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  • Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial

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Intensive care
Protocol
Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial
  1. Luregn J Schlapbach1,2,
  2. Stephen Brian Horton3,4,5,
  3. Debbie Amanda Long1,2,
  4. John Beca6,
  5. Simon Erickson7,
  6. Marino Festa8,9,
  7. Yves d’Udekem10,11,12,13,
  8. Nelson Alphonso14,
  9. David Winlaw15,16,
  10. Kerry Johnson1,2,
  11. Carmel Delzoppo5,17,
  12. Kim van Loon18,
  13. B Gannon19,
  14. Jonas Fooken19,
  15. Antje Blumenthal20,
  16. Paul Young21,
  17. Mark Jones22,
  18. Warwick Butt5,17,
  19. Andreas Schibler1,2
  20. On behalf of the NITRIC Study Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), the Paediatric Critical Care Research group (PCCRG) and the ANZICS Paediatric Study Group (PSG)
    1. 1Paediatric Critical Care Research Group, Child Health Research Institute, The University of Queensland, Brisbane, Queensland, Australia
    2. 2Paediatric Intensive Care Unit, Queensland Children’s Hospital, Children’s Health Queensland, Brisbane, Queensland, Australia
    3. 3Cardiac Surgical Unit, Royal Children’s Hospital, Melbourne, Victoria, Australia
    4. 4Faculty of Medicine, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
    5. 5Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
    6. 6Paediatric Intensive Care Unit, Starship Children’s Hospital, Auckland, New Zealand
    7. 7Paediatric Critical Care, Perth Children’s Hospital, Western Australia and The University of Western Australia, Crawley, Western Australia, Australia
    8. 8Kids Critical Care Research, Paediatric Intensive Care Unit, Children’s Hospital at Westmead, Westmead, New South Wales, Australia
    9. 9Sydney Children’s Hospital Network, Sydney, New South Wales, Australia
    10. 10Department of Cardiac Surgery, Royal Children’s Hospital, Melbourne, Victoria, Australia
    11. 11Heart Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia
    12. 12Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia
    13. 13School of Medicine, Children’s Health Clinical Unit, University of Queensland, Brisbane, Queensland, Australia
    14. 14Cardiac Surgery, Queensland Children’s Hospital, Brisbane, Queensland, Australia
    15. 15Heart Centre for Children, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia
    16. 16Sydney Children’s Hospital Network and Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
    17. 17Paediatric Intensive Care Unit, Royal Children’s Hospital Melbourne, Melbourne, Victoria, Australia
    18. 18Division of Anaesthetics, University Medical Center Utrecht, Utrecht, The Netherlands
    19. 19Centre for the Business and Economics of Health, The University of Queensland, Brisbane, Queensland, Australia
    20. 20The Infection and Inflammation Group, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
    21. 21The Intensive Care Research Programme, Medical Research Institute of New Zealand, Wellington, New Zealand
    22. 22School of Public Health, Bond University, Gold Coast, Brisbane, Australia
    1. Correspondence to Dr Andreas Schibler; a.schibler{at}uq.edu.au

    Abstract

    Introduction Congenital heart disease (CHD) is a major cause of infant mortality. Many infants with CHD require corrective surgery with most operations requiring cardiopulmonary bypass (CPB). CPB triggers a systemic inflammatory response which is associated with low cardiac output syndrome (LCOS), postoperative morbidity and mortality. Delivery of nitric oxide (NO) into CPB circuits can provide myocardial protection and reduce bypass-induced inflammation, leading to less LCOS and improved recovery. We hypothesised that using NO during CPB increases ventilator-free days (VFD) (the number of days patients spend alive and free from invasive mechanical ventilation up until day 28) compared with standard care. Here, we describe the NITRIC trial protocol.

