Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome

Pfister RH, Soll RF, Wiswell T

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

Dates

Date edited: 20/08/2007
Date of last substantive update: 13/08/2007
Date of last minor update: 14/08/2007
Date next stage expected 18/04/2009
Protocol first published: Issue 3, 2006
Review first published: Issue 3, 2007

Contact reviewer

Dr Robert H. Pfister, MD
Fellow in Neonatal Perinatal Medicine
Division of Neonatal Perinatal Medicine
Fletcher Allen Health Care
Smith #582
111 Colchester Avenue
Burlington
VT USA
05401
Telephone 1: 802-656-2296
Facsimile: 802-847-5225
E-mail: robert.pfister@vtmednet.org

Contribution of reviewers

Drs. Robert Pfister (RP) and Roger Soll (RS) excerpted data for analysis. RP drafted the original text of the protocol and review. The protocol and review were reviewed and edited by RS and T. Wiswell.

Internal sources of support

None

External sources of support

None

What's new

This updates the review "Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome" published in The Cochrane Library, Issue 3, 2007 (Pfister 2007).

Our updated search through June 2007 identified one study (Moya 2007) that reports survival, pulmonary, and neurologic outcomes through one year corrected age from the above mentioned two randomized controlled trials of prophylactic therapy using synthetic surfactant containing surfactant protein-B mimics.

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Respiratory distress syndrome (RDS) is a significant cause of illness in preterm infants. Respiratory distress syndrome is caused by a deficiency or a dysfunction of the chemicals that line the lung, called pulmonary surfactant. Numerous preparations that contain surfactants of either animal origin or synthetic design have been developed and tested to treat or prevent respiratory distress syndrome. In general, these surfactant preparations have decreased lung rupture (pneumothorax), decreased the risk of dying, and increased the number of survivors without lung damage. From previous research, the surfactants that are obtained from animals seem to have a better effect than the synthetic surfactants. This might be due to the surfactant proteins contained in animal surfactant that are absent in the previously available synthetic surfactants.

Recently developed synthetic surfactant preparations include whole surfactant proteins or parts of the proteins (called peptides) that act like surfactant protein. These preparations have been recently tested in comparison to the animal derived surfactant preparations.

Two recent trials of protein containing synthetic surfactant compared to animal derived surfactant preparations have demonstrated a trend towards decreasing death and decreasing rates of bowel disease (necrotizing enterocolitis), while other clinical outcomes were similar. Further studies will help refine recommendations concerning use of protein containing synthetic surfactants.

Abstract

Background

Respiratory distress syndrome (RDS) is a significant cause of morbidity and mortality in preterm infants. RDS is caused by a deficiency, dysfunction, or inactivation of pulmonary surfactant. Numerous surfactants of either animal extract or synthetic design have been shown to improve outcomes. New surfactant preparations that include peptides or whole proteins that mimic endogenous surfactant protein have recently been developed and tested.

Objectives

Search strategy

Standard search methods of the Cochrane Neonatal Review Group were used. The search included MEDLINE (1966 - May 2007) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) in all languages. In addition, published abstracts of the Society of Pediatric Research were searched electronically. For abstract books that did not include key words, the search was limited to the relevant sections on pulmonary and neonatology. The bibliography cited in each publication was obtained and searched in order to identify additional relevant articles.

Selection criteria

Randomized and quasi-randomized controlled clinical trials were considered for this review. Studies that enrolled preterm infants or low birth weight infants at risk for or having RDS who were treated with either a synthetic surfactant containing surfactant protein mimics or an animal-derived surfactant preparation were included for this review. Studies that either attempted to treat or prevent respiratory distress syndrome were included.

Data collection & analysis

Primary outcome measures, including mortality, chronic lung disease and multiple secondary outcome measures were abstracted by the reviewers. Statistical analysis was performed using Review Manager software. Categorical data was analyzed using relative risk, risk difference, and number needed to treat. 95% confidence intervals reported. A fixed effects model was used for the meta-analysis. Heterogeneity was assessed using the I-squared statistic.

Main results

Two studies were identified that compared protein containing synthetic surfactants to animal derived surfactant preparations. In a meta-analysis of these two studies, infants who received protein containing synthetic surfactant compared to animal derived surfactant extract did not demonstrate significantly different risks of prespecified primary outcomes: mortality at 36 weeks [typical RR 0.81 (95% CI 0.64, 1.03)], chronic lung disease at 36 weeks [typical RR 0.99 (95% CI 0.84, 1.18)], or the combined outcome of mortality or chronic lung disease at 36 weeks [typical RR 0.96 (95% CI 0.82, 1.12)]. There were also no differences in any of the secondary outcomes regarding complications of prematurity between the two surfactant groups with the exception of necrotizing enterocolitis. A decrease in the risk of necrotizing enterocolitis was noted in infants who received protein containing synthetic surfactants compared to animal derived surfactant extract [typical RR 0.60 (95% CI 0.42, 0.86)]. However, this was a secondary outcome in both of the primary studies and there was moderate heterogeneity between the studies.

Reviewers' conclusions

In two trials of protein containing synthetic surfactants compared to animal derived surfactant extract, no statistically different clinical differences in death and chronic lung disease were noted. In general, clinical outcomes between the two groups were similar. Further well designed studies of adequate size and power will help confirm and refine these findings.

Background

Respiratory distress syndrome (RDS) is a significant cause of morbidity and mortality in preterm infants. Respiratory distress syndrome is caused by a deficiency, dysfunction, or inactivation of pulmonary surfactant. Pulmonary surfactant forms a lipid-rich monolayer that coats the alveoli and airways of the lung and is essential for proper inflation and function (Jobe 1993). Surfactant lowers surface tension and improves pulmonary dynamic compliance. Although predominantly composed of phospholipids, four native surfactant proteins have been detected (SP-A, SP-B, SP-C, and SP-D). SP-A appears to play a minor role in surfactant secretion, recycling, and cooperative functioning with other surfactant proteins and phospholipids (Schurch 1992; Possmayer 1990). SP-D, and to a lesser degree SP-A, plays a major role in the innate host defense of the lung (Wright 1997). 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; Whitsett 1995). Although SP-C seems to have less potent surface assimilation properties when compared to SP-B, it does improve stability of the phospholipid layer as well as respreading after collapse (Beers 1992). However, when interfaced with phospholipids, SP-B reduces surface tension to a much larger degree than SP-C or any of the other surfactant proteins (Revak 1988). In fact, SP-B is the only surfactant protein essential for life. Human newborns with normal SP-A and SP-C, but absent SP-B protein, exhibit severe respiratory distress and ultimately death (Nogee 1993).

Numerous surfactants of either animal extract or synthetic design have been developed and tested. Surfactants from animal derivation include porcine (poractant alfa) and bovine (beractant), calfactant (lung extracts). Non-protein containing surfactants are phospholipid preparations both with (colfosceril palmitate) and without (DPPG/PG) additional dispersion agents and polymers. In very low birth weight preterm infants, the intratracheal administration of these exogenous surfactants has resulted in decreased mortality, reduced severity of RDS, decreased likelihood of pneumothorax, and increased survival without chronic lung disease (Soll 1992). Although both synthetic and animal derived surfactant preparations have been shown to be beneficial, studies comparing animal derived surfactant preparations to non-protein containing synthetic preparations have demonstrated improvement in immediate ventilator support, decreased risk of pneumothorax, and decreased risk of mortality in infants receiving the animal derived products (Soll 2001). Furthermore, there is a marginal decrease in chronic lung disease (CLD) among preterm newborns treated with animal derived surfactant preparations when compared to the non-protein containing synthetic preparations (Soll 2001). The increased efficacy of animal derived surfactants might be due to the surfactant protein content of these animal derived preparations (Tooley 1987). Both animal derived and synthetic surfactant preparations are comprised largely of phospholipids, of which dipalmitoylphosphatidylcholine (DPPC) is the major surface-active component (Clements 1977). However, only animal derived surfactant preparations contain the highly lipophilic proteins that are present in native surfactant in situ.

