Randomized Controlled Trial

. 2025 Feb 3;8(2):e2458040.

doi: 10.1001/jamanetworkopen.2024.58040.

Neurodevelopmental Outcomes After Nitric Oxide During Cardiopulmonary Bypass for Open Heart Surgery: A Randomized Clinical Trial

Debbie A Long^{1

2

3}, Kristen S Gibbons³, Stephen B Horton^{4

5

6}, Kerry Johnson³, David H F Buckley⁷, Simon Erickson⁸, Marino Festa^{9

10}, Yves d'Udekem^{5

11}, Nelson Alphonso^{12

13}, Renate Le Marsney³, David S Winlaw^{14

15}, Kate Masterson^{6

16}, Kim van Loon¹⁷, Paul J Young^{18

19

20

21}, Andreas Schibler^{22

23}, Luregn J Schlapbach^{2

3

24

25}, Warwick Butt^{5

6

17

21

26}; NITRIC Study Group and the Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG)

Collaborators, Affiliations

Collaborators

NITRIC Study Group and the Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG):
Johnny Millar, Carmel DelZoppo, John Beca, Taryn Evans, Shelley Coetzer, Claire Sherring, Killian O'Shaughnessy, Chong Tien Goh, Gail Harper, Sam Barr, Rae Kelly, Hannah Thomson, Kelly Holmes, Nigel Slade, David Andrews, Carla Zazulak, Benjamin Anderson, Jessicah Minogue, Antje Blumenthal, Jonas Fooken, Endrias Ergetu, Brenda Gannon, Trang Pham, Annelies Hennick, Nicole van Bell-van Haaren, Bram van Wijk, Erik Koomen, Breanna Pellegrini, Shane George, Corrine Balit, Felix Oberender, Simon Erickson, Jenipher Chubes Flores, Karina Charles, Sai Raman, Michaela Waak, Tara Williams, Debbie Long, Warwick Butt, Ben Gelbart, Kate Masterson, Johnny Milllar, Anusha Ganeshalingam, Puneet Singh, Vicky Smith, Kristen Gibbons, Luregn Schlapbach, Jessica Schults, Jennifer Darvas, Marino Festa

Affiliations

¹ School of Nursing, Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, Australia.
² Paediatric Intensive Care Unit, Queensland Children's Hospital, Children's Health Queensland, Brisbane, Australia.
³ Children's Intensive Care Research Program, Child Health Research Centre, The University of Queensland, Brisbane, Australia.
⁴ Cardiac Surgical Unit, Royal Children's Hospital, Melbourne, Victoria, Australia.
⁵ Faculty of Medicine, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
⁶ Clinical Sciences Theme, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁷ Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand.
⁸ Paediatric Critical Care, Perth Children's Hospital, Western Australia and The University of Western Australia, Crawley, Australia.
⁹ Kids Critical Care Research, Paediatric Intensive Care Unit, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁰ Sydney Children's Hospital Network, Sydney, New South Wales, Australia.
¹¹ Children's National Hospital and The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
¹² Cardiac Surgery, Queensland Children's Hospital, Brisbane, Australia.
¹³ School of Medicine, Children's Health Clinical Unit, The University of Queensland, Brisbane, Australia.
¹⁴ Heart Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁵ Sydney Children's Hospital Network and Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁶ Paediatric Intensive Care Unit, Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.
¹⁷ Department of Anaesthesiology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, the Netherlands.
¹⁸ Intensive Care Unit, Wellington Hospital, Wellington, New Zealand.
¹⁹ Medical Research Institute of New Zealand, Wellington, New Zealand.
²⁰ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia.
²¹ Department of Critical Care, University of Melbourne, Melbourne, Victoria, Australia.
²² James Cook University, Townsville, Queensland, Australia.
²³ Critical Care Research Group, Wesley Medical Research, St Andrew's War Memorial Hospital, Brisbane, Queensland, Australia.
²⁴ Department of Intensive Care and Neonatology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
²⁵ Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
²⁶ Central Clinical School, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia.

PMID: 39908019
PMCID: PMC11800016
DOI: 10.1001/jamanetworkopen.2024.58040

Randomized Controlled Trial

Neurodevelopmental Outcomes After Nitric Oxide During Cardiopulmonary Bypass for Open Heart Surgery: A Randomized Clinical Trial

Debbie A Long et al. JAMA Netw Open. 2025.

. 2025 Feb 3;8(2):e2458040.

doi: 10.1001/jamanetworkopen.2024.58040.

Authors

Collaborators

NITRIC Study Group and the Australian and New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG):
Johnny Millar, Carmel DelZoppo, John Beca, Taryn Evans, Shelley Coetzer, Claire Sherring, Killian O'Shaughnessy, Chong Tien Goh, Gail Harper, Sam Barr, Rae Kelly, Hannah Thomson, Kelly Holmes, Nigel Slade, David Andrews, Carla Zazulak, Benjamin Anderson, Jessicah Minogue, Antje Blumenthal, Jonas Fooken, Endrias Ergetu, Brenda Gannon, Trang Pham, Annelies Hennick, Nicole van Bell-van Haaren, Bram van Wijk, Erik Koomen, Breanna Pellegrini, Shane George, Corrine Balit, Felix Oberender, Simon Erickson, Jenipher Chubes Flores, Karina Charles, Sai Raman, Michaela Waak, Tara Williams, Debbie Long, Warwick Butt, Ben Gelbart, Kate Masterson, Johnny Milllar, Anusha Ganeshalingam, Puneet Singh, Vicky Smith, Kristen Gibbons, Luregn Schlapbach, Jessica Schults, Jennifer Darvas, Marino Festa

