Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Animal derived surfactant extract for treatment of respiratory distress syndrome

Animal derived surfactant extract for treatment of respiratory distress syndrome

Skip sharing on social media links
Share this:

Authors

Nadine Seger1, Roger Soll

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont, USA [top]
2Division of Neonatal-Perinatal Medicine, University of Vermont, Burlington, Vermont, USA [top]

Citation example: Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD007836. DOI: 10.1002/14651858.CD007836.

Contact person

Nadine Seger

Department of Pediatrics
University of Vermont College of Medicine
McClure 7, Fletcher Allen Health Care
111 Colchester Avenue
Burlington Vermont 05401
USA

E-mail: nadineseger@yahoo.com

Dates

Assessed as Up-to-date: 14 February 2009
Date of Search: 01 December 2008
Next Stage Expected: 14 February 2011
Protocol First Published: Not specified
Review First Published: Issue 2, 2009
Last Citation Issue: Issue 2, 2009

What's new

Date / Event Description

History

Date / Event Description
16 May 2008
Amended

Converted to new review format.

Abstract

Background

Respiratory distress syndrome (RDS) is caused by a deficiency or dysfunction of pulmonary surfactant. A wide variety of surfactant products have been formulated and studied in clinical trials. These include synthetic surfactants and animal derived surfactant extracts. Trials of surfactant replacement have either tried to prevent the development of respiratory distress in high-risk premature infants or treat established respiratory distress in premature infants.

Objectives

To assess the effect of administration of animal derived surfactant extract on mortality, chronic lung disease and other morbidities associated with prematurity in preterm infants with established respiratory distress syndrome. Subgroup analysis were planned according to the specific surfactant product, the degree of prematurity, and the severity of disease.

Search methods

Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, and CINAHL from 1975 through December 2008. In addition, searches were made of previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants and journal hand searching in the English language.

Selection criteria

Randomized or quazi-randomized controlled trials that compared the effect of animal derived surfactant extract treatment administered to infants with established respiratory distress syndrome in order to prevent complications of prematurity and mortality.

Data collection and analysis

Data regarding clinical outcomes were excerpted from the reports of the clinical trials by the review authors. Data analysis was done in accordance with the standards of the Cochrane Neonatal Review Group.

Results

Thirteen randomized controlled trials were included in the analysis. The studies demonstrated an initial improvement in respiratory status (improved oxygenation and decreased need for ventilator support). The meta-analysis supports a significant decrease in the risk of any air leak (typical relative risk 0.47, 95% CI 0.39, 0.58; typical risk difference -0.16, 95% CI -0.21, -0.12), pneumothorax (typical relative risk 0.42, 95% CI 0.34, 0.52; typical risk difference -0.17, 95% CI -0.21, -0.13), and a significant decrease in the risk of pulmonary interstitial emphysema (typical relative risk 0.45, 95% CI 0.37, 0.55; typical risk difference -0.20, 95% CI -0.25, -0.15). There is a significant decrease in the risk of neonatal mortality (typical relative risk 0.68, 95% CI 0.57, 0.82; typical risk difference -0.09, 95% CI -0.13, -0.05), a significant decrease in the risk of mortality prior to hospital discharge (typical relative risk 0.63, 95% CI 0.44, 0.90; typical risk difference -0.10, 95% CI -0.18, -0.03) and a significant decrease in the risk of bronchopulmonary dysplasia (BPD) or death at 28 days of age (typical relative risk 0.83, 95% CI 0.77, 0.90; typical risk difference -0.11, 95 CI -0.16, -0.06). No differences are reported in the risk of patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, BPD or retinopathy of prematurity.

Authors' conclusions

Infants with established respiratory distress syndrome who receive animal derived surfactant extract treatment have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, a decreased risk of mortality, and a decreased risk of bronchopulmonary dysplasia or death.

Plain language summary

Animal derived surfactant extract treatment for respiratory distress syndrome

Respiratory distress syndrome (RDS) is caused by a deficiency or dysfunction of the lining chemicals of the lung known as pulmonary surfactant. A wide variety of surfactant products have been formulated and studied in clinical trials. These include synthetic surfactants and animal derived surfactant extracts. Animal derived surfactant extracts are obtained from animal or human sources. Trials of surfactant replacement have either tried to prevent the development of respiratory distress in high-risk premature infants or treat established respiratory distress in premature infants. Infants with established respiratory distress syndrome who receive animal derived surfactant extract treatment have a decreased risk of lung rupture (pneumothorax), a decreased risk of lung injury (pulmonary interstitial emphysema), a decreased risk of dying, and a decreased risk of chronic lung injury (bronchopulmonary dysplasia) or death.

[top]

Background

Description of the condition

Respiratory distress syndrome (RDS) is caused by a deficiency or dysfunction of pulmonary surfactant. Surfactant lines the alveolar surface and prevents atelectasis at end expiration. Pulmonary surfactant is predominantly dipalmitoylphosphatidylcholine with lesser amounts of other phospholipids including phosphatidylglycerol (PG), phosphatidylethanolamine, and phosphatidylinositol. Pulmonary surfactant also contains neutral lipids and four distinct surfactant proteins (SP-A, SP-B, SP-C and SP-D). Surfactant proteins may play a role in surfactant secretion, recycling, cooperative functioning with other surfactant proteins and phospholipids (Schurch 1992; Possmayer 1990), and innate host defense of the lung (Wright 1997). The physiologic functions of surfactant include the ability to lower surface tension, and the ability to rapidly adsorb, spread, and reform a monolayer in the dynamic conditions associated with the respiratory cycle (Jobe 1993).

Description of the intervention

Investigators in the 1960s attempted to aerosolize dipalmitoylphosphatidylcholine (DPPC) to infants with established respiratory distress syndrome. These investigators could not demonstrate any beneficial effect of surfactant replacement (Robillard 1964; Chu 1967). The poor results were, in part, due to an incomplete understanding of what constitutes pulmonary surfactant. The first successful animal model of surfactant replacement therapy was conducted by Enhorning and co-workers (Enhorning 1972). Enhorning administered a crude animal derived surfactant extract obtained from lavage of the lungs of mature rabbits directly into the trachea of immature rabbits. Improvement in lung compliance and alveolar expansion was noted. Success in animal models led to clinical trials in newborn infants. The first successful experience with surfactant replacement therapy treated infants with established respiratory distress syndrome. Fujiwara 1980 studied a series of ten preterm infants with severe RDS requiring assisted ventilation. The infants improved dramatically following treatment with Surfactant TA, a modified bovine surfactant extract. Since the initial experience of Fujiwara and coworkers, many randomized trials of surfactant in the treatment of established respiratory distress syndrome have been conducted.

How the intervention might work

A wide variety of surfactant products have been formulated and studied in clinical trials. These include synthetic surfactants and animal derived surfactant extracts. Animal derived surfactant extracts are derived from biologic sources including cows, pigs and humans. They are obtained by organic extraction of lavage fluid or minced lung. As currently formulated, animal derived surfactants contain surfactant proteins SP-B and SP-C. SP-A and SP-D, are extremely hydrophilic and do not remain in the preparation of any commercial natural surfactant. SP-B and SP-C are markedly hydrophobic and are thought to be crucial in promoting the adsorption and spread of monolayers of dipalmitoylphosphatidyl-choline (DPPC) (Hawgood 1985; Witsett 1995). Different animal derived surfactants may differ in the amounts of surfactant protein that is retained in production.

Animal derived surfactant extracts can be further classified as either modified or unmodified surfactant extracts; modified animal derived surfactant extract is supplemented with phospholipids or other surface active material while unmodified animal derived surfactant extract contains only the components remaining after the extraction process. Trials of surfactant replacement have either tried to prevent the development of respiratory distress in high-risk premature infants or treat established respiratory distress in premature infants.

Why it is important to do this review

Multiple systematic reviews have addressed the use of animal derived surfactant preparations or synthetic surfactant preparations in the prevention or treatment of respiratory distress syndrome (Soll 1997a; Soll 1998a; Soll 1998b). Systematic reviews have also addressed the benefits of preventive or early treatment and the benefits of different specific surfactant products (Yost 1999; Soll 2001a; Soll 2001b; Pfister 2007; Stevens 2007). Our analysis will include randomized controlled trials of animal derived surfactant extracts in the treatment of established respiratory distress syndrome. Although animal derived surfactant products are now widely used, this review will allow for more precise estimates of effects in the overall population and in sub-populations based on gestational age or disease severity.

Objectives

To assess the effect of administration of animal derived surfactant extract compared to placebo or no treatment on the risk of mortality, chronic lung disease and other morbidities associated with prematurity in preterm infants with established respiratory distress syndrome.

Subgroup analysis were planned according to the specific surfactant product, the degree of prematurity, and the severity of disease.

[top]

Methods

Criteria for considering studies for this review

Types of studies

Only randomized or quasi-randomized controlled clinical trials were considered for this review.

Types of participants

Preterm infants (less than 37 weeks gestation) with clinical and/or radiologic evidence of respiratory distress syndrome requiring assisted ventilation.

Types of interventions

All included studies utilized surfactant products derived from mammalian sources (human amniotic fluid extract, calf lung surfactant extract, and modified bovine surfactant extract, porcine surfactant extract).

Infants with established respiratory distress syndrome randomized to receive animal derived surfactant extract vs. control treatment (intratracheal administration of normal saline or air placebo, or no treatment).

Types of outcome measures

Primary Outcomes
  1. Neonatal mortality (mortality < 28 days of age) from any cause
  2. Mortality prior to hospital discharge (from any cause)
  3. Broncholpulmonary dysplasia (oxygen requirement at 28 to 30 days of age)
  4. Bronchpulmonary dysplasia or death prior to 28 days of age
  5. Chronic lung disease (use of supplemental oxygen at 36 weeks postmenstrual age)
  6. Chronic lung disease (use of supplemental oxygen at 36 weeks postmenstrual age) or death prior to 36 weeks postmenstrual age
Secondary Outcomes
  1. Any air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum)
  2. Any pneumothorax
  3. Pulmonary Interstitial emphysema
  4. Any pulmonary hemorrhage
  5. Patent ductus arteriosus (PDA that has been treated with cyclo-oxygenase inhibitor or surgery)
  6. Any culture proven bacterial sepsis
  7. Any culture proven fungal sepsis
  8. Necrotizing enterocolitis (defined as Bell Stage II or greater)
  9. Periventricular leukomalacia
  10. Retinopathy of prematurity [all stages and severe (stage 3 or greater)]
  11. Intraventricular hemorrhage [any grade and severe (grade 3 to 4)]
  12. Cerebral palsy
  13. Neurodevelopmental outcome at approximately two years corrected age (acceptable range 18 months to 28 months) including: cerebral palsy, mental retardation (Bayley Scales of Infant Development Mental Developmental Index < 70), legal blindness (< 20/200 visual acuity), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" will be defined as having any one of the aforementioned deficits.

Post hoc analyses will be considered for any unexpected adverse effects reported by the studies.

Search methods for identification of studies

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

  1. Published manuscripts: Search included PubMed (1966 to December 2008), CINAHL, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 4, 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 trials and quazi-randomized controlled trials that fulfilled the inclusion criteria were selected. To identify long-term neurodevelopmental sequelae, a search using the following keywords was performed: (outcome OR sequelae OR follow-up OR mental retardation OR cerebral palsy OR hearing OR visual OR motor OR mental OR psychological) AND (surfactant OR pulmonary surfactant) not limited to any age group or language. 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}. For abstract books that do not include keywords, the search was limited to relevant sections such as pulmonary and neonatology.

Data collection and analysis

For each included study, information was collected regarding the method of randomization, blinding, drug intervention, stratification, and whether the trial was single or multicenter. Information regarding trial participants including gestational age criteria, birthweight criteria, and other inclusion or exclusion criteria was noted. Information on clinical outcome was analyzed including pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (any intraventricular hemorrhage and severe intraventricular hemorrhage), bronchopulmonary dysplasia, retinopathy of prematurity, neonatal mortality, mortality prior to hospital discharge, and bronchopulmonary dysplasia or death. All of these outcomes were analyzed for the entire population of enrolled infants. Data was sought on neurodevelopmental follow-up at 18 to 28 months. This outcome was assessed in survivors only.

The standard methods of the Cochrane Neonatal Review Group Guidelines were employed.

Selection process:

All randomized and quasi-randomized controlled trials fulfilling the selection criteria described in the previous section were included. Both review authors reviewed the results of the search and separately selected the studies for inclusion. The review authors resolved any disagreement by discussion.

