BACKGROUND: Available therapeutic surfactants are either animal-derived or non-protein-containing synthetic products. Animal-derived surfactants contain variable amounts of surfactant apoproteins, whereas the older-generation synthetic products contain only phospholipids and lack surfactant proteins (SPs). Both decrease morbidity and mortality rates associated with respiratory distress syndrome (RDS) among preterm infants, compared with placebo. However, excess mortality rates have been observed with non-protein-containing synthetic surfactants, compared with the animal-derived products. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved with the addition of peptides that are functional analogs of SPs. Lucinactant is a new synthetic peptide-containing surfactant that contains sinapultide, a novel, 21-amino acid peptide (leucine and lysine repeating units, KL4 peptide) designed to mimic human SP-B. It is completely devoid of animal-derived components. OBJECTIVE: We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority. METHODS: A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial. RESULTS: The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: -7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, -7.3%, being greater than the prespecified noninferiority margin of -14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1-46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8-41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0-17.6%] vs 16.1% [95% CI: 9.7-22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, including intraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%). CONCLUSIONS: Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.
UNLABELLED: To evaluate the effect of different surfactants on fluid balance in respiratory distress syndrome, we studied 24 premature infants who were randomised to receive either natural or synthetic surfactant. Data were collected on ventilatory parameters, daily urine output, daily weight, fluid intake and serum electrolytes. Ventilatory requirements decreased more rapidly in babies receiving natural surfactant, with significantly greater reductions in mean airway pressure from 1 to 48 h and oxygenation index from 1-18 h (P < 0.05). There were no differences in fluid intake and serum electrolytes. Mean daily urine output was higher in the group receiving natural surfactant (87 ml versus 61 ml, P < 0.05). This group also had a greater weight loss from birth weight (-146 g versus -65 g, P < 0.05).
CONCLUSION: Natural surfactant produces an earlier reduction in ventilatory requirements with an earlier diuresis. This should influence fluid management in respiratory distress syndrome.
The initial clinical response to synthetic or natural surfactant is different and long-term complications from meta-analysis suggest that bronchopulmonary dysplasia and retinopathy of prematurity may be increased in infants given synthetic surfactant. It is possible that this is due to differences in the phospholipid composition of lung fluid following administration of these surfactants. Infants less than 32 weeks gestation with respiratory distress syndrome (RDS) were randomly assigned to receive either Exosurf, an artificial surfactant, or Survanta, a natural surfactant. Endotracheal or hypopharyngeal aspirates were obtained from these infants and from control infants who had normal lungs. The aspirates were taken prior to and up to 28 days following surfactant administration. The different phospholipids were separated by thin layer chromatography and expressed as a percent of total phospholipid measured. Infants with normal lungs had a higher proportion of phosphatidylcholine than those with RDS prior to treatment. The infants with normal lungs had a greater proportion of phosphatidylinositol in their lung aspirates than both treatment groups at 24 h. Infants in the Survanta group had a higher proportion of phosphatidylglycerol at 48 h than the group with normal lungs. No other differences were found in phospholipid composition up to 28 days. There were no major differences in the phospholipid profile in infants with RDS treated with either Exosurf or Survanta. In conclusion, neither the clinical differences initially seen between infants treated with either Exosurf or Survanta, nor the long-term outcome could be explained by the phospholipid composition of serial samples of lung aspirates.
We conducted a randomized clinical trial to compare the effects of a synthetic (Exosurf) and natural (Survanta) surfactant in infants with neonatal respiratory distress syndrome. Eighty-nine patients were randomly allocated to receive one of the two surfactants. Primary outcome variables were the acute and long-term effects of the surfactant preparations, i.e., ventilatory requirements at 24 h of age as judged by the oxygenation index (OI), and the combined incidence of chronic lung disease or death at 28 days. The OIs in the Exosurf and Survanta groups at 24 h were the same (10.1 and 7, respectively; P > 0.05). The magnitude and rapidity of response, however, were greater for Survanta than for Exosurf. When arterial/alveolar oxygen tension ratios (a/A) were compared, the Exosurf group had a significantly worse a/A ratio at 24 h than the Survanta group (0.21 Exosurf vs. 0.37 Survanta; P < 0.05). The long-term outcome as judged by the combined incidence of death or chronic lung disease was not different in the two groups (18.6% Exosurf vs. 15.2% Survanta; P > 0.05). When the complications of prematurity were compared, there were no statistically significant differences between the two groups. We conclude that both preparations are reasonable choices for the treatment of respiratory distress syndrome of prematurity.
To determine the effects of animal and artificial surfactants on cerebral haemodynamics, 20 premature babies receiving mechanical ventilation were randomized to receive Curosurf or Exosurf surfactant. Anterior cerebral artery blood flow velocity (CABFV) was measured using Doppler ultrasound before and up to 2 h after treatment. Following animal surfactant there was a rapid reduction in CABFV (median -36%, range -43% to +8%, p < 0.01), whereas artificial surfactant resulted in a slower rise which was less marked (median +20%, range -7% to +62%, p < 0.05). There were no significant changes in blood pressure. Two hours after administration, the oxygenation index (OI) improved significantly only in babies receiving animal surfactant. In this group there was a significant association between the change in CABFV at 1 min and the change in OI at 2h (r = 0.66, p < 0.05). Animal surfactant produces rapid improvements in ventilation which are associated with marked alterations in cerebral haemodynamics.
