Bronchopulmonary dysplasia (BPD)

Jess is an ex-26 plus 4 weeker, born via spontaneous vaginal delivery. No antenatal corticosteroids were given. She was relatively well at birth and was admitted on CPAP to the NICU. She developed respiratory distress two hours after birth. She was promptly intubated and surfactant administered.

She is currently 37 weeks corrected gestational age and is still on high flow nasal cannula oxygen. Her parents are concerned about the long-term consequences of her chronic lung disease.

In the past, many extremely premature infants, with respiratory distress, did not survive due to limitations in mechanical ventilation. As technology has advanced, the survival of preterm infants has increased. A consequence of this is the increased burden of chronic lung disease, also known as bronchopulmonary dysplasia (BPD). This can result in severe morbidity in later life.

The clinical picture of BPD has changed considerably because of new treatment modalities and ventilation techniques. This makes establishing clear diagnostic criteria challenging.

Pathogenesis of bronchopulmonary dysplasia

Bronchopulmonary dysplasia occurs as a consequence of the early developmental stage of premature lungs and injury secondary to ventilation. Lung development begins early, around 3-6 weeks after gestation, and continues well into adolescence.

Bronchi develop soon after gestation during the pseudoglandular phase, during which acinar buds are formed. These buds develop into acinar tubules in the canalicular phase, at 16-26 weeks. These acinar tubules, in turn, become terminal saccules in which primitive gas exchange is possible. The last trimester of pregnancy is characterised by a process called septation in which alveoli are formed. Gas exchange occurs in the alveoli ex-utero. In extremely preterm babies, the alveoli have yet to form. Because of a complex interplay of factors including surfactant deficiency, mechanical ventilation, and increased oxygen levels, a pro-inflammatory cascade is triggered. This impairs further lung development. As a consequence, the alveoli are underdeveloped and the capillary network dysmorphic, making gas exchange more difficult.

Definition

BPD is defined as oxygen dependency in neonates beyond 28 days of age and classified according to disease severity at 36 weeks post-menstrual age. This limit was chosen as it is predictive of chronic lung disease later in life. Most classification methods rate disease severity based on the need for supplemental oxygen at 36 weeks, but in a 2019 article, Jensen et al. defined disease severity based on respiratory support needed at 36 weeks:

This latter definition predicts death or serious respiratory morbidity in 81% of infants at 18-26 months corrected age. Future classifications may become more accurate at predicting subsequent long term respiratory pathology.

Risk factors

Age of gestation is the most significant risk factor for BPD, with disease severity increasing as gestational age decreases. Other risk factors include extreme low birth weight (<1,000 grams), male gender, intrauterine growth restriction and prolonged ventilator-induced injury. Genetic factors may also play a role, while perinatal infections and maternal smoking increase the likelihood of developing BPD.

Complications

Bronchopulmonary dysplasia has long-term effects on respiratory, nutritional, and neurological development. Neonates with BPD may develop pulmonary vascular disease with features of pulmonary hypertension that may persist after 36 weeks of gestational age and well into later childhood. A small subset of BPD patients may need a tracheostomy to support prolonged mechanical ventilation.

Children with BPD may also experience respiratory problems later on in childhood. They are at higher risk of developing severe respiratory viral infections (around 50% require hospitalisation in early childhood) and asthma, and may have lower exercise tolerance than other children their age. Children with moderate or severe disease should be seen in specialised follow-up clinics, with lung function testing to ensure treatment is commenced promptly. There is a higher risk of developing early-onset COPD if they start smoking later in life.

Some infants are discharged home with supplemental oxygen and may require tube feeding for a prolonged period of time. After weaning off oxygen, nutritional problems may persist due to poor feeding coordination and swallowing dysfunction. Oral aversion problems are commonly seen and speech therapy may be needed.

Children with BPD are at higher risk of adverse neurodevelopmental outcomes. It is unclear whether this is due to a direct effect of the pulmonary disease or whether BPD and poor neurodevelopmental outcomes are shared sequelae of specific risks, such as mechanical ventilation in prematurity and very low birth weight. Children may require concurrent management with a specialised physiotherapist and paediatric neurologist.

Prevention and treatment

Antenatal corticosteroids do not prevent BPD, but prevent short-term mortality and morbidity secondary to respiratory distress syndrome. Peripartum antibiotics do not decrease BPD rates, but avoiding fetal compromise in cases of prolonged premature rupture of membranes or chorioamnionitis, is pivotal in preventing further lung inflammation.

