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Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants

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Authors

Maria Ximena Rojas-Reyes1, Colin J Morley2, a, Roger Soll3

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


1Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Pontificia Universidad Javeriana, Bogota, Colombia [top]
2Department of Obstetrics and Gynecology, University of Cambridge, Cambridge, UK [top]
3Division of Neonatal-Perinatal Medicine, University of Vermont, Burlington, Vermont, USA [top]
aNeonatal Services, Royal Women’s Hospital [top]

Citation example: 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.

Contact person

Roger Soll

Division of Neonatal-Perinatal Medicine
University of Vermont
Fletcher Allen Health Care, Smith 552A
111 Colchester Avenue
Burlington Vermont 05401
USA

E-mail: Roger.Soll@vtmednet.org

Dates

Assessed as Up-to-date: 20 December 2011
Date of Search: 14 December 2011
Next Stage Expected: 20 December 2013
Protocol First Published: Issue 4, 1997
Review First Published: Issue 4, 1997
Last Citation Issue: Issue 3, 2012

What's new

Date / Event Description
13 March 2012
Amended

Minor text copy edits.

History

Date / Event Description
20 December 2011
Updated

This updates the review "Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants" published in the Cochrane Database of Systematic Reviews (Soll 2001b).

Search updated in December 14, 2011

20 December 2011
New citation: conclusions changed

New co-author - Rojas-Reyes MX

New studies and subgroup analyses added to address routine stabilization of infants on positive airway pressure.

Change in conclusions: Although the early trials of prophylactic surfactant administration to infants judged to be at risk of developing RDS compared to selective use of surfactant in infants with established RDS demonstrated a decreased risk of air leak and mortality, recent large trials that reflect current practice (including greater utilization of maternal steroids and routine post delivery stabilization on CPAP) do not support these differences and demonstrate less risk of chronic lung disease or death when using early stabilization on CPAP with selective surfactant administration to infants requiring intubation.

26 February 2010
Amended

Converted to new review format.

07 February 2001
Updated

Systematic search for new trials through December, 2000. Additional study of Bevilacqua (1997) found and added to the review.

07 February 2001
New citation: conclusions not changed

Substantive amendment

Abstract

Background

Surfactant therapy is effective in improving the outcome of very preterm infants. Trials have studied a wide variety of surfactant preparations used either to prevent or treat respiratory distress syndrome (RDS). In animal models, prophylactic surfactant leads to more homogeneous distribution and less evidence of lung damage. However, administration requires intubation and treatment of infants who will not go on to develop RDS. This is of particular concern with the advent of improved approaches to providing continuous distending pressure, particularly in the form of nasal continuous positive airway pressure (NCPAP).

Objectives

To compare the effect of prophylactic surfactant administration with surfactant treatment of established RDS in very preterm infants at risk of RDS.

Search methods

We updated the search of the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and clinical trials.gov register in December 13, 2011.

Selection criteria

Randomized and quasi-randomized controlled trials that compared the effects of prophylactic surfactant administration with surfactant treatment of established RDS in preterm infants at risk of RDS.

Data collection and analysis

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

Results

We identified 11 studies that met inclusion criteria (nine without routine application of continuous positive air way pressure (CPAP) in the selective treatment group; two with routine application of CPAP in the selective treatment group).

The meta-analysis of studies conducted prior to the routine application of CPAP demonstrated a decrease in the risk of air leak and neonatal mortality associated with prophylactic administration of surfactant. However, the analyses of studies that allowed for routine stabilization on CPAP demonstrated a decrease in the risk of chronic lung disease or death in infants stabilized on CPAP. When all studies were evaluated together, the benefits of prophylactic surfactant could no longer be demonstrated.

Authors' conclusions

Although the early trials of prophylactic surfactant administration to infants judged to be at risk of developing RDS compared with selective use of surfactant in infants with established RDS demonstrated a decreased risk of air leak and mortality, recent large trials that reflect current practice (including greater utilization of maternal steroids and routine post delivery stabilization on CPAP) do not support these differences and demonstrate less risk of chronic lung disease or death when using early stabilization on CPAP with selective surfactant administration to infants requiring intubation.

Plain language summary

Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants

Surfactant is essential to normal lung function in babies. Surfactant is deficient in the lungs of many babies born prematurely, and is one aspect of lung immaturity leading to a lung disease known a respiratory distress syndrome (RDS).

Surfactant can be given both to prevent and treat this respiratory problem. Although the initial studies suggested that infants intubated and treated with prophylactic surfactant had improved clinical outcome, more recent studies suggest that stabilization with using continuous "back pressure" (using a device known a continuous positive airway pressure (CPAP)) and surfactant treatment of only those infants who develop breathing problems may be more effective than the more aggressive approach. Prophylactic use of surfactant in babies at high risk of developing RDS does not lead to clinical improvement and may increase the risk of lung injury or death, especially when compared to an approach that incorporates early stabilization on continuous distending pressure.

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Background

Description of the condition

Respiratory distress syndrome (RDS) occurs in very preterm infants who have immature lung structure, an immature cardiovascular system, and a very distensible chest wall. RDS is associated with a deficiency or dysfunction of pulmonary surfactant. 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. In addition, pulmonary surfactant also contains neutral lipids and four distinct surfactant proteins (SP-A, SP-B, SP-C and SP-D). These proteins may play a role in surfactant secretion, recycling, cooperative functioning with other surfactant proteins and phospholipids (Possmayer 1990; Schürch 1992) and innate host defense of the lung (Wright 1997). The physiologic functions of surfactant include the ability to lower surface tension and the ability to rapidly adsorb, spread, and reform a monolayer in the dynamic conditions associated with the respiratory cycle (Jobe 1993).

Description of the intervention

Surfactant therapy has been proven to improve the immediate need for respiratory support and the clinical outcome of very preterm newborns (Soll 1992; Jobe 1993). Trials have studied a wide variety of surfactant preparations used either to prevent (prophylactic or delivery room administration) (Soll 2010) or treat (very early, selective or rescue administration) (Soll 2000; Seger 2009) RDS (Soll 2000; Soll 2001a; Pfister 2007; Pfister 2009; Seger 2009; Soll 2010). Using either approach to treatment, surfactant therapy has been proven to reduce the need for ventilator support and decrease the risk of pneumothorax, death and the combined outcome of death of bronchopulmonary dysplasia (BPD) (Engle 2008). However, the risk of BPD in preterm infants of less than 30 weeks’ gestation who received prophylactic surfactant compared with those who received later selective treatment is unclear (Soll 2001b). Widespread use of surfactant therapy has been credited with significant improvements in survival in preterm infants (Horbar 1993; Schwartz 1994), without a change in the incidence of neurologic, or developmental disability of preterms followed through infancy and school age (Palta 2000; D'Angio 2002).

For the purpose of this review, a "prophylactic strategy" for surfactant administration was defined as a strategy that mandated intubation and bolus administration of surfactant immediately after birth (either prior to the first breath or after a brief period of resuscitation). "Selective" surfactant therapy was defined as administration of surfactant once the infant had evidence of RDS, also known in the literature as "treatment" or "rescue" surfactant.

How the intervention might work

Although both prophylactic surfactant administration and surfactant treatment of infants with established RDS are successful treatment strategies, there are theoretical advantages and disadvantages to each approach. Prophylactic administration offers the theoretical advantage of replacing surfactant before the onset of respiratory insufficiency, decreasing the need for ventilator support and avoiding barotrauma that may result from even short periods of assisted ventilation (Nilsson 1978). Surfactant may distribute more homogeneously when given immediately at birth into lungs still filled with fluid, leading to improvement in response and decreasing the risk of lung injury (Jobe 1984). Surfactant treatment reserved for infants with established RDS offers the advantage of treating only infants with clinical disease, eliminating the potential risks and costs of treating surfactant sufficient infants who would receive no benefit from treatment.

Why it is important to do this review

Multiple systematic reviews have addressed the use of animal derived surfactant preparations or synthetic surfactant preparations in the prevention or treatment of RDS (Soll 2000; Soll 2001a; Soll 2001b; Pfister 2007; Pfister 2009; Seger 2009; Soll 2010). Other treatment strategies, such as the intubation of spontaneously breathing infants and surfactant treatment with rapid extubation and restabilization on nasal continuous positive airway pressure (NCPAP) are addressed in other reviews (Stevens 2007).

In recent years, the increased utilization of antenatal steroids, more gentle resuscitation in the delivery room and the routine use of early delivery room CPAP may have changed the risk/benefit analysis of aggressive universal prophylactic intubation and treatment of infants at high risk of RDS (Gittermann 1997; Sahni 1998; Lindner 1999; Finer 2004; Rojas 2009). This analysis updates previous reviews of the prophylactic versus selective use of any surfactant preparation in preventing morbidity and mortality in preterm infants and allows for subgroup analyses of recent studies that utilize early stabilization on CPAP.

Cochrane reviews that address trials of pulmonary surfactant in neonates

Sinclair J, Bracken M. Effective Care of the Newborn. Oxford University Press

Original controlled trials

Soll R, Ozek E. Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001079. Review.

Soll R, Özek E. Protein free 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. Updated 2011.

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. Updated 2010.

Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD007836. Review.

Comparisons of surfactant preparations

Soll RF, Blanco F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2001;(2):CD000144. Review.

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 Syst Rev. 2009 Oct 7;(4):CD006180. Review.

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 Syst Rev. 2007 Oct 17;(4):CD006069. Review.

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 Dec;128(6):e1588-95. Epub 2011 Nov 28. Review. (NON COCHRANE REVIEW)

Comparison of treatment strategies

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 .

Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2000;(2):CD001456. Review.

Soll R, Ozek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD000141. Review.

Stevens TP, Harrington EW, Blennow M, Soll RF. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003063. Review. PMID: 17943779 [PubMed - indexed for MEDLINE]

Methods of instillation

Abdel-Latif ME, Osborn DA. Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database Syst Rev. 2011 Jul 6;(7):CD008309. Review.

Abdel-Latif ME, Osborn DA. Pharyngeal instillation of surfactant before the first breath for prevention of morbidity and mortality in preterm infants at risk of respiratory distress syndrome. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD008311. Review.

Abdel-Latif ME, Osborn DA. Nebulised surfactant for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD008310. DOI: 10.1002/14651858.CD008310

Surfactant for conditions other than RDS

El Shahed AI, Dargaville P, Ohlsson A, Soll RF. Surfactant for meconium aspiration syndrome in full term/near term infants. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD002054. Review.

Aziz A, Ohlsson A. Surfactant for pulmonary hemorrhage in neonates. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD005254. Review.

Tan K, Lai NM, Sharma A. Surfactant for bacterial pneumonia in late preterm and term infants. Cochrane Database Syst Rev. 2012 Feb 15;2:CD008155.

Hahn S, Choi HJin, Soll R, Dargaville PA. Therapeutic lung lavage for meconium aspiration syndrome in newborn infants. Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD003486. DOI: 10.1002/14651858.CD003486 .

Objectives

To compare the effect of prophylactic surfactant administration to surfactant treatment of established RDS in very preterm infants.

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Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials comparing prophylactic surfactant administration (surfactant given down the endotracheal tube prior to the first breath or immediately after intubation or stabilization in the delivery room) versus selective surfactant treatment of preterm infants with established RDS .

Types of participants

Very preterm infants with or without evidence of RDS.

Types of interventions

Randomized to receive either:

  1. Prophylactic surfactant administration defined as the intubation of infants thought to be at high risk of developing RDS for the purpose of giving surfactant therapy either before (pre-ventilatory) or after (post-ventilatory) the first breath.
  2. Selective surfactant treatment of established RDS defined as the administration of surfactant only to those infants who require intubation and have signs of RDS.

Any surfactant product was eligible (synthetic surfactant, protein containing synthetic surfactant, animal derived surfactant).

The control group could be managed with or without early application of CPAP.

Types of outcome measures

Studies were eligible for inclusion if they reported on one or more of the following clinical outcomes.

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

Search methods for identification of studies

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

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library up to December 2011), MEDLINE (1966 to December 14, 2011), EMBASE (1980 to 2011 week 49), CINAHL (up to December 14, 2011) and the Controlled-Trials.com External Web Site Policy (up to December 14, 2011). MEDLINE was searched using the following terms in conjunction with the highly sensitive search strategy designed by the Cochrane Collaboration for identifying randomized controlled trials (Dickersin 2002). The same strategy was used to search CENTRAL and adapted to search EMBASE.

PubMED Search terms:

1. For surfactant:

"surface-active agents"[MeSH Terms] OR ("surface-active"[All Fields] AND "agents"[All Fields]) OR "surface-active agents"[All Fields] OR "surfactant"[All Fields] OR "surface-active agents"[Pharmacological Action] OR "pulmonary surfactants"[MeSH Terms] OR ("pulmonary"[All Fields] AND "surfactants"[All Fields]) OR "pulmonary surfactants"[All Fields] OR "pulmonary surfactants"[Pharmacological Action]

2. For infant:

"infant, newborn"[MeSH Terms] OR ("infant"[All Fields] AND "newborn"[All Fields]) OR "newborn infant"[All Fields] OR "newborn"[All Fields] OR "neonate"[All Fields] OR "infant, low birth weight"[MeSH Terms] OR ("infant"[All Fields] AND "low"[All Fields] AND "birth"[All Fields] AND "weight"[All Fields]) OR "low birth weight infant"[All Fields] OR ("low"[All Fields] AND "birth"[All Fields] AND "weight"[All Fields]) OR "low birth weight"[All Fields]

3. Final query:

surfactant AND ((infant, newborn[MeSH] OR newborn OR neon* OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh]))

From the resulting studies, we selected randomized or quasi-randomized controlled studies that fulfilled the inclusion criteria.

To identify long-term neurodevelopmental sequelae, we performed a search using the following keywords. There were no language or publication restrictions.

  1. "Mental Retardation"[Mesh]
  2. "Cerebral Palsy"[Mesh]
  3. ("Hearing Loss"[Mesh] OR "Hearing Loss, Functional"[Mesh] OR "Hearing Loss, Mixed Conductive-Sensorineural"[Mesh] OR "Hearing Loss, Sensorineural"[Mesh])
  4. Hearing Impairment[MULTI]
  5. "Vision Disorders"[Mesh]
  6. "Motor Neuron Disease"[Mesh] AND ("Motor Skills Disorders"[Mesh] OR "Ataxia"[Mesh] OR "Polyneuropathies"[Mesh] OR "Pseudobulbar Palsy"[Mesh] OR "Psychomotor Disorders"[Mesh])
  7. Mental[All Fields] OR ("disease"[MeSH Terms] OR disorders[Text Word])
  8. ("Pulmonary Surfactants"[Mesh] OR "Pulmonary Surfactants "[Pharmacological Action])
  9. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7
  10. 9 AND 8

The bibliography cited in each publication obtained was searched in order to identify additional relevant articles.

Searching other resources

To avoid publication bias, we conducted a search to identify unpublished studies from the Society for Pediatric Research (USA). Abstracts for 2000 to 2011 were searched electronically through the Pediatric Academic Societies External Web Site Policy website(abstracts online). For abstract books that do not include keywords, the search was limited to relevant sections such as pulmonary and neonatology.

