Double-blind, randomized trial of one versus three prophylactic doses of synthetic surfactant in 826 neonates weighing 700 to 1100 grams: effects on mortality rate. American Exosurf Neonatal Study Groups I and IIa. Single- versus multiple-dose surfactant replacement therapy in neonates of 30 to 36 weeks' gestation with respiratory distress syndrome.
At 33 hospitals in the United States, a double-blind, randomized clinical trial was performed to compare one versus three prophylactic doses of synthetic surfactant in 700 to 1100 gm inborn infants. All 826 infants received an initial prophylactic dose of surfactant within 30 minutes of birth. Subsequently 410 infants received two doses of placebo (air) 12 and 24 hours later, and 416 infants received two additional doses of surfactant. By the age of 28 days, 70 infants who received one dose of surfactant and 40 infants who received three doses were dead, a 43% relative reduction in the mortality rate (30 fewer deaths; p = 0.002). By the age of 1 year after term, 87 infants who received one dose and 62 infants who received three doses were dead: a 29% relative reduction in the mortality rate (25 fewer deaths; p = 0.027). Infants who received three doses of surfactant required significantly less oxygen and less mean airway pressure for the first week of life. Necrotizing enterocolitis (9 vs 25 infants; p = 0.005), and use of high-frequency ventilation (13 vs 26 infants; p = 0.037); pancuronium (43 vs 62 infants; p = 0.045); and leukocyte transfusions (0 vs 4 infants; p = 0.042) were less frequent in the three-dose group, but air leak, bronchopulmonary dysplasia, intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and infections were not different. These results indicate that physiologic findings, mortality rates, and probably morbidity rates are improved by two additional prophylactic doses of synthetic surfactant. To assess the efficacy of a multiple-dose protocol of surfactant replacement therapy in neonates of 30 to 36 weeks' gestation, 75 neonates were randomly assigned to control, single-dose surfactant, or multiple-dose surfactant groups. Neonates at less than 6 hours of age with a diagnosis of respiratory distress syndrome were eligible. Subjects were randomly assigned to receive either 100 mg/kg of bovine surfactant or air placebo. Neonates in the multiple-dose group were eligible to receive up to three additional doses as indicated. Neonates in both surfactant groups showed a positive response to treatment, with marked improvement in oxygenation by 10 minutes postinstillation (P less than .0001). Both surfactant groups had better oxygenation than control subjects at lower ventilatory parameters over the first 24 hours. A deterioration in oxygenation and ventilatory requirements was seen in both treatment groups starting 6 to 12 hours after the first dose. The deterioration in oxygenation could be minimized by the use of multiple doses; however, extra doses had no effect on diminishing ventilatory requirements or time to extubation. It is concluded that surfactant therapy at less than 6 hours of age is effective in acutely reducing oxygen and ventilatory requirements in neonates of 30 to 36 weeks' gestation with respiratory distress syndrome. It appears that multiple doses of surfactant have a greater effect on sustaining improvements in oxygenation than on ventilatory requirements. Further study is required to determine optimal dosage and retreatment strategy.
In infants with established respiratory distress, a policy of multiple doses of animal derived surfactant extract resulted in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of pneumothorax and a trend toward improved survival.
In infants at high risk of respiratory distress, a policy of multiple doses of synthetic surfactant resulted in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of NEC and decreased mortality.
The ability to give multiple doses of surfactant to infants with ongoing respiratory insufficiency leads to improved clinical outcome and appears to be the most effective treatment policy.