Shaken or Stirred? Evaluating the combination of budesonide–surfactant for survival free of bronchopulmonary dysplasia

The magic bullet that prevents bronchopulmonary dysplasia (BPD) in very low-birthweight infants without increasing long-term side effects remains elusive. Because pulmonary inflammation is likely critical to the pathogenesis of BPD, numerous investigatorshaveattempted toprevent the development of BPD with a wide variety of postnatal corticosteroid regimens (1). Unfortunately, systemic corticosteroids have been linked to increase risk of adverse neurodevelopmental outcomes (2). Inhaled corticosteroids combine more direct action on lung tissue with less systemic effect, but inhaled corticosteroids have also failed to reduce BPD (3,4). Adding budesonide to surfactant potentiates thedeliveryof corticosteroid to theperipheral lung tissue (5). The authors posit that delivering this combination therapy early in the course of illness may unlock the minimum required anti-inflammatorystimulinecessary topreventBPDwhileavoiding adverseoutcomes.Apaucityofdatamakesassessing the impact of the specific surfactant preparationused in this study difficult. This would likely be worthwhile to explore in future research. Yeh et al. found a significant reduction in the incidence of BPD or death after administration of budesonide–surfactant as compared to surfactant alone. The effect can be attributed to a reduction in BPD alone without a significant effect onmortality. Whilenotpowered toexamineneurodevelopmental outcomes, it isencouragingthat thesurvivinginfants exhibited no trend towards adverse outcome at two to three years old. Both findings were confirmed by meta-analysis (6) with the group’s prior pilot study (7). The major limitation of this study is the high incidence of BPD in the control group (50%). In a population with a lower prevalence of BPD, the relative risk reduction and number needed to treat are likely to be many fold different. Many infants experienced significant intervention prior to randomisation that could alter themagnitudeof the treatment effect and thus the number needed to treat, such as mechanical ventilation and oxygen administration. While randomisation prevents the introduction of significant bias in this study, earlier surfactant administration may potentiate the budesonide effect when compared to other strategies shown to reduce BPD (8). The role of budesonide– surfactant administration should be re-evaluated in conjunction with other current treatment strategies known to prevent BPD. This would reassure clinicians that budesonide–surfactant therapy continues to offer benefit in the context of current clinical practice. In the end, Yeh et al. represent a potentially powerful intervention to reduce the risk of BPD. Considering the less than satisfactory results achieved by previous corticosteroid delivery methods, this is a significant achievement. However, the previous failure of postnatal corticosteroid administration has created a paradox, that is difficult to overcome. Clinicians continue to use corticosteroids in infants with moderate-to-severe BPD despite known risks, while at the same time demanding a high bar of evidence be achieved before altering current management. Before budesonide–surfactant can become the standard of care, further large trials are required in populations with a lower prevalence of BPD. We advocate for a multicentre trial in conjunction with noninvasive respiratory management that is powered to evaluate neurodevelopmental outcomes.