Surfactant is essential to normal lung function in babies. Giving surfactant can both prevent and treat respiratory problems. The review found that in babies at risk of RDS, preventive surfactant led to lowers rates of lung injury and death compared to treating only babies with respiratory problems.
Although both prophylactic surfactant administration and surfactant treatment of infants with established respiratory distress syndrome are successful treatment strategies, theoretical advantages have been proposed for each strategy. Prophylactic administration offers the theoretical advantage of replacing surfactant before the onset of respiratory insufficiency, decreasing the need for ventilator support and avoiding barotrauma that may result from even short periods of assisted ventilation (Nilsson 1978). Surfactant may distribute more homogeneously when given immediately at birth into lungs still filled with fluid, leading to improvement in response and decreasing the risk of lung injury (Jobe 1984). Surfactant treatment reserved for infants with established respiratory distress syndrome offers the advantage of treating only infants with clinical disease, eliminating the potential risks and costs of treating surfactant sufficient infants who would receive no benefit from treatment.
To date, eight randomized controlled trials have compared the merits of prophylactic surfactant administration to surfactant treatment of established respiratory distress syndrome. Data from these trials are included in this systematic review. This review updates the review of prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants (Soll RF, Morley, C: Cochrane Library, Issue 4, 2000).
Dunn 1991: Conducted a randomized controlled trial evaluating the influence of the timing of surfactant replacement therapy for the treatment of neonatal respiratory distress syndrome. One hundred and eighty-two neonates of less than 30 weeks' gestation who were randomly assigned prior to delivery to one of three study groups: control (dummy instillation of air given at birth), early surfactant (surfactant given at birth), or late surfactant (surfactant given at less than 6 hours of age). Subjects in the late surfactant group could avoid treatment if they had a clear chest roentgenogram and required no supplemental oxygen at a mean airway pressure of less than 7 cm of water. All treated neonates were eligible to receive up to three additional doses during the first 5 days of life. The three groups were comparable with respect to birth weight, gestational age, and other perinatal parameters with the exception of a lower cord arterial pH and 1-minute Apgar score in the early surfactant group. Of the 60 neonates randomly assigned to late treatment, 29 (48%) were deemed surfactant sufficient and thereby avoided treatment; the other 31 received their first dose at a mean age of 2.9 hours. There was a significant improvement in gas exchange during the first week of life in both surfactant groups compared with the control group, reflected by differences in fraction of inspired oxygen, arterial/alveolar PO2, and ventilation index (peak pressure x rate on the ventilator) (P less than .001). Surfactant therapy also resulted in a lower incidence of pulmonary air leak and severe chronic lung disease (defined as requirement for respiratory support beyond 36 weeks post-conceptional age). There were no differences between early and late surfactant groups in any of these parameters. The only statistically significant difference between the surfactant groups was that the early group had a higher incidence of mild chronic lung disease (respiratory support beyond 28 days of age) than the late treatment group. Neonates in the late treatment group were extubated earlier and had a shorter neonatal intensive care unit stay than control neonates, whereas those in the early group were not significantly different from control neonates in these parameters.
Kendig 1991: Conducted a randomized, multicenter trial of surfactant prophylaxis versus selective treatment. Prior to delivery, 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 FiO2 was at least 0.40 or if the mean airway pressure was at least 7 cm H2O, 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%). 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%). 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%).
Sinkin (1998) published pulmonary and neurodevelopmental outcomes of a cohort of infants enrolled in the Kendig 1991 trial. At 4.5 to 8 years of age, all survivors from one of the three centers were located, and 96% were evaluated. The follow-up test battery included a health-assessment questionnaire, spirometry, 88% saturation test, neurologic examination, and the McCarthy Scales of Children's Abilities (MSCA) and the Conners' Parent Rating Scale-48. Educational achievement was determined by school class placement and teachers' reports of achievement. Of the 192 children originally enrolled, 154 survived. Evaluations were performed on 148 of these infants. An abnormal pulmonary history was found in 45 (30%) of the children: 16 (22%) in the prophylactic group and 29 (39%) in the rescue group. Formal pulmonary function was evaluated in 81 children; 29 (78%) in the prophylactic group and 33 (75%) in the rescue group were considered abnormal. No significant differences were found between the two groups on either cognitive or motor subscales of the MSCA, the Conners' Parent Rating Scale-48, the neurologic examination, the education services received in school, or the teacher ratings of below-average academic performance. Intelligence scores measured on the MSCA were low-normal for both groups. Some level of educational assistance was being provided to 72 (49%) of the cohort studied, and both groups had below average educational performance and increased needs for educational assistance.
