Prophylactic Sildenafil in Preterm Infants at Risk of Bronchopulmonary Dysplasia: A Pilot Randomized, Double-Blinded, Placebo-Controlled Trial

Abstract

Background Bronchopulmonary dysplasia (BPD) is the need for oxygen therapy at 36 weeks postmenstrual age (PMA). Sildenafil has been shown to enhance the lung alveolarization and vascularization in newborn animal models after lung injury and has possible therapeutic potential for the prevention of BPD. Objective To perform a proof-of-concept, Phase II, pilot randomized, double-blind, clinical trial to study the efficacy of sildenafil in preventing BPD, in postnatal (< 24 h), extremely and very preterm infants. Methods This Phase II, pilot randomized, double-blind, clinical trial was conducted in the Neonatal Intensive Care Unit of Women's Wellness and Research Center, Doha, Qatar during 2012-2014. Infants of 24 0/7-29 6/7 weeks' gestation were eligible if they needed respiratory or oxygen support ≥ 25% at randomization, and if they were at a postnatal age of < 24 h at randomization. Forty preterm infants were randomly assigned to receive off-label oral sildenafil (0.5 mg/kg every 6 h) or a placebo solution, for one week. The primary endpoints were the incidence of BPD and death at 36 weeks PMA, and the side effects. Secondary outcomes included the incidence of BPD and the respiratory support at day 28 of life, duration of oxygen use, fraction of inspired oxygen use at 36 weeks and 28 days of life, duration of hospitalization, and the incidence of significant retinopathy of prematurity, severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, patent ductus arteriosus, and late sepsis. Results No significant differences were observed between the sildenafil and placebo study groups in mortality at 36 weeks PMA (10% vs 20%, p = 1), respiratory support at 36 weeks (30% vs 25%, p = 0.57), and side effects (0% vs 0%). For all other secondary outcomes, no significant differences were detected. Conclusions While not associated with side effects, off-label oral sildenafil did not demonstrate benefits in the prevention of BPD or death in the extreme and very preterm infants. Future studies of dosing and efficacy that target different regimens of sildenafil are warranted before sildenafil is recommended for the prevention of BPD.

Sildenafil in the Management of Pulmonary Hypertension in Newborn

“…Systematic review shows that in the treatment of BPD-associated pulmonary hypertension in preterm infants, sildenafil may be associated with improvement in pulmonary artery pressure and respiratory scores. 38 Abounahia et al 39 found oral sildenafil did not benefits in the prevention of BPD or death in the extreme and very preterm infants. A retrospective series of 25 patients with BPD aged <2 years showed hemodynamic improvement in pulmonary hypertension in majority cases, with minimal adverse events.…”

Pharmacotherapy in Bronchopulmonary Dysplasia: What Is the Evidence?

“…Prophylactic sildenafil in neonatal rats exposed to hyperoxia has been shown to improve alveolarization, promote angiogenesis, decrease lung inflammation and fibrin deposition, and thus decrease BPD via activation of hypoxia-inducible factor signaling pathway (208)(209)(210). However, RCTs studying the effect of prophylactic sildenafil in preterm infants did not demonstrate any significant impact on BPD or death (211,212).…”

The feasibility of ultrasound Graf method in screening infants and young children with congenital hip dysplasia and follow-up of treatment effect

“…especially for infants whose hip joints are mainly cartilage, therefore the results of hip ultrasound examination are more reliable (9). Ultrasound Graf method can be used to evaluate development of the hip joint by analyzing the ultrasound images of the hip joint and quantifying the shape of the acetabulum with α and β angles (10). The results of this study showed that there was a significant difference in α and β angles between the cases with congenital acetabular dysplasia and those with normal hip joints by ultrasound Graf method, which is consistent with the reports of Fooladi (11), suggesting that the ultrasound Graf method can be used as one of the methods to screen congenital acetabular abnormalities, with strong operability and high standardization.…”