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In this multicenter, randomized trial involving women at high risk for late preterm delivery, administration of betamethasone significantly reduced the rate of neonatal respiratory complications. Antenatal glucocorticoids are widely used in obstetrics for pregnancies at risk for early preterm delivery. Their use increased especially after a consensus conference held by the National Institutes of Health in 1994, which concluded that there was strong evidence that glucocorticoids reduce adverse neonatal outcomes, including death, the respiratory distress syndrome, and other complications, when administered to women who are likely to deliver before 34 weeks of gestation. 1 – 3 The recommendation was not extended to women at risk for preterm delivery after 34 weeks because of both a lack of data 4 , 5 and the belief that at a threshold of . . .

Background Bronchopulmonary dysplasia (BPD) is the result of a complex process in which several prenatal and/or postnatal factors interfere with lower respiratory tract development, leading to a severe, lifelong disease. In this review, what is presently known regarding BPD pathogenesis, its impact on long-term pulmonary morbidity and mortality and the available preventive and therapeutic strategies are discussed. Main body Bronchopulmonary dysplasia is associated with persistent lung impairment later in life, significantly impacting health services because subjects with BPD have, in most cases, frequent respiratory diseases and reductions in quality of life and life expectancy. Prematurity per se is associated with an increased risk of long-term lung problems. However, in children with BPD, impairment of pulmonary structures and function is even greater, although the characterization of long-term outcomes of BPD is difficult because the adults presently available to study have received outdated treatment. Prenatal and postnatal preventive measures are extremely important to reduce the risk of BPD. Conclusion Bronchopulmonary dysplasia is a respiratory condition that presently occurs in preterm neonates and can lead to chronic respiratory problems. Although knowledge about BPD pathogenesis has significantly increased in recent years, not all of the mechanisms that lead to lung damage are completely understood, which explains why therapeutic approaches that are theoretically effective have been only partly satisfactory or useless and, in some cases, potentially negative. However, prevention of prematurity, systematic use of nonaggressive ventilator measures, avoiding supraphysiologic oxygen exposure and administration of surfactant, caffeine and vitamin A can significantly reduce the risk of BPD development. Cell therapy is the most fascinating new measure to address the lung damage due to BPD. It is desirable that ongoing studies yield positive results to definitively solve a major clinical, social and economic problem.

Early treatment with ibuprofen for a large patent ductus arteriosus did not result in a lower risk of death or moderate or severe bronchopulmonary dysplasia than placebo at 36 weeks of postmenstrual age.

In animal models, inhaled nitric oxide improved gas exchange and lung structural development, but its use in premature infants at risk of developing bronchopulmonary dysplasia remains controversial. We therefore tested the hypothesis that inhaled nitric oxide at a low concentration, started early and maintained for an extended period in babies with mild respiratory failure, might reduce the incidence of bronchopulmonary dysplasia. 800 preterm infants with a gestational age at birth of between 24 weeks and 28 weeks plus 6 days (inclusive), weighing at least 500 g, requiring surfactant or continuous positive airway pressure for respiratory distress syndrome within 24 h of birth were randomly assigned in a one-to-one ratio to inhaled nitric oxide (5 parts per million) or placebo gas (nitrogen gas) for a minimum of 7 days and a maximum of 21 days in a double-blind study done at 36 centres in nine countries in the European Union. Care providers and investigators were masked to the computer-generated treatment assignment. The primary outcome was survival without development of bronchopulmonary dysplasia at postmenstrual age 36 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00551642. 399 infants were assigned to inhaled nitric oxide, and 401 to placebo. 395 and 400, respectively, were analysed. Treatment with inhaled nitric oxide and placebo did not result in significant differences in survival of infants without development of bronchopulmonary dysplasia (258 [65%] of 395 vs 262 [66%] of 400, respectively; relative risk 1·05, 95% CI 0·78–1·43); in survival at 36 weeks' postmenstrual age (343 [86%) of 399 vs 359 [90%] of 401, respectively; 0·74, 0·48–1·15); and in development of bronchopulmonary dysplasia (81 [24%] of 339 vs 96 [27%] of 358, respectively; 0·83, 0·58–1·17). Early use of low-dose inhaled nitric oxide in very premature babies did not improve survival without bronchopulmonary dysplasia or brain injury, suggesting that such a preventive treatment strategy is unsuccessful. INO Therapeutics.

Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. Impact PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.

Abstract Rationale Bronchopulmonary dysplasia is the most common morbidity of prematurity, but the validity and utility of commonly used definitions have been questioned. Objectives To compare three commonly used definitions of bronchopulmonary dysplasia in a contemporary prospective, multicenter observational cohort of extremely preterm infants. Methods At 36 weeks postmenstrual age, the following definitions of bronchopulmonary dysplasia were applied to surviving infants with and without imputation: need for supplemental oxygen (Shennan definition), National Institutes of Health Workshop definition, and “physiologic” definition after a room-air challenge. Measurements and Main Results Of 765 survivors assessed at 36 weeks, bronchopulmonary dysplasia was diagnosed in 40.8, 58.6, and 32.0% of infants, respectively, with the Shennan, workshop and physiologic definitions. The number of unclassified infants was lowest with the workshop definition (2.1%) and highest with the physiologic definition (16.1%). After assigning infants discharged home in room air before 36 weeks as no bronchopulmonary dysplasia, the modified Shennan definition compared favorably to the workshop definition, with 2.9% unclassified infants. Newer management strategies with nasal cannula flows up to 4 L/min or more and 0.21 Fi  O2 at 36 weeks obscured classification of bronchopulmonary dysplasia status in 12.4% of infants. Conclusions Existing definitions of bronchopulmonary dysplasia differ with respect to ease of data collection and number of unclassifiable cases. Contemporary changes in management of infants, such as use of high-flow nasal cannula, limit application of existing definitions and may result in misclassification. A contemporary definition of bronchopulmonary dysplasia that correlates with respiratory morbidity in childhood is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01435187).

Pulmonary hypertension (PH) is associated with poor outcomes among preterm infants with bronchopulmonary dysplasia (BPD), but whether early signs of pulmonary vascular disease are associated with the subsequent development of BPD or PH at 36 weeks post-menstrual age (PMA) is unknown. To prospectively evaluate the relationship of early echocardiogram signs of pulmonary vascular disease in preterm infants to the subsequent development of BPD and late PH (at 36 wk PMA). Prospectively enrolled preterm infants with birthweights 500-1,250 g underwent echocardiogram evaluations at 7 days of age (early) and 36 weeks PMA (late). Clinical and echocardiographic data were analyzed to identify early risk factors for BPD and late PH. A total of 277 preterm infants completed echocardiogram and BPD assessments at 36 weeks PMA. The median gestational age at birth and birthweight of the infants were 27 weeks and 909 g, respectively. Early PH was identified in 42% of infants, and 14% were diagnosed with late PH. Early PH was a risk factor for increased BPD severity (relative risk, 1.12; 95% confidence interval, 1.03-1.23) and late PH (relative risk, 2.85; 95% confidence interval, 1.28-6.33). Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life (P < 0.05). Early pulmonary vascular disease is associated with the development of BPD and with late PH in preterm infants. Echocardiograms at 7 days of age may be a useful tool to identify infants at high risk for BPD and PH.

Bronchopulmonary dysplasia (BPD) is a serious neonatal pulmonary condition associated with premature birth, but the underlying parenchymal disease and trajectory are poorly characterized. The current National Institute of Child Health and Human Development (NICHD)/NHLBI definition of BPD severity is based on degree of prematurity and extent of oxygen requirement. However, no clear link exists between initial diagnosis and clinical outcomes. We hypothesized that magnetic resonance imaging (MRI) of structural parenchymal abnormalities will correlate with NICHD-defined BPD disease severity and predict short-term respiratory outcomes. A total of 42 neonates (20 severe BPD, 6 moderate, 7 mild, 9 non-BPD control subjects; 40 ± 3-wk postmenstrual age) underwent quiet-breathing structural pulmonary MRI (ultrashort echo time and gradient echo) in a neonatal ICU-sited, neonatal-sized 1.5 T scanner, without sedation or respiratory support unless already clinically prescribed. Disease severity was scored independently by two radiologists. Mean scores were compared with clinical severity and short-term respiratory outcomes. Outcomes were predicted using univariate and multivariable models, including clinical data and scores. MRI scores significantly correlated with severities and predicted respiratory support at neonatal ICU discharge (P < 0.0001). In multivariable models, MRI scores were by far the strongest predictor of respiratory support duration over clinical data, including birth weight and gestational age. Notably, NICHD severity level was not predictive of discharge support. Quiet-breathing neonatal pulmonary MRI can independently assess structural abnormalities of BPD, describe disease severity, and predict short-term outcomes more accurately than any individual standard clinical measure. Importantly, this nonionizing technique can be implemented to phenotype disease, and has potential to serially assess efficacy of individualized therapies.

