Medical progress

Can We Understand the Pathobiology of Bronchopulmonary Dysplasia?

There is lack of evidence synthesis on the global consequences of bronchopulmonary dysplasia (BPD) in adolescence.

Assess the impact of bronchopulmonary dysplasia on respiratory and non-respiratory outcomes in adolescents.

A systematic review of studies assessing the outcomes of adolescents aged 10 to 19 years-old with BPD was conducted. We independently screened studies published until 6th March 2023 in PubMed® and Scopus® databases. Data on methodologic design, sample descriptive and findings were extracted from each study. Risk of bias was assessed using quality assessment tools.

Thirty-one studies were included. Adolescents with a history of BPD present with more respiratory symptoms (wheezing, respiratory exacerbations, need for respiratory medication) and twenty-five studies showed a reduction in pulmonary function, with varying impact according to BPD severity and no differences before and after the surfactant era. Spirometry evaluation throughout the years is not consensual, but methacholine and salbutamol response in BPD groups is increased compared to non-BPD groups. Markers of eosinophilic airway inflammation are not increased as in asthma patients. Exercise potential is identical, but data regarding physical capacity and activity are inconsistent. More frequent radiologic abnormalities translate into higher high-resolution computed tomography scores, with linear (72.2 %) and triangular subpleural opacities (58.3 %) as the most common findings. There is a higher risk for special needs in education, but quality of life seems to be equal to non-BPD adolescents.

BPD negatively impacts both pulmonary and non-pulmonary outcomes in adolescents.

Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Despite advances in perinatal care, the incidence of BPD has not improved during the past 2 decades, but this is confounded by the increasing survival rates of preterm infants. Because BPD now affects extreme premature infants born at very early stages of organ development, the consequences of BPD can be associated with lifelong respiratory and neurodevelopmental impairment. BPD is a complex and multifactorial disease affecting an increasingly immature lung, caused by the interaction between antenatal adverse exposures and postnatal factors. The pathologic mechanisms disrupt lung normal growth and lead to abnormal alveolar and microvascular development. Several therapies have been considered to prevent or treat BPD, but none has shown substantial clinical improvement. Respiratory management focuses on preventing positive pressure ventilation and judicious use of oxygen. Pharmacologic approaches target different aspects of BPD pathophysiology. This chapter covers the most commonly used therapies for BPD, including corticosteroids, vitamin A, caffeine, nitric oxide, diuretics, and bronchodilators.

Bronchopulmonary dysplasia (BPD) is a disease of chronic respiratory insufficiency stemming from premature birth and iatrogenic lung injury leading to alveolar simplification, impaired alveolar-capillary development, interstitial fibrosis, and often pulmonary hypertension. BPD is the most common pulmonary sequela of prematurity and is often fatal; however, there remains no FDA-approved therapies to treat or prevent BPD. Sildenafil is increasingly used off-label in premature infants despite scant safety and efficacy data. Sildenafil reduces lung injury and preserves normal vasculature in preclinical models, and improves outcomes in children with pulmonary hypertension, and thus is a promising candidate for BPD. Following phase I studies, we developed the phase II SIL02 trial to describe the safety, pharmacokinetics and preliminary effectiveness of intravenous and enteral sildenafil in premature infants at risk for BPD. SIL02 is a randomized, double-blind, placebo-controlled, 3-cohort, sequential dose-escalating trial of enteral or intravenous (IV) sildenafil dosed every 8 h for up to 34 days. The target IV doses were 0.125, 0.5 and 1 mg/kg/dose in cohorts 1, 2 and 3, respectively; while the enteral doses will be double the IV doses. Eligible infants must be < 29 weeks' gestation at birth and requiring respiratory support at 7–28 days' postnatal age. Adverse events and preliminary effectiveness will be compared by treatment group. Using the final population PK model, empirical Bayesian estimates will be generated for each patient. Preliminary effectiveness will be measured by the incidence of moderate to severe BPD or death at 36 weeks and change in the BPD risk estimation.

