Types of studies

Types of participants

Types of interventions

Types of outcome measures

See: Collaborative Review Group search strategy. The standard search method of the Cochrane Neonatal Review Group were used: 

1. Published manuscripts: Search included Pubmed (1966 to June 2008), Cinhal, and EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 1. 2008). All languages were included. Search terms: {surfactant OR pulmonary surfactant}, limited to humans and further limited to the age group of newborn infants (infant, newborn) and type of publication (clinical trial). From the resulting studies randomized controlled studies that fulfill the inclusion criteria were selected. The bibliography cited in each publication obtained was searched in order to identify additional relevant articles.
2. Published abstracts: The abstracts of the Society for Pediatric Research (USA) (published in Pediatric Research) for the years 1985 to 2008 were searched by hand using the following key words: {surfactant OR pulmonary surfactant} AND {respiratory distress syndrome}.

We used the standard methods of the Cochrane Collaboration as described in the Cochrane Collaboration Handbook and the specific recommendations of the Neonatal Review Group. 

Selection process:
We included randomized controlled trials fulfilling the selection criteria described in the previous section. Both review authors separately selected the studies for inclusion. Any disagreements were resolved by discussion.

Criteria for assessing the methodological quality of the studies:
We used the standard method of the Cochrane Neonatal Review Group. We assessed the methodological quality of the studies by assessing the risk for four types of bias (selection, performance, attrition and detection). Both review authors separately assessed each study. Any disagreements were resolved by discussion.

Data extraction and entry:
Both review authors separately extracted, assessed and coded all data for each study, using a form that was designed specifically for this review. We replaced any standard error of the mean by the corresponding standard deviation. Any disagreements were resolved by discussion. For each study, final data will be entered into RevMan by one review author (RS) and then checked by a second review author (EO).

Statistical analyses:
Statistical analyses were performed using Review manager software. Categorical data were analyzed using relative risk (RR), risk difference (RD) and the number needed to treat (NNT). Continuous data were analyzed using weighted mean difference (WMD). The 95% Confidence interval (CI) was reported on all estimates. Fixed effects model were used for meta-analysis. We estimated the treatment effects of individual trials and examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I² statistic. If statistical heterogeneity was detected, we explored the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc sub group analyses.

The review includes the following studies: Corbet 1995; Dunn 1990; Speer 1992. The methods of randomization, description of participants, description of interventions, and outcomes reported are summarized in the Table of Characteristics of Included Studies.

Studies with animal derived surfactant extract:

Dunn 1990: Dunn and coworkers studied premature infants within a gestational age of 30 - 36 weeks. Included infants had respiratory distress syndrome requiring assisted ventilation and supplemental oxygen. Enrollment occurred before six hours of age. Seventy-five infants were randomly assigned to either control (air placebo), a single dose of bovine lung surfactant extract (100 mg/kg) or multiple doses of bovine lung surfactant extract (100 mg/kg). Infants assigned to the multiple dose group could receive up to three additional doses as indicated during the first 72 hours of life.

Speer 1992: Speer and coworkers conducted a randomized multicenter trial to determine whether the beneficial effects of a single dose of Curosurf (200 mg/kg) in infants with severe respiratory distress syndrome could be enhanced by using multiple doses of surfactant. Preterm neonates (birth weight 700 to 2000 g) with severe respiratory distress syndrome requiring artificial ventilation and a fraction of inspired oxygen greater than or equal to 0.6 were randomized into two groups at an age of 2 to 15 hours (single dose: n = 176, multiple doses: n = 167). Both groups received Curosurf (200 mg/kg) immediately after randomization. In neonates randomized to receive multiple dose treatment, two additional doses of Curosurf (100 mg/kg each) were instilled into the airways (12 and 24 hours after the initial dose) provided that the infant still needed artificial ventilation with a fraction of inspired oxygen greater than 0.21.

Studies with synthetic surfactant:

Corbet 1995: Corbet and coworkers conducted a double-blind, randomized clinical trial at 33 US centers comparing one vs. three prophylactic doses of synthetic surfactant in inborn infants with a birth weight of 700 to 1100 g. All 826 infants received an initial prophylactic dose of synthetic surfactant (Exosurf Neonatal) within 30 minutes of birth. Subsequently 410 infants received two doses of placebo (air) 12 and 24 hours later, and 416 infants received two additional doses of surfactant.