Recently developed surfactant preparations include peptides or whole proteins that, when added in an aqueous dispersion of phospholipids, function in a fashion similar to endogenous pulmonary surfactant protein. One new synthetic surfactant preparation contains peptide fragments that mimic domains of Surfactant protein B (SP-B). This peptide is called Sinapultide (developmental name KL4 peptide). The form and function of SP-B are related to its repeating pattern; stretches of basic hydrophilic residues with intermittent hydrophobic domains (Revak 1988). This unique design is thought to increase lateral stability of the phospholipids layer and thus the ability of pulmonary surfactant to lower surface tension at an air-water interface, which in turn maintains expansion of alveoli (Cochrane 1991). Sinapultide consists of a stretch of four hydrophobic leucines (L) interspersed with cationic lysine (K) to create a sequence KLLLLKLLLLKLLLLKLLLLK whose spatial structure resembles one of the amphipathic domains of SP-B. Lucinactant (Surfaxin, Discovery Laboratories) contains Sinapultide and phospholipids. In vitro studies have demonstrated the ability of lucinactant to lower surface tension at an air-fluid interface in a pulsating bubble surfactometer to a greater magnitude than animal derived surfactants (Manalo 1996). In vivo studies in preterm rhesus monkeys demonstrated that lucinactant successfully expanded the pulmonary alveoli and promoted gas exchange (Revak 1996). Furthermore, this peptide-containing synthetic surfactant demonstrated improved gas exchange, reduced ventilator requirements, and reduced mortality in a small non-randomized uncontrolled pilot study of preterm infants with RDS. Although there was no comparison group, the lucinactant treated infants had a comparable rate of complications when compared to surfactant treated infants in other trials (Cochrane 1996). Other SP-B domains have been modeled with synthetic peptides to produce their own version of SP-B (Walther 2002). This product has a different peptide structure than lucinactant and is not yet commercially available.

Lusupultide (Venticute, Altana Pharma) is a synthetic surfactant preparation that contains recombinant SP-C (rSP-C) and phospholipids. The tendency of native SP-C to aggregate into insoluble amyloid-like fibrils when separated from lipids, has limited its investigation and usage (Walther 2000). Recombinant SP-C is similar to the 34-amino acid human SP-C sequence, but differs from it with the replacement of cysteine by phenylalanine in positions four and five, and of methionine by isoleucine in position 32. rSP-C was designed to circumvent the aggregation characteristics of SP-C while maintaining the physical properties of the dipalmitoylated form of nSP-C (Ikegami 1998). SP-C is palmitoylated at one or more cysteines located near the surface of the membrane which are able to move within and between lipid layers. This biochemical configuration may help create multilayer phospholipids films and facilitate the movement of lipids that line the alveoli, thereby improving film stability (Whitsett 2002). In vitro, Lusupultide was shown to lower surface tension more than sheep surfactant extracts. In addition, in vivo studies of lusupultide utilizing two common preterm animal models of surfactant deficiency (lambs and rabbits) demonstrated similar improvement in ventilation, lung mechanics, and compliance when compared to animal derived surfactants (Davis 1998).

The rationale for the development of protein containing synthetic surfactants includes both practical and theoretical considerations. Synthetic surfactants would have highly reproducible composition with potentially less batch-to-batch surfactant protein (or mimic) variability (Ainsworth 2002), would be more readily available with no dependence on an animal source and could theoretically be produced in large quantities. Furthermore, synthetic surfactants may lessen the risk of inflammation (Moya 1993) and immunogenicity (Merritt 1988) associated with animal derived surfactants, as well as the theoretical risk of infection.

This systematic review evaluates trials that compare synthetic surfactants containing surfactant protein mimics (either as whole protein or as peptide fragments) to animal derived surfactant extract in the treatment or prevention of RDS.

Objectives

To assess the effect of administration of synthetic surfactant containing surfactant protein mimics compared to animal derived surfactant extract on the risk of mortality, chronic lung disease, and other morbidities associated with prematurity in preterm infants at risk for or having RDS.

The following comparisons and subgroup analyses were planned:

I. Studies that treated infants at risk of respiratory distress syndrome (prophylaxis)

A. SP-B mimic containing synthetic surfactants:
1) Studies that utilized peptide containing synthetic surfactant
2) Studies that utilized whole protein containing synthetic surfactant

B. SP-C mimic containing synthetic surfactants:
1) Studies that utilized peptide containing synthetic surfactant
2) Studies that utilized whole protein containing synthetic surfactant

C. Gestational age (infants born at < 30 weeks gestation):
D. Birth weight <1000 grams

II. Studies that treated infants with established respiratory distress syndrome (treatment)

A. SP-B mimic containing synthetic surfactants:
1) Studies that utilized peptide containing synthetic surfactant
2) Studies that utilized whole protein containing synthetic surfactant

B. SP-C mimic containing synthetic surfactants:
1) Studies that utilized peptide containing synthetic surfactant
2) Studies that utilized whole protein containing synthetic surfactant

C. Gestational age (infants born at < 30 weeks gestation)

D. Birth weight <1000 grams

E. Moderate to severe respiratory disease (moderate to severe disease defined as need for assisted ventilation and greater than 40% supplemental oxygen in order to maintain adequate oxygenation)

Criteria for considering studies for this review

Types of studies

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

Types of participants

Preterm infants (gestational age < 37 weeks) or low birth weight infants (birthweight < 2500 grams) at risk for or having respiratory distress syndrome

Types of interventions

Infants randomly allocated to receive either a synthetic surfactant containing surfactant protein mimics (either as whole protein or as peptide fragments, such as Lusupultide/Venticute or Surfaxin/lucinactant) or an animal derived surfactant preparation [including bovine lung lavage extract (CLL, CLSE, BLeS, Infasurf, Alveofact), supplemented bovine surfactant extract (Survanta, Surfactant TA), or porcine surfactant extract (Curosurf)]

Prophylactic surfactant therapy was defined as all treatment strategies in which the intent was to treat a preterm infant based on the risk of RDS within the first hour of life. Risk of RDS was defined as gestational age < 32 weeks or birthweight < 1250 grams.

Treatment of established disease was defined as treatment of a preterm infant requiring respiratory support and having signs and symptoms of RDS.

Types of outcome measures

Primary Outcomes:
1. Incidence of neonatal mortality (mortality < 28 days of age) from any cause
2. Incidence of mortality at 36 weeks postmenstrual age
3. Overall mortality prior to discharge
4. Incidence of chronic lung disease (use of supplemental oxygen) at 28 days
5. Incidence of chronic lung disease (use of supplemental oxygen) at 36 weeks
6. Incidence of chronic lung disease or death at 28 days
7. Incidence of chronic lung disease or death at 36 weeks postmenstrual age

Secondary Outcomes:
1. Pneumothorax
2. Pulmonary interstitial emphysema
3. Air leak syndromes [including pulmonary interstitial emphysema (PIE), pneumothorax, pneumomediastinum]
4. Pulmonary hemorrhage
5. Respiratory distress syndrome at 24 hours
6. Patent ductus arteriosus (PDA) (clinical diagnosis and PDA treated with cyclo-oxygenase inhibitor or surgery)
7. Culture proven sepsis
8. Necrotizing enterocolitis (NEC) (defined as Bell Stage II or greater)
9. Periventricular leukomalacia (PVL)
10. Retinopathy of prematurity (ROP) (all stages and severe; stage 3 or greater)
11. Intraventricular hemorrhage (IVH) (any grade and severe; grade 3 - 4)
12. Neurodevelopmental outcome at approximately two years corrected age (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" was defined as having any one of the aforementioned deficits.
13. Mortality at approximately two years corrected age (range 18 months to 28 months).

Post-Hoc Outcomes:
(Post-hoc analyses were included for any unexpected adverse effects reported by the studies as well as to address data from available studies that reported on pertinent outcome measures at one year of age.)
1. Unilateral or bilateral deafness at one year
2. Unilateral or bilateral blindness at one year
3. Known deaths at one year

Search strategy for identification of studies

The standard search method of the Cochrane Neonatal Review Group was used.

