or diseases associated with respiratory center lesions, or neuromuscular diseases. O₂ concentrations are indicated in %.

In clinical practice, it is permissible to use both classifications (one complements the other).

Complications include chronic RF, pulmonary hypertension (PH), systemic arterial hypertension, and others (Table 4) [48].

Table 4. Complications of bronchopulmonary dysplasia and their diagnostic criteria

¹ - Appendix A3.2. Values of systolic, diastolic, and mean blood pressure in preterm infants depending on postmenstrual age (95th percentile, mm Hg).

Currently, when formulating a diagnosis, distinguishing the form of the disease (classical or new BPD) is considered impractical, since in practical work, an exact separation of these forms is difficult. In the postneonatal period, the diagnosis of BPD is established before the child reaches the age of 2 years; after this age, the disease is indicated in the diagnosis as having occurred in the past.

1.6 Clinical presentation of the disease or condition

The clinical presentation of BPD in preterm newborns is represented by symptoms of chronic respiratory failure. BPD symptoms are non-specific and can be observed in many lung diseases. Clinical signs that make one suspect the initial phase of BPD in a preterm infant usually appear against the background of RDS requiring respiratory support [49].

Predictors of classical BPD development are generally considered to include the forced use of "aggressive" ventilation parameters and high O₂ concentrations for more than 6–7 days. When attempting to reduce the parameters in the infant, an increase in RF is noted, since already in this period lung compliance decreases, the number of capillaries decreases, and edema and fibrosis of the pulmonary interstitium begin to develop.

A feature of the clinical presentation of BPD against the background of the widespread introduction of protective respiratory technologies is the late, delayed onset and gradual development of the disease: after initial clinical improvement, often associated with surfactant administration to a newborn with RDS, there is no positive dynamics in the second to third week of life, persistent respiratory failure develops with increasing oxygen dependency and the appearance of hypoxemia episodes.

In some cases, the severity of RF gradually decreases, the infant may do without assisted ventilation and even without oxygen supplementation (the so-called "honeymoon" period), but after a short time, signs of RF reappear and worsen [50].

Reintubations are a risk factor for a severe course of the disease [51].

During the examination of the patient at the stage of BPD development, changes in the shape of the chest can be noted—it becomes barrel-shaped; mixed or expiratory dyspnea is present, involving accessory muscles, retraction of compliant chest areas, and tachypnea (RR = 80–100 breaths/min). Apnea episodes with the development of bradycardia are possible. The skin of the sick infant is usually pale with a cyanotic tint; cyanosis increases with exertion. Percussion of the chest reveals a box-like percussion sound. Chest percussion is not performed in VLBW and ELBW infants due to the risk of intracranial hemorrhage. The auscultatory picture of BPD is characterized by weakened breath sounds and crepitations, reflecting the development of interstitial edema, as well as the appearance of wheezing and fine moist rales, regardless of the presence or absence of heart failure. Manifestations of bronchoobstructive syndrome (BOS) in premature infants with BPD include episodes of oxygen desaturation clinically accompanied by wheezing, weakened breath sounds, expiratory difficulty, chest rigidity, decreased compliance, and increased airway resistance.

By the time the patient is discharged from the neonatal unit, moderate dyspnea and auscultatory signs of persistent bronchoobstructive syndrome persist in moderate and severe forms of BPD (varying in severity, which may increase with infant agitation). Usually, children with these forms of BPD retain a tendency toward gastrointestinal dyskinesias (regurgitation, vomiting) regardless of the type of feeding, and may show signs of protein-energy malnutrition (PEM), the cause of which—despite adequate caloric intake and feed volume—is uncorrected chronic hypoxemia.

During the first 6–12 months of life, even in the absence of superimposed acute respiratory infections, children with BPD may periodically experience episodes of bronchial obstruction. Laboratory and instrumental diagnostic examinations are necessary to assess the severity of BPD and its complications, predict the clinical course, and select therapy.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criteria for establishing a diagnosis of BPD are [4]:

- prematurity (the vast majority of children have a gestational age <32 weeks);

- persistent parenchymal lung damage confirmed by blood gas analysis (hypoxemia, hypercapnia) and chest radiography (decreased aeration, emphysema, ribbon-like opacities);

- need for invasive/non-invasive mechanical ventilation, continuous positive airway pressure (CPAP) respiratory support, or oxygen supplementation via nasal cannula at 28 days of life and/or 36 weeks postmenstrual age with an oxygen concentration (FiO₂) greater than 0.21 for more than 3 consecutive days to maintain blood hemoglobin oxygen saturation levels in the range of 90–95% (excluding newborns receiving mechanical ventilation for another respiratory tract disease or other conditions associated with respiratory center impairment or neuromuscular diseases).

At 36 weeks PMA, the diagnosis is formulated indicating the degree of severity (mild, moderate, severe form).

2.1 Complaints and Anamnesis

When taking the medical history of a patient with suspected BPD, attention should be paid to the risk factors for this disease, primarily prematurity ≤ 32 weeks and birth weight [19,52]. It is important to consider the characteristics of the intranatally and neonatal periods (suffered intrapartum asphyxia, severity of RDS, duration and method of respiratory therapy, history of infection, incl. sepsis and pneumonia, especially complicated by air leak syndrome and the presence of a hemodynamically significant patent ductus arteriosus) [53–55]. Among the complaints (from parents), special attention is required for the infant's labored and rapid breathing, retraction of compliant areas of the chest, pale and/or cyanotic skin tone of the child, reduced exercise tolerance (suckling, crying), and episodes of cyanosis.

2.2 Physical Examination

• A newborn with BPD and suspected development of BPD is recommended to undergo a visual therapeutic examination [4].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comments: The visual therapeutic examination includes:

- assessment of chest shape and participation of accessory muscles in the respiratory act;

- assessment of respiratory rate;

- assessment of heart rate;

- assessment of auscultatory findings.

Typical clinical signs for children with BPD include: tachypnea (respiratory rate greater than 60–70 breaths per minute), a tendency toward tachycardia with a heart rate greater than 160 beats per minute, unevenly harsh breath sounds on auscultation, and signs of bronchial obstruction—prolonged and reinforced expiration, and dry wheezes.

Percussion is feasible only in premature infants with a body weight ≥1500 g, because in infants with lower weight, percussion can provoke complications (see "Section 1.6 Clinical Picture").

2.3 Laboratory Diagnostics

Comment: Specific changes may be absent in uncomplicated BPD. Evaluation of the complete blood count allows for differential diagnosis between BPD and acute respiratory infections [58,59]. The test is also performed during dynamic follow-up. The frequency is determined by the clinical situation.

Comment: depending on the severity of BPD, the biochemical blood test may reveal the following changes: electrolyte disturbances (most commonly decreased potassium, chlorine, sodium, and calcium levels, especially in infants receiving diuretics and glucocorticoids); decreased total protein and albumin levels, and increased alkaline phosphatase activity (mostly against the background of developing malnutrition and osteopenia of prematurity). The frequency of biochemical blood testing in hospitalized children is on average once a month. The test may also be performed during dynamic follow-up when indicated (see Section 3). In mild forms of BPD outside periods of respiratory infections, performing a general biochemical blood test is not mandatory.

Comment: ABB and blood gas analysis allow the severity of respiratory failure to be assessed (Appendix A3.3).

As a rule, hypoxemia, respiratory acidosis (mixed acidosis is possible in severe BPD), hypercapnia, and an increase in serum bicarbonate are detected. Compensatory changes—metabolic alkalosis with base excess—may be present. Determination of the partial pressure of oxygen in capillary blood is of little informative value for selecting the concentration of supplemental oxygen in the supplied gas-air mixture; it should be supplemented by determining the oxygen saturation of hemoglobin using a pulse oximeter (see "Section 2.4 Instrumental Diagnostic Examinations"). The frequency of examinations is determined individually.

Comment: dynamic determination of NT-proBNP can be used in patients with pulmonary hypertension as one of the criteria for the severity of PH manifestations and the efficacy of ongoing therapy. The frequency of the study is determined individually.

2.4 Instrumental Diagnostics

Comment: pulse oximetry monitoring of hemoglobin oxygen saturation allows for the diagnosis of hypoxemia episodes during physical exertion, increased bronchospasm, concurrent comorbidities, or respiratory infections. Monitoring hemoglobin oxygen saturation is most critical in prolonged oxygen dependency and pulmonary hypertension. To determine the indication for long-term home oxygen therapy, the duration of prolonged pulse oximetry must be at least 6 hours, mandatory encompassing periods of sleep, wakefulness, and feeding. In crisis-type pulmonary hypertension (PH), simultaneous pre- and post-ductal hemoglobin oxygen saturation monitoring can serve as an additional diagnostic method to assess the severity of PH and the likelihood of suprasystemic elevation of systolic pulmonary artery pressure. Pulse oximetry has limitations, as the accuracy of SpO₂ readings can be affected by various patient conditions (arterial hypertension, vasodilation, infant movement, etc.) as well as environmental factors (bright lighting, electromagnetic interference, etc.).

Comment: in the early stages of the disease, typical radiological findings of BPD are often absent; by the 3rd–4th week of life, diffuse decreased aeration (resulting from pulmonary interstitial edema) is observed. As the process progresses, a heterogeneous radiological pattern typically emerges, characterized by alternating areas of intact tissue with areas of emphysema (including interstitial) and atelectasis. As the disease progresses, lung hyperinflation increases; areas of hyperinflation alternate with migratory atelectases and ribbon-like opacities. With the progression of pulmonary hypertension and the development of cardiomegaly, the latter is also detected on radiographs. To assess the severity of radiographic changes in BPD, the scoring scale by A. Greenough et al. is used[62]. High scores on this scale (Appendix G1) correlate with clinical signs of the disease and allow for predicting the persistence of oxygen dependency at 36 weeks postmenstrual age (PMA) and the recurrence of respiratory symptoms at 6 months of corrected age.

The frequency of radiography is determined individually, but is typically no less than 1–2 times per month while the child is in the neonatal intensive care unit.