Merritt 1991: Conducted 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) in 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. Preterm infants 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 doses (or air) were permitted within 48 hours. Approximately 60% of surfactant-treated infants required two or more doses. 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.
Vaucher 1993: compared the neurodevelopmental outcome of infants enrolled in the trial of Merritt 1991. One hundred forty-five infants were alive at 1 year of adjusted age, at which time growth, neurosensory, and neurologic outcome were similar in all three treatment groups at both centers. Cerebral palsy occurred in 20% overall. Five infants (3.5%) were functionally blind. However, infants treated at birth had lower mean mental and motor scores on the Bayley Scales of Infant Development compared with those of infants rescued with surfactant after the onset of respiratory distress syndrome (Mental Development Index: 78 vs 96, p = 0.02; Psychomotor Development Index: 73 vs 87, p = 0.04).
Egberts 1993: Conducted a randomized clinical trial was to evaluate the immediate effects of prophylactic administration of Curosurf and to compare clinical outcome after prophylactic or expectant management. Porcine surfactant (Curosurf, 200 mg/kg) was administered intratracheally within 10 minutes of birth to preterm neonates with a gestational age of 26 to 29 weeks (n = 75); rescue-eligible neonates (n = 72) were initially subjected to a sham maneuver. After 6 to 24 hours, a similar dose of surfactant was given to the neonates of both the prophylaxis and the rescue-eligible group, if they needed mechanical ventilation with an FIO2 greater than or equal to 0.6. At 6 hours the prophylaxis group had significantly higher tcPO2/FIO2 ratios and less severe RDS by radiological scoring. Severe RDS was present in 19% of the prophylactically treated neonates versus 32% in the rescue-eligible group. There were no differences in the incidence or severity of pneumothorax, pulmonary interstitial emphysema, cerebral hemorrhage, periventricular leukomalacia, patent ductus arteriosus, in the duration of mechanical ventilation or time in supplemental oxygen, or in mortality.
Kattwinkel 1993: Conducted a randomized controlled trial evaluate prophylactic versus selective surfactant treatment in infants born between 29 and 32 weeks gestational age. One thousand three hundred ninety-eight neonates estimated to be 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.
Walti 1995: Conducted a randomized controlled trial evaluate prophylactic versus selective surfactant treatment in infants born between 25 and 31 weeks gestational age. The primary outcome was the effect of prophylactic porcine on survival without bronchopulmonary dysplasia. Compared with rescue therapy (n = 122), prophylaxis (n = 134) decreased the need for oxygenation and ventilator support within 3-72 hours. Prophylactic surfactant administration led to an increase survival without bronchopulmonary dysplasia (60% versus 46%), decreased the incidence of severe intraventricular hemorrhage (3% versus 16%) and decreased the incidence of retinopathy of prematurity (2% versus 11%).
Bevilacqua 1996: Conducted a prospective, randomized, multicenter trial 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 (200 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 a 30% reduction in the incidence of grade 3-4 RDS. There was a 32% reduction in the incidence of grade 3-4 RDS in the prophylaxis group. This was associated with a significant reduction in mean maximum fraction of inspired oxygen (57 vs 66%), a decreased incidence of pulmonary interstitial emphysema (7 vs 14%) and a lowered mortality (21 vs 35%). 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%). The favorable effects of prophylactic treatment were noted in all the age groups, including the babies with the lowest gestational age (24-25 weeks).
Bevilacqua 1997: Conducted a randomized controlled trial of prophylactic versus selective surfactant treatment 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 versus rescue treatment of RDS. Babies with gestational age 26-30 weeks were randomized before birth to prophylaxis in the delivery room with 200 mg/kg of porcine surfactant (prophylaxis) or to routine assistance (control). Subsequently, infants developing RDS requiring mechanical ventilation and fraction of inspired oxygen (FiO2) greater than or equal to 0.4 to maintain PaO2 of 50 mmHg were allowed to be treated with Curosurf (200 mg/kg). A sample size of 174 infants was required to demonstrate a 40% reduction in mortality and the incidence of radiological grade 3-4 RDS. Due to logistic problems, the study was stopped after enrollment of 93 babies. Intention to treat analysis did not demonstrate a significant difference in mortality or radiological evidence of severe RDS. The PaO2/FiO2 ratio was significantly improved in the babies given prophylaxis for the first 12 hours of life versus the controls. Fewer infants given prophylaxis required subsequent rescue treatment compared to controls. There was no difference in other complications such as intraventricular hemorrhage, air leak syndromes and infections.
