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Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants

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Authors

Neetu Singh1, Henry L Halliday2, Timothy P Stevens3,Gautham Suresh4, Maria Ximena Rojas-Reyes5, Roger Soll6

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


1Department of Pediatrics, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA [top]
2Honorary Professor of Child Health, Queen's University (Retired), Belfast, UK [top]
3Pediatrics, University of Rochester, Rochester, NY, USA [top]
4Department of Pediatrics, Neonatal Division, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA [top]
5Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia [top]
6Division of Neonatal-Perinatal Medicine, University of Vermont Medical Center, Burlington, Vermont, USA[top]

Citation example: Singh N, Halliday HL, Stevens TP, Suresh G, Rojas-Reyes MX, Soll R. Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2015, Issue 12. Art. No.: CD010249. DOI: 10.1002/14651858.CD010249.pub2.

Contact person

Neetu Singh

Department of Pediatrics
Dartmouth Hitchcock Medical Center
1 Medical Center Drive
Lebanon NH 03784
USA

E-mail: Neetu.Singh@Hitchcock.org

Dates

Assessed as Up-to-date: 31 July 2015
Date of Search: 31 July 2015
Next Stage Expected: 30 June 2017
Protocol First Published: Issue 11, 2012
Review First Published: Issue 12, 2015
Last Citation Issue: Issue 12, 2015

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Abstract

Background

Animal-derived surfactants have been shown to have several advantages over the first generation synthetic surfactants and are the most commonly used surfactant preparations. The animal-derived surfactants in clinical use are minced or lavaged and modified or purified from bovine or porcine lungs. It is unclear whether significant differences in clinical outcome exist among the available bovine (modified minced or lavage) and porcine (minced or lavage) surfactant extracts.

Objectives

To compare the effect of administration of different animal-derived surfactant extracts on the risk of mortality, chronic lung disease, and other morbidities associated with prematurity in preterm infants at risk for or having respiratory distress syndrome (RDS).

Search methods

We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 7), MEDLINE via PubMed (1966 to July 31, 2015), EMBASE (1980 to July 31, 2015), and CINAHL (1982 to July 31, 2015). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials.

Selection criteria

Randomized or quasi-randomized controlled trials that compared the effect of animal-derived surfactant extract treatment administered to preterm infants at risk for or having RDS to prevent complications of prematurity and mortality.

Data collection and analysis

Data regarding clinical outcomes were excerpted from the reports of the clinical trials by the review authors. Subgroup analyses were performed based on gestational age, surfactant dosing and schedule, treatment severity and treatment strategy. Data analysis was performed in accordance with the standards of the Cochrane Neonatal Review Group.

Main results

Sixteen randomized controlled trials were included in the analysis.

Bovine lung lavage surfactant extract to modified bovine minced lung surfactant extract: Seven treatment studies and two prevention studies compared bovine lung lavage surfactant extract to modified bovine minced lung surfactant extract. The meta-analysis did not demonstrate any significant differences in death or chronic lung disease in the prevention trials (typical RR 1.02, 95% CI 0.89 to 1.17; typical RD 0.01, 95% CI −0.05 to 0.06; 2 studies and 1123 infants; high quality evidence) or treatment trials (typical RR 0.95, 95% CI 0.86 to 1.06; typical RD −0.02 , 95% CI −0.06 to 0.02; 3 studies and 2009 infants; high quality evidence)

Modified bovine minced lung surfactant extract compared with porcine minced lung surfactant extract: Nine treatment studies compared modified bovine minced lung surfactant extract to porcine minced lung surfactant extract. Meta-analysis of these trials demonstrate a significant increase in the risk of mortality prior to hospital discharge (typical RR 1.44, 95% CI 1.04 to 2.00; typical RD 0.05, 95% CI 0.01 to 0.10; NNTH 20, 95% CI 10 to 100; 9 studies and 901 infants; moderate quality evidence), death or oxygen requirement at 36 weeks' postmenstrual age (typical RR 1.30, 95% CI 1.04 to 1.64; typical RD 0.11, 95% CI 0.02 to 0.20; NNTH 9, 95% CI 5 to 50; 3 studies and 448 infants; moderate quality evidence), receiving more than one dose of surfactant (typical RR 1.57, 95% CI 1.29 to 1.92; typical RD 0.14, 95% CI 0.08 to 0.20; NNTH 7, 95% CI 5 to 13; 6 studies and 786 infants), and patent ductus arteriosus (PDA) requiring treatment (typical RR 1.86, 95% CI 1.28 to 2.70; typical RD 0.28, 95% CI 0.13 to 0.43; NNTH 4, 95% CI 2 to 8; 3 studies and 137 infants) in infants treated with modified bovine minced lung surfactant extract compared with porcine minced lung surfactant extract. In the subgroup analysis based on initial dose of surfactant, improvement in mortality prior to discharge (typical RR 1.62, 95% CI 1.11 to 2.38; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 16, 95% CI 9 to 100) and risk of death or oxygen requirement at 36 weeks' postmenstrual age (typical RR 1.39, 95% CI 1.08 to 1.79; typical RD 0.13, 95% 0.03 to 0.23; NNTH 7, 95% CI 4 to 33) was limited to higher initial dose of porcine minced lung surfactant (> 100 mg/kg).

Other comparisons: No difference in outcome was noted between bovine lung lavage surfactant extract versus porcine minced lung surfactant extract. There were no studies comparing bovine lung lavage surfactant extract versus porcine lung lavage surfactant; or porcine minced lung surfactant extract versus porcine lung lavage surfactant.

Authors' conclusions

Significant differences in clinical outcome were noted in the comparison trials of modified minced lung surfactant extract (beractant) compared with porcine minced lung surfactant extract (poractant alfa) including a significant increase in the risk of mortality prior to discharge, death or oxygen requirement at 36 weeks' postmenstrual age, PDA requiring treatment and "receiving > 1 dose of surfactant" in infants treated with modified bovine minced lung surfactant extract compared with porcine minced lung surfactant extract. The difference in these outcomes was limited to studies using a higher initial dose of porcine minced lung surfactant extract. It is uncertain whether the observed differences are from differences in dose or from source of extraction (porcine vs. bovine) because of the lack of dose-equivalent comparison groups with appropriate sample size. No differences in clinical outcomes were observed in comparative trials between bovine lung lavage surfactant and modified bovine minced lung surfactants.

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Plain language summary

Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants

 

Review question: Does the use of one animal-derived surfactant preparation compared with an alternative animal-derived surfactant preparation lead to improved outcome in infants at risk for or having respiratory distress syndrome?

Background: A wide variety of surfactant preparations are used to prevent or treat respiratory distress syndrome (RDS) in preterm infants. All commercially available animal-derived surfactant products are effective for prevention and treatment of respiratory distress syndrome in preterm infants. However, it is unclear whether significant differences in clinical outcome exist among the available animal-derived surfactant extracts. This review compared different animal-derived surfactant products based on their source (bovine vs. porcine) and method of extraction (minced lung vs. lung lavage).

Study characteristics: 16 randomized controlled trials met our inclusion criteria.

Results: We found improvement in risk of death before hospital discharge and the risk of combined outcome of death or oxygen requirement at four weeks before due date of birth with the use of higher dose of porcine surfactant (a surfactant product derived from pig's lung) compared with a minced bovine surfactant (surfactant obtained from minced cow's lung). Based on the available evidence, we cannot state with certainty whether the improvement in outcome with high dose porcine-derived surfactant is from dose effect (higher phospholipid levels with use of higher initial dose) or from the effect of source of surfactant extraction (pig vs. cow). Comparison trials of surfactants obtained from bovine sources that used different extraction methods or modifications showed no difference in clinical outcomes.

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Background

Description of the condition

Respiratory distress syndrome (RDS) is caused by a deficiency or dysfunction of pulmonary surfactant (Avery 1959). Surfactant lines the alveolar surface and prevents atelectasis at end expiration. Pulmonary surfactant is predominantly dipalmitoylphosphatidylcholine (DPPC) 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. The physiologic functions of surfactant include the ability to lower surface tension, and the ability to rapidly adsorb, spread, and reform a monolayer in the dynamic conditions associated with the respiratory cycle (Jobe 1993).

Description of the intervention

Investigators in the 1960s attempted to administer aerosolized DPPC to infants with, or at risk of developing, RDS (Chu 1967; Robillard 1964). These investigators could not demonstrate any beneficial effect of surfactant replacement. In part, the poor results were because of an incomplete understanding of what constitutes pulmonary surfactant, and in part because of the inefficiency of the aerosolization. The first successful animal model of surfactant replacement therapy was developed by Enhorning and Robertson in the 1970s (Enhorning 1972). They administered a crude animal-derived surfactant extract obtained from lavage of the lungs of mature rabbits directly into the trachea of immature rabbits. Improvement in lung compliance and alveolar expansion was noted. Success in animal models led to further clinical trials in newborn infants. The first successful experience with surfactant replacement therapy for infants with established RDS was reported in 1980 (Fujiwara 1980). These Japanese researchers studied a series of 10 preterm infants with severe RDS requiring assisted ventilation. The infants improved dramatically following treatment with Surfactant TA, a modified bovine surfactant extract, containing SP-B and SP-C.

Since the initial experience of Fujiwara and coworkers, multiple randomized trials of surfactant in the treatment of established RDS have been conducted (Seger 2009; Soll 1997; Soll 1998; Soll 2010).

A wide variety of surfactant products have been formulated and studied in clinical trials (Halliday 2008). These include synthetic (protein-free) surfactants and animal-derived surfactant extracts. Currently available animal-derived surfactant extracts are mammalian in origin. These can be further classified as either modified or unmodified surfactant extracts; modified animal-derived surfactant extract is supplemented with phospholipids or other surface-active material, while unmodified animal-derived surfactant extract contains only the components remaining after the extraction process. A further classification is based upon whether the surfactant is extracted from minced lungs (for example, beractant and poractant alfa) or lung lavage (for example, calfactant and bovactant). All these animal-derived surfactants contain phospholipids and SP-B and SP-C in differing amounts.

Trials of surfactant replacement have either tried to prevent the development of RDS in high-risk preterm infants (Soll 1997; Soll 2010); or treat established RDS in preterm infants (Seger 2009; Soll 1998). Using either approach, surfactant has been shown to decrease the risk of pneumothorax, decrease mortality, and improve survival without bronchopulmonary dysplasia (at 28 days of life) (Engle 2008). Animal-derived surfactants have been compared with synthetic surfactants, and the advantages reported include lower mortality rates (typical risk ratio (RR) 0.86; 95% confidence interval (CI) 0.76 to 0.98; number needed to treat for an additional beneficial outcome (NNTB) 40), lower inspired oxygen and ventilation requirements early in the course of RDS, and fewer pneumothoraces (typical RR 0.63, 95% CI 0.53 to 0.75; NNTB 22) (Engle 2008; Soll 2001). First-generation protein-free synthetic surfactants (such as colfosceril palmitate and pumactant) are no longer widely available (Engle 2008). New synthetic surfactants containing proteins or peptides that mimic SP activity are under investigation (Pfister 2007; Pfister 2009).

How the intervention might work

Animal-derived surfactants in clinical use are obtained by organic extraction of lung lavage fluid or minced lung and contain surfactant proteins SP-B and SP-C. SP-A and SP-D are extremely hydrophilic and do not remain in the preparation of any commercial natural surfactant. SP-B and SP-C are thought to be crucial in promoting the adsorption and spread of monolayers of dipalmitoylphosphatidylcholine (DPPC) (Hawgood 1985; Whitsett 1995). Different animal-derived surfactants may differ in their source (bovine vs. porcine), method of extraction (minced vs. lavage), composition (viscosity, phospholipid content, amount of surfactant protein (SP B&C), and plasmalogen content), and dosing volume. It is unclear if significant differences in clinical outcomes exist among the available products (Engle 2008; Ramanathan 2009).

The following animal-derived surfactants are known to be available and were included in the review:

  1. Bovine lung lavage surfactant extract (calfactant, CLSE, also known as BLES or SF-RI 1, also known as bovactant):
    • Calfactant (Infasurf/Forest Pharmaceuticals Inc. St Louis. MO, USA) contains high surfactant protein (SP B&C) and phospholipid (33.3 mg/ml); and is given at a dose of 100 mg phospholipid/kg.
    • Bovine Lung Expanding Substance (BLES/BLES Biochemicals, London, ON, Canada) contains 1% SP B&C; 27 mg/ml phospholipid; and is given at a dose of 137 mg phospholipid/kg.
    • Bovactant (Alveofact/Boehringer Ingelheim, Germany; (marketed and manufactured by Lyomark Pharma, Germany) contains 1% SP B&C; 41.7 mg/ml phospholipid and is given at a dose of 50 mg phospholipid/kg (Sweet 2013).
  2. Modified bovine minced lung surfactant extract (beractant or surfactant TA):
    • Beractant (Survanta/ Abbott Laboratories, Abbott Park, IL, USA) contains DPPC, tripalmitin and palmitic acid; less than 0.5% SP B&C; 25 mg/ml phospholipid; and is given at a dose of 100 mg phospholipid/kg.
    • Surfactant TA (Surfacten/ Tokyo Tanabe Co, Tokyo, Japan) contains DPPC, tripalmitin and palmitic acid; less than 0.5% SP B&C; 30 mg/ml phospholipid; and is given at a dose of 120mg phospholipid/kg.
  3. Porcine minced lung surfactant extract (poractant alfa):
    • Poractant alfa (Curosurf/Chiesi Farmaceutici Parma, Italy) contains approximately 1% SP B&C; 80 mg/ml phospholipid; and is given at a dose of 100 to 200 mg phospholipid/kg. This surfactant extract undergoes an additional step during preparation called liquid gel chromatography. As a result, it contains only polar lipids and is more concentrated than any other animal-derived surfactant preparation.
  4. Porcine lung lavage surfactant extract (Surfacen):
    • Surfacen is an inexpensive porcine lung lavage surfactant developed in Cuba (Surfacen/Censa, Cuba).

Other animal-derived products are being developed and tested, particularly in developing countries. At least two other surfactant preparations (Newfacten (Newfacten/Yuhan Co Ltd, Korea) and HL-10 (HL-10/Leo Pharma, Denmark)) were identified during our search; however, no study compared their efficacy with another surfactant preparation. Surfactants derived from human amniotic fluid are not included in this review as they are unavailable and have never been approved for use by regulatory agencies.

Why it is important to do this review

Cochrane reviews that address trials of pulmonary surfactant in neonates

Multiple systematic reviews have addressed the use of animal-derived surfactant preparations or synthetic surfactant preparations in the prevention or treatment of respiratory distress syndrome. Meta-analyses of the original randomized controlled trials of surfactant for the treatment and prevention of RDS were first published in Effective Care of the Newborn Infant (Soll 1992).

Since then, multiple systematic reviews have been published in The Cochrane Library, including reviews of protein-free synthetic surfactant for the prevention and treatment of RDS (Soll 1998; Soll 2010); and reviews of animal-derived surfactant for the prevention and treatment of RDS (Seger 2009; Soll 1997). Trials that compare animal-derived surfactant extract to protein-containing synthetic surfactant and trials that compare protein-free synthetic surfactant to protein-containing synthetic surfactant are addressed by other reviews (Pfister 2007; Pfister 2009). Comparison trials of animal-derived products compared with protein-free synthetic products have been reviewed by Soll and Blanco (Soll 2001). Prophylactic administration of surfactant to infants at high risk of developing RDS, compared with selective use of surfactant in infants with established RDS, has been shown to improve some clinical outcomes (Rojas-Reyes 2012).

Clinical trials that compare various animal-derived surfactant extract preparations to each other are included in this systematic review. The differences in composition of the animal-derived surfactant preparations could potentially lead to differences in clinical efficacy.

The analysis included all randomized controlled trials in which animal-derived surfactant extracts were compared with other animal-derived products in the prevention or treatment of RDS. If similar in effect, differences in cost may be appropriate to consider in deciding which product to use. A previous review addressing only comparisons of bovine surfactant (beractant and calfactant) with porcine surfactant has been published by Singh and colleagues, but did not address comparisons between bovine-derived products (Singh 2011).

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Objectives

To compare the effect of administration of different animal-derived surfactant extracts on the risk of mortality, chronic lung disease, and other morbidities associated with prematurity in preterm infants at risk for or having RDS.

Comparisons:

  1. Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF-RI 1 (bovactant)) versus modified bovine minced lung surfactant extract (beractant or surfactant TA).
  2. Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF RI 1 (bovactant)) versus porcine minced lung surfactant extract (poractant alfa).
  3. Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF-RI 1 (bovactant)) versus porcine lung lavage surfactant (Surfacen).
  4. Modified bovine minced lung surfactant extract (beractant or surfactant TA) versus porcine minced lung surfactant extract (poractant alfa).
  5. Modified bovine minced lung surfactant extract (beractant or surfactant TA) versus porcine lung lavage surfactant (Surfacen).
  6. Porcine minced lung surfactant extract (poractant alfa) versus porcine lung lavage surfactant (Surfacen).

Subgroup analyses

  1. Gestational age:
    1. prevention trials: infants born at less than 28 weeks' gestation;
    2. treatment trials: infants born at less than 30 weeks' gestation.
  2. Surfactant dosage (initial dose up to 100 mg/kg)
  3. Surfactant dosing schedule (single dose, multiple dose)
  4. Treatment strategy (prevention versus treatment of established disease)
  5. For treatment trials: disease severity (moderate to severe disease defined as need for assisted ventilation and supplemental oxygen concentration greater than 40% necessary to maintain adequate oxygenation).

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Methods

Criteria for considering studies for this review

Types of studies

We considered randomized controlled trials, quasi-randomized controlled clinical trials, and cluster randomized trials for this review.

Types of participants

Prevention studies

Preterm infants (less than 32 weeks' gestation) at risk for developing RDS.

Treatment studies

Preterm infants (less than 37 weeks' gestation) with clinical and radiologic evidence of RDS requiring assisted ventilation.

Types of interventions

Prevention

Preterm infants at risk for RDS randomized to receive an animal-derived surfactant preparation versus a different animal-derived surfactant product.

Treatment

Preterm infants with established RDS randomized to receive an animal-derived surfactant preparation versus a different animal-derived surfactant product.

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

In either comparison, any dosing regimen (single dose or multiple dose) and dosage were included.

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 (in all infants):
    1. oxygen requirement at 28 to 30 days of age;
    2. oxygen requirement at 36 weeks' postmenstrual age.
  4. Death or chronic lung disease:
    1. death or oxygen requirement at 28 to 30 days of age;
    2. death or oxygen requirement at 36 weeks' postmenstrual age.
Secondary outcomes
  1. Doses of surfactant.
  2. Pneumothorax.
  3. Air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum).
  4. Pulmonary hemorrhage.
  5. Patent ductus arteriosus (PDA) (that has been treated with cyclo-oxygenase inhibitor or surgery).
  6. Culture-confirmed bacterial sepsis.
  7. Culture-confirmed fungal sepsis.
  8. Necrotizing enterocolitis (defined as Bell Stage II or greater) (Bell 1978).
  9. Periventricular leukomalacia.
  10. Retinopathy of prematurity in infants examined (all stages and severe (stage 3 or greater)) (ICCROP 2005).
  11. Intraventricular hemorrhage (any grade and severe (grade 3 to 4)) (Papile 1978).
  12. Cerebral palsy at approximately two years corrected age (as defined by the study authors).
  13. Neurodevelopmental outcome at approximately two years corrected age (acceptable range 18 months to 28 months) including: cerebral palsy, delayed neurodevelopment (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.

We considered post hoc analyses for any unexpected adverse effects reported by the studies. Post hoc analysis was performed for the outcome "received > one dose of surfactant." For studies that did not report NEC based on Bell's criteria, we reported "any NEC."

We identified critical outcomes for decision making (primary and main secondary outcomes) including mortality prior to hospital discharge, chronic lung disease (defined as supplemental oxygen at 36 weeks' gestation), death or chronic lung disease (CLD) at 36 weeks' postmenstrual age, pneumothorax, pulmonary hemorrhage, severe intraventricular hemorrhage, and neurodevelopmental outcome at approximately two years' corrected age for inclusion in the 'Summary of findings' tables.

