Late administration of surfactant replacement therapy increases surfactant protein-B content: a randomized pilot study

Abstract

Background: Surfactant dysfunction may contribute to the development of bronchopulmonary dysplasia (BPD) in persistently ventilated preterm infants. We conducted a multicenter randomized, blinded, pilot study to assess the safety and efficacy of late administration of doses of a surfactant protein-B (SP-B)-containing surfactant (calfactant) in combination with prolonged inhaled nitric oxide (iNO) in infants ≤1,000 g birth weight (BW).

Methods: We randomized 85 preterm infants ventilated at 7-14 d after birth to receive either late administration of surfactant (up to 5 doses) plus prolonged iNO or iNO alone. Large aggregate surfactant was isolated from daily tracheal aspirates (TAs) for measurement of SP-B content, total protein, and phospholipid (PL).

Results: Late administration of surfactant had minimal acute adverse effects. Clinical status as well as surfactant recovery and SP-B content in tracheal aspirate were transiently improved as compared to the controls; these effects waned after 1 d. The change in SP-B content with surfactant dosing was positively correlated with SP-B levels during treatment (r = 0.50, P = 0.02).

Conclusion: Low SP-B values increased with calfactant administration, but the relationship of this response to SP-B levels suggests that degradation is a contributing mechanism for SP-B deficiency and surfactant dysfunction. We conclude that late therapy with surfactant in combination with iNO is safe and transiently increases surfactant SP-B content, possibly leading to improved short- and long-term respiratory outcomes.

Trial registration: ClinicalTrials.gov NCT00569530.

Figure 1

Enrollment flow diagram for infants admitted to the nine study hospitals during the recruitment period, January 2008–October 2009.

Figure 2

Absolute change in surfactant parameters following study drug dosing (days 1–3). Data are median values for the Control (white bars, n = 43–47 from 20 infants) and Surfactant (black bars, n = 55–64 from 27 infants) groups. (a) Surfactant recovery, phospholipid (PL) normalized to total protein content of tracheal aspirate; (b) total protein in surfactant pellet as a percentage of PL; (c) surfactant protein-B (SP-B) content of surfactant pellet, normalized to PL; and (d) SP-B content normalized to total protein in surfactant pellet. P values are for comparison of the change between groups, *P = 0.04, **P ≤ 0.002.

Figure 3

Absolute change in surfactant parameters in infants treated with surfactant (n = 21) on day 1 vs. mean level of surfactant parameters on subsequent days prior to dosing (days 2–4). Surfactant protein-B (SP-B) content (%) normalized to total protein in surfactant: (a) vs. SP-B content r = 0.50, P = 0.02, and (b) surfactant recovery (μg phospholipid (PL)/μg tracheal aspirate protein): r = 0.05, P = 0.83.