Multicenter trial of single-dose modified bovine surfactant extract (Survanta) for prevention of respiratory distress syndrome. Ross Collaborative Surfactant Prevention Study Group. A multicenter randomized masked comparison trial of synthetic surfactant versus calf lung surfactant extract in the prevention of neonatal respiratory distress syndrome. Decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: a multicenter controlled trial. American Exosurf Pediatric Study Group 1. Endotracheal administration of surfactant in very low birth weight infants with respiratory distress syndrome. A controlled trial of human surfactant replacement therapy for severe respiratory distress syndrome in very low birth weight infants. Prophylaxis of respiratory distress syndrome by treatment with modified porcine surfactant at birth: a multicentre prospective randomized trial. Randomized, placebo-controlled trial of human surfactant given at birth versus rescue administration in very low birth weight infants with lung immaturity. A multicenter randomized, masked comparison trial of natural versus synthetic surfactant for the treatment of respiratory distress syndrome. Prophylactic administration of calf lung surfactant extract is more effective than early treatment of respiratory distress syndrome in neonates of 29 through 32 weeks' gestation.
A multicenter, prospective randomized controlled trial was performed comparing the efficacy of a single intratracheal dose of modified bovine surfactant extract (Survanta, 100 mg/kg, Abbott Laboratory, North Chicago, IL) with air placebo in preventing respiratory distress syndrome. Infants were enrolled if they were estimated to be between 24 and 30 weeks' gestation, weighed between 750 and 1250 g, and were intubated and stabilized within 15 minutes after birth. A total of 160 infants were treated (79 with surfactant, 81 with air placebo) between 4 and 37 minutes after birth (median time 12 minutes). Of these, 5 infants were excluded from the final analysis. The 72-hour average values for the arterial-alveolar oxygen ratio, fraction of inspired oxygen, and mean airway pressure were calculated from the area under the curve of scheduled values measured throughout 72 hours. Clinical status was classified using five ordered categories (no supplemental oxygen or assisted ventilation, supplemental oxygen only, continuous positive airway pressure or assisted ventilation with intermittent mandatory ventilation less than or equal to 6 breaths/min, assisted ventilation with intermittent mandatory ventilation greater than 6 breaths/min, death). Chest radiographs at 24 hours were graded for severity of respiratory distress syndrome. Infants receiving Survanta had less severe radiographic changes at 24 hours of age and decreased average fraction of inspired oxygen (31% vs 42%, P = .002) compared with control infants. No differences were noted in the average arterial-alveolar oxygen ratio, mean airway pressure, or clinical status on days 7 and 28. A beneficial effect was noted in the incidence of pneumothorax (P = .057) and an increase was noted in the incidence of necrotizing enterocolitis (P = .052). No differences in incidence of patent ductus arteriosus, intraventricular hemorrhage, sepsis, or bronchopulmonary dysplasia were seen. According to results of a secondary analysis, there was improvement in the fraction of inspired oxygen and a greater number of survivors without bronchopulmonary dysplasia in the subgroup of infants weighing less than 1000 g who were treated with surfactant. It was concluded that a single dose of Survanta given shortly after birth resulted in decreased severity of chest radiographic findings 24 hours after treatment and improved oxygenation during 72 hours after treatment, but did not improve other acute measures of disease severity or clinical status later in the neonatal period. The group at highest risk for respiratory distress syndrome (infants with birth weights between 750 and 999 g) may benefit the most from preventive therapy. To compare the efficacy and safety of a synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome Co) and a surfactant extract of calf lung lavage (Infasurf, IND #27,169, ONY, Inc) in the prevention of neonatal respiratory distress syndrome (RDS).
                Ten-center randomized masked comparison trial.
                Premature infants (n = 871) <29 weeks gestational age by best obstetric estimate.
                Infants were randomly assigned to a course of treatment with Exosurf Neonatal (n = 438) or Infasurf (n = 433) at birth, and if 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 </=.10) persisted after three doses of the randomized surfactant. Primary
                Three primary outcome measures of efficacy [the incidence of RDS; the incidence of RDS death; and the incidence of survival without bronchopulmonary dysplasia at 28 days after birth] were compared using linear regression techniques.