Affiliations

¹ School of Nursing, Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, Australia.
² Paediatric Intensive Care Unit, Queensland Children's Hospital, Children's Health Queensland, Brisbane, Australia.
³ Children's Intensive Care Research Program, Child Health Research Centre, The University of Queensland, Brisbane, Australia.
⁴ Cardiac Surgical Unit, Royal Children's Hospital, Melbourne, Victoria, Australia.
⁵ Faculty of Medicine, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
⁶ Clinical Sciences Theme, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁷ Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand.
⁸ Paediatric Critical Care, Perth Children's Hospital, Western Australia and The University of Western Australia, Crawley, Australia.
⁹ Kids Critical Care Research, Paediatric Intensive Care Unit, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁰ Sydney Children's Hospital Network, Sydney, New South Wales, Australia.
¹¹ Children's National Hospital and The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
¹² Cardiac Surgery, Queensland Children's Hospital, Brisbane, Australia.
¹³ School of Medicine, Children's Health Clinical Unit, The University of Queensland, Brisbane, Australia.
¹⁴ Heart Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁵ Sydney Children's Hospital Network and Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁶ Paediatric Intensive Care Unit, Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.
¹⁷ Department of Anaesthesiology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, the Netherlands.
¹⁸ Intensive Care Unit, Wellington Hospital, Wellington, New Zealand.
¹⁹ Medical Research Institute of New Zealand, Wellington, New Zealand.
²⁰ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia.
²¹ Department of Critical Care, University of Melbourne, Melbourne, Victoria, Australia.
²² James Cook University, Townsville, Queensland, Australia.
²³ Critical Care Research Group, Wesley Medical Research, St Andrew's War Memorial Hospital, Brisbane, Queensland, Australia.
²⁴ Department of Intensive Care and Neonatology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
²⁵ Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
²⁶ Central Clinical School, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia.

PMID: 39908019
PMCID: PMC11800016
DOI: 10.1001/jamanetworkopen.2024.58040

Abstract

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.

Trial registration: ANZCTR Identifier: ACTRN12617000821392.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Prof Gibbons reported receiving grants from the National Health and Medical Research Council (NHMRC) and Children’s Hospital Foundation during the conduct of the study. Prof d’Udekem reported receiving consultant fees from Bayer outside the submitted work. Dr van Loon reported receiving donations and grants from LivaNova during the conduct of the study. Prof Schlapbach reported receiving grants from the Medical Research Future Fund, NHMRC, and Children‘s Hospital Foundation during the conduct of the study. No other disclosures were reported.

Figures

**Figure 1.. Participant Flow Diagram**
ASQ-3 indicates Ages and Stages Questionnaire, Third Edition; mPOPC, modified Pediatric Overall Performance Category; PedsQL, Pediatric Quality of Life Inventory. ^aFurther detail provided in Schlapbach et al. ^bMissed due to staff unavailability. ^cOther reasons include severe disability (1 patient) and complex social situation (1 patient).

**Figure 2.. Adjusted Estimates of Difference for Total Ages and Stages, Third Edition (ASQ-3) Score and Total Pediatric Quality of Life Inventory (PedsQL) Score**
^aAdjusted for age at randomization, lesion type, and site. ^bAdjusted for lesion type and site. ^cAdjusted for age at randomization and site.

See this image and copyright information in PMC

References

1. Hövels-Gürich HH. Factors influencing neurodevelopment after cardiac surgery during infancy. Front Pediatr. 2016;4:137. doi:10.3389/fped.2016.00137 - DOI - PMC - PubMed
1. Liamlahi R, Latal B. Neurodevelopmental outcome of children with congenital heart disease. Handb Clin Neurol. 2019;162:329-345. doi:10.1016/B978-0-444-64029-1.00016-3 - DOI - PubMed
1. Kırali K, Çekmecelioğlu D, Özer T, Baş T, Yük H. Pathophysiology of cardiopulmonary bypass. In: Kırali K, Coselli JS, Afksendiyos K, eds. Cardiopulmonary Bypass. Elsevier; 2023:135-154. doi:10.1016/B978-0-443-18918-0.00009-7 - DOI
1. Lee A, Butt W. Nitric oxide: a new role in intensive care. Crit Care Resusc. 2020;22(1):72-79. doi:10.51893/2020.1.sr1 - DOI - PMC - PubMed
1. Scallan MJ. Brain injury in children with congenital heart disease. Paediatr Anaesth. 2003;13(4):284-293. doi:10.1046/j.1460-9592.2003.00996.x - DOI - PubMed

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Neurodevelopmental Outcomes After Nitric Oxide During Cardiopulmonary Bypass for Open Heart Surgery: A Randomized Clinical Trial

Collaborators

Affiliations

Neurodevelopmental Outcomes After Nitric Oxide During Cardiopulmonary Bypass for Open Heart Surgery: A Randomized Clinical Trial

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous