Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs
Clinical trials that compare a natural surfactant extract to synthetic surfactant in the treatment or prevention of respiratory distress syndrome have been included in this systematic review. Prophylactic administration of surfactant to infants at high risk of developing RDS, compared to selective use of surfactant in infants with established RDS, has been shown to improve some clinical outcomes (Soll 2000). However, whether these differences are affected by the choice of natural or synthetic surfactant is not known.
This review updates the existing review of natural surfactant extract vs synthetic surfactant in the treatment of established respiratory distress syndrome which was published in the Cochrane Library Issue 3, 1997 (Soll 1997).
Information was collected on clinical outcomes, including the incidence of pneumothorax, patent ductus arteriosus, intraventricular hemorrhage (any intraventricular hemorrhage and severe intraventricular hemorrhage, grades 3 or 4), bronchopulmonary dysplasia, chronic lung disease, retinopathy of prematurity, and mortality. Differences in assessment were resolved by discussion. The standard methods of the Neonatal Review Group were used to analyze data using relative risk (RR) and risk difference (RD) for categorical outcomes. A fixed effect model was used for meta-analysis.
PREVENTION TRIALS
Hudak 1997: Conducted a multicenter randomized controlled trial to compare the efficacy and safety of a synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome) and a surfactant extract of calf lung lavage (Infasurf, Forest Laboratories) in the prevention of neonatal respiratory distress syndrome. Premature less than 29 weeks gestational age were randomly assigned to prophylactic surfactant administration 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 persisted after three doses of the assigned surfactant. The clinicians were unaware of treatment assignment. Primary outcome measures included the incidence of RDS, the incidence of death due to RDS, and the incidence of survival without bronchopulmonary dysplasia at 28 days after birth. 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 decrease in the incidence of RDS (Infasurf 16% vs Exosurf 42%) and a decrease in death due to RDS (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 including lower average FIO2 and lower average mean airway pressure 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%). Infasurf-treated infants had significantly less air leak (Infasurf 8% vs Exosurf 14%). Intraventricular hemorrhage occurred more frequently in Infasurf-treated infants (Infasurf 39.0% vs Exosurf 29.9%), but the incidence of severe intraventricular hemorrhage (IVH) (grade 3 and 4) did not differ between the two groups (Infasurf 11.8% vs Exosurf 8.3%)
SELECTIVE TREATMENT TRIALS
Alvarado 1993 (Abstract): Conducted a randomized controlled trial of modified bovine surfactant extract (Survanta, Ross Laboratories) with synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome) in the treatment of very low birthweight infants with RDS. Sixty-six infants with birthweight less than or equal to 1500 grams who required assisted ventilation, supplemental oxygen greater than 40%, and had radiographic evidence of RDS were entered in the study. Infants received Survanta (n=33) or Exosurf (n=33) by random assignment within 24 hours of birth, and received additional doses at 12 hour intervals (up to four doses) if the infants remained on assisted ventilation and required supplemental oxygen greater than 30%. Infants who received Survanta and Exosurf were similar regarding birthweight (1000 +/- 280 g and 990 +/- 237 g respectively) and gestational age (27 +/- 3 weeks and 27 +/- 2 weeks), baseline clinical characteristics and ventilator settings. Mean time from birth to treatment was comparable between the two groups (Survanta 5+/- 3 hours, Exosurf 4+/- 2 hours). The authors report a significant improvement in the duration of mechanical ventilation, supplemental oxygen and hospital stay associated with Survanta treatment.
Horbar 1993: Conducted a multicenter randomized controlled trial to compare the efficacy of synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome) and modified bovine surfactant extract (Survanta, Ross Laboratories) for the treatment of neonatal respiratory distress syndrome. The study was conducted at 11 tertiary care university neonatal intensive care units participating in the National Institute of Child Health and Human Development Neonatal Research Network. Newborn infants (n = 617) weighing 501 to 1500 gm with respiratory distress syndrome who were receiving assisted ventilation with 30% oxygen or more within 6 hours of birth were enrolled. Infants were randomly assigned to receive up to four intratracheal doses of either Exosurf Neonatal (n = 309) or Survanta (n = 308). During the 72 hours after the first surfactant dose, the average FIO2 (+/- SEM) was 0.50 +/- 0.01 for Exosurf and 0.42 +/- 0.01 for Survanta (difference, 0.08; 95% confidence interval, 0.05 to 0.11); the average MAP (+/- SEM) was 7.64 +/- 0.21 cm H2O for Exosurf and 6.93 +/- 0.21 cm H2O for Survanta (difference, 0.71 cm H2O; 95% confidence interval, 0.13 to 1.29 cm H2O). There was no difference between the groups in the incidence of other neonatal morbidities or in the duration of hospitalization, assisted ventilation, or supplemental oxygen administration.
Pearlman 1993 (Abstract): Conducted a quasi-randomized controlled trial of synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome) with modified bovine surfactant extract (Survanta, Ross Laboratories) in the treatment of RDS. One hundred and twenty one premature infants with evidence of RDS were entered in the study. Infants received Survanta (n=57) or Exosurf (n=64) on alternate months. Subsequent doses were given at the discretion of the attending physician. Infants who received Survanta and Exosurf were similar regarding birthweight (1322 +/- 751 g and 1229 +/- 622 g respectively), gestational age (28.4 +/- 4.2 weeks and 28.7 +/- 3.6 weeks), and baseline Apgar scores. Each group received an equal number of doses (Survanta 1.8 +/- 1.0, Exosurf 2.0 +/-1.0). The authors report no statistically significant difference in the duration of mechanical ventilation, clinical complications, or mortality.
Sehgal 1994: Conducted a prospective, randomized, non-blinded study to determine whether infants with respiratory distress syndrome (RDS) who were treated with modified bovine surfactant extract (Survanta, Ross Laboratories) had earlier and larger responses in gas exchange when compared with similar infants treated with a synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome). 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 over represented 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).
VT Oxford 1996 Vermont-Oxford Neonatal Network: Conducted a multicenter randomized controlled trial to compare the efficacy of synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome Co.) and modified bovine surfactant extract (Survanta, Ross Laboratories) for the treatment of neonatal respiratory distress syndrome. Premature infants (n = 1296) weighing 501 to 1500 g with RDS requiring assisted ventilation with 30% oxygen or more were enrolled within 6 hours of birth at 38 neonatal intensive care units participating in the Vermont-Oxford Neonatal Network. Infants were randomly assigned to receive up to four intratracheal doses of the synthetic surfactant (Exosurf Neonatal, n = 644) or the modified bovine surfactant extract (Survanta, n = 652). The primary outcome measure was the occurrence of death or chronic lung disease 28 days after birth. Death or chronic lung disease occurred in 57% of the infants treated with Exosurf Neonatal and in 54% of those infants treated with Survanta (relative risk 0.95; 95% CI 0.86, 1.04). Infants with birth weights of 1001 to 1500 g who received Survanta had a significantly lower risk of chronic lung disease or death at 28 days (Survanta, 27% vs Exosurf, 34%; relative risk 0.78; 95% CI, 0.60, 0.99). Treatment with Survanta led to significant improvement in several secondary outcome measures. Survanta-treated infants received less supplemental oxygen and had lower mean airway pressure 6 and 72 hours after treatment. Survanta-treated infants had significantly fewer pneumothoraces (Survanta, 9% vs Exosurf, 15%; relative risk 0.60; 95% CI 0.44, 0.81). There were no differences between the groups in the incidence of other neonatal complications.
Hudak 1996: Conducted a randomized controlled trial to compare the efficacy and safety of a synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome) and a surfactant extract of calf lung lavage (Infasurf, Forest Laboratories) in the treatment of neonatal respiratory distress syndrome. Infants with RDS who were undergoing mechanical ventilation were eligible for treatment with two doses of either a synthetic or natural surfactant if the a/A O2 ratio 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 a/A oxygen tension ratios < or = 0.10) persisted after two doses of the randomly assigned surfactant. The trial was conducted at 21 centers. Investigators were unaware of treatment assignment. Primary outcome measures included the incidence of pulmonary air leak, the severity of RDS, the incidence of death from RDS, and the incidence of survival without bronchopulmonary dysplasia (BPD) at 28 days after birth. 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. 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 occurred in 21% of Exosurf treated infants and 11% of Infasurf treated infants (adjusted relative risk, 0.53; 95% CI 0.40, 0.71). During the 72 hours after the initial surfactant treatment, infants who received Infasurf had a lower average fraction of inspired oxygen and a lower average mean airway. The incidence of RDS-related death, total respiratory death, death prior 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.
Modanlou 1997: Conducted a clinical trial to compare the efficacy of a synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome) and a natural surfactant extract (Survanta, Ross Laboratories) on the early course of respiratory distress syndrome, arterial blood gases, ventilator support, outcome morbidity rate, and complications of prematurity. The trial includes infants treated sequentially with Exosurf Neonatal (when Exosurf was the only FDA approved surfactant preparation), and infants randomly assigned to either Exosurf Neonatal or Survanta (once Survanta became available as an approved alternative). During the randomized phase of the study 61 infants were randomly assigned to receive Exosurf Neonatal, and 61 infants were assigned to Survanta. Although the two randomized groups were similar in severity of RDS based on fraction of inspired oxygen and ventilator support, a significantly greater improvement in respiratory function (as evidenced by FIO2, mean airway pressure, alveolar-arterial partial pressure of oxygen difference, and oxygen index) was observed in the Survanta group from 12 hours through 48 hours.
daCosta 1999: Conducted a randomized clinical trial to compare the effects of a synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome) and modified natural surfactant extract (Survanta, Ross Laboratories) in infants with neonatal respiratory distress syndrome. Eighty-nine patients were randomly allocated to receive one of the two surfactants. Primary outcome variables included both acute and long-term effects of the surfactant preparations, specifically the oxygenation index (OI) at 24 hours, and the combined incidence of chronic lung disease or death at 28 days. Oxygenation indices in the Exosurf and Survanta groups at 24 hours were similar. However, the magnitude and rapidity of response was 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 hours than the Survanta group (0.21 Exosurf vs. 0.37 Survanta). The combined incidence of death or chronic lung disease was not different in the two groups (18.6% Exosurf vs. 15.2% Survanta). There were no statistically significant differences in the incidence of other complications of prematurity.
Ainsworth 2000: Conducted a randomized controlled trial to compare a synthetic surfactant (pumactant, Britannia Pharmaceuticals) with a natural porcine surfactant (poractant alfa, Curosurf). Two hundred and twelve neonates born between 25 weeks and 29 weeks and 6 days gestation who required intubation were randomly assigned to poractant alfa (n=105) or pumactant (n=107). Outcome data were analyzed for 199 babies. The trial was stopped on the recommendation of the data and safety monitoring committee because of concern regarding increased mortality in the group receiving synthetic surfactant (poractant alfa 14% vs pumactant 31%, odds ratio 0.37, 95% CI 0.18, 0.76). This difference was sustained after adjustment for center, gestation, birthweight, sex, plurality, and use of antenatal steroids.
Kukkonen 2000: Conducted a randomized controlled trial to compare the efficacy of a natural porcine surfactant (Curosurf) and synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome). In three neonatal intensive care units, 228 neonates with respiratory distress and an a/A O2 ratio <0.22 were randomly assigned to receive either Curosurf (100 mg/kg) or Exosurf Neonatal (5 ml/kg). After Curosurf, the fraction of inspired oxygen was lower from 15 min (0.45 +/- 0.22 vs 0.70 +/- 0.22, p = 0.0001) to 6 h (0.48 +/- 0.26 vs 0.64 +/- 0.23, p = 0.0001) and the mean airway pressure was lower at 1 h (8.3 +/- 3.2 mm H20 vs 9.4 +/- 3.1 mm H20, p = 0.01). Thereafter the respiratory parameters were similar. The duration of mechanical ventilation (median 6 vs 5 days) and the duration of oxygen supplementation (median 5 vs 4 days) were similar for Curosurf and Exosurf. An increased risk of bacteremia was associated with Curosurf treatment (11% vs 4%; RR 3.17, 95% CI 1.05, 9.52).
Summary:
Timing of Treatment: Hudak 1997 reported a comparison of Infasurf and Exosurf Neonatal in the context of prophylactic surfactant administration. All other studies treated infants with signs and symptoms of Respiratory Distress Syndrome. Ainsworth 2000 treated infants requiring intubation for "presumed surfactant deficiency". These infants could be treated within 30 minutes of age. Other treatment studies relied on evidence of established respiratory distress syndrome.
Entry criteria: In his prevention trial, Hudak 1997 attempted to enroll infants at high risk of developing RDS. Enrolled infants were less than 29 weeks gestation. In the treatment trials, Alvarado 1993, Horbar 1993, VT Oxford 1996 and Modanlou 1997 all studied infants with birthweight <1500 grams. The trials of Hudak 1996 and Pearlman 1993 studied premature infants without a specific birthweight limitation. Sehgal 1994 studied infants between birthweights 600-1750 grams. Ainsworth studied infants born between 25 and 29+6 weeks gestation. All studies required that the infants be on assisted ventilation and have respiratory distress syndrome. Ainsworth 2000 required only the clinician's assessment that the infant required intubation and had signs of respiratory distress. In other treatment studies, a variety of criteria for oxygen requirement at entry were used. Alvarado 1993 and daCosta 1999 required that infants be in supplemental oxygen >40%. The study of Horbar 1993 and the VT Oxford 1996 study required that infants be in supplemental oxygen >30%. Hudak 1996, Modanlou 1997, and Kukkonen 2000 required that infants demonstrate an arterial/alveolar oxygen ratio of less than or equal to 0.22. This corresponds to being in approximately 40% supplemental oxygen. A variety of age criteria were set out by investigators. In the treatment trials, age at entry varied from within 30 minutes of birth (Ainsworth 2000) to 72 hours of age (Hudak 1996).
Surfactant preparation: In 10 of the included studies, the synthetic surfactant studied was Exosurf Neonatal (Burroughs Wellcome), a synthetic surfactant containing colfosceril palmitate, cetyl alcohol and tyloxapol. Ainsworth 2000 studied pumactant (Britannia Pharmaceuticals), a synthetic surfactant composed of dipalmitoylphosphatidyl choline and phosphatidylglycerol. In 8 of the studies, the natural surfactant extract tested was Survanta (Ross Laboratories), a modified bovine surfactant extract. Hudak 1996, Hudak 1997 studied the bovine surfactant Infasurf (Forest Laboratories). Infasurf is obtained from the lavage of calf lung. Unlike Survanta, no supplemental lipids are added to this formulation. Ainsworth 2000 and Kukkonen 2000 studied the porcine surfactant Curosurf.
Study outcomes: The majority of studies included initial clinical improvement as well as a variety of complications of prematurity including pneumothorax, patent ductus arteriosus, pulmonary hemorrhage, necrotizing enterocolitis, intraventricular hemorrhage, chronic lung disease, and mortality. This analysis focuses on the major clinical outcomes described in these studies.
Methods of randomization: The methods of randomization were specified in 10 of the studies. Sehgal 1994, Hudak 1996, VT Oxford 1996, Hudak 1997, daCosta 1999, and Kukkonen 2000 all used sealed envelopes opened by the clinical investigators. Horbar 1993 used randomization lists at study center pharmacies. Modanlou 1997 used shuffled color-coded cards. Ainsworth 2000 had a central telephone randomization system. Pearlman 1993 used a quasi-randomized strategy allowing for alternate month treatment. The randomization methods used by Alvarado 1993 are not specified.
Blinding: In both the prevention and treatment trials of Infasurf (Hudak 1997), investigators not involved in clinical care administered surfactant. In the trial of Alvarado 1993 investigators were "blinded" to treatment assignment; however, the methods of masking treatment are not described. In the other trials, treatment concealment was not attempted.
Pneumothorax: Prevention trials: Hudak (1997) reports no difference in the risk of pneumothorax associated with the prophylactic use of Infasurf (relative risk 0.62, 95% CI 0.34, 1.13; risk difference -0.02, 95% CI -0.05, 0.01). Treatment trials: Hudak 1996, VT Oxford 1996, daCosta 1999, and Ainsworth 2000 reported a decreased incidence of pneumothorax associated with natural surfactant extract treatment. For the treatment trials, the meta-analyses support a significant reduction in the risk of pneumothorax (typical relative risk 0.63, 95% CI 0.52, 0.76; typical risk difference -0.05, 95% CI -0.07, -0.03).
Overall, the meta-analyses support a significant reduction in the risk of pneumothorax (typical relative risk 0.63, 95% CI 0.53, 0.75; typical risk difference -0.04, 95% CI -0.06, -0.03).
Patent ductus arteriosus: Prevention trials: Hudak 1997 reports no significant effect of surfactant preparation on the risk of patent ductus arteriosus. Treatment trials: Ainsworth 2000 reported a marginal increase in the risk of patent ductus arteriosus associated with natural surfactant extract treatment (RR 2.02, 95% CI 1.00, 4.09; RD 0.10, 95% CI 0.00, 0.20). For the treatment trials, the meta-analysis demonstrates no effect of surfactant preparation on the risk of patent ductus arteriosus (typical relative risk 0.99, 95% CI 0.90, 1.08; typical risk difference 0.00, 95% CI -0.04, 0.03).
Overall, the meta-analyses support no significant effect of surfactant preparation on the risk of patent ductus arteriosus (typical relative risk 0.98, 95% CI 0.91, 1.06; typical risk difference -0.01, 95% CI -0.04, 0.02).
Sepsis: Prevention trials: Hudak 1997 reports no significant effect of surfactant preparation on the risk of sepsis. Treatment trials: Heterogeneous results were noted in the treatment trials. Hudak 1996 noted a decreased risk of sepsis associated with Infasurf treatment (RR 0.71, 95% CI 0.52, 0.96; RD -0.05, 95% CI -0.09, -0.01). Kukkonen 2000 reported an increase in the risk of sepsis associated with natural surfactant extract treatment (RR 3.17, 95% CI 1.05, 9.52; RD 0.08, 95% CI 0.01, 0.15). For the treatment trials, no overall effect of surfactant preparation on the risk of sepsis is noted (typical relative risk 0.96, 95% CI 0.85, 1.09; typical risk difference -0.01, 95% CI -0.03, 0.02).
Overall, the meta-analyses support no significant effect of surfactant preparation on the risk of sepsis (typical relative risk 1.00, 95% CI 0.90, 1.12; typical risk difference 0.00, 95% CI -0.02, 0.02).
Intraventricular hemorrhage: Prevention trials: Hudak 1997 reports an increase in the risk of intraventricular hemorrhage associated with Infasurf administration (RR 1.31, 95% CI 1.08, 1.58; RD 0.09, 95% CI 0.03, 0.15). Treatment trials: None of the 6 treatment trials that reported on intraventricular hemorrhage reported an effect of surfactant preparation on intraventricular hemorrhage. For the treatment trials, the meta-analysis suggests no effect of surfactant preparation on the risk of intraventricular hemorrhage (typical relative risk 1.04, 95% CI 0.94, 1.14; typical risk difference 0.01, 95% CI -0.02, 0.04).
Overall, the meta-analyses support a marginal increase in the risk of intraventricular hemorrhage associated with natural surfactant treatment (typical relative risk 1.09, 95% CI 1.00, 1.19; typical risk difference 0.03, 95% CI 0.00, 0.06).
Severe intraventricular hemorrhage (grades 3 or 4): Prevention trials: Hudak 1997 reports no significant effect of surfactant preparation on the risk of severe intraventricular hemorrhage (RR 1.43, 95% CI 0.95, 2.15; RD 0.04, 95% CI 0.00, 0.08). Treatment trials: None of the seven trials that report on the incidence of severe intraventricular hemorrhage note an effect of surfactant preparation on the risk of severe intraventricular hemorrhage. For the treatment trials, no effect of surfactant preparation on the risk of severe intraventricular hemorrhage is noted (typical relative risk 1.02; 95% CI 0.86, 1.23; typical risk difference 0.00, 95% CI -0.02, 0.02).