Search methods for identification of studies

We used the criteria and standard methods of Cochrane and the Cochrane Neonatal Review Group (see the Cochrane Neonatal Group search strategy for specialized register External Web Site Policy). The full search strategies for each database are included in Appendix 1.

Electronic searches

We conducted a comprehensive search including: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, issue 7 2015; MEDLINE via PubMed (1996 to July 2015); EMBASE (1980 to July 2015); CINAHL (1982 to July 2015).

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). No language restrictions were applied. We searched the reference lists of any articles selected for inclusion in this review. From the resulting studies, randomized controlled studies that fulfilled the inclusion criteria were selected. To identify long-term neurodevelopmental sequelae, a second 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. We searched the bibliography cited in each publication obtained in order to identify additional relevant articles.

Searching other resources

Published abstracts: We searched by hand the abstracts of the Society for Pediatric Research (US) (published in Pediatric Research) for the years 1985 to 1999 using the following key words: [surfactant OR pulmonary surfactant] AND [respiratory distress syndrome]. We electronically searched the abstracts from 2000 to 2014 through the PAS web site (abstractsonline).

We searched clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov External Web Site Policy; the World Health Organization’s International Trials Registry and Platform (www.who.int/ictrp/search/en/ External Web Site Policy); and the ISRCTN Registry External Web Site Policy). We also searched for conference abstracts from Pediatric Academic Societies (PAS) and European Society for Paediatric Research (ESPR). Searches were carried out in Abstracts to View (2000 to 2014) and Pediatric Research.

Data collection and analysis

Information was collected regarding the method of randomization, blinding, drug intervention, stratification, and whether the trial was single or multicenter for each included study. We noted the information regarding trial participants including gestational age criteria, birth weight criteria, and other inclusion or exclusion criteria. We analyzed the information on clinical outcomes including pneumothorax, pulmonary interstitial emphysema, PDA, necrotizing enterocolitis, intraventricular hemorrhage (any intraventricular hemorrhage and severe intraventricular hemorrhage), chronic lung disease (bronchopulmonary dysplasia), retinopathy of prematurity, neonatal mortality, mortality prior to hospital discharge, and chronic lung disease (bronchopulmonary dysplasia) or death.

Selection of studies

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

Data extraction and management

NS and RS extracted, assessed, and coded all data for each study, using a form designed specifically for this review. Any standard error of the mean was replaced by the corresponding standard deviation. We resolved any disagreement by discussion. For each study, final data was entered into Review Manager (RevMan) 5 (RevMan 2014) by one review author (NS) and then checked by the other review author (RS). All authors reviewed the protocol, analysis and draft manuscript.

Assessment of risk of bias in included studies

We employed the standard methods of the Cochrane Neonatal Group External Web Site Policy. The methodologic 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 criterion, assessment was 'yes', 'no', 'cannot determine.' This information was included in the table 'Characteristics of included studies'.

In addition, the review authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

The methodological quality of the studies was assessed using the following criteria:

  1. Sequence generation (evaluating possible selection bias). For each included study, we described the method used to generate the allocation sequence as: adequate (any truly random process e.g. random number table; computer random number generator); inadequate (any nonrandom process e.g. odd or even date of birth; hospital or clinic record number); or unclear;
  2. Allocation concealment (evaluating possible selection bias). For each included study, we described the method used to conceal the allocation sequence as: adequate (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes); inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or unclear;
  3. Blinding (evaluating possible performance bias). For each included study, we described the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We assessed the methods as: adequate, inadequate, or unclear for participants; adequate, inadequate, or unclear for study personnel; and adequate, inadequate, or unclear for outcome assessors;
  4. Incomplete outcome data (evaluating possible attrition bias through withdrawals, drop-outs, protocol deviations). For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We assessed methods as: adequate (< 20% missing data); inadequate (> 20% missing data), or unclear;
  5. Selective reporting bias. For each included study where the protocol is available (through trials registers), we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as: adequate (where it was clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review had been reported); inadequate (where not all the study's prespecified outcomes had been reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported); or unclear;
  6. Other sources of bias. We noted other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early owing to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as: yes; no; or unclear.

Quality of evidence

We assessed the quality of evidence for the main comparison at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2011a). This methodological approach considers evidence from randomized controlled trials as high quality that may be downgraded based on consideration of any of five areas: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias (Guyatt 2011a). The GRADE approach results in an assessment of the quality of a body of evidence in one of four grades: 1) High: We are very confident that the true effect lies close to that of the estimate of the effect; 2) Moderate: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; 3) Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect; 4) Very Low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect (Schünemann 2013).

Two review authors (MXR, RS) independently assessed the quality of the evidence found for outcomes identified as critical or important for clinical decision making: mortality prior to hospital discharge, chronic lung disease (defined as supplemental oxygen at 36 weeks' gestation), death or CLD at 36 weeks' postmenstrual age, pneumothorax, pulmonary hemorrhage, severe intraventricular hemorrhage, and neurodevelopmental outcome at approximately two years' corrected age.

In cases where we considered the risk of bias arising from inadequate concealment of allocation, randomized assignment, complete follow-up or blinded outcome assessment to reduce our confidence in the effect estimates, we downgraded the quality of evidence accordingly (Guyatt 2011b). Consistency was evaluated by similarity of point estimates, extent of overlap of confidence intervals and statistical criteria including measurement of heterogeneity (I²). The quality of evidence was downgraded when inconsistency across studies' results was present, being large and unexplained (i.e. some studies suggest important benefit and others no effect or harm without a clinical explanation) (Guyatt 2011d). Precision was assessed based on the width of the 95% confidence interval (CI) and by calculating the optimal information size (OIS). If the total number of patients included in the pooled effect estimation was less than the number of patients generated by a conventional sample size calculation for a single adequately powered trial, we considered rating down for imprecision (Guyatt 2011c). When trials were conducted in populations other than the target population, we downgraded the quality of evidence because of indirectness (Guyatt 2011e).

Data (i.e. pooled estimates of the effects and corresponding 95% CI) and explicit judgments for each of the above aspects assessed were entered into the Guideline Development Tool, the software used to create 'Summary of findings' tables (GradePro 2008). All judgements involving the assessment of the study characteristics described above are explained in foot notes or comments in the 'Summary of findings' tables.

Measures of treatment effect

We performed the statistical analyses using Review Manager 5 software (RevMan 2014). We analyzed categorical data using risk ratio (RR), and risk difference (RD). For statistically significant outcomes we calculated the number needed to treat for an additional participant with a beneficial outcome (NNTB) or number needed to treat for an additional participant with a harmful outcome (NNTH). We analyzed continuous data using weighted mean difference (WMD) and the standardized mean difference (SMD). We reported the 95% CI on all estimates.

Assessment of heterogeneity

We estimated the treatment effects of individual trials and examined heterogeneity among trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I² statistic. We graded the degree of heterogeneity as: less than 25% no heterogeneity; 25% to 49% low heterogeneity; 50% to 75% moderate heterogeneity; more than 75% substantial heterogeneity. If statistical heterogeneity (I² > 50%) was noted, the possible causes were explored (for example, differences in study quality, participants, intervention regimens, or outcome assessments).

Data synthesis

If multiple studies were identified and they were thought to be sufficiently similar, meta-analysis was done using RevMan 2014, supplied by Cochrane. For categorical outcomes the typical estimates of RR and RD, each with its 95% CI, was calculated; and for continuous outcomes the WMD or a summary estimate for the SMD, each with its 95% CI, was calculated. We used a fixed-effect model for meta-analysis. When meta-analysis was judged to be inappropriate, individual trials were analyzed and interpreted separately.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses
  1. Treatment strategy (prevention vs. treatment of established disease)
  2. Gestational age:
    1. Prevention trials: infants born at less than 28 weeks' gestation;
    2. Treatment trials: infants born at less than 30 weeks' gestation.
  3. Surfactant dosage (initial dose less than/or equal to 100 mg/kg).
  4. Number of surfactant doses (single dose, multiple dose
  5. For treatment trials: disease severity (moderate to severe disease defined as need for assisted ventilation and supplemental oxygen concentration greater than 40% necessary to maintain adequate oxygenation).

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Results

Description of studies

See the two tables: Characteristics of included studies and Characteristics of excluded studies.

Results of the search

Studies included in this review comprised those that studied the effect of administration of different animal-derived surfactant extracts on clinical outcomes in infants with RDS or at risk for RDS.

2354 studies retrieved by search. Overall 16 studies are included for analysis.

1. Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF-RI 1 (bovactant)) vs. modified bovine minced lung surfactant extract (beractant or surfactant TA).

Prevention studies: Two studies were identified (Bloom 1997; Bloom 2005).

Treatment studies: Seven studies were identified (Attar 2004; Baroutis 2003; Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005; Yalaz 2004).

2. Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF RI 1 (bovactant)) vs. porcine minced lung surfactant extract (poractant alfa).

Prevention studies: No studies identified.

Treatment studies: One study was identified (Baroutis 2003).

3. Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF-RI 1 (bovactant)) vs. porcine lung lavage surfactant (Surfacen).

Prevention studies: No studies were identified.

Treatment studies: No studies were identified.

4. Modified bovine minced lung surfactant extract (beractant or surfactant TA) vs. porcine minced lung surfactant extract (poractant alfa).

Prevention studies: No studies were identified.

Treatment studies: Nine studies were identified. (Baroutis 2003; Didzar 2012; Fujii 2010; Gharehbaghi 2010; Halahakoon 1999; Karadag 2014; Malloy 2005; Ramanathan 2004; Speer 1995).

5. Modified bovine minced lung surfactant extract (beractant or surfactant TA) vs. porcine lung lavage surfactant (Surfacen).

Prevention studies: No studies were identified.

Treatment studies: One study was identified (Sanchez-Mendiola 2005).

6. Porcine minced lung surfactant extract (poractant alfa) vs. porcine lung lavage surfactant (Surfacen).

Prevention studies: No studies were identified.

Treatment studies: No studies were identified.

Excluded studies: Four studies were excluded (Bozdağ 2015; Choi 2005; Proquitté 2007; Rebello 2009)

Studies awaiting classification: Eras 2014; Gharehbaghi 2014; Mercado 2010; Saeidi 2013; Terek 2015.

Included studies

Bovine lung lavage surfactant extract [calfactant, CLSE (BLES) or SF-RI 1 (bovactant)] vs. modified bovine minced lung surfactant extract (beractant or surfactant TA).

Prevention studies: Two studies were identified (Bloom 1997; Bloom 2005).

  1. Bloom 1997: In this multicenter, double-blinded randomized controlled trial, Bloom and colleagues compared relative safety and efficacy of calfactant versus beractant in reducing severity of RDS when given to 374 infants less than 1250 grams and less than 29 weeks' gestation at birth in the prevention arm; and to 608 infants less than 2000 grams with established RDS in the treatment arm. The primary outcome was a decrease in need of a second dose in the prevention arm and a need for a third dose of surfactant in the treatment arm. Thirteen units participated in the treatment arm and seven of those concurrently participated in the prevention arm. Adequate measures were taken to blind the personnel during surfactant administration and for outcome assessment.
  2. Bloom 2005: In this multicenter prospective masked randomized controlled trial, Bloom and colleagues compared relative safety and efficacy of calfactant verus beractant in reducing severity of RDS when given at birth to 749 preterm infants 23 to 29 weeks' of gestation and to 1361 infants less than 2000 grams with established RDS. Forty-two units participated in the trial (21 units participated only in treatment study and 19 units in both treatment and prophylaxis study). The primary outcome was per cent of infants alive without supplemental oxygen requirement at 36 weeks' postmenstrual age. Both trials were halted prematurely for not meeting enrollment targets.

Treatment studies: Seven studies were identified (Attar 2004; Baroutis 2003; Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005; Yalaz 2004).

  1. Bloom 1997: In this multicenter, double-blinded randomized controlled trial, Bloom and colleagues compared relative safety and efficacy of calfactant versus beractant in reducing severity of RDS when given to 374 preterm infants less than 1250 grams and less than 29 weeks' gestation at birth in the prevention arm; and to 608 preterm infants less than 2000 grams with established RDS in the treatment arm. Thirteen units participated in the treatment arm and seven of those concurrently participated in the prevention arm. The primary outcome was a decrease in need for a second dose in the prevention arm and need for a third dose of surfactant in the treatment arm.
  2. Hammoud 2004: In this single center double-blinded randomized controlled trial from Kuwait, Hammoud and colleagues compared the efficacy of bovactant (Alveofact) (SF-RI 1) and beractant in 109 preterm infants less than 34 weeks' gestation with established RDS who needed intubation and mechanical ventilation. The primary outcome was CLD (oxygen requirement at 28 days of age).
  3. Attar 2004: In this single-center randomized controlled trial, Attar and colleagues compared the efficacy of calfactant and beractant in 40 preterm infants less than 37 weeks' gestation with radiographic diagnosis of RDS. The two groups were comparable except for a significantly higher number of males in the calfactant group. Primary outcome was difference in changing dynamic compliance of lungs one hour after surfactant administration. Secondary outcomes included CLD and other complications of prematurity.
  4. Yalaz 2004: In this single center study from Turkey, Yalaz and colleagues compared effectiveness and side effects of bovactant (Alveofact) and beractant in 50 preterm infants less than 36 weeks' gestation with established RDS. They gave standard dose of bovactant (Alveofact) (50 mg/kg) and beractant (100 mg/kg), repeating doses based on blood gases and chest X-ray. The primary outcome was FiO₂ requirement in first 24 hours after surfactant administration. Secondary outcomes were complications of prematurity.
  5. Lam 2005: In this single-center randomized controlled trial from Hong Kong, Lam and colleagues compared the response pattern and treatment outcomes of BLES and beractant in 63 preterm infants less than 1800 grams with established RDS. The primary outcome was oxygenation index and secondary outcomes were complications of prematurity.
  6. Bloom 2005: In this multicenter, prospective masked randomized controlled trial, Bloom and colleagues compared the safety and efficacy of calfactant versus beractant in reducing severity of RDS when given at birth to 749 preterm infants 23 to 29 weeks' gestation and to 1361 infants less than 2000 grams with established RDS. Forty-two units participated in the trial (21 units participated only in treatment study and 19 units in both treatment and prophylaxis study). The primary outcome was the per cent of infants alive without supplemental oxygen requirement at 36 weeks' postmenstrual age. Both trials were halted prematurely for not meeting enrollment targets.
  7. Baroutis 2003: In this single-center randomized controlled trial, Baroutis and colleagues compared three animal-derived surfactants (bovactant, poractant alfa, and beractant) for treatment of established RDS in 82 preterm infants up to 32 weeks' gestation and BW 2000 grams. The initial and repeat dose for all three surfactants was 100 mg/kg. The primary outcome was oxygen dependence at 36 weeks' postmenstrual age. 

Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF RI 1 (bovactant)) vs. porcine minced lung surfactant extract (poractant alfa).

Prevention studies: No studies identified.

Treatment studies: One study was identified (Baroutis 2003).

  1. Baroutis 2003: In this single center study, Baroutis and colleagues compared three animal-derived surfactants (bovactant, poractant alfa, and beractant) for the treatment of established RDS in 82 preterm infants up to 32 weeks' gestation and BW up to 2000 grams. The primary outcome was oxygen dependence at 36 weeks' postmenstrual age. 

Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF-RI 1 (bovactant)) vs. porcine lung lavage surfactant (Surfacen).

Prevention studies: No studies were identified.

Treatment studies: No studies were identified.

Modified bovine minced lung surfactant extract (beractant or surfactant TA) vs. porcine minced lung surfactant extract (poractant alfa).

Prevention studies: No studies were identified.

Treatment studies: Nine studies were identified. (Baroutis 2003; Didzar 2012; Fujii 2010; Gharehbaghi 2010; Halahakoon 1999; Karadag 2014; Malloy 2005; Ramanathan 2004; Speer 1995).

  1. Speer 1995: In this multicenter randomized controlled study from Germany, Speer and colleagues compared the effectiveness of poractant alfa and beractant in treatment of 73 preterm infants less than 1500 grams with RDS. The primary outcome was gas exchange and ventilation requirement.
  2. Halahakoon 1999: As part of her PhD thesis, Halahakoon evaluated the effects of poractant alfa (n = 17), beractant (n = 10) and colfosceril palmitate (Exosurf Neonatal) (n = 12) on cerebral function, hypoxanthine levels, and antioxidant levels in 24 to 32 weeks' gestation infants with RDS requiring assisted ventilation. In this single-center study, 39 preterm infants between 24 to 32 weeks' gestation were randomized into three groups. The study was initially designed to compare only two surfactants (poractant alfa and colfosceril palmitate) and later included beractant, hence differences in number of patients in each group. Death or prolonged dependency on oxygen at 36 weeks’ postmenstrual age with radiological evidence of BPD was considered as primary outcome.
  3. Baroutis 2003: In this single-center study, Baroutis and colleagues compared three animal-derived surfactants (bovactant, poractant alfa, and beractant) for treatment of established RDS in 82 preterm infants up to 32 weeks' gestation and BW up to 2000 grams. The primary outcome was oxygen dependence at 36 weeks' postmenstrual age. 
  4. Ramanathan 2004: In this multicenter masked randomized trial, Ramanathan and colleagues compared onset of clinical response and safety of high dose of poractant alfa (200 mg/kg) compared with low-dose poractant alfa (100 mg/kg) and beractant (100 mg/kg) in the treatment of preterm infants less than 35 weeks' gestation with established RDS. A total of 293 preterm infants were randomized to high-dose poractant alfa (n = 99), low-dose poractant alfa (n = 96), and beractant (n = 98). If needed, the repeat dose was similar for all three groups (100 mg/kg). The primary outcome was FiO₂ requirement during six hours after first dose of surfactant.
  5. Malloy 2005: In this single-center study, Malloy and colleagues compared effects of poractant alfa and beractant in 58 preterm infants less than 37 weeks' gestation with clinical signs of RDS. The primary outcome was FiO₂ requirement at 48 hours after the first dose of surfactant administration.
  6. Fujii 2010: Fujii and colleagues conducted a single-center study assessing the short-term treatment efficacy of poractant alfa and beractant in 58 preterm infants less than 30 weeks' gestation with RDS. The primary outcome of the study was effect on respiratory support (FiO₂ and MAP) and complications of prematurity.
  7. Gharehbaghi 2010: In this single-center quasi-randomized study, Gharehbaghi and colleagues compared the complications with poractant alfa and beractant in 150 preterm infants with RDS. The primary outcome of the study was remaining without ventilator support through seven days of age.
  8. Didzar 2012: In this single-center randomized controlled study, Didzar and colleagues compared the differences in clinical response and short-term outcome between poractant alfa and beractant in 126 infants less than 37 weeks' gestation with RDS. The primary outcome of interest was FiO₂ requirement at 24 hours after surfactant administration.
  9. Karadag 2014 reported results from a randomized controlled trial comparing the perfusion index (PI) variability following administration of two different animal-derived surfactant preparations (poractant alfa and beractant) in 92 preterm infants less than 32 weeks' gestation with RDS.

Modified bovine minced lung surfactant extract (beractant or surfactant TA) vs. porcine lung lavage surfactant (Surfacen).

Prevention studies: No studies were identified.

Treatment studies: One study was identified (Sanchez-Mendiola 2005).

  1. Sanchez-Mendiola 2005: Sanchez-Mendiola and colleagues conducted a randomized controlled trial to compare an inexpensive porcine-derived surfactant, Surfacen, with beractant in 44 preterm infants. The primary outcome studied was oxygenation and ventilation index, days with supplemental oxygen, days on mechanical ventilation, and mortality.

Porcine minced lung surfactant extract (poractant alfa) vs. porcine lung lavage surfactant (Surfacen).

Prevention studies: No studies were identified.

Treatment studies: No studies were identified.

Excluded studies

Excluded studies: Four studies were excluded (Bozdağ 2015; Choi 2005; Rebello 2009; Proquitté 2007)

Choi 2005: In this multicenter study conducted in South Korea, a domestically developed bovine surfactant, Newfacen, was compared with Surfacten, another bovine derived surfactant for efficacy in 492 preterm infants with established RDS with birth weight less than 1500 grams. Short-term responses to surfactant and acute complications such as total doses of surfactant administered and changes in respiratory parameters were studied.

