Method for prediction of bronchopulmonary dysplasia in newborns with very low or extremely low birth body weight

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to paediatric anaesthesiology and resuscitation, and may be used for the prevention of bronchopulmonary displasia in newborns with very low or extremely low birth body weigth. For this purpose, the treatment regimen actual for the newborns on Biphasic/DuoPAP non-invasive artificial pulmonary ventilation through nasal cannula or CPAP artificial pulmonary ventilation through nasal cannula, or on invasive artificial pulmonary ventilation, is added with bolus administration of Surfactant BL from the 3^rd-5^th day of life in sessions of 10-15 min in a dose of 75 mg an hour. Surfactant BL is administered not later than from the 3^rd-5^th day of newborn's life. The preparation is administered in the amount of 75-150 ml within the therapeutic course. Omron or TravelNeb nebuliser is used.

EFFECT: invention reduces the length of newborn's being on artificial pulmonary ventilation.

3 ex

The invention relates to medicine, namely to pediatric anesthesiology and critical care medicine, and can be used as prevention of bronchopulmonary dysplasia in newborns

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that develops in newborns, mostly deeply premature infants receiving long-term oxygen therapy and artificial ventilation of the lungs with a "hard" ventilation parameters. The first picture of this chronic disease, including clinical and radiological changes in the lungs in premature infants who are on mechanical ventilation to treat respiratory distress syndrome (RDS), described in 1967, Northway et al. This disease requires providing the child with additional needs oxygen at the age of 28 days and older to maintain PaO₂more than 50 mm Hg and has a characteristic pathological changes on the radiograph of the lungs. For the diagnosis of BPD in 1988 Shennan it was proposed to use not calendar age (28 days), as it was previously, and post-conceptual, human papillomavirus (HPV) age 36 weeks. This approach helped to reduce the level of over diagnosis of BPD, which was observed in the case of additional criterion needs oxygen to 28 days after birth. Subsequently, a new modification of the definition and classification of BPD, was asked who and Jobe and Bancalari E. in 2001; it is based on gestational age (less than 32 weeks or more than 32 weeks) and the severity of the disease

According to Japanese researchers, in children with very low body weight at birth (ONMT) (more than 2,500 children), 56% of patients required intubation and mechanical ventilation after birth, and 90% of children oxygen therapy, whereas the diagnosis of BPD was put 28-33% of children [Kusuda S. Morbidity and mortality of infants with very low birth weight in Japan: center variation. Paediatrics. 2006; 118: 1130-1138]. Thus, the need for respiratory support and oxygen are not always signs of the development of BPD. Therefore, it is important to follow up the criteria for this condition of the respiratory system of the newborn EMT and extremely low body weight (extremely low body weight) at birth, which would likely to assume the risk of developing BPD to the child in the future. Such criteria in the early stages after birth are as follows: high leukocytosis in the first day of life (over 30%), x-ray data (typical BPD), the need for additional oxygen supply to maintain RAO₂more than 50 mm Hg after surfactant therapy for RDS, high blood pressure in the pulmonary artery by ultrasound examination. It is important to focus on stages I and II disease. I BPD stage lasts up to 2-3-day life is, and is accompanied by a syndrome of respiratory disorders (SDR) and acute lung damage. At roentgenogram of the chest revealed a typical nodose-reticular network and air bronchograms. On 4-10-day life (stage II) these morphological changes are replaced by exudative bronchiolitis, interstitial edema that appears on the radiograph decrease the transparency of the light and the blurred contours of the cardiac shadow.

The frequency of bronchopulmonary dysplasia is 10% of children with body mass (MT) at birth than 1500 g and more than 40% in children less than 1500 MT, With the development of technology nursing and respiratory therapy premature infants observed an increase in the frequency of BPD at the same time with reduced mortality. Thus, in the period from 1975 to 1990 in the United States the mortality rate among children ONMT and extremely low body weight (less than 1000 g and gestational age less than 30 weeks decreased from 45%to 13%, and the incidence of BPD has increased from 67 to 75%, the severity of BPD decreased.

Data on the incidence of BPD in the Russian Federation there are currently no available information related to the frequency of the disease in individual centers in different regions in different populations of children. According to the maternity hospital №6 Moscow frequency BPD reaches 19.9 per cent.

The increased survival of infants EMT at birth affects not only the quantity, but also quality of subsequent lung disease. Instead of reducing the incidence of BPD in General m is tenderly to see the increasing level of the new BPD, while the frequency of the old (classic) BPD is reduced. According to DU Ovsyannikov [Pediatrics/2012/Volume 91 /number 2/ 102 to 106], the frequency of the classical (severe BPD) in the structure of BPD in preterm children is 15%, while a new form of the disease, in most cases of mild severity, recorded in 85% of patients, the incidence of BPD is inversely proportional MT at birth. So, among the children of extremely low body weight it is growing at 47%, in the group of children ONMT - from 41%in children MT at birth 1500-2499 g - 12%.

