Use of surfactant for prophylaxis versus rescue treatment of respiratory distress syndrome: experience from an Italian-Bulgarian trial. Controlled trial of a single dose of synthetic surfactant at birth in premature infants weighing 500 to 699 grams. The American Exosurf Neonatal Study Group I. 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. Initial clinical trial of EXOSURF, a protein-free synthetic surfactant, for the prophylaxis and early treatment of hyaline membrane disease. 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 comparison of surfactant as immediate prophylaxis and as rescue therapy in newborns of less than 30 weeks' gestation. 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. Modified bovine surfactant (Survanta) versus a protein-free surfactant (Exosurf) in the treatment of respiratory distress syndrome in preterm infants: a pilot study.
To show if surfactant applied in different social-sanitary realities as prophylaxis of respiratory distress syndrome (RDS) is equally useful and able to reduce mortality and incidence of 3-4 radiological grade RDS.
                Two neonatal intensive care units (NICU) in Italy, one NICU in Bulgaria and one NICU in Romania were involved in a randomized controlled clinical trial of prophylaxis vs rescue treatment of RDS. Babies with gestational age 26-30 wks were randomized before birth to prophylaxis in the delivery-room with 200 mg/kg of porcine surfactant (prophylaxis) or to routine assistance (control). Subsequently the babies developing RDS requiring mechanical ventilation and fraction of inspired oxygen (FiO2) > or = 0.4 to maintain PaO2 about 50 mmHg were allowed to be treated rescue with 200 mg/kg of the same surfactant. To reach end-points of reducing mortality by 40% and incidence of radiological grade 3-4 RDS a total number of 174 patients were required.
                Due to logistic, practical and social-political problems the study was interrupted after enrollment of 93 babies (61 in Italy and 32 in Bulgaria). The Romanian centre did not start the study because it was impossible in the scheduled times to equip it for mechanical ventilation of the newborn infants. Analysis done on an intention to treat basis did not show significant reductions of mortality and 3-4 radiological grade RDS, even if there was a trend towards a reduction in the babies given prophylaxis. A significantly lower number of babies given prophylaxis required a subsequent rescue treatment compared to controls (p < 0.001). There was no difference in other complications such as intraventricular haemorrhage, air-leak syndromes and infections between prophylaxis and control infants. As regards pulmonary gas exchange, the PaO2/FiO2 ratio was significantly improved in the babies given prophylaxis for the first 12 hours of life vs the controls.
                Even if the study was terminated before term, the analysis of the data shows that prophylaxis with surfactant is equally effective in different social-clinical conditions to improve pulmonary gas-exchange, especially in the first critical hours of life of premature babies. In a multicenter, double-blind, placebo-controlled trial conducted at 23 hospitals in the United States, a single prophylactic 5 ml/kg dose of a synthetic surfactant (Exosurf Neonatal) or air placebo was administered shortly after birth to 215 infants with birth weights of 500 to 699 gm. Despite stratification at entry by birth weight and gender, by chance female infants predominated in the air placebo group and male infants predominated in the surfactant group. Among infants receiving synthetic surfactant, improvements in oxygen requirements were significant at 2 hours after birth (p = 0.014) and persisted for 3 days (p = 0.001); improvements in the alveolar-arterial partial pressure of oxygen gradient were significant at 6 hours after birth (p = 0.01) and persisted for 3 days (p = 0.008). Improvements in mean airway pressure were not significant at 2 or at 6 hours after birth (p = 0.622 and 0.083, respectively), but became significant thereafter and persisted for 3 days (p = 0.002). Pneumothorax was reduced by slightly more than half (25 vs 11; p = 0.014); death from respiratory distress syndrome (RDS) was also reduced (26 vs 15; p = 0.046). Overall neonatal mortality, however, was not significantly reduced (58 vs 46; p = 0.102). Other complications of RDS and prematurity were not altered, except that pulmonary hemorrhage occurred significantly more frequently in infants receiving synthetic surfactant (2 vs 12; p = 0.006). These findings indicate that a single prophylactic dose of synthetic surfactant in infants weighing 500 to 699 gm at birth improves lung function, incidence of air leak, and death from RDS but not overall mortality. The only safety problem identified was an increase in pulmonary hemorrhage. 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. EXOSURF is a protein-free surfactant composed of 85% dipalmitoylphosphatidylcholine, 9% hexadecanol, and 6% tyloxapol by weight. A single dose of 5 mL of EXOSURF per kilogram body weight, which gave 67 mg of dipalmitoylphosphatidylcholine per kilogram body weight, or 5 mL/kg air was given intratracheally in each of two controlled trials: at birth to neonates 700 through 1350 g (the prophylactic trial, n = 74) or at 4 to 24 hours after birth to neonates greater than 650 g who had hyaline membrane disease severe enough to require mechanical ventilation (the rescue trial, n = 104). In both studies, time-averaged inspired oxygen concentrations and mean airway pressures during the 72 hours after entry decreased significantly (P less than .05) in the treated neonates when compared with control neonates. Thirty-six percent of the treated neonates in the rescue study had an incomplete response to treatment or relapsed within 24 hours, suggesting the need for retreatment in some neonates. In the rescue trial, risk-adjusted survival increased significantly in the treated group. There were no significant differences in intracranial hemorrhages, chronic lung disease, or symptomatic patent ductus arteriosus between control and treated infants in either trial. 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) Exogenous pulmonary surfactants are administered into the trachea either to prevent respiratory distress syndrome in premature infants or to treat it. In a randomized, multicenter trial, we compared the results of surfactant therapy initiated as prophylaxis with the results of rescue therapy with surfactant.