In a randomized trial involving extremely-low-birth-weight infants eligible for noninvasive ventilation, the survival rate without bronchopulmonary dysplasia after nasal intermittent positive-pressure ventilation was similar to the rate after nasal continuous positive airway pressure. In extremely-low-birth-weight infants, bronchopulmonary dysplasia remains a leading cause of early death, 1 a strong predictor of later neurologic impairment, 2 and a major reason for resource use 3 and rehospitalization during the first year of life. 4 Improvements in survival rates among such infants have led to rates of bronchopulmonary dysplasia of up to 60% at the lowest gestational ages. 1 , 5 , 6 Tracheal intubation and mechanical ventilation are associated with ventilator-induced lung injury and airway inflammation, leading to bronchopulmonary dysplasia. 7 , 8 Prolonged duration of intubation and mechanical ventilation in extremely-low-birth-weight infants is associated with an increased risk of death or survival with neurologic . . .

Background AVR-48 is a small molecule that modulates toll-like receptor 4 (TLR4) activity, changing macrophage phenotype from pro- to anti-inflammatory and increasing the anti-inflammatory cytokine IL-10. Treatment with AVR-48 via intraperitoneal injection effectively prevented hyperoxia-induced pathology in a newborn mouse model of bronchopulmonary dysplasia (BPD). Objective To evaluate the early and late-stage efficacy of AVR-48 in preventing BPD and associated complications in a mechanically ventilated preterm lamb model that mimics human BPD. Design and methods Preterm lambs were delivered at 128 days (d; about 85% gestation) following the administration of maternal antenatal steroids, intubated, given surfactant, and managed with invasive mechanical ventilation for seven days, followed by three days of noninvasive respiratory support. Either vehicle or AVR-48 was administered to the preterm lambs via intravenous bolus infusion six hours after birth and continued for seven days (every 12 h). Equivalent early (10 d) and late-stage (90 d) endpoints were selected to model human clinical outcomes at 36 weeks and 12–18 months post-natal age, respectively. Survival, growth, pulmonary pathology, respiratory system function, cardiovascular function, and neurobehavioral parameters were evaluated at both early and late stages. The forced oscillation technique was used to assess the resistance and reactance of the respiratory system. Blood samples were collected to determine the pharmacokinetics of AVR-48 and to measure levels of inflammatory and anti-inflammatory cytokines. Lung homogenates were analyzed for TLR4, cleaved caspase-3, p53, PCNA, VEGF, VEGF-R2, and other biomarkers using immunoblot and RT-PCR. Results Compared to the vehicle, AVR-48 at 3.0 mg/kg significantly reduced respiratory severity scores, increased lung compliance, decreased lung resistance, and preserved alveolar formation without inflammation or fibrosis at 10d. In the 90d study, AVR-48 improved respiratory system mechanics, alveolar formation, and neurodevelopmental outcomes compared to vehicle controls. A decrease in the pro-inflammatory cytokines (IL-1β, IL-6) and an increase in the anti-inflammatory cytokine IL-10 in lamb plasma collected between days 1 and 10 were noted. Lung tissue showed decreased TLR4 protein and inflammatory cytokines at 90d. Conclusion AVR-48 is a promising novel candidate drug for further development in preventing BPD and has the potential to reduce the associated adverse neurodevelopmental sequelae in preterm neonates.