This study was excluded because both of the surfactants studied belong to the same comparison group (bovine lung lavage surfactant).

Rebello 2009: In this multicenter study conducted in Brazil, Rebello and colleagues compared the beneficial effects of butantan (a porcine surfactant obtained by organic extraction) with other commercially available surfactants (either beractant or poractant alfa) in 327 preterm infants with RDS. The primary outcome was being alive at 28 days of life.

This study was excluded because the control group received both modified bovine lung lavage surfactant and porcine lung lavage surfactant.

Bozdağ 2015: A prospective randomized controlled trial to compare the efficacy of two animal-derived surfactants for pulmonary hemorrhage in very low birth weight (VLBW) infants. 42 infants were divided into two groups, poractant alfa (n = 21) and beractant (n = 21).

This study was excluded because patient population was VLBW infants with pulmonary hemorrhage.

Proquitté 2007 : Proquitté and colleagues performed a retrospective, observational study comparing the effects of bovactant (Alveofact) and poractant alfa (Curosurf) on gas exchange and outcome in premature infants.

Studies awaiting classification: (Eras 2014; Gharehbaghi 2014; Mercado 2010; Saeidi 2013: Terek 2015)

Mercado 2010: Compared a porcine-derived surfactant to a bovine-derived lung extract. The exact products are not named in the report.

Saeidi 2013: Clinical trial performed during a 2-year period in Ghaem Center's neonatal care unit. Method of allocation unknown.

Terek 2015: Randomized controlled trial. 30 preterm infants with RDS, treated with poractant alfa (n = 15) or beractant (n = 15); 18 preterm infants without RDS served as a control group. Reported physiologic variables.

Eras 2014: Prospective, longitudinal, single-center cohort study of infants born at up to 1500 grams or up to 32 weeks' gestation between 2008 and 2009 who received either poractant alfa (n = 113) or beractant (n = 102) for RDS. Neurological and developmental assessments were performed at a corrected age of 18 to 24 months. It is unclear whether these patients are related to Didzar 2012 study.

Gharehbaghi 2014: Randomized clinical trial in Alzahra Hospital, Tabriz, Iran. Enrolled preterm newborn infants with gestation age less than 32 weeks with RDS. Poractant alfa (Curosurf) (N = 66) and bovactant (Alveofact) (N = 64). Surfactant was administered using the INSURE method (intubation, surfactant administration, extubation).

Ongoing studies: none identified.

Risk of bias in included studies

See 'Risk of bias' tables.

Randomized controlled trials that compared available bovine (modified minced or lavage) and porcine (minced or lavage) surfactant extracts in preterm infants at risk of or with established RDS were included in the analysis. Specific methodologic issues are addressed below:

Randomization and allocation concealment: Six studies did not report on method of randomization (Attar 2004; Baroutis 2003; Didzar 2012; Speer 1995; Sanchez-Mendiola 2005; Yalaz 2004). Randomization was performed and reported adequately in other studies except for Gharehbaghi 2010 which used admission code for randomization (even-odd numbers). Allocation concealment was adequately reported and appropriately performed in only half of the studies (Baroutis 2003; Bloom 1997; Bloom 2005; Halahakoon 1999; Karadag 2014; Ramanathan 2004;Speer 1995) .

Blinding of treatment and of outcome assessors: Blinding of treatment was adequately performed and reported by Bloom 1997 and Bloom 2005. Eight studies did not report any attempt at blinding of the treatment (Didzar 2012; Gharehbaghi 2010; Halahakoon 1999; Karadag 2014; Lam 2005; Ramanathan 2004; Sanchez-Mendiola 2005; Yalaz 2004). Others reported inability to blind the treatment because of differences in appearance or in the method of administration of surfactant product (Attar 2004; Baroutis 2003; Fujii 2010; Malloy 2005; Speer 1995).

Incomplete outcome data or selective reporting: There was complete follow-up of all enrolled patients in the studies with minimal risk of attrition bias or selective reporting bias, with the exception of the study of Sanchez-Mendiola 2005 with unclear risk of bias.

Effects of interventions

Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF-RI 1 (bovactant)) vs. modified bovine minced lung surfactant extract (beractant or surfactant TA) (COMPARISON 1).

Prevention: Two studies were identified (Bloom 1997; Bloom 2005).

Treatment: Seven studies were identified (Attar 2004; Baroutis 2003; Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005; Yalaz 2004).

Primary outcomes

Neonatal mortality (mortality < 28 days of age) from any cause (outcome 1.1):

  • Prevention (outcome 1.1.1): This outcome was reported by one prevention study (Bloom 2005), Bloom and colleagues reported no significant effect from prophylactic administration of bovine lung lavage surfactant or modified bovine minced lung surfactant on the risk of neonatal mortality at less than 28 days from any cause (RR 1.19, 95% CI 0.79 to 1.80; RD 0.02 , 95% CI −0.03 to 0.06; 1 study and 749 infants).
  • Treatment (outcome 1.1.2): This outcome was reported by three studies (Attar 2004; Bloom 2005; Yalaz 2004). None of the individual studies comparing these surfactant preparations showed any effect on neonatal mortality at less than 28 days. The meta-analysis of treatment trials showed no significant difference in the risk of neonatal mortality between bovine lung lavage surfactant and modified bovine minced lung surfactant (typical RR 0.90, 95% CI 0.65 to 1.26; typical RD −0.01, 95% CI −0.04 to 0.02; 3 studies and 1451 infants). There was no heterogeneity among the studies (I² = 0%).

Mortality prior to hospital discharge (from any cause) (outcome 1.2) (Figure 1):

  • Prevention (outcome 1.2.1): This outcome was reported by two studies (Bloom 1997 and Bloom 2005). Neither study individually showed any significant difference in mortality prior to discharge. The meta-analysis of these studies showed no significant difference in mortality prior to discharge with prophylactic administration of bovine lung lavage surfactant or modified bovine minced lung surfactant (typical RR 1.24, 95% CI 0.90 to 1.71; typical RD 0.03, 95% CI −0.01 to 0.06; 2 studies and 1123 infants). Low heterogeneity was present between the studies (I² = 31%). The evidence was graded as moderate quality because of imprecision in estimates.
  • Treatment (outcome 1.2.2): This outcome was reported by six studies (Attar 2004; Baroutis 2003; Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on the mortality prior to discharge (typical RR 0.98, 95% CI 0.79 to 1.21; typical RD −0.00, 95% CI −0.03 to 0.03; 6 studies and 2231 infants). No heterogeneity was noted among the studies (I² = 0%) and the quality of evidence was graded as moderate.

Chronic lung disease:

- Oxygen requirement at 28 to 30 days of age (outcome 1.3):

  • Prevention (outcome 1.3.1): This outcome was reported by one prevention study (Bloom 2005) which reported no significant effect of surfactant preparation on oxygen requirement at 28 to 30 days of age (RR 0.99, 95% CI 0.88 to 1.12; RD −0.00, 95% CI −0.07 to 0.07; 1 study and 749 infants).
  • Treatment (outcome 1.3.2): This outcome was reported by three studies (Attar 2004; Bloom 2005; Hammoud 2004). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on risk of oxygen requirement at 28 to 30 days of age (typical RR 1.09, 95% CI 0.98 to 1.21; typical RD 0.04, 95% CI −0.01 to 0.09; 3 studies and 1510 infants). Moderate heterogeneity was present between the studies (I² = 64%).

- Oxygen requirement at 36 weeks' postmenstrual age (outcome 1.4) (Figure 2):

  • Prevention (outcome 1.4.1): This outcome was reported by one prevention study (Bloom 2005), which reported no significant effect of surfactant preparation on oxygen requirement at 36 weeks' postmenstrual age (RR 0.97, 95% CI 0.79 to 1.19; RD −0.01, 95% CI −0.08 to 0.06; 1 study and 749 infants).
  • Treatment (outcome 1.4.2): This outcome was reported by five studies (Attar 2004; Baroutis 2003; Bloom 2005; Lam 2005; Yalaz 2004). Lam 2005 noted a significant decrease in oxygen requirement at 36 weeks' postmenstrual age (RR 0.51, 95% CI 0.28 to 0.93) favoring bovine lung lavage surfactant, while other studies did not report difference in the outcome. The meta-analysis of treatment trials demonstrated no effect of surfactant preparation on risk of oxygen requirement at 36 weeks' postmenstrual age (typical RR 0.95, 95% CI 0.82 to 1.11; typical RD −0.01, 95% CI −0.06 to 0.03; 5 studies and 1564). No heterogeneity was noted among the studies (I² = 13%) and the quality of evidence was graded as high.

Death or chronic lung disease:

- Death or oxygen requirement at 28 to 30 days of age (outcome 1.5):

  • Prevention (outcome 1.5.1): This outcome was reported by one study (Bloom 2005), which showed no significant effect of surfactant preparation on risk of combined outcome of death or oxygen requirement at 28 to 30 days of age (RR 1.02, 95% CI 0.93 to 1.13; RD 0.02 , 95% CI −0.05 to 0.08; 1 study and 749 infants).
  • Treatment (outcome 1.5.2): This outcome was reported by two studies (Attar 2004; Bloom 2005). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on the risk of the combined outcome of death or oxygen requirement at 28 to 30 days of age (typical RR 1.05, 95% CI 0.96 to 1.15; typical RD 0.03, 95% CI −0.02 to 0.08; 2 studies and 1401 infants). There was no heterogeneity among the studies (I² = 0%).

- Death or oxygen requirement at 36 weeks' postmenstrual age (outcome 1.6):

  • Prevention (outcome 1.6.1): This outcome was reported by two studies (Bloom 1997; Bloom 2005 ) no significant effect of surfactant preparation on risk of combined outcome of death or oxygen requirement at 36 weeks' postmenstrual age. None of the individual studies or the meta-analysis of these prevention trials demonstrated any significant difference in the risk of combined outcome of death or oxygen requirement at 36 weeks' postmenstrual age between the surfactant preparations (typical RR 1.02, 95% CI 0.89 to 1.17; typical RD 0.01, 95% CI −0.05 to 0.06; 2 studies and 1123 infants). There was no statistical heterogeneity among the studies (I² = 0%) and the quality of evidence was graded as high (95% CI was narrow and precise around no effect and total number of events met optimal information size).
  • Treatment (outcome 1.6.2): This outcome was reported by three studies (Attar 2004; Bloom 1997; Bloom 2005). None of the individual studies showed any significant effect of surfactant preparation on combined outcome of death or oxygen requirement at 36 weeks' postmenstrual age. The meta-analysis of these treatment trials did not demonstrate any significant difference in the risk of combined outcome of death or oxygen requirement at 36 weeks' postmenstrual age between the surfactant preparations (typical RR 0.95, 95% CI 0.86 to 1.06; typical RD −0.02, 95% CI −0.06 to 0.02; 3 studies and 2009 infants). There was no heterogeneity among the studies (I² = 0%) and the quality of evidence was graded as high (95% CI was narrow and precise around no effect and total number of events met optimal information size).

Secondary outcomes  

Doses of surfactant.

Post hoc analysis: Received > one dose of surfactant (outcome 1.7):

  • Prevention (outcome 1.7.1): This outcome was reported by two studies (Bloom 1997; Bloom 2005). Neither the individual studies nor the meta-analysis of the prevention trials demonstrated any significant difference in the risk of 'receiving more than one dose of surfactant' based on surfactant preparation used (typical RR 1.02, 95% CI 0.89 to 1.16; typical RD −0.01, 95% CI −0.05 to 0.07; 2 studies and 1123 infants). There was no heterogeneity among the studies (I² = 0%).
  • Treatment (outcome 1.7.2): This outcome was reported by five studies (Attar 2004; Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant difference in the risk of 'receiving more than one dose of surfactant' based on surfactant preparation (typical RR 0.99, 95% CI 0.93 to 1.06; typical RD −0.01, 95% CI −0.05 to 0.04; 5 studies and 2178 infants). There was low heterogeneity among the studies (I² = 46%).

Pneumothorax (outcome 1.8):

  • Prevention (outcome 1.8.1): This outcome was reported by one study (Bloom 2005), which showed no effect of surfactant preparation on risk of pneumothorax (RR 0.76, 95% CI 0.43 to 1.36; one study and 749 infants) and the quality of evidence was graded as moderate.
  • Treatment (outcome 1.8.2): This outcome was reported by six studies (Attar 2004; Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005; Yalaz 2004). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on risk of pneumothorax (typical RR 1.14, 95% CI 0.85 to 1.51; typical RD 0.01, 95% CI −0.01 to 0.03; 6 studies and 2224 infants). There was moderate heterogeneity among the studies (I² = 62%) and the quality of evidence is low (95% CI included both no effect and appreciable harm, and unexplained heterogeneity).

Air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) (outcome 1.9):

  • Prevention (outcome 1.9.1): This outcome was reported by both Bloom 1997 and Bloom 2005. Neither the individual studies nor the meta-analysis of these prevention trials demonstrated any significant effect of surfactant preparation on risk of air leak syndrome (typical RR 1.16, 95% CI 0.84 to 1.60; typical RD 0.02, 95% CI −0.02 to 0.05; 2 studies and 1123 infants). There was no heterogeneity among the studies (I² = 0%).
  • Treatment (outcome 1.9.2): This outcome was reported by three studies (Baroutis 2003; Bloom 1997; Bloom 2005). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on air leak syndrome (typical RR 1.02, 95% CI 0.82 to 1.28; typical RD 0.00, 95% CI −0.03 to 0.03; 3 studies and 2011 infants). There was low heterogeneity among the studies (I² = 41%).

Pulmonary hemorrhage (outcome 1.10):

  • Prevention (outcome 1.10.1): This outcome was reported by both Bloom 1997 and Bloom 2005 . Neither the individual studies nor the meta-analysis of these prevention trials demonstrated any significant effect of surfactant preparation on risk of pulmonary hemorrhage (typical RR 1.44, 95% CI 0.88 to 2.39; typical RD 0.02, 95% CI −0.01 to 0.05; 2 studies and 1123 infants). There was low heterogeneity among the studies (I² = 30%) and the "quality of evidence" is low (95% CI included both no effect and appreciable harm; and total number of events died not meet optimal information size).
  • Treatment (outcome 1.10.2): This outcome was reported by four studies (Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on risk of pulmonary hemorrhage (typical RR 1.08, 95% CI 0.74 to 1.59; typical RD 0.00, 95% CI −0.01 to 0.02; 4 studies and 2138 infants). There was no heterogeneity among the studies (I² = 0%) and the "quality of evidence" is moderate.

Patent ductus arteriosus (PDA) (that has been treated with cyclo-oxygenase inhibitor or surgery) (outcome 1.11):

  • Prevention: This outcome was not reported by any study.
  • Treatment (outcome 1.11.1): This outcome was reported by one study. Attar 2004 reported no effect of surfactant preparation on risk of PDA requiring treatment with cyclo-oxygenase inhibitor or surgery (RR 0.32, 95% CI 0.07 to 1.34).

Culture-confirmed bacterial sepsis (outcome 1.12):

  • Prevention (outcome 1.12.1): This outcome was reported by both Bloom 1997 and Bloom 2005. Neither the individual studies nor the meta-analysis of these prevention trials demonstrated any significant effect of surfactant preparation on the risk of culture-confirmed bacterial sepsis (typical RR 1.08, 95% 0.91 to 1.28; typical RD 0.02, 95% CI −0.03 to 0.08; 2 studies and 1123 infant). There was no heterogeneity among the studies (I² = 0%).
  • Treatment (outcome 1.12.2): This outcome was reported by six studies (Attar 2004; Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005; Yalaz 2004). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on risk of culture-confirmed bacterial sepsis (typical RR 1.00, 95% CI 0.87 to 1.15; typical RD 0.00, 95% CI −0.04 to 0.04, 6 studies and 2228 infants). There was no heterogeneity among the studies (I² = 0%).

Culture-confirmed fungal sepsis:

  • Prevention: This outcome was not reported by any study.
  • Treatment: This outcome was not reported by any treatment study.

Necrotizing enterocolitis (any stage) (Bell 1978) (outcome 1.13):

  • Prevention (outcome 1.13.1): This outcome was reported by both Bloom 1997 and Bloom 2005. Neither study reported NEC based on Bell's criteria. Both studies reported on "any NEC" (outcome 1.13). Neither the individual studies nor the meta-analysis of these prevention trials demonstrated any significant effect of surfactant preparation on the risk of NEC (any stage) (typical RR 1.03, 95% CI 0.74 to 1.42; typical RD 0.00, 95% CI −0.03 to 0.04; 2 studies and 1123 infants). There was no heterogeneity among the studies (I² = 0%).
  • Treatment (outcome 1.13.2): This outcome (any NEC) was reported by five studies (Baroutis 2003; Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on the risk of NEC (any stage) (typical RR 1.02, 95% CI 0.78 to 1.33, typical RD 0.00, 95% CI −0.02 to 0.02; 5 studies and 2191 infants). There was low heterogeneity among the studies (I² = 42%).

Periventricular leukomalacia (in infants who received neuroimaging) (outcome 1.14):

  • Prevention (outcome 1.14.1): This outcome was reported by one study (Bloom 2005), which showed no significant effect from prophylactic administration of bovine lung lavage surfactant or modified bovine minced lung surfactant on the risk of PVL (RR 0.61, 95% CI 0.29 to 1.26; RD −0.02, 95% CI −0.05 to 0.01; 1 study and 713 infants).
  • Treatment (outcome 1.14.2): This outcome was reported by one study (Bloom 2005 ) which showed no significant effect from treatment with bovine lung lavage surfactant or modified bovine minced lung surfactant on the risk of PVL (RR 1.01, 95% CI 0.59 to 1.73; RD 0.00, 95% CI −0.02 to 0.02; 1 study and 1275 infants).

Retinopathy of prematurity in subjects examined.

- ROP all stages (outcome 1.15):

  • Prevention (outcome 1.15.1): This outcome was reported by both Bloom 1997 and Bloom 2005. Neither the individual studies nor the meta-analysis of these prevention trials demonstrated any significant effect of surfactant preparation on ROP (all stages) (typical RR 0.98, 95% CI 0.86 to 1.12; typical RD −0.01, 95% CI −0.7 to 0.05; 2 studies and 1011 infants).
  • Treatment (outcome 1.15.2): This outcome was reported by three studies (Baroutis 2003; Bloom 1997; Bloom 2005). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on ROP (all stages) (typical RR 1.02, 95% CI 0.89 to 1.16; typical RD −0.01, 95% CI −0.07 to 0.05; 3 studies and 1662 infants).

- ROP stage 3 or greater (outcome 1.16):

  • Prevention (outcome 1.16.1): This outcome was reported by one study (Bloom 2005) which showed no significant effect from prophylactic administration of bovine lung lavage surfactant or modified bovine minced lung surfactant on the risk of ROP stage 3 or greater (RR 1.14, 95% CI 0.77 to 1.69; one study and 637 infants).
  • Treatment (outcome 1.16.2): This outcome was reported by one study (Bloom 2005) which showed no significant effect from bovine lung lavage surfactant or modified bovine minced lung surfactant treatment on the risk of ROP stage 3 or greater (RR 0.92, 95% CI 0.64 to 1.33; one study and 1001 infants).

Intraventricular hemorrhage (in infants who received neuroimaging).

- Intraventricular hemorrhage (any grade) (outcome 1.17)

  • Prevention (outcome 1.17.1): This outcome was reported by one study (Bloom 2005) which showed no significant effect from prophylactic administration of bovine lung lavage surfactant or modified bovine minced lung surfactant on the risk of IVH (any grade) (RR 1.04, 95% CI 0.87 to 1.24; RD 0.02 , 95% CI −0.06 to 0.09; one study and 713 infants).
  • Treatment (outcome 1.17.2): This outcome was reported by three studies (Bloom 2005; Hammoud 2004; Yalaz 2004 ). No individual trial demonstrated an effect on intraventricular hemorrhage of any grade and the meta-analysis of treatment trials demonstrated no significant effect of surfactant preparation on the risk of IVH (any grade) (typical RR 1.14, 95% CI 0.98 to 1.33; typical RD 0.04, 95% CI −0.01 to 0.09; 3 studies and 1434 infants). There was no heterogeneity in the studies (I² = 0%).

