Kinsella JP, Cutter GR, Steinhorn RH, Nelin LD, Walsh WF, Finer NN, et al. Noninvasive Inhaled Nitric Oxide Does Not Prevent Bronchopulmonary Dysplasia in Premature Newborns. The Journal of pediatrics. 2014. My Cochrane review (which is in the process of being updated) shows that none of the tested strategies of inhaled NO use in the preterm infant improve survival, or survival without chronic lung disease; with the possible exception of prolonged treatment started at a later postnatal age to prevent BPD. Our individual patient data meta-analysis was also largely negative. One strategy that had not previously been tested was to use iNO in a group of babies who were on non-invasive respiratory support within the first 72 hours of life. In this study 124 babies less than 34 weeks and between 500 and 1250 g, who were on CPAP or receiving O2 via nasal cannulae, were randomized to iNO at 10 ppm or placebo. Both allocation and intervention were masked and 100% of the babies were followed to masked outcome assessment. iNO was given for at least 2 weeks and at least until 30 weeks post-menstrual age.
There were no differences in any important outcome, death, BPD, combined death and BPD or other common complications of prematurity.
Ballard PL, Keller RL, Black DM, Durand DJ, Merrill JD, Eichenwald EC, et al. Inhaled Nitric Oxide Increases Urinary Nitric Oxide Metabolites and Cyclic Guanosine Monophosphate in Premature Infants: Relationship to Pulmonary Outcome. American journal of perinatology. 2014(EFirst). Secondary analysis of data from the pilot study of late surfactant administration (in which babies in both groups were all getting iNO) and from some babies in the full study. There were also a few controls who were not enrolled in the study. The urinary excretion of nitrates and nitrites and GMP were increased during iNO treatment. Nitrate excretion was higher in those babies who did not develop BPD.
Truog WE, Nelin LD, Das A, Kendrick DE, Bell EF, Carlo WA, et al. Inhaled nitric oxide usage in preterm infants in the NICHD neonatal research network: inter-site variation and propensity evaluation. J Perinatol. 2014. Analysis of data from the NICHD network generic database from baies under 29 weeks or under 1 kg. Use of iNO is very variable between centers, and has dropped markedly since the consensus statement was published. Most babies who still get treated are over 7 days of age, and the proportion has dropped from 4.6% among 3000 odd babies before the statement, to 1.6% among 1000 babies afterward.
Although the proportion has dropped, why is iNO still being used in some babies? I think that there are still questions to be answered; although early rescue iNO does not have a benefit in a group of critically ill preterm infants, it is not clear whether a group of preterm babies selected with clear evidence of PPHN, (such babies often have a dramatic acute oxygenation response to iNO), would benefit in terms of clinical outcomes or not. When I am treating a deeply hypoxic 26 week infant who has a serious pre- post-ductal gradient, and who has already had their surfactant, I certainly ask for the iNO, I think that is still reasonable, unless it can be shown that survival is equally good without. The other (larger) group who often get iNO are infants with evolving lung disease who have periods of serious deterioration, often during sepsis. They may become hypoxic and may have echocardiographic evidence of Pulmonary hypertension; a short-term oxygenation response to iNO is not as reliable in such babies, but some of them do saturate better, or with lower oxygen needs. But there were likely few such infants in the RCTs, and I think it is unclear whether iNO helps them or not, in terns of clinical outcomes.
Enjoying and learning from your blog a lot. I am grateful to you for your excellent expertise.
Can I ask your opinion on use of iNO for prevention of BPD in preterm infants? I realize that there is certainly need for more robust evidence. Do you therefore, discourage use of iNO for prevention of BPD outside the context of rigorously conducted randomized clinical trials? Or, you might support using iNO in an older infant to prevent BPD (like what is done in Ballard’s study)?
Thanks a lot in advance.
I think it has become clear that there is no role for iNO for prevention of BPD. The only suggestive trial (Ballard et al) has been complemented by the as yet unpublished newno trial, which was presented at Hoot topics last year. That trial enrolled babies who were similar to the group with the best responses in the noCLD trial of Ballard, but was unable to show a benefit. I am currently updating the preterm iNO Cochrane review at present, and I can’t see any approach that reduces BPD.
That being said there may be uses in the preterm that are reasonable, even without evidence of reduced BPD. Certain preterm babies (especially those who have had ruptured membranes for a little while), have clear evidence of pulmonary hypertension, and their oxygenation improves dramatically with iNO. There are too few babies like that in the studies to know if their outcomes are improve by iNO or not.
There are other babies with developing or established BPD who have episodes of serious deterioration. Oxygenation in such babies may be improved, whether or not they have good evidence of PPHN, and sometimes it seems reasonable to me to give them the chance of a trial of iNO, even though it is the type of baby that has a very high chance that they will develop BPD, anyway.
So in brief, I don’t think you could use iNO in a preterm for prevention of BPD, you could use in certain selected circumstances where there is a chance of short term benefit, but without evidence of long term clinical benefit, for which those famous rigorous clinical trials will be needed.