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

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)

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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.

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.

Original languageEnglish
Pages (from-to)e026664
JournalBMJ Open
Volume9
Issue number8
DOIs
Publication statusPublished - 15 Aug 2019

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Congenital Heart Defects
Cardiopulmonary Bypass
Nitric Oxide
Randomized Controlled Trials
Low Cardiac Output
Organized Financing
Mechanical Ventilators
New Zealand
Heart Diseases
Oxygenators
Extracorporeal Membrane Oxygenation
Manuscripts
Health
Infant Mortality
Critical Care
Clinical Protocols
Ambulatory Surgical Procedures
Artificial Respiration
Research
Health Care Costs

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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) (2019). Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial. BMJ Open, 9(8), e026664. https://doi.org/10.1136/bmjopen-2018-026664
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). / Study protocol : NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial. In: BMJ Open. 2019 ; Vol. 9, No. 8. pp. e026664.
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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.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.",
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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) 2019, 'Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial' BMJ Open, vol. 9, no. 8, pp. e026664. https://doi.org/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. / 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).

In: BMJ Open, Vol. 9, No. 8, 15.08.2019, p. e026664.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Study protocol

T2 - NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial

AU - 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)

AU - Schlapbach, Luregn J

AU - Horton, Stephen Brian

AU - Long, Debbie Amanda

AU - Beca, John

AU - Erickson, Simon

AU - Festa, Marino

AU - d'Udekem, Yves

AU - Alphonso, Nelson

AU - Winlaw, David

AU - Johnson, Kerry

AU - Delzoppo, Carmel

AU - van Loon, Kim

AU - Gannon, B

AU - Fooken, Jonas

AU - Blumenthal, Antje

AU - Young, Paul

AU - Jones, Mark

AU - Butt, Warwick

AU - Schibler, Andreas

N1 - © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - 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.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.

AB - 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.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.

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DO - 10.1136/bmjopen-2018-026664

M3 - Article

VL - 9

SP - e026664

JO - BMJ Open

JF - BMJ Open

SN - 2044-6055

IS - 8

ER -

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