Overall, the meta-analyses support no significant effect of surfactant preparation on the risk of severe intraventricular hemorrhage (typical relative risk 1.08, 95% CI 0.92, 1.28; typical risk difference 0.01, 95% CI -0.01, 0.03).
Retinopathy of prematurity: Prevention trials: Hudak 1997 reports no significant effect of surfactant preparation on the risk of retinopathy of prematurity. Treatment trials: None of the 3 trials that report on retinopathy of prematurity note an association with surfactant preparation. The meta-analysis of treatment trials demonstrates no effect of surfactant preparation on the risk of retinopathy of prematurity (typical relative risk 0.94, 95% CI 0.86, 1.03; typical risk difference -0.04, 95% CI -0.08, 0.01).
Overall, the meta-analyses support no significant effect of surfactant preparation on the risk of retinopathy of prematurity (typical relative risk 0.95, 95% CI 0.88, 1.01; typical risk difference -0.03, 95% CI -0.07, 0.01).
Bronchopulmonary dysplasia (oxygen requirement at 28 days of life): Prevention trials: Hudak 1997 reports no significant effect of surfactant preparation on the risk of bronchopulmonary dysplasia (RR 1.05, 95% CI 0.76, 1.46; RD 0.01, 95% CI -0.04, 0.05). Treatment trials: None of the seven trials that report on the incidence of bronchopulmonary dysplasia note an effect of surfactant preparation on the risk of bronchopulmonary dysplasia. The meta-analysis of the treatment studies demonstrates no effect of surfactant preparation on the risk of bronchopulmonary dysplasia (typical relative risk 1.01, 95% CI 0.93, 1.11; typical risk difference 0.01, 95% CI -0.03, 0.04).
Overall, the meta-analyses support no significant effect of surfactant preparation on the risk of bronchopulmonary dysplasia (typical relative risk 1.02, 95% CI 0.93, 1.11; typical risk difference 0.01, 95% CI -0.02, 0.04).
Chronic lung disease (oxygen requirement at 36 weeks adjusted age): Prevention trials: Hudak 1997 reports no significant effect of surfactant preparation on the risk of chronic lung disease (RR 1.09, 95% CI 0.90, 1.31; RD 0.03, 95% CI -0.03, 0.09). Treatment trials: None of the four trials that report on the incidence of chronic lung disease note an effect of surfactant preparation on the risk of chronic lung disease. The meta-analysis of the treatment studies demonstrates no effect of surfactant preparation on the risk of chronic lung disease (typical relative risk 0.97, 95% CI 0.85, 1.11; typical risk difference -0.01, 95% CI -0.04, 0.03).
Overall, the meta-analyses support no significant effect of surfactant preparation on the risk of chronic lung disease (typical relative risk 1.01, 95% CI 0.90, 1.12; typical risk difference 0.00, 95% CI -0.03, 0.03).
Mortality: Prevention trials: Hudak 1997 reported no decrease in the risk of mortality associated with the prophylactic use of Infasurf (relative risk 0.88, 95% CI 0.64, 1.19; risk difference -0.02, 95% CI -0.07, 0.03). Treatment trials: Ainsworth 2000 reported a decreased risk of mortality associated with natural surfactant extract treatment. For the treatment trials, the meta-analyses support a marginal reduction in the risk of mortality (typical relative risk 0.87, 95% CI 0.75, 0.99; typical risk difference -0.02, 95% CI -0.05, 0.00).
Overall, the meta-analyses support a marginal reduction in the risk of mortality (typical relative risk 0.87, 95% CI 0.76, 0.98; typical risk difference -0.02, 95% CI -0.05, 0.00).
Bronchopulmonary dysplasia or mortality: Prevention trials: Hudak 1997 reports no significant effect of surfactant preparation on the risk of bronchopulmonary dysplasia or mortality (RR 0.98, 95% CI 0.91, 1.06; RD -0.01, 95% CI -0.07, 0.04). Treatment trials: None of the four trials that report on the incidence of bronchopulmonary dysplasia or mortality noted an effect of surfactant preparation on the risk of bronchopulmonary dysplasia or mortality. The meta-analysis of the treatment studies demonstrates no effect of surfactant preparation on the risk of bronchopulmonary dysplasia or mortality (typical relative risk 0.94, 95% CI 0.88, 1.01; typical risk difference -0.03, 95% CI -0.08, 0.01).
Overall, the meta-analyses support a marginal decrease in the risk of bronchopulmonary dysplasia or mortality associated with the use of natural surfactant preparations (typical relative risk 0.95, 95% CI 0.90, 1.01; typical risk difference -0.03, 95% CI -0.06, 0.00).
Chronic lung disease or mortality: Prevention trials: Hudak 1997 reports no significant effect of surfactant preparation on the risk of chronic lung disease or mortality (RR 1.02, 95% CI 0.89, 1.16; RD 0.01, 95% CI -0.06, 0.08). Treatment trials: Kukkonen 2000 notes a marginal increase in the risk of chronic lung disease or mortality (RR 1.35, 95% CI 1.00, 1.82; RD 0.13, 95% CI 0.00, 0.26); whereas the Vermont Oxford Trial (VT Oxford 1996) notes a marginal decrease (RR 0.89, 95% CI 0.78, 1.01; RD -0.05, 95% CI -0.10, 0.00). The meta-analysis of the treatment studies demonstrates no effect of surfactant preparation on the risk of chronic lung disease or mortality (typical relative risk 0.95, 95% CI 0.86, 1.06; typical risk difference -0.02, 95% CI -0.07, 0.02).