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

Data collection and analysis

We applied the standard methods of the Cochrane Neonatal Review Group for this update.

Selection of studies

All randomized and quasi-randomized controlled trials fulfilling the selection criteria described in the previous section were included. Two investigators (MXR and RS) independently scanned all titles identified by the electronic searches. After reviewing the abstracts, the full text of potentially relevant studies was retrieved for inclusion. The review authors resolved any disagreement by discussion.

Data extraction and management

Two of the three review authors (MXR and RS) separately extracted, assessed and recorded all data for each study using a form that was designed specifically for this review. For each included study, the following data were collected from the study report or, if unavailable, by direct contact with the author: whether the trial was conducted at a single center or multiple centers, number of participants, the method of randomization, randomization strata, type of intervention, selection criteria, including gestational age at birth, the time of treatment, disease severity criteria for the rescue treatment group, clinical outcomes including RDS, pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (any intraventricular hemorrhage and severe intraventricular hemorrhage), BPD (oxygen requirement at 28 days), chronic lung disease (CLD) (oxygen requirement at 36 weeks postmenstrual age (PMA)) retinopathy of prematurity (ROP), neonatal mortality, mortality prior to hospital discharge, and BPD or death. Differences in assessment were resolved by discussion. For each study, final data were entered into Review Manager (RevMan) by one review author (MXR) and then checked by a second review author (RS).

We addressed any disagreements with the third review author (CM).

Assessment of risk of bias in included studies

The standard methods of the Cochrane Neonatal Review Group were employed. In addition, for the update in 2011, the following issues were evaluated and entered into the 'Risk of bias' table (Higgins 2011).

  1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated? For each included study, we categorized the method used to generate the allocation sequence as: low risk (any truly random process e.g. random number table; computer random number generator); high risk (any non random process e.g. odd or even date of birth; hospital or clinic record number) or unclear risk.
  2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed? For each included study, we categorized the method used to conceal the allocation sequence as: low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes); high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);or unclear risk.
  3. Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment? For each included study, we categorized 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 categorized the methods as: low risk, high risk or unclear for participants;adequate, inadequate or unclear for personnel; adequate, inadequate or unclear risk for outcome assessors.
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed? For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted 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.Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorized the methods as: low risk (< 20% missing data); high risk (greater than/or equal to 20% missing data) or unclear risk.
  5. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting? For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as: low risk (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported); high risk (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or unclear risk.
  6. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias? For each included study, we described any important concerns we had about 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 due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as: low risk; high risk;or unclear risk.

If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

Measures of treatment effect

We used the standard methods of the Neonatal Review Group. We performed statistical analyses using RevMan software. We analyzed categorical data using risk ratio (RR) and risk difference (RD). For statistically significant results, we reported the number needed to treat to benefit (NNTB). If necessary, we planned to analyze continuous data using mean difference (MD). We reported the 95% Confidence Interval (CI) on all estimates.

Assessment of heterogeneity

We estimated the treatment effects of individual trials and examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic. An I2 value of 0% to 40% was not considered to be important heterogeneity; 30% to 60% was considered moderate heterogeneity; 60% to 90% was considered substantial and I2 > 90% was considerable heterogeneity (Higgins 2003).

Since inconsistency depends on several factors, if we detected moderate, substantial or considerable statistical heterogeneity, we explored the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analyses. We used a fixed-effect model for meta-analysis.

Data synthesis

We performed the meta-analysis using RevMan 5 software, supplied by The Cochrane Collaboration. We used the Mantel-Haenszel method for estimates of typical risk ratio and risk difference. We used the inverse variance method for measured quantities. All meta-analyses were done using the fixed-effect model.

Subgroup analysis and investigation of heterogeneity

Comparison I: Studies that compared the effect of prophylactic surfactant administration with surfactant treatment of established RDS in very preterm infants
  1. Studies that did not routinely place control infants on CPAP (without routine application of CPAP).
  2. Studies that routinely placed control infants on CPAP (with routine application of CPAP).
Comparison 2: Studies that compared the effect of prophylactic surfactant administration with surfactant treatment of established RDS in preterm infants less than 30 weeks gestation
  1. Studies that did not routinely place control infants on CPAP (without routine application of CPAP).
  2. Studies that routinely placed control infants on CPAP (without routine application of CPAP).
Comparison 3: Studies that compared the effect of prophylactic surfactant administration to surfactant treatment of established RDS in very preterm infants
  1. Studies in which less than 50% of infants received antenatal steroids.
  2. Studies in which more than 50% of infants received antenatal steroids.

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Results

Description of studies

Clinical trials included in this review were: Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; Iarŭkova 1999; SUPPORT 2010; Dunn 2011. Details of each study are given in the Characteristics of Included Studies table.

Studies that did not routinely place control infants on CPAP were: Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997 and Iarŭkova 1999.

Dunn 1991:

Conducted a randomized controlled trial evaluating the influence of the timing of surfactant treatment for the treatment of neonatal RDS. One hundred and eighty-two neonates of less than 30 weeks' gestation were randomly assigned prior to birth to one of three study groups: control (dummy instillation of air given at birth), early surfactant (surfactant given at birth), or late surfactant (surfactant given at less than six hours of age). Neonates in the late surfactant group could avoid treatment if they had a clear chest x-ray and required no supplemental oxygen at a mean airway pressure of less than 7 cm H2O. Of the 60 neonates randomly assigned to late treatment, 29 (48%) were deemed surfactant sufficient and thereby avoided treatment; the other 31 received their first dose at a mean age of 2.9 hours. There was a significant improvement in gas exchange during the first week of life in both surfactant groups compared with the control group, reflected by differences in fraction of inspired oxygen, arterial/alveolar oxygen tension ratio (a/A pO2) and ventilation index (peak pressure x rate on the ventilator). Surfactant therapy resulted in a lower incidence of pulmonary air leak and severe CLD (defined as requirement for respiratory support beyond 36 weeks postmenstrual age (PMA)). There were no differences between early and late surfactant groups in any of these parameters. The only statistically significant difference between the surfactant groups was that the early group had a higher incidence of mild CLD (respiratory support beyond 28 days of age) than the late treatment group. Neonates in the late treatment group were extubated earlier and had a shorter neonatal intensive care unit stay than control neonates, whereas those in the early group were not significantly different from control neonates in these parameters.

Kendig 1991:

Conducted a randomized, multicenter trial of surfactant prophylaxis versus selective treatment. Prior to delivery, 479 infants with an estimated gestational age of less than 30 weeks were randomly assigned to receive surfactant as prophylaxis (n = 235) or rescue therapy (n = 244). The infants in the prophylaxis group received a 90 mg intratracheal dose of an exogenous calf lung surfactant extract at the time of delivery, whereas the infants in the rescue therapy group received 90 mg of the surfactant several hours after delivery if the FiO2 was at least 0.40 or if the mean airway pressure (MAP) was at least 7 cm H2O, or both. Infants in both groups received additional doses of surfactant at intervals of 12 to 24 hours if these criteria were met. The proportion of infants surviving until discharge to their homes was significantly higher in the prophylaxis group than in the rescue therapy group (88% versus 80%). This difference was due primarily to the longer survival of very preterm infants (less than or equal to 26 weeks' gestation) in the prophylaxis group than in the rescue therapy group (75% versus 54%). Infants in the prophylaxis group who were delivered at 26 weeks' gestation or earlier had a lower incidence of pneumothorax than similar infants in the rescue therapy group (7% versus 18%).

Merritt 1991:

Conducted a randomized, placebo-controlled trial of human surfactant given intratracheally at birth (prophylactic) versus rescue administration after the onset of severe RDS in preterm infants born at 24 to 29 weeks of gestation. Singleton fetuses were randomly assigned to receive (1) placebo (air), (2) prophylactic surfactant treatment, or (3) rescue surfactant treatment. Infants of multiple births received either (1) prophylactic or (2) rescue treatment. Preterm infants randomly assigned to receive prophylactic treatment received surfactant soon after birth; those assigned to receive rescue surfactant had instillation at a mean age of 220 minutes if the lecithin-sphingomyelin ratio was less than or equal to 2.0 and no phosphatidylglycerol was detected in either amniotic fluid or initial airway aspirate, oxygen requirements were an FiO2 greater than 0.5, and MAP greater than or equal to 7 cm H2O from two to 12 hours after birth. Up to four doses (or air) were permitted within 48 hours. Approximately 60% of surfactant-treated infants required two or more doses. Indices of oxygenation and ventilation were improved in surfactant recipients during the first 24 hours. An intention-to-treat analysis found no significant differences between infants given placebo and surfactant treated infants or between prophylactic and rescue treated infants.

Egberts 1993:

Conducted a randomized clinical trial to evaluate the immediate effects of prophylactic administration of poractant (Curosurf) and to compare clinical outcomes after prophylactic or expectant management. Porcine surfactant (Curosurf 200 mg/kg) was administered intratracheally within 10 minutes of birth to preterm neonates with a gestational age of 26 to 29 weeks (n = 75); rescue eligible neonates (n = 72) were initially subjected to a sham maneuver. After six to 24 hours, a similar dose of surfactant was given to the neonates of both the prophylaxis and the rescue eligible group, if they needed mechanical ventilation with an FiO2 greater than or equal to 0.6. At six hours the prophylaxis group had significantly higher tcPO2/FiO2 ratios and less severe RDS by radiological scoring. Severe RDS was present in 19% of the prophylactically treated neonates versus 32% in the rescue eligible group. There were no differences in the incidence or severity of pneumothorax, pulmonary interstitial emphysema, cerebral hemorrhage, periventricular leukomalacia, patent ductus arteriosus, in the duration of mechanical ventilation or time in supplemental oxygen, or in mortality.

Kattwinkel 1993:

Conducted a randomized controlled trial to evaluate prophylactic versus selective surfactant treatment in infants born between 29 and 32 weeks gestational age. One thousand three hundred ninety-eight neonates estimated to be 29 through 32 weeks' gestation were randomized to receive calf lung surfactant extract (CLSE) at birth or to wait until development of mild RDS. After exclusions for malformations and other factors, data from 1248 were analyzed. Prophylaxis was associated with less development of moderate RDS (7% versus 12%), less need for retreatment (5% versus 9%), less need for mechanical ventilation or supplemental oxygen during the first four days, and fewer deaths or less requirement for supplemental oxygen at 28 days (5% versus 9%). Although one minute Apgar scores were significantly lower in the prophylaxis group, the difference disappeared by the five-minute score and there was no difference in the incidence of asphyxia-related complications. Sixty percent of the neonates assigned to early treatment received endotracheal intubation and 43% received calf lung surfactant extract at a median age of 1.5 hours. When data were analyzed by gestational age and birth weight subgroups, most of the differences could be attributable to babies born at 30 weeks or less or weighing less than 1500 g, probably because of the higher incidence of surfactant deficiency in this more immature subgroup.

Walti 1995:

Conducted a randomized controlled trial to evaluate prophylactic versus selective surfactant treatment in infants born between 25 and 31 weeks gestational age. The primary outcome was the effect of prophylactic porcine surfactant on survival without BPD. Compared with rescue therapy (n = 122), prophylactic surfactant administration (n = 134) led to an increase in survival without BPD (60% versus 46%), decreased the incidence of severe intraventricular hemorrhage (3% versus 16%), decreased the incidence of ROP (2% versus 11%) and decreased the need for oxygenation and ventilator support within 3 to 72 hours.

Bevilacqua 1996:

Conducted a prospective, randomized, multicenter trial to evaluate the efficacy of modified porcine surfactant (Curosurf) administered at birth to prevent the development of RDS in preterm infants. Two hundred and eighty-seven infants with a gestational age of 24 to 30 weeks were randomized to prophylactic treatment with Curosurf (200 mg/kg) or to a control group receiving no surfactant treatment in the delivery room. Infants in both groups were eligible for rescue treatment with surfactant (200 mg/kg) if they developed clinical symptoms of RDS and required mechanical ventilation. The main endpoint was to obtain a 30% reduction in the incidence of grade 3 to 4 RDS. There was a 32% reduction in the incidence of grade 3 to 4 RDS in the prophylaxis group. This was associated with a significant reduction in mean maximum FiO2 (57% versus 66%), a decreased incidence of pulmonary interstitial emphysema (7% versus 14%) and a lowered mortality (21% versus 35%). Combined unfavorable outcome (mortality + BPD and/or grade 3 to 4 intraventricular hemorrhage and/or grade 2 to 4 ROP) was significantly lower in the prophylaxis than in the second group (41% versus 58%). The favorable effects of prophylactic treatment were noted in all the age groups, including the infants with the lowest gestational age (24 to 25 weeks).

Bevilacqua 1997:

Conducted a randomized controlled trial of prophylactic versus selective surfactant treatment to reduce mortality and incidence of 3 to 4 radiological grade RDS. Two neonatal intensive care units (NICU) in Italy, one NICU in Bulgaria and one NICU in Romania were involved in a randomized controlled clinical trial of prophylaxis versus rescue treatment of RDS. Infants with gestational age 26 to 30 weeks were randomized before birth to prophylaxis in the delivery room with 200 mg/kg of porcine surfactant (prophylaxis) or to routine assistance (control). Subsequently, infants developing RDS requiring mechanical ventilation and an FiO2 greater than/or equal to 0.4 to maintain PaO2 of 50 mmHg were allowed to be treated with poractant (Curosurf 200 mg/kg). A sample size of 174 infants was required to demonstrate a 40% reduction in mortality and the incidence of radiological grade 3 to 4 RDS. Due to logistic problems, the study was stopped after enrollment of 93 infants. Intention-to-treat analysis did not demonstrate a significant difference in mortality or radiological evidence of severe RDS. The PaO2/FiO2 ratio was significantly improved in the infants given prophylaxis for the first 12 hours of life versus the controls. Fewer infants given prophylaxis required subsequent rescue treatment compared with controls. There was no difference in other complications such as intraventricular hemorrhage, air leak syndromes and infections.

Iarŭkova 1999:

Conducted a single center randomized controlled trial to evaluate the effect of prophylactic surfactant versus selective surfactant on the incidence of RDS grades III and IV in infants born less than 32 weeks gestational age. The study was carried out in a specialized maternity hospital in Bulgaria. Infants were randomized before delivery to receive either prophylactic surfactant or therapeutic surfactant if indicated later. Infants in the prophylactic arm were intubated immediately after birth, before the first neonatal breath or within the first 20 minutes of life and received 200 mg/kg of Curosurf, followed by manual ventilation (via ambu bag) and then extubated or placed on mechanical ventilation (MV). Infants in the "therapeutic surfactant" arm received 200mg/kg of Curosurf if they need a FiO2 was > 40% to maintain a PaO2 > 50mmHg. In all infants, the FiO2 and the heart rate were monitored with pulse oximetry for two hours on the first day and then daily for the following four days and again at 28 days of life. A second dose of surfactant was administered to infants that required a FiO2 > 40% to maintain a PaO2 > 50 mmHg. Compared with rescue therapy (n = 11), prophylaxis (n = 17) showed a decreased risk in the RDS grades 3 and 4; 73% of infants in the control group required a second dose of surfactant compared with 12% in the prophylactic group (P < 0.05); duration on MV was lower in the prophylactic group as well as the duration with oxygen supplementation. No statistically significant differences were noted in other assessed outcomes such as pneumothorax, pulmonary interstitial emphysema, necrotizing enterocolitis (NEC) or sepsis.

