Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR Trial): Protocol for a Randomized Controlled Trial

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Abstract
Background: Extracorporeal membrane oxygenation (ECMO) provides support for the pulmonary or cardiovascular function of children in whom the predicted mortality risk remains very high. The inevitable host inflammatory response and activation of the coagulation cascade due to the extracorporeal circuit contribute to additional morbidity and mortality in these patients. Mixing nitric oxide (NO) into the sweep gas of ECMO circuits may reduce the inflammatory and coagulation cascade activation during ECMO support. Objective: The purpose of this study is to test the feasibility and safety of mixing NO into the sweep gas of ECMO systems and assess its effect on inflammation and coagulation system activation through a pilot randomized controlled trial. Methods: The Nitric Oxide on Extracorporeal Membrane Oxygenation in Neonates and Children (NECTAR) trial is an open-label, parallel-group, pilot randomized controlled trial to be conducted at a single center. Fifty patients who require ECMO support will be randomly assigned to receive either NO mixed into the sweep gas of the ECMO system at 20 ppm for the duration of ECMO or standard care (no NO) in a 1:1 ratio, with stratification by support type (veno-venous vs veno-arterial ECMO). Results: Outcome measures will focus on feasibility (recruitment rate and consent rate, and successful inflammatory marker measurements), the safety of the intervention (oxygenation and carbon dioxide control within defined parameters and methemoglobin levels), and proxy markers of efficacy (assessment of cytokines, chemokines, and coagulation factors to assess the impact of NO on host inflammation and coagulation cascade activation, clotting of ECMO components, including computer tomography scanning of oxygenators for clot assessments), bleeding complications, as well as total blood product use. Survival without ECMO and the length of stay in the pediatric intensive care unit (PICU) are clinically relevant efficacy outcomes. Long-term outcomes include neurodevelopmental assessments (Ages and Stages Questionnaire, Strength and Difficulties Questionnaire, and others) and quality of life (Pediatric Quality of Life Inventory and others) measured at 6 and 12 months post ECMO cannulation. Analyses will be conducted on an intention-to-treat basis. Conclusions: The NECTAR study investigates the safety and feasibility of NO as a drug intervention during extracorporeal life support and explores its efficacy. The study will investigate whether morbidity and mortality in patients treated with ECMO can be improved with NO. The intervention targets adverse outcomes in patients who are supported by ECMO and who have high expected mortality and morbidity. The study will be one of the largest randomized controlled trials performed among pediatric patients supported by ECMO. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12619001518156; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376869 International Registered Report Identifier (IRRID): DERR1-10.2196/43760

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