In the study the incidence of BPD in children of St. Petersburg and the Leningrad region, including 3024 child, the incidence rate was 0.13 per cent) in St. Petersburg and 0.13% in the Leningrad region. Comparable incidence of BPD (0,17%) was recorded in Germany [Tommiska V, Heinonen K, Kero P, et al. And national two year follow-up study of extremely low birthweight infants born in 1996-1997. Arch. Dis. Child Fetal Neonatal Ed. 2003; 88: F29.].

Currently BPD in developed countries is rare in premature infants weighing at birth more than 1200 g or gestational age of 30 weeks. The vast majority of patients (>75%) in infants of extremely low birth weight at birth (less than 1000 g). The disease may occur in full-term infants, but much less frequently.

In recent years, attempts have been made to explore the possibility prof the prevention and treatment of BPD with surfactant therapy. In some uncontrolled studies have documented the reduction in the incidence of BPD. However, in a multicenter randomized controlled trials of synthetic drug surfactant lucinactant reduce the frequency of BPD have not been reported [M. Laughon, Pediatrics Vol.123, No.1 January 1, 2009 pp.89-96)]. The authors examined 131 child MT from 600 to 900, (44 placebo group, 47 children treated with surfactant at a dose of 90 mg/kg and 45 children treated with the drug at a dose of 175 mg/kg) with insignificant reduction in the requirement of high oxygen concentration to reduce mortality or the development of BPD has not been shown. In the placebo group the figure was 66%and in groups with lucinactant 79% (at a dose of 90 mg/kg), and 58% at 175 mg/kg

Closest to the present invention is a Method of prevention of bronchopulmonary dysplasia in neonates EMT and extremely low body weight at birth by the RF patent №2416388. It is that the patient EMT and extremely low body weight at birth, are on a ventilator or natalina CPAP for at least 7 days, enter the pulmonary surfactant via nebulizer sessions for 10-15 minutes in a single dose 53-75 mg/kg daily or daily interval within 1-5 days. The introduction of Surfactant-BL using the nebulizer with a generator OnQ aerosol Aeroneb Pro is newborns on mechanical ventilation or respiratory support with nasal CPAP or non-invasive ventilation (Biphsic/DuoPAP) 8 the nya respiratory therapy, daily or daily period, before feeding sessions for 10-15 minutes depending on the volume injected emulsion surfactant, a single dose 53-75 mg/kg, maximum 5 sessions. This way, as noted by the authors, prevents the development of patients with RDS and congenital pneumonia, increases survival and reduces disability.

However, the prototype method requires a long stay on newborn respiratory support (from 20 to 50 days), high consumption of surfactant (225-300 mg per treatment) and the need to use expensive nebulizer, which costs 1.5 thousand euros. This makes the method available for General clinical practice.

The technical result of the present invention is to reduce the time of stay of a newborn baby on a ventilator due to the introduction of Surfactant-BL within 3-5 days of his life, but also the possibility of using available nebulizer.

This result is achieved by the known method of prevention of bronchopulmonary dysplasia in neonates EMT and extremely low body weight at birth, are non-invasive mechanical ventilation in the Biphasic mode/DuoPAP via nasal cannula or CPAP via nasal cannula or invasive mechanical ventilation, including the introduction of Surfactant-BL sessions for 10-15 minutes at a dose of 75 mg per session with the help of a nebulizer according to the invention, the introduction of Surfactant-The L begin no later than 3-5 days of life of the newborn, enter it 75-150 mg per treatment course, and as a nebulizer use Omron or TravelNeb.

The introduction of Surfactant-BL no later than 3-5 days of a child's life allows the next day after the first dose of the drug to exuberate it and transfer on non-invasive ventilation. This significantly reduces the duration of stay of the child on the hard settings, mechanical ventilation, reducing the damaging effect of oxygen on the lungs, which can cause secondary surfactant deficiency and respiratory failure. Early introduction of natural pulmonary surfactant - Surfactant-BL helps to maintain the lumen of the bronchi and bronchioles, improves mucociliary clearance, increases the activity of alveolar macrophages, reduces the activity of inflammation in the epithelium of the bronchi, involves breathing atelectasia lung area. Surfactant-BL is an excellent substrate for the synthesis of their own surfactant. In the result, this prevents the development of BPD.

The need for single or double injection of surfactant is dictated by the condition of the child and we found empirically.