When performing chest radiography in infants in their first months of life, the total radiation dose (including the predicted dose) must be taken into account.

Comment: Chest CT is associated with a significant radiation dose; therefore, indications for this study are limited to cases requiring differential diagnosis when concomitant diseases are suspected [66,72].

CT is indicated in the following cases [4,48,49,66,76,77]:

- when differential diagnosis from other bronchopulmonary pathologies is required, including interstitial lung diseases (e.g., congenital surfactant protein deficiency, Wilson-Mikity syndrome, etc.);

- in recurrent pneumothoraces;

- when bronchiolitis obliterans as an outcome of BPD is suspected (in children older than 2 years with persistent symptoms of respiratory failure and auscultatory findings);

- to rule out congenital lung malformations (tracheobronchomalacia, congenital cystic adenomatoid malformation, Campbell de Morgan / Wilson-Mikity syndrome, etc.)[72].

Chest CT makes it possible to detect lung tissue changes that are not visible on a standard chest radiograph, as well as to clarify the predominant localization of pathological changes and the degree of pulmonary fibrosis. Tomographic scans reveal areas of increased lucency combined with linear (ribbon-like) and triangular subpleural opacities. Opacities reflect fibrotic processes, while areas of lucency reflect the degree of hyperinflation and simplification of alveolar structures. The severity of linear opacities reflects the intensity of fibrosis, which does not always correlate with clinical symptoms.

Chest CT also provides the opportunity to assess the bronchial tree and detect its abnormalities (e.g., bronchial wall thickening, traction bronchiectasis).

When evaluating CT data in patients with BPD, the scoring scale [Appendix G2] may be used.

Comment: electrocardiography reveals signs of right ventricular overload in the early stages of PH development, but it is not highly sensitive [48,49], as the absence of ECG changes does not rule out the development of PH. A sign of right heart overload is a tall P wave. ECG is used as an additional diagnostic method. The study may be performed during follow-up monitoring as clinically indicated (presence/suspicion of cardiac pathology).

Comment: EchoCG may be performed during follow-up monitoring as clinically indicated (presence/suspicion of cardiac pathology, therapy monitoring).

The interpretation of EchoCG results for the diagnosis of PH is presented in Tables 5 and 6.

Table 5. Echocardiographic criteria for pulmonary hypertension at a corrected age older than 3 months. [81].

¹ In the absence of tricuspid regurgitation and in the presence of a patent ductus arteriosus (PDA) or ventricular septal defect (VSD), right ventricular pressure can be calculated using Doppler assessment of the direction and velocity of blood flow across the PDA or VSD [82].

Depending on the direction of shunting across the PDA/VSD, the following variants are possible:

o Bidirectional shunt

PASP = Systolic BP (right and left ventricular pressures are equal)

o Right-to-left shunt (from pulmonary artery to aorta)

PASP > Systolic BP (systolic pressure in the pulmonary artery is higher than systemic pressure)

PASP = Systolic BP + pressure gradient across the PDA

o Left-to-right shunt (PDA from aorta to PA)

PASP < Systolic BP (systolic pressure in the pulmonary artery is lower than systemic pressure)

PASP = Systolic BP - aorta/PA gradient

² Additional (indirect) echocardiographic signs of PH that increase confidence in the presence of PH include the following [4]:

- increased flow velocity of pulmonary valve regurgitation;

- short acceleration time of right ventricular ejection into the pulmonary artery;

- enlargement (dilation) of the right heart chambers associated with their diastolic overload;

- abnormal shape (distortion) and function (dyskinesia) of the interventricular septum, characterizing RV systolic overload (a round left ventricle indicates that PA pressure is lower than systemic pressure, a round RV indicates that PA pressure exceeds systemic pressure, and a flattened septum indicates PA pressure equal to systemic pressure);

- dilatation of the pulmonary artery trunk;

- presence of a low-velocity flow, bidirectional or right-to-left blood shunting through the foramen ovale, intracardiac shunts, or patent ductus arteriosus;

- hypertrophy of the RV wall and interventricular septum;

- increase in the left ventricular eccentricity index (ratio of the left ventricular diameters perpendicular and parallel to the septum);

- increase in the ratio of systole to diastole duration across the tricuspid valve.

Table 6. Severity grades of pulmonary hypertension according to echocardiography [4,83].

Notes: RV size, hypertrophy, and function will depend on the duration of PH, and their values should not be used as parameters for assessing RV pressure, but can be used to confirm PH. LV — left ventricle; IVS — interventricular septum; PDA — patent ductus arteriosus; RV — right ventricle; RVSP — right ventricular systolic pressure; TR — tricuspid regurgitation.

• In newborns with suspected BPD development, it is recommended to selectively assess the parenchyma condition using the LUS or eLUS lung ultrasound scale (Appendix G3) for risk stratification of moderate-to-severe BPD [84–90].

GCR ALeE 2Grade of Recommendation A (Level of Evidence - 2)

Comment: Ultrasound assessment of the lung parenchyma on days 7 and 14 of life has a high predictive value for the development of moderate-to-severe BPD when scored 8 or higher on the LUS scale and 14 or higher on the eLUS scale, which may influence the choice of earlier and more active preventive and therapeutic management (Appendix G3). The method has proven its informativeness in the cohort of newborns at 32 weeks of gestation or less [84–94].

Comments: The decision to perform this study is made depending on the indications, capabilities, and experience of a particular medical organization (MO). Currently, there is no convincing evidence supporting the widespread use of bronchophonography.

2.5 Other Procedures

Comment:

Indications for this study may include:

- addressing the issue of discontinuing home oxygen therapy

- flat weight curve

- presence of PH

- suspected obstructive apnea/hypopnea

- determination of sleep quality, as it affects the neurosomatic development of the child.

The decision to perform this study is made depending on the capabilities and experience of a particular medical organization (MO).

During sleep as part of the polysomnographic study, synchronous recording of pulse oximetry (SpO₂), electroencephalography (including video-monitoring), electromyography (cutaneous electromyography [one anatomical site]), electrooculography, heart rate, airflow, and respiratory effort can be performed. This study allows for the detection of, among other things, episodes of bronchial obstruction and apnea.

Interpretation of polysomnography results in infants may be difficult due to the uncertainty of age-specific normative values for this study; the most informative criteria are the number and duration of apneas, as well as the detection of periodic breathing [101]. Central sleep-related breathing disorders in children with BPD rapidly normalize with low-flow home oxygen therapy via nasal cannulas and improve with age[73].

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

3.1 Conservative Treatment

3.1.1. Respiratory therapy / oxygen therapy

• In children with BPD and suspected BPD, it is recommended to perform respiratory therapy under the control of acid-base balance and blood gases to relieve respiratory failure and eliminate hypoxemia [102].

GCR ALOE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: The choice of respiratory therapy method is made individually depending on indications. To reduce ventilator-induced lung injury in children with BPD, acceptable pH and PaCO₂ values under any type of respiratory therapy can be within the range of moderate (permissive) acidosis and permissive hypercapnia [103–105]. The approximate range of permissive acidosis is considered to be a blood pH of 7.25–7.35, and permissive hypercapnia a PaCO₄ of 45–60 mmHg. If a child with BPD requires invasive mechanical ventilation, the mode and parameters of ventilation are determined individually based on the clinical and radiological picture and the stage of the disease. With a stable decrease in oxygen requirement below 40% in a child on mechanical ventilation, transition to non-invasive respiratory therapy—non-invasive positive pressure ventilation, CPAP—is advisable [4,106,107].

Extubation criteria:

- absence of airway anomalies, tracheo-, laryngo-, and bronchomalacia;

- FiO₂ ≤0.4 for at least 48 hours;

- stable oxygenation during handling and feeding;

- stable weight gain for 5–7 days prior to extubation;

- full enteral feeding;

- absence of signs of an active infectious process and failed extubation attempts during the previous 48 hours.

Comments: A patient with BPD is recommended to maintain target hemoglobin oxygen saturation within 91–95% to prevent the development of pulmonary hypertension and cor pulmonale [74,75]. Long-term oxygen therapy is recommended for children with severe BPD complicated by grade II–III respiratory failure (Appendix A3.3) and/or pulmonary hypertension. In children with PH who require oxygen therapy, it is recommended to maintain higher target preductal SpO₂ values—within 92–96%. When oxygen demand drops below 25–30%, it is advisable to switch to O₂ delivery via low-flow nasal cannulas followed by gradual withdrawal [72,100,108].

Long-term oxygen therapy in children with chronic hypoxemia due to BPD is performed at home using an oxygen concentrator monitored by pulse oximetry around the clock via nasal cannulas at SpO₂ <90–92% (in the presence of PH at SpO₂ <92–94%). These SpO₂ values, regarded as indications for prolonged oxygen therapy, must be maintained at the specified level for at least 5% of the total duration of prolonged pulse oximetry (see section 2.4 "Instrumental Diagnostic Examinations"). When deciding on oxygen therapy, SpO₂ measurements should be taken for at least 6–12 hours, necessarily both during sleep and during wakefulness and feeding. The lower limit of SpO₂ must be recorded for at least 95% of the entire duration of the recording [109,110].

If oxygen-dependent children without PH can maintain SpO₂ above 92% on room air for 2 hours, and the oxygen flow rate via nasal cannulas is less than 0.1–0.2 L/min, they can be gradually weaned off supplemental oxygen during wakefulness and subsequently during sleep [4].

• For children with BPD and those suspected of developing BPD who require prolonged invasive mechanical ventilation, it is recommended to adapt ventilation modes and parameters according to the pathophysiological changes in pulmonary mechanics to prevent further lung injury and ensure tissue repair [4,111,112].

GCR CLEL 5Level of recommendation evidence C (level of data reliability 5).

Comments: Most cases of severe BPD are characterized by the predominance of increased airway resistance with relatively normal compliance, which determines functional similarities to bronchial asthma and severe acute bronchiolitis. High resistance, in turn, determines a relatively long time constant. Anatomically and functionally, the lungs in BPD are heterogeneous, with alternating areas of functionally preserved lung tissue and areas of emphysematous distension, interstitial emphysema, and, conversely, areas of consolidation and migrating atelectasis.

Traditional mechanical ventilation parameters recommended for children with severe BPD include: prolonged inspiratory time from 0.45 to 0.6–0.7 s, low mandatory respiratory rate from 30 down to 17–20 breaths/min, high Vte values from 8 to 12 mL/kg to achieve adequate minute ventilation and prevent air trapping, and a PEEP of at least 5–6 cm H2O (in individual cases, up to 6–8 cm H2O).

During mechanical ventilation, it is important to account for the long time constant required for adequate ventilation of affected lung areas and to achieve an optimal ventilation-perfusion ratio. Applying a ventilation strategy with a high tidal volume, low ventilator cycle rate, and long expiration helps normalize ventilation-perfusion ratios, ensures the emptying of affected alveoli, prevents air trapping, promotes lung tissue repair, and achieves adequate neurological development goals by providing respiratory comfort and reducing the need for sedation. Currently, the evidence base for the low-frequency, high-tidal-volume ventilation strategy is insufficient, but this strategy is well-supported by clinical experience and aligns with the current understanding of the pathophysiology of severe BPD[112].

Monitoring flow curves and flow-volume loops can help determine whether expiratory flow is completed before the next breath is initiated; the goal of ventilation is to provide sufficient time for complete lung emptying.

In a small number of patients, the high tidal volume (TV) and low-frequency strategy is ineffective. In such cases, rarer but significant causes of hypoxemia and ventilation-perfusion mismatch should be considered. In the restrictive lung disease pattern (which may dominate in a small number of children), ventilation with a low TV and/or increased positive end-expiratory pressure is effective. Additionally, in patients with tracheobronchomalacia as the primary pathology, an increased PEEP level to stent the airways during the expiratory phase (up to 6–8 cm H2O) is also justified. Another significant cause of impaired ventilation-perfusion ratios is pulmonary hypertension. Therefore, in patients who do not respond to high TV and low frequency with a decreased oxygen requirement, and in those who cannot be successfully weaned from mechanical ventilation for a prolonged period, alternative approaches should be tried empirically.

Differences in radiological findings, pulmonary mechanics, and respiratory strategies in RDS and BPD are presented in Appendix A3.4.

3.1.2. Pharmacotherapy

3.1.2.1 Glucocorticoids

Comments: The prescription of #dexamethasone** (ATX code H02AB) for the treatment of BPD should be considered in infants who continue to require invasive mechanical ventilation at >28 days of life and/or >36 weeks PMA (if prior glucocorticoid therapy (ATX code H02AB) for BPD prevention was not administered or was ineffective), as well as in those with a persistent need for non-invasive respiratory support at >40 weeks PMA [72,113]. In clinical practice, it is difficult to distinguish between the therapeutic and prophylactic administration of #dexamethasone** (ATX code H02AB). Based on the time criterion for diagnosis, the indications for prescribing the drug for BPD prevention are covered separately in the relevant section (Section 5).

An important factor when deciding to prescribe #dexamethasone** (ATX code H02AB) is the risk-benefit balance. Significant adverse effects include neurological sequelae, arterial hypertension, metabolic disorders (hyperglycemia), and sepsis. Since BPD itself is a risk factor for neurodevelopmental impairment, the administration of #dexamethasone** (ATX code H02AB) is justified for patients with a > 60% risk of developing the disease, and the optimal therapeutic "window" is considered to be between 2 and 7 weeks of life.

The most commonly used dosing regimen is: total course dose of #dexamethasone** (ATX code H02AB) — 0.89 mg/kg. Starting dose of #dexamethasone** (ATX code H02AB) is 0.15 mg/day (days 1–3), on days 4–6 — 0.1 mg/kg/day, days 7–8 — 0.05 mg/kg/day, days 9–10 — 0.02 mg/kg/day [4,114].

Treatment efficacy is assessed on day 3 from treatment initiation. If FiO₂ and PIP decrease, administration is continued according to this regimen. If no effect is observed during the first 3 days, the dose is increased on day 4 to 0.3 mg/kg/day for 3 days (days 4–6). Subsequently, the dose is tapered: 0.15 mg/kg/day (days 7–9), 0.1 mg/kg/day on days 10–12, 0.05 mg/kg/day on days 13–14, and 0.02 mg/kg/day on days 15–16 [4,114].

If necessary, repeated courses are administered with an interval of 1–2 weeks. A repeat course of #dexamethasone** (ATX code H02AB) for BPD is less effective compared to the prophylactic course [113].

If adverse effects occur, dosage modification, adjustment of administration frequency, or discontinuation of the drug may be performed.

If a patient who was on invasive mechanical ventilation is successfully extubated while receiving #dexamethasone** (ATX code H02AB) therapy before completing the full course, the duration of the course may be shortened [115].

Treatment with #dexamethasone** (ATX code H02AB) is carried out under the monitoring of blood pressure, blood glucose levels, echocardiography, and bacterial infection markers.

3.1.2.2 Other drugs for obstructive airway diseases for inhalation.

Comment: Routine prescription of inhaled glucocorticoids (ATX code R03BA) for the treatment and prevention of BPD is not used.

Inhalation of #budesonide** (ATX code R03BA) is indicated:

- in children with BPD who meet the criteria for glucocorticoid administration (ATX code H02AB) in the presence of contraindications;

- in the presence of symptoms of bronchial obstruction;

- in cases of recurrent bronchial obstruction during the first and second years of life;

- if a child with BPD develops bronchial asthma.

For the inhalation of #budesonide** (ATX code R03BA), compressor or (preferably) mesh nebulizers are used.

Ultrasonic nebulizers destroy the suspension.

The dose of #budesonide** (ATX code R03BA) is 500 mcg/day once or divided into two inhalations (in the presence of bronchial obstruction syndrome) [4].

A family history of bronchial asthma may be a predictor of a good response to therapy with #budesonide**(ATX code R03BA). The usual duration of a course for BPD is 2 weeks. When prescribing #budesonide**(ATX code R03BA) for a longer course, regular evaluation of its efficacy is required. A decrease in the severity of respiratory failure (RF) and bronchial obstruction syndrome (BOS) will indicate the efficacy of therapy [4].

Comment: the prescription of this type of therapy may be indicated for children with clinically significant signs of bronchial obstruction syndrome, children with severe BPD with exercise intolerance and the need for repeated hospitalizations to relieve bronchial obstruction [72,116]. When prescribing inhalation drugs with bronchodilator properties, it is necessary to evaluate their efficacy. A decrease in the respiratory rate and an increase in SpO₂ after inhalation will indicate the efficacy of therapy [4,117]. #Ipratropium bromide + fenoterol** (ATX code R03AL) in a single dose of 1 drop/kg of the child's body weight per inhalation via a nebulizer, dissolved in 2 ml of sodium chloride** (ATX code B05XA) – a solution for infusion or injection 0.9% [117,118]. #Salbutamol** (ATX code R03AC02) 0.1-0.5 mg every 6 hours (when using a nebulizer/mesh nebulizer), #ipratropium bromide** (ATX code R03BB01) when using a metered-dose inhaler with a spacer: 1 dose (20 mcg) x 3-4 times/day[120]. When using a nebulizer/mesh nebulizer: 75-175 mcg every 6-8 hours [117]. A combination of #ipratropium bromide** and #salbutamol** in a single dose of 175 mcg and 0.04 mg, respectively, is possible [121]. It should be noted that the bronchodilator effect of the drugs listed above lasts, on average, 4-6 hours.

3.1.2.3 Diuretics

Comment: diuretics (ATX code C03) may be prescribed in the presence of:

- heart failure;

- left ventricular diastolic dysfunction according to echocardiography, manifested clinically by recurrent pulmonary edema;

- interstitial pulmonary edema on chest X-rays;

- excessive weight gain.

Sulfonamides are used – #furosemide** (ATX code C03CA), a single parenteral dose is 1 mg/kg, for as short a course as possible to avoid adverse events (nephrocalcinosis, electrolyte and metabolic disorders)[4].

If long-term diuretic therapy is necessary, it is recommended to use #hydrochlorothiazide** (ATX code C03AA) – 3-4 mg/kg per day and/or #spironolactone** (ATX code C03DA) – 2-4 mg/kg per day [4,72].

3.2.1.4 Xanthine derivatives

Comment: in children with BPD, the aforementioned and other effects of caffeine citrate (ATX code N06BC) help reduce the duration of mechanical ventilation and respiratory support in general. Early administration of caffeine citrate (ATX code N06BC) is associated with a decrease in the frequency and severity of BPD. For drug doses, see section 5.1 "Prevention". The optimal duration of treatment with caffeine citrate (ATX code N06BC) has not been established; in clinical practice, treatment may be continued up to 33–37 weeks of postmenstrual age (PMA), and in individual cases, the duration of the course is determined individually depending on the response to treatment, the presence of apnea episodes, and other considerations. The presence of BPD is a risk factor for the persistence of apnea after 37 weeks of PMA.

3.2 Surgical Treatment

Not applicable

3.3 Other Treatment

3.3.1. Diet therapy (nutritional support)

Comments: moderate fluid restriction within 130-150 ml/kg/day is recommended until a body weight of 2000 grams is reached. However, it is necessary to take into account the need for adequate nutritional support to meet increased plastic and energy requirements, as well as the patient's age and condition [4,104].

Comments: To ensure increased protein and calorie supply, extremely preterm infants require multicomponent fortification of breast milk, or (in the absence of maternal breast milk) the use of high-calorie specialized formulas for feeding preterm infants, as well as therapeutic formulas prescribed for protein-energy malnutrition.

Comments: infants with severe BPD are at high risk for malnutrition and osteopenia of prematurity due to high work of breathing, low exercise tolerance, chronic hypoxemia, and the need to restrict daily fluid intake [127]. To ensure linear growth, lung growth, and repair of damaged tissue, infants with BPD require a relatively higher protein intake (in the upper range of the recommended age norm). High-protein and high-calorie enteral formulas are used for nutritional support in infants with BPD. The recommended daily calorie intake for BPD should be at least 130–140 kcal/kg, aiming to provide the maximum number of calories in the minimum volume [99].

Poor weight gain despite a hypercaloric diet indicates chronic hypoxemia and is one of the criteria for the need to continue oxygen therapy [127,134,135].

If enteral feeding is difficult, supplementation via parenteral nutrition is recommended (dextrose** (ATX code B05CX), amino acids for parenteral nutrition** (ATX code V06DD), lipid emulsions for parenteral nutrition** (ATX code B05BA)) [4,127,134].

Complementary foods are introduced in accordance with corrected age, taking into account comorbid conditions (dysphagia, gastrointestinal dysfunctions, food allergy)[133].

3.3.2. Blood transfusion

• For preterm infants with BPD requiring respiratory therapy and/or oxygen therapy, it is recommended to avoid hemic hypoxia and maintain an optimal level of oxygen delivery, if necessary by means of blood transfusions of red blood cell-containing blood components [136].

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

Comments: There is currently evidence that systemic oxygen delivery improves and oxygen consumption decreases in oxygen-dependent infants with bronchopulmonary dysplasia when the hematocrit is maintained above 0.35-0.40 [136,137]. Due to the increased metabolic demands in infants with BPD associated with low arterial oxygen tension, it is important to maintain a relatively high hemoglobin concentration in the blood. It is important to keep in mind that limiting phlebotomy losses is an effective and safe measure for the prevention of anemia [138].

3.3.3. Treatment of PH in BPD (Appendix B2)

• For children with chronic pulmonary hypertension (PH) against the background of BPD, long-term oxygen therapy is recommended to reduce pulmonary vascular resistance and eliminate hypoxemia [4,139].

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

Comments: Oxygen induces selective pulmonary vasodilation via direct activation of calcium-activated K+ channels and enhanced NO production after birth. Hypoxemia, both intermittent and prolonged, remains an important cause and contributing factor to PH in patients with BPD [4]. In children with PH requiring oxygen therapy, it is recommended to maintain target SpO₂ values within 92-96%.

• Children with chronic PH associated with BPD are recommended the selective prescription of urological drugs (ATX code G04B) – #sildenafil – as first-line vasodilator therapy for PH to normalize sPAP and eliminate hypoxemia [140–143].

Level of Evidence AGrade of Recommendation 1Level of Recommendation A (Level of Evidence — 1)

Comments: The use of #sildenafil (ATC code G04B) is indicated when oxygen therapy is ineffective for 4 weeks to normalize pulmonary artery pressure. #Sildenafil (ATC code G04B) selectively inhibits cGMP-specific phosphodiesterase type 5, which produces a pronounced vasodilating effect and reduces pulmonary artery pressure. According to recent studies, a #sildenafil (ATC code G04B) dose of 1-2 mg/kg/day administered orally in 3-4 doses provides the best effect in reducing systolic pulmonary artery pressure without causing severe adverse effects [142]. The maximum safe dose is 5 mg/kg/day in 4 doses for children under 1 year old and in 3 doses per day for children aged 1 to 2 years. If 2nd- and 3rd-line pulmonary hypertension therapies are unavailable, the maximum possible dose of #sildenafil (ATC code G04B) may be increased to 8 mg/kg/day [140].

When prescribing this drug, continuous monitoring of blood pressure and oxygenation levels is required; echocardiography allows assessment of treatment efficacy (see Section 2.4 Instrumental Diagnostic Procedures).

#Sildenafil (ATX code G04B) is generally well tolerated when used at recommended doses, with systemic hypotension being the most frequent adverse effect. The dosage of #sildenafil (ATX code G04B) should be adjusted clinically, as serum levels vary due to clearance rates; special attention should be paid to the concomitant administration of fluconazole** (ATX code J02AC) and other CYP3A4 inhibitors, which reduce #sildenafil (ATX code G04B) clearance by 47–59% [143].

• Children with chronic PH associated with BPD are recommended the selective prescription of antihypertensive agents for the treatment of pulmonary arterial hypertension – #bosentan** (ATX code C02KX) – as second-line vasodilator therapy for PH to normalize sPAP and relieve hypoxemia [4].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: #Bosentan** (ATX code C02KX) is an oral dual endothelin receptor antagonist used to treat children with severe pulmonary hypertension who respond poorly to oxygen therapy and #sildenafil (ATX code G04B). #Bosentan** (ATX code C02KX) may be prescribed if oxygen therapy and #sildenafil therapy (ATX code G04B) are ineffective (efficacy is determined based on echocardiographic dynamics and serum NT-proBNP levels) at the maximum therapeutic dose 4 weeks after treatment initiation, or if adverse effects of sildenafil develop, or if serum NT-proBNP levels increase.

#Bosentan** (ATX code C02KX) should be used with monitoring of serum liver transaminases and ultrasound examination of the liver, both before starting the course and during treatment. The therapeutic dose of #bosentan** (ATX code C02KX) is 4 mg/kg/day orally in two divided doses; the drug is prescribed for at least 4 weeks as monotherapy or in combination with #sildenafil (ATX code G04B) [4].

Concomitant administration of #sildenafil (ATX code G04B) and #bosentan** (ATX code C02KX) leads to a decrease in #sildenafil concentration (ATX code G04B) and an increase in #bosentan concentration (ATX code C02KX) [143].

Comments: nitric oxide (iNO) therapy is recommended for acute PH crises, in case of deterioration or lack of positive dynamics during medical therapy for PH, and to manage acute exacerbations of chronic PH. In patients with severe PH, iNO inhalation is initiated at a starting dose of 10-20 ppm. Nitric oxide therapy is prescribed after 4-6 weeks of monotherapy or combination therapy with #sildenafil (ATX code G04B) and #bosentan** (ATX code C02KX), or earlier in case of deterioration or lack of positive dynamics, which can be confirmed by right heart catheterization and a vasoreactivity test, and is discontinued after stabilization. The drug is withdrawn gradually against the background of stable hemodynamic parameters and after the possibility arises to reduce the fraction of inspired oxygen in the gas mixture. The iNO dose should be reduced at intervals of 2-4 hours to 5 ppm, and then further reduced in steps of 1 ppm at similar time intervals. A complication of iNO therapy is methemoglobinemia (MetHb > 2.5%), which is relatively rare when used at recommended doses [144].

Nitric oxide (iNO) therapy is carried out in two ways:

1. From refillable nitric oxide cylinders containing a gas mixture of NO in N2 with a concentration of up to 1000 ppm, using registered medical equipment for delivery, dosing, and monitoring of NO and NO2 concentrations in the gas mixture supplied to the patient within the invasive and non-invasive respiratory therapy circuit.

2. Through medical equipment – a systemic Nitric Oxide Delivery Unit, which generates a gas mixture containing NO from ambient air, delivers it to the patient's respiratory circuit, and monitors the concentration of NO and NO2 in the breathing mixture supplied to the patient.

3.3.4. Home mechanical ventilation

• Children with severe BPD who are on long-term invasive mechanical ventilation in a stable condition are recommended discharge from the hospital and continuation of mechanical ventilation at home (chronic mechanical ventilation) to continue therapy, reduce the risks of nosocomial infection, and improve quality of life [107,145].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

Comments: the main objectives of long-term home mechanical ventilation in severe BPD are: improving tolerance to care and procedures, reducing the need for chronic sedation, improving quality of life by maintaining the child's social interactions with the family and stimulating neuropsychological development, and reducing the likelihood of nosocomial infection [107]. The required level of stability at the time of transfer from the ICU will differ at home and in inpatient units (Appendix A3.5)[145].

Contraindications to home mechanical ventilation include an unstable clinical condition of the patient requiring a volume of medical care that cannot be provided at home: patient requirement for a fraction of inspired oxygen (FiO2) > 0.4; PEEP > 10 cm H2O; functional instability of the tracheostomy; refusal of the patient's legal representatives; unsafe patient environment (presence of fire hazards, threats to the patient's health or safety, including unsanitary conditions; inadequate home amenities such as heating, air conditioning, electricity); insufficient resources for home care (financial, including for the purchase of consumables; personnel-related (insufficient level of medical observation of the patient at their place of residence due to significant geographical remoteness from the service area of the respiratory service or palliative care mobile team); inadequate opportunities for regular and full personal rest for the child's caregivers; an insufficient number of competent caregivers who have undergone appropriate training [107].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation methods and health resort treatment options for patients with BPD currently lack a high level of evidence. The risk of infection versus benefit should be weighed when BPD patients visit medical organizations for rehabilitation activities.

4.1 Physical rehabilitation

When prescribing physical factors, the following should be considered: the child's age, severity of the condition, degree of bronchial obstruction syndrome, presence or absence of disease exacerbation, and comorbid pathology (the primary limitation is usually severe consequences of perinatal CNS (central nervous system) injury)[146].

Comments: may be considered to improve bronchial drainage and ventilation.

A number of studies have demonstrated improved bronchial drainage and ventilation functions under the influence of sinusoidal modulated currents (SMC); methods for the combined use of SMC and ultrasound therapy targeting the lung projection area in children starting from 2 years of age have been developed.

Dynamic electroneurostimulation using an interferential electrical stimulation system (the universal transcutaneous electrical stimulator — DENAS device), based on short high-amplitude current pulses whose waveform approximates natural electrical signals of the body, may be used [146].

In the presence of persistent infiltrative changes and areas of pulmonary fibrosis, stepwise high-frequency therapy methods — centimeter-wave (microwave) therapy and electrophoresis — may be used [146].

Comments: may be considered to improve metabolic and trophic processes.

This method belongs to relatively new physical factors. To date, several studies have revealed increased cellular enzyme activity, improved tissue respiration, and enhanced metabolic and trophic processes. Of particular interest are data on the photomodifying effect of polarized light on formed blood elements, which, according to available studies, is accompanied by increased immunoglobulin production, enhanced phagocytic activity, and the restoration and stimulation of the body's antibacterial and antiviral defense [146].

4.2 Balneotherapy

The main objectives of balneotherapy are to normalize reactivity, enhance the body's protective mechanisms, and exert a positive effect on the respiratory system, as well as the functional state of the central nervous system (CNS) and autonomic nervous system (ANS).

Comments: starting from the first months of life, in the absence of allergic reactions, conifer and sodium chloride baths (therapeutic mineral baths, therapeutic aromatic baths, therapeutic medicinal baths) can be used; starting from 2 years of age, oxygen baths (air-bubble/pearl baths, gas baths [oxygen, carbon dioxide, nitrogen]), dry-air baths, and iodine-bromine baths may be used.

Comments: studies have shown that under the influence of dry immersion procedures, hemodynamic parameters stabilize and cellular enzyme activity increases, which in turn favorably affects cellular metabolism processes [147].

4.3 Kinesitherapy

To improve bronchial secretion clearance, postural drainage combined with vibration massage is prescribed. Hydrokinesiotherapy for bronchopulmonary diseases or therapeutic exercise classes in a playful format in pools (especially effective in seawater pools) improves respiratory muscle function and has a positive effect on the psycho-emotional state [147].

Comments: Physical rehabilitation may be indicated primarily for children with comorbid pathology (BPD + perinatal nervous system lesion). The following may be used: medical chest massage, therapeutic exercise for bronchopulmonary diseases, therapeutic exercise with biofeedback for bronchopulmonary diseases, apparatus- and equipment-assisted therapeutic exercise for bronchopulmonary diseases, and hydrokinesiotherapy for bronchopulmonary diseases.

4.4 Sanatorium-resort treatment

Comments: is the final stage of rehabilitation and is carried out in general or pulmonology-type children's sanatoriums. It can be carried out according to indications and in agreement with a pulmonologist. The main areas of restorative treatment at this stage are climatotherapy, balneotherapy, thalassotherapy, heliotherapy, and pelotherapy [146,147].

4.5 Psychological support

5. Prevention and Dispensary Observation

5.1 Prevention of BPD development in preterm infants

Comments: BPD prevention strategies using delivery room interventions have high potential to influence long-term outcomes [154]. Currently, the general recommendation, based on an individual analysis of eight RCTs, is to initiate continuous SpO₂ monitoring immediately after birth and titrate supplemental oxygen to achieve SpO₂ > 80% by 5 minutes of life [157]. Newborns with a gestational age of more than 28 weeks should start respiratory therapy with air, while those with a gestational age of less than 28 weeks should start with 30% oxygen.

Comments: Data from a meta-analysis of newborn oxygenation showed that using a lower target range (85–89%) was associated with an increased risk of mortality before discharge [82].

• In preterm newborns at high risk for BPD presenting with respiratory distress, it is recommended to avoid invasive mechanical ventilation whenever possible by utilizing initial non-invasive respiratory therapy with CPAP and other non-invasive strategies (NIPPV) to prevent lung injury [52,53,158–162].

GPP ALoE 1Grade of Recommendation A (Level of Evidence - 1).

• In preterm newborns with RDS and a high risk of developing BPD who undergo invasive conventional mechanical ventilation, it is recommended to monitor and maintain tidal volume (4–6 mL/kg in the early neonatal period, 5.5–6.5 mL/kg in the second and third weeks of life) to prevent volutrauma and barotrauma to the lungs [4,5,31,134,163–166].

GCR CLEL 5Level of recommendation evidence C (level of data reliability 5).

Comment: A meta-analysis of 20 RCTs and quasi-randomized studies showed that volume-targeted ventilation was associated with a 36% reduction in the risk of the combined outcome of death or BPD at 36 weeks postmenstrual age [134].

The target tidal volume, monitored via a proximal flow sensor (located at the patient's breathing circuit Y-piece), is recommended to be set within 4–6 mL/kg for RDS to ensure target SpO₂ levels of 91–95%. To reduce the risk of ventilator-induced lung injury, where technically feasible, a volume-guaranteed ventilation strategy may be used[49,134,167].

Comments: Pulmonary surfactant preparations for early administration within the first 24 hours of life with proven efficacy include beractant** (ATC code R07AA), poractant alfa** (ATC code R07AA), and Alveofact (ATC code R07AA). Doses of the drugs are administered in accordance with the manufacturer's instructions.

Early selective administration of a pulmonary surfactant group drug (ATC code R07AA) compared to delayed selective administration is associated with a reduction in the risk of BPD or mortality at 36 weeks postmenstrual age [134].

A single-center study [169] demonstrated the efficacy of late inhalation of pulmonary surfactant #tauractant**(ATC code R07AA) for the prevention of BPD in newborns with VLBW and ELBW. Therapy with #tauractant**(ATC code R07AA) was administered at the end of the first to the second and third weeks of life in premature infants at high risk of developing BPD who were on mechanical ventilation and had early signs of lung injury (oxygen requirement above 40% and oxygenation index above 5). #Tauractant**(ATC code R07AA) is recommended for the prevention of BPD at a single dose of 53–75 mg, regardless of body weight, administered via an aerosol inhaler without a heating function, in newborns who have been on non-invasive mechanical ventilation for at least 7 days of life in Biphasic/DuoPAP mode via nasal cannulas or in CPAP mode via nasal cannulas, as well as on invasive mechanical ventilation. The recommended course duration is up to 5 daily sessions [169–171].

• For the treatment and prevention of RDS in preterm newborns at high risk for BPD receiving non-invasive respiratory therapy, it is recommended to preferably use minimally invasive methods for administering pulmonary surfactants (ATC code R07AA) [134,172–176].

GCR ALOE 1Grade of Recommendation A (Level of Evidence - 1)

Comments: Early selective minimally invasive administration of pulmonary surfactant (ATC code R07AA) compared to the traditional method and the INSURE method avoids tracheal intubation, reduces the need for invasive mechanical ventilation, and consequently minimizes ventilation-associated lung injury, leading to a reduction in the combined risk of BPD or mortality at 36 weeks postmenstrual age [134,172].

Basic principles for minimally invasive administration of pulmonary surfactant (ATC code R07AA) via a thin catheter:

- Performed while the infant is breathing spontaneously and effectively, receiving respiratory therapy via CPAP/non-invasive mechanical ventilation.

- The procedure must be performed by a qualified physician trained in this technique.

- Continuous monitoring of heart rate, SpO₂, and body temperature must be performed throughout the procedure.

• When performing conventional invasive mechanical ventilation in premature newborns with RDS in the early neonatal period, it is recommended to use a short inspiratory time (0.3–0.33 s), a ventilator cycle frequency close to the physiological respiratory rate of the newborn (50–60 breaths per minute), and a constant PEEP of at least 4–6 cm $H_2O$ to reduce ventilator-induced lung injury [103–105,177].

GCR BLOC 1Recommendation Grade B (Level of Evidence - 1)

Comment: protective respiratory strategies used in the acute phase of RDS in preterm infants focus on the surfactant-deficient lung model. Under conditions of low compliance and normal resistance, the time required for complete lung filling/emptying is relatively short (short time constant). Thus, the gentlest ventilation can be considered ventilation with a small tidal volume of 4-6 mL/kg, a high ventilator rate of 50-60 cycles per minute, a short inspiratory time of 0.3-0.33 s, and a PEEP of 4-6 cm H2O to maintain functional residual lung capacity.

Comments: Early extubation is recommended once mean airway pressure parameters reach 7-8 cm H2O and oxygen demand is no higher than 30-35%.

• In preterm infants at high risk for BPD with a GA < 32 weeks receiving non-invasive mechanical ventilation, as well as invasive mechanical ventilation prior to planned extubation, it is recommended to initiate xanthine derivatives early (ATC code N06BC) - caffeine citrate within the first 72 hours of life to stimulate the respiratory center, treat primary apnea, increase minute ventilation, lower the threshold of sensitivity to hypercapnia, and enhance the response to hypercapnia [124–126, 180–182].

GCR ALOC 2Recommendation Grade A (Level of Evidence - 2)

Comments: Caffeine citrate can be administered via intravenous infusion and orally. The target high-risk group for BPD development is preterm infants with a gestational age of less than 32 weeks [183] on non-invasive therapy or mechanical ventilation prior to planned extubation. Caffeine citrate (ATC code N06BC) is prescribed at a loading dose of 20 mg/kg/day via slow intravenous infusion over 30 minutes using a bedside syringe pump or another device for controlled infusion. The maintenance dose is 5 mg/kg/day IV via slow infusion over 10 minutes or per os every 24 hours, starting 24 hours after the loading dose. Higher maintenance doses of 10 mg/kg may be considered in case of an insufficient therapeutic response.

Early initiation of caffeine citrate therapy (ATC code N06BC) within the first 72 hours of life has a significant impact on reducing the incidence of BPD [49, 154, 181, 184–187] and associated long-term neurological morbidity [126]. Pulmonary function studies at 11 years of age in children with a birth weight <1251 g who had BPD revealed significant improvement in lung function in children who received caffeine citrate (ATC code N06BC) [125]. Questions remain regarding the optimal dosage and timing of initiation to prevent or reduce the severity of BPD. The optimal duration of treatment with caffeine citrate (ATC code N06BC) has not been established; in clinical practice, treatment may be continued up to 37 weeks postmenstrual age, although this limit may be revised depending on the clinical situation, in individual cases depending on the response to treatment, the presence of apnea episodes, and other considerations. A randomized controlled trial is currently underway to compare the effects of earlier (2 hours of life) versus later (12 hours of life) initiation of caffeine citrate (ATC code N06BC) (NCT 03086473)[188].

Comment: prophylactic administration of #dexamethasone** (ATC code H02AB) may be considered in preterm infants older than 7 days receiving invasive mechanical ventilation if they have a high oxygen requirement and high mean airway pressure (FiO2 >0.5 and/or MAP ≥10 cm H2O), radiographic signs of interstitial edema, and repeated failed extubation attempts [114]. For detailed information on drug administration tactics, see section 3.4.2. "Drug therapy, systemic glucocorticoids". See also Appendix B1. "Algorithm of physician actions when prescribing systemic glucocorticoid therapy (#dexamethasone** (ATC code H02AB))".

5.2 Prevention of respiratory infections in infants with BPD

• In all children with BPD in the first year of life and children with BPD in the second year of life, in cases where treatment for BPD was required during the last 6 months, it is recommended to administer the specific immunoglobulin palivizumab** (ATC code J06BB) for the prevention of RSV infection [31, 48, 191–194].

GCR ALOC 3Recommendation Grade A (Level of Evidence – 3)

Comment: Palivizumab** (ATC code J06BB) immunization is effective in reducing the rate of RSV-induced hospitalizations in patients with BPD [195–197]. Palivizumab** (ATC code J06BB) is administered intramuscularly at a dose of 15 mg/kg; the course consists of 5 injections at one-month intervals, regardless of the season [198]. The immunization schedule is determined by current regional/local regulatory documents. Contraindications to immunization: hypersensitivity to palivizumab** (ATC code J06BB), any of the drug's excipients, or other specific immunoglobulins.

• For patients with BPD, vaccination against pneumococcal infection, Haemophilus influenzae type b, and influenza is recommended to prevent respiratory infections that affect the course of BPD [107,191,199,200].

GCR CLEL 5Grade of Recommendation C (Level of Evidence - 5)

Comment: The timing of vaccination within the National Schedule of Preventive Vaccinations[1] is determined taking into account comorbid conditions.

5.3 Dispensary follow-up

Children with BPD require a multidisciplinary approach to care in both inpatient and outpatient settings.

At the outpatient stage of follow-up for children with BPD, mandatory monitoring of weight and height gains with appropriate nutritional correction in the case of protein-energy malnutrition using high-calorie formulas (see Section 3.3 "Dietotherapy (Nutritional Support)"), pulse oximetry, and blood pressure measurement are performed. The principles of long-term home oxygen therapy are outlined in Section 3.1.1 "Respiratory Therapy / Oxygen Therapy". Indications for prescribing pharmacotherapy (bronchodilator therapy, diuretics, or inhaled glucocorticoids) for children with BPD in the outpatient setting are presented in Section 3.1.2 ("Pharmacotherapy").

The multidisciplinary team typically includes: a neonatologist, pediatrician / general practitioner (family physician), pulmonologist, anesthesiologist-resuscitologist, pediatric cardiologist, gastroenterologist, dietitian, medical rehabilitation specialist (medical rehabilitation physician / physical and rehabilitation medicine physician / physical therapy physician / physiotherapist, etc.), otolaryngologist-audiologist, ophthalmologist, as well as specialists in other fields for BPD patients with impairments in relevant organs and systems, a nurse, medical psychologist, social worker, palliative care physician, and others depending on clinical necessity [107].

The frequency of follow-up visits and the composition of subspecialists are determined individually depending on the severity of the disease [4].

• For dynamic monitoring, timely treatment prescription, and exclusion of bronchial asthma, children with BPD are recommended to undergo dispensary follow-up by a pulmonologist [4,66].

GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)

Comments: The scope and frequency of diagnostic examinations are determined by the pulmonologist on an individual basis.

Special attention from the pulmonologist is required for:

• patients with severe BPD, i.e., those who required mechanical ventilation / NCPAP at 36 weeks postmenstrual age or at 56 days of life (depending on gestational age) in the presence of respiratory symptoms;

• patients with clinical signs of chronic respiratory failure (tachypnea, dyspnea) or pulmonary hypertension, including those receiving long-term home oxygen therapy;

• patients with a recurrence of respiratory symptoms or repeated episodes after a "lucid interval," which is characteristic of the development of bronchial asthma and requires its exclusion or confirmation [4].

Comments: assessment of pulmonary function in younger children is difficult, existing studies are insufficient, and available data come from small cohorts of BPD patients, requiring further research in this patient category. Abroad, the impulse oscillation technique and inert gas washout methods are recommended for this purpose [66]. In the Russian Federation, publications are available on tidal breathing flow-volume loops and bronchophonography [48,72]. The frequency is determined individually, depending on clinical necessity.

[1] Order of the Ministry of Health of the Russian Federation No. 1122n dated December 6, 2021, "On Approval of the National Schedule of Preventive Vaccinations, the Schedule of Preventive Vaccinations by Epidemic Indications, and the Procedure for Conducting Preventive Vaccinations"

6. Organization of Medical Care

Patients with BPD may be provided with any type, condition, and form of medical care stipulated by the legislation of the Russian Federation, as clinically indicated.

An indication for hospitalization in a medical organization is the clinical deterioration of a child with BPD managed at home (including during a concomitant infectious process); the need for inpatient treatment due to worsening respiratory failure.

Indications for discharging a patient from a medical organization:

1) no need for mechanical ventilation with strict ventilator settings, provided mechanical ventilation or CPAP can be performed at home;

2) the feasibility of long-term home oxygen therapy using an oxygen concentrator (if continued oxygen therapy is required);

3) stable weight gain.

Indications for organizing palliative care (including at home) in severe BPD:

- chronic respiratory failure and the need for long-term home oxygen therapy;

- chronic respiratory failure and the need for home-based long-term mechanical ventilation;

- severe nutritional failure requiring nasogastric tube placement or gastrostomy [4,97].

7. Additional Information

Mortality in BPD is 4.1% in infants during the first three months of life; 1.2–2.6% during the first year of life. High-risk factors for an unfavorable outcome in BPD include:

- prolonged mechanical ventilation for more than 6 months or the need for O₂ supplementation after 18 months;

- severe comorbid pathology (intraventricular hemorrhage requiring surgical treatment of obstructive hydrocephalus, pulmonary hypertension and cor pulmonale, intrauterine growth restriction, combination of BPD with malformations or genetic disorders).

When BPD is combined with pulmonary hypertension, the risk of mortality can reach 40%.

A diagnosis of BPD remains valid until the child reaches 2 years of age; after this age, the condition is formulated as having a history of BPD [4].

The majority of patients experience regression of respiratory disorders after 2 years of age; however, there remains a risk of severe acute viral bronchiolitis (requiring hospitalization, ICU admission, respiratory support, and mechanical ventilation), recurrent bronchial obstruction, and an increased risk of developing bronchial asthma [72,192,201].

The primary consequence of BPD in children older than 2 years of age with persistent oxygen dependency, need for respiratory therapy, or mechanical ventilation is bronchiolitis obliterans. Other potential sequelae include bronchiectasis, bronchial asthma, emphysema, localized pneumosclerosis, and early development of chronic obstructive pulmonary disease in adulthood. Children with BPD have an increased risk of developing bronchial asthma. High-risk groups include children with a burdened family history (atopic diseases) and personal allergic history (concomitant atopic dermatitis, allergic rhinitis), eosinophilia in complete blood counts, and recurrent bronchial obstruction, especially in children older than 2 years without fever, triggered by aeroallergens, and showing a good response to inhaled bronchodilators and glucocorticoids. To confirm the diagnosis of bronchial asthma, an allergological workup with specific IgE testing to inhalant allergens is performed. Asthma therapy follows general principles. In children older than 5 years with persistent symptoms of respiratory failure and bronchial obstruction, pulmonary function testing with a bronchodilator response test and chest CT (if bronchiolitis obliterans is suspected) are recommended [4,31,97].

Examples of diagnosis formulation

Example 1.

"Severe bronchopulmonary dysplasia. Complications: stage II chronic respiratory failure, pulmonary hypertension, cor pulmonale. Oxygen dependency. Concomitant diseases: retinopathy of prematurity."

Example 2.

"Bronchopulmonary dysplasia, moderate. Complications: grade I chronic respiratory failure, pulmonary hypertension. Concomitant diseases: cerebral palsy."

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Anna A. Alekseeva — PhD in Medical Sciences, Head of the Department of Anesthesiology, Resuscitation and Intensive Care with an Operating Unit and Blood Transfusion Room, National Medical Research Center for Children's Health of the Russian Ministry of Health

2. Ekaterina N. Balashova, PhD in Medical Sciences, Leading Researcher, Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Associate Professor of the Department of Neonatology, Member of the Council of the Russian Society of Neonatologists

3. Alexander A. Baranov, Academician of the RAS, Professor, MD; Honorary President of the Union of Pediatrists of Russia, Advisor to the Head of the Research Institute of Pediatrics and Children's Health, National Medical Research Center No. 2 of the Petrov National Research Center of Surgery, Professor of the Department of Pediatrics and Pediatric Rheumatology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Chief freelance pediatric specialist of the Russian Ministry of Health

4. Milana A. Basargina, PhD in Medical Sciences, Researcher at the Laboratory of Neonatology and Early Childhood Health Problems, Head of the Department of Neonatal Pathology, National Medical Research Center for Children's Health of the Russian Ministry of Health.

5. Tatiana T. Batysheva, MD, Professor, Chief freelance pediatric specialist in medical rehabilitation of the Ministry of Health of the Russian Federation, Chief freelance pediatric specialist in neurology of the Moscow Healthcare Department, Director of the Scientific and Practical Center for Child Psychoneurology of the Moscow Healthcare Department, Head of the Department of Pediatric Neurology, Physical and Rehabilitative Medicine, Medical Institute of the RUDN, Honored Doctor of the Russian Federation

6. Irina A. Belyaeva, MD, Head of the Department of Preconceptional, Antenatal, and Neonatal Medicine, Research Institute of Pediatrics and Children's Health, National Medical Research Center No. 2 of the Petrov National Research Center of Surgery, Professor of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatrists of Russia, Honorary Professor of the Russian Association of Perinatal Medicine Specialists

7. Igor Y. Bogdan, PhD in Medical Sciences, Leading Researcher, Scientific and Practical Center for Child Psychoneurology of the Moscow Healthcare Department

8. Evgenia V. Boytsova, MD, DSc, Professor, Department of Propaedeutics of Children's Diseases with a Course of General Childcare, Saint Petersburg State Pediatric Medical University, Russian Ministry of Health; Head of the Laboratory of Pediatric Pulmonology, Research Institute of Pulmonology, Pavlov First Saint Petersburg State Medical University, Russian Ministry of Health; Chief Pulmonologist of Leningrad Oblast.

9. Elena P. Bombardirova, MD, DSc, Chief Researcher, Department of Preconceptional, Antenatal, and Neonatal Medicine, Research Institute of Pediatrics and Child Health, Petrovsky National Research Center of Surgery, Neonatologist.

10. Artyom A. Burov, MD, PhD, Head of the Department of Anesthesiology, Reanimation, and Neonatal Intensive Care, Department of Neonatal and Pediatric Surgery, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Council Member of the Russian Society of Neonatologists.

11. Olga V. Bykova, MD, DSc, Head of the Research Department, Scientific and Practical Center for Pediatric Psychoneurology, Moscow Healthcare Department; Professor, Department of Neurology, Physical and Rehabilitation Medicine of Childhood, Faculty of Continuing Medical Education, Peoples' Friendship University of Russia (RUDN University).

12. Nato D. Vashakmadze, MD, DSc, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, Petrovsky National Research Center of Surgery; Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Russian Ministry of Health.

13. Elena A. Vishnyova, MD, DSc, Professor of the RAS, Deputy Director for Research, Research Institute of Pediatrics and Child Health, Petrovsky National Research Center of Surgery; Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Russian Ministry of Health; Member of the Union of Pediatricians of Russia.

14. Nikolay N. Volodin, Academician of the RAS, Professor, MD, DSc; President of the Russian Association of Specialists in Perinatal Medicine; President of the Association of Specialists in Perinatal Medicine, Care for Pregnant Women, Fetuses, Newborns, and Children under 3 Years of Age (ASPM+).

15. Vladimir A. Grebennikov, Professor, MD, DSc, Member of the Russian Association of Specialists in Perinatal Medicine, Pirogov Russian National Research Medical University, Moscow.

16. Irina V. Davydova, MD, DSc, Head of the Department of Pediatrics and Public Health, Institute of Medical Personnel Training; Chief Researcher, Laboratory of Neonatology and Early Childhood Health Problems, National Medical Research Center for Children's Health, Russian Ministry of Health; Member of the Children's Health Association.

17. Maria A. Zhestkova, MD, PhD, Associate Professor, Department of Pediatrics, Medical Institute, Peoples' Friendship University of Russia (RUDN University).

18. Dmitry O. Ivanov, Professor, MD, DSc, Rector, Saint Petersburg State Pediatric Medical University, Russian Ministry of Health; Chief Neonatologist of the Russian Ministry of Health; Board Member of the Russian Association of Specialists in Perinatal Medicine, Member of the Union of Pediatricians of Russia, European Association of Perinatal Medicine.

19. Oleg V. Ionov, MD, DSc, Head of the Prof. A.G. Antonov Department of Anesthesiology and Reanimation, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Professor, Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University, Russian Ministry of Health (Sechenov University); Chairman of the Russian Society of Neonatologists.

20. Svetlana V. Ionushene, MD, PhD, Assistant, Department of Pediatrics, Irkutsk State Medical Academy of Continuing Education (branch of Russian Medical Academy of Continuous Professional Education, Russian Ministry of Health); Anesthesiologist-Intensivist, Irkutsk City Perinatal Center; Chief Freelance Neonatologist of the Russian Ministry of Health in the Siberian Federal District; Member of the Russian Society of Neonatologists.

21. Anna L. Karpova, MD, PhD, Deputy Chief Physician for Neonatology, City Clinical Hospital No. 67 named after L.A. Vorokhobov, Moscow Healthcare Department; Assistant, Department of Outpatient Therapy, Clinical Laboratory Diagnostics, and Medical Biochemistry, Institute of Professional Education, Yaroslavl State Medical University, Russian Ministry of Health, Yaroslavl, Russian Federation; Council Member of the Russian Society of Neonatologists.

22. Anna R. Kirtbaya, MD, DSc, Head of Clinical Work, Prof. A.G. Antonov Department of Anesthesiology and Reanimation, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Professor, Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University, Russian Ministry of Health (Sechenov University); Member of the Russian Society of Neonatologists.

23. Yury A. Klimov, MD, PhD, Lead Lecturer, Scientific and Practical Center for Children's Psychoneurology, Moscow Healthcare Department; Associate Professor, Department of Physical Rehabilitation Medicine, Psychology, and Pediatric Neurology, RUDN University.

24. Olga V. Kustova, Radiologist, National Medical Research Center for Children's Health, Russian Ministry of Health.

25. Anna A. Lenyushkina, MD, PhD, Head of Intensive Care Unit No. 2, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Council Member of the Russian Society of Neonatologists.

26. Inessa I. Mebelova, Deputy Chief Physician for Neonatology, Republican Perinatal Center, Republic of Karelia; Chief Freelance Neonatologist of the Ministry of Health of the Republic of Karelia.

27. Alexey V. Mostovoy, MD, PhD, Head of Anesthesiology and Reanimation Service, Neonatal Intensive Care Unit No. 1, City Clinical Hospital No. 67 named after L.A. Vorokhobov, Moscow Healthcare Department; Assistant, Department of Outpatient Therapy, Clinical Laboratory Diagnostics, and Medical Biochemistry, Institute of Professional Education, Yaroslavl State Medical University, Russian Ministry of Health, Yaroslavl, Russian Federation; Council Member of the Russian Society of Neonatologists.

28. Leyla S. Namazova-Baranova, Academician of the RAS, Professor, MD, DSc, President of the Union of Pediatricians of Russia; Past-President of EPA/UNEPSA; Head of the Research Institute of Pediatrics and Child Health, Petrovsky National Research Center of Surgery; Head of the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University, Russian Ministry of Health; Chief Freelance Pediatric Specialist in Preventive Medicine of the Russian Ministry of Health.

29. Dmitry Yu. Ovsyannikov, MD, DSc, Professor, Head of the Department of Pediatrics, Medical Faculty, RUDN University; Pediatrician, Pulmonologist, Allergist-Immunologist; Member of the Russian Association of Specialists in Perinatal Medicine.

30. Elena B. Pavlinova, MD, DSc, Vice-Rector for Academic Affairs, Associate Professor, Head of the Department of Hospital Pediatrics, Omsk State Medical University, Russian Ministry of Health.

31. Natalya A. Petrova, MD, PhD, Associate Professor, Department of Children's Diseases, Institute of Medical Education, Almazov National Medical Research Centre; Head of the Research Laboratory of Physiology and Pathology of Newborns, Almazov National Medical Research Centre, Russian Ministry of Health.

32. Maria M. Platonova, MD, PhD, Senior Researcher, Research Institute of Pediatrics and Child Health, Petrovsky National Research Center of Surgery.

33. Vladislav A. Romanenko, MD, DSc, Professor, Department of Pediatrics and Neonatology, Institute of Additional Professional Education, South-Ural State Medical University, Russian Ministry of Health; Honored Doctor of Russia; Chairman of the Chelyabinsk Regional Branch of the Russian Society of Neonatologists.

34. Alesya A. Rudakova, Senior Researcher, Anesthesiologist-Intensivist, Prof. A.G. Antonov Department of Anesthesiology and Reanimation; Ultrasound Diagnostic Physician, Department of Ultrasound Diagnostics in Neonatology and Pediatrics, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health.

35. Andrey Yu. Ryndin, MD, PhD, Senior Researcher, Prof. A.G. Antonov Department of Anesthesiology and Reanimation, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Russian Ministry of Health; Associate Professor, Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University, Russian Ministry of Health (Sechenov University); Council Member of the Russian Society of Neonatologists.

36. Kirill V. Savostyanov, Doctor of Biological Sciences, Head of the Medical Genetic Center, Head of the Laboratory of Medical Genomics, Professor, Department of Pediatrics and Public Health, Institute of Medical Personnel Training, National Medical Research Center for Children's Health, Russian Ministry of Health; Member of the Children's Health Association.

37. Olga I. Sapun, Head of Neonatal Intensive Care Unit No. 2, Children's Regional Clinical Hospital, Krasnodar; Chief Freelance Neonatologist of the Ministry of Health of Krasnodar Krai; Council Member of the Russian Society of Neonatologists.

38. Elena S. Sakharova, MD, DSc, Professor, Department of Hospital Pediatrics No. 2, Pediatric Faculty, Pirogov Russian National Research Medical University, Russian Ministry of Health.

39. Liliya R. Selimzyanova, Candidate of Medical Sciences, Leading Researcher, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Associate Professor, Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health; Associate Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of the Union of Pediatricers of Russia

40. Sergey V. Tikhonov, Candidate of Biological Sciences, Scientific Secretary, Scientific and Practical Center for Child Psychoneurology of the Moscow Healthcare Department; Associate Professor, Department of Neurology, Physical and Rehabilitation Medicine of Childhood, Faculty of Continuous Medical Education, Peoples' Friendship University of Russia

41. Tatyana V. Turti, Doctor of Medical Sciences, Chief Researcher, Department of Preconceptional, Antenatal and Neonatal Medicine, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of the Union of Pediatricers of Russia

42. Marina V. Fedoseenko, Candidate of Medical Sciences, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Status Deviations and Chronic Diseases, Leading Researcher, Pediatrician, Research Institute of Pediatrics and Child Health, Petrovsky National Research Centre of Surgery; Associate Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of the Union of Pediatricers of Russia

43. Andrey P. Fisenko, Professor, Doctor of Medical Sciences, Honored Physician of the Russian Federation, Active State Councillor of the Russian Federation of the 2nd Class; Director, National Medical Research Center for Children's Health of the Russian Ministry of Health; Chairman of the Association of Child Health

44. Antonina I. Chubarova, Professor, Doctor of Medical Sciences, Member of the Russian Association of Perinatal Medicine Specialists, Pirogov Russian National Research Medical University.

45. Galina V. Yatsyk, Professor, Doctor of Medical Sciences, Member of the Association of Child Health, National Medical Research Center for Children's Health of the Russian Ministry of Health

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 and MEDLINE, Scopus, Web of Science, e-library, clinicaltrials.gov, electronic libraries, and clinical guidelines published 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 34 years.

Methods used for assessing the quality and strength of evidence:

· expert consensus;

· significance assessment according to 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 peer review;

· internal peer 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 latest changes to these recommendations are presented for discussion as a preliminary version. The updated version for broad discussion was posted on the website of the Russian Society of Neonatologists (RSN) www.neonatology.pro, the Russian Association of Perinatal Medicine Specialists (RAPMS) www.raspm.ru, and the Union of Pediatricers of Russia www.pediatr-russia.ru so that all interested parties could participate in discussing and improving the guidelines.

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. Pediatricians, neonatologists;

2. Critical care physicians / Anesthesiologist-resuscitators;

3. Pulmonologists;

4. General practitioners (family physicians);

5. Medical students;

6. Residents and interns.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The update mechanism for clinical guidelines provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific conditions, 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 "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" dated November 21, 2011.

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

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

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

5. Procedure for the Provision of Medical Care in the Profile "Neonatology" (Order of the Ministry of Health of the Russian Federation No. 921n dated November 15, 2012).

6. List of Vital and Essential Drugs for 2023 (Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019).

7. Procedure for the Provision of Medical Care: Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012, "On Approval of the Procedure for the Provision of Pediatric Care"

8. Order of the Russian Ministry of Health No. 1204n dated December 20, 2012, "On Approval of the Standard of Specialized Medical Care for Children with Chronic Respiratory Diseases Developed in the Perinatal Period (Rehabilitation Stage after Discharge from a Neonatal Hospital)"

9. Order of the Ministry of Health of the Russian Federation No. 1122n dated December 6, 2021, "On Approval of the National Calendar of Preventive Vaccinations, the Calendar of Preventive Vaccinations by Epidemiological Indications, and the Procedure for Conducting Preventive Vaccinations"

10. Federal Law No. 18-FZ dated March 6, 2019, "On Amendments to the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' Regarding the Provision of Palliative Medical Care."

11. Order of the Russian Ministry of Health No. 345n, Russian Ministry of Labor No. 372n dated May 31, 2019, "On approval of the Regulations on the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations, and other non-profit organizations operating in the field of health protection."

12. Order of the Russian Ministry of Health No. 348n dated May 31, 2019, "On approval of the list of medical devices intended to maintain human organs and body systems, provided for home use."

13. Order of the Russian Ministry of Health No. 505n dated July 10, 2019, "On approval of the Procedure for the transfer by a medical organization to a patient (their legal representative) of medical devices intended to maintain the functions of human organs and body systems for home use in the provision of palliative medical care."

14. Order of the Russian Ministry of Health and the Ministry of Labor and Social Protection of the Russian Federation No. 345n/372n dated May 31, 2019, "On Approval of the Regulations on the Organization of Palliative Medical Care, Including the Procedure for Interaction between Medical Organizations, Social Welfare Organizations, and Public Associations and Other Non-Profit Organizations Operating in Healthcare".

Appendix A3.2 Blood pressure (mmHg) in term and preterm newborns after 14 days of life [202–204]

SBP ― systolic blood pressure; DBP ― diastolic blood pressure, MAP – mean arterial pressure.

Appendix A3.3 Assessment of respiratory failure severity [4].

PaO2 – partial pressure of oxygen in arterial blood, SaO2 – arterial blood oxygen saturation, RF – respiratory failure

Appendix A3.4 Radiological presentation, pulmonary mechanics, and respiratory strategies in RDS and BPD [111].

Notes: Vt – tidal volume, Tinsp – inspiratory time, RR – respiratory rate, Tinsp – inspiratory time

Appendix A3.5 Clinical stability criteria for a patient with severe BPD for discharge from the ICU home or to a general inpatient ward for long-term mechanical ventilation [145].

Appendix B. Physician Action Algorithms

Appendix B1. Algorithm of physician actions when prescribing systemic glucocorticoid therapy - #dexamethasone**(ATC code H02AB).

Appendix B2. Algorithms of physician actions in pulmonary hypertension associated with BPD

Modified by Krishnan U. et al., 2017 [83]

Appendix C. Patient Information

Bronchopulmonary dysplasia (BPD) is a lung disease developing within the first month of life in premature infants receiving respiratory support (mechanical ventilation, CPAP) due to underdevelopment of the respiratory system. The diagnosis of BPD is established in infants requiring supplemental oxygen during spontaneous or mechanical breathing at 28 days of age and/or 36 weeks postmenstrual age or older.

BPD manifests with symptoms of respiratory failure (tachypnea, dyspnea, chest retractions), bronchial obstruction (wheezing, rales in the lungs). Complications of BPD include nutritional failure, need for supplemental oxygen therapy which may persist after hospital discharge, and elevated pulmonary pressure (pulmonary hypertension).

The outcome of BPD depends on the severity of the disease and is determined by 2 years of age. In most cases, symptoms gradually subside as the child grows and lung tissue develops. Unfavorable, rare complications of BPD include obliterating bronchiolitis and bronchial asthma.

Children with BPD are indicated for RSV infection prevention, in some cases inhaled glucocorticoid therapy and bronchodilator therapy. It is very important to avoid passive smoking, including electronic cigarettes. When these children grow up, they will also be prohibited from smoking and working in hazardous occupations involving inhalation hazards (mines, chemical, metallurgical industries, etc.), as BPD is a risk factor for chronic obstructive pulmonary disease at a young age.

Prevention of severe bronchiolitis through seasonal passive immunization against RSV determines a favorable disease outcome and improves the quality of life in children with BPD.

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

Appendix G1. Radiographic scoring scale for bronchopulmonary dysplasia (A. Greenough et al., 1999, modified).

Russian title: Radiographic scoring scale for bronchopulmonary dysplasia

Original title: Simple chest radiograph scoring system

Source: Greenough A, Kavvadia V, Johnson AH, Calvert S, Peacock J, Karani J. A simple chest radiograph score to predict chronic lung disease in prematurely born infants. Br J Radiol. 1999 Jun;72(858):530-3[62]

Type: rating scale

Purpose:

Content (template)

Note. ¹ - number of posterior rib segments above the diaphragm bilaterally, ² - focal areas of linear or nodular density within the zone (1/2 of the lung on each side); ³ - well-defined radiolucent intraparenchymal lesions

Key (interpretation) and explanations: a high score on this scale (≥3) predicts the persistence of oxygen dependency at 36 weeks postmenstrual age (sensitivity 69%, specificity 85%, positive predictive value 73%).

Appendix G2. CT-based BPD severity radiographic scale.

Russian title: CT-based BPD severity radiographic scale

Original title: CT-based BPD severity radiographic scale

Source (official website of the developers, validation publication): Davydova I.V., Anikin A.V., Kustova O.V., Sidenko A.V., Basargina E.Yu., Pavlyukova E.V., Pozharischenskaya V.K. Bronchopulmonary dysplasia in the post-surfactant era: results of an objective assessment of the disease course. Voprosy sovremennoy pediatrii. 2015; 14 (4): 514-518 [205].

Type: rating scale

Purpose: assessment of BPD severity based on CT data

Content (template), key (interpretation), explanations:

Appendix G3. Technologies for assessing neonatal lung ultrasound characteristics using LUS and eLUS scales.

LUS scale

Russian title: Lung ultrasonography score

Original title: Lung ultrasonography score

Source: Brat R. et al. Lung ultrasonography score to evaluate oxygenation and surfactant need in neonates treated with continuous positive airway pressure //JAMA pediatrics. – 2015. – Vol. 169. – No. 8. – P. doi:10.1001/jamapediatrics.2015.1797 [93]

Type: rating scale

Purpose: assessment of the risk of developing moderate and severe BPD

Content (template):

Figure 1. Method for assessing ultrasound characteristics of the lung parenchyma using the LUS scale [93].

Key (interpretation), explanations:

Longitudinal and transverse scanning of the chest is performed with a high-frequency linear transducer.

Each lung is conventionally divided into anterior upper, anterior lower, and lateral surfaces. Total – 6 zones (Figure 1),

For each specified scanning zone, the lung ultrasound appearance is scored from 0 to 3 points.

0 points – A-lines only (normal lung aeration)

1 point – presence of A-lines and at least 3 B-lines (interstitial pattern)

2 points – presence of coalescing B-lines without consolidations or consolidations limited to the subpleural space (alveolar pattern)

3 points – presence of widespread consolidations

Total LUS score can range from 0 to 18 points

Ultrasonic assessment of the lung parenchyma on days 7 and 14 of life has a high predictive value for the development of moderate and severe forms of BPD when the LUS score is 8 points or more

eLUS scale

Russian title: Lung ultrasonography score (extended version)

Original title: extended version Lung ultrasonography score

Source: Loi B. et al. Lung ultrasound to monitor extremely preterm infants and predict bronchopulmonary dysplasia. A multicenter longitudinal cohort study //American Journal of Respiratory and Critical Care Medicine. – 2021. – Vol. 203. – No. 11. – P. 1398-1409.PubMed: 33352083 [89].

Type: rating scale

Purpose: assessment of the risk of developing moderate and severe BPD

Ultrasonic assessment of the lung parenchyma on days 7 and 14 of life has a high predictive value for the development of moderate and severe forms of BPD with an eLUS score of 14 points or more.

Content (template): Figure 2. Method for assessing ultrasound characteristics of the lung parenchyma using the eLUS scale [89].

Key (interpretation), explanations:

Longitudinal and transverse scanning of the chest is performed with a high-frequency linear transducer.

For the eLUS scale, each lung is conventionally divided into anterior upper, anterior lower, lateral, posterior upper, and posterior lower surfaces. Total 10 zones (Figure 2).

For each specified scanning zone, the lung ultrasound appearance is scored from 0 to 3 points.

0 points – A-lines only (normal lung aeration)

1 point – presence of A-lines and at least 3 B-lines (interstitial pattern)

2 points – presence of coalescing B-lines without consolidations or consolidations limited to the subpleural space (alveolar pattern)

3 points – presence of widespread consolidations

Total eLUS score 0-30 points.