                Of 871 randomized infants, 18 infants did not receive treatment with a study surfactant, and 25 infants did not meet all eligibility criteria. The primary analysis of efficacy was performed in the 846 eligible infants and analysis of safety outcomes in the 853 infants who received study surfactant. Demographic characteristics did not differ between the two treatment groups. Compared with Exosurf, Infasurf treatment resulted in a 62% decrease in the incidence 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 incidence of survival without bronchopulmonary dysplasia at 28 days. Treatment with Infasurf resulted in significant improvement in several secondary outcome measures. Infasurf-treated infants had lower average FIO2 (Infasurf, .33 [SEM] vs Exosurf, .42; difference .08; 95% confidence interval [CI], .06 to .11) and average mean airway pressure (Infasurf, 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 with the Exosurf group (Infasurf, 1% vs Exosurf, 6%). Complications (bradycardia, clinical airway obstruction, and transcutaneous arterial desaturation) associated with second and third, but not initial, surfactant treatments were observed more frequently in the Infasurf treatment group. Infasurf-treated infants had significantly less air leak (</=7 days) (Infasurf, 8% vs Exosurf, 14%; adjusted relative risk [ARR] .55; 95% CI, .37 to .81). Severe intraventricular hemorrhage (IVH) (grade 3 and 4) did not differ between the two groups (Infasurf, 11.8% vs Exosurf, 8.3%; ARR 1.41; 95% CI, .94 to 2.09) but total 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).
                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 the prophylaxis of RDS. However, Infasurf prophylaxis as used in this study was also associated with a greater risk of total but not severe IVH. To determine whether a single prophylactic dose of synthetic surfactant would reduce mortality and morbidity rates, we performed a randomized, controlled trial of Exosurf Neonatal at 19 hospitals in the United States. The Exosurf preparation (5 ml/kg) was instilled into the endotracheal tube of premature infants weighing 700 to 1100 gm during mechanical ventilation, as soon as practical after birth. Control infants were treated with air (5 ml/kg). Dose administration was performed in secrecy by clinicians who did not reveal for 2 years what they had instilled. A total of 222 infants received air and 224 received the synthetic surfactant; 36 infants with congenital pneumonia or malformations were excluded from the primary efficacy analysis. By the age of 28 days, there were 44 deaths in the air group and 27 deaths in the surfactant group (p = 0.022). By the age of 1 year after term there were 61 deaths in the air group and 35 deaths in the surfactant group (p = 0.002). Although there was no reduction in the incidence of respiratory distress syndrome, a significant reduction in the number of deaths attributed to respiratory distress syndrome, a significant reduction in the incidence of pulmonary air leaks, and significantly lower requirements for oxygen and mean airway pressure indicated that lung disease was less severe in the Exosurf-treated infants. There were no significant differences in the incidence of complications such as bronchopulmonary dysplasia, intraventricular hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, and infection. The results indicate that a single prophylactic dose of Exosurf, in high-risk premature infants treated soon after birth, reduces the number of deaths from respiratory distress syndrome and the overall mortality rate. This study was designed to evaluate whether the ventilatory maneuvers associated with surfactant replacement would, per se, influence oxygenation in newborn infants with severe respiratory distress syndrome. Eight patients (700 to 1400 g), all requiring mechanical ventilation with fraction of inspired oxygen greater than 0.6, were included in the trial; four were randomized to receive surfactant, and the others served as controls. Porcine surfactant (2 ml/kg; phospholipid concentration, 100 mg/ml) was instilled via a naso-endotracheal tube at end-expiration and dispersed into the lungs during a period of standardized "sighing" mediated by the ventilator: two prolonged ventilatory cycles (10 sec each) with an inspiration/expiration ratio of 4:1, followed by a 6-min ventilation with a frequency of 60 breath/min and an inspiration/expiration ratio of 4:1. Control babies received no surfactant but were otherwise subjected to the same ventilatory maneuvers. Surfactant-treated infants showed a rapid increase in transcutaneous oxygen associated with improved lung aeration in chest x-rays; the response was transient in three babies and persistent in one. No improvement was observed in control babies. We conclude that the beneficial effect of surfactant replacement cannot be attributed to the ventilatory maneuvers associated with the instillation procedure. In a randomized, controlled study, human surfactant derived from amniotic fluid was administered within 12 hours of birth to infants with severe respiratory distress syndrome who were born at 24 to 32 weeks of gestation weighing less than or equal to 1500 gm. A second dose of surfactant was given to patients in the treatment group if they met ventilator requirements indicating relapse or lack of response to the initial dose. No significant improvement was observed in mortality rate (9/28 vs 15/31) or incidence of bronchopulmonary dysplasia (5/28 vs 3/31) when surfactant-treated infants were compared with control subjects, although there was a significant reduction in initial respirator and inspired oxygen requirements and the arterial/alveolar oxygen ratio improved. In addition, there was a