The use of 75-150 mg of Surfactant BL for the entire course of treatment was sufficient to prevent BPD is due, in our opinion, the beginning of its introduction, as well as the unique properties of the drug, and property named is, a full range of pulmonary surfactant phospholipids and high content (2%to 2.5%) surfactant-associated proteins that are absent in the synthetic surfactant preparations or with their low content in polysynthetically and known natural surfactant preparations.

The use for the introduction of surfactant Omron nebulizers or TravelNeb provides the wide availability of way. The essence of the method is illustrated by examples.

Example 1.

Premature girl with ANMT was born in goose "Presidential perinatal centre MOH CP Chuvash Republic, Cheboksary.

Born 08.11.2011 from his mother, burdened by history (III pregnancy medical abortion) from IV pregnancy occurring with anemia, low placentation, the threat of miscarriage in the period of 9-10 weeks. The weight of the baby 1290 Length 43 see Estimation on Apgar scale 3/6 points. With birthday girl's condition is assessed as severe. Resuscitation in the delivery room: the rehabilitation of the upper respiratory tract (TTP), tracheal intubation, the introduction of Curosurf 120 mg/kg prophylactic method INSURE, further non-invasive ventilation (CPAP) via a nasal cannula, prevention of infections: Sulfacetamide 20% No. 3.

During the early neonatal period: the condition of the child after birth is very difficult, due to congenital pneumonia on a background of piranese the Noah severe asphyxia. Assigned to antibiotic therapy, infusion therapy, started enteral nutrition. It was noted episodes of apnea with bradycardia. Girl on spontaneous breathing at a positive pressure (SDPD) - CPAP via nasal cannula for 1 day with parameters FiO_{2(partial pressure of oxygen in the feed gas mixture)}= 21-30%, MAP_{(mean airway pressure)}= 6,5, Peep_{(positive pressure at the end of exhalation)}= 5 cm

If rentgenografii chest: lung fields uniformly transparent, sinuses available, aperture on the 8th rib.

On the 3rd day of life was observed arrhythmia breath with episodes of apnea, increased dyspnea, increased need for oxygen support. Due to increasing respiratory distress, initiated SDPD via nasal cannula (NCPAP), increased options when conducting CPAP and translation for non-invasive ventilation (Biphasic) at a sufficiently "hard" parameters: FiO₂=40-50%, MAR=7.5 cm, Rear=7, see

The basis of such a negative impact on lung tissue lies a significant overload of the pulmonary circulation due to the return of the greater part of the blood to the lungs, bypassing the systemic circulation, resulting in interstitial edema due to transudation of fluid into the lumen of the alveoli, inactivation of surfactant and poor mechanics is agcih and deterioration of gas exchange. Given these factors and the presence of infection (congenital pneumonia), contributing to the development of BPD, on the 3rd day of life girls it was decided to conduct inhalation introduction of Surfactant-BL. Put 75 mg medication via nebulizer Omron.

On the 5th day girl charged with NCPAP, but another day was needed to supply oxygen through the nasopharyngeal catheter.

With immunogenetically order repeatedly (No. 4) was introduced Pentaglobin, to prevent apnea - caffeine citrate. On the 13th day of life, given respiratory disorders arrhythmia breathing-inhalation of berodual and pulmicort.

On the background of therapy the child with positive dynamics, at the time a discharge is satisfactory. Sucks nipples 65 ml, not spit up. Does not need additional oxygen support. Breathing disorders no. In the lungs, the breath is held in all departments, no wheezing. Hemodynamics stable. Wide umbilical ring. The total number of days of hospitalization 44 days.

Clinical diagnosis in the hospital: congenital pneumonia. Severe birth asphyxia. Cerebral ischemia II. Apnea of prematurity. The oval window. Prematurity. Very low body weight at birth.

Diagnosis at discharge home: retinopathy of prematurity II degree. Prematurity. Dysbacteriosis of the intestine.

Re the query result: Because the risk of developing BPD this child ONMT, were on non-invasive ventilation sufficient "hard" settings and have radiological signs of lung damage was high, we believe that the introduction in the treatment of Surfactant-BL prevented the development of BPD. In a follow-up period up to 6 months respiratory disorders were not observed signs of BPD no. In the process of conducting a preventive course of ART therapy was introduced 75 mg drug Surfactant-BL. With NCPAP girl was removed on the 5th day.

Example 2.

Premature boy extremely low body weight at birth from the first pregnancy of the mother of 23 years, going on in the background anemia with threatened miscarriage. Born in goose "Presidential perinatal centre MOH CP Chuvash Republic, Cheboksary, body mass 989 g, length 35 cm with estimation on Apgar scale 4/5 points.