Studies that routinely placed control infants on CPAP were: SUPPORT 2010 and Dunn 2011).

SUPPORT 2010:

Finer and coworkers conducted a multicenter randomized controlled trial as part of the Neonatal Research Network of the Eunice Kennedy Shriver National Institute of Child Heath and Human Development. Infants between 24 to 27 weeks of gestation at birth were randomized before delivery to receive: CPAP at birth or prophylactic surfactant within the first 60 minutes after birth followed by conventional ventilation in NICU. Subsequently, infants in the surfactant group were extubated after meeting all of the following criteria: PaCO2 < 50mmHg, pH >7.3; FiO2 < 0.35 and SpO2 of 88% or higher. Infants in the CPAP group were intubated if they met any of the following criteria: FiO2 > 0.5 required to have a SpO2 above 88% for one hour and partial pressure of PaCO2 greater than 67 mmHg. A sample size of 1310 infants was required to demonstrate a 10% reduction in the incidence of BPD and the rate of death or survival with neurodevelopmental impairment at 18 to 22 months.

After adjustment for gestational age, center or familial clustering, the rates of the combined outcome death or BPD at 36 weeks PMA did not differ significantly between the two groups. No differences were noted in death or BPD when analyzed independently. No interactions were evident between gestational age strata and treatment strategy with respect to BPD. More infants in the CPAP group than in the surfactant group were alive and free from the need for mechanical ventilation by day seven (P = 0.01), and infants in the CPAP group required fewer days of ventilation than did those in the surfactant group (P = 0.03). The rate of postnatal corticosteroids use was lower in the CPAP group. Secondary outcomes such as air leak syndrome, pneumothorax, NEC, PDA, severe intraventricular hemorrhage or severe ROP did not show significant differences between intervention groups.

Dunn 2011:

Dunn and coworkers conducted a multicenter randomized controlled trial in 27 centers of the Vermont Oxford Network (VON). Infants between 26 to 29 + 6 weeks gestation at birth were enrolled and randomly assigned to one of three study groups: prophylactic surfactant followed by a period of assisted ventilation (PS), intubation-surfactant treatment and rapid extubation to nasal CPAP (ISX) or early stabilization in nasal CPAP (NCPAP).The study was stopped before reaching the desired sample size (876) due to difficulties in the enrollment. A total of 648 infants were recruited in two randomization strata (26 to 27 + 6 weeks PMA and from 28 to 29 + 6 weeks PMA). No differences were seen in the primary outcome "death or CLD at 36 weeks PMA" between groups. The authors failed to identify differences in mortality or in other complications of preterm birth or in the composite outcome "death or major morbidity" perhaps because of the reduced power of this trial.

Follow-up was available from two of the studies. Vaucher 1993 followed the infants enrolled in the trial of Merritt 1991 at one year of age. Sinkin 1998 followed the infants born at one of the centers participating in the trial of Kendig 1991 at five to eight years.

Vaucher 1993:

Compared the neurodevelopmental outcome of infants enrolled in the trial of Merritt 1991. One hundred and forty-five infants were alive at one year of adjusted age, at which time growth, neurosensory, and neurologic outcome were similar in all three treatment groups at both centers. Cerebral palsy occurred in 20% overall. Five infants (3.5%) were functionally blind. However, infants treated at birth had lower mean mental and motor scores on the Bayley Scales of Infant Development compared with those of infants rescued with surfactant after the onset of RDS (Mental Development Index: 78 versus 96, P = 0.02; Psychomotor Development Index: 73 versus 87, P = 0.04).

Sinkin 1998:

Published pulmonary and neurodevelopmental outcomes of a cohort of infants enrolled in the Kendig 1991 trial. At 4.5 to eight years of age, all survivors from one of the three centers were located and 96% were evaluated. The follow-up test battery included a health assessment questionnaire, spirometry, 88% saturation test, neurologic examination, and the McCarthy Scales of Children's Abilities (MSCA) and the Conners' Parent Rating Scale-48. Educational achievement was determined by school class placement and teachers' reports of achievement. Of the 192 children originally enrolled, 154 survived. Evaluations were performed on 148 of these infants. An abnormal pulmonary history was found in 45 (30%) of the children: 16 (22%) in the prophylactic group and 29 (39%) in the rescue group. Formal pulmonary function was evaluated in 81 children; 29 (78%) in the prophylactic group and 33 (75%) in the rescue group were considered abnormal. No significant differences were found between the two groups on either cognitive or motor subscales of the MSCA, the Conners' Parent Rating Scale-48, the neurologic examination, the education services received in school, or the teacher ratings of below-average academic performance. Intelligence scores measured on the MSCA were low-normal for both groups. Some level of educational assistance was being provided to 72 (49%) of the cohort studied and both groups had below average educational performance and increased needs for educational assistance.

Summary:

Although all studies attempted to include infants thought to be at risk of developing RDS, the entry criteria differ between studies. Nine of the studies enrolled infants less than 30 weeks gestation. Kattwinkel 1993 studied infants with gestational age 29 to 32 weeks. The studies of Dunn 1991 and Merritt 1991 excluded infants with mature lung profiles. All studies attempted to exclude infants who had known major congenital anomalies. The studies of Dunn 1991, Merritt 1991, Egberts 1993, Walti 1995 and Bevilacqua 1997 excluded infants with prolonged ruptured membranes greater than two to three weeks.

In all of the studies, animal derived surfactant extracts were used. Dunn 1991, Kendig 1991 and Kattwinkel 1993 utilized surfactant obtained by calf lung lavage. SUPPORT 2010 and Dunn 2011 used animal derived surfactants.

Egberts 1993, Walti 1995, Bevilacqua 1996 and Bevilacqua 1997 all utilized the porcine surfactant Curosurf. Merritt 1991 utilized a surfactant obtained from human amniotic fluid.

Only the SUPPORT 2010 and Dunn 2011 trials routinely stabilized infants in the selective surfactant group on NCPAP.

Study primary outcomes included the incidence of RDS or the need of mechanical ventilation, CLD, composite outcomes such as death or BPD and death or CLD. As secondary outcomes, a variety of complications of preterm birth including pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, NEC, intraventricular hemorrhage and ROP were assessed in the majority of trials.

Studies excluded from this review:

Trials where the administration of surfactant was given early after birth (within the first 30 minutes of infants' life), but only to those infants with evidence of RDS, were classified as "early surfactant" and not as "prophylactic", therefore, excluding them from this review. Trials were excluded when the comparison group was assigned to "early surfactant" instead of selective administration of surfactant.

Morley 2008

Conducted an international multicenter randomized controlled trial, in perinatal centers of Australia, New Zealand, United States, Canada and Europe. Infants were enrolled in the study if they met the following criteria: gestational age at delivery between 25 weeks zero days and 28 weeks six days, no known condition that might adversely affect breathing after birth apart from prematurity, birth in a hospital participating in the trial, and an ability to breathe at five minutes after birth but needing respiratory support because of increased respiratory effort, grunting respiration, or cyanosis. Infants were randomly assigned to receive either NCPAP or intubation and ventilation. Randomization was stratified according to center and gestational age (25 or 26 weeks and 27 or 28 weeks). The primary outcome was death or BPD (defined as the need for oxygen treatment at 36 weeks gestational age). The trial was excluded from this review because the trial did not give "prophylactic" treatment to all infants in a high-risk group, but selected those infants who neither needed acute resuscitation or had no signs of RDS. In the remaining infants, surfactant treatment was not mandated and followed local protocols.

Rojas 2009

Conducted a multicenter randomized controlled trial in eight neonatal intensive care units from eight centers in Colombia. Infants born between 27 and 31weeks’ gestation with evidence of RDS and treated with supplemental oxygen in the delivery room were randomly assigned within the first hour of life to intubation, very early surfactant, extubation, and NCPAP (treatment group) or NCPAP alone (control group). Infants in the control group who met treatment-failure criteria subsequently received an initial dose of surfactant in a standardized manner (selective use of surfactant). A total of 279 infants were randomly assigned, in two randomization strata (27 to 29 weeks PMA and from 30 to 31 weeks PMA), 141 to the treatment group and 138 to the control group. The need for mechanical ventilation was lower in the treatment group (26%) compared with the control group (39%). Air-leak syndrome occurred less frequently in the treatment group (2%) compared with the control group (9%). The incidence of CLD (oxygen treatment at 36 weeks’ postmenstrual age) was 49% in the treatment group compared with 59% in the control group. All other outcomes, including mortality, intraventricular hemorrhage, and periventricular leukomalacia were similar between the groups. This trial was excluded from this review because the treatment group received surfactant as "very early surfactant" once first RDS signs appeared instead of prophylactic administration of surfactant.

Sandri 2010

Conducted an international multicenter randomized controlled trial in centers in Europe. Infants between 25 to 28 + 6 weeks gestation at birth were enrolled and randomly assigned to one of two study groups: prophylactic surfactant intubation-surfactant treatment and rapid extubation to NCPAP or NCPAP alone. In the event of NCPAP failure and after obtaining a chest radiograph, early selective surfactant was administered (Curosurf 200 mg/kg). A total of 208 infants were recruited in two randomization strata (25 to 26 weeks PMA and from 27 to 28 weeks PMA). No differences were seen in the primary outcome "need of mechanical ventilation within the first 5 days of life". There were no differences in mortality or in other complications of prematurity or CLD. Results of this trial showed that in spontaneously breathing preterm newborns who were treated with NCPAP, prophylactic surfactant was not superior to early selective surfactant in terms of requirement of mechanical ventilation in the first five days of life. This trial was excluded from this review because the comparison group received surfactant as "early surfactant" instead of selective administration of surfactant.

Risk of bias in included studies

Only randomized controlled trials which compared the effects of prophylactic surfactant administration (surfactant given down the endotracheal tube prior to the first breath or immediately after intubation or stabilization) to surfactant treatment of established RDS in preterm infants were included in the analysis. Specific methodologic issues are discussed below.

Allocation concealment:
All included studies allocated assigned treatment by randomization. In all 11 studies, sealed envelopes with randomly allocated treatment assignments were provided to participating centers.

Blinding of outcome assessment:
The degree of blinding of outcome assessment is variable between the studies. Only in the study of Merritt 1991 was the assessment of outcome completely blinded. Other studies included blinding only of radiologic evaluation and developmental follow-up.

Incomplete data addressed:
Minimal exclusions were noted after randomization. Merritt 1991 reported an intention-to-treat analysis of certain major outcomes, but reported only those infants with proven lung immaturity for a variety of other complications of preterm birth. (Only data from the intention-to-treat analysis are used in this review.) Walti 1995 excluded 11% of infants originally enrolled. A number of infants from the study of Kattwinkel 1993 were not included because one center was dropped due to a high incidence of protocol deviations.

Effects of interventions

The results of eleven trials identified that met inclusion criteria (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Bevilacqua 1996; Bevilacqua 1997; Walti 1995; Iarŭkova 1999; SUPPORT 2010; Dunn 2011) are discussed in detail below.

Only the SUPPORT 2010 and Dunn 2011 trials routinely stabilized infants in the selective surfactant group on NCPAP.

Studies that compared the effect of prophylactic surfactant administration with surfactant treatment of established respiratory distress in preterm infants (Comparison 1)

Primary outcomes
1.1 Neonatal mortality

Ten studies (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; SUPPORT 2010; Dunn 2011) reported on neonatal mortality.

1.1.1. Neonatal mortality in studies without routine application of continuous positive airway pressure to control infants

Eight studies that did not routinely place control infants on continuous positive airway pressure (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997) reported on neonatal mortality. The trials of Kendig 1991, Kattwinkel 1993 and Bevilacqua 1996 noted a significant decrease in neonatal mortality associated with prophylactic surfactant administration.

Meta-analysis of studies that did not routinely place control infants on CPAP demonstrated a significant decrease in the risk of neonatal mortality associated with the use prophylactic surfactant [8 trials, 2761 infants; typical risk ratio (RR) 0.69, 95% confidence interval (CI) 0.56 to 0.85 (I2 34%); typical risk difference (RD) -0.04, 95% CI -0.06 to -0.02; number needed to treat to benefit (NNTB) 20, 95%CI 10 to 100].

1.1.2. Neonatal mortality in studies with routine application of continuous positive airway pressure to control infants

Two studies routinely placed control infants on CPAP (SUPPORT 2010; Dunn 2011). Neither trial reported a significant effect of prophylactic surfactant on neonatal mortality. Meta-analysis of these two studies, demonstrated a concerning trend towards an increase in the risk of neonatal mortality associated with the use prophylactic surfactant when compared with early stabilization on CPAP with selective use of surfactant in infants with respiratory failure [2 trials, 1746 infants; typical RR 1.24, 95% CI 0.97 to 1.58, (I² 0%); typical RD 0.03, 95% CI -0.00 to 0.06; (I² 0%)]

Combined analysis for neonatal mortality

Meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP did not demonstrate a significant decrease in the risk of neonatal mortality associated with the use prophylactic surfactant [10 trials, 4507 infants; typical RR 0.89, 95%CI 0.76 to 1.04 (I² 59%); typical RD -0.01, 95% CI -0.03 to 0.00 (I² 56%)]. Moderate heterogeneity was noted.

1.2 Mortality at 36 weeks PMA or prior to hospital discharge

Five studies (Kendig 1991; Merritt 1991; Egberts 1993; Walti 1995; Dunn 2011) studies reported on mortality at 36 weeks PMA or prior to discharge.

1.2.1. Mortality at 36 weeks PMA in studies without routine application of continuous positive airway pressure to control infants

Four studies (Kendig 1991; Merritt 1991; Egberts 1993; Walti 1995) did not routinely place control infants on CPAP. Kendig 1991 and Walti 1995 reported a significant decrease in the risk of mortality at 36 weeks PMA with the use of prophylactic surfactant; Egberts 1993 showed a nonstatistically significant reduction on the risk of mortality, but Merritt 1991 reported a nonstatistically significant increasing in the risk of mortality at 36 weeks PMA in the prophylactic surfactant group.

Meta-analysis of these studies demonstrated a significant decrease in the risk of neonatal mortality associated with the use prophylactic surfactant [4 trials, 1030 infants; typical RR 0.72, 95% CI 0.56 to 0.93; I² 53%; typical RD -0.06, 95% CI -0.11 to -0.02 (I² 13%); NNT 17, 95% CI 9 to 50]. Moderate heterogeneity was noted.

