Neurodevelopmental impairment remains a significant concern for infants undergoing open-heart surgery for congenital heart disease (CHD). Cardiopulmonary bypass (CPB) is essential for maintaining circulation during surgery but induces systemic inflammation, which may contribute to neurological injury. Nitric oxide (NO) has been proposed as a potential intervention to mitigate these effects, but its long-term impact on neurodevelopmental outcomes remains unclear.
This study aimed to assess whether administering NO via CPB could improve neurodevelopmental outcomes and health-related quality of life (HRQOL) in infants undergoing open-heart surgery. Conducted as a double-masked, randomized clinical trial across six centers in Australia, New Zealand, and the Netherlands, the study enrolled 1,364 infants under two years of age who required CPB for CHD surgery between 2017 and 2021. The intervention group received 20 ppm of NO via the CPB oxygenator, while the control group underwent standard CPB without NO.
At the 12-month follow-up, neurodevelopment was assessed using the Ages and Stages Questionnaire, Third Edition (ASQ-3), while HRQOL was measured through the Pediatric Quality of Life Inventory (PedsQL). Functional outcomes and overall survival rates were also evaluated. Of the 1,318 infants alive at 12 months, 927 completed follow-up assessments. The results showed no significant differences in neurodevelopmental outcomes between the NO and standard CPB groups. ASQ-3 total scores were nearly identical, with the NO group averaging 196.6 and the standard group 198.7. Similarly, PedsQL total scores did not differ significantly, with no notable improvements in cognitive, motor, or social development among those who received NO.
Further analysis revealed that NO did not provide measurable benefits for high-risk subgroups, including preterm infants and those with univentricular heart lesions. However, several factors were associated with poorer neurodevelopmental outcomes, regardless of NO administration. Prematurity, congenital syndromes, and prolonged ICU stays correlated with lower ASQ-3 scores. Similarly, infants who experienced low cardiac output syndrome or required extended mechanical ventilation demonstrated reduced HRQOL scores. These findings suggest that factors beyond intraoperative NO administration play a more significant role in determining long-term neurodevelopmental health.
Although this study provides strong evidence that NO does not improve neurodevelopment or HRQOL outcomes after CPB, its design had some limitations. Approximately 30% of surviving infants were lost to follow-up, with higher attrition among Indigenous populations and infants with congenital syndromes. Additionally, the 12-month assessment may have been too early to detect subtle cognitive impairments that emerge later in childhood, particularly in executive function and learning. The study cohort included a wide range of CHD complexities, from lower-risk surgeries to highly complex procedures, which may have diluted potential NO-related effects.
Despite these limitations, the findings suggest that NO is unlikely to be an effective neuroprotective agent for infants undergoing CPB. The absence of observable benefits aligns with previous research on inhaled NO therapy, which has shown inconsistent effects on neurodevelopment in neonates. While NO plays a critical role in vascular biology, its administration during CPB does not appear to significantly impact long-term neurological outcomes.
This study redirects focus toward other modifiable factors that could improve neurodevelopmental outcomes for infants undergoing heart surgery. Strategies such as optimizing postoperative ICU care, reducing exposure to prolonged mechanical ventilation, and early childhood interventions may hold greater promise in mitigating the risks associated with CHD and CPB. Future research should explore the effects of higher NO doses, alternative therapeutic agents, and long-term follow-up studies that assess cognitive and executive function at later developmental stages.
In conclusion, while NO administration during CPB does not enhance neurodevelopmental outcomes, this study underscores the importance of identifying other protective strategies. By shifting attention to perioperative and postoperative care, clinicians and researchers can work toward improving the long-term well-being of children with congenital heart disease.