Resuscitation in the delivery room: due to the irregular breathing were intubated and mechanically ventilated transferred on a ventilator. Prophylactic entered Curosurf at a dose of 120 mg/kg bolus. Child in critical condition delivered in a transport incubator in the intensive care unit and a neonatal intensive care on a ventilator.

During the early neonatal period: the condition of the child after birth was regarded as very difficult. Under aseptic conditions produced catheterization of the umbilical vein, which began infusion therapy (dopamine at a dose of 4 mcg/kg/min in accordance with the om reduction of contractile function of the myocardium). After 6 hours after birth, given the high index oxygenate (IO above 4), the oxygen demand of more than 40%, re-entered Curosurf at a dose of 120 mg/kg due To improved oxygenation parameters, the efficiency of breathing child excubitor and transferred to non-invasive ventilation through 10 hours after birth. 30 hours after birth started enteral and parenteral nutrition.

With 3 days of life marked deterioration, increase breathing disorders in the form of frequent episodes of apnea with bradycardia, the child is again transferred on a ventilator when performing ultrasound of the heart diagnosed with hemodynamically significant functioning arterial duct (GBS FAL)assigned to a course of ibuprofen. When the control ultrasound of the heart signs so far not been identified. However, to mitigate the parameters of the ventilator failed, the oxygenation index greater than 4 (MAP=11 cm, FiO₂=45%). According to KHS (acid-alkaline) pH - 7,27, pO_{2(the partial pressure of oxygen in capillary blood)}=43 Hg, pCO_{2(partial pressure}CO_{2 in capillary blood)}=79. on the chest x-ray homogeneous darkening of the lung fields, which is an adverse prognostic factor in the development of BDL, so decided to start surfactant therapy. On the 5th day of life was introduced inhalation Surfactant-BL at a dose of 75 mg through nebul is user TravelNeb. Ha 6th day of life (the next day after inhalation surfactant) child excubitor and transferred to NCPAP with parameters: FiO₂=30-40%, MAP=6,5 see Peep=5 cm, However, significant further improvement was not observed, the child continued to need the increased oxygen content in the feed gas mixture (FiO₂=35%). Lung damage was significant (È0=3), chest x-ray remained homogeneous darkening of the lung fields with no signs of blow-UPS of the lungs. Given these data on the status of the child and at high risk of developing BPD, on the 10th day of life for the prevention of BPD he repeated inhalation introduction of surfactant BL at a dose of 75 mg For 6 days after re-introduction of the drug (i.e. on the 16th day of life) the child is removed from NCPAP. For prevention of apnea was administered caffeine citrate.

On full enteral nutrition child transferred on the 30th day of life, parenteral nutrition canceled.

The child is transferred to stage 2 survival at the age of 34 days of life. In connection with animeseries conducted blood transfusion erythrocyte mass. When ophthalmological screening study identified perminate with high risk of progression was appointed eye drops emoxipin.

The boy was discharged home at the age of 2 months 6 days. Feel satisfactory, sucks well, is active on the review responds, scream loud. The breath in the lungs puerile conducted on all fields, no wheezing.

Diagnosis at discharge home: retinopathy of prematurity II degree. Prematurity. Dysbacteriosis of the intestine. Cerebral ischemia II. Early anemia of prematurity.

The result: Given the birth of a child is extremely low body weight, GBS FAL, worsening the course of RDS requiring increased oxygenation parameters, the child had prevented the development of severe BPD due to the introduction in the treatment of Surfactant-BL. In a follow-up period up to 6 months respiratory disorders are not marked, signs of BPD no. In the process of conducting a preventive course of surfactant therapy was introduced 150 mg drug Surfactant-BL. The child is removed from non-invasive mechanical ventilation on the 16th day.

Example 3.

Premature boy was born 08.11.2011, goose "Presidential perinatal centre MOH CP Chuvash Republic, Cheboksary. The child from the mother burdened with history (I, II pregnancy medical abortion), III pregnancy real, proceeding with the threat of termination for the period of 15 weeks, at 18-19 weeks received inpatient treatment (dropsy pregnant). The child's weight 1370 Length 41 see Estimation on Apgar scale 4/7 points. Resuscitation in the delivery room: the reorganization of the SDT, tracheal intubation, the introduction of Curosurf 120 mg/kg prophylactic method INSURE, then SDPD (CPAP) h is through nasal cannula, prevention of infections - Sulfacetamide 20% No. 3.