- Severe intraventricular hemorrhage (grade 3 or greater) (outcome 1.18)

  • Prevention (outcome 1.18.1): This outcome was reported by two studies (Bloom 1997 and Bloom 2005). Neither the individual studies nor the meta-analysis of these prevention trials demonstrated any effect of surfactant preparation on the risk of severe IVH (typical RR 1.28, 95% CI 0.89 to 1.83; typical RD 0.02, 95% CI −0.01 to 0.06; 2 studies and 1087 infants). There was no heterogeneity among the studies (I² = 0%) and the "quality of evidence" is low (95% CI included both no effect and appreciable harm; and total number of events died not meet optimal information size) .
  • Treatment (outcome 1.18.2): This outcome was reported by five studies (Baroutis 2003; Bloom 1997; Bloom 2005; Hammoud 2004; Lam 2005). Neither the individual studies nor the meta-analysis of these treatment trials demonstrated any significant effect of surfactant preparation on risk of severe IVH (typical RR 0.86, 95% CI 0.68 to 1.09; typical RD −0.02, 95% CI −0.05 to 0.01; 5 studies and 2040 infants). There was no heterogeneity among the studies (I² = 0%) and the "quality of evidence" is moderate (95% CI included both no effect and appreciable harm; and total number of events died not meet optimal information size).

Cerebral palsy at approximately two years' corrected age (as defined by the study authors). Not reported.

Neurodevelopmental outcome at approximately two years' corrected age (acceptable range 18 months to 28 months) including: cerebral palsy, delayed neurodevelopment (Bayley Scales of Infant Development Mental Developmental Index less than 70), legal blindness (less than 20/200 visual acuity), and hearing deficit (aided or less than 60 dB on audiometric testing). The composite outcome 'neurodevelopmental impairment' was defined as having any one of the aforementioned deficits. Not reported by either study.

Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF RI 1 (bovactant)) vs. porcine minced lung surfactant extract (poractant) (COMPARISON 2).

Prevention: No studies were identified.

Treatment: One study was identified (Baroutis 2003).

Primary outcome measures

Prevention Studies:

Not applicable as no studies were identified

Treatment Studies:

Mortality (outcome 2.1): Neonatal mortality (mortality at less than 28 days of age) from any cause was not reported. Baroutis 2003 reported no significant effect from treatment with bovine lung lavage surfactant or porcine minced lung surfactant on the risk of mortality prior to hospital discharge (from any cause) (RR 1.40, 95% CI 0.51 to 3.87; RD 0.07, 95% CI −0.15 to 0.29; one study and 54 infants) . The "quality of evidence" is low because of serious imprecision in analysis and total number of events did not meet optimal information size.

Chronic lung disease (outcome 2.2): Oxygen requirement at 28 to 30 days of age was not reported. Baroutis 2003 reported no significant effect from treatment with bovine lung lavage surfactant or porcine minced lung surfactant on the risk of oxygen requirement at 36 weeks' postmenstrual age (RR 0.75, 95% 0.19 to 3.04; RD −0.04, 95% CI −0.22 to 0.14; one study and 54 infants). The "quality of evidence" is low because of serious imprecision in analysis and total number of events did not meet optimal information size.

Death or chronic lung disease at 28 to 30 days of age or at 36 weeks' postmenstrual age: was not reported.

Secondary outcomes

Air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) (outcome 2.3): Baroutis 2003 reported no significant effect from treatment with bovine lung lavage surfactant or porcine minced lung surfactant on the risk of air leak syndrome (RR 0.67, 95% CI 0.12 to 3.68; RD −0.04 , 95% CI −0.19 to 0.12; one study and 54 infants).

Necrotizing enterocolitis (any stage) (Bell 1978) (outcome 2.4): Baroutis 2003 reported no significant effect from treatment with bovine lung lavage surfactant or porcine minced lung surfactant on the risk of NEC (any stage) (RR 0.67, 95% CI 0.12 to 3.68; RD −0.04, 95% CI −0.19 to 0.12; one study and 54 infants).

Retinopathy of prematurity in subjects examined

- ROP all stages (outcome 2.5): Baroutis 2003 reported no significant effect from treatment with bovine lung lavage surfactant or porcine minced lung surfactant on the risk of ROP (all stages) (RR 0.80, 95% CI 0.24 to 2.66; RD −0.04, 95% CI −0.24 to 0.16; one study and 54 infants).

- ROP stage 3 or greater: not reported.

Intraventricular hemorrhage (in infants who received neuroimaging)

- Intraventricular hemorrhage (any grade): not reported.

- Severe intraventricular hemorrhage (grade 3 or greater) (outcome 2.6): Baroutis 2003 reported no significant effect from treatment with bovine lung lavage surfactant or porcine minced lung surfactant on the risk of severe IVH (RR 0.83, 95% 0.29, 2.41; RD −0.04 , 95% CI −0.25 to 0.18; one study and 54 infants). The "quality of evidence" is very low because of serious imprecision in analysis, risk of bias from lack of blinding of outcome assessment and total number of events not meeting optimal information size.

No other comparison could be made for the remaining secondary outcomes, including doses of surfactant, post hoc analysis: received more than one dose of surfactant, pneumothorax, pulmonary hemorrhage, patent ductus arteriosus (PDA) (that has been treated with cyclo-oxygenase inhibitor or surgery), culture-confirmed bacterial sepsis, culture-confirmed fungal sepsis, periventricular leukomalacia (in infants who received neuroimaging), cerebral palsy at approximately two years' corrected age and neurodevelopmental outcome at approximately two years' corrected age.

Bovine lung lavage surfactant extract (calfactant, CLSE (BLES) or SF-RI 1 (bovactant)) vs. Porcine lung lavage surfactant (Surfacen).

Prevention: No studies were identified.

Treatment: No studies were identified.

Modified bovine minced lung surfactant extract (beractant or surfactant TA) vs. porcine minced lung surfactant extract (poractant alfa) (COMPARISON 3).

Prevention: No studies were identified.

Treatment: Nine studies were identified. (Baroutis 2003; Didzar 2012; Fujii 2010; Gharehbaghi 2010; Halahakoon 1999; Karadag 2014; Malloy 2005; Ramanathan 2004; Speer 1995).

Primary outcomes

Neonatal mortality (mortality < 28 days of age) from any cause (outcome 3.1): This outcome was reported by two studies (Halahakoon 1999; Ramanathan 2004). The meta-analysis did not demonstrate any significant effect of surfactant preparation on the risk of neonatal mortality from any cause (typical RR 1.48, 95% CI 0.72 to 3.07; typical RD 0.03, 95% CI −0.03 to 0.10; 2 studies and 320 infants). There was no heterogeneity among the studies (I² = 0% ).

Mortality prior to hospital discharge (from any cause) (outcome 3.2): This outcome was reported by nine studies (Baroutis 2003; Didzar 2012; Fujii 2010; Gharehbaghi 2010; Halahakoon 1999; Karadag 2014; Malloy 2005; Ramanathan 2004; Speer 1995). None of the individual studies showed any effect of surfactant preparation on the risk of mortality prior to hospital discharge. The meta-analysis of these trials demonstrated an increased risk of mortality prior to hospital discharge associated with beractant treatment compared with poractant alfa treatment (typical RR 1.44, 95% CI 1.04 to 2.00; typical RD 0.05, 95% CI 0.01 to 0.10; NNTH 20, 95% CI 10 to 100; 9 studies and 901 infants). There was no heterogeneity among the studies (I² = 0% ) and the "quality of evidence" is moderate (imprecision in estimates).

Chronic lung disease:

- Oxygen requirement at 28 to 30 days of age (outcome 3.3): This outcome was reported by two studies (Halahakoon 1999; Ramanathan 2004). The meta-analysis demonstrated no significant effect of surfactant preparation on risk of oxygen requirement at 28 to 30 days of age (typical RR 0.97, 95% CI 0.77 to 1.23; typical RD −0.01, 95 % CI −0.13 to 0.10; 2 studies and 320 infants). No heterogeneity was noted among the studies (I² = 0%).

- Oxygen requirement at 36 weeks' postmenstrual age (outcome 3.4): This outcome was reported by nine studies (Baroutis 2003; Didzar 2012; Fujii 2010; Gharehbaghi 2010; Halahakoon 1999; Karadag 2014; Malloy 2005; Ramanathan 2004; Speer 1995). None of the individual studies showed an effect of surfactant preparation on the risk of oxygen requirement at 36 weeks' postmenstrual age. The meta-analysis of these studies demonstrated no significant effect of surfactant preparation on risk of oxygen requirement at 36 weeks' postmenstrual age (typical RR 0.94, 95% CI 0.79 to 1.12; typical RD −0.02, 95% CI −0.08 to 0.04; 9 studies and 899 infants). No heterogeneity was noted among the studies (I² = 0%) and the "quality of evidence" is moderate.

Death or chronic lung disease:

- Death or oxygen requirement at 28 to 30 days of age: This outcome was not reported.

- Death or oxygen requirement at 36 weeks' postmenstrual age (outcome 3.5): This outcome was reported by three studies (Didzar 2012; Fujii 2010; Ramanathan 2004). Didzar 2012 showed increased risk of death or oxygen requirement at 36 weeks' postmenstrual age for modified bovine minced lung surfactant (RR 1.95, 95% CI 1.11 to 3.42). The meta-analysis of these trials demonstrated a significant increase in combined outcome of death or oxygen requirement at 36 weeks' postmenstrual age for modified bovine minced lung surfactant compared with porcine minced lung surfactant (typical RR 1.30, 95% CI 1.04 to 1.64; typical RD 0.11, 95% CI 0.02 to 0.20; NNTH 9, 95% CI 5 to 50). There was low heterogeneity noted among the studies (I² = 45%), and the "quality of evidence" is moderate.

Secondary outcomes  

Post hoc analysis: Received > one dose of surfactant (outcome 3.6): This outcome was reported by six studies (Didzar 2012; Fujii 2010; Gharehbaghi 2010; Karadag 2014; Ramanathan 2004; Speer 1995). Except for Gharehbaghi 2010, all other studies reporting this outcome showed a trend towards increase in risk of receiving more than one dose of surfactant for modified bovine minced lung surfactant. Ramanathan 2004, Karadag 2014 and Didzar 2012 reported a statistically significant increase in risk of receiving more than one dose of surfactant for modified bovine minced lung surfactant. Overall, the meta-analysis of these trials demonstrated a significant increase in risk of receiving more than one dose of surfactant for modified bovine minced lung surfactant compared with porcine minced lung surfactant (typical RR 1.57, 95% CI 1.29 to 1.92; typical RD 0.14, 95% CI 0.08 to 0.20; NNTH 7, 95% CI 5 to 12; 6 studies and 786 infants). No heterogeneity was noted among the studies (I² = 19%).

Pneumothorax (outcome 3.7): This outcome was reported by six studies (Didzar 2012; Halahakoon 1999; Karadag 2014; Malloy 2005; Ramanathan 2004; Speer 1995). None of the individual studies or the meta-analysis showed any effect of surfactant preparation on the risk of pneumothorax (typical RR 1.24, 95% CI 0.71 to 2.17; typical RD 0.02, 95% CI −0.02 to 0.05; 6 studies and 669 infants). No heterogeneity was noted among the studies (I² = 0%) and the quality of evidence was graded as low.

Air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) (outcome 3.8): This outcome was reported by three studies (Baroutis 2003; Fujii 2010; Gharehbaghi 2010). None of the individual studies or the meta-analysis of these studies demonstrated any effect of surfactant preparation on risk of air leak syndrome (typical RR 2.55, 95% 0.98 to 6.68; typical RD 0.07, 95% CI 0.00 to 0.13; 3 studies and 255 infants). No heterogeneity was noted among the studies (I² = 0%).

Pulmonary hemorrhage (outcome 3.9): This outcome was reported by eight studies (Didzar 2012; Fujii 2010; Gharehbaghi 2010; Halahakoon 1999; Karadag 2014; Malloy 2005; Ramanathan 2004; Speer 1995). None of the individual studies showed any effect of surfactant preparation on the risk of pulmonary hemorrhage except for Karadag 2014 which showed increased risk of pulmonary hemorrhage with beractant . The meta-analysis of these studies demonstrated no significant effect of surfactant preparation on risk of pulmonary hemorrhage (typical RR 1.28, 95% CI 0.81 to 2.02; typical RD 0.02, 95% CI −0.02 to 0.06; 8 studies and 871 infants). No heterogeneity was noted among the studies (I² = 0%) and the quality of evidence was graded as low.

Patent ductus arteriosus (PDA) (that has been treated with cyclo-oxygenase inhibitor or surgery) (outcome 3.10): This outcome was reported by three studies (Fujii 2010; Halahakoon 1999; Malloy 2005). Both Fujii 20100 and Malloy 2005 showed a significant increase in the risk of PDA requiring treatment with cyclo-oxygenase inhibitor [Fujii 2010 (RR 2.20, 95% CI 1.18 to 4.09) and Malloy 2005 (RR 2.60, 95% CI 1.06 to 6.36)] with modified bovine minced lung surfactant while Halahakoon 1999 did not show such effect.

The meta-analysis of these trials demonstrated a significant increase in risk of PDA requiring treatment with cyclo-oxygenase inhibitor with modified bovine minced lung surfactant compared with porcine minced lung surfactant (typical RR 1.86, 95% 1.28 to 2.70; typical RD 0.28, 95% CI 0.13 to 0.43; NNTH 4, 95% CI 2 to 8). Moderate heterogeneity was noted (I² = 65%) which was statistically not significant

Culture-confirmed bacterial sepsis (outcome 3.11): This outcome was reported by six studies (Didzar 2012; Gharehbaghi 2010; Halahakoon 1999; Karadag 2014; Malloy 2005; Speer 1995). Neither the individual studies nor the meta-analysis of these studies demonstrated any significant effect of surfactant preparation on culture-confirmed bacterial sepsis (typical RR 1.13, 95% CI 0.87 to 1.46; typical RD 0.03, 95% CI −0.04 to 0.10; 6 studies and 526 infants). No heterogeneity was noted among the studies (I² = 13%).

Culture-confirmed fungal sepsis: This outcome was not reported.

Necrotizing enterocolitis (any stage) (Bell 1978) (outcome 3.12): This outcome was reported by seven studies (Baroutis 2003; Didzar 2012; Fujii 2010; Halahakoon 1999; Karadag 2014; Malloy 2005; Ramanathan 2004). None of the individual studies or meta-analysis of these trials demonstrated any significant effect of surfactant preparation on the risk of NEC (typical RR 0.82, 95% 0.50 to 1.33; typical RD −0.02, 95% CI −0.06 to 0.02; 7 studies and 701 infants). No heterogeneity was noted among the studies (I² = 0%).

Periventricular leukomalacia (in infants who received neuroimaging). (outcome 3.13): This outcome was reported by one study (Fujii 2010). This study reported no significant effect of surfactant preparation on the risk of PVL (RR 1.04, 95% 0.07 to 15.72; one study and 47 infants).

Retinopathy of prematurity in subjects examined.

- ROP all stages (outcome 3.14): This outcome was reported by three studies (Baroutis 2003; Gharehbaghi 2010; Halahakoon 1999). None of the individual studies or the meta-analysis of these trials demonstrated any significant effect of surfactant preparation on the risk of ROP (all stages) (typical RR 0.60, 95% CI 0.29 to 1.26; typical RD −0.06, 95% CI −0.13 to 0.02; 3 studies and 230 infants). No heterogeneity was noted among the studies (I² = 0%).

- ROP stage 3 or greater (outcome 3.15): This outcome was reported by four studies (Fujii 2010; Halahakoon 1999; Karadag 2014; Malloy 2005). None of the studies or the meta-analysis of these trials demonstrated any significant effect of surfactant preparation on the risk of ROP stage 3 or greater (typical RR 1.02, 95% CI 0.57 to 1.80; typical RD 0.00, 95% CI −0.09 to 0.09; 4 studies and 444 infants). Low heterogeneity was noted among the studies (I² = 25%).

Intraventricular hemorrhage (in infants who received neuroimaging).

- Intraventricular hemorrhage (any grade) (outcome 3.16): This outcome was reported by four studies (Didzar 2012; Halahakoon 1999; Karadag 2014; Speer 1995). None of the individual studies or the meta-analysis of these trials demonstrated any effect of surfactant preparation on risk of IVH (any grade) (typical RR 0.98, 95% CI 0.64 to 1.50; typical RD 0.00, 95% CI −0.09 to 0.08; 4 studies and 318 infants ). Low heterogeneity was noted among the studies (I² = 29%).

- Severe intraventricular hemorrhage (grade 3 or greater) (outcome 3.17): This outcome was reported by seven studies (Baroutis 2003; Fujii 2010; Gharehbaghi 2010; Halahakoon 1999; Malloy 2005; Ramanathan 2004; Speer 1995). None of the individual studies or the meta-analysis of these trials demonstrated any significant effect of surfactant preparation on the risk of severe IVH (typical RR 1.28, 95% CI 0.83 to 1.97; typical RD 0.03, 95% CI −0.02 to 0.07; 7 studies and 705 infants). No heterogeneity was noted among the studies (I² = 0%) and the "quality of evidence" is very low.

Cerebral palsy at approximately two years' corrected age (as defined by the study authors): Not reported.

Neurodevelopmental outcome at approximately two years' corrected age: This outcome (acceptable range of assessment 18 months to 28 months corrected age) included: cerebral palsy, delayed neurodevelopment (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. None of the studies reported on this outcome.

Modified bovine minced lung surfactant extract (beractant or surfactant TA) vs. porcine lung lavage surfactant (Surfacen) (COMPARISON 4).

Prevention: No studies were identified.

Treatment: One study was identified (Sanchez-Mendiola 2005).

Primary outcome

Mortality prior to hospital discharge (from any cause) (outcome 4.1): Sanchez-Mendiola 2005 reported no effect of surfactant preparation on mortality prior to discharge (RR 1.10, 95% CI 0.60 to 1.99). The quality of evidence is low (95% CI including both no effect and appreciable harm, and total number of events not meeting optimal information size).

Secondary outcome

Pneumothorax (outcome 4.2): Sanchez-Mendiola 2005 reported highly significant decrease in modified bovine minced lung surfactant compared with porcine lung lavage surfactant (Surfacen) on the risk of pneumothorax (RR 0.10, 95% CI 0.01 to 0.73; typical RD −0.39, 95% CI −0.61 to −0.16; NNTB 2, 95% CI 1 to 6).

No other comparison could be made for the remaining outcomes including neonatal mortality (mortality < 28 days of age) from any cause, chronic lung disease, oxygen requirement at 28 to 30 days of age, oxygen requirement at 36 weeks' postmenstrual age, death or chronic lung disease, received > one dose of surfactant, air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum), pulmonary hemorrhage, patent ductus arteriosus (PDA) (that has been treated with cyclo-oxygenase inhibitor or surgery), culture-confirmed bacterial sepsis, culture-confirmed fungal sepsis, necrotizing enterocolitis (defined as Bell Stage II or greater), periventricular leukomalacia (in infants who received neuroimaging), retinopathy of prematurity in subjects examined, intraventricular hemorrhage (in infants who received neuroimaging), cerebral palsy at approximately two years corrected age (as defined by the study authors), and neurodevelopmental outcome at approximately two years corrected age.

Porcine minced lung surfactant extract (poractant alfa) vs. porcine lung lavage surfactant (Surfacen) .

Prevention: No studies were identified.

Treatment: No studies were identified.

SUBGROUP ANALYSES

Subgroup analyses based on gestational age and surfactant dosing schedule (single dose, multiple dose) were not performed because of lack of sufficient data. The subgroup analysis based on treatment strategy (prevention vs. treatment of established disease) was performed (as noted above) for bovine lung lavage surfactant extract vs. modified bovine minced lung surfactant extract; however, subgroup analysis based on disease severity could not be performed because of lack of data.