Summary: Although all studies attempted to include infants thought to be at risk of developing Respiratory Distress Syndrome, the entry criteria differ between studies. Seven of the studies enrolled infants less than 30 weeks gestation. Kattwinkel 1993 studied infants with gestational age 29-32 weeks. The studies of Dunn 1991 and Merritt 1991 excluded infants with mature lung profiles. All studies attempted to exclude infants who had known major congenital anomalies. The studies of Dunn 1991, Egberts 1993, Merritt 1991, Walti 1995, and Bevilacqua 1997 excluded infants with prolonged ruptured membranes greater than 2-3 weeks.
In all of the studies, the surfactants used were natural surfactant extracts. Dunn 1991, Kendig 1991 and Kattwinkel 1993 utilized surfactant obtained by calf lung lavage. Bevilacqua 1996, Bevilacqua 1997, Egberts 1993 and Walti 1995 all utilized the porcine surfactant Curosurf. Merritt 1991 utilized a surfactant obtained from human amniotic fluid.
Study outcomes included initial respiratory status, the incidence of respiratory distress syndrome, and a variety of complications of prematurity including pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, retinopathy of prematurity, chronic lung disease, and mortality.
Follow up is available from two of the studies. Vaucher 1993 followed the infants enrolled in the trial of Merritt 1991at one year of age. Sinkin followed the infants born at one of the centers participating in the trial of Kendig 1991 at 5 to 8 years.
Randomization: All included studies allocated assigned treatment by randomization. In all eight studies, sealed envelopes with randomly allocated treatment assignments were provided to participating centers.
Blinding of treatment: Only the study of Merritt 1991 specifically notes that investigators were masked to treatment assignment.
Blinding of outcome assessment: The degree of blinding of outcome assessment is variable between the studies. Only in the study of Merritt 1991 was the assessment of outcome completely blinded. Other studies included blinding only of radiologic evaluation and developmental follow-up.
Exclusion after randomization: Minimal exclusions were noted after randomization. Merritt 1991 reports an intention to treat analysis of certain major outcomes, but reports only those infants with proven lung immaturity for a variety of other complications of prematurity. (Only data from the intention to treat analysis are used in this review). Walti 1995 excludes 11% of infants originally enrolled. A number of infants from the study of Kattwinkel 1993 are not included because one center was dropped due to a high incidence of protocol deviations.
Pneumothorax: Six studies reported on pneumothorax. Kendig 1991 noted a decrease in the risk of pneumothorax associated with prophylactic surfactant administration that was of borderline statistical significance (relative risk 0.57, 95% CI 0.32, 1.03; risk difference -0.05, 95% CI - 0.10, 0.00). The typical estimate from the meta-analysis suggests that prophylactic administration of surfactant will lead to significant reduction in the risk of pneumothorax (typical relative risk 0.62, 95% CI 0.42, 0.89; typical risk difference -0.02, 95% CI - 0.04, -0.01).
Pulmonary Interstitial Emphysema: Five studies reported on the risk of pulmonary interstitial emphysema. Bevilacqua 1996 noted a decrease in the risk of pulmonary interstitial emphysema associated with prophylactic surfactant administration (relative risk 0.46, 95% CI 0.22, 0.98; risk difference -0.08, 95% CI-0.15, -0.00). The typical estimate from the meta-analysis suggests that prophylactic administration of surfactant will lead to a significant reduction in the risk of pulmonary interstitial emphysema (typical relative risk 0.54, 95% CI 0.36, 0.82; typical risk difference -0.03, 95% CI -0.04, -0.01).
Necrotizing Enterocolitis: Five studies reported on the risk of necrotizing enterocolitis. None of the individual trials supported a difference in the incidence of necrotizing enterocolitis. The typical estimate of the meta-analysis supports no difference in the risk of necrotizing enterocolitis (typical relative risk 1.01, 95% CI 0.73, 1.40; typical risk difference 0.00, 95% CI -0.02, 0.02).
