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Protein-containing synthetic surfactant versus protein-free synthetic surfactant for the prevention and treatment of respiratory distress syndrome

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Authors

Robert H Pfister1, Roger Soll2, Thomas E Wiswell3

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


1Division of Neonatal Perinatal Medicine, Fletcher Allen Health Care, Burlington, VT, USA [top]
2Division of Neonatal-Perinatal Medicine, University of Vermont, Burlington, Vermont, USA [top]
3Neonatology, Center for Neonatal Care, Orlando, Florida, USA [top]

Citation example: Pfister RH, Soll R, Wiswell TE. Protein-containing synthetic surfactant versus protein-free synthetic surfactant for the prevention and treatment of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006180. DOI: 10.1002/14651858.CD006180.

Contact person

Robert H Pfister

Fellow in Neonatal Perinatal Medicine
Division of Neonatal Perinatal Medicine
Fletcher Allen Health Care
Smith #582
111 Colchester Avenue
Burlington
VT
05401
USA

E-mail: robert.pfister@vtmednet.org

Dates

Assessed as Up-to-date: 16 June 2009
Date of Search: 1 March 2009
Next Stage Expected: 16 June 2011
Protocol First Published: Issue 4 , 2006
Review First Published: Not specified
Last Citation Issue: Issue 4 , 2006

History

Date Event Description
27 October 2008 Amended

Converted to new review format.

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

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

Search methods

Standard search methods of the Cochrane Neonatal Review Group were used. The search included MEDLINE (1966 - March 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) in all languages.

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 a protein free synthetic surfactant were included for this review. Studies of treatment or prevention of respiratory distress syndrome were included.

Data collection and analysis

Data regarding mortality, chronic lung disease and multiple secondary outcome measures were abstracted by the review authors. Statistical analysis was performed using Review Manager software. Categorical data were 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 I2 statistic.

Main results

One study was identified that compared protein containing synthetic surfactants (PCSS) to protein free synthetic surfactants. Infants who received protein containing synthetic surfactant compared to protein free synthetic surfactant did not demonstrate significantly different risks of prespecified primary outcomes: mortality at 36 weeks postmenstrual age (PMA) [RR 0.89 (95% CI 0.71, 1.11)], chronic lung disease at 36 weeks PMA [RR 0.89 (95% CI 0.78, 1.03)], or the combined outcome of mortality or chronic lung disease at 36 weeks PMA [RR 0.88 (95% CI 0.77, 1.01)]. Among the secondary outcomes, a decrease in the incidence of respiratory distress syndrome at 24 hours of age was demonstrated in the group that received PCSS [RR 0.83 (95% CI 0.72, 0.95).

Authors' conclusions

In the one trial comparing protein containing synthetic surfactants compared to protein free synthetic surfactant for the prevention of RDS, no statistically different clinical differences in death and chronic lung disease were noted. Clinical outcomes between the two groups were generally similar although the group receiving protein containing synthetic surfactants did have decreased incidence of respiratory distress syndrome. Further well designed studies comparing protein containing synthetic surfactant to the more widely used animal derived surfactant extracts are indicated.

Plain language summary

Protein-containing synthetic surfactant versus protein-free synthetic surfactant for the prevention and treatment of respiratory distress syndrome

Respiratory distress syndrome (RDS) is a significant cause of illness in preterm infants. RDS 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 RDS. 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 animal lungs 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 naturally occurring surfactant protein. These preparations have been recently tested in comparison to the protein free synthetic surfactant preparations.

A recent trial of protein containing synthetic surfactant compared to protein free synthetic surfactant suggests that these protein containing synthetic surfactants help prevent respiratory distress syndrome and may or may not lead to a decrease in lung injury (chronic lung disease). Other clinical outcomes were similar. Further studies will help refine recommendations concerning use of protein containing synthetic surfactants.

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Background

Description of the condition

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. 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. 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 defences of the lung (Wright 1997).

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 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 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.

Description of the intervention

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 phospholipid 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 vitrostudies 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 natural surfactants (Manalo 1996). In vivostudies in preterm rhesus monkeys demonstrated that lucinactant successfully expanded the pulmonary alveoli and promoted gas exchange (Revak 1996). Furthermore, administration of 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 modelled 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 (nSP-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 that are able to move within and between lipid layers. This biochemical configuration may help create multilayer phospholipid 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 natural sheep surfactants. In addition, in vivostudies 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).