Subgroup analysis based on initial surfactant dosing (initial dose less than/or equal to 100 mg/kg of porcine minced lung and initial dose > 100 mg/kg of porcine minced lung compared with beractant 100 mg/kg) was performed for modified bovine minced lung vs. porcine minced lung surfactant.

Modified bovine minced lung vs. porcine minced lung (based on initial surfactant dosage)(COMPARISON 5)

Primary outcome measures:

Neonatal mortality (mortality < 28 days of age) from any cause (outcome 5.1): This outcome was reported by two studies (Halahakoon 1999 and Ramanathan 2004). In this subgroup analysis based on initial surfactant dosing, no significant difference was noted on risk of neonatal mortality for initial dose less than/or equal to 100 mg/kg porcine minced lung (typical RR 1.20, 95% CI 0.55 to 2.62; typical RD 0.02; 95% CI −0.06 to 0.09; 2 studies and 221 infants) or initial dose > 100 mg/kg porcine minced lung (typical RR 2.69, 95% 0.74 to 9.86; 1 study and 197 infants) compared with 100 mg/kg beractant.

Mortality prior to hospital discharge (from any cause) (outcome 5.2): Three studies reported the effect on mortality prior to discharge (from any cause) for initial dose less than/or equal to 100 mg/kg porcine minced lung surfactant (Baroutis 2003; Halahakoon 1999; Ramanathan 2004). None of the individual studies or the meta-analysis of these trials demonstrated any significant effect of surfactant preparation on the mortality prior to discharge at initial dose less than/or equal to 100 mg/kg porcine minced lung surfactant compared with 100 mg/kg beractant (typical RR 1.10, 95% CI 0.61 to 1.96; typical RD 0.01, 95% CI −0.07 to 0.10, 3 studies and 255 infants). No heterogeneity was noted among the studies (I² = 0%).

In the subgroup analysis for initial dose based on initial dose >100 mg/kg of porcine minced lung surfactant, seven studies reported the risk of mortality prior to discharge (Didzar 2012; Fujii 2010; Gharehbaghi 2010; Karadag 2014; Malloy 2005; Ramanathan 2004). None of the individual studies showed any significant effect of higher initial dose of porcine minced lung surfactant on this outcome. However, in the meta-analysis of these trials, there was a significantly higher mortality prior to discharge in the modified bovine minced lung surfactant (beractant 100mg/kg) compared with those receiving initial dose > 100 mg/kg of porcine minced lung surfactant (typical RR 1.62, 95% 1.11 to 2.38; typical RD 0.06, 95% CI 0.01 to 0.11; NNTH 16, 95% CI 9 to 100). There is low heterogeneity among the studies (I² = 30%).

Chronic lung disease:

- Oxygen requirement at 28 to 30 days of age (outcome 5.3): This outcome was reported by two studies (Halahakoon 1999; Ramanathan 2004). In the subgroup analysis based on initial surfactant dosing, no significant difference was noted on risk of chronic lung disease at 28 to 30 days of age for initial dose less than/or equal to 100 mg/kg of porcine minced lung surfactant (typical RR 0.96, 95% CI 0.73 to 1.25; typical RD −0.02, 95% CI −0.15 to 0.11; 2 studies and 221 infants) or > 100 mg/kg porcine minced lung surfactant (RR 1.01, 95% 0.76 to 1.34; RD 0.01, 95% CI −0.13 to 0.14; one study and 197 infants).

- Oxygen requirement at 36 weeks' postmenstrual age (outcome 5.4): Three studies (Baroutis 2003; Halahakoon 1999; Ramanathan 2004) reported the effect on oxygen requirement at 36 weeks' postmenstrual age for initial dose less than/or equal to 100 mg/kg of porcine minced lung surfactant. None of the individual studies or the meta-analysis of these trials demonstrated any significant effect of surfactant preparation on the risk of oxygen requirement at 36 weeks' postmenstrual age at initial dose less than/or equal to 100 mg/kg of porcine minced lung surfactant (typical RR 0.94, 95% CI 0.65 to 1.37; typical RD −0.02, 95% CI −0.13 to 0.09; 3 studies and 255 infants). No heterogeneity was noted among the studies (I² = 0%).

In the subgroup analysis for initial dose > 100 mg/kg of porcine minced lung surfactant dose, six studies reported the risk of oxygen requirement at 36 weeks' postmenstrual age (Fujii 2010; Gharehbaghi 2010; Karadag 2014; Malloy 2005; Ramanathan 2004; Speer 1995). None of the individual studies showed any significant effect of higher initial dose of porcine minced lung surfactant on this outcome. The meta-analysis of these trials demonstrated no significant effect of initial dose > 100 mg/kg of porcine minced lung surfactant compared with 100mg/kg beractant (typical RR 1.08, 95% CI 0.84 to 1.38; typical RD 0.02, 95% CI −0.05 to 0.09; 6 studies and 608 infants) on the risk of oxygen requirement at 36 weeks' postmenstrual age. No heterogeneity was noted among the studies (I² = 0%).

Death or chronic lung disease:

- Death or oxygen requirement at 36 weeks' postmenstrual age (outcome 5.5): One study (Ramanathan 2004) reported the effect of initial dose less than/or equal to100 mg/kg of porcine minced lung surfactant on this outcome. In the subgroup analysis based on initial surfactant dosing, no significant difference was noted on risk of death or oxygen requirement at 36 weeks' postmenstrual age for initial dose less than/or equal to 100 mg/kg of porcine minced lung surfactant (RR 1.04, 95% CI 0.76 to 1.43; RD 0.02, 95% CI −0.13 to 0.17; one study and 175 infants).

Three studies (Didzar 2012; Fujii 2010; Ramanathan 2004) reported the effect of initial dose > 100 mg/kg of porcine minced lung surfactant on the risk of death or oxygen requirement at 36 weeks' postmenstrual age. Didzar 2012 showed a significant increase in risk of death or oxygen requirement at 36 weeks' postmenstrual age for the modified bovine minced lung surfactant compared with initial dose > 100 mg/kg of porcine minced lung surfactant (RR 1.95, 95% CI 1.11 to 3.42), while the other two trials (Fujii 2010; Ramanathan 2004) did not show such difference. The meta-analysis of these three trials showed a significant increase in risk of death or oxygen requirement at 36 weeks' postmenstrual age for the modified bovine minced lung surfactant (100 mg/kg beractant) compared with initial dose > 100 mg/kg of porcine minced lung surfactant (typical RR 1.39, 95% 1.08 to 1.79; typical RD 0.13, 95% 0.03 to 0.23; NNTH 7, 95% CI 4 to 33). Low heterogeneity was noted among the studies (I² = 23%).

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Discussion

A wide variety of surfactant products have been formulated and studied in clinical trials (Halliday 2008). Animal-derived surfactants seem to confer an advantage over first generation synthetic surfactants (Soll 2001). Differences exist among the commercially available animal-derived surfactant products with respect to their source of extraction (bovine or porcine), method of extraction (minced or lavage), composition (viscosity, phospholipid content, amount of surfactant protein (SP B&C)), and dosing volume (Ramanathan 2009). A variety of animal-derived surfactant products have been studied around the world in randomized or quasi-randomized studies. Widely used and well-studied surfactants included the following: bovine lung lavage surfactant extracts (calfactant, bovactant and BLES); modified bovine minced lung surfactant extracts (beractant and Surfactant TA); and porcine minced lung surfactant extract (poractant alfa). However, whether there are clinically important differences among these animal-derived surfactant products has not been determined unequivocally.

This review compared the effect of administration of different animal-derived surfactant extracts on the risk of mortality, chronic lung disease, and other morbidities associated with prematurity in preterm infants at risk for or having RDS. Sixteen randomized or quasi-randomized studies eligible for inclusion compared bovine lung lavage surfactant extract, modified bovine minced lung surfactant extract, porcine minced lung surfactant, and porcine lung lavage surfactant. Only two prevention studies comparing bovine lung lavage surfactant extract with modified bovine minced lung surfactant extract were identified. Seven treatment studies compared modified bovine minced lung surfactant extract with bovine lung lavage surfactant extract, and seven treatment studies compared modified bovine minced lung surfactant extract with porcine minced lung surfactant extract. Most of the studies were of small sample size with the exception of Bloom 1997, Bloom 2005 and Ramanathan 2004. They varied with respect to range of gestational age (24 to 37 wk), birth weight (400 to 2000 g) and age at enrollment of the included infants. There were differences in the timing of surfactant administration (variable or not reported) and dosing schedule. Most studies reported the primary outcome (mortality and chronic lung disease) and complications associated with prematurity. None of the studies reported any long-term neurodevelopmental outcome.

This meta-analysis demonstrates a significant increase in the risk of mortality prior to discharge, death or oxygen requirement at 36 weeks' postmenstrual age, receiving more than one dose of surfactant, and PDA requiring treatment with modified bovine minced lung surfactant extract compared with porcine minced lung surfactant extract. In the subgroup analysis based on the initial dose of poractant alfa used, the improvement in risk of pre-discharge mortality and risk of death or oxygen requirement at 36 weeks' postmenstrual age was observed in the sub-group of infants receiving an initial dose of more than 100 mg/kg of porcine minced lung surfactant but not in the sub-group receiving an initial dose of less than 100mg/kg of porcine minced lung surfactant (all infants in the bovine surfactant comparison arm received the same dose of bovine surfactant).

The meta-analysis of studies comparing modified bovine minced lung surfactant extract with bovine lung lavage surfactant extract did not demonstrate significant differences in the primary outcomes. No meaningful comparison could be made for bovine lung lavage surfactant extract versus porcine lung lavage surfactant; bovine lung lavage surfactant extract versus porcine minced lung surfactant extract; or porcine minced lung surfactant extract versus porcine lung lavage surfactant extract because of the lack of adequate studies.

In summary, significant differences were noted between modified bovine minced lung surfactant extract (beractant) and porcine minced lung surfactant extract (poractant alfa), but not between other comparison groups or subgroups. The clinically meaningful differences include increase in the risk of mortality prior to discharge, risk of death or oxygen requirement at 36 weeks' postmenstrual age, risk of PDA requiring treatment, and risk of "receiving > 1 dose of surfactant" with modified bovine minced lung surfactant extract compared with porcine minced lung surfactant extract. The quality of evidence is moderate for primary outcomes because of imprecision.

The improved outcome noted with porcine minced lung surfactant extract compared with modified bovine minced lung surfactant extract could be either due to differences in biophysical/biochemical composition of porcine minced lung surfactant extract or from the higher phospholipid content associated with higher initial dose of porcine surfactant. The subgroup analysis based on initial dose of surfactant showed improvement in outcomes limited to the use of higher initial phospholipid/kg dose of porcine minced lung surfactant extract. This suggests possible dose effect from higher phospholipid administered with higher initial dose of porcine minced lung extract. However, our inability to detect any improvement with the lower initial dose of porcine minced lung surfactant extract from a Type II error (smaller sample size) cannot be ruled out. Also, in absence of adequately powered studies comparing dose equivalent porcine and modified bovine lung surfactant, the effect of dose or biophysical/biochemical profile of surfactant obtained from different animal sources on the clinical outcome cannot be determined with certainty.

A major limitation of this review was absence of dose equivalent trials comparing animal-derived surfactants from different sources or by different method of extractions. Another limitation was the small sample size for individual studies (except for Bloom 1997 and Bloom 2005) and the pooled data which was not powered to detect significant differences for the primary outcomes. Lack of blinding in majority of the studies might have introduced potential for bias and affected the results.

Insufficient data are available to demonstrate any cost benefit with use of one animal-derived surfactant over another. The outcome relevant to economic impact included in this review was "received > 1 dose surfactant." A significant increase in the outcome "receiving > 1 dose of surfactant" with modified bovine minced lung surfactant extract compared with porcine minced lung surfactant extract was observed in this review which is in agreement with the review by Singh 2011.

Agreements and disagreements with other studies or reviews

The results of this review are in agreement with other systematic reviews comparing animal-derived surfactants. A recent systematic review of five studies comparing modified bovine minced lung surfactant extract with porcine minced lung surfactant found decrease in mortality prior to discharge with high dose poractant compared to beractant (Singh 2011), which is similar to the results of the current review. A meta-analysis of five randomized trials by Halliday 2008 also supports the beneficial effect of higher initial dose of porcine minced lung surfactant extract compared with modified minced lung surfactant. Other reviews limited to comparing specific animal-derived surfactant products also showed differences in mortality favoring porcine minced lung surfactant, but no significant difference between modified bovine minced lung surfactant extract and bovine lung lavage surfactant (Ramanathan 2009; Moya 2009).

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Authors' conclusions

Implications for practice

Both bovine- and porcine-derived surfactant products are effective in treatment of respiratory distress syndrome in preterm infants. Whether significant differences in clinical outcome exists among the available animal-derived surfactant extracts had been unclear.

This review shows clinically significant differences in the risk of mortality prior to hospital discharge between porcine minced lung surfactant extract (poractant alfa) compared with modified bovine minced lung surfactant extract (beractant); however, these differences are limited to the use of a higher dose poractant alfa. Caution should be used in the interpretation of this result because of the imprecision in analysis from the small sample size of the studies.

Due to the lack of information about long-term neurodevelopment, respiratory, and other health effects, no conclusions can be drawn about the superiority or inferiority of one animal-derived surfactant over another with respect to long-term outcomes.

Implications for research

Animal-derived surfactant extract in prevention and treatment of respiratory distress syndrome has been proven to improve clinical outcome. Improved outcomes with porcine minced lung surfactant extract compared with modified bovine minced lung surfactant extract were noted in trials that utilized a higher initial dose. Further research should focus on studying specific biophysical or biochemical properties of surfactant preparations and effect of dosing on clinical outcomes in dose-equivalent comparison groups, and on comparing long-term outcomes between different animal-derived surfactant products. This is especially relevant with the change in management of RDS with selective and non-invasive surfactant administration practices such as LISA (less invasive surfactant administration) (Kribs 2007); and MIST (minimally invasive surfactant therapy) (Dargaville 2011). 

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Acknowledgements

We would like to thank Paola Orrego, medical student participant of the "Seed Research Program in Systematic Reviews" at the Department of Clinical Epidemiology and Biostatistics, Pontificia Universidad Javeriana, Bogotá, Colombia for input and assistance in creating the 'Summary of Findings' tables.

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Contributions of authors

Drs Singh, Halliday, Soll, and Stevens all participated in drafting and reviewing the protocol for the systematic review of 'Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants'. Dr. Suresh performed an independent literature search, and reviewed the content and the language of the review. Dr. Rojas performed the assessment of the evidence quality following the GRADE approach, developed the 'Summary of findings' tables and included the quality-of-evidence-related aspects to the review.

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Declarations of interest

Dr Soll has previously acted as a consultant for several of the pharmaceutical companies that manufacture surfactant preparations (Abbott Laboratories, Ross Laboratories, Chiesi Farmaceutici, Dey Laboratories, Burroughs Wellcome). Dr. Soll has not acted as a paid consultant for the past nine years.

Dr Halliday is currently a consultant for Chiesi Farmaceutici, a pharmaceutical company that manufactures a porcine-derived surfactant preparation; and has been an invited speaker at meetings supported by Abbott Laboratories, Ross Laboratories and Burroughs Wellcome.

Dr Stevens has no known conflicts of interest. This will be further clarified prior to publication of the review.

Dr Singh has no conflict of interest to report.

Dr Suresh has no conflict of interest to report.

Dr. Rojas has no conflict of interest to report.

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Differences between protocol and review

Methodology for 'Summary of findings' tables added.

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Characteristics of studies

Characteristics of included studies

Attar 2004

Methods

Randomized Single Center

Participants

Total participants = 40

Preterm infants < 37 weeks' gestation

Chest radiograph consistent with RDS

Required intubation and mechanical ventilation

Need for surfactant determined by the care providing team

Randomized 40 infants to receive calfactant (n = 19, BW (g) 1621 ± 442 and GA (wk) 30.0 ± 2.1)) and beractant (n = 21, BW (g) 1309 ± 642 and GA (wk) 29.0 ± 3.6)).

Interventions

Calfactant (n = 19)

Dose: 100 mg/kg phospholipid

Beractant (n = 21)

Dose = 100 mg/kg phospholipid

Repeat dose given as per manufacturer’s instruction

Criteria for re-dosing: Objective

Same technique for surfactant administration

Outcomes

Primary: Dynamic compliance 1 hour following first dose of surfactant administration

Secondary outcomes: chronic lung disease (need for oxygen at 36 weeks' PMA); Early onset sepsis

PDA; survival (alive at hospital discharge)

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Randomly assigned to treatment options by sampling replacement. Unclear sequence generation.

Allocation concealment (selection bias) Unclear risk

Not described

Blinding of participants and personnel (performance bias) High risk

Unmasked

Blinding of outcome assessment (detection bias) High risk

Unmasked

Incomplete outcome data (attrition bias) Low risk

No infants lost to follow-up

Selective reporting (reporting bias) Low risk

Reported on primary outcome (dynamic compliance 1 hour after first dose of surfactant) as well as important secondary outcomes (chronic lung disease (need for oxygen at 36 weeks' PMA); early onset sepsis; PDA; survival (alive at hospital discharge).

Other bias Low risk  

Baroutis 2003

Methods

Randomized Single Center

Participants

Total participants = 82

Preterm infants less than/or equal to 32 weeks' gestational age and less than/or equal to 2000 g

RDS requiring mechanical ventilation and FiO₂ requirement greater than/or equal to 0.30

The groups were comparable for GA and BW (29.0 ± 1.2 wk and 1195 ± 390 g in bovactant (Alveofact) group; 28.7 ± 0.5 wk and 1233 ± 380 g in poractant alfa group; and 29.2 ± 1.0 wk and 1180 ± 410 g in beractant group).

Interventions

Bovactant (Alveofact) (n = 27)

Dose 100 mg/kg

Poractant alfa (n = 27)

Dose: 100 mg/kg

Beractant (n = 28)

Dose: 100 mg/kg

Repeat dose after 12 h

Outcomes

Chronic lung disease (oxygen requirement at 36 weeks' PMA); PDA; pulmonary air leak; ROP; IVH

Notes

Bovactant (Alveofact) and poractant alfa given as rapid bolus

Beractant was given slowly by pump via adaptor (not as bolus as recommended by manufacturer)

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method of randomization not described

Allocation concealment (selection bias) Low risk

Sealed envelope

Blinding of participants and personnel (performance bias) High risk

Different method of administration of surfactant, hence blinding of personnel not possible

Blinding of outcome assessment (detection bias) High risk

Standardized ventilator protocol for initiation and weaning of ventilator, but description of an attempt to blind outcome assessment

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Report on key morbidities related to prematurity

Other bias Low risk  

Bloom 1997

Methods

Randomized Multicenter Double Blinded

Participants

Treatment arm: Total participants: 483

Preterm infants with birth weight < 2000 g with established RDS and < 48 h of age

Requiring intubation and mechanical ventilation

FiO₂ greater than/or equal to 0.40

Prevention arm: Total participants = 499

Preterm infants less than/or equal to 29 weeks' gestation and birth weight less than/or equal to 1250 g

Infants in the treatment arm were more mature and heavier compared with the prevention arm.

In treatment arm, the mean (SD) gestational age and birth weight were 29.2 ± 2.8 wk & 1162 ± 408 g in calfactant group and 29.2 ± 2.8 wk & 1166 ± 401 g in beractant group.

In prevention arm, mean (SD) gestational age and birth weight were 27.1 ± 2.2 wk & 891 ± 221 g in calfactant group and 27.1 ± 2.1 wk and 845 ± 205 g in beractant group.