significant reduction in pulmonary air leak in treated infants (10/28 vs 20/31; p less than 0.05). Retreatment was associated with an attenuated ventilatory response and with a higher mortality rate (7/14) than that of infants who did not require a second dose (2/14; p = 0.05), indicating a more severe form of disease. Multiple discriminant analysis, including eight independent variables, revealed that increasing birth weight, earlier age at surfactant treatment, and female gender were significantly associated with survival. These data suggest that early surfactant treatment may reduce mortality rates in very low birth weight infants with severe respiratory distress syndrome, as well as reduce ventilator requirements and the incidence of pulmonary air leaks. The objective of this prospective, multicentre trial, carried out at 18 third level hospitals in Italy, was to evaluate efficacy of modified porcine surfactant (Curosurf), administered at birth to prevent the development of respiratory distress syndrome (RDS) in premature infants. 287 babies with a gestational age of 24-30 weeks were randomized to prophylactic treatment with Curosurf (80 mg/ml; dose 20 mg/kg) or to a control group receiving no surfactant treatment in the delivery-room. Babies in both groups were eligible for rescue treatment with surfactant (200 mg/kg) if they developed clinical symptoms of RDS and required mechanical ventilation. The main end-point was to obtain, in the prophylaxis group, a 30% reduction in the incidence of grade 3-4 RDS. Median gestational age was 28 weeks in both groups and mean birth weight 1010 and 1002 g, respectively for prophylaxis and control babies. There was a 32% reduction in the incidence of grade 3-4 RDS in the prophylaxis group (p < 0.05). This was associated with a significant reduction in mean maximum fraction of inspired oxygen (0.57 vs 0.66%; p < 0.01), a decreased incidence of pulmonary interstitial emphysema (7 vs 14%; p < 0.05) and a lowered mortality (21 vs 35%; p < 0.01). Combined unfavourable outcome (mortality + bronchopulmonary dysplasia and/or grade 3-4 intraventricular hemorrhage and/or grade 2-4 retinopathy of prematurity) was significantly lower in the prophylaxis than in the second group (41 vs 58%; p < 0.01). The favourable effects of prophylactic treatment were equally recorded in all the age groups, including the babies with the lowest gestational age (24-25 weeks). Multiple and logistic regression analysis confirmed that high gestational age and surfactant prophylaxis were, independently, associated with a lower degree of RDS (p = 0.0001 and p = 0.0008, respectively) and a lower mortality (p = 0.0001 and p = 0.0045, respectively). We conclude that prophylaxis with modified natural surfactant effectively prevents RDS in newborn babies between 24 and 30 weeks' gestation. A randomized, placebo-controlled trial of human surfactant given intratracheally at birth (prophylactic) versus rescue administration after the onset of severe respiratory distress syndrome (RDS) was conducted among preterm infants born at 24 to 29 weeks of gestation. Singleton fetuses were randomly assigned to receive (1) placebo (air), (2) prophylactic surfactant treatment, or (3) rescue surfactant treatment; infants of multiple births received either (1) prophylactic or (2) rescue treatment. Of 282 potentially eligible fetuses, 246 infants received treatments at birth and 200 infants had RDS. Outcomes are presented both as an intention-to-treat analysis (including infants who met exclusion criteria at or after birth) and as a full treatment protocol analysis for those infants with RDS and likely to benefit from surfactant. Preterm infants (mean 1.0 kg birth weight, 27 to 28 weeks of gestational age) randomly assigned to receive prophylactic treatment received surfactant soon after birth; those assigned to receive rescue surfactant had instillation at a mean age of 220 minutes if the lecithin-sphingomyelin ratio was less than or equal to 2.0 and no phosphatidylglycerol was detected in either amniotic fluid or initial airway aspirate, oxygen requirements were a fraction of inspired oxygen of greater than 0.5, and mean airway pressure was greater than or equal to 7 cm H2O from 2 to 12 hours after birth. Up to four treatment doses (or air) were permitted within 48 hours; approximately 60% of surfactant-treated infants required two or more doses. Surfactant-treated infants had significantly less pulmonary interstitial emphysema than placebo-treated infants (p = 0.02), but there were no other significant differences in mortality rates or morbidity. Indexes of oxygenation and ventilation were improved in surfactant recipients during the first 24 hours. An intention-to-treat analysis found no significant differences between infants given placebo and surfactant-treated infants or between prophylactic- and rescue-treated infants; an improved total mortality rate (p = 0.002) was found among surfactant-treated infants in Helsinki but not in San Diego. Among infants with RDS, the total mortality rate was significantly improved (p = 0.004) with surfactant treatment but not the proportion alive and without bronchopulmonary dysplasia at 28 days (p = 0.052), or the proportion alive and without bronchopulmonary dysplasia at 38 weeks of postconceptional age (p = 0.18) to adjust for differences in prematurity. Deaths caused by RDS or bronchopulmonary dysplasia were significantly reduced among surfactant recipients (p = 0.0001). Neither among singletons nor among multiple-birth infants was there a selective advantage to prophylactic versus rescue treatment.(ABSTRACT TRUNCATED AT 400 WORDS) To compare the efficacy and safety of two surfactant preparations in the treatment of respiratory distress syndrome (RDS).