How the intervention might work

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.

Why it is important to do this review

This systematic review will evaluate trials that compare synthetic surfactants containing surfactant protein mimics (either as whole protein or as peptide fragments) to protein-free synthetic surfactant in the treatment or prevention of RDS. A companion review of trials that compare synthetic surfactants containing surfactant protein mimics to animal derived surfactant extract can be found in the Cochrane Library (Pfister 2007).

Objectives

To assess the effect of administration of synthetic surfactant containing surfactant protein mimics compared to protein free synthetic surfactant on the risk of mortality, chronic lung disease, and other morbidities associated with prematurity in preterm infants at risk for or having RDS. Separate comparisons were planned for studies that addressed the prophylactic use of surfactant and studies that addressed the treatment of established disease. Subgroup analysis were planned according to which surfactant protein is being mimicked, whether the mimic is a whole protein or peptide fragment, the degree of prematurity, and the severity of disease.

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Methods

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 RDS.

At risk for RDS was defined as a preterm infant in the first hour of life with gestational age < 32 weeks or birthweight < 1250 grams. Established disease was defined as a preterm infant requiring respiratory support and having signs of RDS.

Types of interventions

Infants randomly allocated to receive either a synthetic surfactant containing surfactant protein mimic (either as whole proteins or peptide fragments (e.g. Venticute/lusupultide or Surfaxin/lucinactant) or a protein-free synthetic surfactant preparation (e.g. pumactant/ALEC®, colfosceril/Exosurf®, or aposurf).

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. Chronic lung disease (use of supplemental oxygen at 36 weeks postmenstrual age);
  4. Death or chronic lung disease at 36 weeks postmenstrual age.
Secondary Outcomes
  1. Pneumothorax;
  2. Air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum);
  3. Pulmonary hemorrhage;
  4. RDS at 24 hours;
  5. Patent ductus arteriosus (PDA) (PDA that has been treated with cyclo-oxygenase inhibitor or surgery);
  6. Culture proven bacterial sepsis;
  7. Culture proven fungal sepsis;
  8. Necrotizing enterocolitis (NEC) (defined as Bell Stage II or greater);
  9. Intraventricular hemorrhage (IVH) [any grade and severe (grade 3 - 4)];
  10. Periventricular leukomalacia (PVL);
  11. Retinopathy of prematurity (ROP) [all stages and severe (stage 3 or greater)];
  12. Use of oxygen at 28 days of life;
  13. Use of oxygen at 36 weekly postmenstrual age;
  14. Neurodevelopmental outcome at approximately two years corrected age (acceptable range 18 months to 28 months) including: cerebral palsy, mental delay (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.

Post hocanalyses were 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.

Electronic searches

Published manuscripts: Search included PubMed (1966 - March 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2009). 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). A similar search was performed using the following text words: lucinactant, surfaxin, venticute, KL4, SP-B, SP-C with similar limits noted above. From the resulting studies randomized or quasi-randomized controlled studies 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.

Searching other resources

Published abstracts: The abstracts of the Society for Pediatric Research (USA) (published in Pediatric Research) for the years 1985 - 1999 were searched by hand using the following key words: {surfactant OR pulmonary surfactant} AND {respiratory distress syndrome}. Abstracts from 2000 - 2009 were searched electronically through the Pediatric Academic Societies External Web Site Policy website (abstracts online). For abstract books that do not include keywords, the search was limited to relevant sections such as pulmonary and neonatology.

Clinical trials registries were also searched for ongoing or recently completed trials (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Data collection and analysis

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

Selection of studies

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 select the studies for inclusion. The review authors resolved any disagreement by discussion.

Data extraction and management

Two of the three review authors (RP, RFS) 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 was entered into RevMan by one review author (RP) and then checked by a second review author (RFS). Any disagreements were addressed by the third reviewer (TW).

Assessment of risk of bias in included studies

The standard methods of the Cochrane Neonatal Review Group were employed. The methodological quality of the studies were 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 criterion, assessment was yes, no, can't tell. Two review authors separately assessed each study (RP, RFS). Any disagreement was resolved by discussion. This information was added to the table "Characteristics of Included Studies".

In addition, following issues were evaluated and entered into the the Risk of Bias Table:

  1. Sequence generation: Was the allocation sequence adequately generated?
  2. Allocation concealment: Was allocation adequately concealed?
  3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
  4. Incomplete outcome data: Were incomplete outcome data adequately addressed?
  5. Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?
  6. Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?.