Study outcomes included initial clinical improvement (measurements of oxygenation and ventilatory support) as well as complications of prematurity including pneumothorax, patent ductus arteriosus, pulmonary hemorrhage, necrotizing enterocolitis, sepsis, intraventricular hemorrhage, bronchopulmonary dysplasia, and mortality. This review focuses on clinical outcomes described in these three studies.

Only randomized clinical trials that compared multiple doses of exogenous surfactant to single doses of exogenous surfactant in premature infants at risk for or having respiratory distress syndrome were included in the analysis.

Trials comparing various other dosage strategies are not included in this review.

All three studies used of sealed, opaque envelopes for randomization. In the study of Dunn 1990, randomization was stratified by gestational age, exposure to antenatal steroids, and the infant's gender. Speer 1992 stratified infants by birthweight. In the study of Corbet 1995, randomization used stratification by gestational age and the infant's gender.

Dunn 1990 attempted to minimize bias by having staff not involved with the care of the patient administer surfactant. Speer 1992 made no attempt to conceal treatment assignment. Corbet 1995 attempted to minimize bias by having a "drug administration team" (staff not involved with the care of the patient) administer any subsequent surfactant doses.

COMPARISON 1: Multiple vs. single doses of exogenous surfactant for the prevention or treatment of respiratory distress syndrome

Dunn 1990 administered multiple doses to 70% of the infants randomized to multiple dose policy. Speer 1992 administered multiple doses to 65% of infants randomized to a multiple dose policy. The percentage of infant's receiving multiple doses in the study of Corbet 1995 is unclear.

All three studies demonstrated more sustained improvement in oxygenation and decreased requirement for ventilatory support in the group of infants allowed to receive multiple doses of exogenous surfactant. Other clinically important outcomes are detailed below:

Pneumothorax (Outcome 1.1):

Animal derived surfactant extract: Both trials reported on the outcome pneumothorax.  Speer 1992 reported a reduction in the incidence of pneumothorax in the multiple dose group (9% vs. 18%, relative risk 0.49, 95%CI 0.28, 0.88; risk difference -0.09, 95%CI -0.15, -0.02). The meta-analysis supports a decreased risk of pneumothorax associated with multiple dose surfactant therapy (typical relative risk 0.42, 95% CI 0.35, 0.52; typical risk difference -0.18, 95% CI -0.22, -0.14).

Synthetic surfactant: Corbet 1995 did not report a statistically significant reduction in the risk of pneumothorax (relative risk 0.82, 95% CI 0.57, 1.17). 

Pulmonary Hemorrhage (Outcome 1.2):

Animal derived surfactant extract: Only Speer 1992 reported on the outcome pulmonary hemorrhage. There was no statistically significant difference in the risk of pulmonary hemorrhage in the multiple dose group (relative risk 0.79, 95%CI 0.18, 3.48; risk difference -0.00, 95%CI -0.03, 0.03).

Synthetic surfactant: Corbet 1995 did not report a statistically significant difference in the risk of pulmonary hemorrhage (relative risk 1.24, 95% CI 0.69, 2.24). 

Patent Ductus Arteriosus (Outcome 1.3):

Animal derived surfactant extract: Both Dunn 1990 and Speer 1992 reported on the outcome Patent Ductus Arteriosus (PDA). Neither study reported a reduction in Patent Ductus Arteriosus. The meta-analysis does not support a decreased in the risk of Patent Ductus Arteriosus associated with multiple dose surfactant therapy (typical relative risk 1.12, 95% CI 0.93, 1.36; typical risk difference -0.18, 95% CI -0.22, -0.14).

Synthetic surfactant: Corbet 1995 did not report a statistically significant reduction in the risk of Patent Ductus Arteriosus (relative risk 1.02, 95% CI 0.90, 1.14).

Necrotizing Eneterocolitis (Outcome 1.4):

Animal derived surfactant extract: Only Speer 1992 reported on the outcome necrotizing enterocolitis. There was a trend towards a decrease in the risk of necrotizing enterocolitis in the multiple dose group (relative risk 0.10, 95%CI 0.01, 1.72; risk difference -0.03, 95%CI -0.06, 0.00).

Synthetic surfactant: Corbet 1995 reported a statistically significant difference in the risk of necrotizing enterocolitis (relative risk 0.20, 95% CI 0.08, 0.51; risk difference -0.05, 95%CI -0.06, -0.02).