Criteria for assessing the methodological quality of the studies:

The standard method of the Cochrane Neonatal Review Group were employed. The methodological quality of the studies will be assessed using the following key criteria: allocation concealment (blinding of randomization), blinding of intervention, completeness of follow-up, and blinding of outcome measurement/assessment. For each criteria, assessment will be yes, no, can't tell. Both review authors separately assessed each study. They resolved any disagreement 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. Any standard error of the mean was replaced by the corresponding standard deviation. We resolved any disagreement by discussion. For each study, final data was entered into RevMan by one reviewer (RS) and then checked by a second reviewer (NS).

Statistical analyses was performed using Review Manager software. Categorical data was analyzed using relative risk (RR), risk difference (RD) and the number needed to treat (NNT). Continuous data was analyzed using weighted mean difference (WMD). The 95% Confidence interval (CI) was reported on all estimates. 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 I-squared statistic. If noted, the possible causes of statistical heterogeneity were explored (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc sub group analyses. We used a fixed effects model for meta-analysis.

Subgroup analyses:
  1. Surfactant product: bovine extract, modified bovine extract, porcine extract, human amniotic fluid extract
  2. Gestational age (infants born at < 30 weeks gestation)
  3. Birtweight (< 1000 g, greater than/or equal to 1000 g)
  4. Moderate to severe respiratory disease (moderate to severe disease defined as need for assisted ventilation and supplemental oxygen greater than 0.60 necessary to maintain adequate oxygenation)

[top]

Results

Description of studies

Studies included in this review include studies of human amniotic fluid surfactant extract (Hallman 1985; Lang 1990), bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Gitlin 1987; Raju 1987; Soll 1988; Horbar 1989; Gortner 1990; Horbar 1990; Liechty 1991; Fujiwara 1990; Chen 1990) and porcine surfactant extract (Svenningsen 1987; European 1988).

Details of each study are given in the table "Characteristics of Included Studies" and references and are discussed below:

Bovine Surfactant Extract:

Gortner 1990: In a multicenter, randomized controlled trial, Gortner and colleagues (Gortner 1990; Gortner 1992 German) studied multiple doses of a bovine lung extract (SF-RI1, Alveofact). Infants between 25 to 30 weeks gestation were enrolled. Although described in the manuscript as a "prevention trial", in fact, infants were eligible only if they were intubated and on assisted ventilation at one hour of life. Thirty-four infants [GA 28.0 ± 1.5 SD weeks, birth weight (BW), 1, 048 ± 299 g] received 50 mg/kg BW surfactant, whereas 35 infants (GA, 27.6 ± 1.5 weeks, BW 969 ± 269 g) served as controls. Retreatment with surfactant (up to three identical doses) 12 - 24 hours after the previous dose was permitted if FiO2 was greater than 0.5. The primary outcomes studied were the effects of surfactant administration on gas exchange and survival without BPD. In addition, Gortner et al investigated the incidence of bronchopulmonary dysplasia, pneumothorax, PIE, intracranial hemorrhage, PDA and the need for its surgical ligation, NEC, pneumonia as well as mortality.

Modified Bovine Surfactant Extract:

Modified Bovine Surfactant Extract - Surfactant TA

Gitlin 1987: Gitlin and coworkers (1987) conducted a prospective, randomized, unblinded, controlled trial of modified bovine surfactant extract (Surfactant TA) in premature infants requiring ventilator support for the treatment of severe hyaline membrane disease. Forty-one low birth weight infants weighing between 1000 - 1500 g with severe hyaline membrane disease (on assisted ventilation and supplemental oxygen > 40%) were randomly assigned to a single dose of surfactant therapy or saline control and treated within eight hours of birth.

Ware and colleagues (1990) reported the results of health and development assessment at one and two years of age in 32 survivors of a total of 41 premature infants enrolled in a randomized clinical trial of bovine surfactant therapy Gitlin 1987.

Raju 1987: Raju and coworkers (1987) conducted a double-blind controlled trial of the effects of a single dose of modified bovine surfactant extract (Surfactant TA) in 30 premature infants (birthweight 751 - 1750 g) with severe hyaline membrane disease. 17 infants had a sonicated saline suspension of 100 mg/kg surfactant phospholipid instilled into the trachea at 5.0 (SD 0.7) hours of age and 13 infants received saline by the same route at 4.3 (1.1) hours of age.

Soll 1988: Soll and coworkers (1988) conducted a small pilot study of modified bovine surfactant extract (Surfactant TA) at five European centers. 31 infants weighing 750 - 1750 g with respiratory distress syndrome requiring assisted ventilation and supplemental oxygen > 40% were enrolled.

Chen 1990: Chen and colleagues (1990) conducted a prospective, randomized, controlled trial to evaluate the efficacy and safety of modified bovine surfactant extract (Surfactant TA) in the treatment of respiratory distress syndrome (RDS). Eighteen premature infants with RDS were studied. Group I consisted of nine premature infants with a mean birth weight of 1, 455 ± 265.9 g and a mean gestational age of 31.4 ± 1.3 weeks. Group II consisted of nine premature infants with a mean birth weight of 1, 411 ± 379.0 g and a mean gestational age of 30.6 ± 1.7 weeks. Reconstituted bovine surfactant (Surfactant TA, Tokyo Tanabe Co., Japan), 120 mg/kg body weight was suspended in 4 ml normal saline and delivered to the lungs of the patients in group I through an endotracheal tube via a catheter in five divided doses (mean age at this point was 5.7 ± 4.5 hours). An air placebo (4 ml per kilogram) was given to the patients in group II.

Fujiwara 1990 conducted a multicenter randomized controlled trial of a modified bovine surfactant extract (Surfactant TA) at 21 centers in Japan. Infants weighing 750 - 1750 g were enrolled if they had RDS requiring assisted ventilation and supplemental oxygen > 40%. Only neonates with surfactant deficiency and without ultrasonographic evidence ofintracranial hemorrhage greater than or equal to grade II were enrolled. Fifty-four patients received a single dose of modified bovine surfactant extract (Surfactant TA 100 mg of phospholipid/kg) and 46 patients received an air placebo within eight hours of life. The severity of RDS was categorized based on radiographic findings and the ventilatory index (VI). In addition, secondary outcome data was collected looking at the impact of surfactant TA use on other common complications of prematurity, such as bronchopulmonary dyplasia, PIE, pneumothorax, intracranial hemorrhage, patent ductus arteriosus and mortality.

Modified Bovine Surfactant Extract- Survanta

Two identical single dose trials of modified bovine surfactant extract (Survanta) in the treatment of established respiratory distress syndrome have been reported (Horbar 1989; Horbar 1990).

Horbar 1989: Horbar and coworkers (1989) conducted a multicenter randomized, placebo-controlled trial to evaluate the efficacy and safety of surfactant in the treatment of respiratory distress syndrome. The study population was made up of 159 premature infants (78 treated and 81 controls) weighing 750 to 1750 g who were receiving assisted ventilation with greater than/or equal to 40% oxygen. The eligible infants received a single dose of either modified bovine surfactant extract [Survanta 100 mg of phospholipid/kg (4 ml per kilogram)] or an air placebo (4 ml/kg), administered into the trachea within eight hours of birth by an investigator not involved in the clinical care of the infant. The study evaluated the effect of a single dose of surfactant on the requirement for supplemental oxygen and clinical status at one week of age. In addition, the study reported on the occurrence of bronchopulmonary dysplasia, PDA, pneumothorax, NEC and periventricular-intraventricular hemorrhage.

Horbar 1990 Horbar and colleagues (Horbar 1990) performed a similar multicenter prospective randomized controlled trial to determine the efficacy and safety of the modified bovine surfactant preparation, Survanta (Abbott Laboratories, Chicago, USA), for 750 - 1750 g infants with respiratory distress syndrome receiving assisted ventilation with greater than/or equal to 40% oxygen. One hundred and six eligible infants from the eight participating centers were randomly assigned between March 1986 and June 1987 to receive either modified bovine surfactant (Survanta 100 mg phospholipid/kg, 4 ml/kg) or air (4 ml/kg) administered into the trachea within eight hours of birth (median time of treatment 6.2 h, range 3.2 - 9.1 h). The study was stopped before enrollment was completed at the request of the United States Food and Drug Administration when significant differences were observed in incidence of periventricular-intraventricular hemorrhage (PIH), between the surfactant treated and control infants.

Liechty 1991: Liechty and colleagues (1991) reported on a large multicenter trial using multiple doses of modified bovine surfactant extract (Survanta) in the treatment of established respiratory distress syndrome. Infants with birthweights between 600 and 1750 g were enrolled if they had respiratory distress syndrome requiring assisted ventilation and supplemental oxygen of 40% or greater. 798 infants (403 treated and 395 controls) were randomized to multiple doses of Survanta or sham air treatment prior to eight hours of age. The primary outcome was the incidence of death secondary to respiratory distress as well as the incidence of death and bronchopulmonary dyplasia. Secondary outcomes included respiratory function and ventilatory requirements, pulmonary air leaks, periventricular/intraventricular hemorrhage, PDA, NEC, PIE, pulmonary hemorrhage, sepsis and rate of infection.

A follow-up study of the Survanta Multidose Study Group published in 1994 reported data on the clinical status of over 900 surviving infants who were subjects in four double-blind, controlled clinical trials on multiple dosing of bovine surfactant in the prevention and treatment of RDS. Health and developmental status was evaluated at 6, 12, and 24 months adjusted age.

Porcine Surfactant Extract:

Svenningsen 1987: Svenningsen and coworkers (1987) studied whether the ventilatory maneuvers associated with surfactant replacement would influence oxygenation in newborn infants with severe respiratory distress syndrome. Eight patients (700 to 1400 g), all requiring mechanical ventilation with fraction of inspired oxygen greater than 0.6, were included in the trial; four were randomized to receive surfactant, and the others served as controls. Porcine surfactant (2 ml/kg; phospholipid concentration, 100 mg/ml) was instilled via a naso-endotracheal tube at end-expiration and dispersed into the lungs during a period of standardized "sighing" mediated by the ventilator: two prolonged ventilatory cycles (10 sec each) with an inspiration/expiration ratio of 4:1, followed by a 6-min ventilation with a frequency of 60 breath/min and an inspiration/expiration ratio of 4:1. Control babies received no surfactant but were otherwise subjected to the same ventilatory maneuvers. Few clinical outcomes were reported.

European 1988. The Collaborative European Multicenter Study Group (European 1988) conducted a randomized multicenter trial of porcine surfactant extract (Curosurf) involving the collaboration of eight European neonatal intensive care units. Infants with birthweight 700 - 2000 g were studied if they had RDS requiring assisted ventilation and supplemental oxygen of > 60%. 146 infants (x surfactant, y control) were randomized to be given either a single large dose of porcine surfactant extract (Curosurf 200 mg/kg) or sham treatment. The median age of treatment was nine hours (range 2 - 15 hours). Average FiO2 before treatment was the same (0.80) for both surfactant-treated patients and control patients.

Robertson and coworkers (1992) examined the postnatal growth, respiratory status, and neurodevelopmental outcome of surviving infants enrolled in a European multicenter trial of porcine surfactant replacement treatment for severe respiratory distress syndrome European 1988. The infants were assessed at corrected ages of one and two years.

Human Amniotic Fluid Surfactant Extract:

Hallman 1985: Hallman and coworkers (1985) performed a randomized, prospective clinical trial comparing intratracheal administration of human amniotic fluid surfactant extract with conventional ventilatory treatment with intermittent mandatory mechanical ventilation alone for treatment of severe respiratory distress syndrome in preterm infants of less than 30 weeks gestation. Fifty-three infants weighing < 1500 g with severe RDS who required assisted ventilation and supplemental oxygen of > 60% were enrolled at two centers. Twenty-two infants (mean gestational age 27.0 weeks, mean birth weight 987 g) were given surfactant, and 23 infants (mean gestational age 27.2 week, mean birth weight 1055 g) received only intermittent mandatory ventilation. Infants were allowed to receive repeat treatments if they still required supplemental oxygen or assisted ventilation.

Vaucher (1988) assessed postnatal growth, neurodevelopmental outcome, and occurrence of respiratory illnesses at 12 to 24 months in 46 infants enrolled in this trial. In a second study published in 1993, Vaucher et al compared the neurodevelopmental outcome of extremely premature infants who received either prophylactic surfactant, rescue surfactant after diagnosis of respiratory distress syndrome, or placebo.

Lang 1990 studied human amniotic fluid extract in a population similar to the infants studied by Hallman 1985. In infants with severe respiratory distress syndrome who were born at 24 to 32 weeks of gestation weighing less than or equal to 1500 g, Lang and colleagues (1990) randomly assigned infants to receive human surfactant derived from amniotic fluid (N = 28) or control treatment (N = 31) within 12 hours of birth. A second dose of surfactant was given to patients in the treatment group if they met ventilator requirements indicating relapse or lack of response to the initial dose.

