Neurodevelopmental outcome in high‐risk preterm infants treated with inhaled nitric oxide

Abstract

Inhaled nitric oxide (iNO) is used to treat preterm infants with hypoxaemic respiratory failure. In this study we describe the long‐term survival and neurodevelopmental status of high‐risk preterm infants enrolled into a randomized controlled trial of iNO therapy. Information regarding long‐term outcome was available for all 25 children enrolled in the original trial who survived until discharge from hospital. Formal, blinded, developmental assessment and neurological examinations were performed in 21 out of 22 children still alive at 30 mo of age, corrected for prematurity. No significant differences were found in long‐term mortality (12/20 vs 8/22, RR 1.65,95% CI 0.87–3.3), neurodevelopmental delay (4/7 vs 9/14, RR 0.89,95% CI 0.37–1.75), severe neurodisability (0/7 vs 5/14, p= 0.12) or cerebral palsy (0/7 vs 2/14, p= 0.53) between iNO‐treated and control infants. Conclusion: In this study there was no evidence of a significant effect on either survival or long‐term neurodevelopmental status in infants treated with iNO.

The INNOVO multicentre randomised controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years

“…This significant benefit in the iNO group was primarily due to a 47% decrease in the risk of cognitive impairment. Follow-up of the infants in the study by Subhedar et al 2 at the age of 30 months found no significant differences in neurodevelopmental delay (4/7 vs 9/14, RR 0.89, 95% CI 0.37 to 1.75), severe neurodisability (0/7 vs 5/14, p = 0.12) or cerebral palsy (0/7 vs 2/14, p = 0.53) between iNO-treated and control infants 10. A more recent follow-up study, from the National Institutes of Child Health and Human Development (NICHD) study7 indicated no evidence of a difference in the health status of the two groups at a corrected age of 2 years 11…”

“…The most recent Cochrane review1 includes seven controlled trials2 – 8 and showed no significant effect of iNO on mortality, bronchopulmonary dysplasia or risk of intraventricular haemorrhage, although short-term improvements in oxygenation were identified. Follow-up data on babies included in those studies are limited 6 9 10. A follow-up of infants in the single-centre study3 at the age of 2 has reported that 24% of babies treated with iNO had abnormal neurodevelopmental outcomes compared to 46% of controls 9.…”

Efficacy of inhaled nitric oxide in preterm infants ≤ 34 weeks: a systematic review and meta—analysis of randomized controlled trials

“…The process of study selection is shown in Figure 1 . Additionally, to analyze and investigate long-term neurological outcomes, including MDI scores below 70, CP, or NDI, this study also collected and analyzed 7 other follow-up studies ( Bennett et al, 2001 ; Mestan et al, 2005 ; Hintz et al, 2007 ; Huddy et al, 2008 ; Watson et al, 2009 ; Walsh et al, 2010 ; Durrmeyer et al, 2013 ).…”

“…Among the long-term neurological outcomes, meta-analyses showed that iNO did not lead to poor long-term neurological outcomes (including Bayley MDI <70, CP or NDI) (RR: 0.89, 1.08, 0.96; CI: 0.68–1.16, 0.81–1.43, 0.85–1.08; I 2 = 44%, 0%, 28%; p = 0.39, 0.61, 0.50; 5 trials ( Mestan et al, 2005 ; Hintz et al, 2007 ; Van Meurs et al, 2007 ; Durrmeyer et al, 2013 ; Hasan et al, 2017 ), 8 trials ( Bennett et al, 2001 ; Mestan et al, 2005 ; Hintz et al, 2007 ; Van Meurs et al, 2007 ; Watson et al, 2009 ; Walsh et al, 2010 ; Durrmeyer et al, 2013 ; Hasan et al, 2017 ), 9 trials ( Bennett et al, 2001 ; Mestan et al, 2005 ; Hintz et al, 2007 ; Van Meurs et al, 2007 ; Huddy et al, 2008 ; Watson et al, 2009 ; Walsh et al, 2010 ; Durrmeyer et al, 2013 ; Hasan et al, 2017 ); respectively) ( Figures 4A–C ).…”

Inhaled Nitric Oxide and Neuroprotection in Preterm Infants

“…At 30 months corrected age, surviving infants (N = 25) underwent formal, blinded developmental assessments 33. Children were classified as having mild, moderate, or severe neurodevelopmental delay based on mental or physical developmental indices (MDI or PDI) of the Bayley7 (mild: 71–85 [1–2 standard deviations below the mean], moderate: 50–75 [>2 standard deviations below the mean]; severe < 50).…”