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Off-label NO: No... or Yes?




Recent articles about off-label use of inhaled Nitric Oxide (iNO) in the preterm infant shows that such use is :

a. extremely variable from one center to another, (Truog WE, et al. Inhaled nitric oxide usage in preterm infants in the NICHD neonatal research network: inter-site variation and propensity evaluation. J Perinatol. 2014.)

and b. increasing in some places. Ellsworth MA, et al. Off-Label Use of Inhaled Nitric Oxide After Release of NIH Consensus Statement. Pediatrics. 2015;135(4):643-8.)

As you can tell from the title of the 2nd article, the authors wished to see what effect the release of the NIH consensus statement had. I was involved in the hearings that led to production of that statement, which concluded, as the authors of this article put it :

The resulting NIH statement and American Academy of Pediatrics clinical report indicated that available evidence did not support the routine use of iNO in preterm infants, though rare clinical situations and new management strategies did merit further study.

The first of these 2 references suggested that use might have been decreasing after the consensus statement, at least among the extremely low birth weight infants in the Neonatal Research Network generic database. The second article suggests the opposite, in the NICUs in the Pediatrix network. In those units iNO is used more often off-label than 'on-label', very nearly 50% of all the NO days are in babies less than 29 weeks gestation, and those babies average 7 days of treatment, compared to 5 days for the term babies.

If you recall, both the Cochrane Systematic Review (Barrington KJ, Finer N. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane database of systematic reviews (Online). 2010;12:CD000509), and the IPD meta-analysis that we published (Askie LM, et al. Inhaled Nitric Oxide in Preterm Infants: An Individual-Patient Data Meta-analysis of Randomized Trials. Pediatrics. 2011;128(4):729-39.) show no clear advantage of iNO in any subgroup of preterm babies. The possible benefit in babies with early evolving chronic lung injury, shown in the NOCLD trial, was not confirmed by the NewNO trial, presented at a Hot Topics, and not yet published, (As soon as it is published we will be updating the Cochrane Review).

So why is there still any use in the preterm? Are we all anti-evidence based medicine cooks? I don't think so, I think there are still unanswered questions in the preterm, and as a result situations where it is reasonable to consider the use of iNO.

The studies of early rescue use of iNO, which show no benefit (and a possible increase in intracranial hemorrhage) enrolled preterm infants with severe respiratory failure. But only a minority of those infants have severe pulmonary hypertension, in particular those who had oligohydramnios after PPROM. Some babies like that have a very limited response to surfactant, and after surfactant they have clear lungs on x-ray, and often have a big ductal saturation gradient, i.e. evidence of right to left shunting and supra-systemic PA pressures. When I have given iNO to such babies (and others have reported this also) they often have a dramatic response and go from being hypoxic to rapid weaning of their oxygen requirements.

When we did the IPD meta-analysis of iNO in the preterm we wanted to specifically address whether preterm infants with evidence of PPHN had a different response, and potentially a benefit from iNO. Unfortunately there were very few babies who had a record of either having, or not having, pulmonary hypertension. So although there were more survivals without BPD among preterm infants who had a diagnosis of PPHN it was not clear whether or not this might have been due to chance. Other case series, and one subgroup analysis of one of the RCTs, also suggest that there may be a benefit, but all we can say at present is that such babies often have a big improvement in oxygenation in the short term.

The other situation in which iNO is being used is during acute deteriorations in oxygenation in babies who are developing BPD. In those babies you can also get improvements in oxygenation, even among those who don't have clear evidence of pulmonary hypertension, presumably because you improve VQ matching.

I think, therefore that there is room to perform more trials in those 2 groups of babies, to see whether the acute improvements in oxygenation lead to improved survival or reduced complications.

Randomizing very sick, hypoxic, preterm babies who have clear evidence of PPHN in the first few hours of life to iNO or placebo will be difficult, but not impossible. It could even be done with a rescue phase for babies who stay hypoxic after a period of placebo use. It is possible that the placebo babies would gradually improve without iNO, and that improving gradually, rather than suddenly, would lead to a smoother clinical course, and less intracranial hemorrhage.

The second group of babies would be easier to study, I think; babies who at a couple of weeks of age have signs of early lung injury, and very high oxygen requirements, this represents about half of the babies in the Ellsworth publication. In those babies, who often get iNO for very long periods if there is an initial response, I think there is a chance of benefit, but a real risk of very high costs without overall clinical benefit.

This is not the same group of babies as studied in NOCLD or the NewNO trial. The babies in those trials were typically on low oxygen and respiratory support, so it will require targeted trials to investigate the highest risk babies.

Now I know I'm on the right track when what I say agrees, largely, with what Neil Finer and Nick Evans write! (Finer NN, Evans N. Inhaled Nitric Oxide for the Preterm Infant: Evidence Versus Practice. Pediatrics. 2015;135(4):754-6).


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