                Before birth, 479 infants with an estimated gestational age of less than 30 weeks were randomly assigned to receive surfactant as prophylaxis (n = 235) or rescue therapy (n = 244). The infants in the prophylaxis group received a 90-mg intratracheal dose of an exogenous calf-lung surfactant extract at the time of delivery, whereas the infants in the rescue-therapy group received 90 mg of the surfactant several hours after delivery if the fractional inspiratory oxygen concentration was at least 0.40 or if the mean airway pressure was at least 0.686 kPa (7 cm of water), or both. Infants in both groups received additional doses of surfactant at intervals of 12 to 24 hours if these criteria were met.
                The proportion of infants surviving until discharge to their homes was significantly higher in the prophylaxis group than in the rescue-therapy group (88 vs. 80 percent, P = 0.028). This difference was due primarily to the longer survival of very premature infants (less than or equal to 26 weeks' gestation) in the prophylaxis group than in the rescue-therapy group (75 vs. 54 percent, P = 0.006). According to proportional-hazards regression analysis, the distribution of survival times was better for all infants in the prophylaxis group (P = 0.007) and for the subgroup of infants in the prophylaxis group who were delivered at 26 weeks' gestation or earlier (P = 0.0048). Infants in the prophylaxis group who were delivered at 26 weeks' gestation or earlier had a lower incidence of pneumothorax than similar infants in the rescue-therapy group (7 vs. 18 percent, P = 0.03).
                We found a significant advantage to the administration of the initial dose of surfactant as prophylaxis rather than as rescue therapy in very premature infants. 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. We undertook a prospective, randomized, non-blinded pilot study to determine whether infants with respiratory distress syndrome (RDS) who were treated with protein-containing bovine surfactant (Survanta, Ross/Abbott Laboratories, Columbus, Ohio) had earlier and larger responses in gas exchange when compared with similar infants treated with a synthetic surfactant (Exosurf, Burroughs Wellcome, Research Triangle Park, North Carolina). Forty-one infants weighing between 600 g and 1750 g at birth with RDS of sufficient severity to require assisted ventilation with an FiO2 > 0.39 were enrolled in the study and treated with surfactant from 1 to 8 hours after birth. Infants were randomly selected to receive treatment with either Exosurf or Survanta. Despite randomization, the Survanta group was overrepresented with factors associated with greater severity of RDS (lower birthweight, more males, and fewer African Americans). No statistically significant difference was found in the primary outcome measure (arterial/alveolar PaO2 > 0.3 at 24 hours) by univariate or multivariate analysis. The percentage of responders in the Survanta-treated group was significantly increased 24 hours after treatment in two of four secondary measures of oxygenation when analyzed by univariate tests using one-tailed P values. Based on these results, we anticipate that acute outcomes after Survanta or Exosurf will approximate those found in this trial and that differences in measures of oxygenation between treatment groups will approximate 30% to 50% 24 hours after initial treatment.
Prophylactic intratracheal administration of protein free synthetic surfactant to infants at risk of developing respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who receive prophylactic protein free SS have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, and a decreased risk of neonatal mortality. Infants who receive prophylactic protein free SS have an increased risk of developing patent ductus arteriosus and pulmonary hemorrhage.