Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide

Abstract

Objectives To assess whether late surfactant treatment of extremely low gestational age newborn (ELGAN) infants requiring ventilation at 7–14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). Study design ELGAN infants (≤ 28 0/7 weeks) who required mechanical ventilation at 7–14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide (INO) and either surfactant (calfactant/Infasurf®) or sham instillation every 1–3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, evaluated by physiologic oxygen/flow reduction. Results Between January 2010 and September 2013, 511 infants were enrolled. There were no differences between treatment groups in mean birth weight (701±164 g), gestational age (25.2±1.2 weeks), percentage <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or co-morbidities of prematurity. Survival without BPD was not different between treated vs. controls at 36 weeks PMA (31.3% vs. 31.7%; relative benefit 0.98 (95% CI: 0.75, 1.28 p=0.89) or 40 weeks (58.7% vs. 54.1%; relative benefit 1.08:0.92, 1.27 p=0.33). There were no differences between groups in serious adverse events, co-morbidities of prematurity, nor in the severity of lung disease to 36 weeks. Conclusions Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving iNO was well tolerated but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing.

Early Cumulative Supplemental Oxygen Predicts Bronchopulmonary Dysplasia in High Risk Extremely Low Gestational Age Newborns

“…Infants were predominantly male, with mean gestational age and birth weight similar to those enrolled in the trial (25.2±1.2 weeks and 700 ±165 grams, respectively; Table I). 13 Although 143 infants were products of multiple gestation, only 105 (21%) had a sibling enrolled in TOLSURF.…”

“…The study protocol and initial outcomes have been described in detail. 13 In brief, 511 infants ≤28 0/7 weeks’ gestational age, who required endotracheal intubation anytime between 7–14 days of life placing them at high risk for BPD or death, were randomized to late surfactant and inhaled nitric oxide (iNO) versus iNO alone. 1, 14 The primary outcome for the trial was survival without BPD at 36 weeks’ PMA, determined by physiologic oxygen/flow reduction challenge.…”

“…This date was chosen based on the timing of the SUPPORT publication and a pause in TOLSURF enrollment for an interim safety analysis. 13 …”

Can We Prevent Bronchopulmonary Dysplasia?

“…18 A large RCT of the use of late surfactant therapy in premature intubated infants did not show reduced BPD. 19 …”

Advances in emerging treatment options to prevent bronchopulmonary dysplasia

“…A further RCT [104] confirmed that iNO given non-invasively in the first 72 hours after birth did not reduce BPD. Infants receiving iNO all born less than or equal to 28 weeks of gestation and requiring mechanical ventilation at 7 to 14 days were randomised to receive up to five doses of surfactant or sham instillation every one to three days [105]. Although the surfactant administration was well tolerated it did not improve survival without BPD at 36 or 40 weeks.…”