Inhalation or Instillation of Steroids for the Prevention of Bronchopulmonary Dysplasia
Authors: Bassler Dirk 
Published: June 2015

Survival of extremely preterm infants has increased over recent years, but bronchopulmonary dysplasia (BPD) remains a major cause of morbidity. In the USA, BPD is the most common chronic respiratory disorder of infancy and affects the pulmonary and overall health of 10,000 preterm infants annually [1]. Preclinical and clinical studies suggest a crucial role for lung inflammation and host immune response in the pathogenesis of BPD [2]. Inflammation may result from, amongst others, chorioamnionitis, postnatal infection, ventilation, and the administration of oxygen [2]. Infants with BPD have worse long-term outcomes than those without chronic lung disease. They are more than twice as likely to be readmitted to hospital in their first year of life and, having survived their primary hospitalizations, they are more likely to die than very preterm infants without chronic lung disease [3,4]. Survivors with BPD have an increased risk of neurodevelopmental impairment [5] and their respiratory function remains compromised well into adolescence [6,7]. As the first generations of extremely low birth weight (ELBW) survivors have not yet reached retirement age, there are currently no reliable data addressing the association between BPD and pulmonary diseases of the elderly such as chronic obstructive pulmonary disease. Although BPD is quite common in ELBW infants, there are infants who do not develop BPD, which supports the argument that BPD is a preventable disease, emphasizing the need for high-quality safety and efficacy prevention studies. However, according to an Institute of Medicine statement regarding pediatric drug studies, the therapeutic area that has the fewest drugs indicated for neonates is BPD [8]. As inflammation seems to be a primary mediator of injury in the pathogenesis of BPD, anti-inflammatory agents such as steroids have long been the focus of preventive research activities. However, systemic steroids, although reducing BPD, have frequently been linked to adverse neurodevelopmental outcomes and these considerations may have contributed to the recently reported widespread use of inhaled corticosteroids in neonatal units in North America and Europe. Inhaled corticosteroids were prescribed to 25% of infants born at <29 weeks of gestation with birth weights <1,500 g in neonatal units of 35 children's hospitals in the USA [9]. According to a survey across all neonatal units in Germany, 46% administered inhaled corticosteroids to preterm infants either as prophylaxis or treatment for BPD [10]. Pediatricians and neonatologists should ask themselves whether the off-label use of inhaled corticosteroids in preterm infants is justifiable in view of the available evidence. The authors of the pertinent review from the Cochrane Collaboration, including 7 studies and 492 infants, conclude that there is currently no evidence to support the routine use of inhaled steroids for the prevention of BPD [11]. Recently, the primary outcome results of the Neonatal European Study of Inhaled Steroids (NEUROSIS), including 863 very preterm infants (gestational age 23-27 weeks), have been presented at scientific conferences, but the full study report is not yet published [12]. By contrast, intratracheal instillation of budesonide using surfactant as a vehicle has not yet become part of clinical practice. There are fewer studies addressing the risks and benefits of this mode of administration. In a randomized blinded pilot study in 116 very low birth weight infants who had severe radiographic respiratory distress syndrome and required mechanical ventilation shortly after birth, early intratracheal instillation of budesonide using surfactant as a vehicle resulted in significantly lower mean airway pressure on day 1 and day 3 and a significantly lower oxygen index and PCO<sub>2</sub> during the first 3 days compared with infants in the control group who had received surfactant without corticosteroids [13]. More infants were extubated in the treatment group than in the controls at 1 and 2 weeks and the combined outcome of death or chronic lung disease was significantly lower in the treatment group than in the control group (19 of 60 vs. 34 of 56). No clinically significant adverse effects were observed during the study and at the time of the follow-up assessment at 2-3 years of age [14]. In the future, intratracheal instillation of budesonide using surfactant as a vehicle may play a role in the prevention of BPD in ELBW infants. However, before this therapy can be introduced into routine clinical care, remaining open questions need to be answered and appropriately powered studies need to be performed.