Overall, the meta-analyses support no significant effect of surfactant preparation on the risk of chronic lung disease or mortality (typical relative risk 0.98, 95% CI 0.90, 1.06; typical risk difference -0.01, 95% CI -0.05, 0.03).
However, a marginal increase in the overall risk of intraventricular hemorrhage (typical relative risk 1.09, 95% CI 1.00, 1.19; typical risk difference 0.03, 95% CI 0.00, 0.06) is associated with natural surfactant treatment. The increased risk in overall intraventricular hemorrhage is not reflected in an increased risk of severe intraventricular hemorrhage (typical relative risk 1.08, 95% CI 0.92, 1.28; typical risk difference 0.01, 95% CI -0.01, 0.03). This increased risk was noted in the initial randomized controlled trials and was thought to be related to changes in cerebral blood flow after surfactant administration (Gunkel 1993).
Dr. F. Blanco has no specific conflict of interest.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Ainsworth 2000 | Randomized
Multicenter trial Blinding of randomization: yes (central telephone randomization using sealed envelopes) Blinding of intervention: no Complete follow-up: no (excluded 13 randomized ineligible infants) Blinding of outcome measurement: yes Stratification by referral center |
Gestational age 25-30 weeks
Intubated for presumed surfactant deficiency Clinical signs of RDS No evidence of life-threatening congenital malformation pumactant n= 100 Curosurf (poractant alfa) n= 99 |
Curosurf (poractant alfa)
v pumactant Multiple doses |
PRIMARY:
Days spent in "high dependency care" (including assisted ventilation, NCPAP, supplemental oxygen greater than 40%, thoracostomy tube, weight less than 1000 grams) SECONDARY: Neonatal mortality Complications of prematurity |
A | |
| Alvarado 1993 | Randomized
Single center trial Blinding of randomization: yes Blinding of intervention: can't tell Complete follow-up: yes Blinding of outcome measurement: can't tell |
Birthweight less than 1500 grams
Assisted ventilation Supplemental oxygen greater than 40% Respiratory distress syndrome Age less than 24 hours Exosurf Neonatal n=33 Survanta n=33 |
Survanta v. Exosurf
Multiple doses |
Clinical Improvement
Days on assisted ventilation Days on supplemental oxygen Days in hospital Mortality |
A | |
| daCosta 1999 | Randomized
Single center trial Blinding of randomization: yes (Sealed envelopes) Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no Stratification: none stated |
Gestational age less than 37 weeks
Birthweight greater than 999 grams Assisted ventilation Supplemental oxygen greater than or equal to 40% Mean Airway Pressure greater than or equal to 7.5 cm H2O Respiratory distress syndrome Age less than or equal to 8 hours No evidence of life-threatening congenital malformation, sepsis, pulmonary hypoplasia, circulatory collapse, pneumothorax, IVH grade 3-4 Exosurf Neonatal n= 43 Survanta n= 46 |
Survanta v. Exosurf
Multiple doses |
PRIMARY:
Oxygenation Index at 24 hours Death or chronic lung disease at 28 days SECONDARY: Ventilator requirement Complications of prematurity |
A | |
| Horbar 1993 | Randomized
Multicenter trial Blinding of randomization: yes (randomization lists at study center pharmacy) Blinding of intervention: no Complete follow-up: no (3 excluded) Blinding of outcome measurement: yes Stratification by birthweight |
Birthweight 501-1500 grams
Assisted ventilation Supplemental oxygen greater than or equal to 30% Respiratory distress syndrome Age less than or equal to 6 hours No mature L/S ratio No evidence of life-threatening congenital malformation Exosurf Neonatal n= 309 Survanta n= 308 |
Survanta v. Exosurf
Multiple doses |
PRIMARY:
Death or BPD at 28 days Average FiO2, mean airway pressure SECONDARY: Complications of prematurity Complications associated with dosing |
A | |
| Hudak 1996 | Randomized
Multicenter trial Blinding of randomization: yes (sealed envelopes) Blinding of intervention: yes Complete follow-up: no (7 excluded) Blinding of outcome measurement: yes Stratification by birthweight |
Respiratory distress syndrome
Assisted ventilation a/A ratio less than or equal to 0.22 Age less than 72 hours No evidence of life-threatening congenital malformation. Exosurf Neonatal n= 508
|
Infasurf v. Exosurf
Treatment crossover for persistent respiratory insufficiency allowed after second dose |
PRIMARY:
Pulmonary airleak SECONDARY: Crossover treatment Severity of RDS Mortality Survival without chronic lung disease Complications of prematurity Days on assisted ventilation Days in oxygen Days in hospital |
A | |
| Hudak 1997 | Randomized
Multicenter trial Blinding of randomization: yes Blinding of intervention: yes Complete follow-up: no (25 excluded) Blinding of outcome measurement: yes |
Gestational age less than or equal to 29 weeks
Intubated and stabilized by 15 minutes of age No life-threatening congenital anomaly Exosurf Neonatal n=423 Infasurf n=423 |
