The NEUROSIS trial was a high quality trial of inhaled budesonide started before 12 hours in extremely preterm infants (23 to <28 weeks gestation) receiving positive pressure respiratory support. The primary outcome of the trial was survival without needing oxygen at 36 weeks post-menstrual age. “The dose of budesonide was two puffs (200 μg per puff) administered every 12 hours in the first 14 days of life and one puff administered every 12 hours from day 15 until the infants no longer required supplemental oxygen and positive-pressure support or until they reached a postmenstrual age of 32 weeks”.
The initial publication of the results showed a reduction in oxygen needs at 36 weeks, but a possible increase in mortality. The combined outcome was less frequent with budesonide, a difference which had a p-value of exactly 0.05, i.e. a probability that the finding was due to chance alone of exactly 1/20. The initial report was of O2 requirement at 36 weeks, and mortality at 36 weeks, so later deaths were not included.
Since that original report the authors have been following the babies and have just published the neurological and developmental follow up at 2 years corrected age. (Bassler D et al. Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia. N Engl J Med. 2018;378(2):148-57). The cutoff they used for developmental delay was a BSID (version 2) score on the MDI of <85. There was no difference between groups, cerebral palsy was marginally higher in the budesonide group, and blindness, deafness, and developmental delay were marginally less frequent. The composite outcome was about 50% in each group, almost all due to the (very liberal definition of) developmental delay. More marked developmental delay and the average Bayley scores were very similar between groups.
They also note that there were more deaths in the budesonide group, an effect which was not likely due to chance (19.9% vs. 14.5%; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04). They note that there were 9 deaths after the 36 weeks limit set for the initial primary outcome, 8 of which were in the budesonide group, and 1 of which was in the controls. So eventually they had 82 deaths of the 413 in the budesonide group, and 58 deaths of 400 in the controls.
There was also the same proportion of babies in each group who had a hospital readmission for medical reasons (46% budesonide vs 48% control), the same number of long term inhaled steroids, bronchodilators, and leukotriene agonists (needing them for more than 2 months after discharge) the same number needing home oxygen for more than 2 months1 week after discharge.
In other words, there is no sign of long term pulmonary advantage, and no indication of long term developmental impact. The only possible benefit of prophylactic inhaled budesonide in extremely preterm babies is that more babies came out of oxygen before 36 weeks post-menstrual age, as shown by the results from the first publication, but they did not get off CPAP any earlier (median post-menstrual age of stopping positive pressure was 33.1 vs 33.4 weeks), nor get home any earlier (duration of hospitalisation 91 vs 93 days).
This is another good indication of why we should re-think our definition of BPD. Early, prophylactic use of potent anti-inflammatory steroids given by inhalation reduced the number of babies needing oxygen at 36 weeks, but does not seem to have had any other measurable benefit for the babies. Indeed a substantial increase in mortality, relatively unlikely to have been due to chance, is the only clinically important finding from this study.
I would love to see some more detailed pulmonary outcomes from this study, to determine if there is some other benefit, but at present this study has only shown that the babies were more likely to stop oxygen after 36 weeks if they were control babies compared to stopping before 36 weeks if they were budesonide receivers, but that doesn’t seem to have had any other impact on their lives. And the control babies mostly stopped their oxygen between 36 weeks and discharge, to have the same number going home with O2 tanks.
If we put this in the context of other studies, where are we now? There are 2 recent systematic reviews that are relevant. Unfortunately they both mix studies of very early prophylaxis using inhaled steroids, with early treatment of babies still ventilated after a few days, and one of them includes treatment of established BPD also.
The most recent is Shah VS, et al. Early administration of inhaled corticosteroids for preventing chronic lung disease in very low birth weight preterm neonates. Cochrane database of systematic reviews (Online). 2017;1:Cd001969. In that review of inhaled steroids, most of the studies were early ‘prophylactic’ type studies, albeit with differing entry criteria. But all, other than NEUROSIS, were tiny with less than 31 babies per group, except for one trial which enrolled babies between 3 days and 14 days of age who were being ventilated, babies were less than 30 weeks and less than 1250 g. That study had a reasonable sample size of 253. The other tiny studies enrolled kids within 12 hours, ❤ days, 3 to 4 days, and one study was 6 to 10 hours after the second surfactant dose. I don’t think that there is enough comparable between the Cole study (the one with 253 babies) and the truly prophylactic use of steroids in very early life. If we delete that study from this consideration we are left, basically with the NEUROSIS trial with about 420 per group, and about 90 steroid and 90 control babies from the other trials.
I think there is a huge problem with the first report of the NEUROSIS trial, which reported a different number of deaths to this follow-up study. Clearly the study was designed with the primary outcome being death or BPD at 36 weeks, as such that should normally remain the reported primary outcome. But by the time of writing the first report they must already have known there were 9 extra deaths in the budesonide group (they reported average age to discharge and state in the manuscript that the babies were followed until discharge). Why didn’t they report in the initial publication that the number of deaths were significantly higher in the budesonide group than the controls? There was a 37% increase in mortality by discharge (RR 1.37, 95% CI 1.01-1.86), but I can see no mention of that in the publication or the supplemental data.
There really is no good reason for censoring deaths at 36 weeks, just because the diagnosis of BPD is made at that time. “Death or NEC” is another (questionable) composite outcome used in neonatal trials, and, of course NEC can occur at any time after birth, I don’t think that there are reports of the combined outcome of NEC at any time or death before 36 weeks. Death before discharge is a much more relevant outcome for babies and their families than death before 36 weeks.
Neonatal trials should always report death before discharge, even if death at some other point is also reported.
Earlier this year the Canadian Neonatal Network published an analysis showing that diagnosing BPD at 36 weeks is not very predictive of respiratory morbidity during the first year of life. Isayama T, et al. Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates. JAMA Pediatr. 2017;171(3):271-9. It was noted that oxygen use at 36 weeks was not that good at discriminating between those infants with and without serious respiratory morbidity. The need for either oxygen or respiratory support (or both) at 40 weeks was substantially better. This is particularly important in the setting of a trial, where an intervention might reduce inflammation and reduce O2 needs at 36 weeks, but not improve long term respiratory problems.
We could imagine, for example, a randomized trial of intravenous dexamethasone as a single day’s treatment at 35 weeks and 5 days. Such an intervention would probably enormously reduce “BPD” but is unlikely to have much effect on clinically important pulmonary function!
Given the apparent increase in mortality, and the lack of clinically important impact on respiratory outcomes, prophylactic very early inhaled steroids should be avoided.