1.2.2. Mortality at 36 weeks PMA in studies with routine application of continuous positive airway pressure to control infants

Dunn 2011 was the only study that routinely placed control infants on CPAP that reported on mortality at 36 weeks PMA. This study did not find a statistically significant difference on 36 weeks PMA mortality between surfactant treatment groups [1 trial, 428 infants, RR 1.76, 95% CI 0.79 to 3.94; RD 0.03, 95% CI -0.01 to 0.08]. Test for heterogeneity not applicable.

Combined analysis for mortality at 36 weeks PMA

Meta-analysis that included all studies regardless of whether or not control infants were routinely placed on positive airway pressure showed a decrease in the risk of mortality at 36 weeks PMA associated with the use prophylactic surfactant, that was of borderline statistical significance [5 trials, 1458 infants; typical RR 0.79, 95% CI 0.63 to 1.00 (I² 61%); typical RD -0.04, 95% CI -0.07 to 0.00 (I² 72%)]. Substantial heterogeneity was noted.

1.3. Bronchopulmonary dysplasia (oxygen requirement at 28 to 30 days of age)

Ten studies (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; Iarŭkova 1999; Dunn 2011) reported on BPD at 28 to 30 days of age.

1.3.1. Bronchopulmonary dysplasia in studies without routine application of continuous positive airway pressure to control infants

Studies reporting on BPD at 28 to 30 days of age that did not routinely place control infants on CPAP were Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; Iarŭkova 1999. All of them, with the exception of Dunn 1991, reported no statistically significant difference in the risk of BPD associated with the strategy of surfactant administration.

Meta-analysis of these nine studies that did not routinely place control infants on CPAP did not demonstrate a significant difference on the risk of BPD between prophylactic or selective surfactant administration [9 trials, 2789 infants; typical RR 0.95, 95% CI 0.81 to 1.11 (I² = 40%); typical RD -0.01, 95% CI -0.03 to 0.02 (I² = 37%)]. Moderate heterogeneity was noted.

1.3.2. Bronchopulmonary dysplasia in studies with routine application of continuous positive airway pressure to control infants

Dunn 2011 was the only study with routine application of CPAP that reported on this outcome and reported a concerning trend towards increased risk of BPD with the prophylactic administration of surfactant [1 trial, 402 infants, RR 1.16, 95% CI 0.99 to 1.36; RD 0.09, 95% CI -0.01 to 0.18]. Test for heterogeneity not applicable.

Combined analysis for bronchopulmonary dysplasia

Meta-analysis that included all studies regardless of whether or not control infants were routinely placed on CPAP revealed no differences between groups of surfactant treatment in the risk of BPD [10 trials, 3191 infants; typical RR 1.02, 95% CI 0.91 to 1.14 (I² = 45%); typical RD 0.00, 95% CI -0.02 to 0.03 (I² = 52%)]. Moderate heterogeneity was noted.

1.4. Bronchopulmonary dysplasia or death prior to 28 to 30 days of age

Eight studies (Dunn 1991; Kendig 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; Dunn 2011) reported on the combined outcome of BPD or death at 28 days.

1.4.1. Studies without routine application of continuous positive airway pressure to control infants

Seven trials (Dunn 1991; Kendig 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997) that did not routinely place control infants on CPAP reported on BPD or death at 28 days. Kattwinkel 1993, Walti 1995 and Bevilacqua 1996 reported a significant reduction in the risk of BPD or death in association with the prophylactic surfactant administration. Dunn 1991 reported a significant increase in the risk of BPD or death in the prophylactic administration group. All others did not find statistically significant differences between treatment groups on this outcome.

Meta-analysis of these trials revealed a trend towards a decreasing risk of BPD or death at 28 days with the prophylactic surfactant administration [7 trials; 2613 infants; typical RR 0.82, 95% CI 0.73 to 0.92 (I² = 72%); typical RD -0.05, 95% CI -0.08 to -0.02 (I² = 71%)]. Substantial heterogeneity was noted.

1.4.2. Studies with routine application of continuous positive airway pressure to control infants

Dunn 2011 was the only study with routine application of CPAP that reported on this outcome. Dunn 2011 reported a nonstatistically significant increase on the risk of BPD with the prophylactic administration of surfactant when compared with early stabilization on CPAP with selective use of surfactant in infants with respiratory failure (1 trial, 420 infants; RR 1.12, 95% CI 0.96 to 1.31; RD 0.07, 95%CI -0.02 to 0.16). Test for heterogeneity not applicable.

Combined analysis for bronchopulmonary dysplasia or death prior to 28 to 30 days of age

Meta-analysis including all studies regardless of whether or not control infants were routinely placed on CPAP showed a nonstatistically significant trend towards decreasing risk of BPD or death with the prophylactic administration of surfactant [8 trials; 3033 infants; typical RR 0.89, 95% CI 0.81 to 0.98 (I² = 77%); typical RD -0.04, 95% CI -0.06 to -0.01 (I² = 73%)]. Substantial heterogeneity was noted.

1.5 Chronic lung disease (use of supplemental oxygen at 36 weeks postmenstrual age)

Only six studies (Dunn 1991; Egberts 1993; Walti 1995; Bevilacqua 1997; SUPPORT 2010; Dunn 2011) reported on CLD at 36 weeks postmenstrual age.

1.5.1. CLD in studies without routine application of continuous positive airway pressure to control infants

The studies of Dunn 1991; Egberts 1993; Walti 1995; Bevilacqua 1997 did not routinely place control infants on CPAP. All these trials reported a nonstatistically significant increase in the risk of CLD with prophylactic surfactant administration. The meta-analysis of these studies does not demonstrate differences on the risk of CLD between treatment prophylactic and selective administration of surfactant [4 trials; 558 infants; typical RR 1.30, 95% CI 0.77 to 2.17 (I² = 0%); typical RD 0.02, 95% CI -0.02 to 0.07 (I² = 0%)]. No heterogeneity was noted.

1.5.2. CLD in studies with routine application of continuous positive airway pressure to control infants

SUPPORT 2010 and Dunn 2011 reported an increased risk of CLD with the prophylaxis administration of surfactant when compared with selective use of surfactant in infants with respiratory failure early stabilized on CPAP. The meta-analysis of these studies revealed a trend towards an increasing risk of CLD with the prophylactic administration in comparison with the selective administration in infants early placed on CPAP [2 trials; 1512 infants; typical RR 1.12, 95% CI 0.99 to 1.26 (I² = 0%); typical RD 0.04, 95% CI -0.00 to 0.09 (I² = 0%)]. No heterogeneity was noted.

Combined analysis for chronic lung disease

Meta-analysis including all studies regardless of whether or not control infants were routinely placed on CPAP showed a trend towards increased risk of CLD with the use of prophylactic surfactant [6 trials; 2070 infants; typical RR 1.13, 95% CI 1.00 to 1.28 (I² = 0%); typical RD 0.04, 95%CI 0.00 to 0.08 (I²=0%)]. No heterogeneity was noted.

1.6. Chronic lung disease or death (use of supplemental oxygen or death at 36 weeks postmenstrual age)

Only three studies reported information for the combined outcome CLD or death (SUPPORT 2010; Dunn 2011; Dunn 1991).

1.6.1. CLD or death in studies without routine application of continuous positive airway pressure to control infants.

Dunn 1991 did not routinely place control infants on CPAP. Dunn 1991 did not demonstrate a statistically significant difference in the risk of combined outcome CLD or death, between surfactant administration groups [1 trial, 122 infants; RR 1.29, 95% CI 0.67 to 2.49; RD 0.06, 95%CI -0.09 to 0.21]. Test for heterogeneity not applicable.

1.6.2. CLD or death in studies with routine application of continuous positive airway pressure to control infants

Both trials (SUPPORT 2010, Dunn 2011) with routine application of CPAP reported a concerning trend towards increased risk of CLD or death in the prophylactic surfactant administration group. Meta-analysis of this two studies demonstrated a significant increase in the risk of CLD or death with the prophylaxis administration of surfactant when compared to selective use of surfactant in infants with respiratory failure early stabilized on CPAP [2 trials; 1744 infants; typical RR 1.12, 95% CI 1.02 to 1.24; (I² = 0%); typical RD 0.06, 95%CI 0.01 to 0.10, (I² = 0%); number needed to harm (NNTH) 17 95% CI 10 to 100]. No heterogeneity was noted.

Combined analysis for chronic lung disease or death

The general meta-analysis including all studies, regardless of whether or not control infants were routinely placed on CPAP, demonstrated an increased risk in the combined outcome CLD or death related to the prophylactic surfactant use when compared with selective use of surfactant in infants with respiratory failure early stabilized on CPAP [3 trials; 1866 infants; typical RR 1.13, CI 95% 1.02 to 1.25; (I²= 0%); typical RD 0.06, 95% CI 0.01 to 0.10, (I² = 0%); NNTH 17 95%CI 10 to 100]. No heterogeneity was noted.

Secondary Outcomes
1.7. Any air leak (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum)

Nine studies (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; SUPPORT 2010) reported on any air leak.

1.7.1. Air leak in studies without routine application of continuous positive airway pressure to control infants

Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996 and Bevilacqua 1997 did not routinely place control infants on CPAP. Results from these trials varied widely; Kendig 1991; Walti 1995 and Bevilacqua 1996 found a significant decrease in the risk of air leak with the use of prophylactic surfactant, but Merritt 1991 found an increased risk of air leak in the group treated with prophylactic surfactant. All other trials did not identify statistically significant differences between groups on this outcome.

The meta-analysis of these studies, showed a significant decrease in the risk of any air leak with the use of prophylactic surfactant [8 trials; 2760 infants; typical RR 0.79, 95% CI 0.63 to 0.98 (I² = 60%); typical RD -0.02, 95% CI -0.04 to -0.00 (I² = 67%)]. Substantial heterogeneity was noted.

1.7.2. Air leak in studies with routine application of continuous positive airway pressure to control infants

Only SUPPORT 2010 reported on air leak and did not find a statistically significant difference on the risk of air leak between prophylactic administration of surfactant group and selective administration of surfactant in infants with respiratory failure early stabilized on CPAP group [1 trial, 1316 infants; RR 1.08, 95% CI 0.73 to 1.60; RD 0.01, 95% CI -0.02 to 0.03]. Test for heterogeneity not applicable.

Combined analysis for air leak

The meta-analysis including all studies regardless of whether or not control infants were routinely placed on CPAP revealed a trend towards a decreased risk of air leak with the prophylactic surfactant administration [9 trials; 4076 infants; typical RR 0.86, 95% CI 0.71 to 1.04 ( I² = 58%); typical RD 0.01, 95% CI -0.03 to 0.00]. Moderate heterogeneity was noted.

1.8 Pneumothorax

Eight studies (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Dunn 2011) reported on pneumothorax.

1.8.1. Pneumothorax in studies without routine application of continuous positive airway pressure to control infants

Dunn 1991; Kendig 1991; Egberts 1993; Kattwinkel 1993; Walti 1995 and Bevilacqua 1996 did not routinely place control infants on CPAP. Kendig 1991 noted a decrease in the risk of pneumothorax associated with prophylactic surfactant administration that was of borderline statistical significance (479 infants; RR 0.57, 95% CI 0.32 to 1.03). All other studies did not find statistically significant differences between both surfactant administration strategies.

The meta-analysis of these trials suggested a trend towards a decreasing risk of pneumothorax with the use of prophylactic surfactant in comparison with selective administration of surfactant in infants with respiratory failure, the estimation was borderline statistical significance [7 trials; 2663 infants; typical RR 0.75, 95% CI 0.53 to 1.05 (I² = 23%); typical RD -0.01, 95% CI -0.03 to 0.00 (I² = 38%)]. No important heterogeneity was noted.

1.8.2. Pneumothorax in studies with routine application of continuous positive airway pressure to control infants

Only Dunn 2011 reported on this outcome, and did not find a statistically significant difference on the risk of pneumothorax between treatment groups [one trial, 431 infants; RR 0.89, 95% CI 0.39 to 2.01; RD -0.01, 95% CI -0.05 to 0.04]. Test for heterogeneity not applicable.

Combined analysis for pneumothorax

The general meta-analysis including all studies regardless of whether or not control infants were routinely placed on CPAP reveals a trend towards a decreasing risk of pneumothorax with the prophylactic surfactant administration, however, the estimation is borderline statistical significance [8 trials; 3094 infants; typical RR 0.76, 95% CI 0.56 to 1.04 (I² = 12%); typical RD -0.01, 95% CI -0.03 to 0.00 (I² = 26%)]. No important heterogeneity was noted.

1.9. Pulmonary Interstitial Emphysema

Six studies (Dunn 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997) reported on the risk of pulmonary interstitial emphysema. All of these trials did not routinely place control infants on CPAP. Bevilacqua 1996 noted a decrease in the risk of pulmonary interstitial emphysema associated with prophylactic surfactant administration [268 infants; typical RR 0.46, 95% CI 0.22 to 0.98; RD -0.08, 95% CI -0.15 to -0.00].

The meta-analysis of these trials showed a trend towards increased risk of pulmonary interstitial emphysema with prophylactic surfactant, the estimation is borderline statistical significance [6 trials; 2185 infants; typical RR 0.73, 95% CI 0.53 to 1.02 (I² = 43%); typical RD -0.02, 95% CI -0.04 to 0.00 (I² = 43%)]. Moderate heterogeneity was noted.

Any of the studies that routinely place control infants on CPAP, reported on this outcome.

10. Any pulmonary hemorrhage

Four studies (Kattwinkel 1993; Walti 1995; Bevilacqua 1997; Dunn 2011) reported on pulmonary hemorrhage.

1.10.1. Pulmonary hemorrhage in studies without routine application of continuous positive airway pressure to control infants

Kattwinkel 1993; Walti 1995 and Bevilacqua 1997 did not routinely placed control infants on CPAP. None of the three trials reported a significant effect of prophylactic surfactant on the risk of pulmonary hemorrhage. The meta-analysis of these three trials shows a nonstatistically significant reduction in the risk of pulmonary hemorrhage with the prophylactic surfactant administration [3 trials; 1592 infants; typical RR 0.73, 95% CI 0.28 to 1.87 (I² = 2%); typical RD 0.00, 95% CI -0.01 to 0.01 (I² = 0%)]. No heterogeneity was noted.

1.10.2. Pulmonary hemorrhage in studies with routine application of continuous positive airway pressure to control infants

Only Dunn 2011 reported on this outcome, and found a nonstatistically significant increase on the risk of air leak in the prophylactic surfactant group [1 trial, 431 infants; RR 2.12, 95% CI 0.54 to 8.39; RD 0.02, 95% CI -0.01 to 0.04]. Test for heterogeneity not applicable.

Combined analysis for pulmonary hemorrhage

The meta-analysis including all studies regardless of whether or not control infants were routinely placed on CPAP, did not show any significant difference in the risk of pulmonary hemorrhage with between prophylactic versus selective administration of surfactant [4 trials, 2023 infants; typical RR 1.05, 95% CI 0.49 to 2.22 (I² = 10%); typical RD 0.00, 95% CI -0.01 to 0.01 (I² = 29%)]. No important heterogeneity was noted.

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

Eight of the randomized control trials (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Dunn 2011 ) reported on the incidence of patent ductus arteriosus.

