At the 12 month follow-up of infants in the NO CLD trial, fewer infants treated with iNO than placebo had received medications for wheezing. In addition, fewer infants in the iNO group had received diuretics or home oxygen, and fewer were still on supplemental oxygen at the time of follow-up. Reduction in medication use in the iNO group suggests improved post-discharge pulmonary health. However, there were no significant differences in re-hospitalizations or parental report of wheezing.
The odds ratios were similar for all of the medications studied; this is more consistent with a true effect of iNO than with a spurious finding. For bronchodilator use, post-hoc exploratory analyses showed no evidence of confounding or interaction for the variables tested (race, sex, age at study entry, birth weight, and BPD status). There was a similar reduction for infants enrolled at both 7–14 days of age and 15–21 days, despite the fact that infants enrolled earlier had more improvement in survival without BPD.(13
) The non-significance of the effect of iNO in some of the demographic subgroups tested in the underpowered exploratory analysis should be interpreted cautiously. The similarity of the point-estimates for the odds ratios and the tests for interaction do not identify differences in response to iNO. Of note, the statistically significant decrease in bronchodilator use in the smaller birth weight group differs from the results for BPD in the study by Kinsella et al, in which infants <1000g did not seem to benefit from iNO in post-hoc analysis.(19
) However, this study used different eligibility critieria, age at treatment, iNO dosing, and duration of therapy than the NO CLD study. Post-hoc analyses in both studies should be interpreted with caution.
Animal models suggest several possible biological mechanisms.(21
) INO may decrease baseline airway resistance by inhibiting abnormal elastin deposition or smooth muscle proliferation.(22
) Increased alveolarization could improve pulmonary compliance and oxygenation(21
). Stimulation of angiogenesis and/or inhibition of vascular smooth muscle proliferation could also improve oxygenation.(23
) Improved surfactant function could limit overall lung injury.(21
) There could also be alterations in dynamic respiratory responses, such as bronchoconstriction or inflammation in response to allergens or infection.
INO did not decrease respiratory re-hospitalizations. One explanation is that hospitalization is a good marker of respiratory severity, and iNO did not prevent severe disease. Alternatively, re-hospitalization may act as a poor marker of severity of illness; non-biological factors such as holidays, insurance status, socioeconomic status, and provider-patient interactions may influence the decision to hospitalize a child.(27
Similarly, there was no significant difference in parental report of “wheezing or whistling in the chest.” Although a true lack of drug effect is possible, another explanation is that parents did not accurately identify wheezing. Parents of infants with a history of prolonged ventilation may be sensitized to respiratory symptoms and prone to over-identify wheezing. Such non-differential misclassification of wheezing in the iNO and placebo groups would tend to bias results towards an odds ratio of 1, thereby decreasing the ability to detect an effect of iNO.
Compared with other trials of iNO for the prevention of BPD,(19
) the NO CLD protocol was notable for later postnatal age of initiation, a higher initial concentration (20 ppm), and a longer duration of treatment (median 25 days).(13
) Although this approach seems to improve survival without BPD and the need for pulmonary medications in infancy, pending results from the 24-month neurodevelopmental assessments should be included in any risk-benefit analysis. The greater exposure to iNO in this study than in other trials precludes extrapolation of data about neurological outcome from other studies.
The strengths of this study include the large sample size and the randomized blinded design. Families and physicians remained blinded to treatment allocation before and after NICU discharge. Stratified randomization by site should balance both known and unknown social and biologic confounders associated with medication use and rehospitalization – including regional variations in patient populations and medical practice -- between the iNO and placebo groups.
The primary limitation of this study is the extent to which differences in reported medication use reflect actual differences in health. Although there may be some misclassification due misreported medication histories, or non-ideal prescription practices by providers, it is unlikely that such misclassification would be differential with regard to iNO exposure because parents and physicians remained blinded. Similarly, although some of the individual pulmonary morbidities reported may be unrelated to prematurity, we would expect this number to be relatively small and non-differential with respect to study drug. In addition, the NO CLD sample size was chosen to detect a 12.5% absolute increase in survival without BPD. Among the smaller group of infants who survived and presented to follow-up, we are likely under-powered to detect clinically important differences in some secondary outcomes. Finally, medication use may not capture nuances of pulmonary health as well as more detailed validated measures of quality of life, symptoms, and pulmonary mechanics.
We cannot exclude the possibility that, despite randomization, unmeasured differences between the iNO and placebo groups biased the results towards a larger or smaller apparent effect. In addition, although we found no significant differences in the demographic variables tested between the infants who were followed-up and those who were lost, the groups could be different in other unmeasured ways. Previous studies have shown that children who are difficult to follow may have more neurodevelopmental disability and socioeconomic disadvantage than children who are easily followed.(37
) It is reasonable to hypothesize then that a higher rate of pulmonary disability would have been seen in both the iNO and placebo groups if all infants had been followed-up. However, it is uncertain whether loss to follow-up was a source of bias in this study.
Another important limitation of all trials is generalizability. The infants in this study met criteria that placed them at high risk for death or BPD; however, iNO was used as a preventative strategy and not as a rescue treatment. If iNO use becomes prevalent in a more general population at higher or lower risk for death or BPD, the benefit from iNO may be different.
In conclusion, very low birth weight infants randomized to iNO were significantly less likely to use bronchodilators, steroids, diuretics, or oxygen after NICU discharge. Although the pulmonary benefit seems promising, any decision to institute routine use of this dosing regimen should also take into account the results of the 24 month neurodevelopmental assessment.