1. Published manuscripts: MEDLINE was searched using PubMed (publication dates 1966 - June 2007) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2006) in all languages. Search terms: { lucinactant OR Surfaxin OR Venticute OR Lusupultide OR KL4 OR SP-B OR SP-C }, limited to humans and further limited to the age group of newborn infants (infant, newborn) and type of publication (clinical trial). From the resulting studies, randomized controlled studies that fulfilled the inclusion criteria were selected. To identify long-term neurodevelopmental sequelae, a search using the following keywords: (outcome OR sequelae OR follow-up OR mental retardation OR cerebral palsy OR hearing OR visual OR motor OR mental OR psychological) AND (pulmonary surfactant) limited to humans and clinical trials but not limited to any age group or language was performed.

2. Published abstracts: The abstracts of the Society for Pediatric Research (USA) (published in Pediatric Research) for the years 1985 - 2007 was 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.

3. The bibliography cited in each publication obtained was searched in order to identify additional relevant articles. Manual searches of bibliographies distributed by surfactant manufacturer websites were also performed (http://www.discoverylabs.com/publications.html).

Methods of the review

The standard methods of the Cochrane Neonatal Review Group were used.

Selection process: All randomized and quasi-randomized controlled trials fulfilling the selection criteria described in the previous section were included. All three investigators reviewed the results of the search and separately selected the studies for inclusion. They resolved any disagreement by discussion.

Criteria for assessing the methodological quality of the studies: The standard methods of the Cochrane Neonatal Review Group were employed. The methodological quality of the studies was 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 was yes, no, can't tell. All three review authors separately assessed each study. They resolved any disagreement by discussion.

Data extraction and entry: Two review authors (RP, RS) 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. Any disagreement was resolved by discussion. For each study, final data were entered into RevMan by one review author (RP) and then checked by a second review author (RS).

Statistical analyses were performed using Review Manager (RevMan) software. Categorical data were analyzed using relative risk (RR), risk difference (RD) and the number needed to treat (NNT). Continuous data were analyzed using weighted mean difference (WMD). The 95% confidence interval (CI) was reported on all estimates. A fixed effects model for meta-analysis was used. The treatment effects of individual trials and heterogeneity between trials was examined by inspecting the forest plots and quantifying the impact of heterogeneity using the I-2 statistic. If statistical heterogeneity was detected, the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) were explored using post-hoc subgroup analyses.

Subgroup analyses:
Specific subgroup analyses were performed according to the 'Objectives' section of this review.

Description of studies

For details of inclusion, see Search Strategy for Identification of Studies.

Included Studies:
The initial search identified two randomized controlled trials of prophylactic therapy with synthetic surfactant containing surfactant protein-B mimics that met inclusion criteria (Moya 2005; Sinha 2005). No studies were identified that met inclusion criteria for surfactant protein-C mimics nor were studies identified that reported on whole protein containing synthetic surfactants. Both studies fulfilled inclusion criteria of a gestational age < 37 weeks and birthweight < 2500 grams. A total of 1037 infants were enrolled in these two trials. Sinha et al (Sinha 2005) used a surfactant administration strategy that was clearly prophylactic. High risk infants were intubated for the purpose of surfactant administration. In this study, infants were stratified according to birthweight but not gestational age. This subgroup analysis is provided below. In the trial by Moya et al (Moya 2005), infants were enrolled after intubation within 20 - 30 minutes of birth and required no clinical signs or symptoms of RDS to be eligible for inclusion. No outcome data stratified according to gestational age, birthweight, or disease severity were presented and as such these subgroup analyses were unable to be performed. The studies were performed in 15 countries (Brazil, Canada, Chile, Ecuador, France, Hungary, Mexico, Panama, Poland, Portugal, Russia, Spain, Uruguay, the U.K., and the U.S.) and included 74 centers.
The updated search (through June 2007) identified one study (Moya 2007) that reports survival, pulmonary, and neurologic outcomes through one year corrected age from the above mentioned two randomized controlled trials of prophylactic therapy using synthetic surfactant containing surfactant protein-B mimics (Moya 2005, Sinha 2005).

Moya 2005 was a 50 center study performed in Brazil, Chile, Mexico, Ecuador, Hungary, Panama, Poland, Russia, and Uruguay.

* Objective: To compare the efficacy and safety of a synthetic surfactant containing a SP-B mimic to non-protein containing synthetic surfactant and an animal derived surfactant in the prevention of RDS and RDS-related death.

* Population: Preterm infants between 24 and 32 weeks gestational age, with birth weights between 600 and 1200 grams, and having undergone endotracheal intubation. 785 infants were included in this prophylaxis trial and were similar with respect to their baseline demographic and clinical characteristics.

* Intervention: The synthetic surfactant containing surfactant protein mimics group received 5.8 mL/kg of lucinactant, a synthetic surfactant containing a SP-B mimic with phospholipids and the animal derived surfactant group received 4 mL/kg of beractant, a bovine lung extract containing phospholipids and bovine surfactant proteins. In this study, a third group received a synthetic surfactant composed of colfosceril palmitate, cetyl alcohol, and tyloxapol. this comparison is not included in this review. The infants in this third group are addressed in a companion review comparing trials of synthetic surfactants with mimics to those without. All groups were administered the pulmonary surfactant intratracheally within 20 - 30 minutes of birth. Infants were randomized in a masked manner to receive lucinactant, colfosceril palmitate, or beractant in a 2:2:1 ratio. The need for additional surfactant therapy was determined individually based on pre-determined clinical and respiratory status and ventilator management and was kept uniform for both groups by adherence to specific guidelines developed for the study.

* Outcomes assessed: The primary comparison of interest within the trial was between lucinactant and colfosceril palmitate. The group that received beractant contained half as many patients. The beractant group was included as a reference arm, and was not included in the sample size computation. The pre-specified primary endpoints from which the sample size were generated were development of RDS at 24 hours and the occurrence of death related to RDS by 14 days. Other outcomes included mortality, BPD, air leaks, IVH, PVL, ROP, pulmonary hemorrhage, and sepsis.

Sinha 2005 was a 19 center study performed in Canada, France, Hungary, Poland, Portugal, Spain, the United Kingdom, and the United States.

* Objective: To demonstrate that outcomes of infants administered synthetic surfactant containing a SP-B mimic would not be inferior to those administered an animal derived surfactant preparation.

* Population: Preterm infants between 24 and 28 weeks gestational age, with birth weights between 600 and 1250 grams who were successfully intubated at birth. 252 infants were included in this prophylaxis trial and were similar with respect to their baseline demographic and clinical characteristics.

* Intervention: The synthetic surfactant containing surfactant protein mimics group received 5.8 mL/kg of lucinactant, a synthetic surfactant containing a SP-B mimic with phospholipids. The animal derived surfactant group received 2.2 mL/kg of poractant alfa, a porcine lung extract containing phospholipids and porcine surfactant proteins. Although poractant alfa is approved and commercially available at initial dosage concentrations of 100 mg/kg and 200 mg/kg, 175 mg/kg was used in the study. Both groups were administered the pulmonary surfactant intratracheally within 30 minutes of birth. Additional surfactant therapy need of either group was determined individually based on pre-determined clinical and respiratory status; sham surfactant was administered to maintain blinding integrity in the event of dosing discrepancies. Ventilator management was kept uniform for both groups by adherence to specific guidelines developed for the study.

* Outcomes assessed: The primary outcome measure of this study was survival without BPD at 28 days of life. The investigators generated the sample size for the primary outcome by structuring the trial as a "non-inferiority trial". In order to model the data for non-inferiority, the investigators referenced historical data regarding the primary outcome in infants from a study comparing poractant alfa to placebo control. For lucinactant to be deemed "non-inferior", the lower margin of the 95% confidence interval of the treatment difference between lucinactant and poractant alfa would need to be at least 50% of the treatment difference observed in the historical trial of poractant alfa versus placebo. Secondary outcomes included mortality, air leaks, IVH, PVL, NEC, ROP, sepsis, apnea, pulmonary hemorrhage, and PDA.

Moya 2007 reports follow up data from the aforementioned randomized controlled trials of protein containing synthetic surfactants given as prophylaxis for RDS (Moya 2005, Sinha 2005).

* Objective: To determine survival, rehospitalization, growth, neurologic, and pulmonary outcomes through one year corrected age of infants administered synthetic surfactant containing a SP-B mimic.

* Population: 1018 preterm infants enrolled in the Moya (2005) and Sinha (2005) trials (described above) who were either known to have died or successfully seen at follow-up at approximately by one year of age were included.

* Intervention: Described above in the Moya (2005) and Sinha (2005) trials.

* Outcomes assessed: Postdischarge rehospitalization rates, respiratory morbidity after 36 weeks post-menstrual age, growth parameters at one year of age, neurologic assessment at one year of age, and total death by one year of age were recorded. Included in the neurologic examination were assessment of gross motor tone, reflex abnormalities, presence of unilateral or bilateral deafness, presence of unilateral or bilateral blindness, or a history of seizures that required treatment with anticonvulsants. For survival comparisons, infants who were lost to follow-up or who had of consent withdrawn were analyzed and reported both as if they had died and separately as if they were not in the study.

Excluded Studies:
One study (Cochrane 1996) used a protein containing synthetic surfactant as prophylaxis of RDS but did so in a non-blinded trial without a comparison group and accordingly was excluded.

Ongoing Studies:
A search of clinicaltrials.gov revealed no ongoing trials of protein containing synthetic surfactants used as treatment or as prophylaxis of RDS.

No studies were found that met criteria for the comparison of protein containing synthetic surfactant to animal derived surfactant extract for the treatment of established RDS.

Methodological quality of included studies

Trials were evaluated for their methodological quality in terms of concealment of allocation, masking of intervention, completeness of follow-up, and masking of outcome assessment.

Moya 2005
Infants were randomized in a masked manner to receive lucinactant, colfosceril palmitate, or beractant in a 2:2:1 ratio, with randomization stratified according to birthweight (600 - 800 grams; 801 - 1000 grams; 1001 - 1250 grams). Birthweight stratum randomization codes were computer-generated by an independent university-based statistical center. Each participating institution received sealed envelopes with randomization codes to be opened sequentially.

To mask the intervention, the identity of the surfactant assignment was not known to the neonatologists, staff, or families, but only to those who prepared and administered the drugs. These individuals included nurses, respiratory therapists, and pharmacists who were trained in administering surfactant, but who worked in other areas of the hospital. Following the surfactants preparation and/or administration, these individuals did not further participate in the management of the infants nor did they unblind the intervention. All treatments were administered in four aliquots using syringes covered with adhesive opaque paper. In cases of dosing interval discrepancy between the three surfactants, sham air was administered.

1294 infants (527 lucinactant, 509 colfosceril palmitate, and 258 beractant) were randomized. Six infants (three lucinactant, three colfosceril palmitate) comprising 0.46% of the total randomized population were not dosed with any surfactant. Four patients received the incorrect treatment. One beractant patient received lucinactant, another beractant patient received colfosceril palmitate. Two colfosceril palmitate patients received beractant. Infants were analyzed according to the intention-to-treat principle. 522 of 527 of the lucinactant treated infants, 505 of 509 of the colfosceril palmitate treated infants, and all 258 beractant treated infants were followed and either died or were accounted for at the final evaluation, which took place at 36 weeks postmenstrual age.

An independent adjudication committee, masked to surfactant group assignment, used clinical and radiological data to ascertain whether prespecified criteria were met for the authors' definitions of the primary outcomes, RDS at 24 hours or death from RDS at 14 days. In addition, two secondary outcomes, airleaks and mortality causation, were evaluated by the independent adjudication committee.

Sinha 2005
Infants were randomized to receive either lucinactant or poractant alfa. Randomization was stratified according to estimated birthweight (600 - 1000 grams and 1001 - 1250 grams) at each study site. The treatment assignment was accomplished using sequentially numbered, opaque, sealed drug identification envelopes.

To ensure masking of intervention, an independent dosing/drug preparation team not involved in the infants care was designated at each site. Syringes were covered with opaque white paper and study surfactant was given in two aliquots at a time. Infants in both groups were treated in an identical manner. The clinicians caring for the infants remained masked to the identity of the assigned surfactant throughout the study.

Two hundred and fifty-two infants (124 lucinactant, 128 poractant alfa) were randomized. An estimated sample size of 496 patients was sought; however enrolment was stopped prematurely due to unexpectedly slow recruitment. Nine infants (five lucinactant, four poractant alfa) comprising 3.6% of the total randomized population were randomized, but did not receive surfactant within 30 minutes and were excluded from analysis. This is not in accordance with the intention-to-treat principle. All infants not otherwise excluded were followed and either died or were accounted for at the final evaluation which took place at 36 weeks postmenstrual age.

Final outcomes were assessed by the clinicians caring for the infants, not by a separate adjudication group. However, these treating clinicians were kept masked throughout the study.

Moya 2007
Issues regarding baseline demographical characteristics of included infants, randomization, stratification, and blinding of the original intervention are described above (Moya 2005, Sinha 2005). Clinicians providing care to enrolled infants remained blinded to surfactant assignment throughout their initial NICU hospitalizations and through one year corrected age. The clinicians involved in the follow-up procedures were similarly blind to surfactant assignment.

The exact population included in the follow-up analysis is unclear. The larger of the original trials, Moya 2005, enrolled 527 infants randomized to Lucinactant and 258 infants randomized to beractant. This trial was analyzed according to the intention-to-treat principle and all subjects accordingly appear in the follow-up report (Moya 2007). However, the smaller of the original trials, Sinha 2005, enrolled 124 infants randomized to Lucinactant and 128 infants randomized to poractant alfa but only reported on 119 Lucinactant treated infants and 124 poractant treated infants. The remaining 9 infants did not receive their assigned treatments and were subsequently omitted from analysis. Although this methodology was prespecified, it is not in accordance to the intention-to-treat principle. These 9 infants, however, do appear to be included in the one year follow-up report (Moya 2007). Therefore although the original trials report on 1028 infants, the follow-up trial reports on 1037 infants.

Of the 1037 infants who were to receive either a protein containing synthetic surfactant or an animal derived surfactant extract from the original two studies, 264 died and 19 either were lost to follow-up or withdrew consent from the study. 1018 were either known to have died or were available for follow-up at one year corrected age. Of these, 754 infant survivors were available for follow-up at one year corrected age and 649 (86%) of these infants received a neurologic evaluation.

Results

PROTEIN CONTAINING SYNTHETIC SURFACTANT VS. ANIMAL DERIVED SURFACTANT IN INFANTS AT RISK FOR RDS (ALL PATIENTS) (COMPARISON 01):

PRIMARY OUTCOMES:

Neonatal mortality (mortality < 28 days of age) from any cause (Outcome 01.01):

Two studies enrolling 1028 infants reported on this outcome. Neither study of protein containing synthetic surfactant compared to animal derived surfactant extract individually demonstrated a statistically significant difference in mortality at 28 days. Meta-analysis of the two studies also did not demonstrate a significant difference in mortality at 28 days, although there was a trend towards decreased mortality in the group that received protein containing synthetic surfactant [typical RR 0.79 (95% CI 0.61, 1.02); typical RD -0.05 (95% CI -0.10, 0.01)].

Mortality at 36 weeks postmenstrual age (Outcome 01.02):

Two studies enrolling 1028 infants reported on this outcome. Neither study of protein containing synthetic surfactant compared to animal derived surfactant extract individually demonstrated a statistically significant difference in death at 36 weeks adjusted age. Meta-analysis also did not demonstrate a significant difference in death at 36 weeks adjusted age, although there was a trend towards decreased mortality in the group that received protein containing synthetic surfactant [typical RR 0.81 (95% CI 0.64, 1.03); typical RD -0.05 (95% CI -0.10, 0.01)].

Overall Mortality prior to discharge:

Overall mortality prior to discharge was not reported by either of the two studies that met inclusion criteria.

