EDITED BY Giovanni Vento, Catholic University of the Sacred Heart, Italy REVIEWED BY Ozge Surmeli Onay, Eskis ̧ ehir Osmangazi University, Turkey James B. Fink, Texas State University System, United States *CORRESPONDENCE Renata Bokiniec renata.bokiniec@wum.edu.pl SPECIALTY SECTION This article was submitted to Neonatology, a section of the journal Frontiers in Pediatrics RECEIVED 03 October 2022 ACCEPTED 20 December 2022 PUBLISHED 12 January 2023 CITATION Madajczak D, Daboval T, Lauterbach R, Łoniewska B, Błaż W, Szczapa T, Sadowska-Krawczenko I, Michalak-Kloc M, Sławska H, Borszewska-Kornacka M, Bokiniec R and the REFSAL Study Group (2023) Protocol for a multicenter, double-blind, randomized, placebo-controlled phase III trial of the inhaled β2-adrenergic receptor agonist salbutamol for transient tachypnea of the newborn (the REFSAL trial). Front. Pediatr. 10:1060843. doi: 10.3389/fped.2022.1060843 COPYRIGHT © 2023 Madajczak, Daboval, Lauterbach, Łoniewska, Błaż, Szczapa, Sadowska- Krawczenko, Michalak-Kloc, Sławska, Borszewska-Kornacka, Bokiniec and the REFSAL Study Group. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Protocol for a multicenter, double-blind, randomized, placebo-controlled phase III trial of the inhaled β2-adrenergic receptor agonist salbutamol for transient tachypnea of the newborn (the REFSAL trial) Dariusz Madajczak 1 , Thierry Daboval 2 , Ryszard Lauterbach 3 , Beata Łoniewska 4 , Witold Błaż 5 , Tomasz Szczapa 6 , Iwona Sadowska-Krawczenko 7 , Marzena Michalak-Kloc 8 , Helena Sławska 9 , Maria Borszewska-Kornacka 1 , Renata Bokiniec 1 * and the REFSAL Study Group 1 Department of Neonatology and Neonatal Intensive Care, Medical University of Warsaw, Warsaw, Poland, 2 Department of Pediatrics – Division of Neonatology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada, 3 Neonatology Clinic, University Hospital, Krakow, Poland, 4 Department of Neonatology and Intensive Neonatal Care, Pomeranian Medical University, Szczecin, Poland, 5 Clinical Department of Neonatology With Neonatal Intensive Care Unit, University of Rzeszow, Saint Jadwiga the Queen Clinical Provincial Hospital No 2, Rzeszow, Poland, 6 Department of Neonatology, Poznań University of Medical Sciences, Poznań, Poland, 7 Department of Neonatology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland, 8 Neonatology Clinical Department, Karol Marcinkowski University Hospital, Zielona Góra, Poland, 9 Neonatology Unit, Specialist Hospital No 2, Bytom, Medical University of Silesia, Bytom, Poland Background: Transient tachypnea of the newborn (TTN), which results from inadequate absorption of fetal lung fluid, is the most common cause of neonatal respiratory distress. Stimulation of β-adrenergic receptors enhances alveolar fluid absorption. Therefore, the β2-adrenergic receptor agonist salbutamol has been proposed as a treatment for TTN. This study aims to evaluate the efficacy and safety of salbutamol as supportive pharmacotherapy together with non-invasive nasal continuous positive airway pressure (NIV/nCPAP) for the prevention of persistent pulmonary hypertension of the newborn (PPHN) in infants with TTN. Methods and analysis: This multicenter, double-blind, phase III trial will include infants with a gestational age between 32 and 42 weeks who are affected by respiratory disorders and treated in eight neonatal intensive care units in Poland. A total of 608 infants within 24 h after birth will be enrolled and randomly assigned (1:1) to receive nebulized salbutamol with NIV or placebo (nebulized 0.9% NaCl) with NIV. The primary outcome is the percentage of infants with TTN who develop PPHN. The secondary outcomes are the severity of respiratory distress (assessed with the modified TTN Silverman score), frequency of need for intubation, duration of NIV and hospitalization, acid–base balance (blood pH, partial pressure of O 2 and CO 2 , and base excess), and blood serum ionogram for Na + ,K + , and Ca 2+ . Discussion: The Respiratory Failure with Salbutamol (REFSAL) study will be the first clinical trial to evaluate the efficacy and safety of salbutamol in the prevention of persistent pulmonary hypertension in newborns with tachypnea, and will improve short term outcomes. If successful, the study will demonstrate the feasibility of early intervention with NIV/nCPAP together with nebulized salbutamol in the management of TTN. TYPE Methods PUBLISHED 12 January 2023 | DOI 10.3389/fped.2022.1060843 Frontiers in Pediatrics 01 frontiersin.org