Measures of treatment effect

Statistical analyses were performed using Review Manager 5 (RevMan 5) 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.

Assessment of heterogeneity

We planned to estimate the treatment effects of individual trials and examine heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic. If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hocsub group analyses. We planned to use a fixed effects model for meta-analysis.

Data synthesis

If multiple studies were identified and meta-analysis was judged to be appropriate, the analysis would have been performed using RevMan 5, supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference, we planned to use the Mantel-Haenszel method. For measured quantities, we planned to use the inverse variance method. All meta-analyses were to be done using the fixed effect model.

Subgroup analysis and investigation of heterogeneity

Comparison I: Studies that treated infants at risk of RDS (prophylaxis)
  1. SP-B mimic containing synthetic surfactants
    1. Studies that utilized peptide containing synthetic surfactant
    2. Studies that utilized whole protein containing synthetic surfactant
  2. SP-C mimic containing synthetic surfactants
    1. Studies that utilized peptide containing synthetic surfactant
    2. Studies that utilized whole protein containing synthetic surfactant
Comparison 2: Studies that treated infants with established RDS (treatment)
  1. SP-B mimic containing synthetic surfactants
    1. Studies that utilized peptide containing synthetic surfactant
    2. Studies that utilized whole protein containing synthetic surfactant
  2. SP-C mimic containing synthetic surfactants
    1. Studies that utilized peptide containing synthetic surfactant
    2. Studies that utilized whole protein containing synthetic surfactant
  3. Gestational age (infants born at < 30 weeks gestation)
  4. Moderate to severe respiratory disease (moderate to severe disease defined as need for assisted ventilation and > 40% supplemental oxygen necessary to maintain adequate oxygenation)

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Results

Description of studies

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

The search identified one study reporting the prophylactic administration of synthetic surfactant containing surfactant protein-B mimics that met inclusion criteria (Moya 2005). The study of Moya 2005includes two reports: the initial report of the trial (Moya 2005) and the follow-up report of Moya 2007 that analyzed survival, pulmonary, and neurologic outcomes through one year corrected age.

No randomised controlled trials of treatment of established RDS with synthetic surfactant containing surfactant protein-B mimics that met inclusion criteria were identified.

No randomised controlled trials were identified that met inclusion criteria for surfactant protein-C mimics nor were studies identified that reported on whole protein containing synthetic surfactants.

Included Studies:

Moya 2005:

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

Objective:To compare the efficacy and safety of a synthetic surfactant containing a SP-B mimic to a 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. 1294 infants were randomised in this trial; 527 to lucinactant, 509 to colfosceril palmitate, and 258 to beractant. Therefore, for the purposes of this review, the relevant population are the 1036 infants randomised to either lucinactant or colfosceril palmitate. These infants 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 protein-free synthetic surfactant group received 5 mL/kg of colfosceril palmitate, a protein-free synthetic surfactant that contains a single phospholipid, DPPC, cetyl alcohol, and tyloxapol. In this study, a third group received a beractant, a bovine lung extract containing phospholipids and bovine surfactant proteins. 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 surfactant protein mimics to animal derived surfactant extract preparations. In all groups, the pulmonary surfactant was administered intratracheally within 20 - 30 minutes of birth. Infants were randomised 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 was 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 haemorrhage, and sepsis.

Moya 2007 reports follow-up data from the aforementioned randomised controlled trial as well as data from a second RDS prophylaxis trial of protein containing synthetic surfactants that did not have a protein-free synthetic surfactant comparison group (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:1269 infants preterm infants enrolled in the Moya 2005trial (described above) who were either known to have died or successfully seen at follow-up at approximately one year of age were included. Of these infants, 1018 were randomised to either lucinactant or colfosceril palmitate. 288 of these infants were known to have died (lucinactant N = 140; colfosceril palmitate N = 148) and 730 were known to have survived and to potentially be available for follow-up (lucinactant N = 379; colfosceril palmitate N = 351).

Intervention: Described above in the Moya 2005.

Outcomes assessed:Postdischarge rehospitalization rates, respiratory morbidity after 36 weeks postmenstrual age, growth measurements at one year of age, neurologic assessment at one year of age, and death by one year of age were recorded. Included in the neurologic examination was 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 consent withdrawn were analyzed and reported both as if they had died and separately as if they were not in the study.