During the early neonatal period: the condition of the child after birth was regarded as a very heavy, pronounced respiratory disorders, child moans, General edema syndrome, hemodynamic disturbances. Under aseptic conditions produced catheterization of the umbilical vein, which began infusion therapy (dopamine at a dose of 4 mcg/kg/min with regard to the reduction of contractile function of the myocardium). 10 hours after birth the child is transferred to the intensive care unit, is transported on the ventilator. Given respiratory disorders, high oxygenation index (above 4), the oxygen demand of more than 40%, was introduced Curosurf dose of 180 mg/kg per rengenografii chest: lung fields uniformly transparent, sinuses available, the aperture in the 9th intercostal space, mediastinum occupies a middle position. In view of improvement of parameters of oxygenation and adequate performance of the breathing of the child was extubated and transferred to non-invasive ventilation. By the end of the 1st day of life started enteral and parenteral nutrition.

On the 3rd day of life the child's condition worsened - developed hemorrhagic syndrome (stomach bleeding), appointed hemostatic therapy and transferred Etnography FFP (fresh frozen plasma) at a rate of 15 ml/kg

On the 4th day of life Uwe who icelos retraction of the sternum during breathing and appeared dependent on the increased oxygen content in the inhaled mixture. When conducting rengenografii chest: lung fields reduced transparency, appeared swelling of the lung fields, the diaphragm on the 9th rib, increased options when conducting NCPAP. Translation into non-invasive ventilation (Biphasic): FiO₂=40%, MAR=6.5 cm, Rear=5,5 see Taking into account these signs of respiratory distress and eligibility risk of developing BPD, it was decided to hold the inhalation introduction of surfactant-BL. The drug was entered twice (on the 4th and 5th day of life) via nebulizer Omron in the amount of 75 mg per session, for a total of 150 mg.

On the 7th day of life the child is removed from NCPAP, on the following day needed oxygen flow through the nasopharyngeal catheter. Has been a gradual increase in the volume of enteral nutrition, and correction of anemia by Carmona (to stimulate erythropoiesis), multiferon, folic acid. With immunogenetically order repeatedly (No. 6) was introduced Pentaglobin.

On the 9th day of life the child is transferred to the second stage follow-up within 3 days remained arrhythmia respiratory, CNS depression syndrome.

The duration of respiratory therapy was 9 days. The total duration of hospitalization 43 days.

Discharged home in good condition, sucks well, 60 ml, weight at discharge 2250, active Boy, to explore react, scream loud. Breathing in l is gcih puerile, carried out all fields, no wheezing.

Diagnosis at discharge home: prematurity. Very low body weight at birth. Cerebral ischemia II. Retinopathy of prematurity first degree. Early anemia of prematurity.

The result: we Believe that early introduction of Surfactant-BL was reduced duration of respiratory support, reduced ventilation modes, prevented further deterioration and, as a result, are not allowed progression to severe BPD. In a follow-up period up to 6 months respiratory disorders are not marked, signs of BPD no. In the process of conducting a preventive course of surfactant therapy was introduced 150 mg drug Surfactant-BL.

To date, with the aim of preventing the development of severe BPD in neonates EMT and extremely low body weight treatment 35 infants, 21 ONMT and 14 extremely low body weight. Only two children weighing 600 g or 700 g at birth failed to prevent the development of severe BPD. The rest of newborns with a high risk of developing BPD were in fairly early stages removed from non-invasive mechanical ventilation and did not show signs of this disease in future monitoring up to 6 months of life.

The proposed method is compared with the known has a number of advantages:

- Significantly reduces the time a newborn as invasive and neonazi the Noah ventilation - to 5-16 days, while in the prototype it is from 20 to 50 days.

- Reduces the amount of surfactant up to 75-150 mg of treatment, while in the prototype spent 225-300 mg

- Allows usage for the introduction of surfactant available and inexpensive nebulizers - Omron is 7600 rubles, TravelNeb - 4700 rubles), while in the prototype used a nebulizer cost 1.5 thousand Euro.

The method developed in goose "Presidential perinatal centre MOH CP of the Chuvash Republic in cooperation with RSC RCT (SPb) and passed to date, clinically tested in 35 neonates with a positive result.

The way to prevent bronchopulmonary dysplasia in neonates very low and extremely low body weight at birth, are non-invasive mechanical ventilation in the Biphasic mode/DuoPAP via nasal cannula or CPAP via nasal cannula or invasive mechanical ventilation in the background of supportive therapy, including the introduction of Surfactant BL sessions for 10-15 min at a dose of 75 mg per session using the nebulizer, characterized in that the introduction of Surfactant BL begin no later than 3-5 days in the life of a newborn, enter it in the number of 75-150 mg of treatment, and as a nebulizer use Omron or TravelNeb.