There are many case series of surfactant treatment of infants with respiratory distress syndrome. These are not listed in the section on excluded studies. Studies in which it was more difficult to determine how treatment assignment was made or had other reasons for exclusion are noted in the table "Characteristics of Excluded Studies".

Risk of bias in included studies

Randomized controlled trials that compared the effect of natural surfactant extract treatment of established respiratory distress syndrome compared to control treatment are included in the analysis. The 12 studies are of high methodological quality. Specific methodological issues are discussed below:

Randomization: All included studies allocated assigned treatment by randomization. In all of the studies, sealed envelopes with randomly allocated treatment assignments were provided to participating centers.

Blinding of the treatment: Approximately half of the studies attempted to blind clinicians from knowing treatment assignment by having the treatment administered by "dosing investigators" who did not participate in the infant's ongoing care or assessment. These studies include Fujiwara 1990; Raju 1987; Soll 1988; Horbar 1989; Horbar 1990.

Blinding of outcome assessment: Investigators who were not involved with treatment assignment or administration assessed the study outcomes.

Exclusions after randomization: Minimal exclusions were noted after randomization. Hallman 1985 excluded eight of the 53 infants initially enrolled due to sepsis or cardiac disease mimicking RDS. Other studies allowed for exclusion of infants with proven sepsis established prior to treatment.

Effects of interventions

ANIMAL DERIVED SURFACTANT EXTRACT VS. CONTROL IN THE TREATMENT OF RESPIRATORY DISTRESS SYNDROME IN NEONATES (Comparison 1):

Multiple randomized controlled trials have demonstrated that animal derived surfactant extract treatment of premature infants with established respiratory distress syndrome improves oxygenation (improved arterial/alveolar oxygen ratio, decreased inspired oxygen concentration) and ventilation (decreased mean airway pressure, improved ventilator efficiency index) during the first 48 - 72 hours of life. These short-term outcomes are not reviewed in the following analysis.

Animal derived surfactant extract treatment of established RDS has the following clinical impact:

Air leak (Outcome 1.1): Studies of bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Horbar 1989; Horbar 1990; Liechty 1991), porcine surfactant extract (European 1988) and human amniotic surfactant extract (Hallman 1985; Lang 1990) all reported on the effect of animal derived surfactant extract on the risk of air leak. Overall, there is a highly significant decrease in the risk of air leak associated with animal derived surfactant extract treatment (typical relative risk 0.47, 95% CI 0.39, 0.58;typical risk difference -0.16, 95% CI -0.21, -0.12). The number needed to treat to prevent one airleak is 6 (95% CI 5, 8). No heterogeneity was noted in the evaluation of these studies (I-squared statistic = 0%).

In the subgroups based on type of animal derived surfactant extract, significant decreases were noted in the risk of air leak in the studies that evaluated modified bovine surfactant extract (typical relative risk 0.44, 95% CI 0.34, 0.58;typical risk difference -0.16, 95% CI -0.20, -0.11), porcine surfactant extract (relative risk 0.60, 95% CI 0.36, 0.99;risk difference -0.16, 95% CI -0.31, -0.01) and human amniotic fluid surfactant extract (typical relative risk 0.45, 95% CI 0.26, 0.78;typical risk difference -0.28, 95% CI -0.44, -0.11).

Pneumothorax (Outcome 1.2): Studies on bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Chen 1990; Fujiwara 1990; Gitlin 1987; Horbar 1989; Horbar 1990; Liechty 1991; Raju 1987; Soll 1988), porcine surfactant extract (European 1988, Svenningsen 1987) and human amniotic fluid surfactant extract (Hallman 1985) all reported on the effect of animal derived surfactant extract treatment on the risk of pneumothorax. Overall, there is a highly significant reduction in the risk of pneumothorax associated with animal derived surfactant extract treatment (typical relative risk 0.42, 95% CI 0.34, 0.52;typical risk difference -0.17, 95% CI -0.21, -0.13). The number needed to treat to prevent one pneumothorax is 6 (95% CI 5, 8).

In the subgroup analyses based on product type, highly significant reductions in the risk of pneumothorax were noted with treatment with modified bovine surfactant extracts (typical risk ratio 0.40, 95% CI 0.32, 0.51;typical risk difference -0.18, 95% CI -0.22, -0.14) as well as the studies of porcine surfactant extract (typical relative risk 0.58, 95% CI 0.34, 1.00;typical risk difference -0.14, 95% CI -0.28, -.01).

Pulmonary interstitial emphysema (Outcome 1.3): Studies with using bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Chen 1990; Fujiwara 1990; Gitlin 1987; Liechty 1991; Raju 1987), porcine surfactant extract (European 1988), and human amniotic surfactant extract (Hallman 1985) reported on pulmonary interstitial emphysema. Overall, there was a highly significant reduction in the risk of pulmonary interstitial emphysema (typical relative risk 0.45, 95% CI 0.37, 0.55;typical risk difference -0.20, 95% CI -0.25, -0.15). The number needed to treat to prevent one case of pulmonary interstitial emphysema is 5 (95% CI 4, 7). Little heterogeneity was noted (I-squared = 5%).

In the subgroup analysis, studies using modified bovine surfactant extract (typical risk ratio 0.43, 95% CI 0.35, 0.54) and the one study using porcine surfactant extract (relative risk 0.60, 95% CI 0.36, 0.99) demonstrated a reduction in the risk of pulmonary interstitial emphysema.

Pulmonary hemorrhage (Outcome 1.4): Fewer studies reported on the effect of animal derived surfactant extract treatment on pulmonary hemorrhage. Only studies using modified bovine surfactant extract treatment prospectively reported on this outcome (Fujiwara 1990; Liechty 1991). In this subgroup of studies, there was no evidence of effect on pulmonary hemorrhage (typical relative risk 1.29, 95% CI 0.77, 2.15; typical risk difference 0.02, 95% CI -0.02, 0.05).

Patent ductus arteriosus (Outcome 1.5): Studies of bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Chen 1990; Fujiwara 1990; Gitlin 1987; Horbar 1989; Horbar 1990; Liechty 1991; Raju 1987; Soll 1988), porcine surfactant extract (European 1988; Svenningsen 1987), and human amniotic fluid surfactant extract (Hallman 1985; Lang 1990) reported on the effect of animal derived surfactant extract treatment on patent ductus arteriosus. In the overall analysis of all studies, no effect was demonstrated (typical relative risk 0.98, 95% CI 0.89, 1.08; typical risk difference -.0.01, 95% CI -0.06, 0.04).

None of the subgroups based on surfactant type demonstrated an impact on the risk of patent ductus arteriosis. Some heterogeneity was noted between the studies (I-squared statistic = 27%).

Necrotizing enterocolitis (Outcome 1.6): Studies of bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Fujiwara 1990, Gitlin 1987, Horbar 1989, Horbar 1990, Liechty 1991, Raju 1987), and human amniotic fluid surfactant extract (Hallman 1985) reported on the risk of necrotizing enterocolitis. Overall, no effect on the risk of necrotizing enterocolitis was demonstrated (typical relative risk 1.13, 95% CI 0.70, 1.82; typical risk difference 0.01, 95% CI -0.02, 0.03).

None of the individual studies of bovine surfactant extract, modified bovine surfactant extract, or human amniotic fluid extract demonstrated an impact on necrotizing enterocolitis).

Sepsis (Outcome 1.7): Fewer studies reported on sepsis in newborns treated with animal derived surfactant extract. One study of bovine surfactant extract (Gortner 1990), two studies of modified bovine surfactant extract (Fujiwara 1990; Liechty 1991), and one study of human amniotic fluid surfactant extract (Hallman 1985) reported on sepsis in these infants. Overall, no impact on the risk of sepsis was demonstrated (typical relative risk 1.14, 95% CI 0.87, 1.48; typical risk difference 0.02, 95% CI -0.02, 0.07). None of the individual studies nor any of the subgroup analyses demonstrated an impact on the risk of sepsis.

Periventricular/intraventricular hemorrhage (Outcome 1.8): Studies of bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Fujiwara 1990; Gitlin 1987; Horbar 1989; Horbar 1990; Liechty 1991; Raju 1987; Soll 1988), porcine surfactant extract (European 1988), and human amniotic fluid surfactant extract (Hallman 1985) reported on the effect of animal derived surfactant extract treatment on periventricular/intraventricular hemorrhage. Overall, no significant effect was noted on the risk of periventricular/intraventricular hemorrhage (typical relative risk 0.97, 95% CI 0.87, 1.07; typical risk difference -0.02, 95% CI -0.07, 0.03). A fair degree of heterogeneity was noted in these studies (I-squared = 65%). Some individual trials demonstrated a decrease in periventricular/intraventricular hemorrhage (Fujiwara 1990) while others demonstrated an increase in risk (Horbar 1990). However, in neither the overall analysis or the analysis by surfactant type were any significant differences noted.

Severe periventricular/intraventricular hemorrhage (Outcome 1.9): Studies of bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Fujiwara 1990; Gitlin 1987; Horbar 1989; Horbar 1990; Liechty 1991; Raju 1987), porcine surfactant extract (European 1988), and human amniotic fluid surfactant extract (Hallman 1985; Lang 1990) all reported on the effect of animal derived surfactant extract treatment on severe periventricular/intraventricular hemorrhage. Overall, no significant impact was noted on severe periventricular/intraventricular hemorrhage (typical relative risk 0.93, 95% CI 0.79, 1.10; typical risk difference -0.02, 95% CI -0.06, 0.02). Although certain individual studies reported on an increase in the risk of severe periventricular/intraventricular hemorrhage (Horbar 1990), the overall analysis and the subgroup analyses do not support a significant increase in the risk of severe periventricular/intraventricular hemorrhage.

Bronchopulmonary dysplasia (Outcome 1.10): Bronchopulmonary dysplasia was defined as a requirement for supplemental oxygen at 28 to 30 days of life. Studies of bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Chen 1990; Fujiwara 1990; Gitlin 1987; Horbar 1989; Horbar 1990; Liechty 1991; Raju 1987; Soll 1988), porcine surfactant extract (European 1988), and human amniotic fluid surfactant extract (Hallman 1985; Lang 1990) all reported on the risk of bronchopulmonary dysplasia. In the overall analysis, no significant impact of animal derived surfactant extract treatment was noted (typical relative risk 0.95, 95% CI 0.84, 1.08;typical risk difference -0.02, 95% CI -0.06, 0.03). The single trial of bovine surfactant extract (Gortner 1990) reported a decrease in the risk of BPD (relative risk 0.21, 95% CI 0.05, 0.87).

Chronic lung disease: No studies reported on the outcome of chronic lung disease (defined as need for supplemental oxygen at 36 weeks postmenstrual age)

Neonatal mortality (Outcome 1.11):Trials of modified bovine surfactant (Chen 1990; Fujiwara 1990; Gitlin 1987; Horbar 1989; Horbar 1990; Liechty 1991; Raju 1987; Soll 1988), porcine surfactant extract (European 1988), and human amniotic fluid surfactant extract (Hallman 1985) all reported on neonatal mortality. Overall, the meta-analysis demonstrates that animal derived surfactant extracts decreased the risk of neonatal mortality (typical relative risk 0.68, 95% CI 0.57, 0.82;typical risk difference -0.09, 95% CI -0.13, -0.05). The number needed to treat to prevent one neonatal death is 11 (95% CI 8, 20). No heterogeneity was noted between these trials.

The individual trial of porcine surfactant extract (European 1988) demonstrated a decrease in the risk of mortality (relative risk 0.61, 95% CI 0.41, 0.92). In the subgroup of trials using modified bovine surfactant extract, a significant decrease in the risk of neonatal mortality was noted (typical relative risk 0.70, 95% CI 0.57, 0.86;typical risk difference -0.08, 95% CI -0.12, -0.03).

Mortality prior to hospital discharge (Outcome 1.12): Trials of bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Chen 1990; Gitlin 1987; Horbar 1989; Raju 1987), and trials of human amniotic fluid surfactant extract (Hallman 1985; Lang 1990) reported on mortality prior to hospital discharge. Overall, a significant decrease in the risk of mortality prior to hospital discharge was noted (typical relative risk 0.63, 95% CI 0.44, 0.90; typical risk difference -0.10, 95% CI -0.18, -0.03). The number needed to treat to prevent one death prior to hospital discharge is 10 (95% CI 6, 33).

None of the individual trials nor the subgroup analyses demonstrated a significant decrease on the risk of mortality prior to hospital discharge.

