A couple of weeks ago I discussed a new multicenter RCT which examined the effects of multiple repeated doses of steroids, given by inhalation starting on the first day of life, and continuing, at least until the infants reached 14 days of age. That study showed an improvement in the primary outcome of survival without BPD with the inhaled steroids.
A newly published trial Yeh TF, et al. Intratracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2016;193(1):86-95. examines a similar question, but with a somewhat different intervention, and eligibility. The subjects of the trial were very low birth weight infants who were intubated and requiring more than 50% oxygen within the first 4 hours of life. Infants then received either surfactant alone (4 mL/kg of Survanta) or 4 mL/kg of surfactant and 1 ml/kg of budesonide suspension, mixed in a syringe with a label placed to hide the volume. Thy had 858 VLBW infants intubated in the NICU at less than 4 hours of age, of whom 287 had severe enough lung disease to qualify.
Babies received repeat dosing, every 8 hours, if they needed more than 30% oxygen, up to 6(!) doses. The budesonide dose was 0.25 mg/kg/dose. They note that 65% of the budesonide infants only received one dose, compared to 37% of the controls, presumably because of an acute clinical response; indeed the FiO2 over the first few hours after intervention was lower in the budesonide treated babies.
The primary outcome of survival without BPD was improved in the intervention group (death or BPD was 42% with budesonide and 66% in controls). Both components of the primary outcome were improved with budesonide, (death 13%vs 16%, BPD 29% vs 50%).
The paper also includes some summary long-term outcome data from 172 of the survivors. I have no idea why this important data is stuck on as, what seems like an afterthought, when it is not yet complete, (as they note in the discussion). I presume some incompetent peer-reviewer asked them to throw whatever data they have into this publication, when it really needs a separate appropriately presented publication. There aren’t enough details about the methodology or the results to say a lot. For example the authors state the follow up was done at 2 to 3 years of age, but they don’t say whether they corrected for prematurity (presumably they did, but it would be nice to have the details). The scores on the Bayley version2 Mental development and Motor scales were very similar, with a similar proportion under 70.
They also did a lot of other surveillance for safety, such as presenting blood sugars, and electrolytes, blood pressure and growth data, all of which were unaffected by the intervention.
The online supplement also has some pretty pictures of rats under a PET scan getting budesonide mixed with surfactant, showing it getting rapidly distributed, and staying in the lungs.
I find this very interesting, and worthy of a confirmation trial. Other things I would like to know are : can you safely give prophylactic indomethacin when you have had intra-tracheal budesonide? Are the results still positive if you give surfactant sooner, at 30% oxygen (which is when most of us would give surfactant, rather than waiting to get to 50%)? Are there other respiratory practices which might affect the efficacy of budesonide? Does it work as well if you limit to 2, or 3 doses? Is there any improvement in long-term respiratory health?
It is interesting that the long-term differences are minimal between groups, so, although there is less “BPD”, there is no major long term benefit to the babies. There are very few details as I said, but the authors note no health advantage to early budesonide use, in terms of respiratory or overall health.
I think, before starting to do this more widely, we need at least one more large multi-center RCT, powered for the long term follow-up. Outcomes should include respiratory health, to prove a real benefit, rather than just the reduction in a diagnostic label, and neurological and developmental outcomes, to ensure safety.