Neurodevelopmental Outcomes After Nitric Oxide During Cardiopulmonary Bypass for Open Heart Surgery
Authors: Long Debbie A. , Gibbons Kristen S. , Horton Stephen B. , Johnson Kerry , Buckley David H. F. , Erickson Simon , Festa Marino , d’Udekem Yves , Alphonso Nelson , Le Marsney Renate , Winlaw David S. , Masterson Kate , van Loon Kim , Young Paul J. , Schibler Andreas , Schlapbach Luregn J. , Butt Warwick ,   NITRIC Study Group and the Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG), Millar Johnny , DelZoppo Carmel , Beca John , Evans Taryn , Coetzer Shelley , Sherring Claire , O'Shaughnessy Killian , Goh Chong Tien , Harper Gail , Barr Sam , Kelly Rae , Thomson Hannah , Holmes Kelly , Slade Nigel , Andrews David , Zazulak Carla , Anderson Benjamin , Minogue Jessicah , Blumenthal Antje , Fooken Jonas , Ergetu Endrias , Gannon Brenda , Pham Trang , Hennick Annelies , van Bell-van Haaren Nicole , van Wijk Bram , Koomen Erik , Pellegrini Breanna , George Shane , Balit Corrine , Oberender Felix , Erickson Simon , Chubes Flores Jenipher , Charles Karina , Raman Sai , Waak Michaela , Williams Tara , Long Debbie , Butt Warwick , Gelbart Ben , Masterson Kate , Milllar Johnny , Ganeshalingam Anusha , Singh Puneet , Smith Vicky , Gibbons Kristen , Schlapbach Luregn , Schults Jessica , Darvas Jennifer , Festa Marino 
Published: February 2025

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 &amp;lt;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.

Trial Registration

ANZCTR Identifier: ACTRN12617000821392