Infasurf v. Exosurf
Multiple doses Crossover treatment allowed for persistent respiratory insufficiency |
PRIMARY:
Incidence of RDS Incidence of death due to RDS Survival without BPD at 28 days SECONDARY: Clinical Improvement Complications of prematurity Mortality |
A | |
| Kukkonen 2000 | Randomized
Multicenter trial (3 centers) Blinding of randomization: yes (Sealed envelopes) Blinding of intervention: no Complete follow-up: no (7 randomized infants excluded due to early mortality) Blinding of outcome measurement: no Stratification by birthweight, gender |
Newborn infants
Assisted ventilation Respiratory distress syndrome a/A ratio < 0.22 No major congenital anomaly Exosurf Neonatal n= 115 Curosurf n= 113 |
Curosurf v. Exosurf
Multiple doses |
PRIMARY:
Duration of assisted ventilation Duration of supplemental oxygen SECONDARY: Complications of prematurity |
A | |
| Modanlou 1997 | Randomized and historical controls (only randomized subjects included
in this review) Single center trial
Blinding of randomization: yes Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no |
Birthweight 500-1500 grams
Premature infants Assisted ventilation Respiratory distress syndrome age less than or equal to 8 hours a/A ratio less than or equal to 0.22 or supplemental oxygen greater than or equal to 0.4 No evidence of life-threatening congenital malformation Randomized infants: Exosurf Neonatal n= 61 Survanta n= 61 |
Survanta vs. Exosurf
Multiple doses |
Average FiO2
Mean airway pressure Duration of ventilation Duration of supplemental oxygen Mortality Complications of prematurity |
A | |
| Pearlman 1993 | Quasi randomized
(alternate month strategy) Single center trial Blinding of randomization: no Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no |
Premature infants
Respiratory distress syndrome Exosurf Neonatal n= 64 Survanta n= 57 |
Survanta v. Exosurf | Days on assisted ventilation
Pulmonary hemorrhage Mortality Complications of prematurity |
C | |
| Sehgal 1994 | Randomized
Single center trial Blinding of randomization: yes (sealed envelopes) Blinding of intervention: no Complete follow-up: no (1 excluded infant) Blinding of outcome measurement: no |
Birthweight 600-1750 grams
Assisted ventilation Supplemental oxygen greater than or equal to 40% Respiratory distress syndrome Age less than 8 hours No evidence of life-threatening congenital malformation Exosurf Neonatal n= 21 Survanta n= 19 |
Survanta v. Exosurf
Multiple doses |
PRIMARY:
Initial response (a/A ratio greater than 0.3 at 24 hours) SECONDARY: Complications of prematurity |
A | |
| VT Oxford 1996 | Randomized
Multicenter trial Blinding of randomization: yes (Sealed envelopes) Blinding of intervention: no Complete follow-up: no (one center omitted from analysis n=22 infants) 32 randomized ineligible infants excluded Blinding of outcome measurement: no Stratification by birthweight |
Birthweight 501-1500 grams
Assisted ventilation Supplemental oxygen greater than or equal to 30% Respiratory distress syndrome Age less than or equal to 6 hours Excluded if known mature L/S ratio Exosurf Neonatal n= 644 Survanta n= 652 |
Survanta v. Exosurf
Multiple doses |
PRIMARY:
Death or chronic lung disease at 28 days SECONDARY: Complications of prematurity |
A |
| Study | Reason for exclusion |
| Bassiouny 1997 | No clinical outcomes given. |
| Choukroun 1994 | No clinical outcomes given. Assessment limited to changes in pulmonary function. |
| Cotton 1992 | Not assigned treatment by randomization |
| Grauaug 1994 | No clinical outcomes given |
| Murdoch 1998 | No clinical outcomes given. Assessment limited to changes in cerebral hemodynamics. |
| Rollins 1993 | Not assigned treatment by randomization |
| Stenson 1994 | Not assigned treatment by randomization |
Ainsworth SB, Beresford MW, Millligan DWA, et al.. Pumactant and poractant alfa for treatment of respiratory distress syndrome in neonates born at 25-29 weeks' gestation: a randomized trial.. Lancet 2000;355:1387-92.
Alvarado 1993 {published data only}
Alvarado M, Hingre R, Hakason D, Gross S.. Clinical trial of Survanta versus Exosurf in Infants <1500g with respiratory distress syndrome.. Pediatr Res 1993;33:314A.
daCosta 1999 {published data only}
daCosta DE; Pai Mg; Al Khusabiby SM. Comparative trial of artificial and natural surfactants in the treatment of respiratory distress syndrome of prematurity: experiences in a developing country. Pediatr Pulmonol 1999;27(5):303-4.
Horbar 1993 {published data only}
Horbar JD, Wright LL, Soll RF, et al. A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. J Pediatr 1993;123:757-66.
Hudak 1996 {published data only}
Hudak ML, Farrell EE, Rosenberg AA, et al. A multicenter randomized masked comparison trial of natural versus synthetic surfactant for the treatment of respiratory distress syndrome. J Pediatr 1996;128:396-406.
