In this follow-up analysis of the multicenter, randomized, controlled trial of iNO for premature infants with severe respiratory failure, we found that iNO was not associated with a reduction in death or NDI, or with improved neurodevelopmental outcomes among survivors at 18–22 months of age corrected for prematurity. Indeed, we found a slightly increased risk of moderate to severe CP among survivors given iNO, and post hoc analyses suggested a higher risk of death or CP with iNO treatment among infants <1000 grams.
In follow-up to the single-center, double-masked, randomized, placebo-controlled trial by Schreiber, et. al. (9
), Mestan, et. al. (10
) found a significant reduction in neurodevelopmental impairment in the iNO group (24%) compared with the placebo group (46%). Although our findings may appear to be inconsistent with these results, the NICHD trial differed substantially from the previous study. Eligibility for the Schreiber trial (9
) was open to infants <34 weeks gestation and <72 hours of age who had received surfactant, and were mechanically ventilated; there were no OI eligibility criteria. This likely contributed not only to the earlier age at study entry for patients in the Schreiber trial, but also to a significantly lower median OI at randomization in the follow-up cohort (6.94 in the Schreiber trial vs. 17 in the PiNO trial). The early, more “routine” approach to intervention with iNO for mechanically ventilated preterm infants (25
) and a potentially longer period of exposure in a less severely ill population may have played roles in the observed reduction in severe morbidities and adverse neurodevelopmental outcomes. In fact, subgroup analysis in the Schreiber trial (9
) demonstrated that only those infants with OI less than 6.94 (median) benefited from the treatment. These observations underscore the differences between the trials: indeed, in our present analysis, only 11 of 193 survivors to follow-up had an OI at randomization of less than 7. Of note, the Mestan study (10
) demonstrated that iNO was significantly associated with improved neurodevelopmental outcomes, even after adjustment for treatment group differences in intermediate variables such as severe IVH and BPD. This finding may implicate previously reported nitric oxide mechanisms involving tolerance to cerebral ischemia (26
), and inhibition of cytokines (27
). Such protective processes could attenuate subtle brain injury not easily demonstrated by cranial US, suggesting the need for more advanced neuroimaging such as magnetic resonance imaging (MRI) to be included in future trial designs.
The short-term results of two further multicenter, double-masked, randomized, placebo-controlled trials have also been published (11
). Long-term neurodevelopmental outcome results from these trials are yet to come, but these study designs should be contrasted to the NICHD trial. The trial by Kinsella, et. al. (11
) had no OI entry criteria, and subsequently enrolled mildly to moderately ill preterm infants (iNO mean OI=5.4; placebo mean OI=5.8). Similar to the NICHD trial, there was no significant difference in death or BPD between treatment groups, but subgroup analysis showed that iNO was beneficial in infants 1000–1250 g. The Ballard trial (12
) targeted preterm infants with more established lung disease. In both the Ballard and Kinsella trials, exposure to iNO was longer than that in the PiNO trial; this prolonged exposure may be needed for NO-associated lung growth and functional changes to occur (28
). Overall, the NICHD PiNO trial sought to “rescue” a vastly more ill cohort than any of the other recent trials, and iNO exposure was relatively brief. Thus, it is not surprising that our cohort did not appear to benefit from the purported pulmonary or neuroprotective mechanisms of iNO treatment.
Our finding of an increased adjusted RR for moderate to severe CP with iNO is concerning, although it is only one of several secondary outcomes examined, and patient numbers are quite small. But our findings indicate that iNO use, as administered to this critically ill study cohort, certainly does not reduce the risk for moderate to severe CP. The results of our post-hoc analysis are also intriguing, but should be approached with considerable caution. Infants of ≤ 1000 g BW given iNO appear to be at increased risk for death and death or CP. The results of our sub-stratified birth weight analysis () suggest that this finding may be primarily explained by the outcomes of the very smallest preterm infants (401–750 g BW), which could prompt the need for circumspection in future trial designs. Infants given iNO on conventional ventilation at randomization also appear to be at increased risk. However, it is important to remember that mode of ventilation was not randomized in this trial, and indications for conventional ventilation or HFV may have varied substantially among centers. Therefore, discussion regarding the potential mechanism for this post-hoc finding would be purely speculative.
In conclusion, our findings demonstrate no benefit from iNO exposure on death or neurodevelopmental impairment, or neurodevelopmental outcomes in early childhood among the severely ill premature infants in this trial. In light of previous analyses (10
) suggesting a reduction in adverse neurodevelopmental outcomes when iNO is administered earlier to a less severely ill preterm patient cohort, we await the follow-up studies of recently completed trials (11
) to determine the appropriate premature population, optimal timing for initiation of iNO, and length of treatment exposure. Until further data are available, routine iNO use among premature infants should be limited to research settings.