La bronchodysplasie est une maladie chronique fréquente de l’enfant né prématuré. Elle résulte d’agressions multiples survenant sur un poumon immature. Des avancées récentes permettent de mieux appréhender sa physiopathologie. La bronchodysplasie associe une atteinte des voies aériennes et une atteinte vasculaire. L’atteinte des voies aériennes associe une simplification alvéolaire, des lésions de l’épithélium bronchique, et une trachéo-bronchomalacie. L’atteinte vasculaire associe une dysangiogenèse, des remaniements des parois artérielles et une dysfonction endothéliale. L’atteinte vasculaire est au premier plan des nouvelles bronchodysplasies : elle détermine largement la morbidité et le pronostic. Les principales conséquences cliniques sont une tendance à l’hypoxie, une hyperréactivité bronchique et une élévation des pressions artérielles pulmonaires. Les formes cliniques sont très hétérogènes, avec des présentations de gravité variable. Chez la plupart des patients, les symptômes ne persistent pas au-delà de la première année de vie. La prise en charge anesthésique diffère selon l’âge et le terrain. Chez le nourrisson de moins d’un an, l’anesthésie doit prendre en compte le risque lié à l’hyperréactivité bronchique, et éviter tous les facteurs pouvant induire une poussée d’hypertension artérielle pulmonaire. Chez le plus d’un an présentant une forme sévère, avec persistance de symptômes ou nécessitant un traitement chronique et un suivi spécialisé, la prise en charge anesthésique est similaire à celle des nourrissons. Chez l’enfant de plus d’un an asymptomatique, le syndrome obstructif peut persister jusqu’à l’âge adulte, mais il n’existe pas de données sur la persistance de niveaux élevés de pressions artérielles pulmonaires : l’anesthésie correspond à celle d’un terrain d’hyperréactivité bronchique.

Pulmonary bronchodysplasia is a chronic disease frequently associated with premature birth. It results from multiple aggressions occurring on an immature lung. Recent advances in the field of physiopathology allow a better understanding of this disease. Bronchodysplasia associates an airway disease and a vascular disease. The airway disease combines alveolar simplification, lesions of the bronchial epithelium, and tracheobronchomalacia. The vascular disease combines dysangiogenesis, alterations in the structure of the vascular walls, and endothelial dysfunction. The vascular disease is the most important component of the “new bronchodysplasia”: it is the main determinant of the morbidity and prognosis of the disease. The main clinical consequences of bronchodysplasia are hypoxia, bronchial hyperreactivity and elevated pulmonary arterial pressures. There is an important heterogeneity in the clinical presentation and the severity of the disease. Most patients remain asymptomatic after the first year of life. Anaesthetic management depends on age, and severity of the disease. In infants, anaesthesia should take into account the risks of airway susceptibility and acute pulmonary hypertension. In older children with a severe disease, still experiencing symptoms and requiring chronic medication, anaesthetic management should be very cautious, and similar to what is described for infants. In older asymptomatic children, airway susceptibility might persist until adulthood, but no data are available to assess the risk of elevated pulmonary arterial pressure: anaesthesia should be managed as in other contexts of bronchial hyperreactivity.

In evaluating vitamin E (VE) nutritional status of preterm infants, it is essential that any data should be compared with those of healthy term infants, and never with those of adults. Moreover, it should be evaluated in terms of gestational age (GA), not birth weight (BW), because placental transfer of most nutrients from mother to fetus is dependent on GA, not BW. Judging from the limited data during the last 75 years, there was no significant correlation between GA and VE concentrations in circulation or in the red blood cells (RBCs), leukocytes, and buccal mucosal cells. In addition, the oxidizability of polyunsaturated fatty acids (PUFAs) in plasma or RBCs, as targets for protection by VE chain-breaking ability, was lower in preterm infants. However, because of the minimal information available about hepatic VE levels, which is considered a key determinant of whole body VE status, the decision on whether VE status of preterm infants is comparable with that of term infants should be postponed.

Clinical trials of VE supplementation in preterm infants were repeatedly undertaken to investigate whether VE reduces severity or inhibits development of several diseases specific to preterm infants, namely retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and germinal matrix hemorrhage - intraventricular hemorrhage (GMH-IVH). Most of these trials resulted in a misfire, with a few exceptions for IVH prevention. However, almost all these studies were performed from 1980s to early 1990s, in the pre-surfactant era, and the study populations were composed of mid-preterm infants with GAs of approximately 30 weeks (wks). There is considerable difference in ‘preterm infants’ between the pre- and post-surfactant eras; modern neonatal medicine mainly treats preterm infants of 28 wks GA or less. Therefore, these results are difficult to apply in modern neonatal care.

Before considering new trials of VE supplementation, we should fully understand modern neonatal medicine, especially the recent method of oxygen supplementation. Additionally, a deeper understanding of recent progress in pathophysiology and therapies for possible target diseases is necessary to decide whether VE administration is still worth re-challenging in modern neonatal intensive care units (NICUs). In this review, we present recent concepts and therapeutic trends in ROP, BPD, and GMH-IVH for those unfamiliar with neonatal medicine.

Numerous studies have reported the possible involvement of reactive oxygen species (ROS)-induced damage in relation to supplemental oxygen use, inflammation, and immature antioxidant defense in the development of both BPD and ROP. Various antioxidants effectively prevented the exacerbation of BPD and ROP in animal models. In the future, VE should be re-attempted as a complementary factor in combination with various therapies for BPD, ROP, and GMH-IVH. Because VE is a natural and safe supplement, we are certain that it will attract attention again in preterm medicine.