1.11.1. Patent ductus arteriosus in studies without routine application of continuous positive airway pressure to control infants

Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993;Kattwinkel 1993; Walti 1995 and Bevilacqua 1996 did not routinely place control infants on CPAP. Kattwinkel 1993, reported a small decrease in the incidence of patent ductus arteriosus associated with prophylactic administration of surfactant [1248 infants; RR 0.81, 95% CI 0.66 to 0.99; typical RD -0.05, 95% CI -0.10 to 0.00]. All other trials did not find statistically significant differences between prophylaxis or selective administration of surfactant on this outcome.

The meta-analysis of trials that did not routinely place control infants on CPAP, supported no differences in the risk of patent ductus arteriosus between groups [7 trials; 2663 infants; typical RR 0.98, 95% CI 0.88 to 1.10 (I² = 42%); typical RD -0.01, 95% CI -0.04 to 0.03 (I² = 41%)]. Moderate heterogeneity was noted.

1.11.2. Patent ductus arteriosus in studies with routine application of continuous positive airway pressure to control infants

Only Dunn 2011 reported on this outcome.No statistically significant effect on the risk of patent ductus arteriosus was noted between prophylactic or selective administration strategies [1 trial, 430 infants; RR 0.97, 95% CI 0.79 to 1.20; RD -0.01, 95% CI -0.11 to 0.08]. Test for heterogeneity not applicable.

Combined analysis for patent ductus arteriosus

Meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP did not demonstrate a significant difference in the risk of patent ductus arteriosus between prophylactic surfactant administration and selective administration when infants presented respiratory failure [8 trials, 3093 infants; typical RR 0.98, 95% CI 0.89 to 1.08 (I² = 33%); typical RD 0.01, 95% CI -0.04 to 0.03 (I²=31%)]. Moderate heterogeneity was noted.

1.12. Any culture proven bacterial sepsis

Six studies (Merritt 1991; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; Dunn 2011) reported proven bacterial sepsis.

1.12.1. Bacterial sepsis in studies without routine application of continuous positive airway pressure to control infants

Merritt 1991; Kattwinkel 1993; Walti 1995; Bevilacqua 1996 and Bevilacqua 1997 are in this subgroup. Walti 1995 found significant reduction in the risk of sepsis with the use of prophylactic surfactant [256 infants; RR 0.10, 95% CI 0.03, 0.33 ]. The meta-analysis of these studies demonstrated a significant decrease in the risk of proven bacterial sepsis with the use of prophylactic surfactant [5 trials; 2013 infants; typical RR 0.68, 95% CI 0.51 to 0.92 (I² = 74%); typical RD -0.03, 95% CI -0.05 to 0.01 (I² = 86%)]. However substantial heterogeneity was present. This cannot be easily explained based on differences in clinical population, intervention or trial methodology.

1.12.2. Bacterial sepsis in studies with routine application of continuous positive airway pressure to control infants

Dunn 2011 was the only study with routine application of CPAP that reported on sepsis. Results showed a concerning trend towards increased risk of bacterial sepsis associated with prophylactic surfactant administration when compared with selective administration of surfactant in infants early stabilized on CPAP [1 trial, 425 infants; RR 1.70, 95% CI 0.96 to 3.03; RD 0.05, 95% CI -0.00 to 0.11]. Test for heterogeneity not applicable.

Combined analysis for bacterial sepsis

The general meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP was not conclusive about differences between prophylactic or selective administration strategies, however, it revealed a trend towards a decreasing risk of proven bacterial sepsis with the prophylactic administration of surfactant [6 studies; 2438 infants; typical RR 0.83, 95% CI 0.64 to 1.08 (I² = 76%); typical RD -0.02, 95% CI -0.04 to 0.01 (I² = 84%)]. Substantial heterogeneity was noted.

1.12.4. Any culture proven fungal sepsis

Dunn 2011 study was the only trial reporting fungal sepsis. Results did not show any statistically significant difference between treatment groups.

1.13. Necrotizing enterocolitis (NEC defined as Bell Stage II or greater)

Eight studies (Dunn 1991; Kendig 1991; Merritt 1991; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; SUPPORT 2010; Dunn 2011) reported on the risk of NEC.

1.13.1. NEC in studies without routine application of continuous positive airway pressure to control infants

Dunn 1991; Kendig 1991; Merritt 1991 ; Kattwinkel 1993; Walti 1995 and Bevilacqua 1996 are the trials in this subgroup that reported on NEC. None of these trials reported a significant effect of prophylactic surfactant on the incidence of NEC. Meta-analysis of these studies did not support any difference in the risk of NEC, with the prophylactic or selective administration of surfactant [6 trials; 2516 infants; typical RR 1.05, 95% CI 0.76 to 1.44 (I² = 0%); typical RD 0.00, 95% CI -0.02 to 0.02 (I² = 0%)]. No heterogeneity was noted.

1.13.2. NEC in studies with routine application of continuous positive airway pressure to control infants

SUPPORT 2010 and Dunn 2011 routinely placed control infants on CPAP. Neither trial reported a significant effect of prophylactic surfactant on NEC. Meta-analysis of these two studies, revealed a trend towards an increasing risk of NEC associated with the use prophylactic surfactant when compared with selective use of surfactant in infants with respiratory failure stabilized on CPAP (2 trials, 1721 infants; typical RR 0.79, 95% CI 0.60 to 1.04 (I² = 0%); typical RD -0.02, 95% CI -0.05 to 0.00 (I² = 0%)]. No heterogeneity was present.

Combined analysis for necrotizing enterocolitis

Meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP did not demonstrate a significant decrease in the risk of NEC associated with the use prophylactic surfactant [8 trials, 4237 infants; typical RR 0.90, 95% CI 0.73 to 1.10 (I² = 0%); typical RD -0.01, 95% CI -0.02 to 0.01 (I² = 0%)]. No heterogeneity was present.

1.14. Intraventricular hemorrhage (IVH Any Grade)

Ten of the included studies (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; Iarŭkova 1999 and Dunn 2011) reported on the incidence of intraventricular hemorrhage.

1.14.1. IVH in studies without routine application of continuous positive airway pressure to control infants

Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997 and Iarŭkova 1999 did not routinely place control infants on CPAP. Walti 1995 reported a significant reduction in the risk of IVH associated with prophylactic administration of surfactant [245 infants; RR 0.73, 95% CI 0.62 to 0.86]. Bevilacqua 1996 reported a decrease in the risk of IVH with prophylactic surfactant administration, but this estimation showed borderline statistical significance (268 infants; RR 0.78, 95% CI 0.60 to 1.00). None of the other trials reported a significant effect of prophylactic surfactant on IVH.

Meta-analysis of these studies, revealed a marginal decrease in the risk of IVH associated with the prophylactic surfactant administration [9 trials; 2684 infants; typical RR 0.89, 95% CI 0.81 to 0.99 (I² = 39%); typical RD -0.04, 95% CI -0.07 to -0.00 (I² = 61%)]. Substantial heterogeneity was noted.

1.14.2. IVH in studies with routine application of continuous positive airway pressure to control infants

Dunn 2011 was the only study with routine application of CPAP that reported on any grade of IVH. Results did not show any significant difference on the risk of IVH between prophylactic surfactant administration and selective use of surfactant in infants early stabilized on CPAP [1 trial, 421 infants; RR 1.05, 95% CI 0.73 to 1.50; RD 0.01, 95% CI -0.07 to 0.09]. Test for heterogeneity not applicable.

Combined analysis for intraventricular hemorrhage (IVH any grade)

Meta-analysis that included all studies regardless of whether or not control infants were routinely placed on CPAP showed a trend towards decreased risk of IVH associated with the use prophylactic surfactant when compared with early stabilization on CPAP with selective use of surfactant in infants with respiratory failure [10 trials; 3105 infants; typical RR 0.91, 95% CI 0.82 to 1.00; (I² = 38%); typical RD -0.03, 95% CI -0.06 to -0.00 (I² = 58%)]. Substantial heterogeneity was noted.

1.15. Severe Intraventricular hemorrhage (grades 3 and 4 IVH)

Ten trials (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; SUPPORT 2010; Dunn 2011) reported severe IVH grades 3 and 4.

1.15.1. Severe IVH in studies without routine application of continuous positive airway pressure to control infants

Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995; Bevilacqua 1996 and Bevilacqua 1997 did not routinely place control infants on CPAP. Walti 1995 reported a significant reduction in the risk of severe IVH associated with prophylactic surfactant administration [245 infants; RR 0.19, 95% CI 0.07 to 0.54; RD -0.13, 95% CI -0.21 to -0.06]. The other trials reported a significant effect of prophylactic surfactant on severe IVH.

Meta-analysis of these studies, suggested that prophylactic surfactant may reduce the risk of IVH, however, the estimation was borderline statistical significance and moderate heterogeneity was noted [8 trials; 2656 infants; typical RR 0.87, 95% CI 0.70 to 1.08 (I² = 46%); RD -0.01 95% CI -0.04 to 0.01 (I² = 60%)]. Substantial heterogeneity was noted.

1.15.2. Severe IVH in studies with routine application of continuous positive airway pressure to control infants

SUPPORT 2010 and Dunn 2011 routinely placed control infants on CPAP. SUPPORT 2010 reported a nonstatistically significant decreased IVH with prophylactic surfactant administration in comparison with selective administration of surfactant in infants early stabilized on CPAP [1260 infants; RR 0.80, 95% CI 0.60 to 1.07]. Dunn 2011 reported a nonstatistically significant increase the risk of severe IVH with the prophylactic surfactant administration [421 infants; RR 2.15, 95%CI 0.82 to 5.62].

Meta-analysis of these studies, suggested a concerning trend towards decreasing IVH with prophylactic surfactant administration compared with early stabilization on CPAP with selective use of surfactant, important heterogeneity is noted [2 trials; 1691 infants; typical RR 0.88, 95% CI 0.67 to 1.16 (I² = 73%); typical RD -0.01, 95% CI -0.04 to 0.02 (I² = 83%)]. Substantial heterogeneity was noted.

Combined analysis for severe intraventricular hemorrhage

General meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP revealed a trend towards decreased risk of IVH with prophylactic surfactant administration in comparison with selective administration of surfactant. Estimation was borderline statistical significance and moderate heterogeneity was noted [10 trials; 4347 infants; typical RR 0.87, 95% CI 0.74 to 1.04 (I² = 46%); typical RD -0.01, 95% CI -0.03 to 0.00 (I² = 61%)]. Substantial heterogeneity was noted.

1.16. Retinopathy of prematurity (ROP)

Seven studies (Dunn 1991; Merritt 1991; Kattwinkel 1993; Walti 1995; Bevilacqua 1996; SUPPORT 2010; Dunn 2011) reported on the incidence of all stages retinopathy (only in survivors).

1.16.1. ROP in studies that without routine application of continuous positive airway pressure to control infants

Dunn 1991; Merritt 1991; Kattwinkel 1993; Walti 1995 and Bevilacqua 1996 did not routinely place control infants on CPAP. None of these trials reported a significant effect of prophylactic surfactant on the incidence of ROP. Results from meta-analysis did not demonstrate a significant increase in the risk of ROP associated with the use prophylactic surfactant. Important heterogeneity was noted [5 trials; 2042 infants; typical RR 1.34, 95% CI 0.92 to 1.94 (I² = 66%); typical RD 0.01, 95% CI -0.00 to 0.03 (I² = 74%)]. Substantial heterogeneity was noted.

1.16.2. ROP in studies with routine application of continuous positive airway pressure to control infants

SUPPORT 2010 and Dunn 2011 routinely place control infants on CPAP and reported on this outcome. The meta-analysis of these trials did not support any significant effect of surfactant administration of the risk of ROP compared with selective use of surfactant in infants early stabilized on CPAP [2 trials; 1359 infants; typical RR 0.91, 95% CI 0.75 to 1.11 (I² = 42%); typical RD -0.02, 95% CI -0.06 to 0.02 (I² = 69%)]. Modetare to substantial heterogeneity was noted.

Combined analysis for retinopathy of prematurity

General meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP did not demonstrate a significant increase in the risk of ROP associated with the use prophylactic surfactant administration. Important heterogeneity was noted [7 trials, 3401 infants; typical RR 1.01, 95% CI 0.85 to 1.20 (I² = 66%); typical RD 0.00, 95% CI -0.02 to 0.02 (I² = 70%)]. Substantial heterogeneity was noted.

1.17. Retinopathy of prematurity stages 2 or greater

Five trials (Dunn 1991; Kattwinkel 1993; Bevilacqua 1996; SUPPORT 2010; Dunn 2011) reported on ROP stages 3 or greater.

1.17.1. ROP Stages 2 or greater in studies without routine application of continuous positive airway pressure to control infants

Dunn 1991; Kattwinkel 1993 and Bevilacqua 1996 were the trials that did not routinely place control infants on CPAP reported on this outcome. None of these trials reported a significant effect of prophylactic surfactant on ROP stages 2 or greater. The meta-analysis of these trials did not support any significant effect of prophylactic surfactant on the incidence of ROP stages 2 or more [3 trials;1379 infants; typical RR 0.97, 95% CI 0.46 to 2.04 (I² = 0%); typical RD -0.00, 95% CI -0.01 to 0.01 (I² = 0%)]. No heterogeneity was present.

1.17.2. ROP Stages 2-4 in studies with routine application of continuous positive airway pressure to control infants

SUPPORT 2010 and Dunn 2011 reported on ROP stages 2 or more. Neither trial reported a significant effect of prophylactic surfactant on ROP stages 2 or greater. The meta-analysis of these trials did not support any significant differences in the risk of stage 2-4 retinopathy between prophylactic surfactant administration and early stabilization on CPAP with selective use of surfactant in infants with respiratory failure [2 trials; 1359 infants; typical RR 0.97, 95% CI 0.72 to 1.30 (I² = 39%); typical RD -0.00, 95% CI -0.04 to 0.03 (I² = 32%)]. No important heterogeneity was noted.

Combined analysis for retinopathy of prematurity stages 2 or greater

General meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP did not demonstrate differences in the risk of stage 2-4 retinopathy between prophylactic surfactant administration and selective surfactant administration in infants with respiratory failure [5 trials, 2738 infants; typical RR 0.97, 95% CI 0.73 to 1.28 (I² = 0%); typical RD -0.00, 95% CI -0.02 to 0.02 (I² = 20%)]. Non important heterogeneity was noted.

1.18. Periventricular leukomalacia (PVL)

Five studies Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995 and Dunn 2011 reported on PVL.

1.18.1. PVL in studies without routine application of continuous positive airway pressure to control infants

Merritt 1991; Egberts 1993; Kattwinkel 1993; Walti 1995 did not routinely place control infants on CPAP. None of these trials reported a significant effect of prophylactic surfactant on the incidence of PVL. Meta-analysis of these studies showed a nonstatistically significant increase in the risk of PVL associated with the prophylactic surfactant administration compared to selective administration [4 trials; 1604 infants; typical RR 1.29, 95% CI 0.76 to 2.16 (I² = 0%); typical RD 0.01, 95% CI -0.01 to 0.03 (I² = 0%)]. No heterogeneity was present.