Interventions

Calfactant

Dose: 100 mg/kg

Beractant

Dose: 100 mg/kg

Repeat dosing: 3 repeat treatments given if infant remained intubated for RDS and FiO₂ greater than/or equal to 0.30 within first 96 h of life

Outcomes

Primary outcome

Decrease in need for third dose of surfactant with established RDS

Decrease in need for second repeat dose with prophylactic surfactant administration

Notes

Special 25 mg/ml concentration of calfactant used in the trial to maintain masking. Administration, storage and dispensing of surfactant followed beractant package insert

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random assignment

Variable block size randomizations by pseudo-random number generation

Allocation concealment (selection bias) Low risk

Allocation of patient by selection of the next vial from box of sequentially numbered vials

Blinding of participants and personnel (performance bias) Low risk

Surfactants were provided in a vial covered by two layers of opaque labels. The surfactant products were similar in consistency, concentration and color

Blinding of outcome assessment (detection bias) Low risk

A data co-ordinator and a neonatologist designated to collect data

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Report on key morbidities related to prematurity

Other bias Low risk  

Bloom 2005

Methods

Randomized Multicenter

Participants

Total participants:

Treatment arm (n = 1361)

Preterm infants with birth weight 401 to 2000 g and < 36 h of age

FiO₂ requirement greater than/or equal to 0.40
No previous surfactant therapy

Prevention arm (n = 749)

Preterm infants 23 to 29 + 6/7 weeks' gestation, randomized at birth

Infants in the treatment arm were older and larger compared with the prevention arm.

In treatment arm, the mean (SD) for GA (wk) and BW (g) were 28.4 ± 2.8 & 1154 ± 402 in beractant group and 28.4 ± 2.7 & 1155 ± 408 in calfactant group.

In prevention arm, the mean (SD) GA (wk) and BW (g) were 26.6 ± 1.9 & 907 ± 275 in beractant group and 26.5 ± 2 & 910 ± 287 in calfactant group.

Interventions

Calfactant

Dose: 105 mg/kg

Beractant

Dose: 100 mg/kg

Repeat dosing: maximum of 3 repeat doses 6 h apart if infant remained intubated for RDS and had FiO₂ requirement greater than/or equal to 0.30 to keep SpO₂ > 90%

Outcomes

Primary outcome: Percent infants alive at 36 weeks' PMA without use of supplemental oxygen requirement

Secondary outcome: Death from respiratory failure; air leak; severe brain injury (IVH grade 3 or 4 or PVL)

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Balanced randomization schedule

Computerized random number generation

Twins and multiples randomized as individuals

Allocation concealment (selection bias) Low risk

Sealed envelopes used

Blinding of participants and personnel (performance bias) Low risk

Masked syringes used to administer surfactant by personnel not involved in direct patient care

Blinding of outcome assessment (detection bias) Low risk

Reported to maintain blind during statistical analysis

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Report on key morbidities related to prematurity

Other bias Unclear risk

Terminated early due to poor enrollment

Didzar 2012

Methods

Randomized Single Center

Participants

Total participants = 126

Preterm infants < 37 weeks' gestation

Clinical and radiological diagnosis of RDS within 6 h of birth

FiO₂ greater than/or equal to 0.30 to maintain SpO₂ 88% to 96%

The median gestational age and birth weight was 28 wk and 1165 g in poractant group; and 28 wk and 1080 g in beractant group. The rate of antenatal steroid coverage was 63% for poractant group and 51% for beractant group

Interventions

Poractant alfa (n = 61)

Dose: 200 mg/kg

Beractant (n = 65)

Dose: 100 mg/kg

Repeat dose given if FiO₂ greater than/or equal to 0.30 at 100 mg/kg for both poractant alfa and beractant

Outcomes

Primary outcome: FiO₂ requirement after 24 h following surfactant administration

Secondary outcomes: Need for repeat dose; duration for respiratory support; duration of hospitalization; and other key morbidities related to prematurity

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Randomization process not described

Allocation concealment (selection bias) Unclear risk

Not reported

Blinding of participants and personnel (performance bias) Unclear risk

Not reported

Blinding of outcome assessment (detection bias) Unclear risk

Not reported

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Reported on key morbidities related to prematurity

Other bias Low risk  

Fujii 2010

Methods

Randomized Single Center

"open label" trial

Participants

Total participants = 52

Preterm infants between 24 + 0/7 to 29 + 6/7 weeks’ GA

Inborn

RDS requiring mechanical ventilation

Randomized within 6 h

The mean (SD) gestational age and birth weight was 27.1 (1.6) wk and 930 (231) g in poractant group; and 26.7(1.7) wk and 900 (271) g in beractant group.

Interventions

Portactant alfa (n = 25)

Dose: 200 mg/kg

Beractant (n = 27)

Dose: 100 mg/kg

Repeat dose at 100 mg/kg for both groups if FiO₂ requirement remains greater than/or equal to 0.30

Outcomes

Primary outcome: Short-term outcome of prematurity

FiO₂ requirement, MAP and MAP X FiO₂ until 72 h

Secondary outcomes: Key morbidities related to prematurity.

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Randomization using SAS software with variable block size design

Allocation concealment (selection bias) Unclear risk

Not reported

Blinding of participants and personnel (performance bias) High risk

No blinding for either the participants or personnel was reported.

Blinding of outcome assessment (detection bias) High risk

None

Incomplete outcome data (attrition bias) Low risk

Complete follow-up.

Selective reporting (reporting bias) Low risk

Report on key morbidities related to prematurity

Other bias Low risk  

Gharehbaghi 2010

Methods

Quasi-randomized Single Center

Participants

Total participants = 150

Newborns diagnosed with RDS requiring exogenous surfactant

The mean (SD) gestational age and birth weight was 29.4 (2.4) wk and 1435 (642) g in poractant group; and 29.5 (2.7) wk and 1450 (519) g in beractant group.

The groups were similar in characteristics. The rate of antenatal steroid exposure was only 45.5% for poractant group and 42.3% for beractant group.

Interventions

Poractant alfa (n = 79)

Dose: 200 mg/kg

Beractant (n = 71)

Dose: 100 mg/kg

Repeat dosing if FiO₂ requirement greater than/or equal to 0.50 and radiographic evidence of RDS in presence of continued respiratory distress

Outcomes

Ventilation support requirement at 7 days of age

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Odd or even number of admission code

Allocation concealment (selection bias) High risk

Odd or even number of admission code

Blinding of participants and personnel (performance bias) Unclear risk

Not reported

Blinding of outcome assessment (detection bias) Low risk

Outcome reported by two senior neonatologists who did not know the group assignment

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Report on key morbidities related to prematurity

Other bias Low risk  

Halahakoon 1999

Methods

As part of her PhD thesis, Halahakoon evaluated the effects of poractant alfa, beractant and colfosceril palmitate (Exosurf Neonatal)

Participants

infants 24 to 32 weeks' gestation with RDS requiring assisted ventilation and FiO₂ > 0.40 at < 12 h of age

poractant alfa at 100 mg/kg (n = 17, mean (SD) birth weight of 926 (278) g, mean (SD) gestational age of 26.8 (2.4) wk),

colfosceril palmitate at 67.5 mg/kg (n = 12, mean (SD) birth weight of 956 (233) g, mean (SD) gestational age of 26.9 (1.9) wk) and beractant at 100 mg/kg (n = 10, mean (SD) birth weight of 1011 (327) g, mean (SD) gestational age of 27.3 (2.0) wk).

Interventions

poractant alfa (n = 17), beractant (n = 10) and colfosceril palmitate (Exosurf neonatal) (n = 12)

Outcomes

cerebral function, hypoxanthine levels and antioxidant levels

Notes

Clinical data are being sought for possible inclusion

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Not described

Allocation concealment (selection bias) Low risk

Sealed envelopes opened at the time of randomization

Blinding of participants and personnel (performance bias) Unclear risk

Not reported

Blinding of outcome assessment (detection bias) Unclear risk

Not reported

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

Selective reporting (reporting bias) Low risk

No

Other bias Low risk  

Hammoud 2004

Methods

Randomized Single Center

Participants

Total participants = 109

Preterm infants < 34 weeks' gestation

Requiring intubation and mechanical ventilation for RDS within 6 h of birth

FiO₂ greater than/or equal to 0.40 to maintain SpO₂ > 90%

The mean (SD) GA and BW were 28.5 ± 4.4 wk & 1031 ± 298 g in the bovactant (Alveofact) group and 29.2 ± 2.3 wk & 1078 ± 279 g in beractant group

Interventions

Bovactant (n = 54)

Dose: 50 mg/kg phospholipid

Beractant (n = 55)

Dose: 100 mg/kg phospholipid

Repeat dosing (up to 3 doses) given if patient still requiring mechanical ventilation and FiO₂ greater than/or equal to 0.30 until 48 h of age

Outcomes

Primary outcome: Chronic lung disease (oxygen requirement at 28 days)

Secondary outcomes: Severity of RDS as assessed by FiO₂; oxygenation index, a/A PO₂; MAP; Pneumothorax; IVH; PDA; days on mechanical ventilation; days of hospitalization

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Unclear risk  
Blinding of participants and personnel (performance bias) Low risk  
Blinding of outcome assessment (detection bias) Low risk

Assessment team drawn from the NICU who were not involved in surfactant administration

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk  
Other bias Low risk  

Karadag 2014

Methods

The objective of this study was to compare the perfusion index (PI) variability in premature infants with respiratory distress syndrome (RDS) following administration of two different animal-derived surfactant preparations.

Participants

Prospective study on 92 preterm infants with RDS.

The mean (SD) birth weight and gestational age was 1098 (256) g and 29.6 (1.8) wk in poractant alfa group; and 1086 (248) g and 29 (1.9) wk in beractant group. The rate of antenatal steroid coverage was 76% in poractant alfa group and 82% in beractant group.

Interventions

Patients were randomized into two groups. Group 1 (n = 46) received beractant; Group 2 (n = 46) received poractant alfa.

Outcomes

Surfactant dosing, oxygenation index (OI), perfusion index (PI). Clinical outcomes including pulmonary hemorrhage, intraventricular hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, and mortality.

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random number generation

Allocation concealment (selection bias) Low risk

Sealed envelops contained cards that were randomly assigned to the groups

Blinding of participants and personnel (performance bias) Unclear risk

Not reported

Blinding of outcome assessment (detection bias) Unclear risk

Not reported

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Reported on key morbidities of prematurity

Other bias Low risk  

Lam 2005

Methods

Randomized Single Center

Participants

Total participants = 63

Preterm infants with birth weights 500 to 1800 g

Clinical or radiological diagnosis of RDS

Requiring intubation and mechanical ventilation for RDS

The mean (SD) BW and GA were 1038 ± 263 g and 27.5 ± 1.9 wk in the bLES group and 971 ± 299 g and 26.9 ± 2.3 wk in beractant group.

Interventions

bLES (n = 29)

Dose: 135 mg/kg phospholipid

Beractant (n = 31)

Dose: 100 mg/kg phospholipid

Objective criteria for repeat dosing: FiO₂ > 0.10 compared with FiO₂ requirement after first dose of surfactant

Outcomes

Primary outcome: Oxygenation Index

Secondary outcomes: Chronic lung disease (oxygen requirement at 36 weeks' PMA); duration on ventilator; days on oxygen; mortality before hospital discharge

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Randomization based on computer-generated codes

Stratified by birth weight

Allocation concealment (selection bias) Unclear risk

Not reported

Blinding of participants and personnel (performance bias) Unclear risk

Not reported

Blinding of outcome assessment (detection bias) Unclear risk

Not reported

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Report on key morbidities related to prematurity

Other bias Low risk  

Malloy 2005

Methods

Randomized Single Center

Participants

Total = 58

Preterm infants < 37 weeks' gestation

Clinical signs and symptoms of RDS requiring intubation and surfactant as per clinical judgement

Surfactant administration routine at less than/or equal to 28 weeks' gestation

The mean (SD) gestational age and birth weight was 29.6 (3.6) wk and 1394 (699) g in poractant alfa group; and 29.3 (2.9) wk and 1408 (534) g in beractant group

Interventions

Poractant alfa (n = 29)

Dose: 200 mg/kg

Beractant (n = 29)

Dose: 100 mg/kg

Redosing if FiO₂ requirement greater than/or equal to 0.30 and infant remains on mechanical ventilation

Outcomes

Primary outcome: FiO₂ requirement at 48 h after first surfactant dose

Secondary outcomes: Pneumothorax; PDA; IVH, PVL; BPD (oxygen requirement at 28 days and at 36 weeks' PMA); ROP; death

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk  
Allocation concealment (selection bias) Low risk  
Blinding of participants and personnel (performance bias) High risk

Not stated, but infants received different re-treatment schedules that would be obvious to staff. Written standard protocols for ventilator management and oxygen weaning provided and mandated to minimize performance bias

Blinding of outcome assessment (detection bias) High risk

The radiologist and cardiologist reported to be masked

Masking for other outcome assessment not reported

Incomplete outcome data (attrition bias) Low risk  
Selective reporting (reporting bias) Low risk  
Other bias Low risk  

Ramanathan 2004

Methods

Randomized

Multicenter Masked Trial

Participants

Total participants = 293

Preterm infants with BW 750 to 1750 g and GA < 35 wk

Clinical or radiographic evidence of RDS

Intubated and mechanically ventilated

FiO₂ greater than/or equal to 0.30 OR a/A ratio of less than/or equal to 0.33

The groups were comparable with mean BW (SD) being 1511 (259), 1148 (265), 1187 (275) g and mean GA (SD) being 28.7 (2.0), 28.8 (2.0), 28.7 (2.0) wk for high-dose poractant alfa, low-dose poractant alfa, and beractant respectively.

Interventions

Poractant alfa (n = 96)

Dose 100 mg/kg

Poractant alfa (n = 99)

Dose 200 mg/kg

Beractant (n = 98)

Dose 100 mg/kg

Repeat doses for both surfactants at 100 mg/kg

Outcomes

Primary outcome: Area of FiO₂ under curve during 6-hour period after first dose of surfactant

Secondary outcome: Change in FiO₂, MAP (measured at baselines, 1, 2, 4 and 6 h after first dose); total number of doses of surfactant needed; median duration of oxygen and mechanical ventilation; complications of prematurity

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Using random number, stratified by birth weight

Allocation concealment (selection bias) Low risk

Opaque and sealed envelopes

Blinding of participants and personnel (performance bias) Unclear risk

Administration of first dose was masked; repeat doses were "unmasked" and given based on individual product recommendations

Blinding of outcome assessment (detection bias) Unclear risk

Outcome assessors blinded to type or dose of first dose of surfactant (re: assessment of primary outcome)

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Report on key morbidities related to prematurity

Other bias Low risk  

Sanchez-Mendiola 2005

Methods

Randomized Single Center

Participants

Total participants = 44

Interventions

Surfacen: n = 21

Beractant: n = 23

Outcomes

Oxygenation and ventilation index; days on ventilator; days on supplemental oxygen; complications of prematurity; mortality

Notes

Article in Spanish - data obtained from abstract and tables. Further translation requested to determine risk of bias.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Article in Spanish - data obtained from abstract and tables. Further translation requested to determine risk of bias.

Allocation concealment (selection bias) Unclear risk  
Blinding of participants and personnel (performance bias) Unclear risk  
Blinding of outcome assessment (detection bias) Unclear risk  
Incomplete outcome data (attrition bias) Unclear risk  
Selective reporting (reporting bias) Unclear risk  
Other bias Unclear risk

Spanish article with limited data

Speer 1995

Methods

Randomized Multicenter Study

Participants

Total participants = 73

Preterm infants with birth weight 700 to 1000 g

Clinical and radiological findings consistent with RDS

FiO₂ requirement greater than/or equal to 0.40

The mean (SD) BW and GA were 1095 ± 225 g and 28.9 ± 2.3 wk in the poractant group and 1082 ± 252 g and 28.8 ± 2.2 wk in the beractant group.

Interventions

Poractant alfa (n = 33)

Dose: 200 mg/kg

Beractant (n = 40)

Dose: 100 mg/kg

Repeat dosing with surfactant if FiO₂ greater than/or equal to 0.30 and infant remains on mechanical ventilator

Outcomes

Primary outcome: FiO₂ requirement and ventilatory support in first 48 h after surfactant administration

Secondary outcomes; Complications diagnosed within first 28 days of life: PIE; PDA; IVH; pulmonary hemorrhage; sepsis; BPD and death

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Method of randomization not reported

Allocation concealment (selection bias) Low risk

Opaque and sealed envelopes

Blinding of participants and personnel (performance bias) High risk

"Because the recommended doses, volumes, dose interval and dose procedures differed between both surfactant preparations, blinding of surfactant administration was not feasible"

Blinding of outcome assessment (detection bias) High risk

Masking of radiologist to the intervention. Masking for other outcome assessment not reported.

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Report on key morbidities related to prematurity

Other bias Low risk  

Yalaz 2004

Methods

Randomized Single Center

Participants

Total participants = 50

Preterm infants < 36 weeks' gestation

Radiographic diagnosis of RDS

The groups were comparable with respect to BW, GA and antenatal steroid exposure.

The mean (SD) BW and GA were 1250 ± 356 g and 30.0 ± 2.6 wk in the calfactant group and 1172 ± 397 g and 29.3 ± 2.9 wk in the beractant group.

Interventions

BovactantAlveofact (n = 25)

Dose: 50 mg /kg phospholipid

Beractant (n = 25)

Dose: 100 mg/kg phospholipid

Dose repeated as per manufacturers’ instructions as required based on blood gases and chest X-ray

Outcomes

Primary outcome: FiO₂, a/A PO₂ and mean airway pressure before and after treatment

Duration of mechanical ventilation

Secondary outcomes: Bronchopulmonary dysplasia (oxygen requirement at 36 weeks' PMA); pneumothorax; mortality

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Not described

Allocation concealment (selection bias) Unclear risk

Not described

Blinding of participants and personnel (performance bias) Unclear risk

Not described. However, it was unlikely as surfactant was administered "according to the manufacturers recommendations, for dosing and method of administration"

Blinding of outcome assessment (detection bias) Unclear risk

Not described

Incomplete outcome data (attrition bias) Low risk

Complete follow-up

Selective reporting (reporting bias) Low risk

Report on key morbidities related to prematurity

Other bias Low risk  
Footnotes

BW: birth weight

g: grams

GA: gestational age

h: hours

IVH: intraventricular hemorrhage

PDA: patent ductus arteriosus

PMA: postmenstrual age

RDS: respiratory distress syndrome

ROP: retinopathy of prematurity

SD: standard deviation

wk: weeks

Characteristics of excluded studies

Bozdağ 2015

Reason for exclusion

Bozdağ and colleagues conducted a prospective randomized controlled trial to compare the efficacy of two animal-derived surfactants for pulmonary hemorrhage in very low birth weight (VLBW) infants.

42 infants were divided into two groups, poractant alfa (n = 21) and beractant (n = 21).

Excluded because patient population was VLBW infants with pulmonary hemorrhage.

Choi 2005

Reason for exclusion

Choi and colleagues conducted a multicenter study of a domestically developed bovine surfactant Newfacen compared with Surfacten, another bovine-derived surfactant for efficacy. A total of 492 preterm infant with established RDS with birth weight < 1500 g were randomly assigned to receive either Newfacen (n = 224) or Surfacten (n = 268). Short-term responses to surfactant and acute complications such as total doses of surfactant administered and changes in respiratory parameters were studied.

This study was excluded because both the surfactants studied belong to the same comparison group (bovine lung lavage surfactant).

Proquitté 2007

Reason for exclusion

Proquitté and colleagues performed a retrospective, observational study comparing the effects of bovactant (Alveofact) and poractant alfa (Curosurf) on gas exchange and outcome in premature infants.

During a 5-year period in one German neonatal intensive care unit (NICU), 187 premature infants were treated with surfactant, with 82 receiving bovactant and 105 receiving poractant alfa. The investigators recorded FiO₂ and gas exchange (PaO₂/FiO₂ ratio, PaCO₂, SaO₂) during the first 72 h after surfactant administration and the incidence of outcome parameters at day 28 (bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH grade III or IV), patent ductus arteriosus (PDA), pneumothorax, necrotizing enterocolitis (NEC) and death).

The study was excluded as it is not a randomized controlled trial.

Rebello 2009

Reason for exclusion

Rebello and colleagues compared the effects of butantan (a porcine surfactant obtained by organic extraction) with other commercially available surfactants (either beractant or poractant) in preterm infants with RDS.