Patent Ductus Arteriosus: Six of the randomized control trials reported the incidence of patent ductus arteriosus. Kattwinkel 1993 reported a small decrease in the incidence of patent ductus arteriosus associated with prophylactic administration of surfactant (relative risk 0.81, 95% CI 0.66, 0.99; risk difference -0.05, 95% CI -0.10, 0.00). The meta-analysis supports no difference in the risk of patent ductus arteriosus (typical relative risk 0.96, 95% CI 0.85, 1.09; typical risk difference -0.01, 95% CI -0.04, 0.02).
Intraventricular Hemorrhage: Seven of the included studies reported on the incidence of intraventricular hemorrhage. Dunn 1991 reported a non statistically significant increase in the incidence of intraventricular hemorrhage associated with prophylactic surfactant administration. Walti 1995 and Bevilacqua 1996 reported a trend towards decreasing intraventricular hemorrhage with prophylactic surfactant administration. The typical estimate from the meta-analysis of these seven trials suggests that prophylactic surfactant administration has no effect on the risk of intraventricular hemorrhage (typical relative risk 0.92, 95% CI 0.82, 1.03; typical risk difference -0.03, 95% CI -0.06, 0.01).
Severe Intraventricular Hemorrhage: The seven trials that reported on
all grades of intraventricular hemorrhage also reported on severe intraventricular
hemorrhage (grades 3 & 4). Walti 1995 reported
a significant reduction in the risk of severe intraventricular hemorrhage
associated with prophylactic surfactant administration (relative risk 0.19,
95% CI 0.07, 0.54; risk difference -0.13, 95% CI -0.21, -0.06). Dunn
1991 reported a trend towards increased risk of severe intraventricular
hemorrhage in association with prophylactic surfactant administration,
although this observation was not statistically significant.
The meta-analysis does not support an increase in severe intraventricular
hemorrhage with either treatment strategy (typical relative risk 0.84,
95% CI 0.66, 1.06; typical risk difference -0.02, 95% CI -0.04, 0.01).
Bronchopulmonary Dysplasia: All eight studies reported on bronchopulmonary
dysplasia at 28 days of age. Kattwinkel 1993
reported a trend towards decreased risk of bronchopulmonary dysplasia in
association with prophylactic surfactant administration. On the other hand,
Dunn 1991 reported a statistically significant
increase in the risk of bronchopulmonary dysplasia associated with the
use of prophylactic surfactant administration (relative risk 1.88, 95%
CI 1.15, 3.05; risk difference 0.23, 95% CI 0.07, 0.40).
The meta-analysis of these eight trials does not support any difference
in the risk of bronchopulmonary dysplasia (typical relative risk 0.96,
95% CI 0.82, 1.12; typical risk difference -0.01, 95% CI -0.03, 0.02).
Mortality: Investigators reported both on neonatal mortality and mortality
prior to hospital discharge. Seven studies reported on neonatal mortality.
Kendig 1991, Kattwinkel
1993 and Bevilacqua 1996 noted a significant
decrease in neonatal mortality associated with prophylactic surfactant
administration. Kendig 1991 and Walti
1995 reported significant reductions in mortality prior to hospital
discharge associated with prophylactic surfactant therapy.
Meta-analyses supported a decrease in the risk of both neonatal mortality
and in mortality prior to hospital discharge associated with prophylactic
surfactant administration. Typical relative risk for neonatal mortality
is 0.61, 95% CI 0.48, 0.77 (typical risk difference -0.05, 95% CI -0.07,
-0.02) and the typical relative risk for mortality prior to hospital discharge
is 0.75, 95% CI 0.59, 0.96 (typical risk difference -0.05, 95% CI -0.09,
-0.01).
Bronchopulmonary Dysplasia or Death: All eight studies reported on the combined outcome of bronchopulmonary dysplasia or death at 28 days. Kattwinkel 1993, Walti 1995 and Bevilacqua 1996 report a significant reduction in the risk of bronchopulmonary dysplasia or death in association with prophylactic surfactant administration. Dunn 1991 reported an increase in the risk of bronchopulmonary dysplasia or death (relative risk 1.84, 95%CI 1.25, 2.73; risk difference 0.30, 95%CI 0.13, 0.46). Meta-analysis supports a decreased risk of bronchopulmonary dysplasia or death (typical relative risk 0.85, 95% CI 0.76, 0.95; typical risk difference -0.04 95% CI -0.07, -0.01), although significant heterogeneity was noted.
Retinopathy of Prematurity: Four studies reported on the incidence of
retinopathy. Data presented in the analysis include all infants enrolled.
Walti 1995 reported a decreased risk of any stage
of retinopathy in infants who received prophylactic surfactant (relative
risk 0.18, 95% CI 0.04, 0.81; risk difference -0.07, 95% CI -0.12, -0.01),
whereas Kattwinkel 1993 reports a trend
toward an increased risk of retinopathy in infants who received prophylactic
treatment.
The meta-analysis does not support any difference in the risk of retinopathy
of prematurity (typical relative risk 1.09, 95% CI 0.72, 1.66; typical
risk difference 0.00, 95% CI -0.01, 0.02), or any difference in the risk
of Stage 2-4 retinopathy (typical relative risk 0.97, 95% CI 0.45, 2.10;
typical risk difference 0.00, 95% CI -0.05, 0.05).
Neonatal Mortality in Infants <30 weeks gestation: In a secondary analysis of only infants less than 30 weeks gestation, the meta-analysis suggests a significant decrease in neonatal mortality in this high risk group (typical relative risk 0.62, 95% CI 0.49, 078; typical risk difference -0.06, 95% CI -0.09, -0.03).
Bronchopulmonary Dysplasia or Death in Infants <30 weeks gestation: In a secondary analysis of only infants less than 30 weeks gestation, the meta-analysis suggests a significant decrease in the incidence of bronchopulmonary dysplasia or death in this subgroup (typical relative risk 0.87, 95% CI 0.77, 0.97; typical risk difference -0.05, 95% CI -0.09, -0.01
Of particular interest are the differences in criteria for late treatment. Trials varied from liberal criteria (intubation and respiratory insufficiency) to more stringent criteria (moderate to severe respiratory distress syndrome requiring supplemental oxygen greater than or equal to 60%). Previous trials have demonstrated that treatment is less effective when given later in the course of respiratory distress syndrome (OSIRIS 1992). However, even in individual trials (Kattwinkel 1993) where selective treatment criteria were liberal, clinical improvement is noted in the group that received prophylactic therapy.
Recent studies have demonstrated that prophylactic surfactant does not need to be instilled prior to the first breath. Kendig and co-workers (1996) demonstrated that initial stabilization and immediate post ventilatory surfactant administration may be a more appropriate approach to treatment.
Recent reports have suggested that early delivery room stabilization on nasal continuous positive airway pressure (NCPAP) may decrease the risk of lung injury and subsequent development of chronic lung disease (Gittermann 1997, Lindner 1999, Sahni 1998). Centers have reported their success using this approach, but few formal trials have been conducted to compare this less invasive approach with routine intubation and prophylactic surfactant administration. Innovative approaches that combine delivery room intubation, surfactant administration and immediate extubation may prove to be a valid approach to treatment in high risk infants (Verder 1999).
The meta-analysis supports a significant decrease in the risk of pneumothorax, the risk of pulmonary interstitial emphysema, the risk of mortality and the risk of bronchopulmonary dysplasia or death associated with prophylactic surfactant administration. The meta-analysis suggests that for every 100 infants treated prophylactically, there will be 2 fewer pneumothoraces, and 5 fewer deaths. Although prophylactic administration will increase exposure to treatment and cost of treatment (approximately twice as many infants at risk for respiratory distress will receive surfactant using the prophylactic approach), the clinical benefits appear great enough to warrant these expenses.
Other than expense, no mitigating outcomes are noted in the meta-analysis to lead to concern about using the prophylactic approach. In a secondary analysis including only enrolled infants less than 30 weeks gestation, similar clinical improvements are noted.
Dr. C. Morley is a consultant to Britannia Pharmaceuticals.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Bevilacqua 1996 | Randomized
Multicenter trial Blinding of randomization: yes (sealed envelopes) Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: can't tell Stratification based on gestational age |
Premature infants
Gestational age 24-30 weeks No major congenital anomaly |
Prophylactic Curosurf (200 mg/kg) within 10 minutes after birth v.
Curosurf treatment (200 mg/kg) of intubated infants with respiratory distress
syndrome within 24 hours of age
Second dose of Curosurf (200 mg/kg) allowed in prophylactic treatment group if infant has RDS requiring assisted ventilation within 24 hours of age. |
PRIMARY OUTCOME:
Reduction in RDS SECONDARY OUTCOME:
|
A | |
| Bevilacqua 1997 | Randomized
Multicenter trial Blinding of randomization: yes (sealed envelopes) Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: can't tell Stratification based on gestational age |
Premature infants
Gestational age 24-30 weeks No major congenital anomaly |
Prophylactic Curosurf (200 mg/kg) within 10 minutes after birth v.
Curosurf treatment (200 mg/kg) of intubated infants with respiratory distress
syndrome within 24 hours of age
Second dose of Curosurf (200 mg/kg) allowed in prophylactic treatment group if infant has RDS requiring assisted ventilation within 24 hours of age. |
PRIMARY OUTCOME:
Reduction in RDS SECONDARY OUTCOME: Complications of Prematurity |
A | |
| Dunn 1991 | Randomized
Single center Blinding of randomization: yes (sealed envelopes) Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no Stratification based on gestational age and exposure to antenatal steroids |
Premature infants
Gestational age <30 weeks No known congenital anomaly No ROM >2 weeks No mature L/S ratio |
Prophylactic BLSE (75-100 mg) prior to initiation of respiration v.
BLSE treatment (75-100 mg) of intubated infants with respiratory insufficiency
less than 6 hours of age v. control (no treatment)
Up to 3 additional treatments allowed in either surfactant treatment group. |
PRIMARY OUTCOME:
Improvement in a/A ratio. SECONDARY OUTCOME:
|
A | |
| Egberts 1993 | Randomized
Multicenter trial Blinding of randomization: yes (sealed envelopes) Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: can't tell |
Premature infants
Gestational age 26-30 weeks No major congenital anomaly ROM <3 weeks |
Prophylactic Curosurf (200 mg/kg) within 10 minutes after birth v.
Curosurf treatment (200 mg/kg) in intubated infants with moderate-severe
respiratory distress syndrome (supplemental oxygen equal to or greater
than 60%).
6-24 hours of age. Second dose of Curosurf (200 mg/kg) allowed in prophylactic treatment group if infant on assisted ventilation and supplemental oxygen 60% or greater |
PRIMARY OUTCOME
Reduction in RDS SECONDARY OUTCOME
|
A | |
| Kattwinkel 1993 | Randomized
Multicenter trial Blinding of randomization: yes (sealed envelopes) Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: can't tell |
Premature infants
Gestational age 29-32 weeks Excluded if noted to have congenital malformation congenital sepsis perinatal asphyxia judged too mature |
Prophylactic CLSE (150 mg) within 5 minutes after birth v. CLSE treatment
(150 mg) in infants with mild respiratory distress syndrome (compatible
radiograph, greater than 30% supplemental oxygen).
Retreatment of either group allowed if infant reached criteria for severe RDS (MAP 10 cmH2O or greater, supplemental oxygen 60% or greater). |
PRIMARY OUTCOME:
Development of moderate RDS. SECONDARY OUTCOME:
|
A | |
| Kendig 1991 | Randomized
Multicenter trial Blinding of randomization: yes (sealed envelopes) Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no |
Premature infants
Gestational age <30 weeks No lethal congenital anomaly |
Prophylactic CLSE (90mg) prior to initiation of respiration v. CLSE
treatment (90 mg) in intubated infants with RDS requiring greater than
40% supplemental oxygen or MAP greater than 7 cmH20.
Retreatment of either group allowed at 12 hours if infant remained on assisted ventilation, requiring greater than 40% supplemental oxygen or MAP greater than 7 cmH2O. |
PRIMARY OUTCOME:
Mortality SECONDARY OUTCOME:
|
A | |
| Merritt 1991 | Randomized
Multicenter Trial Blinding of randomization: yes (sealed envelopes) Blinding of intervention: yes Complete follow-up: yes Blinding of outcome measurement: yes Stratification based on gestational age Separate randomization schedules for multiple births |
Premature infants
Gestational age 24-29 weeks No congenital malformation No mature L/S ratio ROM <3 weeks |
Prophylactic human amniotic fluid extract (70 mg/kg) immediately post intubation/minimal ventilation vs. treatment with human amniotic fluid extract (70 mg/kg) in intubated infants with RDS requiring greater than 50% supplemental oxygen and MAP of 7 cmH2O or greater prior to 12 hours of age vs. control treatment. | PRIMARY OUTCOME:
Death or bronchopulmonary dysplasia SECONDARY OUTCOME:
|
A | |
| Walti 1995 | Randomized
Multicenter trial Blinding of randomization: yes (sealed envelopes) Blinding of interventions: no Complete follow-up: yes Blinding of outcome measurement: no |
Premature infants
Gestational Age 25-31 weeks No congenital anomaly ROM <3 weeks |
Prophylactic Curosurf (100 mg/kg) within 15 min after birth vs.