Excluded Studies:

Cochrane 1996: Cochrane and coworkers studied 47 seven infants with RDS who were treated within 4 h of birth with the KL4-peptide/phospholipid mixture to determine the effect of this protein containing synthetic surfactant (a precursor to lucinactant) on lung expansion and gas exchange in premature human infants with respiratory distress syndrome (RDS). Infants were not randomized and there was no control group.

Sinha 2005was a 19 center study performed in Canada, France, Hungary, Poland, Portugal, Spain, the United Kingdom, and the United States. The objective of the study was 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. This study enrolled preterm infants between 24 and 28 weeks gestational age with birth weights between 600 and 1250 grams who were successfully intubated at birth. The trial compared lucinactant, a synthetic surfactant containing a SP-B mimic with phospholipids with poractant alfa, a porcine lung extract containing phospholipids and porcine surfactant proteins. The trial is not included in this review as it did not have an arm that included a non-protein containing synthetic surfactant.

Ongoing Studies:

A search of ClinicalTrials.gov revealed no ongoing trials of protein containing synthetic surfactants used as treatment or as prophylaxis of RDS.

Risk of bias in included studies

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.Details are given in the table "Characteristics of Included Studies" and the Risk of Bias table.

Moya 2005

In the initial trial of Moya and coworkers (Moya 2005), infants were randomised in a masked manner to receive lucinactant, colfosceril palmitate, or beractant in a 2:2:1 ratio, with randomizations stratified according to birthweight (600 - 800 grams; 801 - 1000 grams; 1001 - 1250 grams). Birthweight stratum randomizations codes were computer-generated by an independent university-based statistical center. Each participating institution received sealed envelopes with randomizations 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 surfactant 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 randomised. Six infants (three lucinactant, three colfosceril palmitate) comprising 0.46% of the total randomised population were not dosed with any surfactant. Four patients received the incorrect treatment. One patient assigned to receive beractant received lucinactant and another patient assigned to receive beractant received colfosceril palmitate. Two patients assigned to receive colfosceril palmitate 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.

Clinicians providing care to study infants remained blinded to surfactant assignment throughout their initial NICU hospitalizations and through one year corrected 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 cause of death, were evaluated by the independent adjudication committee.

In the follow-up report of Moya 2007 that analyzed survival, pulmonary, and neurologic outcomes through one year corrected age, clinicians involved in the follow-up procedures were similarly blind to surfactant assignment.

Of the 1036 infants who were to receive either a protein containing synthetic surfactant or a protein-free synthetic surfactant from the original study, 288 died and 18 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, 730 infant survivors were available for follow-up at one year corrected age and 585 (80%) of these infants had a neurologic evaluation.

Subgroup Analysis

The single prophylaxis study that met inclusion criteria (Moya 2005) did not report subgroups based on gestational age and, therefore, no subgroup analyses could be performed.

Effects of interventions

PROTEIN CONTAINING SYNTHETIC SURFACTANT VS. PROTEIN-FREE SYNTHETIC SURFACTANT IN INFANTS AT RISK FOR RDS (ALL PATIENTS) (COMPARISON 1):

PRIMARY OUTCOMES:
Neonatal mortality (mortality less than/or equal to 28 days of age) from any cause (Outcome 1.1):

Mortality on or before 28 days of life was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in mortality at 28 days [RR 0.89 (95% CI 0.70, 1.14); RD -0.02 (95% CI -0.07, 0.03)].

Mortality at 36 weeks postmenstrual age (Outcome 1.2):

Mortality on or before 36 weeks postmenstrual age was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in mortality at 36 weeks postmenstrual age [RR 0.89 (95% CI 0.71, 1.11); RD -0.03 (95% CI -0.08, 0.02)].

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 1.3):

Chronic lung disease defined as use of supplemental oxygen at 28 days was reported by Moya et al (Moya 2005) in a study that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of chronic lung disease at 28 days [RR 0.93 (95% CI 0.84, 1.03); RD -0.04 (95% CI -0.10, 0.02)].

Chronic lung disease (use of supplemental oxygen) at 36 weeks postmenstrual age (Outcome 1.4):

Mortality on or before 36 weeks postmenstrual age was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of chronic lung disease at 36 weeks postmenstrual age [RR 0.89 (95% CI 0.78, 1.03); RD -0.05 (95% CI -0.11, 0.01)].