A total of 327 preterm infants with BW < 1500 g with RDS were randomly assigned to receive butantan (n = 154) and compared with a control group receiving either beractant or poractant (n = 173). The mean BW (SD) and mean GA (SD) were 990 g (245) and 28 wk (2.1) for butantan group and 996 g (235) and 28.1 wk (2.2) for control group respectively.

This study was excluded because control group received both modified bovine lung lavage surfactant and porcine lung lavage surfactant.

Footnotes

BW: birth weight

RDS: respiratory distress syndrome

SD: standard deviation

Characteristics of studies awaiting classification

Eras 2014

Methods

Prospective, longitudinal, single-center cohort study

Participants

infants born at less than/or equal to 1,500 g and/or less than/or equal to 32 wk with RDS

Conducted between 2008 and 2009

Interventions

Poractant alfa (n = 113) or beractant (n = 102)

Outcomes

Neurological and developmental assessments were performed at a corrected age of 18 to 24 months

Notes

Unclear whether the patients reported are related to the study of Didzar 2012

Gharehbaghi 2014

Methods

Randomized clinical trial in Alzahra Hospital, Tabriz, Iran

Participants

Preterm newborn infants with gestation age less than 32 wk with RDS

Interventions

Poractant alfa (Curosurf) (N = 66) and bovactant (Alveofact) (N = 64)

Surfactant was administered using the INSURE method (intubation, surfactant administration, extubation)

Outcomes

Ventilator support through 7 days, mean duration of oxygen supplementation and hospital stay and other complications associated with prematurity

Notes  

Mercado 2010

Methods

Randomized Single Center

Participants

Total participants = 40

Preterm infants < 30 wk gestation and birth weight < 1000 g

Interventions

Surfactant A (porcine lung extract) (n = 20)

Dose: 200 mg/kg, repeat dose at 100 mg/kg

Surfactant B (Bovine lung extract)(n = 20)

Dose: 100 mg/kg (initial and repeat dose)

Outcomes

Primary outcome: Airway inflammatory response (Cytokine IL-6 and IL-8)

Secondary outcomes: BPD (oxygen requirement at 36 weeks' PMA); FiO₂ and oxygenation index at 7 days of life; days of mechanical ventilation; days of hospitalization

Notes  

Saeidi 2013

Methods

Clinical trial performed during a 2-year period in Ghaem Center's neonatal care unit. Method of allocation unknown.

Participants

104 preterm infants were treated with surfactant; 74 in beractant (Survanta) group and 30 in the poractant (Curosurf) group.

Mean gestational age (beractant (Survanta) 30.58 vs poractant (Curosurf) 29.00 wk)

Mean birth weight (beractant (Survanta) 1388 vs poractant (Curosurf) 1330 g)

Interventions

Beractant (Survanta) vs poractant (Curosurf)

Outcomes

bronchopulmonary dysplasia at 28 days, Intraventricular hemorrhage grades III/IV, pneumothorax, patent ductus arteriosis, and death.

Notes  

Terek 2015

Methods

Randomized controlled non-blinded study

Participants

30 preterm infants with RDS, treated with poractant alfa (n = 15) or beractant (n = 15); 18 preterm infants without RDS served as a control group.

Interventions

poractant alfa (n = 15) or beractant (n = 15)

Outcomes

Oxygenation and hemodynamic parameters were recorded and compared through the first 6 h of treatment. Perfusion index (PI) and tissue carbon monoxide (TCO) values were measured prior to (Tp), immediately after (T0), and at 5 minutes (T5), 30 minutes (T30), 60 minutes (T60), and 360 minutes (T360) after the bolus surfactant administration. The mean arterial pressure, oxygenation index, pH, and lactate levels were recorded simultaneously.

Notes

Both study groups had lower Tp PI and higher Tp TCO levels than controls. Both surfactant preparations improved the PI, TCO, mean arterial pressure, oxygenation index, pH, and lactate levels at the end point of T360. However, the median Tp PI value of 1.3 first decreased to 0.86 at T0 (P < 0.001), and then it increased to 0.99 at T5 (p < 0.001) and to 1.25 at T30 (p = 0.037). The median Tp TCO value of 3 decreased to 2, 1.5, 0, and 0 at T0, T5, T30, and T60, respectively (p < 0.001). PI more quickly recovered to Tp values (30 minutes vs. 60 minutes) and reached the control group values (30 minutes vs. 360 minutes) with beractant compared with that with poractant alfa. TCO recovered to Tp values in both groups at the same time (5 minutes vs. 5 minutes), but reached the control group values more quickly (5 minutes vs. 30 minutes) with poractant alfa than with beractant.

Footnotes

BPD: bronchopulmonary dysplasia

g: grams

PMA: postmenstrual age

wk: weeks

[top]

Summary of findings tables

1 Bovine lung lavage surfactant extract compared with modified bovine minced lung surfactant extract in preterm infants for prevention of RDS

Bovine lung lavage surfactant extract compared with modified bovine minced lung surfactant extract in preterm infants for prevention of RDS (Comparision 1: Prevention studies)

Patient or population: Preterm infants for prevention of RDS
Setting: Hospital
Intervention: Bovine lung lavage surfactant extract
Comparison: Modified bovine minced lung surfactant extract

Outcomes

Anticipated absolute effects * (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with modified bovine minced lung surfactant extract

Risk with Bovine lung lavage surfactant extract

Mortality prior to discharge (from any cause)

107 per 1000

133 per 1000
(96 to 183)

RR 1.24
(0.90 to 1.71)

1123
(2 RCTs)

⨁⨁⨁◯
MODERATE 1

Downgraded one level due to imprecision (95% CI includes both no effect and appreciable harm) and and the total number of events does not meet the optimal information size (OIS).

Oxygen requirement at 36 weeks' postmenstrual age

341 per 1000

331 per 1000
(270 to 406)

RR 0.97
(0.79 to 1.19)

749
(1 RCT)

⨁⨁⨁◯
MODERATE 2

Downgraded one level due to imprecision (95% CI includes both no effect and appreciable harm).

Death or oxygen requirement at 36 weeks' postmenstrual age

409 per 1000

418 per 1000
(364 to 479)

RR 1.02
(0.89 to 1.17)

1133
(2 RCTs)

⨁⨁⨁⨁
HIGH

We did not downgrade evidence for imprecision as it was considered that 95% CI is narrow and precise around the no effect. The total number of events meets the OIS

Pneumothorax.

67 per 1000

51 per 1000
(29 to 91)

RR 0.76
(0.43 to 1.36)

749
(1 RCT)

⨁⨁⨁◯
MODERATE 2

Downgraded one level due to imprecision (95% CI includes both no effect and appreciable harm)

Pulmonary hemorrhage

44 per 1000

63 per 1000
(39 to 105)

RR 1.44
(0.88 to 2.39)

1123
(2 RCTs)

⨁⨁◯◯
LOW 3

Downgraded two levels due to very serious imprecision: 1) the 95% CI includes both no effect and appreciable harm. 2) the total number of events does not meet the optimal information size (OIS to detect a clinically beneficial effect if there is one is > 3000)

Severe IVH in infants receiving neuroimaging

87 per 1000

112 per 1000
(78 to 160)

RR 1.28
(0.89 to 1.83)

1087
(2 RCTs)

⨁⨁◯◯
LOW 4

Downgraded two levels due to very serious imprecision: 1) 95% CI includes both no effect and appreciable harm.2) The total number of events does not meet the optimal information size (OIS to detect a clinically beneficial effect if there is one is > 2000).

Neurodevelopmental outcome at approximately two years' corrected age

see comments

see comments

     

Not reported in any of the studies

* The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Footnotes

1 95% CI includes benefit, no effect and appreciable harm and the total number of events does not meet the optimal information size

2 95% CI includes benefit, no effect and appreciable harm

3 95% CI includes benefit, no effect and appreciable harm and the OIS to detect a clinically beneficial effect if there is one is > 3000

4 95% CI includes benefit, no effect and appreciable harm and the OIS to detect a clinically beneficial effect if there is one is > 2000

2 Bovine lung lavage surfactant extract compared with modified bovine minced lung surfactant extract in preterm infants for treatment of RDS

Bovine lung lavage surfactant extract compared with modified bovine minced lung surfactant extract in preterm infants for treatment of RDS

Patient or population: Preterm infants for treatment of RDS
Setting: Hospital
Intervention: Bovine lung lavage surfactant extract
Comparison: Modified bovine minced lung surfactant extract

Outcomes

Anticipated absolute effects * (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with modified bovine minced lung surfactant extract

Risk with Bovine lung lavage surfactant extract

Mortality prior to discharge

131 per 1000

128 per 1000
(103 to 158)

RR 0.98
(0.79 to 1.21)

2231
(6 RCTs)

⨁⨁⨁◯
MODERATE 1

Downgraded one level due to imprecision (95% CI includes both no effect and appreciable harm) and the total number of events does not meet the OIS.

Oxygen requirement at 36 weeks' postmenstrual age (all infants)

312 per 1000

297 per 1000
(256 to 347)

RR 0.95
(0.82 to 1.11)

1564
(5 RCTs)

⨁⨁⨁⨁
HIGH

We did not downgrade evidence for imprecision as it was considered that 95% CI is narrow and precise around the probability of no effect. Estimations are based in more than 300 events in each arm.

Death or oxygen requirement at 36 weeks' postmenstrual age

421 per 1000

400 per 1000
(362 to 446)

RR 0.95
(0.86 to 1.06)

2009
(3 RCTs)

⨁⨁⨁⨁
HIGH

We did not downgrade evidence for imprecision as it was considered that 95% CI is narrow and precise around the probability of no effect. Estimations are based in more than 300 events in each arm.

Pneumothorax

73 per 1000

83 per 1000
(62 to 110)

RR 1.14
(0.85 to 1.51)

2224
(6 RCTs)

⨁⨁◯◯
LOW 1 2

Downgraded two levels due to:

  1. Serious imprecision (95% CI includes both no effect and appreciable harm).
  2. Inconsistency: Unexplained heterogeneity, with point estimates widely different; 95% CI not overlapping and leading to different conclusions (P value 0.03, Chi² 10.66, I² = 62%)

Pulmonary hemorrhage

44 per 1000

48 per 1000
(33 to 71)

RR 1.08
(0.74 to 1.59)

2138
(4 RCTs)

⨁⨁⨁◯
MODERATE 1

Downgraded one level due to imprecision (95% CI includes both no effect and appreciable harm)

Severe IVH in infants receiving neuroimaging

125 per 1000

108 per 1000
(85 to 136)

RR 0.86
(0.68 to 1.09)

2040
(5 RCTs)

⨁⨁⨁◯
MODERATE 3

Downgraded one level due to imprecision (95% CI includes benefits, no effect and appreciable harm). The optimal information size to reliably detect a clinically beneficial effect if there is one is > 7000

Neurodevelopmental outcome at approximately two years' corrected age

see comments

see comments

     

Not reported in any of the studies

* The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Footnotes

1 95% CI includes benefits, no effect and appreciable harm, and the total number of events does not meet the OIS

2 Unexplained heterogeneity, with point estimates widely different and CI not overlapping and leading to different conclusions (P value 0.03, Chi² 10.66, I² = 62%)

3 95% CI of the pooled effect crosses 1 and the optimal information size to reliably detect a clinically beneficial effect if there is one is > 7000

3 Bovine lung lavage surfactant extract compared with porcine minced lung surfactant extract in preterm infants for treatment of RDS

Bovine lung lavage surfactant extract compared with porcine minced lung surfactant extract in preterm infants for treatment of RDS

Patient or population: Preterm infants for treatment of RDS
Setting: Hospital
Intervention: Bovine lung lavage surfactant extract
Comparison: Porcine minced lung surfactant extract

Outcomes

Anticipated absolute effects *

(95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with porcine minced lung surfactant extract

Risk with Bovine lung lavage surfactant extract

Mortality prior to discharge

185 per 1000

259 per 1000
(94 to 717)

RR 1.40
(0.51 to 3.87)

54
(1 RCT)

⨁⨁◯◯
LOW 1

Downgraded two levels due to very serious imprecision: 1) the 95% CI includes both no effect and appreciable harm.

2) the total number of events does not meet the optimal information size (OIS to detect a clinically beneficial effect if there is one is > 1000)

Oxygen requirement at 36 weeks' postmenstrual age

148 per 1000

111 per 1000
(28 to 450)

RR 0.75
(0.19 to 3.04)

54
(1 RCT)

⨁⨁◯◯
LOW 1

Downgraded two levels due to:

  1. Serious imprecision (95% CI includes both no effect and appreciable harm).
  2. Total number of events does not meet the optimal information size (OIS to detect a clinically beneficial effect if there is one is > 1000)

Death or oxygen requirement at 36 weeks' postmenstrual age

see comments

see comments

     

Not reported in any of the studies

Pneumothorax

see comments

see comments

     

Not reported in any of the studies

Pulmonary hemorrhage

see comments

see comments

     

Not reported in any of the studies

Severe intraventricular hemorrhage in infants who received neuroimaging

222 per 1000

184 per 1000
(64 to 536)

RR 0.83
(0.29 to 2.41)

54
(1 RCT)

⨁◯◯◯
VERY LOW 2 3

Downgraded three levels due to:

  1. potential risk of bias (lack of blinding of outcome assessment)
  2. very serious imprecision: (95% CI includes both no effect and appreciable harm) and the total number of events does not meet the optimal information size (OIS to detect a clinically beneficial effect if there is one is > 1000)

Neurodevelopmental outcome at approximately two years' corrected age

see comments

see comments

     

Not reported in any of the studies

* The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Footnotes

1 95% CI of the pooled effect crosses 1 and the optimal information size to detect a clinically beneficial effect if there is one is > 1000

2 We downgraded because lack of blinding of patients, providers and blinding of outcome assessment

3 95% CI of the pooled effect crosses 1 and the optimal information size to detect a clinically beneficial effect if there is one is > 1000

4 Modified bovine minced lung surfactant extract compared with porcine minced lung surfactant extract in preterm infants for treatment of RDS

Modified bovine minced lung surfactant extract compared with porcine minced lung surfactant extract in preterm infants for treatment of RDS

Patient or population: Preterm infants for treatment of RDS
Setting: Hospital
Intervention: Modified bovine minced lung surfactant extract
Comparison: Porcine minced lung surfactant extract

Outcomes

Anticipated absolute effects *

(95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with porcine minced lung surfactant extract

Risk with Modified bovine minced lung surfactant extract

Mortality prior to hospital discharge (from any cause)

113 per 1000

162 per 1000
(117 to 225)

RR 1.44
(1.04 to 2.00)

901
(9 RCTs)

⨁⨁⨁◯
MODERATE 1

Downgraded one level due to imprecision (95% CI includes both no effect and appreciable harm).

Despite the high risk of bias 4 we did not downgrade the quality because of its lower impact on this outcome.

Oxygen requirement at 36 weeks' postmenstrual age

282 per 1000

293 per 1000
(234 to 370)

RR 1.04 (0.83 to 1.31)

773
(8RCTs)

⨁⨁⨁◯
MODERATE 2

Downgraded one level due to imprecision (95% CI includes both no effect and appreciable harm).

Despite the high risk of bias 4 we did not downgrade the quality because of its lower impact on this outcome.

Death or oxygen requirement at 36 weeks' postmenstrual age

380 per 1000

494 per 1000
(395 to 623)

RR 1.30
(1.04 to 1.64)

448
(3 RCTs)

⨁⨁⨁◯
MODERATE 1

Downgraded one level due to imprecision (total number of events does not meet the OIS)

Pneumothorax

63 per 1000

78 per 1000
(45 to 137)

RR 1.24
(0.71 to 2.17)

669
(6 RCTs)

⨁⨁◯◯
LOW 3

Downgraded two levels due to very serious imprecision:

  1. the 95% CI includes both no effect and appreciable harm.
  2. The total number of events does not meet the optimal information size (OIS to detect a clinically beneficial effect if there is one is > 5000)

Pulmonary hemorrhage

72 per 1000

92 per 1000
(58 to 146)

RR 1.28
(0.81 to 2.02)

871
(8 RCTs)

⨁⨁◯◯
LOW 3

Downgraded two levels due to very serious imprecision:

  1. the 95% CI includes both no effect and appreciable harm.
  2. The total number of events does not meet the optimal information size (OIS to detect a clinically beneficial effect if there is one is > 5000)

Severe intraventricular hemorrhage in infants who received neuroimaging

97 per 1000

124 per 1000
(80 to 190)

RR 1.28
(0.83 to 1.97)

705
(7 RCTs)

⨁◯◯◯
VERY LOW 4 5

Downgraded three levels due to:

1. Potential risk of bias and 2. serious imprecision: 1) the 95% CI includes both no effect and appreciable harm; and 2) Total number of events does not meet the optimal information size (OIS to detect a clinically beneficial effect if there is one is > 3000)

Neurodevelopmental outcome at approximately two years' corrected age

see comments

see comments

     

Not reported in any studies

* The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Footnotes

1 The total number of events does not meet the OIS

2 95% CI includes benefit, no effect and appreciable harm. Total number of events does not meet the optimal information size.

3 95% CI of the pooled effect crosses 1 and the optimal information size to detect a clinically beneficial effect if there is one is > 5000

4 Studies that carried large weight for the overall effect estimate are classified as high or unclear risk of bias due to lack of blinding in patients, and outcome assessment

5 95% CI of the pooled effect widely crosses 1 and the optimal information size to detect a clinically beneficial effect if there is one is > 3000

5 Modified bovine minced lung surfactant extract compared with porcine lung lavage surfactant in preterm infants for treatment of RDS

Modified bovine minced lung surfactant extract compared with porcine lung lavage surfactant in preterm infants for treatment of RDS

Patient or population: Preterm infants for treatment of RDS
Setting: Hospital
Intervention: Modified bovine minced lung surfactant extract
Comparison: Porcine lung lavage surfactant

Outcomes

Anticipated absolute effects *

(95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with porcine lung lavage surfactant

Risk with Modified bovine minced lung surfactant extract

Mortality prior to hospital discharge (from any cause)

476 per 1000

524 per 1000
(286 to 948)

RR 1.10
(0.60 to 1.99)

44
(1 RCT)

⨁⨁◯◯
LOW 1

Downgraded two levels due to serious imprecision:

  1. The 95% CI includes both no effect and appreciable harm.
  2. Total number of events does not meet the optimal information size (OIS to detect a clinically beneficial effect if there is one is > 700).

Oxygen requirement at 36 weeks' postmenstrual age

see comments

see comments

     

Not reported in any of the studies

Death or oxygen requirement at 36 weeks' postmenstrual age

see comments

see comments

     

Not reported in any of the studies

Pneumothorax

429 per 1000

43 per 1000
(4 to 313)

RR 0.10
(0.01 to 0.73)

44
(1 RCT)

⨁⨁⨁⨁
HIGH

 

Pulmonary hemorrhage

see comments

see comments

     

Not reported in any of the studies

Severe intraventricular hemorrhage in infants who received neuroimaging

see comments

see comments

     

Not reported in any of the studies

Neurodevelopmental outcome at approximately two years corrected age

see comments

see comments

     

Not reported in any of the studies

* The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Footnotes

1 95 % CI of the pooled effect crosses 1 and the optimal information size to detect a clinically beneficial effect if there is one is > 700

[top]

References to studies

Included studies

Attar 2004

Attar MA, Becker MA, Dechert RE. Immediate change in lung compliance following natural surfactant administration in premature infants with respiratory distress syndrome. Journal of Perinatology 2004;24(10):626-30.

Baroutis 2003

Baroutis G, Kaleyias J, Liarou T. Comparison of three treatment regimens of the natural surfactant preparations in neonatal respiratory distress syndrome. European Journal of Pediatrics 2003;162(7-8):476-80.

Bloom 1997

Bloom BT, Kattwinkel J, Hall RT, Delmore PM, Egan EA, Trout JR, et al. Comparison of Infasurf (calf lung surfactant extract) to Survanta (Beractant) in the treatment and prevention of respiratory distress syndrome. Pediatrics 1997;100(1):31-8.