Chronic lung disease (use of supplemental oxygen) at 28 days (Outcome 01.03):

Two studies enrolling 1028 infants reported on this outcome. Neither study individually demonstrated a statistically significant difference in the incidence of chronic lung disease at 28 days. Meta-analysis also did not demonstrate a statistically different difference in the incidence of chronic lung disease at 28 days [typical RR 1.00 (95% CI 0.89, 1.12); typical RD 0.00 (-0.06, 0.06)].

Chronic lung disease (use of supplemental oxygen) at 36 weeks (Outcome 01.04):

Two studies enrolling 1028 infants reported on this outcome. Neither study individually demonstrated a statistically significant difference in the incidence of chronic lung disease at 36 weeks. Meta-analysis did not demonstrate a significant difference in the incidence of chronic lung disease at 36 weeks [typical RR 0.99 (95% CI 0.84, 1.18); typical RD 0.00 (-0.06, 0.06)].

Chronic lung disease or death at 28 days (Outcome 01.05):

Two studies enrolling 1028 infants reported on this outcome. Neither study individually demonstrated a statistically significant difference in the combined outcome of incidence of chronic lung disease or death at 28 days. Meta-analysis also did not demonstrate a significant difference in the combined outcome of incidence of chronic lung disease or death at 28 days [typical RR 0.99 (95% CI 0.88, 1.11); typical RD -0.01 (95% CI -0.07, 0.06)].

Chronic lung disease or death at 36 weeks postmenstrual age (Outcome 01.06):

Two studies enrolling 1028 infants reported on this outcome. Neither study individually demonstrated a statistically significant difference in the combined outcome of incidence of chronic lung disease or death at 36 weeks adjusted age. Meta-analysis also did not demonstrate a significant difference in the combined outcome of incidence of chronic lung disease or death at 36 weeks adjusted [typical RR 0.96 (95% CI 0.82, 1.12); typical RD -0.02 (95% CI -0.08, 0.04)].

SECONDARY OUTCOMES:

Pneumothorax:

Pneumothorax rates were not reported by either of the two studies that met inclusion criteria.

Pulmonary interstitial emphysema (Outcome 01.07):

One study (Moya 2005) enrolling 785 infants reported on this outcome. No statistically significant difference in PIE between the two groups was noted [RR 1.14 (95% CI 0.73, 1.80); RD 0.01 (95% CI -0.03, 0.06)]

Air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) (Outcome 01.08):

Two studies enrolling 1028 infants reported on this outcome. Neither study individually demonstrated a statistically significant difference in the combined incidence of all varieties of air leak syndromes. Meta-analysis also did not demonstrate a significant difference in the incidence of air leak syndromes [typical RR 1.00 (95% CI 0.73, 1.37); typical RD 0.00 (95% CI -0.04, 0.04)].

Pulmonary hemorrhage (Outcome 01.09):

Two studies enrolling 1028 infants reported on this outcome. Neither study individually demonstrated a statistically significant difference in the incidence of pulmonary hemorrhage. Meta-analysis also did not demonstrate a statistically significant difference between the two groups, although a trend was observed towards less pulmonary hemorrhage associated with the use of protein containing synthetic surfactant compared to animal derived surfactant extract [typical RR 0.73 (95% CI 0.51, 1.06); typical RD -0.03 (95% CI -0.07, 0.01)].

Respiratory distress syndrome at 24 hours (Outcome 01.10):

One study (Moya 2005) enrolling 785 infants reported on this outcome. This did not demonstrate a statistically significant decrease in incidence of RDS at 24 hours of age between the two groups [RR 1.17 (95% CI 0.96, 1.44); RD 0.06 (95% CI -0.01, 0.13)].

Patent ductus arteriosus (Outcome 01.11):

One study (Sinha 2005) enrolling 243 infants reported on this outcome. This study did not demonstrate a statistically significant difference in PDA between the two groups [RR 0.98 (95% CI 0.74, 1.31); RD -0.01 (95% CI -0.13, 0.12)].

Culture proven sepsis (Outcome 01.12):

One study (Moya 2005) enrolling 785 infants reported on this outcome. This study did not demonstrate a statistically significant difference in rates of proven sepsis between the two groups [RR 1.01 (95% CI 0.85, 1.19); RD 0.00 (95% CI -0.07, 0.08)].

Necrotizing enterocolitis (Outcome 01.13):

Two studies enrolling 1028 infants reported on this outcome. One study enrolling 785 infants (Moya 2005) demonstrated a statistically significant decrease in the rates of NEC in those infants who received a protein containing synthetic surfactant compared those who received an animal derived surfactant extract [RR 0.48 (95% CI 0.30, 0.74); RD -0.07 (95% CI -0.12, -0.02)]. The second study (Sinha 2005) did not demonstrate a statistically significant difference in rates of NEC between the two groups, nor was there a trend towards benefit or harm. Meta-analysis of the two studies demonstrates a statistically significant decrease in the rates of NEC in the protein containing synthetic surfactant group [typical RR 0.60 (95% CI 0.42, 0.86); typical RD -0.06 (95% CI -0.10, -0.01); NNT 17 (95% CI 10, 100). There was moderate heterogeneity (p = 0.09, I2 = 65.4%) for RR, but not for RD (p = 0.23, I2 = 30.8%).

Intraventricular hemorrhage - any stage (Outcome 01.14):

Two studies enrolling 1028 infants reported on this outcome. Neither study of protein containing synthetic surfactant compared to animal derived surfactant extract individually demonstrated a statistically significant difference in intraventricular hemorrhage. Meta-analysis also did not demonstrate a significant difference in intraventricular hemorrhage [typical RR 1.01 (95% CI 0.88, 1.15); typical RD 0.00 (-0.06, 0.07)].

Severe intraventricular hemorrhage Stage III or greater (Outcome 01.15):

One study (Sinha 2005) enrolling 243 infants reported on this outcome. This study did not demonstrate a statistically significant difference in severe IVH between the two groups [RR 1.52 (95% CI 0.73, 3.13); RD 0.05 (95% CI -0.03, 0.12)].

Periventricular leukomalacia (Outcome 01.16):

Two studies enrolling 1028 infants reported on this outcome. Both studies demonstrated a trend towards decreased PVL in those infants who received a protein containing synthetic surfactant compared those who received an animal derived surfactant extract; however, neither was statistically significant. Meta-analysis of the two studies did not demonstrate a significant difference in the risk of PVL among those infants who received a protein containing synthetic surfactant compared to those who received an animal derived surfactant extract [typical RR 0.79 (95% CI 0.53, 1.19); typical RD -0.02 (95% CI -0.06, 0.02)].

Retinopathy of prematurity - any stage (Outcome 01.17):

Two studies enrolling 1028 infants reported on this outcome. Neither study demonstrated a statistically significant difference in incidence of ROP among those infants who received a protein containing synthetic surfactant compared to those who received an animal derived surfactant extract. Meta-analysis similarly does not demonstrate a statistically significant difference between the two groups [typical RR 1.07 (95% CI 0.86, 1.32); typical RD 0.02 (95% CI -0.04, 0.07)].

Severe retinopathy of prematurity Stage III or greater (Outcome 01.18):

One study (Sinha 2005) enrolling 243 infants reported on this outcome. This study did not demonstrate a statistically significant difference in rates of severe ROP between the two surfactant preparations [RR 0.77 (95% CI 0.50, 1.20); RD -0.06 (95% CI -0.17, 0.04)].

Neurodevelopmental outcome at approximately two years corrected age:

Neurodevelopmental outcomes at follow-up at 2 years corrected age were not provided by any of the studies that met inclusion criteria.

POST-HOC OUTCOMES:
One year follow up data have recently been published; post-hoc analysis for known deaths, blindness, and deafness at one year of are presented.

Unilateral or bilateral deafness at one year:

One study (Moya 2007) reporting on a total of 1037 infants reported this outcome from the Moya 2005 and Sinha 2005 initial studies. This study did not demonstrate a statistically significant difference in rates of deafness at one year between the two surfactant preparations [typical RR 4.77 (95% CI 0.62, 36.92); typical RD 0.02 (95% CI 0.00, 0.03)].

Unilateral or bilateral blindness at one year:

One study (Moya 2007) reporting on a total of 1037 infants reported this outcome from the Moya 2005 and Sinha 2005 initial studies.. This study did not demonstrate a statistically significant difference in rates of blindness at one year between the two surfactant preparations [typical RR 1.29 (95% CI 0.38, 4.41); typical RD 0.00 (95% CI -0.02, 0.03)].

Known deaths at one year:

One study (Moya 2007) reporting on a total of 1037 infants reported this outcome from the Moya 2005 and Sinha 2005 initial studies. This study did not demonstrate a statistically significant difference in rates of death at one year between the two surfactant preparations [typical RR 0.92 (95% CI 0.74, 1.14); typical RD -0.02 (95% CI -0.08, 0.03)].

Subgroup Analysis

Among the two prophylaxis studies that met inclusion criteria (Sinha 2005; Moya 2005), only Sinha reported subgroups based on gestational age. In this trial, outcomes of infants <28 weeks gestation were reported and have been included in our subgroup analysis of infants < 30 weeks gestation.

PROTEIN CONTAINING SYNTHETIC SURFACTANT VS. ANIMAL DERIVED SURFACTANT IN INFANTS AT RISK FOR RDS (INFANTS < 1000 GRAMS BIRTHWEIGHT) (COMPARISON 02):

Neonatal mortality (mortality < 28 days of age) from any cause (Outcome 02.01):

One study (Sinha 2005) enrolling 160 infants reported on this outcome. This study did not demonstrate a statistically significant difference in mortality at 28 days among infants born at < 30 weeks gestation or < 1000 grams [RR 0.78 (95% CI 0.41, 1.51); RD -0.05 (95% CI -0.17, 0.08)].

Mortality at 36 weeks postmenstrual age (Outcome 02.02):

One study (Sinha 2005) enrolling 160 infants reported on this outcome. This study did not demonstrate a statistically significant difference in mortality at 36 weeks postmenstrual age among infants born at < 30 weeks gestation or < 1000 grams [RR 0.92 (95% CI 0.53, 1.61); RD -0.02 (95% CI -0.15, 0.11)].

Overall Mortality prior to discharge:

Overall mortality prior to discharge was not reported by the study that met inclusion criteria.

Chronic lung disease (use of supplemental oxygen) at 28 days (Outcome 02.03):

One study (Sinha 2005) enrolling 160 infants reported on this outcome. This study did not demonstrate a statistically significant difference chronic lung disease at 28 days among infants born at < 30 weeks gestation or < 1000 grams [RR 1.05 (95% CI 0.81,1.35); RD 0.03 (-0.12, 0.18)].

Chronic lung disease (use of supplemental oxygen) at 36 weeks postmenstrual age (Outcome 02.04):

One study (Sinha 2005) enrolling 160 infants reported on this outcome. This study did not demonstrate a statistically significant difference chronic lung disease at 36 weeks among infants born at < 30 weeks gestation or < 1000 grams [RR 1.28 (95% CI 0.72, 2.29); RD 0.06 (95% CI -0.07, 0.18)].

Chronic lung disease or death at 28 days (Outcome 02.05):

One study (Sinha 2005) enrolling 160 infants reported on this outcome. This study did not demonstrate a statistically significant difference in the combined outcome of death or chronic lung disease at 28 days among infants born at < 30 weeks gestation or < 1000 grams [RR 0.98 (95% CI 0.83, 1.15); RD -0.02 (95% CI -0.15, 0.11)].

Chronic lung disease or death at 36 weeks postmenstrual age (Outcome 02.06):

One study (Sinha 2005) enrolling 160 infants reported on this outcome. This study did not demonstrate a statistically significant difference in the combined outcome of death or chronic lung disease at 36 weeks among infants born at < 30 weeks gestation or < 1000 grams [RR 1.08 (95% CI 0.77, 1.51); RD 0.04 (95% CI -0.12, 0.19)].

Discussion

Both animal derived surfactant extracts and synthetic surfactant preparations containing only phospholipids have been shown to be beneficial in the treatment and prevention of neonatal RDS. However, greater efficacy of the animal derived surfactant extracts has been demonstrated. This is thought to be secondary to surfactant protein content retained in the manufacture of these preparations, but absent from the approved synthetic surfactants (Soll 2001). Newer synthetic surfactants that include surfactant protein or peptide mimics have recently been developed, introduced, and tested. Hypothetical benefits of these protein (or peptide) containing synthetic surfactants include increased resistance to inactivation, freedom from the need of an animal reservoir, less infectious risk, less risk of inflammation and immunogenicity, less batch-to-batch variability and potentially less cost. Potential limitations of the utility of protein (or peptide) containing synthetic surfactants include unknown cost, involved preparation process, and drug tolerability.

Lucinactant is currently the only peptide containing synthetic surfactant that has been tested in human neonatal clinical trials. The efficacy of lucinactant compared to animal derived surfactant extracts in the prevention of neonatal RDS has been evaluated in two well-conducted randomized, double blinded, controlled multicenter trials. Lucinactant was compared to commercially approved animal derived surfactant extract from porcine derivation, poractant alfa, (Sinha 2005) and bovine derivation, beractant (Moya 2005). Inclusion criteria were a gestational age of 24 - 28 weeks (Sinha 2005) or 24 - 32 weeks (Moya 2005), a birth weight between 600 g and 1250 g, and successful endotracheal intubation. Lucinactant was administered intratracheally within 20 - 30 minutes of birth. Both trials had similar exclusion criteria: Apgar score of less than three at five minutes, congenital malformations, chorioamnionitis, or CPR in the delivery room. The smaller trial (Sinha 2005) used non-inferiority analysis and excluded nine infants who did not receive lucinactant within 30 minutes of birth and, as such, was not an intention-to-treat trial. The calculated sample size for this trial, 248 infants in each group, was not reached due to slow recruitment and the early trial stoppage. A total of 252 infants were entered into the trial. The larger trial (Moya 2005) had adequate sample size: 1294 infants were analyzed based on the principle intention-to-treat. In the study by Sinha et al (Sinha 2005), the dosage of animal derived surfactant that was administered was not consistent with the surfactant manufacturers recommendation (either 100 mg/kg or 200 mg/kg) but, rather, was between the two recommended dosages (175 mg/kg). None of these methodological limitations represented a serious threat to their respective study's validity.

No statistically significant differences were noted in the primary outcomes of interest, although a trend towards decreased mortality was noted in the group that received protein containing synthetic surfactant both at 28 days [typical RR 0.79 (95% CI 0.61, 1.02); typical RD -0.05 (95% CI -0.10, 0.01)] and at 36 weeks postmenstrual age [typical RR 0.81 (95% CI 0.64, 1.03); typical RD -0.05 (95% CI -0.10, 0.01)]. No statistically significant differences between infants who received animal derived surfactant extract and protein containing synthetic surfactant were noted in incidence of chronic lung disease or in the combined outcome of chronic lung disease or death.

Previous meta-analysis comparing trials of animal derived surfactant extract to non-protein containing synthetic surfactant (Soll 2001) demonstrated a statistically significant decrease in rates of pneumothorax. While pneumothorax rates alone were not reported, this meta-analysis of protein containing synthetic surfactant compared to animal derived surfactant extract did not demonstrate a statistically significant difference in the combined incidence of all varieties of air leak syndromes (pneumothorax, pneumomediastinum, PIE) [typical RR 1.00 (95% CI 0.73, 1.37); typical RD 0.00 (95% CI -0.04, 0.04)]. One of the two studies (Moya 2005) demonstrated a statistically significant decrease in the rates of NEC in those infants who received a protein containing synthetic surfactant compared those who received an animal derived surfactant extract [RR 0.48 (95% CI 0.30, 0.74); RD -0.07 (95% CI -0.12, -0.02)] while the other did not (Sinha 2005). Meta-analysis of the two studies did demonstrate a statistically significant decrease in the rates of NEC in the protein containing synthetic surfactant group [typical RR 0.60 (95% CI 0.42, 0.86); typical RD -0.06 (95% CI -0.10, -0.01); NNH 17 (95% CI 10, 100). It is important to note, however, that the larger of the two studies being reviewed carried 73% of the weight of the meta-analysis, that this was not a pre-specified outcome in either study, and that the studies were not powered to detect a difference in rates of the incidence of NEC. Little is known about the participating centers local feeding practices and customs that may affect the rates of NEC. In addition, for this outcome, there was moderate heterogeneity (p = 0.09, I2 = 65.4%) for RR, but not for RD (p = 0.23, I2 = 30.8%).