There are several studies that look at Neonatal Life Support (NLS) strategies to prevent BPD. Avoiding intubation is the best strategy to date reducing ventilation-associated damage to the lungs. However, if intubation is indicated, maintaining an adequate PEEP of 4-8 cm H₂O and avoiding volume-induced trauma by limiting tidal volumes to 4-7 ml/kg is key. Whether volume-targeted ventilation strategies are better than pressure-targeted ones is still under debate.

A 2016 Cochrane review suggested that high-frequency oscillation ventilation (HFOV) may be better at preventing moderate/severe BPD than Synchronized Intermittent Mandatory Ventilation (SIMV). However, BPD rates among extreme premature neonates remain high in most studies, no matter the ventilation strategy. It is important to note that permissive hypoxia does not prevent BPD. There is no agreement on what ventilation strategy to follow once BPD is established.

Early surfactant therapy decreases the incidence of BPD by preventing intubation. Surfactant may be delivered through Less-Invasive Surfactant Administration (LISA) using a McGill forceps, or by Minimally Invasive Surfactant Therapy (MIST) using a firm catheter. Whether all extreme premature neonates, irrespective of their need for ventilatory support, should receive early surfactant therapy is still under debate. Studies looking at regular caffeine are promising as it appears to reduce ventilation time. Given that Vitamin A is required for lung development and is low in premature neonates intramuscular vitamin A may reduce BPD rates

Giving neonates corticosteroids, such as dexamethasone or hydrocortisone, to prevent BPD is controversial. In clinical practice, corticosteroids are often used to wean ventilatory support, but it is not yet clear whether this leads to long-term improvement in respiratory development. Hydrocortisone is preferable because of the neurological sequelae of dexamethasone. An interesting trial by Watterberg, published in the New England Journal of Medicine earlier this year, showed no benefit of hydrocortisone over placebo when considering the primary outcome of survival without moderate or severe BPD at 36 weeks. There were also no differences in neurodevelopmental impairment at two years (corrected). There are clinical studies underway to combine late surfactant administration in combination with corticosteroids.

Conclusion

Our understanding of BPD has evolved since it was first described 50 years ago. While advances in neonatal care have resulted in improved survival rates of premature infants, this in turn has led to an increase in long-term BPD survivors in the community. A multidisciplinary approach is essential in supporting the complex pulmonary, nutritional, and developmental requirements of these children. It is important that future studies investigate factors influencing long-term morbidity and disease burden.

References

Brady JM et al. Living with severe bronchopulmonary dysplasia – parental views of their child’s quality of life. J Pediatr 2019;207:117-22.

Chakkarapani AA et al. “Current concepts in assisted mechanical ventilation in the neonate” – Part 2: Understanding various modes of mechanical ventilation and recommendations for individualized disease-based approach in neonates. Int J Ped Adol Med 2020;7:201-8.

Fischer HS and Buhrer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis. Pediatrics 2013;132(5):e1351–e1360.

Greenough A et al. Synchronized mechanical ventilation for respiratory support in newborn infants (Review). Cochrane Database Syst Rev 2016;CD000456.

Jensen EA, Schmidt B. Epidemiology of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol 2014;100:145-157.

Jensen EA et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. An evidence-based approach. Am J Respir Crit Care Med 2019;200:751-9.

Keszler M and Sant’Anna G. Mechanical ventilation and bronchopulmonary dysplasia. Clin Perinatol 2015;42:781-96

Klingenberg C et al. Volume-targeted versus pressure-limited ventilation in neonates. Cochrane Database Syst Rev 2017;10:CD003666.

Moschino L et al. Lung growth and pulmonary function after prematurity and bronchopulmonary dysplasia. Pediatr Pulmonol 2021;56:3499-508.

Resch B et al. Prematurity and the burden of influenza and respiratory syncytial virus disease. World J Pediatr 2016;12:8-18.

Thébaud B et al. Bronchopulmonary dysplasia. Nat Rev Dis Prim 2019;5:78.

Watterberg KL et al. Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. N Engl J Med 2022;386:1121-31.

Younge N et al. Survival and neurodevelopmental outcomes among periviable infants. N Eng J Med 2017;376:617-28.