Can We Enhance Long Term Respiratory Outcomes of Neonatal Pulmonary Diseases?

ABSTRACT

Infants born prematurely and infants born with neonatal pulmonary diseases are at risk for long term abnormal lung functions. In this review we will discuss efforts to enhance long term respiratory outcomes in premature infants, including the use of tracheostomy in those with severe bronchopulmonary dysplasia (BPD). We will further discuss long term respiratory abnormalities in newborns with congenital diaphragmatic hernia (CDH), representing infants with lung hypoplasia.

Infants born prematurely are born in a “critical developmental time period” and because of arrest of lung maturation their pulmonary functions are below the normal for their age. Lung function abnormalities include airway obstruction and ventilation inhomogeneity. Prematurity, low birth weight and intra uterine growth restriction (IUGR) might have lifelong effects and predispose to asthma (or “asthma like” symptoms) and chronic obstructive pulmonary disease (COPD).

Can we improve the outcome of chronic lung disease of prematurity? Efforts to achieve that goal are done and being studied during the prenatal period, the neonatal period, and during childhood (preventing RSV bronchiolitis and other infections), puberty and beyond (avoiding smoking).

During the neonatal period a comprehensive strategy needs to be implemented. Non‐invasive ventilation and gentle support to keep the functional residual capacity, and non‐invasive methods of surfactant administration are used. If endotracheal ventilation is mandatory, lung protective modes of ventilation (volume guarantee or high frequency) are recommended. Adequate oxygenation and permissive hypercapnia are kept. Caffeine and nutrition are used to avoid ventilation and allow lung growth. The literature supports this strategy, and new RCT were recently published, trying to identify new strategies to improve the respiratory outcomes of these infants.

Intratracheal administration of budesonide‐surfactant for prevention of BPD was studied by Manley et al. [1] in a large RCT including 1059 extremely premature infants. They concluded that in extremely preterm infants receiving surfactant for respiratory distress syndrome (RDS), early intratracheal budesonide may have little to no effect on survival free of BPD.

Nasal intermittent positive pressure ventilation (NIPPV) was shown to be superior to nasal continuous positive pressure (NCPAP) in preventing intubation and reducing BPD. Dargaville et al. studied the effect of adding minimal invasive surfactant therapy (MIST) while infants are on nasal respiratory support in a RCT including 485 infants born at 25−28 weeks gestational age. Selective use was performed in infants with FiO₂ > 0.3 in their first 6 h of life and on nasal support. The primary outcome of death or BPD was not changed but BPD was significantly reduced. At 2 years, death or neurodevelopmental outcomes did not change, but MIST appeared to considerably improve respiratory health in the first 2 years [2].

The effect of nasal continuous positive airway pressure (NCPAP) on lung growth was studied by McEvoy et al. [3]. They reported pulmonary functions at 6 months of age in infants who were exposed to extended 2 weeks of NCPAP and found an increased alveolar volume and diffusing capacity of the lungs for carbon monoxide (DLCO) in the extended NCPAP group. Thus, such a therapy may lead to improved infant respiratory health and improved lung function trajectory.

Infants with severe BPD, who are ventilator dependent at 40−44 weeks corrected gestational age are a subpopulation that needs extra attention. The tracheostomy might facilitate home discharge and improved respiratory stability. Furthermore, it might increase comfort and decrease the use of neurosedatives and promote developmental therapies [4]. However, there are short term procedural risks and emotional stress to the family. The literature suggests that a reasonable approach is that chronically ventilated infants should be assessed at 3 months of age what is close to being around or shortly after 40 weeks corrected gestational age. If the respiratory support remains high and there is no evidence of improvement for 2 months, then infants should be considered for tracheostomy placement, even if the infants are on high ventilation settings.

Does tracheostomy enhance the long term respiratory and developmental outcomes of these infants? In this review will summarize the current knowledge for infants during the hospitalization and for infants who were discharged with tracheostomies. It is possible to conclude that although extreme prematurity associated with severe BPD necessitating positive pressure ventilation at home carries significant risks of morbidity and mortality, successful liberation from mechanical ventilation and decannulation are likely to occur.

Unfortunately, while survival of extremely premature infants improves, the rate of BPD is not reduced, and even increased despite our efforts. BPD is a multifactorial disease with prenatal and postnatal factors. The prenatal and the neonatal periods are critical developmental time periods for the lungs. Thus, prematurity may result in arrest of lung maturation with long term consequences which are difficult to be influenced.

It is interesting to assess the outcome of infants with congenital diaphragmatic hernia (CDH) who are known to have hypoplastic lungs. Do they recover over time or do they have common pathways with premature infants with arrested lung maturation?

A study assessing the long term outcome of these infants found in a cohort of CDH survivors that average pulmonary function declines with age relative to expected population normative values. Severity of the neonatal disease and size of the defect affected the outcome. It was speculated that the progressive decrease in pulmonary function tests among CDH survivors may be related to an arrest in pulmonary parenchymal growth or may represent evolving emphysema, which predisposes these patients to future development of obstructive lung diseases [5]. A more recent publication by Miles KG, et al. (Pediatric Pulmonology 2023), reported abnormal cardiopulmonary exercise testing (CPET) and abnormal spirometry in these infants that was associated with gestational age, and the severity of the neonatal respiratory condition. To my knowledge, there are no long term studies to show that gentle ventilation will enhance long term outcome in theses infants.

To conclude, lung development and arrest of lung maturation are key factors in the long term respiratory outcome of preterm infants, including “late preterms,” and in term infants with lung abnormalities such as CDH and hypoplastic lungs.

Author Contributions

Kugelman A was responsible for the idea, performing the review and for the proof of this article.

Conflicts of Interest

The author declares no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are openly available in the pubmed, references 1–5.