Chronic lung disease or death at 28 days (Outcome 1.5):

Chronic lung disease or death at 28 days was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of chronic lung disease or death at 28 days [RR 0.93 (95% CI 0.84, 1.03); RD -0.04 (95% CI -0.10, 0.02)].

Chronic lung disease or death at 36 weeks postmenstrual age (Outcome 1.6):

Chronic lung disease or death on or before 36 weeks postmenstrual age was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, demonstrated a borderline statistically significant decrease in the incidence of chronic lung disease or death at 36 weeks PMA in the group that received protein containing synthetic surfactant [RR 0.88 (95% CI 0.77, 1.01); RD -0.06 (95% CI -0.12, 0.00).

SECONDARY OUTCOMES:

Pneumothorax:

Pneumothorax rates were not reported by Moya 2005.

Pulmonary interstitial emphysema (Outcome 1.7):

Incidence of pulmonary interstitial emphysema was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of pulmonary interstitial emphysema [RR 0.85 (95% CI 0.60, 1.18); RD -0.02 (95% CI -0.06, 0.02)].

Air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) (Outcome 1.8):

Incidence of all air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the combined incidence of all varieties of air leak syndromes [RR 0.85 (95% CI 0.65, 1.12); RD -0.03 (95% CI -0.07, 0.02)].

Pulmonary hemorrhage (Outcome 1.9):

Incidence of pulmonary hemorrhage was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of pulmonary hemorrhage [RR 0.88 (95% CI 0.62, 1.25); RD -0.01 (95% CI -0.05, 0.02)].

Respiratory distress syndrome at 24 hours (Outcome 1.10):

Incidence of respiratory distress syndrome at 24 hours was reported in a study (Moya 2005) that enrolled 1036 infants. This study demonstrated a statistically significant decrease in the incidence of RDS at 24 hours in those infants who received a protein containing synthetic surfactant compared those who received a protein-free synthetic surfactant [RR 0.83 (95% CI 0.72, 0.95); RD -0.08 (95% CI -0.14, -0.02)].

Patent ductus arteriosus:

Incidence of patent ductus arteriosus was not reported by Moya 2005.

Culture proven sepsis (Outcome 1.11):

Incidence of culture proven sepsis was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of culture proven sepsis [RR 1.00 (95% CI 0.87, 1.14); RD 0.00 (95% CI -0.06, 0.06)].

Necrotizing enterocolitis (Outcome 1.12):

Incidence of necrotizing enterocolitis was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of necrotizing enterocolitis [RR 0.78 (95% CI 0.51, 1.21); RD -0.02 (95% CI -0.05, 0.01)].

Periventricular leukomalacia (Outcome 1.13):

Incidence of periventricular leukomalacia was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of periventricular leukomalacia [RR 0.80 (95% CI 0.56, 1.15); RD -0.02 (95% CI -0.06, 0.01)].

Retinopathy of prematurity - any stage (Outcome 1.14):

Incidence of any retinopathy of prematurity was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of retinopathy of prematurity of any stage [RR 1.01 (95% CI 0.82, 1.24); RD 0.00 (95% CI -0.05, 0.06)].

Severe retinopathy of prematurity Stage III or greater:

Severe retinopathy of prematurity rates were not reported by Moya 2005.

Intraventricular hemorrhage - any stage (Outcome 1.15):

Incidence of any intraventricular hemorrhage was reported in a study (Moya 2005) that enrolled 1036 infants. This study, which compared protein containing synthetic surfactant to protein-free synthetic surfactant, did not demonstrate a statistically significant difference in the incidence of intraventricular hemorrhage of any stage [RR 1.00 (95% CI 0.89, 1.13); RD 0.00 (95% CI -0.06, 0.06)].

Severe intraventricular hemorrhage Stage III or greater (Outcome 1.16):

Incidence of severe intraventricular hemorrhage was reported by Moya and coworkers (Moya 2005). Moya and coworkers did not demonstrate a statistically significant difference in the incidence of Grade III or IV intraventricular hemorrhage [RR 0.99 (95% CI 0.79, 1.25); RD -0.00 (95% CI -0.05, 0.05)].

Neurodevelopmental outcome at approximately two years corrected age:

Neurodevelopmental outcomes at follow-up at two years corrected age were not provided by Moya 2005.

POST-HOC OUTCOMES:

The following outcomes and their follow up intervals were not originally stated in our protocol, however one year follow up data have recently been published. These post-hoc analysis for known deaths, blindness, and deafness at one year of are presented.