Reported mortality (Outcome 1.13): Trials of bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Chen 1990; Fujiwara 1990; Gitlin 1987; Horbar 1989; Horbar 1990; Liechty 1991; Raju 1987; Soll 1988), porcine surfactant extract (European 1988; Svenningsen 1987), and human amniotic fluid surfactant extract (Hallman 1985; Lang 1990) all reported mortality at some time during the study or at hospital discharge. Overall, a significant decrease in the risk of mortality was noted (typical relative risk 0.68, 95% CI 0.57, 0.80;typical risk difference -0.10, 95% CI -0.14, -0.06). The number needed to treat to prevent one death is 10 (95% CI 7, 17).

In the subgroup analysis of modified bovine surfactant extract and porcine surfactant extract, overall mortality was noted to be decreased. For modified bovine surfactant extract, the typical relative risk was 0.70 (95% CI 0.57, 0.86);for trials of porcine surfactant extract, the typical relative risk was 0.66 (95% CI 0.45, 0.97).

Bronchopulmonary dysplasia or death (Outcome 1.14): Trials of bovine surfactant extract (Gortner 1990), modified bovine surfactant extract (Chen 1990; Fujiwara 1990; Gitlin 1987; Horbar 1989; Horbar 1990; Liechty 1991; Raju 1987; Soll 1988), porcine surfactant extract (European 1988), and human amniotic fluid surfactant extract (Hallman 1985; Lang 1990) all reported on the combined outcome of bronchopulmonary dysplasia or death. Overall, a significant decrease in the risk of bronchopulmonary dysplasia or death was noted with treatment with animal derived surfactant extract (typical relative risk 0.83, 95% CI 0.77, 0.90; typical risk difference -0.11, 95% CI -0.16, -0.06). The number needed to treat to prevent one infant from either dying or having bronchopulmonary dysplasia is 9 (95% CI 6, 17). A moderate amount of heterogeneity was noted in these studies (I-squared approximately 50%).

The individual trial of bovine surfactant extract (Gortner 1990) demonstrated a decrease in the risk of bronchopulmonary dysplasia or death (relative risk 0.39, 95% CI 0.20, 0.76). The lone trial that reported on bovine surfactant extract (European 1988) also demonstrated a decrease in the risk of bronchopulmonary dysplasia or death (typical relative risk 0.61, 95% CI 0.46, 0.82). The individual trials of Fujiwara (Fujiwara 1990) and Liechty (Liechty 1991) both showed a decrease in the risk of bronchopulmonary dysplasia or death with modified bovine surfactant extract. In the subgroup analysis of all trials with modified bovine surfactant extract, a decrease in the risk of bronchopulmonary dysplasia or death was noted (typical relative risk 0.89, 95% CI 0.82, 0.97;typical risk difference -0.07, 95% CI -0.12, -0.02).

Retinopathy of prematurity (Outcome 1.15): Studies of modified bovine surfactant extract (Fujiwara 1990; Gitlin 1987; Raju 1987) and studies of human amniotic fluid surfactant extract (Hallman 1985) reported on retinopathy of prematurity. None of the individual trials nor the meta-analysis demonstrated an impact on retinopathy of prematurity. The overall estimate from the trials is still broad and consistent with a significant worsening or a significant improvement in retinopathy of prematurity (typical relative risk 0.77, 95% CI 0.41, 1.44;typical risk difference -0.04, 95% CI -0.14, 0.05).

Severe retinopathy of prematurity (Stage 3 or greater) (Outcome 1.16): Few studies reported on severe retinopathy of prematurity. In a study of modified bovine surfactant extract, Raju and coworkers (Raju 1987) reported a non-significant increase in the risk of retinopathy of prematurity (relative risk 1.53, 95% CI 0.15, 15.09). In a study of human amniotic fluid surfactant extract, Lang and coworkers (Lang 1990) reported a non-significant risk increasing the risk of retinopathy of prematurity (relative risk 1.11, 95% CI 0.07, 16.88). The meta-analysis including these two studies demonstrates no significant impact of animal derived surfactant extract on severe retinopathy of prematurity (typical relative risk 1.34, 95% CI 0.23, 7.67;typical risk difference 0.02, 95% CI -0.08, 0.11).

Cerebral palsy (Outcome 1.17):Only one follow up study reported on the incidence of cerebral palsy. The European Collaborative Study (European 1988) reported on one and two year follow-up (Robertson 1992). No difference in the risk of cerebral palsy is noted in this study (relative risk 0.88, 95% CI 0.34, 2.27; risk difference -0.03, 95% CI -0.21, 0.16).

Visual impairment in survivors (Outcome 1.18): No studies reported on visual impairment as defined in the review protocol (visual acuity < 2/200). Two studies reported on visual impairment (undefined) (European 1988; Gitlin 1987). One study of modified bovine surfactant extract (Gitlin 1987) demonstrated a non-significant reduction in visual impairment in survivors (relative risk 0.38, 95% CI 0.02, 8.59). The one study of porcine surfactant extract (European 1988) did not show any impact on visual impairment. No infants were reported in either group (relative risk not estimable;risk difference 0.00, 95% CI -0.04, 0.04). The meta-analysis does not suggest any effect of animal derived surfactant on visual impairment in survivors (typical relative risk 0.38, 95% CI 0.02, 8.59; typical risk difference -0.02, 95% CI -0.08, 0.05).

Major developmental disability in survivors (Outcome 1.19): No studies reported on major neurodevelopmental disability in survivors as defined in the review protocol. The European study (European 1988) reported on major neurodevelopmental disabilty defined as severe forms of cerebral palsy, blindness, deafness requiring hearing aids or a Griffiths Developmental Quotient < 70. There is no evidence of an effect on major neurodevelopmental disabilty. Given the small sample size, the estimate is extremely imprecise (relative risk 3.30, 95% CI 0.41, 26.78; risk difference 0.08, 95% CI -0.04, 0.19).

ANIMAL DERIVED SURFACTANT EXTRACT TREATMENT OF RESPIRATORY DISTRESS SYNDROME (INFANTS < 1000 g) (Comparison 2):

Few studies reported on the subset of infants < 1000 g.

Bronchopulmonary dysplasia (Outcome 2.1): Only the study Liechty (Liechty 1991) using a modified bovine surfactant extract reported on bronchopulmonary dysplasia in infants < 1000 g. No statistically significant impact was noted on the risk of bronchopulmonary dysplasia (relative risk 1.1, 95% CI 0.92, 1.33;risk difference 0.06, 95% CI -0.04, 0.15).

Neonatal Mortality (Outcome 2.2): Only one study reported on neonatal mortality in infants < 1000 g (Liechty 1991). In this study of a modified bovine surfactant extract, mortality in infants < 1000 g was noted to decrease (relative risk 0.75, 95% CI 0.57, 0.98;risk difference -0.10, 95% CI -0.19, -0.01).

Reported mortality (Outcome 2.3): Three studies reported on mortality in the subset of infants < 1000 g;two studies of modified bovine surfactant extract (Liechty 1991; Raju 1987) and one small study of porcine surfactant extract (Svenningsen 1987). The study of modified bovine surfactant by Liechty (Liechty 1991) demonstrated a decrease in the risk of mortality (relative risk 0.75, 95% CI 0.57, 0.98;risk difference -0.10, 95% CI -0.19, -0.01). The study by Raju 1987 had a trend towards decreased mortality that was not statistically significant. In the meta-analysis of these two studies, a significant decrease in the risk of mortality is noted (typical relative risk 0.73, 95% CI 0.56, 0.95;typical risk difference -0.11, 95% CI -0.20, -0.02). The one study of porcine surfactant extract by Svenningsen (Svenningsen 1987) did not show a difference in mortality in the few patients studied. Overall, the meta-analysis in this subgroup supports a reduction in the risk of mortality in infants < 1000g (typical relative risk 0.75, 95% CI 0.58, 0.97;typical risk difference -0.10, 95% CI -0.19, -0.01).

Bronchopulmonary dysplasia or death (Outcome 2.4): Only this study of modified bovine surfactant published by Liechty and colleagues (Liechty 1991) reported on the combined outcome of bronchopulmonary dysplasia or death in infants < 1000 g. There is a trend towards reduced risk of BPD or death in this population, athough it did not reach statistical significance (relative risk 0.95, 95% CI 0.89, 1.02;risk difference -0.04, 95% CI -0.11, 0.02).

ANIMAL DERIVED SURFACTANT EXTRACT TREATMENT OF RESPIRATORY DISTRESS SYNDROME (INFANTS greater than/or equal to 1000 g) (Comparison 3):

Few studies reported clinical outcome data restricted to infants greater than/or equal to1000 g.

Pneumothorax (Outcome 3.1): Two studies report on the risk of pneumothorax in infants greater than/or equal to 1000 g. In the study of Fujiwara (Fujiwara 1990), an infant who got modified bovine surfactant extract had a significantly decreased risk of pneumothorax (relative risk 0.16, 95% CI 0.04, 0.66;risk difference -0.35, 95% CI -0.57, -0.13). In the small study of porcine surfactant extract done by Svenningsen (Svenningsen 1987), no difference in the rate of pneumothorax could be demonstrated. In the combined analysis of these two studies, there is a significant decrease in the risk of pneumothorax associated with animal derived surfacatnt treatment in infants greater than/or equal to1000 g (typical relative risk 0.16, 95 CI 0.04, 0.66;typical risk difference -0.33, 95% CI -0.55, -0.12).

Pulmonary Interstitial Emphysema (Outcome 3.2): Only the study of modified surfactant extract done by Fujiwara and colleagues (Fujiwara 1990) reported on the risk of pulmonary interstitial emphysema in infants greater than/or equal to1000 g. There was a trend towards less pulmonary interstitial emphysema in infants greater than/or equal to 1000 g who received modified bovine surfactant extract (relative risk 0.07, 95% CI 0.00, 1.26;risk difference, -0.21, 95% CI -0.38, -0.04).

Pulmonary Hemorrhage (Outcome 3.3): Only the study Fujiwara and colleagues (Fujiwara 1990) reported on the risk of pulmonary hemorrhage in infants greater than/or equal to 1000 g birth weight. In this small number of patients, no difference in the risk of pulmonary hemorrhage risk was noted (relative risk 5.65, 95% CI 0.31, 104, 104.25;risk difference 0.10, 95% CI -0.02, 0.22).

Patent Ductus Arteriosis (Outcome 3.4): Two studies reported on the risk of patent ductus arteriosis associated with animal derived surfactant treatment. In one study of modified bovine surfactant extract, Fujiwara and colleagues (Fujiwara 1990) showed no difference in the risk of patent ductus arteriosis (relative risk 1.16, 95% CI 0.60, 2.23;risk difference 0.06, 95% CI, -0.20, 0.32). In a small study of porcine surfactant extract, Svenningsen and colleagues (Svenningsen 1987) demonstrated no difference in the risk of patent ductus arteriosis (relative risk 2.25, 95% CI 0.13, 38.09;risk difference 0.33, 95% CI, -0.30, 0.97). In a meta-analysis including these two small studies, no difference in the risk of patent ductus arteriosis was noted (typical relative risk 1.21, 95% CI 0.64, 2.31;typical risk difference 0.08, 95% CI -0.17, 0.33).

Necrotizing Enterocolitis (Outcome 3.5): Only Fujiwara and colleagues (Fujiwara 1990) reported on the risk of necrotizing enterocolitis in this population. No cases of necrotizing enterocolitis were identified in either group (risk difference 0.00, 95% CI -0.07, 0.07).

Sepsis (Outcome 3.6): Only the study of Fujiwara reported on sepsis in infants with birth weight greater than/or equal to 1000 g. No cases of septic infants were identified. No difference in the risk of sepsis was noted (risk difference 0.00, 95% CI -0.07, 0.07).

Periventricular Intraventricular Hemorrhage (Outcome 3.7): Fujiwara and coworkers (Fujiwara 1990) reported on the risk of periventricular intraventricular hemorrhage in infants with birth weight greater than/or equal to 1000 g. No significant difference was noted in the risk of periventricular intraventricular hemorrhage (relative risk 0.71, 95% CI 0.32, 1.56;risk difference -0.11, 95% CI -0.36, 0.14).

Severe Periventricular Intraventricular Hemorrhage (Outcome 3.8): Fujiwara also reported on the risk of severe periventricular intraventricular hemorrhage (defined as grade 3 or 4 intraventricular hemorrhage) in infants greater than/or equal to 1000 g. In his study of modified bovine surfactant extract, Fujiwara did not identify any difference in the risk of severe periventricular intraventricular hemorrhage (relative risk 1.07, 95% CI 0.26, 4.31;risk difference, 0.01, 95% CI -0.17, 0.19).

