A MULTICENTER RANDOMIZED MASKED COMPARISON TRIAL OF SYNTHETIC SURFACTANT VERSUS CALF LUNG SURFACTANT EXTRACT IN THE PREVENTION OF NEONATAL RESPIRATORY-DISTRESS SYNDROME

Objective. To compare the efficacy and safety of a synthetic surfactan t (Exosurf Neonatal, Burroughs Wellcome Co) and a surfactant ex-tract of calf lung lavage (Infasurf, IND #27,169, ONY, Inc) in the preventio n of neonatal respiratory distress syndrome (RDS). Design and Setting. Ten-center randomized masked comparison trial. Patients. Premature in fants (n = 871) <29 weeks gestational age by best obstetric estimate. Interventions. Infants were randomly assigned to a course of treatment with Exosurf Neonatal (n = 438) or Infasurf (n = 433) at birth, and i f still intubated, at 12 and 24 hours of age. Crossover treatment was allowed within 72 hours of age if severe respiratory failure (defined as two consecutive a/A PO2 ratios less than or equal to.10) persisted after three doses of the randomized surfactant. Primary Outcome Measur es. Three primary outcome measures of efficacy [the incidence of RDS; the incidence of RDS death; and the incidence of survival without bron chopulmonary dysplasia at 28 days after birth] were compared using lin ear regression techniques. Results. Of 871 randomized infants, 18 infa nts did not receive treatment with a study surfactant, and 25 infants did not meet all eligibility criteria. The primary analysis of efficac y was performed in the 846 eligible infants and analysis of safety out comes in the 853 infants who received study surfactant. Demographic ch aracteristics did not differ between the two treatment groups. Compare d with Exosurf, Infasurf treatment resulted in a 62% decrease in the i ncidence of RDS (Infasurf, 16% vs Exosurf, 42%) and a 70% decrease in RDS death (Infasurf, 1.7% vs Exosurf, 5.4%) but did not increase the i ncidence of survival without bronchopulmonary dysplasia at 28 days. Tr eatment with Infasurf resulted in significant improvement in several s econdary outcome measures. Infasurf-treated infants had lower average FIO2 (Infasurf, .33 [SEM] vs Exosurf, 42; difference .08; 95% confiden ce interval [CI], .06 to .11) and average mean airway pressure (Infasu rf, 6.0 cm H2O vs Exosurf, 7.1 cm H2O; difference 1.1 cm H2O; 95% CI, .7 to 1.6 cm H2O) for the first 72 hours of life. Crossover surfactant treatment was significantly less frequent in the Infasurf compared wi th the Exosurf group (Infasurf, 1% vs Exosurf, 6%). Complications (bra dycardia, clinical airway obstruction, and transcutaneous arterial des aturation) associated with second and third, but not initial, surfacta nt treatments were observed more frequently in the Infasurf treatment group. Infasurf-treated infants had significantly less air leak (less than or equal to 7 days) (Infasurf, 8% vs Exosurf, 14%; adjusted relat ive risk [ARR] .55; 95% CI, .37 to .81). Severe intraventricular hemor rhage (IVH) (grade 3 and 4) did not differ between the two groups (Inf asurf, 11.8% vs Exosurf, 8.3%; ARR 1.41; 95% CI, .94 to 2.09) but tota l IVH occurred more frequently in Infasurf-treated infants (Infasurf, 39.0% vs Exosurf, 29.9%; ARR, 1.30; 95% CI, 1.08 to 1.57). Conclusion. Significant reductions in the incidence of RDS, the severity of early respiratory disease, the incidence of pulmonary air leaks associated with RDS, and the mortality attributable to RDS suggest that Infasurf is a more effective surfactant preparation than Exosurf Neonatal in th e prophylaxis of RDS. However, Infasurf prophylaxis as used in this st udy was also associated with a greater risk of total but not severe IV H.