    Methods and analysis The NITRIC trial is a randomised, double-blind, controlled, parallel-group, two-sided superiority trial to be conducted in six paediatric cardiac surgical centres. One thousand three-hundred and twenty infants <2 years of age undergoing cardiac surgery with CPB will be randomly assigned to NO at 20 ppm administered into the CPB oxygenator for the duration of CPB or standard care (no NO) in a 1:1 ratio with stratification by age (<6 and ≥6 weeks), single ventricle physiology (Y/N) and study centre. The primary outcome will be VFD to day 28. Secondary outcomes include a composite of LCOS, need for extracorporeal membrane oxygenation or death within 28 days of surgery; length of stay in intensive care and in hospital; and, healthcare costs. Analyses will be conducted on an intention-to-treat basis. Preplanned secondary analyses will investigate the impact of NO on host inflammatory profiles postsurgery.

    Ethics and dissemination The study has ethical approval (HREC/17/QRCH/43, dated 26 April 2017), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12617000821392) and commenced recruitment in July 2017. The primary manuscript will be submitted for publication in a peer-reviewed journal.

    Trial registration number ACTRN12617000821392

    • cardiopulmonary bypass
    • child
    • congenital heart disease
    • infant
    • inflammation
    • ventilation
    • nitric oxide
    • mortality

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

    https://doi.org/10.1136/bmjopen-2018-026664

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      Footnotes

      • Contributors The study protocol first draft was designed by LJS and AS based on the previous pilot study design established by SBH and WB. MJ wrote the section on statistical analyses. JF and BG wrote the section on health economic analyses The present study protocol has been revised with input from SBH, DAL, JB, SE, MF, YdU, NA, DW, KJ, CD, KvL, BG, JF, PY, AB, MJ and WB. LJS prepared the final protocol manuscript which was reviewed and approved by all authors.

      • Funding This work was supported by grants from the Heart Kids Foundation, Australia; the Children’s Health Foundation, Brisbane, Australia; and by a grant from the Australian National Health and Medical Research Council (1140322). LJS, YdU and AS hold a NHMRC Clinical Practitioner Fellowship. The Victorian Government’s Operational Infrastructure Support Program supported this research project. PY holds a Clinical Practitioner Fellowship from the Health Research Council of New Zealand. Mallinckrodt Pharmaceuticals will provide nitric oxide delivery devices to study centres but has no involvement in study design, conduct, nor analyses.

      • Competing interests YdU is a consultant for MSD and Actelion.

      • Ethics approval The study was approved by human research ethics committee (Children’s Health Queensland, Brisbane, HREC/17/QRCH/43).

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Collaborators Warwick Butt, Steve Horton, Johnny Millar, Carmel Delzoppo and Yves d’Udekem: Cardiac and Paediatric Intensive Care Services of Royal Children’s Hospital, Melbourne, Australia. John Beca, David Buckley, Taryn Evans, Claire Sherring and John Artrip: Starship Children’s Hospital Auckland, New Zealand. Marino Festa, Killian O’Shaughnessy, David Winlaw, Rebecca Fletcher and Simon Byrne: The Children’s Hospital at Westmead, Sydney, Australia. Simon Erickson, Sam Barr, Rae Kelly and David Andrews: Perth Children’s Hospital, Perth, Australia. Luregn J Schlapbach, Andreas Schibler, Deborah Long, Kerry Johnston, Carla Zuzak, Nelson Alphonso and Benjamin Anderson: Queensland Children’s Hospital, Brisbane, Australia. Antje Blumenthal: The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia. Jonas Fooken and Brenda Gannon: Centre for the Business and Economics of Health, The University of Queensland, Brisbane, Australia. Paul Young: Medical Research Institute of New Zealand, Wellington, New Zealand. Mark Jones: School of Public Health, The University of Queensland, Brisbane, Australia. Kim van Loon, Nicole JCW van Belle-van Haaren, Bram van Wijk and Erik Koomen: Wilhelmina Children’s Hospital Utrecht, Utrecht, The Netherlands.

      • Patient consent for publication Not required.