Unilateral or bilateral deafness at one year in examined survivors (Outcome 01.17):

Incidence of deafness at one year follow up was reported by Moya et al (Moya 2007). The study reported on the outcome of 585 surviving infants followed from the original Moya 2005study. This study did not demonstrate a statistically significant difference in rates of deafness at one year between the two surfactant preparations [RR 1.30 (95% CI 0.50, 3.38); RD 0.01 (95% CI -0.02, 0.03)].

Unilateral or bilateral blindness at one year in examined survivors (Outcome 01.18):

Incidence of blindness at one year follow up was reported by Moya et al (Moya 2007). The study reported on the outcome of 585 surviving infants followed from the original Moya 2005study. This study did not demonstrate a statistically significant difference in rates of blindness at one year between the two surfactant preparations [RR 0.73 (95% CI 0.29, 1.82); RD -0.01 (95% CI -0.04, 0.02)].

Known deaths at one year (Outcome 1.19):

Mortality rates at age one year were reported by in a study (Moya 2007) reporting on a total of 585 infants followed from the Moya 2005initial study. This study did not demonstrate a statistically significant difference in rates of death at one year between the two surfactant preparations [RR 0.91 (95% CI 0.75, 1.11); RD -0.03 (95% CI -0.08, 0.03)].

PROTEIN CONTAINING SYNTHETIC SURFACTANT VS. PROTEIN-FREE SYNTHETIC SURFACTANT IN THE TREATMENT OF INFANTS WITH RDS (ALL PATIENTS) (COMPARISON 2):

No studies were identified.

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. Although greater efficacy of the animal derived surfactant extracts has been demonstrated, the synthetic surfactant preparations have been shown to cause statistically significant reductions in rates of pneumothorax, pulmonary interstitial emphysema, and mortality when given as prophylaxis (Soll 1992). The clinical differences in outcomes noted between the animal derived surfactant extracts and the protein free synthetic surfactants suggests an important role of surfactant protein. 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 lower 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 protein-free synthetic surfactant extracts in the prevention of neonatal RDS has been evaluated in a well-conducted randomized, double blinded, controlled multicenter trial. Lucinactant was compared to a commercially approved protein-free synthetic surfactant, colfosceril palmitate, composed of DPPC (~84%), cetyl alcohol, and tyloxapol (Moya 2005). In this study, a third group received beractant, a bovine lung extract containing phospholipids and bovine surfactant proteins. This comparison is not included in this review. Inclusion criteria were a gestational age 24 - 32 weeks, a birth weight between 600 g and 1250 g, and successful endotracheal intubation (Moya 2005). Lucinactant was administered intratracheally within 20 - 30 minutes of birth. Exclusion criteria were reasonable: Apgar score of less than three at five minutes, congenital malformations, chorioamnionitis, or cardiopulmonary resuscitation in the delivery room. The trial had adequate sample size: 1294 infants were analyzed based on the intention-to-treat principle (Moya 2005).

No statistically significant differences were noted in the primary outcomes of interest, although a trend towards decreased incidence of chronic lung disease was noted in the group that received protein containing synthetic surfactant at both 28 days and at 36 weeks postmenstrual age. Additionally trends were noted towards decreased incidence of the combined outcomes of death or chronic lung disease at both 28 days and at 36 weeks postmenstrual age. No statistically significant differences between infants who received protein-free synthetic surfactant and protein containing synthetic surfactant were noted in incidence of neonatal mortality at any follow-up interval.

The recently developed protein containing synthetic surfactant is meant to function in a fashion similar to endogenous and animal derived surfactant pulmonary surfactants. Previous meta-analysis comparing trials of animal derived surfactant extract to protein-free 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 protein-free synthetic surfactant did not demonstrate a statistically significant difference in the combined incidence of all varieties of air leak syndromes (pneumothorax, pneumomediastinum, PIE). A statistically significant decrease in the rates of RDS at 24 hours was demonstrated in those infants who received a protein containing synthetic surfactant compared those who received a protein-free synthetic surfactant (Moya 2005). The determination of both of these two outcomes, RDS at 24 hours and the presence of airleaks, was determined by an independent adjudication committee, masked to surfactant group assignment, which used clinical and radiological data to ascertain whether criteria were met for the authors’ prespecified definitions.

No data have been reported on mortality or neurodevelopmental outcomes at two 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 protein-free synthetic surfactant.