Curosurf treatment (100 mg/kg) in intubated infants with moderate respiratory distress syndrome (PaO2/FiO2 <150 mmHg on assisted ventilation with MAP >8cmH20) 3-18 hours of age Retreatment of either group allowed with up to 3 doses of Curosurf (100 mg/kg) within 48 hours if above criteria met. |
PRIMARY OUTCOME:
Survival without BPD at 28 days after birth SECONDARY OUTCOME:
|
A |
Bevilacqua G, Parmigiani S, Robertson B and the Italian Collaborative Multicentre Study Group. Prophylaxis of respiratory distress syndrome by treatment with modified porcine surfactant at birth: a multicentre prospective randomized trial. J Perinat Med 1996;24:1-12.
Bevilacqua 1997 {published data only}
Bevilacqua G, Chernev T, Parmigiani S, Iarakova N, Gaioni L, Volante E, Gambini L, Bussolati G. Use of surfactant for prophylaxis versus rescue treatment of respiratory distress syndrome: experience from an Italian-Bulgarian trial. Acta Biomed Ateneo Parmense 1997;68(Suppl 1):47-54.
Dunn 1991 {published data only}
Dunn MS, Shennan AT, Zyack D, Possmayer F. Bovine surfactant replacement therapy in neonates of less than 30 weeks' gestation: a randomized controlled trial of prophylaxis vs treatment. Pediatrics 1991;87:377-386.
Egberts 1993 {published data only}
Egberts J, DeWinter JP, Sedin G, deKleine MJK, Broberger U, VanBel F, Curstedt T and Robertson B. Comparison of prophylaxis and rescue treatment with Curosurf in neonates less than 30 weeks gestation: a randomized trial. Pediatrics 1993;92:768-774.
Kattwinkel 1993 {published data only}
Kattwinkel J, Bloom BT, Delmore P, Davis CL, Farrell E, Friss H, Jung AL, King K and Mueller D. 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. Pediatrics 1993;92:90-98.
Kendig 1991 {published data only}
*Kendig JW, Notter RH, Cox C, Reubens LJ, Davis JM, Maniscalco WM, Sinkin RA, Bartoletti A, Dweck HS, Horgan MJ, Rosemberg H, Phelps DL, Shapiro DL. A comparison of surfactant as immediate prophylaxis and as rescue therapy in newborns of less than 30 weeks' gestation. N Engl J Med 1991;324:865-871.
Sinkin RA, Kramer BM, Merzbach JL, Myers GJ, Brooks JG, Palumbo DR, Cox C, Kendig JW, Mercier CE, Phelps DL. School-age follow-up of prophylactic versus rescue surfactant trial: pulmonary, neurodevelopmental, and educational outcomes. Pediatrics 1998;101:E11.
Merritt 1991 {published data only}
*Merritt TA, Hallman M, Berry C, Pohjavuori M, Edwards DK, Jaaskelainen J, Grafe MR, Vaucher Y, Wozniak P, Heldt G, Rapola J. Randomized, placebo-controlled trial of human surfactant given at birth vs rescue administration in very low birthweight infants with lung immaturity. J Pediatr 1991;118:581-594.
Vaucher YE, Harker L, Merritt TA, Hallman M, Gist K, Bejar R, Heldt GP, Edwards D, Pohjavuori M. Outcome at twelve months of adjusted age in very low birth weight infants with lung immaturity: a randomized, placebo-controlled trial of human surfactant. J Pediatr 1993;122:126-32.
Walti 1995 {published data only}
Walti H, Paris - Llado J, Breart G, Couchard M, and the French Collaborative Multicentre Study Group. Porcine surfactant replacement therapy in newborns of 25-31 weeks' gestation: a randomized multicentre trial of prophylaxis versus rescue with multiple low doses. Acta Paediatr 1995;84:913-21.
* indicates the primary reference for the study
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