1.18.2. PVL in studies with routine application of continuous positive airway pressure to control infants

Dunn 2011 was the only trial of this subgroup reporting on PVL and found a nonstatistically significant increase in the risk of PVH with the prophylactic surfactant administration compared with selective use of surfactant in infants early stabilized on CPAP [1 trial, 396 infants, RR 0.72, 95% CI 0.12 to 4.28; RD -0.00, 95% CI -0.03 to 0.02]. Test for heterogeneity not applicable.

Combined analysis for periventricular leukomalacia

General meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP did not demonstrate differences in the risk of PVL between prophylactic surfactant administration and selective surfactant administration in infants with respiratory failure [5 trials, 2000 infants; typical RR 1.23, 95%CI 0.75 to 2.01 (I²=0%); typical RD 0.01, 95% CI -0.01 to 0.02 (I²=0%)]. No heterogeneity was present.

Neurodevelopmental outcome

For this outcome, we considered any trial reporting at approximately two years corrected age (acceptable range 18 months to 28 months) any of the following entities cerebral palsy, intellectual disability or developmental delay (Bayley Scales of Infant Development Mental Developmental Index < 70), legal blindness (< 20/200 visual acuity), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome "neurodevelopmental impairment" would be defined as having any one of the aforementioned deficits. Two trials Sinkin 1998; Vaucher 1993 performed a follow-up study including infants recruited in the Kendig 1991 and Merritt 1991 trials respectively. Sinkin 1998 reported cerebral palsy but in 148 children at school age, no data were available from ages between 18 and 28 months. Vaucher 1993 reported on cerebral palsy and developmental delay in 145 survivors at 12 months corrected age.

No one study reporting neurodevelopmental outcomes at 24 months corrected age was found.

Studies that compared the effect of prophylactic surfactant administration with surfactant treatment of established respiratory distress in preterm infants less than 30 weeks gestation (Comparison 2)

A total of nine studies (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997; SUPPORT 2010; Dunn 2011) were conducted in population of infants less than 30 weeks PMA. Kattwinkel 1993 was the only study that included a bigger population and did not report desegregated data for infants less than 30 weeks PMA.

2.1. Neonatal mortality in infants < 30 weeks gestation
2.1.1. Studies with routine application of continuous positive airway pressure to control infants

The neonatal mortality in infants born with less than 30 weeks gestation, was reported by seven trials (Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997). The meta-analysis of these trials demonstrated a significant reduction in the neonatal mortality associated with the use of prophylactic surfactant [7 trials; 1513 infants; typical RR 0.71, 95% CI 0.58 to 0.88 (I² = 27%); typical RD -0.06, 95% CI -0.10 to -0.02 (I² = 13%)]. No important heterogeneity was noted.

2.1.2. Studies with routine application of continuous positive airway pressure to control infants

SUPPORT 2010 and Dunn 2011 reported on this outcome. The meta-analysis showed nonstatistically significant differences in risk of neonatal mortality < 30 weeks between groups [2 trials, 1476 infants, typical RR 1.24, 95% CI 0.97 to 1.58 (I² = 0%); typical RD -0.03, 95% CI -0.00 to 0.06, (I² = 0%)].

Combined analysis for neonatal mortality in infants < 30 weeks gestation

Meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP did not support a significant decrease in the risk of neonatal mortality associated with the use prophylactic surfactant (nine trials, 3259 infants; typical RR 0.91, 95% CI 0.78 to 1.07 (I² = 57%); typical RD -0.01, 95% CI -0.04 to 0.01 (I² = 61%)]. Substantial heterogeneity was noted.

2.2. Bronchopulmonary dysplasia (BDP) in infants < 30 weeks gestation at birth
2.2.1. Studies without routine application of continuous positive airway pressure to control infants

BPD in infants born with less than 30 weeks gestation was reported by Dunn 1991; Kendig 1991; Merritt 1991; Egberts 1993; Walti 1995; Bevilacqua 1996 and Bevilacqua 1997. Meta-analysis shows nonstatistically significant differences in the risk of BPD between prophylactic or selective administration of surfactant in this population [7 trials; 1513 infants; typical RR 1.02, 95% CI 0.87 to 1.20 (I² = 38%); typical RD 0.01, 95% CI -0.04 to 0.05, I² = 45%]. Moderate heterogeneity was present.

2.2.2. Studies with routine application of continuous positive airway pressure to control infants

Dunn 2011 was the only trial in this subgroup reporting on BPD and has been discussed previously in Comparison 1; Outcome 1.3. There was no statistically significant trend towards increased risk of BPD with the prophylactic administration of surfactant compared with selective administration in infants early stabilized on CPAP.

Combined analysis for bronchopulmonary dysplasia in infants < 30 weeks gestation at birth

Meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP does not support any significant difference in BPD between prophylactic and selective administration of surfactant [8 trials; 1915 infants; typical RR 1.07, 95% CI 0.95 to 1.21 (I²= 35%); typical RD 0.02, 95% CI -0.02 to 0.06 (I² = 51%)]. Moderate heterogeneity was present.

2.3. Bronchopulmonary dysplasia or death in infants < 30 weeks gestation at birth
2.3.1. Studies without routine application of continuous positive airway pressure to control infants

Six studies in this subgroup (Dunn 1991; Kendig 1991; Egberts 1993; Walti 1995; Bevilacqua 1996; Bevilacqua 1997) reported BPD or death in infants less than 30 weeks gestation. The meta-analysis of these trials did not show significant differences in the risk of this combined outcome between prophylactic or selective surfactant administration strategies. Important heterogeneity was noted [6 trials; 1365 infants; typical RR 0.86, 95% CI 0.76 to 0.97 (I² = 72%); typical RD -0.07, 95% CI -0.12 to -0.02 (I² = 74%); NNTB 14, CI 95% 8 to 50]. Substantial heterogeneity was noted.

2.3.2. Studies with routine application of continuous positive airway pressure to control infants

Dunn 2011 was the only study in this subgroup reporting on this outcome, and found a nonstatistically significant increase on the risk of BPD with the prophylactic administration of surfactant when compared with early stabilization on CPAP with selective use of surfactant in infants with respiratory failure. Results are the same presenting in Comparison 1.

Combined analysis for bronchopulmonary dysplasia or death in infants < 30 weeks gestation at birth

Meta-analysis that includes all studies regardless of whether or not control infants were routinely placed on CPAP does not support any significant difference in BPD between prophylactic and selective administration of surfactant. Important heterogeneity was noted [7 trials; 1785 infants; typical RR 0.93, 95% CI 0.85 to 1.02 (I² = 76%); typical RD -0.04, 95% CI -0.08 to 0.01 (I² = 77%)]. Substantial heterogeneity was noted.

2.4. Chronic lung disease (use of supplemental oxygen at 36 weeks postmenstrual age)

For this outcome, all the same studies included in Outcome 1.5 reported on infants less than 30 weeks of gestation.

2.4.1. Studies without routine application of continuous positive airway pressure to control infants

All the same trials included in Outcome 1.5 reported this outcome for infants less than 30 weeks gestation (Dunn 1991; Egberts 1993; Walti 1995; Bevilacqua 1997).The meta-analysis of these studies does not demonstrate differences on the risk of CLD between treatment prophylactic and selective administration of surfactant [4 trials; 558 infants; typical RR 1.30, 95% CI 0.77 to 2.17 (I² = 0%); typical RD 0.02, 95% CI -0.02 to 0.07 (I² = 0%)]. No heterogeneity was present.

2.4.2. Studies with routine application of continuous positive airway pressure to control infants

SUPPORT 2010 and Dunn 2011 reported an increased risk of CLD with the prophylaxis administration of surfactant when compared with selective use of surfactant in infants with respiratory failure early stabilized on CPAP. Again, the meta-analysis of these studies revealed a trend towards increasing risk of CLD with the prophylactic administration in comparison with the selective administration in infants early placed on CPAP [2 trials; 1512 infants; typical RR 1.12, 95% CI 0.99 to 1.26 (I² = 0%); typical RD 0.04, 95% CI -0.00 to 0.09 (I² = 0%)]. No heterogeneity was present.

Combined analysis for chronic lung disease in infants < 30 weeks gestation at birth

General meta-analysis including all studies regardless of whether or not control infants were routinely placed on NCPCP, show a concerning trend towards increased risk of CLD associated with the use of prophylactic surfactant [6 trials; 2070 infants; typical RR 1.13, 95% CI 1.00 to 1.28 (I²= 0%); typical RD 0.04, 95% CI 0.00 to 0.08 (I²=0%)]. No heterogeneity was present.

2.5. Chronic lung disease (use of supplemental oxygen at 36 weeks postmenstrual age) or death in infants < 30 weeks gestation at birth

For this outcome, all of the same studies (Dunn 1991; SUPPORT 2010; Dunn 2011) included in the Outcome 1.6 reported on infants less than 30 weeks of gestation.

Combined analysis

The general meta-analysis including all studies regardless of whether or not control infants were routinely placed on CPAP shows a statistically significant increase in the risk of CLD or death associated with the use of prophylactic surfactant [3 studies; 1866 infants; typical RR 1.13, 95% CI 1.02 to 1.25 (I² = 0%); typical RD 0.06, 95% CI 0.01 to 0.10 (I² = 0%); NNH 17, 95% 10 to 100]. No heterogeneity was present.

Studies that compared the effect of prophylactic surfactant administration with surfactant treatment of established respiratory distress in preterm infants who have mostly received antenatal steroids (Comparison 3)

Three of the selected studies Dunn 1991; SUPPORT 2010; Dunn 2011 enrolled a population of infants in whom over 50% had received antenatal steroids (defined as one complete course of steroids). This specific subgroup analyses were performed for the following reported outcomes:

3. 1. Neonatal mortality (mortality < 28 days of age) from any cause

Reported by all three studies (Dunn 1991; SUPPORT 2010; Dunn 2011). The meta-analysis showed a trend towards to an increased risk of neonatal mortality with the use of prophylactic surfactant in preterminfants whose mothers had received steroids [3 trials; 1868 infants; typical RR 1.23, 95% CI 0.97 to 1.55 (I² = 0%); typical RD 0.03, 95% CI -0.00 to 0.06 (I² = 0%)]. No heterogeneity was present.

3.2. Broncholpulmonary dysplasia (oxygen requirement at 28 to 30 days of age)

Only Dunn 1991 and Dunn 2011 reported on this outcome. The meta-analysis demonstrated a significant increase in the risk of BPD in this population associated with the use prophylactic surfactant administration. Important heterogeneity was noted [2 trials; 528 infants; typical RR 1.23, 95% CI 1.06 to 1.43 (I² = 84%); typical RD 0.12, 95% CI 0.04 to 0.20 (I² = 82%); NNH 9 95% CI 5 to 25]. Substantial heterogeneity was noted.

3.3. Bronchpulmonary dysplasia or death prior to 28 to 30 days of age

Dunn 1991and Dunn 2011 reported on this outcome. The meta-analysis demonstrated a statistically significant increase in the risk of BPD in this population associated with the use prophylactic surfactant administration [2 trials, 552 infants; typical RR 1.54, 95% CI 1.09 to 2.18 (I² = 0%); typical RD 0.06, 95% CI 0.02 to 0.11; NNH 17 95% CI 9 to 50]. No heterogeneity was present.

3.4. Chronic lung disease (use of supplemental oxygen at 36 weeks postmenstrual age)

All the three studies reported on this outcome (Dunn 1991; SUPPORT 2010; Dunn 2011). The meta-analysis showed a trend towards an increase in the risk of CLD associated with the prophylactic surfactant strategy [3 trials; 1642 infants; typical RR 1.11, 95% CI 0.98 to 1.26 (I² = 0%); typical RD 0.04, 95% CI -0.01 to 0.08 (I² = 0%)]. No heterogeneity was present.

3.5. Chronic lung disease (use of supplemental oxygen at 36 weeks postmenstrual age) or death prior to 36 weeks postmenstrual age

As has been stated above Dunn 1991; SUPPORT 2010; Dunn 2011 were the only trials reporting on this outcome. The meta-analysis results were the same as showed in previous comparisons, and showed a trend towards an increase in the risk of chronic lung disease or death with the prophylactic surfactant strategies [3 trials; 1868 infants; typical RR 1.24, 95% CI 0.99 to 1.56 (I² = 0%); typical RD 0.03. 95% CI 0.00 to 0.06 (I² = 0%)]. No heterogeneity was present.

Discussion

The initial animal models supported the early prophylactic use of surfactant therapy. In animal studies, more uniform distribution of surfactant was achieved when surfactant was administered into a fluid-filled lung (Jobe 1984; Seidner 1995). Even brief (15 to 30 minute) periods of mechanical ventilation prior to surfactant administration were shown to cause acute lung injury resulting in alveolar-capillary damage, leakage of proteinaceous fluid into the alveolar space and release of inflammatory mediators (Ikegami 1998; Jobe 1998) and to decrease the subsequent response to surfactant replacement (Rider 1992; Bjorklund 1997). Surfactant deficient animals who receive assisted ventilation develop necrosis and desquamation of the bronchiolar epithelium as early as five minutes after the onset of ventilation (Nilsson 1978).

We identified eleven studies that compared prophylactic administration of surfactant to surfactant treatment of established RDS (selective treatment). Five of these studies were not included in the previous review (Soll 2001b). All of these studies utilized an animal derived surfactant extract in both treatment groups. Although all of the eleven studies attempted to identify high risk infants, entry criteria differ between them; importantly, two were done in the context of current clinical care practices (SUPPORT 2010; Dunn 2011) including the routine use of CPAP and increased utilization of antenatal steroids.

To address these differences in the baseline risk of the population (the increased utilization of antenatal steroids) as well as the introduction of less invasive methods of respiratory support (CPAP), we conducted several subgroup analyses: the primary analysis evaluated studies with routine application of CPAP and studies without routine application of CPAP. We carried out separate subgroup analyses for infants less than 30 weeks of gestation at birth and those infants who had mostly received steroids.

According to the results from the previous version of this review (Soll 2001b), prophylactic surfactant administration significantly decreased the risk of pneumothorax, the risk of pulmonary interstitial emphysema, the risk of mortality and the risk of BPD or death in comparison with surfactant treatment of established RDS. The updated meta-analysis including the newest trials shows similar findings for those studies without routine application of CPAP. However, for the subgroup analysis of studies with routine application of CPAP, the benefit of the prophylactic surfactant administration is not as clear; in fact, the risk of CLD or death is lower in the arm that allowed stabilization on CPAP and selective treatment with surfactant compared with the prophylactic arm. For other important clinical outcomes such as neonatal mortality, BPD, CLD, any air leak, or sepsis, there was no statistical difference in risk associated with the use of prophylactic surfactant.

