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

Luregn J Schlapbach; Stephen Brian Horton; Debbie Amanda Long; John Beca; Simon Erickson; Marino Festa; Yves d'Udekem; Nelson Alphonso; David Winlaw; Kerry Johnson; Carmel Delzoppo; Kim van Loon; B Gannon; Jonas Fooken; Antje Blumenthal; Paul Young; Mark Jones; Warwick Butt; Andreas Schibler; 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)

doi:10.1136/bmjopen-2018-026664

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

BMJ Open. 2019 Aug 15;9(8):e026664. doi: 10.1136/bmjopen-2018-026664.

Authors

Luregn J Schlapbach^{1

2}, Stephen Brian Horton^{3

4

5}, Debbie Amanda Long^{1

2}, John Beca⁶, Simon Erickson⁷, Marino Festa^{8

9}, Yves d'Udekem^{10

11

12

13}, Nelson Alphonso¹⁴, David Winlaw^{15

16}, Kerry Johnson^{1

2}, Carmel Delzoppo^{5

17}, Kim van Loon¹⁸, B Gannon¹⁹, Jonas Fooken¹⁹, Antje Blumenthal²⁰, Paul Young²¹, Mark Jones²², Warwick Butt^{5

17}, Andreas Schibler^{1

2}; 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)

Collaborators

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):
Warwick Butt, Steve Horton, Johnny Millar, Carmel Delzoppo, Yves D'Udekem, John Beca, David Buckley, Taryn Evans, Claire Sherring, John Artrip, Marino Festa, Killian O'Shaughnessy, David Winlaw, Rebecca Fletcher, Simon Byrne, Simon Erickson, Sam Barr, Rae Kelly, David Andrews, Luregn J Schlapbach, Andreas Schibler, Deborah Long, Kerry Johnston, Carla Zuzak, Nelson Alphonso, Benjamin Anderson, Antje Blumenthal, Jonas Fooken, Brenda Gannon, Paul Young, Mark Jones, Kim van Loon, Nicole J C W van Belle-van Haaren, Bram van Wijk, Erik Koomen

Affiliations

¹ Paediatric Critical Care Research Group, Child Health Research Institute, The University of Queensland, Brisbane, Queensland, Australia.
² Paediatric Intensive Care Unit, Queensland Children's Hospital, Children's Health Queensland, Brisbane, Queensland, Australia.
³ Cardiac Surgical Unit, Royal Children's Hospital, Melbourne, Victoria, Australia.
⁴ Faculty of Medicine, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
⁵ Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁶ Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand.
⁷ Paediatric Critical Care, Perth Children's Hospital, Western Australia and The University of Western Australia, Crawley, Western Australia, Australia.
⁸ Kids Critical Care Research, Paediatric Intensive Care Unit, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
⁹ Sydney Children's Hospital Network, Sydney, New South Wales, Australia.
¹⁰ Department of Cardiac Surgery, Royal Children's Hospital, Melbourne, Victoria, Australia.
¹¹ Heart Research, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.
¹² Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
¹³ School of Medicine, Children's Health Clinical Unit, University of Queensland, Brisbane, Queensland, Australia.
¹⁴ Cardiac Surgery, Queensland Children's Hospital, Brisbane, Queensland, Australia.
¹⁵ Heart Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁶ Sydney Children's Hospital Network and Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁷ Paediatric Intensive Care Unit, Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia.
¹⁸ Division of Anaesthetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁹ Centre for the Business and Economics of Health, The University of Queensland, Brisbane, Queensland, Australia.
²⁰ The Infection and Inflammation Group, The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
²¹ The Intensive Care Research Programme, Medical Research Institute of New Zealand, Wellington, New Zealand.
²² School of Public Health, Bond University, Gold Coast, Brisbane, Australia.

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.

Keywords: cardiopulmonary bypass; child; congenital heart disease; infant; inflammation; mortality; nitric oxide; ventilation.

Publication types

Clinical Trial Protocol
Research Support, Non-U.S. Gov't

MeSH terms

Cardiac Surgical Procedures / methods*
Cardiopulmonary Bypass* / adverse effects
Cardiopulmonary Bypass* / methods
Cardiotonic Agents / administration & dosage
Double-Blind Method
Female
Heart Defects, Congenital / surgery*
Humans
Infant
Male
Nitric Oxide / administration & dosage*
Randomized Controlled Trials as Topic
Risk Adjustment / methods

Substances

Cardiotonic Agents
Nitric Oxide

Associated data

ANZCTR/ACTRN12617000821392