In a well-controlled trial for prevention of RDS, lucinactant has shown clinical efficacy in improving survival and decreasing complications of prematurity similar to animal derived surfactants (Sinha 2005; Pfister 2007). No significant differences in our prespecified primary outcomes were noted between infants who received a protein containing synthetic surfactants and a protein-free synthetic surfactants although a trend towards decreased chronic lung disease was noted with use of protein containing synthetic surfactant. A statistically significant decrease in the incidence of RDS at 24 hours was associated with the use of protein containing synthetic surfactant. More well designed studies of adequate size and power are needed to evaluate the effects of these new surfactant preparations.

Authors' conclusions

Implications for practice

Intratracheal administration of protein-free synthetic surfactant has been previously shown to be effective in decreasing risk of pneumothorax, pulmonary interstitial emphysema, and neonatal mortality (Soll 2001). The lone study that compared protein containing synthetic surfactant to protein-free synthetic surfactant identified in this review suggests that the protein containing synthetic surfactant lucinactant decreases the severity of RDS and may or may not help decrease the risk of CLD. Contemporarily, most infants are treated with surfactant extracts from mammalian derivation which have been shown to be superior to protein-free synthetic surfactant due to decreased mortality, reduced severity of RDS, decreased likelihood of pneumothorax, and increased survival without chronic lung disease (Soll 1992). A companion review has been performed that compares the outcomes of infants given protein containing synthetic surfactant compared to animal derived suractant extracts (Pfister 2007).

While protein containing synthetic surfactant holds great promise of improved efficacy when compared to existing protein-free synthetic surfactants, they are not currently approved for use. In addition, no studies are available using protein containing synthetic surfactants to treat existing disease. 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

Future independent studies of adequate size and power are needed to precisely compare the effect of protein containing synthetic surfactants to the widely used animal derivied surfactant preparations. The sample size should be structured to evaluate differences between important clinical outcomes such as mortality and chronic lung disease. This should include trials of other synthetic surfactants with mimics of surfactant proteins B and C.

Acknowledgements

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

Contributions of authors

Dr. Robert Pfister drafted the protocol, performed the literature search, extracted data, drafted the review.
Dr. R. Soll reviewed the protocol, independently extracted data, and edited the review.
Dr. T. Wiswell reviewed the articles located in the search and reviewed and edited the protocol and review.

Declarations 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, Discovery Laboratories).

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.

Differences between protocol and review

Details of assessing risk of bias changed to conform to current recommendations for Risk of Bias table.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Moya 2005

Methods

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

Blinding of randomization: Yes. 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, 1001-1250 grams). Randomization was accomplished by the use of sealed sequential envelopes.

Blinding of intervention: Somewhat. The intervention was masked by having surfactant administration teams. Infants were analyzed according to intention to treat analysis.

Completeness of follow-up: Yes (for initial in hospital outcomes including death prior to 36 weeks postmenstrual age and chronic lung disease). 80% for follow-up at one year.

Blinding of outcome measurement/assessment: Yes.

Participants

Preterm infants between 24-32 weeks gestation, birth weight between 600-1200 grams, on assisted ventilation. 785 infants enrolled.

Interventions

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

Outcomes

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.

Notes

Part of a trial with three groups: lucinactant, colfosceril, and beractant given in a 2:2:1 ratio.

Risk of bias table
Item Authors' judgement Support for judgement
Adequate sequence generation? Yes

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, 1001-1250 grams).

Allocation concealment? Yes

Randomization accomplished by sealed sequential envelopes.

Blinding? Yes

Intervention masked by having surfactant administration teams. Infants were analyzed according to intention to treat analysis.

Incomplete outcome data addressed? Yes

All prespecified end points reported.

Free of selective reporting? No

Clinical outcomes including pneumothorax and mortality at hospital discharge not reported

Free of other bias? Yes

Characteristics of excluded studies

Cochrane 1996

Reason for exclusion

Non-blinded trial with no comparison group.

Sinha 2005

Reason for exclusion

The trial compared lucinactant, a synthetic surfactant containing a SP-B mimic with phospholipids with poractant alfa, a porcine lung extract containing phospholipids and porcine surfactant proteins. The trial is not included as it did not have an arm that included a non-protein containing synthetic surfactant.