                We conducted a randomized, masked comparison trial at 21 centers. Infants with RDS who were undergoing mechanical ventilation were eligible for treatment with two doses of either a synthetic (Exosurf) or natural (Infasurf) surfactant if the ratio of arterial to alveolar partial pressure of oxygen was less than or equal to 0.22. Crossover treatment was allowed within 96 hours of age if severe respiratory failure (defined as two consecutive arterial/alveolar oxygen tension ratios < or = 0.10) persisted after two doses of the randomly assigned surfactant. Four primary outcome measures of efficacy (the incidence of pulmonary air leak (< or = 7 days); the severity of RDS; the incidence of death from RDS; and the incidence of survival without bronchopulmonary dysplasia (BPD) at 28 days after birth) were compared by means of linear regression techniques.
                The primary analysis of efficacy was performed in 1033 eligible infants and an analysis of safety outcomes in the 1126 infants who received study surfactant. Preentry demographic characteristics and respiratory status were similar for the two treatment groups, except for a small but significant difference in mean gestational age (0.5 week) that favored the infasurf treatment group. Pulmonary air leak (< or = 7 days) occurred in 21% of Exosurf- and 11% of infasurf-treated infants (adjusted relative risk, 0.53; 95% confidence interval, 0.40 to 0.71; p < or = 0.0001). During the 72 hours after the initial surfactant treatment, the average fraction of inspired oxygen (+/-SEM) was 0.47 +/- 0.01 for Exosurf- and 0.39 +/- 0.01 for infasurf-treated infants (difference, 0.08; 95% confidence interval, 0.06 to 0.10; p < 0.0001); the average mean airway pressure (+/-SEM) was 8.6 +/- 0.1 cm H2O; for Exosurf- and 7.2 +/- 0.1 cm H2O for Infasurf-treated infants (difference, 1.4 cm H2O; 95% confidence interval, 1.0 to 1.8 cm H2O; p < 0.0001). The incidences of RDS-related death, total respiratory death, death to discharge, and survival without bronchopulmonary dysplasia at 28 days after birth did not differ. The number of days of more than 30% inspired oxygen and of assisted ventilation, but not the duration of hospitalization, were significantly lower in Infasurf-treated infants.
                Compared with Exosurf, Infasurf provided more effective therapy for RDS as assessed by significant reductions in the severity of respiratory disease and in the incidence of air leak complications. Although numerous trials have demonstrated the efficacy of exogenous surfactant for prophylaxis or treatment of neonatal respiratory distress syndrome (RDS), optimum timing of administration remains controversial. One previous study showed that administration of calf lung surfactant extract immediately following birth, to neonates born before 30 weeks postconceptional age, was preferable to delaying administration until after development of RDS. The current study was designed to test a similar hypothesis for babies born between 29 and 32 weeks gestational age.
                One thousand three hundred ninety-eight neonates with obstetric estimates of 29 through 32 weeks' gestation were randomized to receive CLSE at birth or to wait until development of mild RDS. After exclusions for malformations and other factors, data from 1248 were analyzed.
                Prophylaxis was associated with less development of moderate RDS (7% vs 12%), less need for retreatment (5% vs 9%), less need for mechanical ventilation or supplemental oxygen during the first 4 days, and fewer deaths or less requirement for supplemental oxygen at 28 days (5% vs 9%). Although 1-minute Apgar scores were significantly lower in the prophylaxis group, the difference disappeared by the 5-minute score and there was no difference in the incidence of asphyxia-related complications. Sixty percent of the neonates assigned to early treatment received endotracheal intubation and 43% received calf lung surfactant extract at a median age of 1.5 hours. When data were analyzed by gestational age and birth weight subgroups, most of the differences could be attributable to babies born at 30 weeks or less or weighing less than 1500 g, probably because of the higher incidence of surfactant deficiency in this more immature subgroup.
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.