It is known that CPAP might reduce the work of breathing and augment gas exchange by facilitated diffusion (Greenough 2007). CPAP was introduced into neonatal intensive care in the 1970s. However, the potential magnitude of the benefits of CPAP were not fully appreciated until the survey conducted by Avery and coworkers in 1987 (Avery 1987). Avery and coworkers conducted a retrospective study involving 1, 625 infants with birth weights between 700 to 1, 500 g admitted to eight premier intensive care nurseries in North America between January 1982 to December 1984. Avery sought to identify differences between centers regarding the incidence of CLD. Even when birth weight, race, and sex were taken into consideration through a multivariate logistic regression analysis, significant differences were found between institutions in the incidence of CLD. The NICU at Columbia Presbyterian Hospital was the center that demonstrated the best outcomes in low birth weight infants and the lowest incidence of CLD. The Columbia group routinely placed all infants who showed signs of RDS on NCPAP (Avery 1987). Ho and colleagues conducted a systematic review of randomized controlled trials (Ho 2002) to determine if continuous distending pressure (CDP) reduces the need for Intermitent Positive Pressure Ventilation (IPPV) and associated morbidity without adverse effects in spontaneously breathing preterm infants with RDS. Some of the included trials were conducted in the presurfactant era (performed in the 1970s). The meta-analysis demonstrated that in preterm infants with RDS, the application of CDP as CPAP is associated with a reduced risk of respiratory failure and mortality, but is associated with an increased risk of pneumothorax. The early management of preterm infants at risk of pulmonary respiratory failure with CPAP has been associated with a reduced need for assisted ventilation and thereby protecting the lung of preterm infants from developing BPD (Ho 2002; Nowadsky 2009). A large randomized controlled trial (Morley 2008) conducted to investigate whether NCPAP rather than intubation and ventilation shortly after birth would reduce the rates of death or BPD in spontaneously breathing preterm infants demonstrated that in infants born at 25 to 28 weeks PMA, early nasal CPAP (NCPAP) was associated with lower need of oxygen supplementation at 28 days and fewer days of mechanical ventilation.

The growing appreciation of the role of non-invasive support using CPAP leads us to rethink the real benefit of using prophylactic surfactant in high risk preterm infants. Evidence from recent randomized controlled trials (Rojas 2009; Sandri 2010) suggest that for patients treated with CPAP, an "early strategy" of surfactant treatment (administration of surfactant during a brief period of intubation soon after the first symptoms of RDS appears) may in fact be a better approach than immediate intubation and prophylactic surfactant administration.

Rojas 2009 conducted a multicenter trial to address the question of whether the use of very early surfactant therapy (within the first hour of life) in addition to the early use of NCPAP in spontaneously breathing preterm infants with RDS would further improve their outcomes in comparison with the early use of NCPAP and selective use of surfactant in more established RDS. Infants 27 to 31 weeks gestational age were eligible if within the first 60 minutes of life they presented evidence of increased work of breathing (tachypnea, intercostal retractions, nasal flaring, or grunting) and need for supplemental oxygen administration. All eligible infants were initially placed on NCPAP of 6 cm h3O. Infants in the treatment group were temporarily intubated for surfactant administration and received a dose of 100 mg/kg of surfactant in two aliquots, two minutes apart. Infants in control group remained on NCPAP. The authors found that the need for mechanical ventilation was lower in the treatment group compared with the control group. Airleak occurred less frequently in the treatment group compared with the control group. The incidence of CLD (oxygen treatment at 36 weeks’ postmenstrual age) was 49% in the treatment group compared with 59% in the control group. All other outcomes, including mortality, intraventricular hemorrhage, and periventricular leukomalacia were similar between the groups.

Sandri 2010 conducted a randomized, controlled trial to investigate whether prophylactic surfactant followed by NCPAP compared with early NCPAP application with early surfactant would reduce the need for mechanical ventilation in the first five days of life. Newborn infants with gestational ages from 25 weeks zero days and 28 weeks six days were included. Infants who were randomly assigned to prophylactic surfactant were intubated for administration of a dose of 200 mg/kg of porcine surfactant. Infants who were assigned to NCPAP were stabilized on NCPAP alone. Results from this trial showed that in spontaneously breathing preterm newborns who were treated with NCPAP, prophylactic surfactant given within 30 minutes of birth was not superior to early selective surfactant in terms of requirement of mechanical ventilation in the first five days of life and there were no significant differences between groups for any secondary outcome, even when the two GA strata were analyzed separately. Prophylactic surfactant treatment within 15 minutes of birth was not associated with reduced risk of mortality in comparison with the early surfactant group, in any gestational age subgroup.

Others changes in practice may have influenced the results of these studies. There is strong evidence that supports the effectiveness of the use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth (Roberts 2006). Use of antenatal steroids has almost tripled in the last two decades. The trials included in the original review in general had a low rate of steroid exposure; in fact, antenatal steroid use was not even reported in two studies (Merritt 1991; Kattwinkel 1993). In those studies that commented on the use of antenatal steroids, antenatal steroids were administered to mothers prior to delivery in as few as 14% (Walti 1995) to as many as 50% (Dunn 1991) of pregnancies. In two of the new trials in this updated review (SUPPORT 2010; Dunn 2011) at least 50% of population had received steroids. As these trials dominate the subgroup analysis regarding antenatal steroid exposure, the results are consistent with the findings regarding the routine stabilization on NCPAP. It is interesting to speculate that these two interventions could act synergically to reduce the risk of lung damage.

We analyzed a subgroup of infants less than 30 weeks gestation. Meta-analysis shows that in infants less than 30 weeks gestational age without routine application of CPAP, the use of prophylactic surfactant reduces the risk on neonatal mortality. As with the other analyses, the risk of CLD or death is decreased in patients that received CPAP routinely. This again reflects the difference in fundamental study design and the probable benefits of early stabilization on CPAP.

With the evidence provided by these recent studies, the real benefit of the prophylactic surfactant administration in infants treated under current practices is no longer clear. It seems that infants who have received antenatal steroids and are able to be stabilized early after birth on CPAP, may not need to be treated with prophylactic surfactant and could have better outcomes if they are treated with early selective surfactant.

Authors' conclusions

Implications for practice

In studies conducted in the 1990's, organized before the widespread use of antenatal steroids and early CPAP, prophylactic surfactant administration to infants judged to be at risk for developing RDS compared with selective use of surfactant in infants with established RDS demonstrated improved clinical outcomes. In this study population, infants who received prophylactic surfactant had a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema and a decreased risk of mortality. However, recent large trials that reflect current practice (including greater utilization of maternal steroids and routine post delivery stabilization on CPAP) do not support these differences and demonstrate less risk of chronic lung disease or death when using early stabilization on CPAP with selective surfactant administration to infants requiring intubation.

Implications for research

Improved identification of lung maturity in the perinatal period might influence who receives prophylactic surfactant administration and allow this approach to be more cost effective. Further trials are needed to explore this issue and other issues of patient selection.

The merits of prophylactic synthetic surfactant administration compared with treatment with synthetic surfactants remain unknown; none of the current randomized controlled trials utilized synthetic surfactant products.

Acknowledgements

To the Doctoral Program in Salud Pública y Metodología de la Investigación Biomédica of the Department of Paediatrics and Preventive Medicine, School of Medicine, Universidad Autónoma de Barcelona, Spain. Associate Professor MX Rojas is PhD candidate at this program.

Associate Professor MX Rojas thanks Sergio Mario Castro the research assistant at the Clinical Epidemiology and Biostatistic Department of PUJ who contributed with the risk of bias assessment of included studies as well as assisted to MXR in all the review process.

Contributions of authors

Associate Professor MX. Rojas and Dr. R. Soll searched for trials, selected trials, extracted data, conducted the meta-analyses and wrote the text of review.
Dr. C. J. Morley searched for trials, selected trials and extracted data for the previous version of the review and reviewed the text of the updated review.

Declarations of interest

Dr. MX Rojas has participated as co-investigator of independent trials supported in part by Abbott Laboratories and Fisher and Pickell Ind.

Dr. R. Soll has acted as a consultant and invited speaker for several of the pharmaceutical companies which manufacture surfactant preparations (Abbott Laboratories, Ross Laboratories, Chiesi Pharmaceuticals, Dey Laboratories, Burroughs Wellcome).

Dr. C. Morley is a consultant to Fisher and Paykel Healthcare and is paid for lecturing on behalf of Drager Medical.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Bevilacqua 1996

Methods

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measurement: can't tell
Stratification based on gestational age

Participants

Preterm infants
Gestational age 24-30 weeks
No major congenital anomaly

Interventions

Prophylactic Curosurf (200 mg/kg) within 10 minutes after birth vs. Curosurf treatment (200 mg/kg) for intubated infants with respiratory distress syndrome within 24 hours of age.

Second dose of Curosurf (200 mg/kg) was allowed in the prophylactic group if infant presented RDS requiring assisted ventilation within 24 hours of age.

Outcomes

PRIMARY OUTCOME:
Reduction in RDS

SECONDARY OUTCOME:
Complications of Prematurity

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

Randomized multicenter trial

Stratification based on gestational age

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes
(sealed envelopes)

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: no
Blinding of outcome measurement: an independent radiologist

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

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

Bevilacqua 1997

Methods

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measurement: can't tell
Stratification based on gestational age

Participants

Preterm infants
Gestational age 24-30 weeks
No major congenital abnormality

Interventions

Prophylactic Curosurf (200 mg/kg) within 10 minutes after birth vs. Curosurf treatment (200 mg/kg) for intubated infants with respiratory distress syndrome within 24 hours of age.
Second dose of Curosurf (200 mg/kg) was allowed in prophylactic group if infant presented RDS requiring assisted ventilation within 24 hours of age.

Outcomes

PRIMARY OUTCOME:
Reduction in RDS
SECONDARY OUTCOME:
Complications of prematurity

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

Randomized multicenter trial
Stratification based on gestational age

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes (sealed envelopes)

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no
Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk

Dunn 1991

Methods

Randomized single center trial
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measurement: no
Stratification based on gestational age and exposure to antenatal steroids

Participants

Preterm infants
Gestational age < 30 weeks
No known congenital anomaly
No ROM > 2 weeks
No mature L/S ratio

Interventions

Prophylactic BLSE (75-100 mg) prior to first breath vs BLSE treatment (75-100 mg) for intubated infants with respiratory insufficiency less than 6 hours of age vs. control (no treatment)

Up to 3 additional treatments allowed in either surfactant treatment group.

Outcomes

PRIMARY OUTCOME:
Improvement in a/A ratio.

SECONDARY OUTCOME:
Ventilatory requirements
Duration of ventilation
Complications of prematurity

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

Randomized single center
Blinding of randomization: yes (sealed envelopes)
Stratification based on gestational age and exposure to antenatal steroids

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes (sealed envelopes)

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no
Blinding of outcome measurement: no but measurements were done using hard methods

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

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

Dunn 2011

Methods

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measurement: can't tell

Study stopped prematurely

Participants

Infants between 26 to 29 + 6 weeks gestation at birth

No congenital malformations at birth

Interventions

Prophylactic surfactant followed by a period of assisted ventilation

or

intubation-surfactant treatment and rapid extubation to nasal CPAP

or

early stabilization in nasal CPAP

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

Randomized multicenter trial

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes (sealed envelopes)

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no
Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias) Unclear risk

Complete follow-up: yes

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk

Study stopped prematurely

Egberts 1993

Methods

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measurement: can't tell

Participants

Preterm infants 6-24 hours of age
Gestational age 26-30 weeks
No major congenital anomaly
ROM < 3 weeks

Interventions

Prophylactic Curosurf (200 mg/kg) within 10 minutes after birth vs. Curosurf treatment (200 mg/kg) for intubated infants with moderate-severe RDS (supplemental oxygen equal to or greater than 60%).

Second dose of Curosurf (200 mg/kg) was allowed in prophylactic group if infant required assisted ventilation and supplemental oxygen 60% or greater

Outcomes

PRIMARY OUTCOME:
Reduction in RDS

SECONDARY OUTCOME:
Requirement for ventilatory support.
Complications of prematurity

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

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no
Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk

Iarŭkova 1999

Methods

Randomized multicenter trial
Blinding of randomization: yes
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measurement: can't tell

Participants

Very low weight preterm infants
Gestational age < 32 weeks at birth
No major congenital abnormality

Interventions

Prophylactic Curosurf (200 mg/kg)

Rescue Curosurf treatment (200 mg/kg) if indicated.

Outcomes

PRIMARY OUTCOME:
Respiratory distress syndrome

SECONDARY OUTCOME:

Incidence of bronchopulmonary dysplasia and Intraventricular hemorrhage; duration of ventilation; duration of oxygen supplement.

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

Randomized controlled trial

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes (sealed envelopes)

Blinding (performance bias and detection bias) Unclear risk

Blinding of interventions: not reported
Blinding of outcome measurement: not reported

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

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

Kattwinkel 1993

Methods

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measurement: can't tell

Participants

Preterm infants
Gestational age 29-32 weeks
Excluded if noted to have: Congenital malformation, congenital sepsis, perinatal asphyxia, judged too mature

Interventions

Prophylactic calf lung surfactant extract (CLSE) (150 mg) within 5 minutes after birth vs. CLSE treatment (150 mg) in infants with mild RDS (compatible radiograph, greater than 30% supplemental oxygen)

Re-treatment of either group was allowed if infant reached criteria for severe RDS (MAP 10 cmH2O or greater, supplemental oxygen 60% or greater)

Outcomes

PRIMARY OUTCOME:
Development of moderate RDS

SECONDARY OUTCOME:
Complications of prematurity

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

Randomized multicenter trial

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes (sealed envelopes)

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no
Blinding of outcome measurement: not but the outcome measurement are not likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk

Kendig 1991

Methods

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measurement: no

Participants

Preterm infants
Gestational age < 30 weeks
No lethal congenital anomaly

Interventions

Prophylactic CLSE (90 mg) prior to first breath vs. CLSE treatment (90 mg) in intubated infants with RDS requiring greater than 40% supplemental oxygen or MAP greater than 7 cmH20

Retreatment of either group was allowed at 12 hours if infant remained on assisted ventilation, requiring greater than 40% supplemental oxygen or MAP greater than 7 cmH2O

Outcomes

PRIMARY OUTCOME:
Mortality

SECONDARY OUTCOME:
Severity of RDS
Complications of prematurity

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

Randomized multicenter trial

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes (sealed envelopes)

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no
Blinding of outcome measurement: no

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk

Merritt 1991

Methods

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: yes
Complete follow-up: yes
Blinding of outcome measurement: yes
Stratification based on gestational age
Separate randomization schedules for multiple births

Participants

Preterm infants
Gestational age 24-29 weeks
No congenital malformation
No mature L/S ratio
ROM < 3 weeks

Interventions

Prophylactic human amniotic fluid extract (70 mg/kg) immediately post intubation/minimal ventilation vs. treatment with human amniotic fluid extract (70 mg/kg) in intubated infants with RDS requiring greater than 50% supplemental oxygen and MAP of 7 cmH2O or greater prior to 12 hours of age vs. control treatment

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

Randomized multicenter trial
Variation of the biased-coin method

Stratification based on gestational age
Separate randomization schedules for multiple births

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes (sealed envelopes)

Blinding (performance bias and detection bias) Low risk

Blinding of intervention: yes
Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk

SUPPORT 2010

Methods

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: yes
Complete follow-up: yes
Blinding of outcome measurement: yes
Stratification based on gestational age
Separate randomization schedules for multiple births

Participants

Preterm infants
Gestational age 24-27.6 weeks
No congenital malformation

Interventions

Prophylactic surfactant given within the first 60 minutes after birth followed by conventional ventilation in NICU vs selective surfactant. All infants received CPAP at birth

Outcomes

PRIMARY OUTCOME:

Death or BPD (physiological definition)

SECONDARY OUTCOMES:

Need of mechanical ventilation, air leak, pneumothorax, necrotizing enterocolitis, patent ductus arteriosus, severe intraventricular hemorrhage, severe ROP

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

Randomized multicenter trial

Randomization stratified by age (24-25 + 6 weeks; 26-27 + 6 weeks) and center

Allocation concealment (selection bias) Low risk

Double sealed envelopes

Blinding (performance bias and detection bias) Unclear risk
Incomplete outcome data (attrition bias) Low risk

All randomized infants were analyzed in intention-to-treat analysis

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk

Walti 1995

Methods

Randomized multicenter trial
Blinding of randomization: yes (sealed envelopes)
Blinding of interventions: no
Complete follow-up: yes
Blinding of outcome measurement: no

Participants

Preterm infants 3-18 hours of age
Gestational Age 25-31 weeks
No congenital anomaly
ROM < 3 weeks

Interventions

Prophylactic Curosurf (100 mg/kg) within 15 min after birth vs. Curosurf treatment (100 mg/kg) in intubated infants with moderate respiratory distress syndrome (PaO2/FiO2 < 150 mmHg on assisted ventilation with MAP > 8 cmH20)
Retreatment of either group was allowed with up to 3 doses of Curosurf (100 mg/kg) within 48 hours if above criteria met

Outcomes

PRIMARY OUTCOME:
Survival without BPD at 28 days after birth

SECONDARY OUTCOME:
Radiographic evidence of RDS
Immediate respiratory course
Complications of prematurity

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

Randomized multicenter trial

Allocation concealment (selection bias) Low risk

Blinding of randomization: yes (sealed envelopes)

Blinding (performance bias and detection bias) High risk

Blinding of interventions: no
Blinding of outcome measurement: no

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

Selective reporting (reporting bias) Unclear risk
Other bias Unclear risk
Footnotes

a/A ratio: arterial/alveolar oxygen tension ratio
BLSE: bovine lung surfactant extract
BPD: bronchopulmonary dysplasia
CLSE: calf lung surfactant extract
CPAP: continuous positive airway pressure
L/S ratio: lecithin-sphingomyelin ratio
MAP: mean airway pressure
NICU: neonatal intensive care unit
RDS: respiratory distress syndrome
ROM: rupture of membranes
ROP: retinopathy of prematurity

Characteristics of excluded studies

Lefort 2003

Reason for exclusion

Excluded from this review because the treatment group received surfactant as "very early surfactant" once first RDS signs appears instead of prophylactic administration of surfactant.

Morley 2008

Reason for exclusion

Excluded from this review because the trial did not give "prophylactic" treatment to all infants in a high risk group, but selected those infants who neither needed acute resuscitation or had no signs of respiratory distress. In the remaining infants, surfactant treatment was not mandated and followed local protocols.

Rojas 2009

Reason for exclusion

Excluded from this review because the treatment group received surfactant as "very early surfactant" once first RDS signs appears instead of prophylactic administration of surfactant.

Sandri 2010

Reason for exclusion

Excluded because of the comparison, the control group received "early surfactant" soon after treatment failure on CPAP instead of selective, according with definitions of interventions used in this review.

Footnotes

CPAP: continuous positive airway pressure
RDS: respiratory distress syndrome

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.

Summary of findings tables

  • None noted.

Additional tables

  • None noted.

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References to studies

Included studies

Bevilacqua 1996

Bevilacqua G, Parmigiani S, Robertson B and the Italian Collaborative Multicentre Study Group. Prophylaxis of respiratory distress syndrome by treatment with modified porcine surfactant at birth: a multicentre prospective randomized trial. Journal of Perinatal Medicine 1996;24:1-12.

Bevilacqua 1997

Bevilacqua G, Chernev T, Parmigiani S, Yarakova N, Gaioni L, Volante E, et al. Use of surfactant for prophylaxis versus rescue treatment of respiratory distress syndrome: experience from an Italian-Bulgarian trial. Acta Biomed Ateneo Parmense 1997;68(Suppl 1):47-54.

Dunn 1991

Dunn MS, Shennan AT, Zyack D, Possmayer F. Bovine surfactant replacement therapy in neonates of less than 30 weeks' gestation: a randomized controlled trial of prophylaxis vs treatment. Pediatrics 1991;87:377-86.

Dunn 2011

Published and unpublished data

Dunn M, Kaempf J, de Klerk A, de Klerk R, Reilly M, Howard D, et al. Delivery room management of preterm infants at risk for respiratory distress syndrome (RDS). In: Pediatric Academic Societies Conference Proceedings. 2010.

* Dunn MS, Kaempf J, de Klerk A, de Klerk R, Reilly M, Howard D, et al; for the Vermont Oxford Network DRM Study Group. Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 2011;128:e1069-76.

Egberts 1993

Egberts J, De Winter JP, Sedin G, De Kleine MJK, Broberger U, Van Bel F, et al. Comparison of prophylaxis and rescue treatment with Curosurf in neonates less than 30 weeks gestation: a randomized trial. Pediatrics 1993;92:768-74.

Iarŭkova 1999

Published data only (unpublished sought but not used) [Other: ]

Iarŭkova N, Vakrilova L, Slŭncheva B, Dancheva S, Popivanova A, Emilova Z, et al. Administration of exogenous surfactant in very low birth weight infants with RDS. Akuserstvo i Ginekologija 1999;38:23-6. [Other: ISSN 0324-0959]

Kattwinkel 1993

Kattwinkel J, Bloom BT, Delmore P, Davis CL, Farrell E, Friss H, et al. Prophylactic administration of calf lung surfactant extract is more effective than early treatment of respiratory distress syndrome in neonates of 29 through 32 weeks' gestation. Pediatrics 1993;92:90-8.

Kendig 1991

* Kendig JW, Notter RH, Cox C, Reubens LJ, Davis JM, Maniscalco WM, . A comparison of surfactant as immediate prophylaxis and as rescue therapy in newborns of less than 30 weeks' gestation. New England Journal of Medicine 1991;324:865-71.

Sinkin RA, Kramer BM, Merzbach JL, Myers GJ, Brooks JG, Palumbo DR, et al. School-age follow-up of prophylactic versus rescue surfactant trial: pulmonary, neurodevelopmental, and educational outcomes. Pediatrics 1998;101:E11.

Merritt 1991

* Merritt TA, Hallman M, Berry C, Pohjavuori M, Edwards DK, Jaaskelainen J, et al. Randomized, placebo-controlled trial of human surfactant given at birth vs rescue administration in very low birthweight infants with lung immaturity. Journal of Pediatrics 1991;118:581-94.

Vaucher YE, Harker L, Merritt TA, Hallman M, Gist K, Bejar R, et al. Outcome at twelve months of adjusted age in very low birth weight infants with lung immaturity: a randomized, placebo-controlled trial of human surfactant. Journal of Pediatrics 1993;122:126-32.

SUPPORT 2010

SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Early CPAP versus surfactant in extremely preterm infants. New England Journal of Medicine 2010;362:1970-9.

Walti 1995

Walti H, Paris-Llado J, Breart G, Couchard M, and the French Collaborative Multicentre Study Group. Porcine surfactant replacement therapy in newborns of 25-31 weeks' gestation: a randomized multicentre trial of prophylaxis versus rescue with multiple low doses. Acta Paediatrica 1995;84:913-21.

Excluded studies

Lefort 2003

Lefort S, Diniz EM, Vaz FA. Clinical course of premature infants intubated in the delivery room, submitted or not to porcine-derived lung surfactant therapy within the first hour of life. Journal of Maternal-Fetal and Neonatal Medicine 2003;14:187-96.

Morley 2008

Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB; COIN Trial Investigators. Nasal CPAP or intubation at birth for very preterm infants. The New England Journal of Medicine 2008;358:700-8.

Rojas 2009

Rojas MA, Lozano JM, Rojas MX, Laughon M, Bose CL, Rondon MA, et al. Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics 2009;123:137-42.

Sandri 2010

Sandri F, Plavka R, Ancora G, Simeoni U, Stranak Z, Martinelli S, et al. Prophylactic or early selective surfactant combined with nCPAP in very preterm infants. Pediatrics 2010;125:e1402-9.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Abdel-Latif 2010

Abdel-Latif ME, Osborn DA. Nebulised surfactant for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome (Protocol). Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD008310. DOI: 10.1002/14651858.CD008310.

Abdel-Latif 2011

Abdel-Latif ME, Osborn DA. Laryngeal mask airway surfactant administration for prevention of morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD008309. DOI: 10.1002/14651858.CD008309.pub2.

Abdel-Latif 2011a

Abdel-Latif ME, Osborn DA. Pharyngeal instillation of surfactant before the first breath for prevention of morbidity and mortality in preterm infants at risk of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD008311. DOI: 10.1002/14651858.CD008311.pub2.

Avery 1987

Avery ME, Tooley WH, Keller JB, Hurd SS, Bryan MH, Cotton RB, et al. Is chronic lung disease in low birth weight infants preventable? A survey of eight centers. Pediatrics 1987;79:26-30.

Aziz 2008

Aziz A, Ohlsson A. Surfactant for pulmonary hemorrhage in neonates. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD005254. DOI: 10.1002/14651858.CD005254.pub2.

Bjorklund 1997

Bjorklund LJ, Ingimarsson J, Curstedt T, John J, Robertson B, Werner O, et al. Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs. Pediatric Research 1997;42:348-55.

D'Angio 2002

D'Angio CT, Sinkin RA, Stevens TP, Landfish NK, Merzbach JL, Ryan RM, et al. Longitudinal, 15-year follow-up of children born at less than 29 weeks gestation after introduction of surfactant therapy into a region: neurologic, cognitive, and educational outcomes. Pediatrics 2002;110:1094-102.

Dargaville 2002

Dargaville PA, Mills JF, Soll R. Therapeutic lung lavage for meconium aspiration syndrome in newborn infants (Protocol). Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD003486. DOI: 10.1002/14651858.CD003486.

Dickersin 2002

Dickersin K, Manheimer E, Wieland S, Robinson KA, Lefebvre C, McDonald S. Development of the Cochrane Collaboration's CENTRAL Register of controlled clinical trials. Evaluation and the Health Professions 2002;25:38-64.

El Shahed 2007

El Shahed AI, Dargaville P, Ohlsson A, Soll RF. Surfactant for meconium aspiration syndrome in full term/near term infants. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD002054. DOI: 10.1002/14651858.CD002054.pub2.

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;121:419-32.

Finer 2004

Finer NN, Carlo WA, Duara S, Fanaroff AA, Donovan EE, Wright L, et al. Delivery room continuous positive airway pressure/positive end-expiratory pressure in extremely low birth weight infants: A feasibility trial. Pediatrics 2004;114:651-7.

Gittermann 1997

Gittermann MK, Fusch C, Gittermann AR, Regazzoni BM, Moessinger AC. Early nasal continuous positive airway pressure treatment reduces the need for intubation in very low birth weight infants. European Journal of Pediatrics 1997;156:384-8.

Greenough 2007

Greenough A, Donn SM. Matching ventilatory support strategies to respiratory pathophysiology. Clinics in Perinatology 2007;34:35-53. [Other: ]

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003 Sep;6;327(7414):557-60.

Higgins 2011

Higgins JPT, 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.

Ho 2002

Ho JJ, Subramaniam P, Henderson-Smart DJ, Davis PG. Continuous distending pressure for respiratory distress in preterm infants. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD002271. DOI: 10.1002/14651858.CD002271.

Horbar 1993

Horbar JD, Wright EC, Onstad L. Decreasing mortality associated with the introduction of surfactant therapy: an observational study of neonates weighing 601-1300 grams at birth. The Members of the National Institute of Child Health and Human Development Neonatal Research Network. Pediatrics 1993;92:191-6.

Ikegami 1998

Ikegami M, Wada K, Emerson GA, Rebello CM, Hernandez RE, Jobe AH. Effects of ventilation style on surfactant metabolism and treatment response in preterm lambs. American Journal of Respiratory and Critical Care Medicine 1998;157:638-44.

Jobe 1984

Jobe A, Ikegami M, Jacobs H, Jones S. Surfactant and pulmonary blood flow distributions following treatment of premature lambs with natural surfactant. Journal of Clinical Investigation 1984;73:848-56.

Jobe 1993

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

Jobe 1998

Jobe AH, Ikegami M. Mechanisms initiating lung injury in the preterm. Early Human Development 1998;53:81-94.

Lindner 1999

Lindner W, Vossbeck S, Hummler H, Pohlandt F. Delivery room management of extremely low birth weight infants: spontaneous breathing or intubation? Pediatrics 1999;103:961-7.

Nilsson 1978

Nilsson R, Grossman G, Robertson B. Lung surfactant and the pathogenesis of neonatal bronchiolar lesions induced by artificial ventilation. Pediatric Research 1978;12:249-55.

Nowadsky 2009

Nowadzky T, Pantoja A, Britton JR. Bubble continuous positive airway pressure, a potentially better practice, reduces the use of mechanical ventilation among very low birth weight infants with respiratory distress syndrome. Pediatrics 2009;123:1534-40.

Palta 2000

Palta M, Sadek-Badawi M, Evans M, Weinstein MR, McGuinness G. Functional assessment of a multicenter very low birth-weight cohort at age 5 years. Newborn Lung Project. Archives of Pediatrics and Adolescent Medicine 2000;154:23-30.

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.

Possmayer 1990

Possmayer F. The role of surfactant-associated proteins. American Review of Respiratory Disease 1990;142:749-52. [Other: PubMed PMID: 2221577]

Rider 1992

Rider ED, Jobe AH, Ikegami M, Sun B. Different ventilation strategies alter surfactant responses in preterm rabbits. Journal of Applied Physiology 1992;73:2089-96.

Roberts 2006

Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004454. DOI: 10.1002/14651858.CD004454.pub2.

Sahni 1998

Sahni R, Wung JT. Continuous positive airway pressure (CPAP). Indian Journal of Pediatrics 1998;65:265-71.

Schwartz 1994

Schwartz RM, Luby AM, Scanlon JW, Kellogg RJ. Effect of surfactant on morbidity, mortality and resource use in newborn infants weighing 500-1500 gms. New England Journal of Medicine 1994;330:1476-80.

Schürch 1992

Schürch S, Possmayer F, Cheng S, Cockshutt AM. Pulmonary SP-A enhances adsorption and appears to induce surface sorting of lipid extract surfactant. American Journal of Physiology 1992;263:L210-8. [Other: PubMed PMID: 1514646]

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.

Seidner 1995

Seidner SR, Ikegami M, Yamada T, Rider ED, Castro R, