List of Abbreviations
FiO2 – fraction of inspired oxygen in the breathing gas mixture
INSURE – INtubation-SURfactant-Extubation (method of surfactant administration)
LISA – Less Invasive Surfactant Administration using a thin catheter
LUS – Lung Ultrasound Score
MIST – Minimally Invasive Surfactant Therapy
pCO2 – partial pressure of carbon dioxide
PEEP – positive end-expiratory pressure
SpO2 – oxygen saturation measured by pulse oximetry
BP – blood pressure
BPD – bronchopulmonary dysplasia
IVH – intraventricular hemorrhage
HFOV – high-frequency oscillatory ventilation
IMV – invasive mechanical ventilation
ABDS – acid-base balance status
mg/kg/day – drug dosage in milligrams per kilogram of newborn body weight per day
Ministry of Health of the Russian Federation – Ministry of Health of the Russian Federation
HC – healthcare organization
NEC – necrotizing enterocolitis
VLBW – very low birth weight
NICU – neonatal intensive care unit
RDS – respiratory distress syndrome
RCT – randomized controlled trial
CPAP – continuous positive airway pressure
TTN – transient tachypnea of the newborn
bpm – beats per minute
RR – respiratory rate
HR – heart rate
ELBW – extremely low birth weight
ETT – endotracheal tube
Terms and Definitions
Respiratory distress syndrome or newborn «respiratory distress syndrome» (RDS) – respiratory disorder in infants in the first days of life caused by primary surfactant deficiency and morphofunctional immaturity of the lungs.
Very low birth weight (VLBW) – birth weight of 1,499 grams or less.
Extremely low birth weight (ELBW) – birth weight of 999 grams or less.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Respiratory distress syndrome or newborn «respiratory distress syndrome» (RDS) – respiratory disorder in infants in the first days of life caused by primary surfactant deficiency and morphofunctional immaturity of the lungs [1,2].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
RDS is the most common cause of respiratory failure in the early neonatal period in newborns. Its incidence is higher the lower the gestational age and birth weight of the infant [1,3-5].
The main causes of RDS in newborns are:
Insufficient synthesis and excretion of surfactant by type II alveolar epithelial cells, associated with functional and structural immaturity of the lungs [6].
Congenital qualitative defect in surfactant structure, which is an extremely rare cause [7,8].
Pulmonary surfactant is a complex multicomponent substance consisting of phospholipids, neutral lipids, and specific proteins, which is synthesized and secreted by type II alveolar epithelial cells. Surfactant is a surface-active agent that prevents alveolar collapse and maintains alveoli in an expanded state throughout the respiratory cycle [1,9-11].
The pathogenesis of RDS is based on primary surfactant deficiency, which leads to alveolar collapse and the development of atelectasis in the lungs [6]. In summary, the pathogenesis of RDS is as follows: alveolar collapse contributes to a reduction in functional residual capacity, decreased lung compliance, and increasing respiratory disorders. In turn, alveolar collapse leads to blood shunting through extra-alveolar shunts and alveolar capillaries surrounding alveoli where gas exchange is absent. Intrapulmonary blood shunting leads to hypoxemia, increased pulmonary vascular resistance - persistent pulmonary hypertension of the newborn (PPHN), accompanied by an extra-alveolar right-to-left shunt through the ductus arteriosus and/or foramen ovale. Pulmonary hypertension, in turn, leads to increased right ventricular afterload and acute heart failure. Acute heart failure leads to a number of other complications, including intraventricular hemorrhage, acute kidney injury, shock, etc.
1.3 Epidemiology of the Disease or Condition
According to the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers database, RDS occurs in 98% of infants born at 24 weeks of gestation, compared to only 5% of infants born at 34 weeks and less than 1% of those born at 37 weeks [12,13].
According to Rosstat, in the Russian Federation for 2024, the incidence of RDS among all newborns is 3.6%, and 44.2% among preterm infants. Furthermore, the incidence of RDS among ELBW infants is 65.5%. Mortality among all newborns with RDS in our country is 0.46%, 0.57% among preterm infants, and 4.2% among ELBW infants. Early neonatal mortality up to 7 days of life among all newborns who developed RDS is 0.38%, 0.5% among preterm infants, and 3.5% among ELBW infants.
1.4 Features of Coding the Disease or Condition
P22.0 - Respiratory distress syndrome of newborn.
1.5 Classification of the disease or condition
There is no universally accepted classification.
1.6 Clinical presentation of the disease or condition
Clinical symptoms of RDS include: dyspnea occurring within the first minutes to hours of life; expiratory sounds («grunting»), caused by the development of compensatory spasm of the vocal cords during expiration; chest wall retraction during inspiration (recession of the xiphoid process, epigastric region, intercostal spaces, and supraclavicular fossae) accompanied by nasal flaring and cheek puffing («trumpeting» respiration); decreased breath sounds in the lungs, crepitant rales, cyanosis. The described clinical manifestations are non-specific and may be observed in newborns with other pathological conditions.
2. Diagnostics, medical indications and contraindications for diagnostic methods
Criteria for establishing the diagnosis of RDS
The diagnosis of RDS can be established based on the following data set:
medical history data;
clinical manifestations: presence of respiratory disorders (see clinical presentation) and other manifestations of respiratory failure;
instrumental examination: characteristic changes on the radiograph (reduction of the pulmonary field area, diffuse decrease in the transparency of the pulmonary fields of varying severity due to the fine granular structure of the lung tissue ("ground-glass" sign), decreased lung transparency down to "white lungs" with indistinguishable heart borders, enhanced bronchial pattern mainly at the periphery (air bronchogram) – air contrast).
2.1 Complaints and Anamnesis
It is recommended to study the maternal history to identify risk factors for the development of RDS [14-18].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: predisposing factors for the development of RDS that can be identified before the child's birth or in the first minutes of life include:
■ Premature birth;
■ Development of RDS in siblings;
■ Gestational diabetes and type 1 diabetes mellitus in the mother;
■ Hemolytic disease of the fetus;
■ Premature placental abruption;
■ Placenta accreta [19];
■ Male fetal sex in preterm birth;
■ Cesarean section prior to the onset of labor;
■ Neonatal asphyxia;
■ Low birth weight or small for gestational age;
■ Chorioamnionitis and endometritis [20].
2.2 Physical Examination
It is recommended to perform a physical examination of a newborn infant presenting with respiratory disorders using rating scales to assess the severity of respiratory distress and determine the respiratory therapy tactics [21-25].
GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).
Comments: see Appendix G1 and G2. Assessment of the severity of respiratory disorders in newborns using the Silverman-Andersen or Downes scale is performed for the purpose of dynamic evaluation of the severity of respiratory disorders, as well as to determine indications for early initiation of respiratory support and assess its effectiveness.
It is important to keep in mind that both scales were developed in the years when neonatal respiratory therapy methods differed significantly from modern ones, and the survival rate of extremely premature infants with RDS was extremely low.
There is no consensus on the informativeness of the Silverman-Andersen and Downes scales for assessing the severity of respiratory distress in modern conditions. Despite the fact that both scales are based on recording obvious clinical signs, the accuracy of assessment and its reproducibility in dynamics depend not only on the choice of a specific scale, but also on the practical experience of its application by medical staff.
The risk of error in assessing the severity of respiratory distress increases when using both scales in extremely premature infants.
It should also be borne in mind that in the Downes scale, one of the evaluated signs is cyanosis. This clinical sign is scored 1 point if the cyanosis detected in the child disappears when FiO2 in the breathing mixture is increased up to 0.4 (40 %) inclusive, and 2 points if its elimination requires the administration of a breathing mixture with FiO2 greater than 0.4 (40 %). Considering that when oxygen dependence is detected in an infant with RDS (including the appearance of cyanosis), respiratory support should currently be initiated not by increasing FiO2 in the breathing mixture, as was customary during the period when the scale was created, but by improving pulmonary ventilation, this limits the application of the Downes scale in cases where it is necessary to dynamically evaluate the effectiveness of early initiated respiratory support.
2.3 Laboratory Diagnostics
It is recommended to perform acid-base balance (ABB) and blood gas analysis, blood lactic acid levels, and blood glucose levels in a newborn infant with respiratory disorders suspected of having RDS to assess hypoxia and metabolic disorders, determine further respiratory therapy tactics, and adjust parameters [26-29].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: the frequency of testing depends on the clinical condition of the infant and the ongoing respiratory therapy. Determination of blood lactic acid levels depends on the technical capabilities of the point-of-care laboratory and its availability.
It is recommended to perform a complete blood (clinical) count with differential white blood cell count (leukocyte formula) and calculation of the neutrophil index in a newborn infant with respiratory disorders suspected of having RDS to rule out an inflammatory process associated with an infectious disease [30-32].
GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).
It is recommended to measure blood serum C-reactive protein levels in a newborn infant with respiratory disorders suspected of having RDS in order to rule out an infectious genesis of respiratory disorders [33,34].
GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).
It is recommended to perform a microbiological (culture) blood test for sterility and (in case of tracheal intubation) a microbiological (culture) sputum test for aerobic and facultatively anaerobic microorganisms along with susceptibility testing of microorganisms to antimicrobial chemotherapeutic drugs in a newborn infant with respiratory disorders suspected of having RDS, in order to identify the pathogen and determine antibacterial therapy tactics to rule out an infectious etiology of the disease [30,35,36].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4) for blood culture sterility testing and microbial susceptibility testing to antimicrobial chemotherapeutic drugs.
GPP CLOE 5Grade of Recommendation C (Level of Evidence – 5) for sputum testing for aerobic and facultatively anaerobic microorganisms.
2.4 Instrumental Diagnostics
It is recommended to measure heart rate and determine hemoglobin oxygen saturation continuously from the first minutes of life in a newborn with respiratory disorders when providing care in the delivery room to determine further stabilization tactics [37,38].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: recording of heart rate (HR) and hemoglobin oxygen saturation (SpO2) by pulse oximetry starts from the first minute of life. The pulse oximeter sensor is placed on the wrist or forearm of the child's right hand ("preductally") during initial procedures. Pulse oximetry in the delivery room has 3 main applications: continuous HR monitoring, prevention of hyperoxia (SpO2 not exceeding 95 % at any stage of resuscitation if the infant is receiving supplemental oxygen), prevention of hypoxia (SpO2 at least 80 % by the 5th minute of life and at least 85 % by the 10th minute of life).
It is recommended to perform a chest X-ray in a newborn infant with respiratory disorders to detect lung tissue changes [39-41].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: typical signs of RDS include: diffuse decrease in the transparency of pulmonary fields, "ground-glass" sign, reticulogranular pattern, and lucency lines in the lung root area (air bronchogram) [41,42]. However, these changes are nonspecific and may be detected in early neonatal sepsis and congenital pneumonia. The radiological picture of RDS depends on the severity of the disease – from a slight decrease in aeration to "white lungs".
It is recommended to perform 24-hour bedside monitoring of vital signs and parameters (HR, RR, BP, SpO2, body temperature, diuresis) in a newborn infant with respiratory disorders for an objective assessment of the condition, timely prescription, and adjustment of therapy [43-54].
GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).
Comments: temperature measurement (general thermometry) should be started immediately after the child's birth to prevent hypothermia. The newborn's body temperature must be maintained within the range of 36.5-37.5°C throughout the entire nursing period [55,56]. The main measures to ensure thermal protection are carried out in accordance with the methodological letter on the provision of resuscitation care in the delivery room [37].
It is recommended to selectively perform a lung ultrasound in a newborn infant with respiratory disorders to detect signs of RDS, provided the medical organization has the appropriate capabilities [57-59].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comment: see Appendix G3. Assessment of parenchyma status using the LUS or eLUS lung ultrasound scale.
This scale allows:
- to differentiate respiratory distress syndrome (RDS) from transient tachypnea of the newborn (TTN). RDS is characterized by poorly aerated lungs with the absence of A-lines, the presence of small subpleural consolidations, and a diffuse white lung (confluent B-lines). Conversely, in TTN, the interstitial pattern alternates with areas of nearly normal lung (with A-lines) [57].
- to assess the severity of RDS [59-61];
- to clarify the indications for exogenous surfactant administration [62];
- to evaluate the risks of bronchopulmonary dysplasia (BPD).
It is recommended that a newborn infant with RDS undergo ultrasound examinations—neurosonography (NSG), echocardiography (EchoCG), comprehensive abdominal ultrasound, and renal ultrasound—to rule out complications and conditions that aggravate the course of the disease [63-71].
Level of Evidence CLevel of Confidence 4Level of recommendation C (level of evidence – 4) for neurosonography.
Level of Evidence CLevel of Confidence 4Level of recommendation C (level of evidence – 4) for abdominal and renal ultrasound.
Level of Evidence CLevel of Confidence 4Level of recommendation C (level of evidence – 4) for echocardiography.
Comments: in case of concomitant disorders of various organs and systems, EchoCG, NSG, and abdominal ultrasound can facilitate timely administration and correction of therapy.
2.5 Other Procedures
Not applicable.
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Conservative Treatment
It is recommended that a newborn infant with respiratory disorders and suspected RDS receive initial respiratory therapy starting at FiO2 = 0.3 for children born at a gestational age of 28 weeks or less. Respiratory therapy in infants of greater gestational age is carried out with air (FiO2 = 0.21) [2,72,73].
Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).
Comments: starting from the end of the 1st minute of life, one should be guided by pulse oximeter readings (target saturation) (see Appendix A3.2) and follow the delivery room algorithms [37,74].
It is recommended to initiate non-invasive mechanical ventilation via CPAP in the delivery room for a newborn infant with respiratory disorders and suspected RDS in order to treat the respiratory distress [2,37,38,75-78].
GGR BLOC 1Grade of Recommendation B (Level of Evidence – 1).
Comments: for spontaneously breathing premature infants with a gestational age of 32 weeks or less, including those with respiratory disorders, initial therapy with CPAP at a pressure of at least 6-8 cm H2O is considered preferable. For premature infants with a gestational age greater than 32 weeks, CPAP should be administered in the presence of respiratory disorders [2,76,79].
Further tactics involve initiating non-invasive mechanical ventilation if the infant lacks spontaneous breathing and/or has persistent bradycardia, followed by a transition to CPAP (upon restoration of breathing and heart rate) or to endotracheal intubation and mechanical ventilation (in the absence of breathing and/or persistent bradycardia) [37,38]. In the absence of spontaneous breathing from birth, respiratory support options with various pressure levels (8-10-15 cm H2O) are possible [80–82]. However, the optimal method for establishing functional residual capacity, as well as the optimal level of CPAP during stabilization of preterm infants in the delivery room, has not been definitively determined [83]. In the absence of local protocols for stabilizing premature infants in the delivery room, one should be guided by the methodological letter "Resuscitation and Stabilization of Newborn Infants in the Delivery Room" [37].
CPAP/non-invasive mechanical ventilation in the delivery room can be performed using a mechanical ventilator with appropriate functions, a manual T-piece resuscitator (breathing circuit), or various CPAP/non-invasive ventilation devices, including high-frequency ones. Self-inflating resuscitation bags (Ambu manual resuscitators) should not be used in extremely premature infants for delivery room stabilization. CPAP/non-invasive ventilation can be delivered using various devices: facial or nasal masks (oxygen mask), nasopharyngeal tubes (nasopharyngeal airway), endotracheal tubes (used as nasopharyngeal tubes), and various models of bi- or mononasal prongs (nasal cannula) [84].
It is recommended that if non-invasive respiratory therapy is ineffective in a newborn infant with respiratory disorders and suspected RDS, endotracheal intubation and invasive mechanical ventilation should be performed [85].
Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).
Comments: indications for transferring infants with RDS to mechanical ventilation include the ineffectiveness of non-invasive respiratory support methods, as well as severe concurrent conditions: shock, status epilepticus, pulmonary hemorrhage, choanal atresia, or other congenital craniofacial malformations that prevent the proper placement of nasal prongs / mask (oxygen mask) / nasopharyngeal tube (endotracheal tube); diagnosed tension pneumothorax; congenital diaphragmatic hernia, pulmonary hemorrhage.
The necessary conditions for effective mechanical ventilation in extremely premature newborns are: airway pressure control; mandatory maintenance of PEEP of at least +6 cm H2O; the ability to smoothly adjust the oxygen concentration from 21% to 100%; continuous monitoring of heart rate and SpO2.
The main indicator of the effectiveness of mechanical ventilation in the delivery room is an increase in heart rate >100 bpm. Performing invasive mechanical ventilation in the delivery room with a target tidal volume, as well as high-frequency ventilation in extremely premature patients, is a promising technology that minimizes ventilator-induced lung injury [86,87]. Verification of endotracheal tube placement by auscultation in infants with extremely low birth weight can present certain difficulties due to the low intensity of breath sounds and their significant radiation. The use of exhaled CO2 detectors allows for faster and more reliable confirmation of correct endotracheal tube placement in the trachea than other methods. In the NICU, verification of endotracheal tube position can be performed using radiological and/or ultrasound methods [88].
If technical capabilities are available, preterm infants with RDS requiring mechanical/invasive ventilation should be ventilated using protective lung ventilation methods (volume-targeted ventilation and high-frequency oscillatory ventilation) [89–93].
Hypocarbia and severe hypercarbia should be avoided as factors contributing to brain injury. In case of pulmonary hypoventilation, a single recruitment maneuver may be performed. A recruitment maneuver helps to open up the lung tissue, thereby optimizing compliance and improving oxygenation, which contributes to a reduction in mortality and the rate of disabling complications. Repeated performance of the recruitment maneuver increases the risk of barotrauma in recruited alveoli [94]. The duration of mechanical ventilation in infants with RDS should be kept to a minimum whenever possible [95]. In the absence of contraindications, extubation should be performed regardless of ventilator rate if the infant has active spontaneous breathing [96]. High-frequency mechanical ventilation (high-frequency oscillatory ventilation (HFOV)) can be used as an alternative to conventional mechanical ventilation in newborns with RDS [91].
It is recommended that a newborn infant with RDS or suspected RDS receive endotracheal administration of pulmonary surfactants (ATX code R07AA) (poractant alfa**, beractant**) when indicated, in order to relieve respiratory failure and reduce the risk of death or BPD [97-120].
GCR ALoE 2Grade of Recommendation A (Level of Evidence – 2).
Comments: surfactant therapy is indicated:
Within the first 20 minutes of life for all infants with a gestational age of 26 weeks or less. In the case of an incomplete course of antenatal glucocorticoid prophylaxis (ATX code H02AB), maternal diabetes mellitus, or chorioamnionitis, the indications for administering pulmonary surfactant (ATX code R07AA) to premature infants in the delivery room may be broadened.
For all infants with a gestational age of 32 weeks or less who required endotracheal intubation in the delivery room. The most effective administration time for this category of infants is the first 20 minutes of life.
For premature infants on initial non-invasive respiratory therapy who have an FiO2 requirement ≥ 0.3 and clinical, anamnestic, and instrumental data indicative of an RDS diagnosis. Early selective/therapeutic administration (in the first 2 hours of life) is advisable.
In the delivery room, children on initial non-invasive respiratory therapy may be administered pulmonary surfactant (ATC code R07AA) for indicated conditions using either traditional or minimally invasive methods.
In the neonatal intensive care unit, premature infants with RDS receiving CPAP/non-invasive mechanical ventilation who exhibit increased work of breathing (Silverman-Andersen respiratory score of 3 or more points on the first day of life) and/or an increased FiO2 requirement up to 0.3, or negative chest X-ray dynamics, should be administered pulmonary surfactant (ATC code R07AA). The administration method can be chosen depending on the patient's gestational age, available conditions, and staff skills.
Repeat administration of pulmonary surfactant (ATC code R07AA) in RDS may be indicated: in preterm infants with RDS on CPAP, with repeated worsening of respiratory disturbances to 3 or more points on the Silverman-Andersen scale and/or an increase in FiO2 requirement > 0.3. Also in preterm infants on mechanical ventilation (ATC code R07AA), with escalation of ventilation parameters: MAP up to 8 cm H2O and FiO2 up to 0.3 in patients < 1000 g in the first day of life. Repeat administration should preferably be performed after chest X-ray. A third dose may be indicated in preterm infants with severe RDS on mechanical ventilation. The interval between repeat administrations may be shortened depending on the time of onset of indications for administration [121].
Broadening or narrowing of indications for pulmonary surfactant (ATC code R07AA) administration can be regulated by local protocols, taking into account the conditions and capabilities of a specific medical organization.
Administration of pulmonary surfactant (ATC code R07AA), both initial and repeated, is performed endotracheally via an endotracheal tube (ETT), using the INSURE method, or via minimally invasive techniques (LISA/MIST). The use of the LISA method during non-invasive mechanical ventilation reduces the likelihood of invasive mechanical ventilation and lowers the risk of severe bronchopulmonary dysplasia (BPD). Other minimally invasive methods of pulmonary surfactant (ATC code R07AA) administration may also be used [122].
Following the administration of pulmonary surfactant (ATC code R07AA), peak/mean airway pressures and FiO2 should be reduced, as the need for supplemental oxygen decreases, pulmonary compliance increases, and the risk of alveolar overdistension rises.
It is recommended to provide non-invasive mechanical ventilation to newborns with RDS or suspected RDS for the treatment of respiratory distress [37,38,123,124].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comments: non-invasive mechanical ventilation includes high-flow nasal cannula, CPAP, and various modes of non-invasive ventilation via nasal cannula or nasal mask. Currently, non-invasive mechanical ventilation via nasal cannula or nasal mask is used as the optimal initial method of non-invasive respiratory support, especially after pulmonary surfactant administration (ATC code R07AA) and/or post-extubation. Furthermore, the use of non-invasive mechanical ventilation reduces the risk of ventilator-induced lung injury and BPD. Thus, the anatomical dead space is reduced, atelectatic alveoli are recruited, and the ventilation-perfusion ratio is normalized [125].
The use of non-invasive mechanical ventilation post-extubation compared to CPAP, as well as after pulmonary surfactant administration (ATC code R07AA), results in a lower need for reintubation and a lower incidence of apnea [123]. Variable-flow non-invasive mechanical ventilation has an advantage over variable-flow CPAP only when an inspiratory time of 1 sec and a respiratory rate of 30 breaths/min are set [126]. The use of variable-flow generator non-invasive mechanical ventilation post-extubation compared to CPAP, as well as following pulmonary surfactant administration (ATC code R07AA), results in a reduced need for reintubation [127].
Indications: as initial respiratory therapy after minimally invasive pulmonary surfactant administration (ATC code R07AA); as respiratory therapy in premature infants post-extubation (including after the INSURE method); occurrence of apnea resistant to CPAP and xanthine derivatives (ATC code N06BC); progression of respiratory failure, increased work of breathing (3 or more points on the Silverman-Andersen scale) and/or increased FiO2 > 0.3 requirement in premature infants on CPAP. Contraindications: Shock, seizures, pulmonary hemorrhage, air leak syndrome.
Recommended is the early administration of xanthine derivatives (ATC code N06BC) — #caffeine citrate to prevent apnea, minimize the need for and duration of invasive mechanical ventilation, and reduce long-term complications in extremely premature newborns on spontaneous breathing or non-invasive respiratory therapy, as well as those on mechanical ventilation prior to planned extubation [38,128-133].
GCR BLOE 2Grade of Recommendation B (Level of Evidence – 2).
Comments: early prophylactic administration of #caffeine citrate (ATC code N06BC) refers to administration within the first 72 hours of life to newborns weighing less than 1500 g and/or with a gestational age of less than 32 weeks, who are on spontaneous breathing or non-invasive respiratory therapy, as well as those on mechanical ventilation prior to planned extubation.
Dosing regimen: for infants with no prior history of therapy with #caffeine citrate (ATC code N06BC), the recommended starting loading dose is 20 mg/kg/day administered as a slow intravenous infusion over 30 minutes. Starting from the second day of therapy, the recommended "maintenance" dose is 5 mg/kg/day administered as a slow intravenous infusion over 10 minutes. The drug should be diluted with the following solutions: parenteral nutrition solutions (ATC code B05BA) — dextrose** (5% intravenous solution), electrolyte solutions (ATC code B05CB) — sodium chloride**
(solution for injection or solvent for preparation of dosage forms for injection 0.9%).
In case of an insufficient therapeutic effect during treatment with #caffeine citrate (ATC code N06BC): recurrent apnea persisting despite caffeine citrate therapy, it is permissible to increase the "maintenance" dose of the drug up to 10 mg/kg/day, divided into 2 doses at 12-hour intervals.
Prophylactic administration of #caffeine citrate (ATC code N06BC) has become widespread based on the results of retrospective cohort studies, despite a significant risk of bias, because an association was found between early initiation of treatment and a reduction in apnea episodes, the need for respiratory therapy, the incidence of bronchopulmonary dysplasia (BPD), hemodynamically significant patent ductus arteriosus (hsPDA), and retinopathy of prematurity.
Studies evaluating the efficacy of early prophylactic administration of #caffeine citrate (ATC code N06BC) with a prospective randomized design are few and show conflicting results. The positive effect of early prophylactic administration of #caffeine citrate (ATC code N06BC) has been proven only in extremely premature newborns without the need for invasive mechanical ventilation at the time of the first drug administration. When #caffeine citrate (ATC code N06BC) was administered within the first 72 hours of life, there was a decrease in the need for invasive mechanical ventilation and its duration, BPD, retinopathy of prematurity, and hsPDA, without an increased risk of necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), or mortality compared to newborns who received a placebo or later administration.
In clinical practice, the use of #caffeine citrate (ATC code N06BC) is continued until the infant reaches a postmenstrual age of 37 weeks. However, this limit may be reconsidered depending on the clinical situation, in individual cases based on the response to treatment, persistence of apnea spells despite treatment, or for other clinical considerations.
The use of #caffeine citrate (ATC code N06BC) should be discontinued if the patient has not experienced significant apnea spells for 5-7 days. If the patient experiences a recurrence of apnea, treatment with #caffeine citrate (ATC code N06BC) is resumed either at the maintenance dose or at half the loading dose, depending on the time interval elapsed since the discontinuation of #caffeine citrate (ATC code N06BC) and the onset of apnea recurrence. Because caffeine is slowly eliminated in this patient population, there is no need for a tapering dose when discontinuing treatment. Given the risk of apnea recurrence after stopping #caffeine citrate (ATC code N06BC) therapy, patient monitoring should be continued for approximately one more week [129,131,132,134-139].
It is recommended to prescribe systemic antimicrobial drugs (ATC code J) to a newborn infant with respiratory disorders and suspected infectious disease, followed by their discontinuation if the infectious diagnosis is ruled out [140,141].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: during the diagnostic process carried out in the first 48–72 hours of life, it is advisable to prescribe antibacterial therapy with its subsequent rapid discontinuation if negative results of systemic inflammatory response markers and blood microbiological culture are obtained. The prescription of antibacterial therapy during the differential diagnosis of respiratory disorders may be indicated for infants with a birth weight of less than 1000 g, infants receiving invasive mechanical ventilation, and infants in whom the results of systemic inflammatory response marker tests performed in the first hours of life are equivocal. The drugs of choice may include a combination of broad-spectrum penicillins (ATC code J01CA) and other aminoglycosides (ATC code J01GB), or a combination of penicillins, including combinations with beta-lactamase inhibitors (ATC code J01CR) [142–145]. Antimicrobial therapy is carried out in accordance with local protocols adopted in a specific medical organization.
3.2. Surgical treatment
Not applicable.
3.3 Other Treatment
The developmental care regime involves creating optimal conditions for nursing newborns.
The infant is indicated to stay in a thermoneutral environment, have restricted sensory stimulation (protection from light, sound, and touch), postural support, and pain management;
The infant is indicated to receive adequate enteral and, if necessary, parenteral nutrition.
It is recommended to feed a newborn with respiratory distress syndrome (RDS) with breast milk from the first days of life; in case of insufficient lactation or contraindications to breastfeeding on the part of the mother, the newborn is fed with an adapted infant formula for feeding term infants from birth or a dry/liquid formula for feeding premature and low-birth-weight infants [146,147].
Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).
Comments: early initiation of enteral feeding (in the first 24 hours of life) with breast milk improves enteral nutrition tolerance, reduces the time to reach full enteral nutrition, decreases the likelihood of late-onset neonatal sepsis, and is not associated with worsening respiratory status or the risk of necrotizing enterocolitis. In preterm infants at high risk of enteral feeding intolerance, it is advisable to start enteral nutrition in trophic volumes, followed by an increase by 10–20 ml/kg/day if tolerated. For preterm infants not belonging to risk groups for enteral feeding intolerance, the volume can be advanced by 30 ml/kg/day. A progressive increase in the volume of enteral nutrition should be used [148,149]. In the absence of breast milk, feeding with an adapted infant formula is possible [147].
It is recommended to selectively administer infusion therapy and parenteral nutrition to a newborn with RDS to provide fluids, electrolytes, proteins, fats, and carbohydrates based on physiological requirements and pathological losses, and to maintain the body's water and electrolyte balance [150-154].
GoR ALoE 2Grade of Recommendation A (Level of Evidence – 2).
Comments: parenteral nutrition is carried out using parenteral nutrition solutions (ATC code B05BA) if it is impossible to deliver the gestational age-appropriate requirement for proteins, fats, carbohydrates, electrolytes, and fluid volume via enteral nutrition. The requirements for fluids, proteins, fats, carbohydrates, and electrolytes depending on gestational age and birth weight are specified in Appendix A3.3. For infusion therapy and parenteral nutrition, the following are used: amino acids for parenteral nutrition (ATC code B05BA01), fat emulsions for parenteral nutrition (ATC code B05BA02), carbohydrates (ATC code B05BA03), electrolyte solutions (ATC code B05XA), and calcium preparations (ATC code A12AA) [155-159].
It is recommended to synchronize newborns with RDS on mechanical ventilation with the ventilator by adjusting ventilation parameters. Routine use of opioids (ATC code N02A) for synchronization with the ventilator is not recommended [2,160].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: routine use of opioids (ATC code N02A) is not advisable for all newborns on mechanical ventilation [160], given the lack of convincing data on pharmacokinetics, efficacy, safety, and impact on the neurocognitive development of preterm infants [161]. Tachyphylaxis develops rapidly in this patient group, and the efficacy of analgesia decreases. It is advisable to synchronize the patient with the ventilator by adjusting ventilation parameters.
Analgosedation should be used if it is necessary to apply "harsh" mechanical ventilation parameters or high-frequency oscillatory ventilation (HFOV), and/or in case of severe pain syndrome.
The use of long- and short-acting muscle relaxants (ATC code M03) for synchronization with the ventilator in preterm infants is not advisable due to the risk of arterial hypotension, hypoxemia, and post-ventilation muscle weakness.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Not applicable.
5. Prevention and Dispensary Observation
In accordance with the clinical guidelines "Preterm Birth", pregnant women at a gestation period of less than 34 weeks with threatened preterm birth should be transported to a level III hospital (perinatal center)1 to improve the quality of medical care [162,163].
In the event of preterm birth at 22 weeks of gestation or more, the woman is hospitalized in an obstetric hospital with a neonatal intensive care unit (wards). If it is impossible to deliver a woman with preterm birth to a level III obstetric hospital, the pregnant woman (woman in labor) is delivered to the nearest maternity hospital (department), while an out-of-hospital pediatric anesthesiology and resuscitation emergency team is called to provide emergency and urgent medical care to the newborn. Indications for hospitalization in a level III hospital may vary depending on the regional routing system for pregnant women.
Pregnant women at a gestational age of 24.0–33.6 weeks with onset (imminent) of preterm birth and premature rupture of membranes (PROM) are recommended antenatal prevention of RDS with systemic corticosteroids (ATC code H02A) (#dexamethasone**, #betamethasone) [164].
GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).
Comments: there are two alternative regimens for prenatal prevention of RDS [164]:
#Betamethasone (ATC code H02A) – 12 mg intramuscularly twice with an interval of 24 hours;
#Dexamethasone** (ATC code H02A) – 6 mg intramuscularly 4 times with an interval of 12 hours or 12 mg twice with an interval of 24 hours.
A positive effect is observed as early as the first hours after the administration of the first dose, triggering the process of lung and vascular maturation (peak concentrations of systemic corticosteroids in cord blood are detected 1 hour after administration to the mother).
The most pronounced reduction in the risk of neonatal mortality and morbidity begins 6 hours after the administration of the first dose of systemic corticosteroids.
The maximum positive effect regarding neurological outcomes is observed with an exposure duration in the range of "48 hours to 7 days". The maximum therapeutic effect develops 24 hours after the initiation of therapy and lasts for a week. By the end of the second week, the effect of systemic corticosteroid therapy (ATC code H02A) decreases significantly. Prophylaxis of fetal RDS at 34–35 weeks of gestation may be prescribed if a previous course of antenatal prophylaxis has not been performed, as well as in the presence of clinical feasibility (diabetes mellitus in a pregnant woman, etc.). A repeated course of fetal RDS antenatal prophylaxis is not routine, and the decision on its use should be made based on the time elapsed since the last course of prophylaxis, gestational age, and the probability of delivery in the next 48 hours [165,163,166,167].
It is recommended to perform delayed cord clamping and transection 60–120 seconds after birth in preterm newborns to improve hemodynamics and reduce mortality, provided there is no need for immediate resuscitation of the mother or infant [37,38,168-171].
GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).
Comments: the decision to perform this procedure is made jointly by obstetrician-gynecologists and neonatologists. Delayed cord clamping should be performed for at least 60 seconds, provided there are no contraindications on the part of the mother and infant. The use of delayed cord clamping reduces the risk of anemia in the early neonatal period, severe intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity, which leads to a reduction in severe disabling complications and mortality [172-174].
Immediately after birth, if the umbilical cord pulsation persists and there is no need for urgent maternal care (determined by obstetrician-gynecologists), delayed cord clamping is performed while maintaining the chain of warmth. During a cesarean section, obstetrician-gynecologists make the initial decision by assessing the woman's condition. If there is no need for emergency maternal care and cord pulsation persists, the infant is placed in a specially prewarmed sterile blanket at the mother's feet and covered with it to prevent excessive heat loss.
An alternative to delayed cord clamping may be cord milking. Routine use of cord milking is not recommended due to insufficient evidence of its safety in extremely preterm newborns, especially infants with a gestational age of less than 28 weeks or extremely low birth weight [37, 171].
1 Order of the Ministry of Health of the Russian Federation No. 1130n dated October 20, 2020, "On Approval of the Procedure for Providing Medical Care in the Field of 'Obstetrics and Gynecology'."
6. Organization of Medical Care
Indications for hospitalization of a pregnant woman with threatened labor or a woman in labor to a Level III medical organization (group):
Pregnancy less than 34 weeks.
Pregnant women from the high-risk group.
Preterm newborns with RDS requiring respiratory support and/or hemodynamic disorders.
Indications for hospitalization in a Level III hospital (group) may vary depending on the regional routing system for pregnant women and newborns.
Indications for discharging a patient from a medical organization:
Stable, satisfactory condition of the infant.
Stabilization of laboratory parameters.
Absence of contraindications for discharge.
7. Additional Information
The prognosis of the disease in the absence of comorbid conditions is generally favorable. Depending on the severity of RDS, severe internal organ damage is possible, in particular the development of BPD. The prognosis depends on concomitant diseases.
Differential diagnosis should be performed with the following diseases and conditions:
Transient tachypnea of the newborn;
Early-onset neonatal sepsis, congenital pneumonia;
Meconium aspiration syndrome;
Air leak syndrome;
Persistent pulmonary hypertension of the newborn;
Lung aplasia/hypoplasia;
Congenital diaphragmatic hernia.
Criteria for Evaluating the Quality of Medical Care
References
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Appendix A1. Working Group Composition
Andreyev Artem Vladimirovich – PhD in Medical Sciences, Anesthesiologist-Resuscitator at the Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor at the Department of Neonatology, Institute of Professional Education, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.
Baybarina Elena Nikolaevna – MD, Professor, Honored Scientist of the Russian Federation, Chief Researcher at the Department of Neonatal and Preterm Infant Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Council Member of the Russian Society of Neonatologists.
Balashova Ekaterina Nikolaevna – PhD in Medical Sciences, Leading Researcher at the Prof. A.G. Antonov NICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor at the Department of Neonatology, Institute of Professional Education, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor at the Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Council Member of the Russian Society of Neonatologists.
Burov Artem Alexandrovich – PhD in Medical Sciences, Head of the Neonatal and Pediatric ICU, 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 of the Russian Ministry of Health; Associate Professor at the Department of Anesthesiology and Intensive Care, Institute of Professional Education, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Council Member of the Russian Society of Neonatologists.
Volodin Nikolay Nikolaevich – MD, Professor, Academician of the Russian Academy of Sciences, President of the Association of Specialists in Perinatal Medicine, Healthcare Provision for Pregnant Women, Fetuses, Newborns, and Children Under 3 Years of Age (ASPM).
Degtyarev Dmitry Nikolaevich – MD, Professor, Deputy Director for Research, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Head of the Department of Neonatology, Pediatric Faculty, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Council Member of the Russian Society of Neonatologists.
Zubkov Viktor Vasilievich – MD, Professor, Director of the Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Head of the Department of Neonatology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor at the Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Council Member of the Russian Society of Neonatologists.
Ionov Oleg Vadimovich – MD, Head of the Prof. A.G. Antonov NICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor at the Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), President of the Russian Society of Neonatologists.
Ionushene Svetlana Vladimirovna – PhD in Medical Sciences, Assistant at the Department of Pediatrics, Irkutsk State Medical Academy of Continuing Education, branch of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health; Chief freelance neonatologist of the Russian Ministry of Health in the Siberian Federal District, Anesthesiologist-Resuscitator at the Irkutsk City Perinatal Center.
Krog-Jensen Olga Alexandrovna – PhD in Medical Sciences, Anesthesiologist-Resuscitator at the 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 of the Russian Ministry of Health; Associate Professor at the Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Russian Society of Neonatologists.
Karpova Anna Lvovna – PhD in Medical Sciences, Head of the Neonatology Inpatient Unit, City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow City Health Department; Associate Professor at the Prof. V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health; Assistant at the Department of Outpatient Therapy, Clinical Laboratory Diagnostics, and Medical Biochemistry, Institute of Professional Development, Yaroslavl State Medical University of the Russian Ministry of Health, Council Member of the Russian Society of Neonatologists.
Kirtbaya Anna Revazievna – MD, Deputy Director for Research, Institute of Neonatology and Pediatrics, Head of Clinical Work at the Prof. A.G. Antonov NICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor at the Department of Neonatology, N.F. Filatova Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Member of the Russian Society of Neonatologists.
Kryuchko Daria Sergeevna – MD, Professor at the Department of Neonatology, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Council Member of the Russian Society of Neonatologists.
Lenyushkina Anna Alekseevna – PhD in Medical Sciences, Head of Clinical Work at ICU No. 2, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Council Member of the Russian Society of Neonatologists.
Mezhinsky Semyon Sergeevich – PhD in Medical Sciences, Anesthesiologist-Resuscitator at the Neonatal Intensive Care Unit, Morozov Children's City Clinical Hospital of the Moscow City Health Department, Assistant at the Prof. V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation.
Mostovoy Alexey Valerievich – PhD in Medical Sciences, Head of the Anesthesiology and Intensive Care Service, City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow City Health Department, Associate Professor at the Prof. V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Assistant at the Department of Outpatient Therapy, Clinical Laboratory Diagnostics, and Medical Biochemistry, Institute of Professional Development, Yaroslavl State Medical University of the Russian Ministry of Health, Chief freelance neonatologist of the Ministry of Health of the Russian Federation in the North Caucasian Federal District, Council Member of the Russian Society of Neonatologists.
Nikitina Irina Vladimirovna – MD, Leading Researcher at the 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 of the Russian Ministry of Health, Head of Studies, Professor at the Department of Neonatology, Institute of Professional Education, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Member of the Russian Society of Neonatologists.
Mark E. Prutkin – Head of the Department of Anesthesiology, Resuscitation, and Intensive Care of Newborns and Preterm Infants at Perinatal Center No. 1, Children's Regional Clinical Hospital, Yekaterinburg; Member of the Council of the Russian Society of Neonatologists
Anna F. Pupysheva – Head of Clinical Work at the ICU No. 2, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.
Andrey Yu. Ryndin – PhD in Medical Sciences, Senior Researcher at the Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University); Member of the Russian Society of Neonatologists.
Alesya A. Rudakova – Senior Researcher, Anesthesiologist-Resuscitator at the A.G. Antonov Neonatal Intensive Care Unit, Ultrasound Diagnostics Physician at the 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 of the Russian Ministry of Health.
Konstantin V. Romanenko – PhD in Medical Sciences, Head of the Neonatal Intensive Care Unit, Regional Perinatal Center.
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; Member of the Council of the Russian Society of Neonatologists.
Elena A. Filippova – PhD in Medical Sciences, Head of the 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 of the Russian Ministry of Health; Member of the Russian Society of Neonatologists.
Diyana R. Sharafutdinova – PhD in Medical Sciences, Anesthesiologist-Resuscitator at the Professor A.G. Antonov Neonatal Intensive Care Unit, Assistant Professor at the Department of Continuing Professional Education and Simulation Technologies, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University).
Appendix A2. Methodology for Developing Clinical Guidelines
Methods used for collecting/selecting evidence: electronic database search.
Description of methods used for collecting/selecting evidence: the evidence base for the recommendations included publications from the Cochrane Library, PubMed, EMBASE, MEDLINE, Scopus, Web of Science, eLIBRARY, ClinicalTrials.gov, electronic libraries, and clinical guidelines 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 covered 69 years.
Methods used for assessing the quality and strength of evidence:
expert consensus;
assessment of significance in accordance with the rating scheme.
Scales for assessing levels of evidence (LoE) (Table P1) for diagnostic, preventive, therapeutic, and rehabilitation methods (diagnostic, preventive, therapeutic, and rehabilitation interventions) with definitions, and the scale for assessing grades of recommendation (GoR) (Table P2) for preventive, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, and 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 reviewed to ensure its validity. Methodological evaluation was based on questions focused on study design features that significantly affect the validity of the 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 reviewed.
Method of guidelines validation:
external expert review;
internal expert review.
Description of the guidelines validation method:
The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.
Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.
The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.
Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.
Consultation and peer review:
Recent modifications to these guidelines are presented for discussion in a preliminary version. The updated version for broad discussion was posted on the website of the Russian Society of Neonatologists (RSN) and the Association of Specialists in Perinatal Medicine, Healthcare for Pregnant Women, Fetuses, Newborns, and Children under 3 Years of Age (ASPM+) www.neonatology.pro and www.raspm.ru, and the Russian Ministry of Health public discussion portal https://portalcr.minzdrav.gov.ru/ to provide all interested parties with the opportunity to participate in the discussion and improvement of 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:
neonatologists
anesthesiologists-resuscitators
pediatricians
obstetricians and gynecologists;
Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
Appendix A3.1. Related Documents
Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Health Protection of Citizens in the Russian Federation."
Order of the Russian Ministry of Health No. 203n of May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."
International Classification of Diseases, Injuries and Causes of Death, 10th Revision (ICD-10) (World Health Organization), 2019 version.
Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on September 24, 2020, with amendments dated October 26, 2022) "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808).
Methodological Letter of the Russian Ministry of Health No. 15-4/I/2-2570 dated March 4, 2020, "Resuscitation and Stabilization of Newborn Infants in the Delivery Room." Edited by E.N. Baybarina. Moscow: Ministry of Health of the Russian Federation; 2020.
Order of the Russian Ministry of Health No. 222n dated April 17, 2025, "On Approval of the Procedure for Providing Medical Care in the Field of 'Neonatology'." (Registered with the Ministry of Justice of Russia on June 2, 2025, No. 82516).
Order of the Russian Ministry of Health No. 1130n dated October 20, 2020, "On Approval of the Procedure for Providing Medical Care in the Field of 'Obstetrics and Gynecology'."
Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On Approval of the List of Vital and Essential Drugs, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for the Provision of Medical Care."
State Register of Medicines: https://grls.rosminzdrav.ru
Appendix A3.2. Target Oxygenation Parameters
Target oxygenation values according to preductal SpO2 in the first 10 minutes of life [74].
Appendix A3.3 Newborn's requirement for fluids, energy, proteins, fats, carbohydrates, and electrolytes
Appendix A3.3.1. Approximate Fluid Requirements in Newborns (mL/kg/day)[175]
Phase 1 – transitional (days 1–5 of life) | ||||
|---|---|---|---|---|
Term | Preterm | |||
Day of life (d.l.) | Body weight > 1500 g | Body weight 1000–1500 g | Body weight < 1000 g | |
1 d.l. | 40-60 | 60-80 | 70-90 | 80-100 |
2 d.l. | 50-70 | 80-100 | 90-110 | 100-120 |
3 d.l. | 60-80 | 100-120 | 110-130 | 120-140 |
4 d.l. | 60-100 | 120-140 | 130-150 | 140-160 |
5 d.l. | 100-140 | 140-160 | 160-180 | 160-180 |
Intermediate phase | 140-170 | 140-160 | ||
Stable growth phase | 140-160 (135-200) | |||
Phase 1 – transitional (days 1–5 of life) Phase 2 – (intermediate) days 7–10 of life Phase 3 – (stable growth phase) after 10 days of life | ||||
Appendix A3.3.2. Recommended Nutrient Doses in Total Parenteral Nutrition [176–178]
Provision of calories [179].
The initial recommended range of E is 40 to 60 kcal/kg/day (energy equivalent to resting metabolic rate). The recommended target total energy value of parenteral nutrition (amino acids + carbohydrates + lipids) for preterm infants is 90-120 kcal/kg/day, and for term infants 85-100 kcal/kg/day.
1 g of protein – 4 kcal
1 g of carbohydrates – 4 kcal
1 g of fat – 9.25-10 kcal
Appendix A.3.3.3. Daily requirement for electrolytes (potassium, sodium, calcium, phosphorus, and magnesium) during total parenteral nutrition [180]
*- start after diuresis is established;
** - doses are indicated with an adequate supply of phosphorus; in the absence of phosphorus, the calcium dose is reduced by 2–4 times (0.4–0.7 mmol/kg) and prescribed taking into account the monitoring of blood calcium levels in the child;
*** - in the first days of life, avoid hypermagnesemia if the mother received magnesium sulfate** (ATX code B05XA) before delivery.
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
An insufficient amount of surfactant in the lungs of a preterm infant leads to the alveoli collapsing (collapsing at expiration), forcing the infant to re-inflate them with each breath. This requires significant energy expenditure, resulting in the newborn's energy being depleted and severe respiratory failure developing. In 1959, American scientists M.E. Avery and J. Mead discovered pulmonary surfactant deficiency in premature infants suffering from respiratory distress syndrome, thereby establishing the primary cause of RDS. The incidence of RDS is inversely proportional to the gestational age at birth. Thus, it affects an average of 60% of infants born at less than 28 weeks of gestation, 15-20% at 32-36 weeks, and only 5% at 37 weeks or more. It is difficult to predict whether RDS will develop in a specific child, but researchers have identified certain high-risk groups. Factors predisposing to the syndrome include maternal diabetes mellitus, infections and smoking during pregnancy, delivery by Cesarean section, being the second twin, and birth asphyxia. Furthermore, boys are known to suffer from RDS more frequently than girls. Prevention of RDS comes down to the prevention of premature birth. Preterm infants require a lot of time for treatment and recovery. Maintaining a positive attitude and supporting breastfeeding are crucial—these two factors are the key to success.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Appendix G1. Respiratory Distress Scoring Scale
Russian title: Silverman-Andersen Respiratory Severity Score.
Original title: The Silverman Andersen respiratory severity score.
Source (official developer website, validation publication):
Silverman W.A., Andersen D.H. A controlled clinical trial of effects of water mist on obstructive respiratory signs, death rate and necropsy findings among premature infants. Pediatrics. 1956;17(1):1-10 [24].
Type: rating scale.
Purpose: assessment of respiratory disorders.
Content (template):
Clinical signs | Score | ||
|---|---|---|---|
0 | 1 | 2 | |
Chest movements | chest and abdomen move synchronously during breathing | arrhythmic, uneven breathing | retraction of the upper chest during inspiration |
Intercostal retractions on inspiration | none | mild retraction | marked retraction |
Xiphoid process retraction on inspiration | absent | slight retraction | marked depression |
Lower jaw position | mouth closed, lower jaw does not lag | mouth closed, chin drops on inspiration | mouth open, chin drops on inspiration |
Expiratory sound | breathing calm and even | expiratory grunting audible upon auscultation | expiratory grunting audible at a distance |
Key (interpretation) and notes:
A score of 1-2 points indicates a compensated condition of the child against the background of ongoing therapeutic measures. An increase in the severity of respiratory disorders ≥ 3 points indicates [24,181-185] the need for escalation of respiratory therapy. Dynamic assessment of respiratory disorders is necessary not so much for diagnostic purposes, but to evaluate the effectiveness of ongoing respiratory therapy or as an indication for its initiation. When performing non-invasive respiratory therapy, the assessment is carried out without disconnecting the patient from the ventilator circuit.
Appendix G2. Respiratory Distress Scoring Scale
Russian title: Downes' Newborn RDS Scoring System.
Original title: Clinical Respiratory Distress Scoring System.
Source (official developer website, validation publication):
Downes J.J. et al. respiratory distress syndrome of newborn infants. I. New clinical scoring system (RDS score) with acid--base and blood-gas correlations. // Clin. Pediatr. (Phila). United States, 1970. Vol. 9, № 6. P. 325–331 [25].
Type: rating scale.
Purpose: assessment of RDS.
Content (template):
Scale | 0 | 1 | 2 |
|---|---|---|---|
Respiratory rate, breaths per minute | < 60 | 60 – 80 | > 80 |
Cyanosis | absent breathing in room air FiO2 = 0,21 | present breathing with FiO2 = 0,21 – 0,4 | present or absent breathing with FiO2 > 0.4 |
Retractions of compliant chest areas | absent | moderate | severe |
Grunting | none | audible with a stethoscope | audible at a distance |
Breath sounds in lungs | clear | delayed or decreased | inaudible or very poorly transmitted |
Key (interpretation) and notes:
When assessing respiratory failure using the Downes score, points are calculated depending on the clinical manifestations in a patient breathing spontaneously:
A score of 0 indicates the absence of respiratory distress syndrome (RDS);
A score of 1 to 3 points indicates early signs of RDS;
A score of 4–6 points indicates moderate RDS (an indication to step up respiratory support);
A total score of 7 points or more in newborns indicates severe RDS.
Appendix G3. Technologies for assessing neonatal lung ultrasound characteristics using LUS and eLUS scales.
Russian title: lung ultrasound 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 [62].
Type: lung ultrasound scoring scale.
Purpose: ultrasound assessment of oxygenation and surfactant replacement therapy needs in newborns managed with CPAP respiratory support.
Content (template):
Figure 1. Method for assessing ultrasound characteristics of lung parenchyma using the LUS scale [62].
Key (interpretation), explanations:
Longitudinal and transverse scanning of the chest is performed using a high-frequency linear transducer.
Each lung is conventionally divided into anterior upper, anterior lower, and lateral regions. A total of 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 coalescent B-lines without consolidations or consolidations limited to the subpleural space (alveolar pattern);
3 points – presence of widespread consolidations;
The total LUS score can range from 0 to 18 points.
The score shows good reliability for predicting surfactant administration in preterm infants with a gestational age of less than 34 weeks treated with nasal CPAP from birth.
eLUS Scale
Russian title: Lung ultrasound 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 RDS.
Ultrasound assessment of the lung parenchyma on days 7 and 14 of life has a high predictive value for the development of moderate and severe BPD when evaluated using the eLUS scale at 14 points or more.
Content (template):
Figure 2. Method for assessing ultrasound characteristics of lung parenchyma using the eLUS scale [89].
Longitudinal and transverse scanning of the chest is performed using 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 regions. A total of 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 coalescent B-lines without consolidations or consolidations limited to the subpleural space (alveolar pattern);
3 points – presence of widespread consolidations.
Total score on the eLUS scale is 0–30 points.
Ultrasound RDS Severity Scale
Russian title: Ultrasound diagnostics and grading criteria for neonatal respiratory distress syndrome.
Original title: Ultrasound diagnosis and grading criteria of neonatal respiratory distress syndrome.
Source: Liu J. Ultrasound diagnosis and grading criteria of neonatal respiratory distress syndrome. J Matern Fetal Neonatal Med. 2023 Dec;36(1):2206943. doi: 10.1080/14767058.2023.2206943 [59].
Type: rating scale.
Purpose: ultrasound assessment of RDS severity.
Based on the clinical picture, a scoring scale for ultrasound lung changes is proposed, which allows distinguishing three grades of RDS severity:
Mild grade refers to a low-intensity type of pulmonary consolidation with interstitial changes, manifesting as a "ground-glass" sign, and may affect all lung fields or only some intercostal spaces;
Moderate grade is characterized by the appearance of subpleural consolidation areas with air bronchograms as a "snowflake sign";
Severe grade refers to any one or more of the following criteria: 1) on ultrasound, pulmonary consolidation appears as a "snowflake sign" and has involved all lung zones; 2) the extent and range of pulmonary consolidation, regardless of severity, have led to serious complications such as pulmonary hemorrhage, pneumothorax, extensive atelectasis (affecting at least one lung zone), or persistent pulmonary hypertension.
New terminology for RDS diagnostics
1- Ground-glass sign (GOS)
is a type of mild lung consolidation without evident consolidation areas containing air bronchograms. Echogenicity in the near field is higher and then gradually decreases from the superficial to the deep field (signal attenuation effect).
Novice or inexperienced physicians can easily confuse GOS with coalescing B-lines.
Fig. 1. Identification of GOS and B-lines. It can be seen that the echogenicity of the B-line (A) and coalescing B-line (B) in the far lung field did not decrease significantly, whereas the echogenicity of the GOS line (C) attenuated significantly in the far field.
The snowflake sign (SFS) is a type of pulmonary consolidation with distinct air bronchograms. It is a characteristic ultrasound finding of the progressive stage (grade II or higher) of RDS.
Figure 2. In B-mode, pulmonary consolidation with air bronchograms is detected in the affected area.
