Long-term follow-up of neonatal ventilation with inhaled nitric oxide versus ventilatory support alone in preterm infants

The early trials of inhaled nitric oxide (iNO) in preterm infants were focused on babies with major respiratory problems despite antenatal steroids and surfactant replacement therapy. The most recent Cochrane review showed no significant effect of iNO on mortality, bronchopulmonary dysplasia or risk of intraventricular haemorrhage, although short-term improvements in oxygenation were identified. However, follow-up data on babies included in those studies are still limited and controversial. Moreover, no trials have presented a follow up to 4 years of age.
Recently, the results of the INNOVO trial for preterm babies have been reported. In this study on 108 infants, 59% died and 84% of the survivors had some signs of impairment or disability at the age of one year. 20% of them were classified as severely disabled. A trend towards benefit for iNO on mortality appeared to be outweighed by the suggestion of an increase in impairment or disability in the survivors. Noteworthy, developmental assessment at one year often lacks precision regarding the prediction of later health status.
The investigators of the INNOVO trial have recently published the follow-up data at 4-5 years in order to assess long-term clinical effectiveness and costs of a policy of adding or not adding iNO to the ventilator gases for preterm neonates with severe respiratory failure.
In the INNOVO trial, infants of < 34 weeks' gestation, aged less than 28 days and with severe respiratory failure requiring ventilatory support were randomized to be treated with either iNO added to ventilatory gases, or with ventilatory support without iNO. In this follow-up analysis, 38 children were assessed at age 4-5 years by interview, examination, cognitive and behavioural assessments. The outcome data were divided into seven domains and were classified as normal, impaired or disabled (mild, moderate or severe) by the degree of functional loss.
The results show that, in the iNO group, the 62% of the children originally included in the trial (34/55) had died or were severely disabled, compared to 70% (37/53) of those included in the no iNO group (relative risk, RR: 0.89; 95% confidence interval, CI 0.67-1.16). At 4-5 years, there was no evidence of difference in the levels of impairment or disability between the two groups in any of the domains studied, or of cost differences among the survivors.
Taken together, these findings may suggest that there is no difference in the long-term outcome between babies with severe respiratory failure treated or untreated with iNO. It must be emphasized that this was the first trial of preterm babies with follow-up to 4-5 years and using functional outcomes that matter to families. Other studies published recently showed some clinically important improvements in the babies treated with iNO, but only in subsets of patients. The present challenge is to identify those premature babies who are able to respond to nitric oxide with clinically important health improvements.

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