Importance  Children with congenital heart defects who undergo cardiopulmonary bypass (CPB) surgery are at risk for delayed or impaired neurodevelopmental outcomes. Nitric oxide (NO) added to the CPB oxygenator may reduce systemic inflammation due to CPB and improve recovery from surgery, including improved neurodevelopmental outcomes.

Objective  To investigate neurodevelopment, health-related quality of life (HRQOL), and factors associated with impaired neurodevelopment at 12 months post surgery in infants who received CPB with NO or standard CPB.

Design, Setting, and Participants  This double-masked randomized clinical trial was conducted in 6 centers in Australia, New Zealand, and the Netherlands between July 19, 2017, and April 28, 2021, with a preplanned prospective follow-up 12 months postrandomization completed on August 5, 2022. The cohort included 1364 infants younger than 2 years who underwent open heart surgery with CPB for congenital heart disease.

Interventions  The intervention group received NO 20 ppm into the CPB oxygenator. The control group received standard CPB.

Main Outcomes and Measures  The primary outcome was neurodevelopment, defined as the Ages and Stages Questionnaire, Third Edition (ASQ-3) total score. Secondary outcomes were HRQOL and functional status as measured by Pediatric Quality of Life Inventory and modified Pediatric Overall Performance Category scores, respectively. Sensitivity analyses modeled the outcome for patients lost to follow-up.

Results  Of 1318 infants alive 12 months after randomization, follow-up was performed in 927, with 462 patients in the NO group and 465 in the standard care group (median [IQR] age at follow-up, 16.6 [13.7-19.8] months; median [IQR] time since randomization, 12.7 [12.1-13.9] months; 516 male [55.7%]). There were no differences between the NO and standard care groups in ASQ-3 total score (mean [SD], 196.6 [75.4] vs 198.7 [73.8], respectively; adjusted mean difference, −2.24; 95% CI, −11.84 to 7.36). There were no differences in secondary outcomes. Prematurity (gestational age <37 weeks), univentricular lesions, congenital syndromes, and longer intensive care unit length of stay were associated with lower ASQ-3 total scores in adjusted multivariable analyses.

Conclusions and Relevance  In this randomized clinical trial of infants with congenital heart disease, NO administered via the CPB oxygenator did not improve neurodevelopmental outcomes or HRQOL 12 months after open heart surgery. Further research should explore homogenous cohorts with higher surgical risk and higher-dose or alternative therapies.