No data have been reported on mortality or neurodevelopmental outcomes at 2 years corrected age. However follow up data on deafness, blindness, and mortality at one year were presented and have been analyzed post-hoc. No statistically significant differences were noted at one year of age in the rates of blindness, deafness, or mortality in those infants who received a protein containing synthetic surfactant compared those who received an animal derived surfactant extract.

In two well-controlled trials for prevention of RDS, lucinactant has shown clinical efficacy in improving survival and decreasing RDS similar to animal derived surfactants. No significant differences in our prespecified primary outcomes were noted between infants who received the protein containing synthetic surfactants and the animal derived synthetic surfactants. More well designed studies of adequate size and power will help confirm and refine these findings.

Reviewers' conclusions

Implications for practice

Meta-analysis of two recent trials of protein containing synthetic surfactants compared to animal derived synthetic surfactant extracts suggests that these protein containing synthetic surfactants seem to be similarly efficacious in terms of prevention of RDS, incidence of chronic lung disease, and in other common complications of prematurity. Of note, a trend towards decreased mortality and a significant decrease in rates of NEC was observed. However, there is currently insufficient evidence to justify choosing between protein containing synthetic surfactants and animal derived surfactants for prevention of RDS. In addition, no studies are available using protein containing synthetic surfactants to treat existing disease. While protein containing synthetic surfactants hold great promise of similar or improved efficacy when compared to existing animal derived surfactants, they are not currently approved for use. Further studies will be needed to refine these estimates prior to any specific recommendations regarding their use in lieu of animal-derived surfactants.

Implications for research

Further well designed, independent studies of adequate size and power are needed to confirm and refine these findings. The sample size should be structured to evaluate differences between important clinical outcomes such as mortality and chronic lung disease. In addition, trials of other synthetic surfactants with mimics of surfactant proteins B and C are warranted.

Acknowledgements

We would like to acknowledge Susan Hayward for preparation of the manuscript.

Potential conflict of interest

Dr. R. Soll has acted as a paid consultant and invited speaker for several of the pharmaceutical companies that manufacture surfactant preparations discussed in this review (Abbott Laboratories, Ross Laboratories, Chiesi Farmaceutici, Dey Laboratories, Burroughs Wellcome).

Dr T. Wiswell has acted as a paid consultant and an invited speaker for one of the pharmaceutical companies that manufacture surfactant preparations discussed in this review (Discovery Laboratories).

Dr. Robert Pfister has no conflict of interests to acknowledge.

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Moya 2005	50 center study performed in Brazil, Chile, Mexico, Ecuador, Hungary, Panama, Poland, Russia, and Uruguay. Infants were randomized in a masked manner to receive lucinactant or colfosceril palmitate, or beractant in a 2:2:1 ratio. Randomization was stratified by birth weight (600-800 grams, 801-1000 grams, 1001 to 1250 grams). Randomization accomplished by sealed sequential envelopes. Intervention masked by having surfactant administration team. Infants were analyzed according to intention to treat analysis	Preterm infants between 24-32 weeks gestation, birth weight between 600-1200 grams, on assisted ventilation. 785 infants enrolled.	Lucinactant (n=527), 5.8 ml/kg versus beractant (n=258), 4 mg/kg, versus colfosceril (n=509). All groups received pulmonary surfactant intratracheally within 20-30 minutes of birth	Primary comparison of interest in the trial was between lucinactant and colfosceril palmitate. Prespecified primary end points included RDS at 24 hours and the occurrence of death related to RDS by 14 days. Other outcomes included mortality, BPD, air leaks, IVH, PVL, ROP, pulmonary hemorrhage, and sepsis.	Part of a trial with three groups: lucinactant, colfosceril, and beractant given in a 2:2:1 ratio	A
Sinha 2005	19 center study performed in Canada, France, Hungary, Poland, Portugal, Spain, United Kingdom, and U.S. Randomization was stratified according to estimated birth weight (600-1000 grams, 1001-1250 grams). Treatment assignment accomplished using sequentially numbered opaque, sealed drug identification envelopes. Independent dosing drug preparation team not involved in the study administered treatment.	Preterm infants 24-28 weeks gestation, birth weight 600-1200 grams, successfully intubated at birth. 252 infants included in prophylaxis trial. Nine infants (5 lucinactant, 4 poractant alpha) comprising 3.6% of total randomized population, did not receive surfactant within 30 minutes and were excluded.	Lucinactant (n=124), 5.8 ml/kg, versus poractant alpha (n=128), 2.2 ml/kg. Both groups were administered pulmonary surfactant intratracheally within 30 minutes of birth	Primary outcome measure was survival without BPD at 28 days of life. Sample size calculated based on "non-inferiority trial". Other outcomes included mortality, air leaks, IVH, PVL, NEC, ROP, sepsis, apnea, pulmonary hemorrhage, and PDA.	A non-inferiority trial that did not analyze by intention-to-treat. Poractant dosage given to control group was between commercially approved dosages. Trial ended prior to goal sample size was achieved.	A

Characteristics of excluded studies

Study	Reason for exclusion
Cochrane 1996	Non-blinded trial with no comparison group.

References to studies

References to included studies

Moya 2005 {published data only}

Moya F, Gadzinowski J, Bancalari E, Salinas V, Kopelman B, Bancalari A et al. A multicenter, randomized, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome in very preterm infants. Pediatrics 2005;115:1018-29.

Sinha 2005 {published data only}

Sinha S, Lacaze-Masmonteil T, Valls i Soler A, Gadzinowski J, Hadju J, Bernstein G et al. A multicenter, randomized, controlled trial of lucinactant versus poractant alfa in very premature infants at high risk for respiratory distress syndrome. Pediatrics 2005;115:1030-8.

References to excluded studies

Cochrane 1996 {published data only}

Cochrane CG, Revak SD, Merritt TA, Heldt GP, Hallman M, Cunningham MD et al. The efficacy and safety of KL4-Surfactant in preterm infants with RDS. American Journal of Respiratory and Critical Care Medicine 1996;153:404-10.

* indicates the primary reference for the study

Other references

Additional references

Ainsworth 2002

Ainsworth SB, Milligan DW. Surfactant therapy for respiratory distress syndrome in premature neonates: a comparative review. American Journal of Respiratory Medicine 2002;1:417-3.

Beers 1992

Beers MF, Fisher AB. Surfactant protein C: a review of its unique properties and metabolism. American Journal of Physiology 1992;263:151-60.

Clements 1977

Clements JA. Functions of the alveolar lining. American Review of Respiratory Disease 1977;115:67-71.

Cochrane 1991

Cochrane CG, Revak SD. Pulmonary surfactant protein B (SP-B): structure-function relationships. Science 1991;254:566-8.

Davis 1998

Davis AJ, Jobe AH, H�fner D, Ikegami M. Lung function in premature lambs and rabbits treated with a recombinant SP-C surfactant. American Journal of Respiratory and Critical Care Medicine 1998;157:553-9.

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.

Ikegami 1998

Ikegami M, Horowitz AD, Whitsett JA, Jobe AH. Clearance of SP-C and recombinant SP-C in vivo and in vitro. American Journal of Physiology. Lung Cellular and Molecular Physiology 1998;274:L933-9.

Jobe 1993

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

Manalo 1996

Manalo E, Merritt TA, Kheiter A, Amirkhanian J, Cochrane C. Comparative effects of some serum components and proteolytics products of fibrinogen on surface tension-lowering abilities of beractant and a synthetic peptide containing surfactant KL4. Pediatric Research 1996;39:947-52.

Merritt 1988

Merritt TA, Strayer DS, Hallman M, Spragg RD, Wozniak P. Immunologic consequences of exogenous surfactant administration. Seminars in Perinatology 1988 Jul.;12:221-30.

