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
- congenital heart disease
- nitric oxide
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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.
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