Bronchopulmonary Dysplasia (Outcome 3.9): Two studies of modified bovine surfactant extract reported on the risk of bronchopulmonary dysplasia (Fujiwara 1990; Liechty 1991). Neither study individually demonstrated a statistically significant decrease in the risk of bronchopulmonary dysplasia. The combined analysis of the two studies does not demonstrate a statistically significant decrease in the risk of bronchopulmonary dysplasia associated with animal derived surfactant extract treatment in this larger population of babies (typical relative risk 0.88, 95% CI 0.69, 1.13;typical risk difference -0.04, 95% CI, -0.13, 0.04).

Neonatal Mortality (Outcome 3.10): Two studies of modified bovine surfactant extract reported on neonatal mortality (Fujiwara 1990, Liechty 1991). The study of Liechty and coworkers (Liechty 1991) demonstrated a statistically significant decrease in the risk of neonatal mortality (relative risk 0.44, 95% CI 0.24, 0.81;risk difference -0.09, 95% CI -0.15, -0.02). In the meta-analysis of these two studies, a significant decrease in neonatal mortality is noted (typical relative risk 0.54, 95% CI 0.30, 0.95;typical risk difference -0.06, 95% CI -0.12, -0.01).

Reported Mortality (Outcome 3.11): Four studies reported mortality in infants treated with animal derived surfactant extract treatment who weighed more than 1000 g. In the three studies of modified bovine surfactant extract, only the study of Liechty and colleagues (Liechty 1991) demonstrated a decrease in reported mortality. The subgroup analyses that includes all three of these studies shows a significant decrease in the risk of overall mortality (typical relative risk 0.51, 95% CI 0.29, 0.88;typical risk difference -0.07, 95% CI, -0.13, -0.02). The small study of Svenningsen and colleagues (Svenningsen 1987), using porcine surfactant extract, reported no difference in mortality. The overall analysis including all studies supports a reduction in risk of mortality in these larger infants treated with animal derived surfactant extract (typical relative risk 0.54, 95% CI 0.32, 0.90;typical risk difference -0.07, 95% CI, -0.13, -0.01).

Bronchopulmonary Dysplasia or Death (Outcome 3.12): Two studies of modified bovine surfactant reported on the combined outcome of bronchopulmonary dysplasia or death in infants greater than/or equal to 1000 g at birth (Fujiwara 1990; Liechty 1991). Only the study of Liechty demonstrated significant reduction in the combined risk of BPD or death. In the combined analysis of these two studies, a significant reduction in BPD or death in these larger babies is noted (typical relative risk 0.73, 95% CI 0.60, 0.88;typical risk difference -0.15, 95% CI -0.24, -0.06).

Retinopathy of Prematurity (Outcome 3.13): Only the study of Fujiwara (Fujiwara 1990) reported on the risk of retinopathy of prematurity in these larger babies. There was no statistically significant difference in risk noted (relative risk 0.53, 95% CI 0.10, 2.94;risk difference -0.06, 95% CI -0.22, 0.10).

Discussion

Thirteen randomized controlled trials were identified that compared animal derived surfactant extract (ADSE) treatment of established respiratory distress syndrome to control treatment. A variety of animal derived surfactant products were tested. Since investigators were treating infants with clinical signs and symptoms of respiratory distress syndrome, a broad range of gestational ages and birthweights are included. Age at enrollment and dosing schedules also varied between studies. The larger studies all report improvement in the immediate respiratory course. In the studies of all ADSE there are reports of improvement in oxygenation and ventilatory requirements in the 48 to 72 hours after treatment.

The meta-analysis suggests that animal derived surfactant extract treatment of established respiratory distress syndrome leads to a significant decrease in the risk of pneumothorax, pulmonary interstitial emphysema, mortality and the combined outcome death or bronchopulmonary dysplasia. The meta-analysis suggests that for every 100 infants given animal derived surfactant extract for the treatment of established respiratory distress syndrome, there will be six fewer pneumothoraces, five fewer cases of pulmonary interstitial emphysema, ten fewer deaths, and nine fewer cases of death or bronchopulmonary dysplasia.

Statistical heterogeneity was noted in the analyses of the effect of animal derived surfactant extract treatment on periventricular/intraventricular hemorrhage (PIH) and bronchopulmonary dysplasia. Individual studies suggested that there may be an increase in the risk of intraventricular hemorrhage associated with animal derived surfactant treatment (Horbar 1990). However, this is not supported in the meta-analysis. It is difficult to speculate regarding the source of the heterogeneity regarding the effect on PIH. It does not appear to be related to the specific modified surfactant preparation used. Perhaps aspects of administration and early ventilator weaning practices might have led to cardiovascular instability that contributed to the increased rate of PIH in certain studies. The source of the heterogeneity in the analysis of BPD is difficult to determine. Differences in the various surfactant preparartions could theoretically be the source of this heterogeneity.

Unlike the trials of prophylactic synthetic surfactant (Soll 1998a), no increase in the risk of patent ductus arteriosus and no increase in the risk of pulmonary hemorrhage was demonstrated. In animals treated with surfactant products, earlier and more severe shunting through the patent ductus arteriosus has been noted. Pulmonary hemorrhage is thought to occur as a consequence of massive ductal shunting. Although not reported in the randomized controlled trials of synthetic surfactant treatment of established respiratory distress syndrome, pulmonary hemorrhage was addressed retrospectively in analyses by Raju (1993). The risk of pulmonary hemorrhage appears to occur with both synthetic surfactant products and animal derived surfactant extracts. In clinical practice, pulmonary hemorrhage may be preventable by aggressive treatment of the patent ductus arteriosus and appropriate ventilator management. No other side effects of animal derived surfactant extract treatment were reported.

The trials included in this review compared animal derived surfactant extract treatment of established respiratory distress syndrome with no surfactant treatment. After the demonstration of the efficacy of surfactant in both preventing and treating respiratory distress syndrome, trials were conducted which compared the policies of prophylactic surfactant administration in infants at risk of RDS with selective treatment of infants who develop RDS. These trials were conducted using animal derived surfactant extract preparations. In these studies, prophylactic animal derived surfactant extract was noted to be superior to late selective treatment of babies with established RDS (Soll 1997a).

Studies have also evaluated the differences between synthetic surfactant and animal derived surfactant extract. These trials were only done in the context of treating established respiratory distress syndrome. In these studies, the use of animal derived surfactant extract appears superior in decreasing the risk of pneumothorax and increasing survival (Soll 1997b).

Authors' conclusions

Implications for practice

Animal derived surfactant extract treatment of infants with established respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants with established RDS who received animal derived surfactant extract treatment have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, a decreased risk of intraventricular hemorrhage, a decreased risk of bronchopulmonary dysplasia, a decreased risk of neonatal mortality, a decreased risk of mortality prior to hospital discharge and at one year of age. Animal derived surfactant extract treatment of established respiratory distress syndrome may lead to an increase in intraventricular hemorrhage. However, this complication does not overshadow the positive impact on outcome (including reductions in neonatal mortality and late mortality).

Implications for research

Animal derived surfactant extract treatment of established respiratory distress syndrome has been proven to improve clinical outcome. Further placebo controlled trials of animal derived surfactant extract are no longer warranted. Trials which compared the prophylactic treatment strategy to treatment of established disease have been tested using animal derived surfactant extract (see review: Prophylactic Surfactant vs. Treatment with Surfactant). Trials which have compared currently available synthetic surfactant to animal derived surfactant extract have been conducted. Overview analysis of these trials suggests that animal derived surfactant extract may be preferred to synthetic surfactant due to the decreased risk of pneumothorax associated with animal derived surfactant extract treatment (see review: Animal Derived Surfactant Extract vs. Synthetic Surfactant). New formulations of synthetic surfactants, such as lucinactant, are promising and warrant further evaluation (Pfister 2007).

Acknowledgements

We would like to thank Susan Hayward for help in preparation of the manuscript.

Contributions of authors

N. Seger and R. Soll searched the literature, excerpted data, wrote the text.

Declarations of interest

Dr. R. Soll has acted as a consultant and invited speaker for several of the pharmaceutical companies that manufacture surfactant preparations (Abbott Laboratories, Ross Laboratories, Chiese Pharmaceuticals, Dey Laboratories, Burroughs Wellcome).
N. Seger has no conflict of interest to report.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

[top]

Characteristics of studies

Characteristics of Included Studies

Chen 1990

Methods

Randomized

Single center

Blinding of randomization: Not described

Blinding of intervention: Not described

Complete Follow-up: Short-term: Yes; Long-term: No

Blinding of outcome measurement: Not described

Stratification: No

Participants

Participants: Premature neonates

Birthweight between 900 and 1950 g

Clinical and radiological findings consistent with RDS

Surfactant deficiency based on Pattle’s micro-bubble stability test or shake test

Mechanical ventilation

Interventions

Intervention: beractant [Surfactant TA (120mg/kg)] versus air placebo

Single dose

Infants Randomized:

Surfactant TA = 9; Control = 9

Outcomes

PRIMARY OUTCOMES:

Oxygenation

Need for ventilatory support

SECONDARY OUTCOMES:

Bronchopulmonary dysplasia

Pulmonary interstitial emphysema

Pneumothorax

Patent ductus arteriosus

Mortality

Notes
Risk of bias table

European 1988

Methods

Randomized

Multicenter

Blinding of randomization: Yes (sealed envelopes)

Blinding of intervention: No

Complete Follow-up: Short-term: Yes; Long-term: Yes
(reported by Collaborative European Multicenter Study Group 1992: Neurological assessment and examination at 1 and 2 years corrected age; formal developmental assessment using the Griffiths Scale was performed as possible)

Blinding of outcome measurement: Not reported

Stratification: Based on birthweight

Participants

Participants: Neonates

Birthweight between 700 and 2000 gm

Clinical and radiological findings consistent with RDS

Requiring assisted ventilation

FiO2 greater than/or equal to 0.6

No complicating disease

No prolonged rupture of membranes

No intraventricular hemorrhage of grade III to IV at randomization

No birth asphyxia as indicated by early onset seizures

No major congenital anomalies (including chromosomal aberrations, cardiovascular malformations, Potter syndrome, myelomeningocele)

No streptococcal infection (gastric aspirates tested)

Treated with surfactant/placebo between 2 and 15 hours of life

Interventions

Intervention: poractant (Curosurf) 200 mg/kg

Single dose

No placebo was administered

Infants Randomized: Curosurf = 77; Control = 69

Outcomes

PRIMARY OUTCOMES:

Oxygenation

Duration of artificial ventilation

Neonatal mortality

SECONDARY OUTCOMES:

Pulmonary function in terms of oxygenation, ventilation and compliance

Intracerebral hemorrhage

Patent ductus arteriosus

Pulmonary interstitial emphysema

Pneumothorax

Bronchopulmonary dysplasia

Notes
Risk of bias table

Fujiwara 1990

Methods

Randomized

Multicenter

Blinding of randomization: Yes (opaque, sealed envelopes)

Blinding of intervention: Yes (drug administration team)

Complete Follow-up: Short-term: Yes; Long-term: No

Blinding of outcome measurement: Yes

Stratification: Based on birthweight

Participants

Participants: premature neonates

Birthweight between 750 and 1749 g

Clinical and radiological findings consistent with RDS

Surfactant deficiency based on micro-bubble rating test

Assisted ventilation

Mean airway pressure > 7 cm H2O after initial stabilization

FiO2 > 0.4 after initial stabilization

Admission within 6 hours of birth with arterial line within 8 hours of birth

No IVH > Grade II on initial CUS

No PIE > Grade II or pneumothorax on initial CXR

No congenital infection

No congenital heart disease

No multiple malformation or status deemed incompatible with life

Interventions

Infants randomized:

Surfactant TA = 54

Control = 46

Interventions: Intratracheal surfactant TA (100 mg phospholipid/kg) or air placebo (4 ml/kg)

No repeat doses were given

Outcomes

PRIMARY OUTCOME:

Severity of RDS based on ventilatory index (VI) and radiographic findings

SECONDARY OUTCOMES:

Bronchopulmonary dysplasia

Pulmonary interstitial emphysema

Pneumothorax

Intracranial hemorrhage

Patent ductus arteriosus

Mortality

Notes
Risk of bias table

Gitlin 1987

Methods

Randomized

Multicenter

Blinding of randomization: Yes (sealed envelopes)

Blinding of intervention: No

Complete Follow-up: Short-term: Yes; Long-term: Yes (reported by Ware 1990: Examination, history review and cognitive/motorassessment using Bayley Scales of Development at 11-13 and 23-25 months corrected age)

Stratification: No

Participants

Neonates

Birthweight between 1000-1500 g (appropriate for gestational age)

Clinical and radiological findings consistent with RDS

Assisted ventilation

FiO2 > 0.4 to maintain arterial PaO2 > 50 mm Hg

Treated by 8 hours of life

Interventions

Intervention: Surfactant TA (100mg/kg) versus sterile saline

Single dose

Infants Randomized: Surfactant TA = 18; Control = 23

Outcomes

PRIMARY OUTCOMES:

Oxygenation

Mean airway pressure required

SECONDARY OUTCOMES:

Days FiO2 > 0.4

Days in oxygen

Days to extubation

Bronchopulmonary dysplasia

Mortality

Pulmonary interstitial emphysema

Pneumothorax

Intracranial hemorrhage

Hydrocephalus

Patent ductus arteriosus

Necrotizing enterocolitis

Retinopathy of prematurity

Notes
Risk of bias table

Gortner 1990

Methods

Randomized

Multicenter

Blinding of randomization: Yes (random permuted blocks)

Blinding of intervention: Yes (dosing investigator)

Complete Follow-up: Short-term: Yes; Long-term: No

Blinding of outcome measurement: Yes

Stratification: Based on gestational age

Participants

Neonates

Gestational age 25 to 30 weeks

assisted ventilation

age less than/or equal to 1hour of life

No congenital bacterial sepsis or pneumonia

No oligohydramnios for more than 3 weeks

No major congenital malformations

Interventions

SF-RI (bovine lung extract) (50mg/kg) vs. saline

Multiple doses: Retreatment with identical doses if FiO2 > 0.5 or PIP > 22 cm H2O for infants 25-26 weeks, 25 cm H2O for infants 27-28 weeks and 28 cm H2O for infants 29-30 weeks GA

Infants Randomized: Bovine surfactant = 34; Control = 35

Outcomes

PRIMARY OUTCOMES:

Oxygenation

Ventilatory support

SECONDARY OUTCOMES:

Bronchopulmonary dysplasia

Pulmonary interstitial emphysema

Pneumothorax/ air leak syndrome

Intracranial hemorrhage

Patent ductus arteriosus

Necrotizing enterocolitis

Nosocomial infections

Notes

Participants

Risk of bias table

Hallman 1985

Methods

Randomized

Bicenter

Blinding of randomization: Yes (sealed envelopes)

Blinding of intervention: No

Complete Follow-up: Short-term: Yes; Long-term: Yes (reported by Vaucher 1988: Assessments at 6-8, 12, 18 and 24 months corrected age, as well as at 36 and 48 months chronological age. Examinations were performed using the Amiel-Tison at 12 months, the Knoblauch-Gesell Developmental Screening Inventory, the Bayley Scales of Infant Development, or Griffith’s scale at 12-36 months, and the Stanford-Binet test at 36-48 months)

Blinding of outcome measurement: No

Stratification: No

Participants

Neonates

Birthweight less than/or equal to 1500 g

Clinical and radiological findings consistent with severe RDS

FiO2 greater than/or equal to 0.6 to sustain PaO2 greater than/or equal to 50 torr

Intermittent mandatory ventilation with PIP 18-25 cm H2O, PEEP 2-4 cm H2O, and ventilatory rates 30 to 40 cpm, with resulting mean airway pressure of 8-10 cm H2O within 6 hours of life

Phospholipid analysis consistent with lung immaturity (retrospective)

Absence of bacteria on gram stain of tracheal aspirate

age less than/or equal to ten hours of life

Interventions

Human Amniotic Fluid Surfactant Extract (60 mg/kg, 60mg minimum dose)

Multiple dose: retreatment was possible if FiO2 was 0.5 to 0.8 in order to maintain PaO2 > 50 torr

No placebo was administered

Infants Randomized: Human Surfactant = 22; Control = 23

Outcomes

PRIMARY OUTCOME:

Pulmonary function

SECONDARY OUTCOMES:

Mortality

Bronchopulmonary dysplasia

Pulmonary interstitial emphysema

Pneumothorax

Intraventricular hemorrhage

Patent ductus arteriosus

Sepsis

Retinopathy of prematurity

Necrotizing enterocolitis

Notes
Risk of bias table

Horbar 1989

Methods

Randomized

Multicenter

Blinding of randomization: Yes (opaque, sealed envelopes)

Blinding of intervention: Yes (Drug administration team)

Complete Follow-up: Short-term: Yes;
Long-term: Yes (reported by Survanta Multidose Study Group 1994: Data on clinical status were for surviving infants at hospital discharge and at 6, 12, and 24months of adjusted age.)

Blinding of outcome measurement: unclear (weaning of vent done by care team)

Stratification: Based on birthweight

Participants

Neonates

Birthweight between 750 and 1750 gm

Birth at participating center

Diagnosis of RDS between three and six hours of life based on clinical and radiographic findings

Assisted ventilation

FiO2 greater than/or equal to 0.4 with arterial oxygen tension less than/or equal to 10.6 kPa (80 mm Hg)

Patent postductal arterial catheter

Normal blood pressure

Blood glucose level greater than/or equal to 2.2 mmol per liter (40 mg per deciliter)

Absence of seizure at study entry

No major congenital malformations

No pulmonary air leak on initial chest x-ray

No congenital infection

Interventions

Intratracheal administration of modified bovine surfactant extract (Survanta 4 ml/kg) or 4 ml/kg of air placebo.

Infants Randomized: Survanta = 78; Control = 81

Outcomes

PRIMARY OUTCOMES:

Ventilatory/oxygen requirement

Mortality

SECONDARY OUTCOMES:

Bronchopulmonary dysplasia

Pulmonary air leaks

Periventricular/ intraventricular hemorrhage

Patent ductus arteriosus

Necrotizing enterocolitis

Notes
Risk of bias table

Horbar 1990

Methods

Randomized

Multicenter

Blinding of randomization: Yes (opaque, sealed envelopes)

Blinding of intervention: Yes (dosing investigator)

Complete Follow-up: Short-term: Yes; Long-term: No

Blinding of outcome measurement: Yes

Stratification: based on birthweight

Participants

Neonates

Birthweight between 750 and 1750 gm

Diagnosis of RDS between three and six hours of life based on clinical and radiographic findings

Assisted ventilation

FiO2 greater than/or equal to0.4

Arterial catheter

Normal blood pressure

Blood glucose level greater than/or equal to 40 mg per deciliter

Absence of seizure at study entry

No major congenital malformations

No pulmonary air leak on initial chest x-ray

No maternal use of IV narcotics during pregnancy

Interventions

Intratracheal administration of modified bovine surfactant extract (Survanta 4 ml/kg) or 4 ml/kg of air placebo

Infants Randomized: Survanta = 53; Control = 53

Outcomes

PRIMARY OUTCOMES:

Ventilatory/oxygen requirement

Mortality

SECONDARY OUTCOME:

Bronchopulmonary dysplasia

Pulmonary air leaks

Periventricular/ intraventricular hemorrhage

Patent Ductus Arteriosus

Necrotizing enterocolitis

Notes
Risk of bias table

Lang 1990

Methods

Randomized

Bicenter

Blinding of randomization: Yes (sealed opaque envelopes)

Blinding of intervention: No

Complete Follow-up: Short-term: Yes; Long-term: No

Blinding of outcome measurement: Not reported

Stratification: No

Participants

Premature neonates

Gestational age 24 to 32 weeks

Birthweight less than/or equal to1500g

Severe RDS based on clinical and radiographic criteria

Intubation and mechanical ventilation

PIP >18 cm H2O and FiO2 > 0.8 needed to produce arterial oxygen pressure > 15 torr

No suspected pneumonia or sepsis

No major congenital malformations

No hydrops fetalis

No preexisting pulmonary leak

Age less than/or equal to12 hours of life

Interventions

Human Amniotic Fluid Surfactant Extract 70 mg/kg (70 mg minimum dose)

Multiple doses: Retreatment dose given if FiO2 > 0.8, PIP increased> 5 cm H2O or MAP increased > 2 cm H2O in order to maintain PaO2 > 5 torr.

No placebo was administered

Infants randomized: Human Surfactant = 29; Controls = 31

Outcomes

PRIMARY OUTCOME:

Mortality

SECONDARY OUTCOMES:

Bronchopulmonary dysplasia

Intraventricular hemorrhage

Patent ductus arteriosus

Retinopathy of prematurity

Pulmonary air leak

Pulmonary function

Notes
Risk of bias table

Liechty 1991

Methods

Randomized

Multicenter

Blinding of randomization: not reported

Blinding of intervention: Yes (treatment administration team)

Complete Follow-up: Short-term: yes; Long-term: No (pending)

Blinding of outcome measurement: Yes

Stratification: based on birthweight

Participants

Neonates

Birthweight between 600 and 1750 g

RDS

Assisted ventilation

FiO2 greater than/or equal to 0.4, producing PaO2 less than/or equal to 10.6 kPa (80 mm Hg) between 1 and 6 hours of life

Patent postductal arterial catheter

Normotensive

Normoglycemic

Absence of seizure at study entry

No major congenital malformations

No pulmonary air leak on initial chest x-ray

Interventions

Intratracheal administration of modified bovine surfactant extract (Survanta100 mg phospholipid/kg).

Multiple dose: Repeat doses as clinically indicated -up to four doses total within the first 48 hrs of life

No placebo was administered

Infants Randomized: Survanta = 402; Control = 396

Outcomes

PRIMARY OUTCOMES:

Ventilatory/oxygen requirement

Mortality

SECONDARY OUTCOMES:

Bronchopulmonary dysplasia

Pulmonary air leaks

Periventricular/ intraventricular hemorrhage

Patent ductus arteriosus

Necrotizing enterocolitis

Notes

PRIMARY OUTCOMES:

Ventilatory/oxygen requirement

Mortality

SECONDARY OUTCOMES:

Bronchopulmonary dysplasia

Pulmonary air leaks

Periventricular/ intraventricular hemorrhage

Patent ductus arteriosus

Necrotizing enterocolitis

Risk of bias table

Raju 1987

Methods

Randomized

Single Center

Blinding of randomization: randomized stratification scheme

Blinding of intervention: Yes (Drug administration team)

Complete Follow-up: Short-term: Yes; Long-term: No

Blinding of outcome measurement: Yes

Stratification: based on gender and birthweight

Participants

Neonates

Birthweight between 751-1750 g

Clinical and radiological findings consistent with severe RDS

Assisted ventilation

Minimum FiO2 of 0.5 and 8 cm H2O mean airway pressure

Poor oxygenation with alveolar PO2 ratio of 0.24

Age less than 6 hours

No major malformations

No karyotype abnormalities

Age less than 6 hours

No major malformations

No karyotype abnormalities

Interventions

Intratracheal administration of modified bovine surfactant extract (surfactant TA 100 mg/kg in 3.3 ml of saline) or physiological saline (1 ml/kg with maximum dose of 1 ml)

Infants Randomized: Surfactant TA = 17; Control = 13

Outcomes

PRIMARY OUTCOMES:

Mortality

Ventilatory course

SECONDARY OUTCOMES:

Bronchopulmonary dysplasia

Pulmonary interstitial emphysema

Pneumothorax

Intracranial hemorrhage

Patent ductus arteriosus

Apnea of prematurity

Necrotizing enterocolitis

Retinopathy of prematurity

Seizures

Age at discharge

Notes
Risk of bias table

Soll 1988

Methods

Randomized

Multicenter

Blinding of randomization: Yes (opaque, sealed envelopes)

Blinding of intervention: Yes

Complete Follow-up: Short-term: Yes; Long-term: No

Blinding of outcome measurement: Yes

Stratification: based on birthweight

Participants

Neonates

Birthweight between 750 and 1750 g

Diagnosis of RDS between three and six hours of life based on clinical and radiographic findings

Assisted ventilation

FiO2 greater than/or equal to 0.4

Arterial catheter

Normal blood pressure

Blood glucose level greater than/or equal to 40 mg per deciliter

Absence of seizure at study entry

No major congenital malformations

No pulmonary air leak on initial chest x-ray

No maternal use of IV narcotics during pregnancy

Interventions

Intratracheal administration of modified bovine surfactant extract (Surfactant TA 100 mg/kg) or 4 ml/kg of air placebo

Infants Randomized (N 31): Surfactant TA = 17; Control = 14

Outcomes

PRIMARY OUTCOMES:

Ventilatory/oxygen requirement

Mortality

SECONDARY OUTCOMES:

Bronchopulmonary dysplasia

Pulmonary air leaks

Periventricular/ intraventricular hemorrhage

Patent ductus arteriosus

Necrotizing enterocolitis

Notes
Risk of bias table

Svenningsen 1987

Methods

Randomized

Single Center

Blinding of randomization: Not described

Blinding of intervention: Yes (intervention blinded to pediatric radiologist)

Complete Follow-up: Short-term: Yes; Long-term: No

Blinding of outcome measurement: No

Stratification: No

Participants

Very low birthweight neonates

Gestational age between 26 and 29 weeks

Assisted ventilation

FiO2 > 0.6 for 3 hours or more, with IMV 60 breaths/min, I/E ratio 1:1, PEEP 2 cm H2O, PIP and FiO2 adjusted to keep PaCO2 at 25 to 50 torr and PaO2 at 45 to 75 torr

Interventions

porcine surfactant extract (Curosurf 200 mg/kg) vs. air

Infants Randomized: Surfactant = 4; Control = 4

Outcomes

PRIMARY OUTCOME:

Oxygenation

SECONDARY OUTCOMES:

Mortality

Pneumothorax

Intracranial hemorrhage

Patent ductus arteriosus

Notes
Risk of bias table
Item Judgement Description
Allocation concealment? Unclear

Characteristics of excluded studies

Buky 1990

Reason for exclusion

Buky and colleagues reported on the clinical efficacy of a poractant in 10 preterm newborn infants (birth weight 850-1850 g) artificially ventilated for severe hyaline membrane disease. Infants received a single dose of endotracheal poractant (200 mg/kg). The investigators reported rapid improvement of oxygenation. It is unclear whether these infants were randomly assigned to surfactant and if these infants were part of a larger multicenter randomized controlled trial.

Dolfin 1994

Reason for exclusion

Dolfin and colleagues reported on the outcome of 31 preterm infants with moderate to severe neonatal respiratory distress syndrome (RDS) treated with surfactant compared to that of 74 preterm infants with RDS treated conventionally by positive pressure ventilation and supportive care. Infants were not randomly assigned to treatment groups. They reported a significant decrease in mortality resulting from surfactant treatment (36.6% in the untreated group vs. 12.9% in the surfactant-treated group). The incidence of pneumothorax was also lower in the surfactant treated group (42% vs. 13%).

Gortner 1992 German

Reason for exclusion

Gortner and colleagues investigated the effects of a bovine surfactant (SF-RI 1, Alveofact) in a series of very low birth weight infants with established respiratory distress syndrome (RDS; definition: FiO2 greater than/or equal to 0.6 or peak inspiratory pressure greater than 22-28 cm H2O). Bovine surfactant (50 mg/kg) was administered intratracheally as a bolus, if the acute response was unsatisfactory (FiO2 greater than 0.5), further administrations of surfactant up to a maximum cumulative dose of 200 mg/kg were permitted. No formal control group was enrolled. One hundred and sixty-four VLBW infants (gestational age 28.0 ± 2 wks; b.w. 1054 ± 251 g; mean ± SD) with a mean FiO2 of 0.84 ± 0.15 were enrolled in the study. Maximum improvement in oxygen requirements was observed 1/2 h post administration (FiO2 0.53 ± 0.22); incidence of complications during the neonatal period: pulmonary interstitial emphysema 26%, pneumothorax 10%, patent ductus arteriosus 37%, intracranial hemorrhage 47%. The overall survival rate was 61%, survival rate without bronchopulmonary dysplasia (BPD) was 47%.

Sanghvi 1998

Reason for exclusion

Case series utilizing a variety of surfactant preparations in mechanically ventilated inborn infants with RDS.

Speer 1988

Reason for exclusion

Speer and colleagues treated 14 preterm infants with severe respiratory distress syndrome (birthweight 1170 ± 369 g) with a single dose of poractant (Curosurf, 200 mg/kg). Outcome data were compared with matched controls (birthweight 1200 ± 288 g, n = 20) (not assigned by randomization). Treated infants showed improved oxygenation and gas exchange within minutes after surfactant application. Pneumothorax occurred in 7 of the 20 control infants (35%) but in none of the treated patients. Hemodynamically significant patent ductus arteriosus (PDA) occurred more often in the surfactant group (50% vs. 30%). The incidence of PDA requiring treatment was the same in both groups. Occurrence of intracranial haemorrhage, bronchopulmonary dysplasia and retinopathy of prematurity was identical in both groups. Mortality was 25% in controls and 7% in treated babies.

Walti 1990

Reason for exclusion

Walti and colleagues report on 30 preterm infants weighing 700 to 2000 g with severe HMD [mechanical ventilation and oxygen requirement (FiO2) greater than 60%] randomly allocated to porcine surfactant treatment (poractant) or control at 2 to 15 hours postnatal age. Eight of the 30 patients included in this group participated in a multicenter European trial and are reported in Collaborative European Multicenter Study Group 1988 (included in this review). The fifteen infants with mean gestational age (GA) of 29.5 weeks included in the treatment group, were treated at 8.6 hours of life with a single dose of 200 mg/kg poractant given intratracheally while 15 infants of mean GA 30 weeks formed the control group. Treated infants showed an immediate, dramatic and sustained improvement of oxygenation as reflected by increased PaO2/FiO2 and arterial to alveolar PO2 ratios within 1 hour. Despite this early improvement obtained with poractant, the survival rate at 28 days of life and the incidence of associated HMD complications were not significantly modified.

Summary of findings tables

  • None noted.

Additional tables

[top]

References to studies

Included studies

Chen 1990

Chen JY. Exogenous surfactant for treatment of respiratory distress syndrome in premature infants. Journal of the Formosan Medical Association 1990;89:110-4.

European 1988

Collaborative European Multicenter Study Group. Surfactant replacement therapy for severe neonatal respiratory distress syndrome: an international randomized clinical trial. Pediatrics 1988;82:683-91.

Robertson B, Curstedt T, Tubman R, Strayer D, Berggren P, Kok J, Koppe J, van Sonderen L, Halliday H, McClure G, et al: A 2-year follow-up of babies enrolled in a European multicentre trial of porcine surfactant replacement for severe neonatal respiratory distress syndrome. Collaborative European Multicenter Study Group. European Journal of Pediatrics 1992;151(5):372-6.

Fujiwara 1990

Fujiwara T, Konishi M, Chida S, Okuyama K, Ogawa Y, Takeuchi Y, Nishida H, Kito H, Fujimura M, Nakamura H, Hashimoto T et al. Surfactant replacement therapy with a single postventilatory dose of a reconstituted bovine surfactant in preterm neonates with respiratory distress syndrome: final analysis of a multicenter, double-blind, randomized trial and comparison with similar trials. Pediatrics 1990;86:753-64.

Gitlin 1987

Gitlin JD, Soll RF, Parad RB, Horbar JD, Feldman HA, Lucey JF, Taeusch HW. Randomized controlled trial of exogenous surfactant for the treatment of hyaline membrane disease. Pediatrics 1987;79:31-7.

Ware J, Taeusch HW, Soll RF, McCormick MC. Health and developmental outcomes of a surfactant controlled trial: follow-up at 2 years. Pediatrics 1990;85(6):1103-7.

Gortner 1990

Gortner L, Bernsau U, Hellwege HH, Hieronimi G, Jorch G, Reiter HL. A multicenter randomized controlled clinical trial of bovine surfactant for prevention of respiratory distress syndrome. Lung 1990;168(Suppl):864-9.

Gortner L. Bartmann P. Pohlandt F. Bernsau U. Porz F. Hellwege HH. Seitz RC. Hieronimi G. Bremer C. Jorch G. et al. Early treatment of respiratory distress syndrome with bovine surfactant in very preterm infants: A multicenter controlled clinical trial. Pediatric Pulmonology 1992;14(1):4-9.

Hallman 1985

Hallman M, Merritt TA, Jarvenpaa AL, Boynton B, Mannino F, Gluck L, Moore T, Edwards D. Exogenous human surfactant for treatment of severe respiratory distress syndrome: a randomized prospective clinical trial. Journal of Pediatrics 1985;106:963-9.

Vaucher YE, Merritt TA, Hallman M, Jarvenpaa AL, Telsey AM, Jones. Neurodevelopmental and respiratory outcome in early childhood after human surfactant treatment. American Journal of Diseases of Children 1988;142:927-30.

Horbar 1989

Horbar JD, Soll RF, Sutherland JM, Kotagal U, Philip AG, Kessler DL, Little GA., Edwards WH, Vidyasagar D, Raju TN, et al. A multicenter, randomized, placebo-controlled trial of surfactant therapy for respiratory distress syndrome. New England Journal of Medicine 1989;320:959-65.

Horbar 1990

Horbar JD, Soll RF, Schachinger H, Kewitz G, Versmold HT, Lindner W, Duc G, Mieth D, Linderkamp O, Zilow EP, et al. A European multicenter randomized controlled trial of single dose surfactant therapy for idiopathic respiratory distress syndrome. European Journal of Pediatrics 1990;149:416-23.

Lang 1990

Lang MJ, Hall RT, Reddy NS, Kurth CG, Merritt TA. A controlled trial of human surfactant replacement therapy for severe respiratory distress syndrome in very low birthweight infants. Journal of Pediatrics 1990;116:295-300.

Liechty 1991

Liechty EA, Donovan E, Purohit D, Gilhooly J, Feldman B, Noguchi A, Denson SE, Sehgal SS, Gross I, Stevens D, et al. Reduction of neonatal mortality after multiple doses of bovine surfactant in low birth weight neonates with respiratory distress syndrome. Pediatrics 1991;88:19-28.

Survanta Multidose Study Group. Two-year follow-up of infants treated for neonatal respiratory distress syndrome with bovine surfactant. J Pediatr 1994 1994;124:962-967.

Raju 1987

Raju TN, Vidyasagar D, Bhat R, Sobel D, McCulloch KM, Anderson M, Maeta H, Levy PS, Furner S. Double-blind controlled trial of single-dose treatment with bovine surfactant in severe hyaline membrane disease. Lancet 1987;1:651-6.

Soll 1988

Soll RF et al. European study of single dose surfactant TA (STA) for treatment of respiratory distress syndrome (RDS). Pediatr Res 1988;23:525A.

Svenningsen 1987

Svenningsen N, Robertson B, Andreason B, Berggren P, Jonson B, Lindroth M. Endotracheal administration of surfactant in very low birth weight infants with respiratory distress syndrome. Critical Care Medicine 1987;15(10):918.

Excluded studies

Buky 1990

Buky B, Devai G, Varady E, Rozsavolgyi A, Kovach I, Kovacs A., Jancso G, Waldinger K, Gorgenyi A, Zsolnai B, et al. Treatment of severe hyaline membrane disease with surfactant (Curosurf). A collaborative clinical study. Acta Paediatrica Hungarica 1990;30:351-65.

Dolfin 1994

Dolfin T, Zamir C, Regev R, Ben Ari J, Wolach B. Effect of surfactant replacement therapy on the outcome of premature infants with respiratory distress syndrome. Israel Journal of Medical Sciences 1994;30:267-70.

Gortner 1992 German

Gortner L, Bartmann P, Bernsau U, Hellwege HH, Hieronimi G, Jorch G, Reiter HL, Versmold H. The effect of bovine surfactant in premature infants with respiratory distress syndrome: Results of an open, multicenter study distress syndrome. Results of an open, multicenter study. Zeitschrift fur Geburtshilfe und Perinatologie 1992;196:159-64.

Sanghvi 1998

Sanghvi KP, Merchant RH. Single dose surfactant rescue therapy in neonatal respiratory distress syndrome. Indian Pediatrics 1998;35:533-6.

Speer 1988

Speer CP, Harms K, Muller U, Schroter W, Curstedt T, Robertson B. Treatment of severe respiratory distress syndrome in the premature infant with natural surfactant. Monatsschrift Kinderheilkunde 1988;136:65-70.

Walti 1990

Walti H, Relier JP, Huon C, Monset-Couchard M, Scemama M, De Gamarra E, Moriette G, Curstedt T, Robertson B. Treatment of severe hyaline membrane disease with a single-dose of natural exogenous surfactant of porcine origin. A randomized trial: immediate effects and outcome at 28 days of life. Archives Francaises de Pediatrie 1990;47(5):329-34.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Chu 1967

Chu J, Clements JA, Cotten E, Klaus MH, Sweet AY, Tooley WH. Neonatal pulmonary ischemia. Pediatrics 1967;40 Suppl:709-82.

Enhorning 1972

Enhorning G, Robertson B. Lung expansion in the premature rabbit fetus after tracheal deposition of surfactant. Pediatrics 1972;50:58-66.

Fujiwara 1980

Fujiwara T, Maeta H, Chida S et al. Artificial surfactant in hyaline membrane disease. Lancet 1980;1:55-9.

Hawgood 1985

Hawgood S, Benson BJ, Hamilton Jr RL. Effects of surfactant-associated proteins and calcium ions on the structure and surface activity of lung surfactant lipids. Biochemistry 1985;24:184-90.

Jobe 1993

Jobe AH. Pulmonary surfactant therapy. New England Journal of Medicine 1993;328:861-8.

Pfister 2007

Pfister RH, Soll RF, Wiswell T. Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD006069. DOI: 10.1002/14651858.CD006069.pub3.

Possmayer 1990

Possmayer F. The role of surfactant-associated proteins. American Review of Respiratory Disease 1990;142:749-52.

