Late Surfactant Administration in Very Preterm Neonates With Prolonged Respiratory Distress and Pulmonary Outcome at 1 Year of Age

Abstract

IMPORTANCE Although immature neonate survival has improved, there is an increased risk of developing bronchopulmonary dysplasia, leading to significant respiratory morbidity. Measures to reduce bronchopulmonary dysplasia are not always effective or have important adverse effects. OBJECTIVE To evaluate the effect of late surfactant administration in infants with prolonged respiratory distress on ventilation duration, respiratory outcome at 36 weeks' postmenstrual age, and at 1 year postnatal age. DESIGN, SETTING, AND PARTICIPANTS Double-blind randomized clinical trial at 13 level III French perinatal centers. Participants included 118 neonates at less than 33 weeks' gestation who still required mechanical ventilation on day 14 (SD, 2) with fraction of inspired oxygen of more than 0.30. All survivors were eligible for follow-up. We performed an intent-to-treat analysis. INTERVENTIONS Infants received 200 mg/kg of poractant alfa (surfactant) or air after randomization. At 1 year, after parents' interview, infants underwent physical examination by pediatricians not aware of the randomization. MAIN OUTCOMES AND MEASURES The duration of ventilation was the primary outcome. The combined outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age and respiratory morbidity at 1 year of age were the main secondary outcome measures. RESULTS Of the 118 infants who participated in the study, 65 (55%) were male. Fraction of inspired oxygen requirements dropped after surfactant, but not air, for up to 24 hours after instillation (0.36 [0.11] vs 0.43 [0.18]; P < .005). Severe bronchopulmonary dysplasia/death rates at 36 weeks' postmenstrual age were similar (27.1% vs 35.6%; P = .32). Less surfactant-treated infants needed rehospitalization for respiratory problems after discharge (28.3% vs 51.1%; P = .03); 39.5% vs 50% needed respiratory physical therapy (P = .35). No difference was observed for weight (7.8 [1.2] kg vs 7.6 [1.1] kg), height (69 [5] cm vs 69 [3] cm), and head circumference (44.4 [1.7] cm vs 44.2 [1.7] cm) measured at follow-up, nor for neurodevelopment outcome. CONCLUSIONS AND RELEVANCE Late surfactant administration did not alter the early course of bronchopulmonary dysplasia. However, surfactant-treated infants had reduced respiratory morbidity prior to 1 year of age. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01039285

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age

“…Notably, the results of the current study represent the effects of late surfactant in infants receiving iNO, which, when administered by this protocol in the NO CLD study, decreased home oxygen use and respiratory medication exposure from all drug classes. Thus, the effects of late surfactant administration alone (without iNO), as administered by Hascoet et al, may differ from the effects seen in the current study (12). …”

“…Similarly, Stevens et al demonstrated fewer respiratory exacerbations by 22 months corrected age in children randomized at birth to primary nasal continuous positive airway pressure (CPAP) versus intubation with surfactant administration and mechanical ventilation (4). Akin to our findings, infants who were intubated and mechanically ventilated at 14 days of age and received a single dose of poractant alpha (Curosurf, Chiesi USA Inc., Cary NC) had lower rates of respiratory hospitalization by 9½ months corrected age, although there were no other significant differences in respiratory status during the neonatal hospitalization or among other follow-up outcomes (12). …”

“…A number of these have failed to identify benefit in the neonatal period but have subsequently demonstrated advantage in at least one measure of respiratory status at follow-up (4–6, 10, 12, 16). Although Zivanovic et al found no difference in symptomatic lung disease at follow-up, measures of air flow obstruction and diffusing capacity were less compromised in children who were randomized to primary high frequency ventilation compared to conventional mechanical ventilation (16).…”

“…Although BPD is an imperfect predictor of later pulmonary morbidity (1, 4, 9), clinical trials have not reported broadly accepted later respiratory outcomes. Outcomes previously evaluated at 1–2 years of age include respiratory symptoms, medication use, respiratory exacerbations and hospitalizations due to respiratory disease (2–4, 10–12). …”

Review shows that using surfactant a number of times or as a vehicle for budesonide may reduce the risk of bronchopulmonary dysplasia

“…Survival without BPD at 36 weeks of PMA was not different between the two groups (31.3% versus 31.7%) . Likewise, in the CURDYS trial , the primary outcome was the time to first successful extubation. A difference of 10 days between the groups with regard to mechanical ventilation would have been considered to be clinically significant in a two‐sided test with an alpha risk of 5% and a power of 90%.…”