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References to studies

Included studies

Moya 2005

Moya F, Sinha S, Gadzinowski J, D'Agostino R, Segal R, Guardia C, Mazela J, Liu G; SELECT and STAR Study Investigators. One-year follow-up of very preterm infants who received lucinactant for prevention of respiratory distress syndrome: results from 2 multicenter randomized, controlled trials. Pediatrics 2007;119(6):e1361-70.

* Moya FR, Gadzinowski J, Bancalari E, Salinas V, Kopelman B, Bancalari A, Kornacka MK, Merritt TA, Segal R, Schaber CJ, Tsai H, Massaro J, d'Agostino R; International Surfaxin Collaborative Study Group. A multicenter, randomized, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome among very preterm infants. Pediatrics 2005;115(4):1018-29.

Cochrane 1996

Cochrane CG, Revak SD, Merritt TA, Heldt GP, Hallman M, Cunningham MD, Easa D, Pramanik A, Edwards DK, Alberts MS. The efficacy and safety of KL4-surfactant in preterm infants with respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 1996;153(1):404-10.

Sinha 2005

Sinha SK, Lacaze-Masmonteil T, Valls i Soler A, Wiswell TE, Gadzinowski J, Hajdu J, Bernstein G, Sanchez-Luna M, Segal R, Schaber CJ, Massaro J, d'Agostino R; Surfaxin Therapy Against Respiratory Distress Syndrome Collaborative Group. A multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome. Pediatrics 2005;115(4):1030-8.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

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;1:417-33.

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, Häfner 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.

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;12:221-30.

Moya 1993

Moya FR, Hoffman DR, Zhao B, Johnston JM. Platelet-activating factor in surfactant preparations. Lancet 1993;3:858-60.

Pfister 2007

Pfister RH, Soll R, Wiswell TE. 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 4.10.1002/14651858.

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, Cochrane CG. 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, Kheiter A. 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, McQueen MC. Respiratory Distress Syndrome. In: Sinclair J and Bracken M, editors(s). Effective Care of the Newborn Infant. 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. Art. No.: CD000144 DOI: 10.1002/14651858.CD000144 .

Tooley 1987

Tooley WH, Clements JA, Muramatsu K, Brown CL, Schlueter 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;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 2002

Whitsett 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.

Other published versions of this review

  • None noted.

Classification pending references

  • None noted.

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Data and analyses

1 PROTEIN CONTAINING SYNTHETIC SURFACTANT VS. PROTEIN-FREE SYNTHETIC SURFACTANT IN INFANTS AT RISK FOR RDS (ALL PATIENTS)

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Neonatal Mortality 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.89[0.70, 1.14]
1.2 Mortality at 36 weeks postmenstrual age 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.89[0.71, 1.11]
1.3 Chronic Lung Disease at 28 days 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.93[0.84, 1.03]
1.4 Chronic Lung Disease at 36 weeks postmenstrual age 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.89[0.78, 1.03]
1.5 Chronic Lung Disease or Death at 28 days 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.93[0.84, 1.03]
1.6 Chronic Lung Disease or Death at 36 weeks PMA 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.88[0.77, 1.01]
1.7 Pulmonary Interstitial Emphysema 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.85[0.60, 1.18]
1.8 Air Leak Syndrome 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.85[0.65, 1.12]
1.9 Pulmonary Hemorrhage 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.88[0.62, 1.25]
1.10 Respiratory Distress Syndrome at 24 hours 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.83[0.72, 0.95]
1.11 Culture Proven Sepsis 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 1.00[0.87, 1.14]
1.12 Necrotizing Enterocolitis 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.78[0.51, 1.21]
1.13. Effect on Periventricular Leukomalacia 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.80[0.56, 1.15]
1.14 Retinopathy of Prematurity (any stage) 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 1.01[0.82, 1.24]
1.15 Intraventricular Hemorrhage (any grade) 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 1.00[0.89, 1.13]
1.16 Severe Intraventricular Hemorrhage (grades III and IV) 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.99[0.79, 1.25]
1.17 Deafness at 1 year in examined survivors 1 585 Risk Ratio(M-H, Fixed, 95% CI) 1.30[0.50, 3.38]
1.18 Blindness at 1 year in examined survivors 1 585 Risk Ratio(M-H, Fixed, 95% CI) 0.73[0.29, 1.82]
1.19 Known Deaths at 1 year 1 1036 Risk Ratio(M-H, Fixed, 95% CI) 0.91[0.75, 1.11]

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Sources of support

Internal sources

  • No sources of support provided.

External sources

  • NICHHD, USA

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 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.