Robillard 1964

Robillard E, Alarie Y, Dagenais-Perusse P, Baril E, Guilbeault A. Micro-aerosol administration of synthetic dipalmitoyl lecithin in the respiratory distress syndrome: A preliminary report. Canadian Medical Association Journal 1964;90:55-7.

Schurch 1992

Schurch S, Possmayer F, Cheng S, Cockshutt AM. Pulmonary SP-A enhances adsorption and appears to induce surface sorting of lipid extract surfactant. American Journal of Physiology 1992;263:L210-8.

Soll 1997a

Soll RF. Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 1997, Issue 4. Art. No.: CD000511. DOI: 10.1002/14651858.CD000511.

Soll 1998a

Soll RF. Prophylactic synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 1998, Issue 2. Art. No.: CD001079. DOI: 10.1002/14651858.CD001079.

Soll 1998b

Soll RF. Synthetic surfactant for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 1998, Issue 3. Art. No.: CD001149. DOI: 10.1002/14651858.CD001149.

Soll 2001a

Soll RF, Blanco F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD000144. DOI: 10.1002/14651858.CD000144.

Soll 2001b

Soll RF, Morley CJ. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD000510. DOI: 10.1002/14651858.CD000510.

Stevens 2007

Stevens TP, Blennow M, Myers EH, Soll R. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003063. DOI: 10.1002/14651858.CD003063.pub3.

Witsett 1995

Whitsett JA, Nogee LM, Weaver TE, Horowitz AD. Human surfactant protein B: structure, function, regulation, and genetic disease. Physiological Reviews 1995;75:749-57.

Wright 1997

Wright JR. Immunomodulatory functions of surfactant. Physiological Reviews 1997;77:931-62.

Yost 1999

Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 1999, Issue 4. Art. No.: CD001456. DOI: 10.1002/14651858.CD001456.

Other published versions of this review

  • None Noted.

Classification pending references

  • None Noted.

[top]

Data and analyses

1 Animal derived surfactant extract treatment of RDS (all infants)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1. Effect on Air Leak 7 1380 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.39, 0.58]
1.1.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.29, 1.49]
1.1.2 Modified bovine surfactant extract 3 1061 Risk Ratio (M-H, Fixed, 95% CI) 0.44 [0.34, 0.58]
1.1.3 Porcine surfactant extract 1 146 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.36, 0.99]
1.1.4 Human amniotic fluid surfactant extract 2 104 Risk Ratio (M-H, Fixed, 95% CI) 0.45 [0.26, 0.78]
1.2. Effect on Pneumothorax 12 1549 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.34, 0.52]
1.2.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.19, 3.20]
1.2.2 Modified bovine surfactant extract 8 1281 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.32, 0.51]
1.2.3 Porcine surfactant extract 2 154 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.34, 1.00]
1.2.4 Human amniotic fluid surfactant extract 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.15 [0.02, 1.12]
1.3. Effect on Pulmonary Interstitial Emphysema 8 1247 Risk Ratio (M-H, Fixed, 95% CI) 0.45 [0.37, 0.55]
1.3.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.21, 2.22]
1.3.2 Modified bovine surfactant extract 5 987 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.35, 0.54]
1.3.3 Porcine surfactant extract 1 146 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.36, 0.99]
1.3.4 Human amniotic fluid surfactant extract 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.09 [0.01, 1.62]
1.4. Effect on Pulmonary Hemorrhage 2 898 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.77, 2.15]
1.4.1 Bovine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.4.2 Modified bovine surfactant extract 2 898 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.77, 2.15]
1.4.3 Porcine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.4.4 Human amniotic fluid surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.5. Effect on Patent Ductus Arteriosus 13 1605 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.89, 1.08]
1.5.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.33, 1.32]
1.5.2 Modified bovine surfactant extract 8 1278 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.85, 1.06]
1.5.3 Porcine surfactant extract 2 154 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.94, 1.73]
1.5.4 Human amniotic fluid surfactant extract 2 104 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.70, 1.82]
1.6. Effect on Necrotizing Enterocolitis 8 1346 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [0.70, 1.82]
1.6.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.07, 15.80]
1.6.2 Modified bovine surfactant extract 6 1232 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.74, 2.02]
1.6.3 Porcine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.6.4 Human amniotic fluid surfactant extract 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.35 [0.04, 3.10]
1.7. Effect on Sepsis 4 1012 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.87, 1.48]
1.7.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.48, 2.89]
1.7.2 Modified bovine surfactant extract 2 898 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.89, 1.56]
1.7.3 Porcine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.7.4 Human amniotic fluid surfactant extract 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.15 [0.01, 2.73]
1.8. Effect on Periventricular/Intraventricular Hemorrhage 10 1473 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.87, 1.07]
1.8.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.58, 2.19]
1.8.2 Modified bovine surfactant extract 7 1213 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.89, 1.11]
1.8.3 Porcine surfactant extract 1 146 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.62, 1.17]
1.8.4 Human amniotic fluid surfactant extract 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.40, 1.20]
1.9. Effect on Severe Periventricular/Intraventricular Hemorrhage 10 1501 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.79, 1.10]
1.9.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.16, 2.39]
1.9.2 Modified bovine surfactant extract 6 1182 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.77, 1.11]
1.9.3 Porcine surfactant extract 1 146 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.63, 1.98]
1.9.4 Human amniotic fluid surfactant extract 2 104 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.53, 1.57]
1.10 Effect of Bronchopulmonary Dysplasia 12 1568 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.84, 1.08]
1.10.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.05, 0.87]
1.10.2 Modified bovine surfactant extract 8 1249 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.891.16]
1.10.3 Porcine surfactant extract 1 146 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.31, 1.24]
1.10.4 Human amniotic fluid surfactant extract 2 104 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.29, 1.64]
1.11. Effect on Neonatal Mortality 10 1469 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.57, 0.82]
1.11.1 Bovine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.11.2 Modified bovine surfactant extract 8 1278 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.57, 0.86]
1.11.3 Porcine surfactant extract 1 146 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.41, 0.92]
1.11.4 Human amniotic fluid surfactant extract 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.15, 1.84]
1.12. Effect on Mortality Prior to Hospital Discharge 7 421 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.44, 0.90]
1.12.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.23, 1.35]
1.12.2 Modified bovine surfactant extract 4 248 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.41, 1.15]
1.12.3 Porcine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.12.4 Human amniotic fluid surfactant extract 2 104 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.34, 1.06]
1.13. Effect on Reported Mortality 13 1605 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.57, 0.80]
1.13.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.23, 1.35]
1.13.2 Modified bovine surfactant extract 8 1278 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.57, 0.86]
1.13.3 Porcine surfactant extract 2 154 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.45, 0.97]
1.13.4 Human amniotic fluid surfactant extract 2 104 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.34, 1.06]
1.14. Effect on Bronchopulmonary Dysplasia or Death 12 1596 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.77, 0.90]
1.14.1 Bovine surfactant extract 1 69 Risk Ratio (M-H, Fixed, 95% CI) 0.39 [0.20, 0.76]
1.14.2 Modified bovine surfactant extract 8 1277 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.82, 0.97]
1.14.3 Porcine surfactant extract 1 146 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.46, 0.82]
1.14.4 Human amniotic fluid surfactant extract 2 104 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.45, 1.02]
1.15. Effect on Retinopathy of Prematurity 4 216 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.41, 1.44]
1.15.1 Bovine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.15.2 Modified bovine surfactant extract 3 171 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.45, 1.62]
1.15.3 Porcine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.15.4 Human amniotic fluid surfactant extract 1 45 Risk Ratio (M-H, Fixed, 95% CI) 0.21 [0.01, 4.12]
1.16. Effect on Severe Retinopathy of Prematurity 2 89 Risk Ratio (M-H, Fixed, 95% CI) 1.34 [0.23, 7.67]
1.16.1 Bovine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.16.2 Modified bovine surfactant extract 1 30 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [0.15, 15.09]
1.16.3 Porcine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.16.4 Human amniotic fluid surfactant extract 1 59 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.07, 16.88]
1.17. Effect on Cerebral Palsy 1 73 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.34, 2.27]
1.17.1 Bovine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.17.2 Modified bovine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.17.3 Porcine surfactant extract 1 73 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.34, 2.27]
1.17.4 Human amniotic fluid surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.18. Effect on visual impairment in survivors 2 119 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.02, 8.59]
1.18.1 Bovine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.18.2 Modified bovine surfactant extract 1 30 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.02, 8.59]
1.18.3 Porcine surfactant extract 1 89 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.18.4 Human amniotic fluid surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.19. Effect on major neurodevelopmental disability in survivors 1 73 Risk Ratio (M-H, Fixed, 95% CI) 3.30 [0.41, 26.78]
1.19.1 Bovine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.19.2 Modified bovine surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable
1.19.3 Porcine surfactant extract 1 73 Risk Ratio (M-H, Fixed, 95% CI) 3.30 [0.41, 26.78]
1.19.4 Human amniotic fluid surfactant extract 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not Estimable

2 Animal derived surfactant extract treatment of RDS (infants < 1000g)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Effect of Bronchopulmonary Dysplasia 1 403 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.92, 1.33]
2.1.1 Modified bovine surfactant extract 1 403 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.92, 1.33]
2.2. Effect on Neonatal Mortality 1 403 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.57, 0.98]
2.2.1 Modified bovine surfactant extract 1 403 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.57, 0.98]
2.3. Effect on Reported Mortality 3 417 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.58, 0.97]
2.3.1 Modified bovine surfactant extract 2 414 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.56, 0.95]
2.3.2 Porcine surfactant extract 1 3 Risk Ratio (M-H, Fixed, 95% CI) 4.50 [0.32, 63.94]
2.4. Effect on Bronchopulmonary Dysplasia or Death 1 403 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.89, 1.02]
2.4.1 Modified bovine surfactant extract 1 403 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.89, 1.02]

3 Animal derived surfactant extract treatment of RDS (infants =1000g)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1. Effect on Pneumothorax 2 57 Risk Ratio (M-H, Fixed, 95% CI) 0.16 [0.04, 0.66]

3.1.1 Modified bovine surfactant extract
1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.16 [0.04, 0.66]
3.1.2 Porcine surfactant extract 1 3 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
3.2. Effect on Pulmonary Interstitial Emphysema 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.07 [0.00, 1.26]
3.3. Effect on Pulmonary Hemorrhage 1 54 Risk Ratio (M-H, Fixed, 95% CI) 5.65 [0.31, 104.25]
3.3. Effect on Pulmonary Hemorrhage 1 54 Risk Ratio (M-H, Fixed, 95% CI) 5.65 [0.31, 104.25]
3.4. Effect on Patent Ductus Arteriosis 2 54 Risk Ratio (M-H, Fixed, 95% CI) 1.21 [0.64, 2.31]
3.4.1 Modified bovine surfactant extract 1 59 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.60, 2.23]
3.4.2 Porcine surfactant extract 1 54 Risk Ratio (M-H, Fixed, 95% CI) 2.25 [0.13, 38.09]
3.5. Effect on Necrotizing Enterocolitis 1 5 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
3.5.1 Modified bovine surfactant extract 1 54 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
3.6. Effect on Sepsis 1 54 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
3.6.1 Modified bovine surfactant extract 1 54 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
3.7. Effect on Periventricular/Intraventricular Hemorrhage 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.32, 1.56]
3.7.1 Modified bovine surfactant extract 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.32, 1.56]
3.8. Effect on Severe Periventricular/Intraventricular Hemorrhage 1 54 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.26, 1.31]
3.8.1 Modified bovine surfactant extract 1 54 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.26, 1.31]
3.9. Effect on Bronchopulmonary Dysplasia 2 448 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.69, 1.13]
3.9.1 Modified bovine surfactant extract 2 448 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.69, 1.13]
3.10. Effect on Neonatal Mortality 2 448 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.30, 0.95]
3.10.1 Modified bovine surfactant extract 2 448 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.30, 0.95]
3.11. Effect on Reported Mortality 4 372 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.32, 0.90]
3.11.1 Modified bovine surfactant extract 3 467 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.29, 0.88]
3.11.2 Porcine surfactant extract 1 5 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.27, 6.61]
3.12. Effect on Bronchopulmonary Dysplasia or Death 2 448 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.60, 0.88]
3.12.1 Modified bovine surfactant extract 2 448 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.60, 0.88]
3.13. Effect on Retinopathy of Prematurity 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.10, 2.94]
3.13.1 Modified bovine surfactant extract 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.10, 2.94]

[top]

Sources of support

Internal sources

  • No sources of support provided.

External sources

  • [Information not provided], Not specified

This review is published as a Cochrane review in The Cochrane Library, Issue 2, 2009 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.