Bloom 2005

Bloom BT, Clark RH for Infasurf Survanta Clinical Trial group. Comparision of Infasurf (calfactant) and Survanta (beractant) in the prevention of respiratory distress syndrome. Pediatrics 2005;116(2):392-9.

Didzar 2012

Dizdar EA, Sari FN, Aydemir C, Oguz SS, Erdeve O, Uras N, et al. A randomized, controlled trial of poractant alfa versus beractant in the treatment of preterm infants with respiratory distress syndrome. American Journal of Perinatology 2012;29(2):95-100.

Fujii 2010

Fujii AM, Patel SM, Allen R. Poractant alfa and beractant treatment of very premature infants with respiratory distress syndrome. Journal of Perinatology 2010;30(10):665-70.

Gharehbaghi 2010

Gharehbaghi MM, Sakha SH, Ghojazadeh M, Firoozi F. Complications among premature neonates treated with beractant and poractant alfa. Indian Journal of Pediatrics 2010;77(7):751-4.

Halahakoon 1999

Halahakoon WL. A study of cerebral function following surfactant treatment for respiratory distress syndrome (Doctoral dissertation). Queen's University of Belfast (UK) 1999.

Hammoud 2004

Hammoud M, Al-Kazmi N, Alshemmiri M, Thalib L, Ranjani VT, Devarajan LV, et al. Randomized clinical trial comparing two natural surfactant preparations to treat respiratory distress syndrome. Journal of Maternal Fetal and Neonatal Medicine 2004;15(3):167-75.

Karadag 2014

Karadag N, Dilli D, Zenciroglu A, Aydin B, Beken S, Okumus N. Perfusion index variability in preterm infants treated with two different natural surfactants for respiratory distress syndrome. American Journal of Perinatology 2014;31(11):1015-22. [PubMed: 24566756]

Lam 2005

Lam BC, Ng YK, Wong KY. Randomized trial comparing two natural surfactants (Survanta vs bLES) for treatment of neonatal respiratory distress syndrome. Pediatric Pulmonology 2005;39(1):64-9.

Malloy 2005

Malloy CA, Nicoski P, Muraskas JK. A randomized trial comparing beractant and poractant treatment in neonatal respiratory distress syndrome. Acta Paediatrica 2005;94(6):779-84.

Ramanathan 2004

Ramanathan R, Rasmussen MR, Gerstmann DR, Finer N, Sekar K; North American Study Group. A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants. American Journal of Perinatology 2004;21(3):109-19.

Sanchez-Mendiola 2005

Sánchez-Mendiola M, Martínez-Natera OC, Herrera-Maldonado N, Ortega-Arroyo J. Treatment of hyaline membrane disease in the preterm newborn with exogenous lung surfactant: a controlled study [Estudio controlado del tratamiento de la enfermedad de membrana hialina del recien nacido pretermino con surfactante pulmonar exogeno (porcino vs bovino)]. Gaceta medica Mexico 2005;141(4):267-71.

Speer 1995

Speer CP, Gefeller O, Groneck P. Randomized clinical trial of two treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome. Archives of Disease in Childhood 1995;72(1):F8-13.

Yalaz 2004

Yalaz M, Aslanoglu S, Akisu M, Atik T, Ergun O, Kultursay N. A comparison of efficacy between two natural exogenous surfactant preparations in premature infants with respiratory distress syndrome. Klinische Padiatrie 2004;216(4):230-5.

Excluded studies

Bozdağ 2015

Bozdağ S, Dilli D, Gökmen T, Dilmen U. Comparison of two natural surfactants for pulmonary hemorrhage in very low-birth-weight infants: a randomized controlled trial. American Journal of Perinatology 2015;32(3):211-8.

Choi 2005

Choi CW, Hwang JH, Yoo EJ, Kim KA, Koh SY, Lee YK, et al. Comparison of clinical efficacy of Newfactan versus Surfacten for the treatment of respiratory distress syndrome in he newborn infants. Journal of Korean Medical Science 2005;20(4):591-7.

Proquitté 2007

Proquitté H, Dushe T, Hammer H, Rüdiger M, Schmalisch, G, Wauer RR, et al. Observational study to compare the clinical efficacy of the natural surfactants Alveofact and Curosurf in the treatment of respiratory distress syndrome in premature infants. Respiratory Medicine 2007;101(1):169-76.

Rebello 2009

Unpublished data only

Rebello CM, Mascaretti RS, Precioso AR. A multicenter randomized double blind trial of a new low cost animal surfactant in premature infants with respiratory distress syndrome. In: E-PAS. 2009.

Rebello CM, Precioso AR, Mascaretti RS; Grupo Colaborativo do Estudo Brasileiro Multicêntrico de Surfactante. A multicenter, randomized, double-blind trial of a new porcine surfactant in premature infants with respiratory distress syndrome. Einstein (Sao Paulo) 2014;12(4):397-404. [DOI: 10.1590/S1679-45082014AO3095]

Studies awaiting classification

Eras 2014

[PMID: 23884719]

Eras Z, Dizdar EA, Kanmaz G, Guzoglu N, Aksoy HT, Altunkaya GB, et al. Neurodevelopmental outcomes of very low birth weight preterm infants treated with poractant alfa versus beractant for respiratory distress syndrome. American Journal of Perinatology 2014;31(6):463-8. [DOI: 10.1055/s-0033-1351659]

Gharehbaghi 2014

Gharehbaghi MM, Yasrebi S. Comparing the efficacy of two natural surfactants, Curosurf and Alveofact, in treatment of respiratory distress syndrome in preterm infants. International Journal of Women’s Health and Reproduction Sciences 2014;2(4):245-8.

Mercado 2010

Mercado VV, Cristea I, Ali N, Pham CC, Buescher E, Yang J, et al. Does surfactant type cause a differential proinflammatory response in preterm infant with respiratory distress syndrome? Advances in Therapy 2010;27(7):476-82.

Saeidi 2013

Saeidi R, Hamedi A, Javadi A, Robatsangi MG, Dinparvar SK. Comparison of side effects of survanta and curosurf in decreasing mortality due to respiratory distress syndrome (RDS) in premature infants admitted in NICU of Ghaem Hospital on 2006-2008. Iranian Journal of Neonatology 2013;4(3):7-12. [Other: AN:2013708341]

Terek 2015

[DOI: 10.1016/j.pedneo.2014.11.004]

Terek D, Gonulal D, Koroglu OA, Yalaz M, Akisu M, Kultursay N. Effects of two different exogenous surfactant preparations on serial peripheral perfusion index and tissue carbon monoxide measurements in preterm infants with severe respiratory distress syndrome. Pediatric Neurology 2015;56(4):248-55.

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Other references

Additional references

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Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. American Journal of Diseases in Children 1959;97(5 Pt 1):517-23.

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187(1):1-7.

Chu 1967

Chu J, Clements JA, Cotton EK, Klaus MH, Sweet AY, Tooley WH. Neonatal pulmonary ischemia. I. Clinical and physiological studies. Pediatrics 1967;40(4):709-82.

Dargaville 2011

Dargaville PA, Aiyappan A, Cornelius A, Williams C, Antonio G De Paoli. Preliminary evaluation of a new technique of minimally invasive surfactant therapy. Archive of Disease in Childhood - Fetal and Neonatal Edition 2011;96(4):F243–8.

Engle 2008

Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn. Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Pediatrics 2008;121(2):419-32.

Enhorning 1972

Enhorning G, Robertson B. Lung expansion in the premature rabbit fetus after tracheal deposition of surfactant. Pediatrics 1972;50(1):58-66.

Fujiwara 1980

Fujiwara T, Maeta H, Chida S, Morita T, Watabe YJ, Abe T. Artificial surfactant therapy in hyaline membrane disease. Lancet 1980;I(8159):55-9.

GradePro 2008

GradePro [Version 3.2 for Windows] [Computer program]. Jan Brozek, Andrew Oxman, Holger Schünemann. 2008.

Guyatt 2011a

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. Journal of clinical epidemiology 2011;64(4):383-94. [PubMed: 21195583]

Guyatt 2011b

Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). Journal of Clinical Epidemiology 2011;64(4):407-15. [PubMed: 21247734]

Guyatt 2011c

Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence--imprecision. Journal of clinical epidemiology 2011;64(12):1283-93. [PubMed: 21839614]

Guyatt 2011d

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 7. Rating the quality of evidence--inconsistency. Journal of clinical epidemiology 2011;64(12):1294-302. [PubMed: 21803546]

Guyatt 2011e

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. GRADE guidelines: 8. Rating the quality of evidence--indirectness. Journal of clinical epidemiology 2011;64(12):1303-10. [PubMed: 21802903]

Halliday 2008

Halliday HL. Surfactants: past, present and future. Journal of Perinatology 2008;28(Suppl 1):S47-S56.

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(1):184-90.

Higgins 2011

Higgins A, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

ICCROP 2005

International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Archives of Ophthalmology 2005;123(7):991-9.

Jobe 1993

Jobe AH. Pulmonary surfactant therapy. New England Journal of Medicine 1993;328(1):861-8.

Kribs 2007

Kribs A, Pillekamp F, Hunseler C. Early administration of surfactant in spontaneous breathing with nCPAP: feasibility and outcome in extremely premature infants (postmenstrual age < 27 weeks). Pediatric Anesthesia 2007;17(4):364-9.

Moya 2009

Logan JW, Moya FR. Animal derived surfactants for the treatment and prevention of neonatal respiratory distress syndrome: summary of clinical trials. Therapeutic and Clinical Risk Management 2009;5(1):251-60.

Papile 1978

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. Journal of Pediatrics 1978;92(4):529-34.

Pfister 2007

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

Pfister 2009

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 2009, Issue 4. Art. No.: CD006180. DOI: 10.1002/14651858.CD006180.pub2.

Ramanathan 2009

Ramanathan R. Animal derived surfactants: where are we? The evidence from randomized controlled trials. Journal of Perinatology 2009;29(Suppl 2):s38-43.

RevMan 2014

Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Robillard 1964

Robillard E, Alarie Y, Dagenais-Perusse P, Baril E, Guilbeault A. Microaerosol administration of synthetic beta-gamma-dipalmitoyl-L-alpha-lecithin in the respiratory distress syndrome. Canadian Medical Association Journal 1964;90:55-7.

Rojas-Reyes 2012

Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD000510. DOI: 10.1002/14651858.CD000510.pub2.

Schünemann 2013

Schünemann H, Brożek J, Guyatt G, Oxman A; editors. The GRADE Working Group. GRADE handbook for grading quality of evidence and strength of recommendations. Available from www.guidelinedevelopment.org/handbook. Updated October 2013.

Seger 2009

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

Singh 2011

Singh N, Hawley KL, Viswanathan K. Efficacy of porcine versus bovine surfactants for preterm newborns with respiratory distress syndrome: systematic review and meta-analysis. Pediatrics 2011;128(6):e1588-95.

Soll 1992

Soll RF, McQueen MC. Respiratory Distress Syndrome. In: Sinclair J, Bracken M: Effective Care of the Newborn Infant. New York: Oxford University Press, 1992:325-58. [Other: ISBN 0-19-261737-0]

Soll 1997

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

Soll 1998

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

Soll 2001

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

Soll 2010

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

Sweet 2013

Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants--2013 update. Neonatology 2013;103(4):353-68.

Whitsett 1995

Whitsett JA, Nogee LM, Weaver TE, Horowitz AD. Human surfactant protein B: structure, function, regulation, and genetic disease. Physiological Reviews 1995;75(4):749-57.

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Data and analyses

1 Bovine lung lavage surfactant extract vs. modified bovine minced lung surfactant extract

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Neonatal mortality 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.1.1 Prevention 1 749 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.79, 1.80]
  1.1.2 Treatment 3 1451 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.65, 1.26]
1.2 Mortality prior to discharge 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.2.1 Prevention 2 1123 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.90, 1.71]
  1.2.2 Treatment 6 2231 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.79, 1.21]
1.3 Oxygen requirement at 28 to 30 days of age (all infants) 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.3.1 Prevention 1 749 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.88, 1.12]
  1.3.2 Treatment 3 1510 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.98, 1.21]
1.4 Oxygen requirement at 36 weeks postmenstrual age (all infants) 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.4.1 Prevention 1 749 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.79, 1.19]
  1.4.2 Treatment 5 1564 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.82, 1.11]
1.5 Death or oxygen requirement at 28 to 30 days of age 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.5.1 Prevention 1 749 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.93, 1.13]
  1.5.2 Treatment 2 1401 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.96, 1.15]
1.6 Death or oxygen requirement at 36 weeks postmenstrual age 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.6.1 Prevention 2 1123 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.89, 1.17]
  1.6.2 Treatment 3 2009 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.86, 1.06]
1.7 Received > one dose of surfactant 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.7.1 Prevention 2 1123 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.89, 1.16]
  1.7.2 Treatment 5 2178 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.93, 1.06]
1.8 Pneumothorax 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.8.1 Prevention 1 749 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.43, 1.36]
  1.8.2 Treatment 6 2224 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.85, 1.51]
1.9 Air leak syndromes 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.9.1 Prevention 2 1123 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.84, 1.60]
  1.9.2 Treatment 3 2022 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.82, 1.28]
1.10 Pulmonary hemorrhage 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.10.1 Prevention 2 1123 Risk Ratio (M-H, Fixed, 95% CI) 1.44 [0.88, 2.39]
  1.10.2 Treatment 4 2138 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.74, 1.59]
1.11 Treated patent ductus arteriosus (PDA) 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.11.1 Treatment 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.07, 1.34]
1.12 Culture-confirmed bacterial sepsis 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.12.1 Prevention 2 1123 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.91, 1.28]
  1.12.2 Treatment 6 2228 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.87, 1.15]
1.13 Necrotizing enterocolitis (any stage) 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.13.1 Prevention 2 1123 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.74, 1.42]
  1.13.2 Treatment 5 2191 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.78, 1.33]
1.14 Periventricular leukomalacia 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.14.1 Prevention 1 713 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.29, 1.26]
  1.14.2 Treatment 1 1275 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.59, 1.73]
1.15 Retinopathy of prematurity in infants examined (all stages) 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.15.1 Prevention 2 1011 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.86, 1.12]
  1.15.2 Treatment 3 1662 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.89, 1.16]
1.16 Retinopathy of prematurity in infants examined (severe stage 3 or greater) 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.16.1 Prevention 1 637 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.77, 1.69]
  1.16.2 Treatment 1 1001 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.64, 1.33]
1.17 Intraventricular hemorrhage in infants receiving neuroimaging (all grades) 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.17.1 Prevention 1 713 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.87, 1.24]
  1.17.2 Treatment 3 1434 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.98, 1.33]
1.18 Severe IVH in infants receiving neuroimaging 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.18.1 Prevention 2 1087 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [0.89, 1.83]
  1.18.2 Treatment 5 2040 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.68, 1.09]
 

2 Bovine lung lavage surfactant vs. porcine minced lung

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Mortality prior to discharge 1 54 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [0.51, 3.87]
2.2 Oxygen requirement at 36 weeks postmenstrual age 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.19, 3.04]
2.3 Air leak syndromes 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.12, 3.68]
2.4 Necrotizing enterocolitis (any stage) 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.12, 3.68]
2.5 Retinopathy of prematurity in infants examined (all stages) 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.24, 2.66]
2.6 Severe IVH 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.29, 2.41]
 

3 Modified bovine minced lung vs. porcine minced lung

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Neonatal mortality 2 320 Risk Ratio (M-H, Fixed, 95% CI) 1.48 [0.72, 3.07]
3.2 Mortality prior to discharge 9 901 Risk Ratio (M-H, Fixed, 95% CI) 1.44 [1.04, 2.00]
3.3 Oxygen requirement at 28 to 30 days of age 2 320 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.77, 1.23]
3.4 Oxygen requirement at 36 weeks postmenstrual age 9 899 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.79, 1.12]
3.5 Death or oxygen requirement at 36 weeks postmenstrual age 3 448 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [1.04, 1.64]
3.6 Received > one dose of surfactant 6 786 Risk Ratio (M-H, Fixed, 95% CI) 1.57 [1.29, 1.92]
3.7 Pneumothorax 6 669 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.71, 2.17]
3.8 Air leak syndromes 3 255 Risk Ratio (M-H, Fixed, 95% CI) 2.55 [0.98, 6.68]
3.9 Pulmonary hemorrhage 8 871 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [0.81, 2.02]
3.10 Treated patent ductus arteriosus (PDA) 3 137 Risk Ratio (M-H, Fixed, 95% CI) 1.86 [1.28, 2.70]
3.11 Culture-confirmed bacterial sepsis 6 526 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [0.87, 1.46]
3.12 Necrotizing enterocolitis (any stage) 7 701 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.50, 1.33]
3.13 Periventricular leukomalacia 1 47 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.07, 15.72]
3.14 Retinopathy of prematurity in infants examined (all stages) 3 230 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.29, 1.26]
3.15 Retinopathy of prematurity in infants examined (severe stage 3 or greater) 4 222 Risk Difference (M-H, Fixed, 95% CI) 0.00 [-0.09, 0.09]
3.16 Intraventricular hemorrhage (all grades) 4 318 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.64, 1.50]
3.17 Severe IVH 7 705 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [0.83, 1.97]
 

4 Modified bovine minced lung vs. porcine lung lavage

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
4.1 Mortality prior to discharge 1 44 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.60, 1.99]
4.2 Pneumothorax 1 44 Risk Ratio (M-H, Fixed, 95% CI) 0.10 [0.01, 0.73]
 

5 Modified bovine minced lung vs. porcine minced lung (based on initial surfactant dosage)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
5.1 Neonatal mortality 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  5.1.1 Initial dose less than/or equal to 100 mg/kg porcine minced lung 2 221 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.55, 2.62]
  5.1.2 Initial dose ˃ 100 mg/kg porcine minced lung 1 197 Risk Ratio (M-H, Fixed, 95% CI) 2.69 [0.74, 9.86]
5.2 Mortality prior to discharge 9 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  5.2.1 Initial dose less than/or equal to 100 mg/kg porcine minced lung 3 255 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.61, 1.96]
  5.2.2 Initial dose ˃ 100 mg/kg porcine minced lung 7 736 Risk Ratio (M-H, Fixed, 95% CI) 1.62 [1.11, 2.38]
5.3 Oxygen requirement at 28 to 30 days of age 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  5.3.1 Initial dose less than/or equal to 100 mg/kg porcine minced lung 2 221 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.73, 1.25]
  5.3.2 Initial dose ˃ 100 mg/kg porcine minced lung 1 197 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.76, 1.34]
5.4 Oxygen requirement at 36 weeks postmenstrual age 8 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  5.4.1 Initial dose less than/or equal to 100 mg/kg porcine minced lung 3 255 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.65, 1.37]
  5.4.2 Initial dose ˃ 100 mg/kg porcine minced lung 6 608 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.84, 1.38]
5.5 Death or oxygen requirement at 36 weeks postmenstrual age 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  5.5.1 Initial dose less than/or equal to 100 mg/kg porcine minced lung 1 175 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.76, 1.43]
  5.5.2 Initial dose ˃ 100 mg/kg porcine minced lung 3 363 Risk Ratio (M-H, Fixed, 95% CI) 1.39 [1.08, 1.79]
 

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Figures

Figure 1 (Analysis 1.2)

Refer to Figure 1 caption below.

Forest plot of comparison: 1 Bovine lung lavage surfactant extract vs. modified bovine minced lung surfactant extract, outcome: 1.2 Mortality prior to discharge (Figure 1).

Figure 2 (Analysis 1.4)

Refer to Figure 2 caption below.

Forest plot of comparison: 1 Bovine lung lavage surfactant extract vs. modified bovine minced lung surfactant extract, outcome: 1.4 Oxygen requirement at 36 weeks postmenstrual age (all infants) (Figure 2).

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Sources of support

Internal sources

  • No sources of support provided

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

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Appendices

1 Standard search methodology

CNRG routine search terms

PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial[ptyp] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh]))

EMBASE: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)

CINAHL: (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

Cochrane Library: (infant or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW)


This review is published as a Cochrane review in The Cochrane Library, Issue 12, 2015 (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 recent version of the review.