Bacterial sepsis (Outcome 1.5):

Animal derived surfactant extract: Only Speer 1992 reported on the outcome bacterial sepsis. There was a trend towards a decrease in the risk of bacterial sepsis in the multiple dose group (relative risk 0.66, 95%CI 0.41, 1.08; risk difference -0.07, 95%CI -0.15, 0.01).

Synthetic surfactant: Corbet 1995 reported no statistically significant difference in the risk of bacterial sepsis (relative risk 0.20, 95% CI 0.08, 0.51; risk difference -0.03, 95%CI -0.09, 0.03).

Intraventricular hemorrhage (Outcome 1.6):

Animal derived surfactant extract: Both Dunn 1990 and Speer 1992 reported on Intraventricular hemorrhage (IVH). Neither study reported a reduction in IVH overall. The meta-analysis does not support a decreased in the risk of Intraventricular hemorrhage associated with multiple dose surfactant therapy (typical relative risk 0.98, 95% CI 0.77, 1.25; typical risk difference -0.01, 95% CI -0.10, 0.09).

Synthetic surfactant: Corbet (1995) did not report on the overall incidence of Intraventricular hemorrhage.

Severe Intraventricular hemorrhage (Outcome 1.7):

Animal derived surfactant extract: Neither the study of Dunn 1990 or Speer 1992 reported a reduction in the risk of severe intraventricular hemorrhage. The meta-analysis does not support a decreased risk of severe intraventricular hemorrhage associated with multiple dose animal derived surfactant extract therapy (typical relative risk 1.14, 95% CI 0.76, 1.71; typical risk difference -0.18, 95% CI -0.22, -0.14).

Synthetic surfactant: Corbet 1995 did not report a statistically significant reduction in the risk of severe intraventricular hemorrhage (relative risk 0.96, 95% CI 0.72, 1.26).

Bronchopulmonary Dysplasia (Outcome 1.8):

Animal derived surfactant extract: Neither the study of Dunn 1990 or Speer 1992 reported a reduction in the risk of bronchopulmonary dysplasia. The meta-analysis does not support a decreased risk of bronchopulmonary dysplasia associated with multiple dose animal derived surfactant extract therapy (typical relative risk 1.00, 95% CI 0.58, 1.71; typical risk difference 0.00, 95% CI -0.06, 0.06).

Synthetic surfactant: Corbet (1995) did not report a statistically significant reduction in the risk of pneumothorax (relative risk 1.20, 95% CI 0.82, 1.76).

Mortality (Outcome 1.9):

Animal derived surfactant extract: Both trials reported on mortality. Speer 1992 reported a trend towards a reduction in the risk of mortality in the multiple dose group (relative risk 0.63, 95%CI 0.39, 1.02; risk difference -0.08, 95%CI -0.16, 0.00). The meta-analysis supports a decreased risk of mortality associated with multiple dose surfactant therapy (typical relative risk 0.63, 95% CI 0.39, 1.02; typical risk difference -0.07, 95% CI -0.14, 0.00).

Synthetic surfactant: Corbet 1995 reported a statistically significant reduction in the risk of mortality (relative risk 0.56, 95% CI 0.39, 0.81; risk difference -0.07, 95% CI -0.12, -0.03).

Bronchopulmonary Dysplasia or death (Outcome 1.10):

Animal derived surfactant extract: Only Speer 1992 reported on the combined outcome Bronchopulmonary Dysplasia or death. There was no decrease in the risk of Bronchopulmonary Dysplasia or death in the multiple dose group (relative risk 0.80, 95%CI 0.57, 1.11; risk difference -0.07, 95%CI -0.16, 0.03).

Synthetic surfactant: Corbet 1995 reported no statistically significant difference in the risk of Bronchopulmonary Dysplasia or death (relative risk 0.84, 95% CI 0.66, 1.08; risk difference -0.04, 95%CI -0.10, 0.02).

A more sustained response is seen in infants with respiratory distress syndrome who are allowed multiple doses of exogenous surfactant. Meta-analysis suggests improvement in clinical outcomes including decreasing the risk of pneumothorax. The ability to give multiple doses of exogenous surfactant appears to be the most desirable approach to treatment.

Multiple clinical trials have compared a variety of dosing issues including timing of treatment (prophylactic administration of surfactant vs. treatment of established respiratory distress syndrome); a variety of high dose and low dose regimens, and single v. multiple doses (discussed in this analysis). Specific criteria for repeat doses and timing of repeat doses could be refined in future studies.

Risk of bias table

Risk of bias table

Risk of bias table