Protocol for a multicenter, double-blind, randomized, placebo-controlled phase III trial of the inhaled ß2-adrenergic receptor agonist salbutamol for transient tachypnea of the newborn (the REFSAL trial).

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 ß-adrenergic receptors enhances alveolar fluid absorption. Therefore, the ß2-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 O2 and CO2, and base excess), and blood serum ionogram for Na+, K+, and Ca2+. 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. Ethics and dissemination: The study protocol was approved by the Bioethics Committee of the Medical University of Warsaw, Warsaw, Poland on November 16, 2020 (decision number KB/190/2020). All procedures will follow the principles of the Declaration of Helsinki. The results of the study will be submitted for knowledge translation in peer-reviewed journals and presented at national and international pediatric society conferences. Clinical Trial Registration: It is registered at ClinicalTrials.gov NCT05527704, EudraCT 2020-003913-36; Protocol version 5.0 from 04/01/2022.

The significance of IL-1ß +3953C>T, IL-6 -174G>C and -596G>A, TNF-α -308G>A gene polymorphisms and 86 bp variable number tandem repeat polymorphism of IL-1RN in bronchopulmonary dysplasia in infants born before 32 weeks of gestation.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects primarily preterm infants. Genetic factors are also taken into consideration in the pathogenesis of BPD. Genetic predispositions to higher production of inflammation mediators seem to be crucial. MATERIAL AND METHODS: The aim of this study was to evaluate the possible relationship between polymorphisms: interleukin-1ß +3953 C>T, interleukin-6 -174 G>C and -596 G>A, tumour necrosis factor -308 G>A and interleukin-1RN VNTR 86bp and the occurrence of BPD in a population of 100 preterm infants born from singleton pregnancy, before 32+0 weeks of gestation, exposed to antenatal steroids therapy, and without congenital abnormalities. RESULTS: In the study population BPD was diagnosed in 36 (36%) newborns. Among the studied polymorphisms we found the higher prevalence for BPD developing of the following genotypes: 1/2 (OR 1.842 [0.673-5.025] and 2/2 IL-1RN (OR 1.75 [0.418-6.908] 86bpVNTR; GC (2.222 [0.658-8.706]) and CC IL-6 -174G>C (1.6 [0.315-8.314]) and GA (2.753 [0.828-10.64]) and AA (1.5 [0.275-8.067] IL-6 -596G>A), GA 1.509 (0.515-4.301) TNF-α -308G>A. However, these finding were not statistically significant. CONCLUSIONS: Genetic factors are undeniably involved in the pathogenesis of BPD. In the times of individualised therapy finding genes responsible for BPD might allow the development of new treatment strategies. A new way of specific therapy could ensure the reduction of complications connected with BPD and treatment costs.

Myocardial performance index (Tei index) in term and preterm neonates during the neonatal period.

BACKGROUND: The myocardial performance index (MPI) is a noninvasive method to measure global systolic and diastolic myocardial function. In both term and premature neonates, changes in the systolic and diastolic function of the left ventricle (LV) and right ventricle (RV) reflect the degree of neonatal myocardial immaturity and the co-existence of foetal circulation. AIM: To assess MPI (or Tei indices) of both ventricles in term and preterm newborns, and to observe MPI trends throughout the neonatal period. METHODS: Heart ultrasound imaging was performed on the first day of life (DOL), after patent ductus arteriosus (PDA) closure, and on the 28th DOL, in 29 term and 29 preterm newborns. RVMPI and LVMPI were measured within the preterm group at 40 weeks of post-conception age (PCA). RESULTS: A statistically significant reduction in RVMPI was observed in both term and preterm newborns. In term newborns, the RVMPI value on the first DOL was 0.42 ± 14, dropping to 0.29 ± 0.09 after PDA closure, and finally reaching 0.22 ± 0.09 on the 28th DOL. The respective RVMPI values for the preterm newborns were 0.44 ± 0.15, 0.30 ± 0.12, and 0.21 ± 0.08. Little variability in the mean values of LVMPI was observed in both groups throughout the neonatal period. The LVMPI for term neonates in successive measurements was 0.37 ± 0.10, 0.39 ± 0.07, and 0.37 ± 0.11, respectively, and for the preterm neonates it was 0.37 ± 0.10, 0.35 ± 0.09, and 0.36 ± 0.10, respectively. The MPI values from preterm newborns taken at 40 weeks PCA (RVMPI = 0.28 ± 0.09; LVMPI = 0.37 ± 0.05) were comparable to those measured in term newborns after PDA closure. CONCLUSIONS: Observed postnatal changes in RVMPI correspond to changes in ventricular function, reflecting the haemodynamic changes of the transitional circulation. The relatively small postnatal changes in LVMPI in term and preterm newborns may reflect an immature myocardium. The RVMPI and LVMPI values at 40 weeks PCA in preterm newborns correlate best with MPI values in term newborns just after PDA closure.