Hudak 1997 {published data only}
Hudak ML, Martin DJ, Egan EA et al. A multicenter randomized masked comparison trial of synthetic surfactant versus calf lung surfactant extract in the prevention of neonatal respiratory distress syndrome. Pediatrics 1997;100:39-50.
Kukkonen 2000 {published data only}
Kukkonen AK, Virtanen M, Jarvenpaa AL, Pokela ML, Ikonen S, Fellman V.. Randomized trial comparing natural and synthetic surfactant: increased infection rate after natural surfactant? Acta Paediatr 2000;89(5):556-561.
Modanlou 1997 {published data only}
Modanlou H, Beharry K, et al. Comparative efficacy of Exosurf and Survanta surfactants on early clinical course of respiratory distress syndrome and complications of prematurity. J Perinatol 1997;17:455-60.
Pearlman 1993 {published data only}
Pearlman SA, Leef KH, Stefano JL, et al. A randomized trial comparing Exosurf versus Survanta in the treatment of neonatal RDS. Pediatr Res 1993;33:340A.
Sehgal 1994 {published data only}
Sehgal SS, Ewing CK, Richards T and Taeusch HW. Modified bovine surfactant (Survanta) versus a protein free surfactant (Exosurf) in the treatment of respiratory distress syndrome in preterm infants: a pilot study. J Natl Med Assoc 1994;86:46-52.
VT Oxford 1996 {published data only}
The Vermont Oxford Neonatal Network. A multicenter randomized trial comparing synthetic surfactant with modified bovine surfactant extract in the treatment of neonatal respiratory distress syndrome. Pediatrics 1996;97:1-6.
Bassiouny MR, Remo C, Cherian E. Comparison of the changes in the a/A oxygen ratio after administration of two surfactants for the treatment of neonatal respiratory distress syndrome. J Trop Pediatr 1997;43:38-41.
Choukroun 1994 {published data only}
Choukroun ML, Llanas B, Apere H, Fayon M, Galperine RI, Guenard H, Demarquez JL. Pulmonary mechanics in ventilated preterm infants with respiratory distress syndrome after exogenous surfactant administration: A comparison between two surfactant preparations. Pediatr Pulmonol 1994;18:273-278.
Cotton 1992 {unpublished data only}
Cotton RB, Law AB, Lindstrom DP et al. Differential effects of synthetic and bovine surfactants on lung volume and oxygenation in premature infants with RDS [abstract]. Pediatr Res 1992;31:304A.
Grauaug 1994 {published data only}
Grauaug A, Kohan R, Sly P, et al: Exosurf and Survanta. Are there advantages of one over the other when used as rescue therapy [abstract]. Pediatr Res 1994;35:335A.
Murdoch 1998 {published data only}
Murdoch E, Kempley ST. Randomized trial examining cerebral haemodynamics following artificial or animal surfactant. Acta Paediatrica 1998;87:411-415.
Rollins 1993 {published data only}
Rollins M, Jenkins J, Tubman R, et al. Comparison of clinical responses to natural and synthetic surfactants. J Perinat Med 1993;21:341-347.
Stenson 1994 {published data only}
Stenson BJ, Glover RM, Pappy GJ et al. Static respiratory compliance in the newborn. III. Early changes after exogenous surfactant treatment. Arch Dis Child 1994;70:F19-F24.
Lloyd J, Todd DA, John E. Serial phospholipid analysis in preterm infants: comparison of Exosurf and Survanta. Early Hum Dev 1999;54:157-68.
Peliowski 1998 {published data only}
Peliowski A, Finer NN for the Canadian Surfactant Study Group. A randomized, blinded, Canadian multicenter trial to compare a bovine surfactant, bLES(R) (b), with a synthetic, Exosurf (E), for the rescue treatment of respiratory distress syndrome (RDS) in premature newborns <=1250 g [abstract]. Pediatr Res 1998;43:293A.
* indicates the primary reference for the study
Gunkel JH, Banks PL. Surfactant therapy and intracranial hemorrhage: review of the literature and results of new analyses. Pediatrics 1993;92:775-786.
Horbar JD, Wright EC, Onstad L et al. Decreased mortality associated with the introduction of surfactant therapy: An observational study of neonates weighing 601-1300 grams at birth. Pediatrics 1993;92:191-196.
Schwartz RM, Luby AM, Scanlon JW, Kellogg RJ. Effect of surfactant on morbidity, mortality and resource use in newborns weighing 500-1500 gr. New Eng J Med 1994;(330):1476-1480.
Soll RF, McQueen MC. Respiratory distress syndrome. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:325-358.
Soll RF, Morley CJ. Prophylactic vs selective use of surfactant in preventing morbidity and mortality in preterm infants. In: The Cochrane Library, Issue 3, 2000. Oxford.
Tooley WH, Clements JA, Muramatsu K et al. Lung function in prematurely delivered rabbits treated with a synthetic surfactant. Am Rev Respir Dis 1987;136:651-656.
Soll RF. Natural surfactant extract vs synthetic surfactant in the treatment of established respiratory distress syndrome (Cochrane Review). In: The Cochrane Library, Issue 3, 1997. Oxford: Update Software.