Moya 1993

Moya FR, Hoffman DR, Zhao B, Johnston JM. Platelet-activating factor in surfactant preparations. Lancet 1993;341:858-60.

Nogee 1993

Nogee LM, de Mello DE, Dehner LP, Colten HR. Brief Report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. New England Journal of Medicine 1993;328:406-10.

Possmayer 1990

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

Revak 1988

Revak SD, Merritt TA, Degryse E, Stefani L, Courtney M, Hallman M et al. Use of human surfactant low molecular weight apoprotein in the reconstitution of surfactant biologic activity. Journal of Clinical Investigation 1988;81:826-33.

Revak 1996

Revak SD, Merritt TA, Cochrane CG, Heldt GP, Alberts MS, Anderson DW et al. Efficacy of synthetic peptide-containing surfactants in the treatment of respiratory distress syndrome in preterm infant rhesus monkeys. Pediatric Research 1996;39:715-24.

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 1992

Soll RF, McQueenMC. Respiratory Distress Syndrome. In: Sinclair J, Bracken M, editor(s). Effective Care of the Newborn. Oxford: Oxford University Press, 1992.

Soll 2001

Soll RF, Blanco F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 2001, Issue 1.

Tooley 1987

Tooley WH, Clements JA, Muramatsu K, Brown CL, Schleuter MA. Lung function in prematurely delivered rabbits treated with a synthetic surfactant. American Review of Respiratory Disease 1987;136:651-6.

Walther 2000

Walther FJ, Gordon LM, Zasadzinski JA, Sherman MA, Waring AJ. Surfactant protein B and C analogues. Molecular Genetics and Metabolism 2000 Sep-Oct;71:342-51.

Walther 2002

Walther FJ, Hernandez-Juviel JM, Gordon LM, Sherman MA, Waring AJ. Dimeric surfactant protein B peptide sp-b (1-25) in neonatal and acute respiratory distress syndrome. Experimental Lung Research 2002;28:623-40.

Whitsett 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.

Whitsett 2002

Whisett JA, Weaver TE. Hydrophobic surfactant proteins in lung function and disease. New England Journal of Medicine 2002;347:2141-8.

Wright 1997

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

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Protein containing synthetic surfactant vs animal derived sufactant (all patients)
01 Mortality at 28 days	2	1028	RR (fixed), 95% CI	0.79 [0.61, 1.02]
02 Mortality at 36 weeks postmenstrual age	2	1028	RR (fixed), 95% CI	0.81 [0.64, 1.03]
03 Chronic lung disease at 28 days	2	1028	RR (fixed), 95% CI	1.00 [0.89, 1.12]
04 Chronic lung disease at 36 weeks	2	1028	RR (fixed), 95% CI	0.99 [0.84, 1.18]
05 Chronic lung disease or death at 28 days	2	1028	RR (fixed), 95% CI	0.99 [0.88, 1.11]
06 Chronic lung disease or death at 36 weeks postmenstrual age	2	1028	RR (fixed), 95% CI	0.96 [0.82, 1.12]
07 Pulmonary interstitial emphysema	1	785	RR (fixed), 95% CI	1.14 [0.73, 1.80]
08 Air leaks	2	1028	RR (fixed), 95% CI	1.00 [0.73, 1.37]
09 Pulmonary hemorrhage	2	1028	RR (fixed), 95% CI	0.73 [0.51, 1.06]
10 Respiratory distress syndrome at 24 hours	1	785	RR (fixed), 95% CI	1.17 [0.96, 1.44]
11 Patent ductus arteriosis	1	243	RR (fixed), 95% CI	0.98 [0.74, 1.31]
12 Proven sepsis	1	785	RR (fixed), 95% CI	1.01 [0.85, 1.19]
13 Necrotizing enterocolitis	2	1028	RR (fixed), 95% CI	0.60 [0.42, 0.86]
14 Intraventricular hemorrhage	2	1028	RR (fixed), 95% CI	1.01 [0.88, 1.15]
15 Severe intraventricular hemorrhage (Grade III and IV)	1	243	RR (fixed), 95% CI	1.52 [0.73, 3.13]
16 Periventricular leukomalacia	2	1028	RR (fixed), 95% CI	0.79 [0.53, 1.19]
17 Retinopathy of prematurity	2	1028	RR (fixed), 95% CI	1.07 [0.86, 1.32]
18 Severe retinopathy of prematurity (Stage III or greater)	1	243	RR (fixed), 95% CI	0.77 [0.50, 1.20]
02 Protein containing synthetic surfactant vs animal derived surfactant in infants at risk for RDS <1000g
01 Mortality at 28 days	1	160	RR (fixed), 95% CI	0.78 [0.41, 1.51]
02 Mortality at 36 weeks postmenstrual age	1	160	RR (fixed), 95% CI	0.92 [0.53, 1.61]
03 Chronic lung disease at 28 days	1	160	RR (fixed), 95% CI	1.05 [0.81, 1.35]
04 Chronic lung disease at 36 weeks	1	160	RR (fixed), 95% CI	1.28 [0.72, 2.29]
05 Chronic lung disease or death at 28 days	1	160	RR (fixed), 95% CI	0.98 [0.83, 1.15]
06 Chronic lung disease or death at 36 weeks postmenstrual age	1	160	RR (fixed), 95% CI	1.08 [0.77, 1.51]
03 Post Hoc Outcomes
01 Unilateral or bilateral Deafness in survivors evaluated at 1 year	2	642	RR (fixed), 95% CI	4.77 [0.62, 36.92]
02 Unilateral or bilateral Blindness in survivors evaluated at 1 year	2	642	RR (fixed), 95% CI	1.29 [0.38, 4.41]
03 Known Deaths at 1 year	2	1037	RR (fixed), 95% CI	0.92 [0.74, 1.14]

01 Protein containing synthetic surfactant vs animal derived sufactant (all patients)

01.01 Mortality at 28 days

01.02 Mortality at 36 weeks postmenstrual age

01.03 Chronic lung disease at 28 days

01.04 Chronic lung disease at 36 weeks

01.05 Chronic lung disease or death at 28 days

01.06 Chronic lung disease or death at 36 weeks postmenstrual age

01.07 Pulmonary interstitial emphysema

01.08 Air leaks

01.09 Pulmonary hemorrhage

01.10 Respiratory distress syndrome at 24 hours

01.11 Patent ductus arteriosis

01.12 Proven sepsis

01.13 Necrotizing enterocolitis

01.14 Intraventricular hemorrhage

01.15 Severe intraventricular hemorrhage (Grade III and IV)

01.16 Periventricular leukomalacia

01.17 Retinopathy of prematurity

01.18 Severe retinopathy of prematurity (Stage III or greater)

02 Protein containing synthetic surfactant vs animal derived surfactant in infants at risk for RDS <1000g

02.01 Mortality at 28 days

02.02 Mortality at 36 weeks postmenstrual age

02.03 Chronic lung disease at 28 days

02.04 Chronic lung disease at 36 weeks

02.05 Chronic lung disease or death at 28 days

02.06 Chronic lung disease or death at 36 weeks postmenstrual age

03 Post Hoc Outcomes

03.01 Unilateral or bilateral Deafness in survivors evaluated at 1 year

03.02 Unilateral or bilateral Blindness in survivors evaluated at 1 year

03.03 Known Deaths at 1 year

Contact details for co-reviewers

Dr Roger Soll
Coordinating Editor, Cochrane Neonatal Review Group
Division of Neonatal-Perinatal Medicine
University of Vermont
Fletcher Allen Health Care, Smith 581
111 Colchester Avenue
Burlington
Vermont USA
05401
Telephone 1: 802 847 2392
Facsimile: 802 847 5225
E-mail: Roger.Soll@vtmednet.org

Dr Thomas E Wiswell
Center for Neonatal Care
2718 North Orange Avenue
Suite B
Orlando
Florida USA
32804
Telephone 1: 407 894 1405
Facsimile: 407 894 9176
E-mail: thomas_wiswell@yahoo.com

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2007 (see http://www.thecochranelibrary.com 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.