Luregn J Schlapbach1,2,3, Kristen S Gibbons1, Stephen B Horton4,5,6, Kerry Johnson1,2, Debbie A Long1,7, David H F Buckley8, Simon Erickson9, Marino Festa10,11, Yves d'Udekem5,12,13, Nelson Alphonso1,14,15, David S Winlaw16,17, Carmel Delzoppo5,18, Kim van Loon19, Mark Jones20, Paul J Young21, Warwick Butt5,6,18,22,23, Andreas Schibler24. 1. Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia. 2. Paediatric Intensive Care Unit, Queensland Children's Hospital, Children's Health Queensland, Brisbane, Queensland, Australia. 3. Department of Intensive Care and Neonatology, and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland. 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. School of Nursing, Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, Queensland, Australia. 8. Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand. 9. Paediatric Critical Care, Perth Children's Hospital, Western Australia and The University of Western Australia, Crawley, Western Australia, Australia. 10. Kids Critical Care Research, Paediatric Intensive Care Unit, Children's Hospital at Westmead, Westmead, New South Wales, Australia. 11. Sydney Children's Hospital Network, Sydney, New South Wales, Australia. 12. Children's National Hospital and The George Washington University School of Medicine and Health Sciences, Seattle, Washington. 13. Heart Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia. 14. Cardiac Surgery, Queensland Children's Hospital, Brisbane, Queensland, Australia. 15. School of Medicine, Children's Health Clinical Unit, University of Queensland, Brisbane, Queensland, Australia. 16. Heart Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia. 17. Sydney Children's Hospital Network and Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia. 18. Paediatric Intensive Care Unit, Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia. 19. Department of Anaesthesiology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, the Netherlands. 20. Institute of Evidence Based Healthcare, Bond University, Gold Coast, Australia. 21. The Intensive Care Research Programme, Medical Research Institute of New Zealand, Wellington, New Zealand. 22. Department of Critical Care, Melbourne Medical School University of Melbourne, Victoria, Australia. 23. Central Clinical School Faculty of Medicine Monash University, Melbourne, Victoria, Australia. 24. Critical Care Research Group, Wesley Medical Research, St Andrew's War Memorial Hospital, Brisbane, Queensland, Australia.
Abstract
Importance: In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation). Objective: To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease. Design, Setting, and Participants: Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. Interventions: Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). Main Outcomes and Measures: The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. Results: Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of -0.01 days (95% CI, -0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. Conclusions and Relevance: In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery. Trial Registration: anzctr.org.au Identifier: ACTRN12617000821392.
Importance: In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation). Objective: To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease. Design, Setting, and Participants: Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. Interventions: Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). Main Outcomes and Measures: The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. Results: Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of -0.01 days (95% CI, -0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. Conclusions and Relevance: In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery. Trial Registration: anzctr.org.au Identifier: ACTRN12617000821392.
Authors: Paul A Harris; Robert Taylor; Robert Thielke; Jonathon Payne; Nathaniel Gonzalez; Jose G Conde Journal: J Biomed Inform Date: 2008-09-30 Impact factor: 6.317
Authors: Tiffany Riehle-Colarusso; Andrew Autry; Hilda Razzaghi; Coleen A Boyle; William T Mahle; Kim Van Naarden Braun; Adolfo Correa Journal: Pediatrics Date: 2015-08-17 Impact factor: 7.124
Authors: Nikolay O Kamenshchikov; Irina A Mandel; Yuriy K Podoksenov; Yulia S Svirko; Vladimir V Lomivorotov; Sergey L Mikheev; Boris N Kozlov; Vladimir M Shipulin; Aleksandra A Nenakhova; Yana J Anfinogenova Journal: J Thorac Cardiovasc Surg Date: 2018-10-13 Impact factor: 5.209
Authors: Christopher James; Johnny Millar; Stephen Horton; Christian Brizard; Charlotte Molesworth; Warwick Butt Journal: Intensive Care Med Date: 2016-09-30 Impact factor: 17.440
Authors: Mark D Reller; Matthew J Strickland; Tiffany Riehle-Colarusso; William T Mahle; Adolfo Correa Journal: J Pediatr Date: 2008-07-26 Impact factor: 4.406
Authors: Michael G Gaies; James G Gurney; Alberta H Yen; Michelle L Napoli; Robert J Gajarski; Richard G Ohye; John R Charpie; Jennifer C Hirsch Journal: Pediatr Crit Care Med Date: 2010-03 Impact factor: 3.624
Authors: Regina M Simeone; Matthew E Oster; Cynthia H Cassell; Brian S Armour; Darryl T Gray; Margaret A Honein Journal: Birth Defects Res A Clin Mol Teratol Date: 2014-06-27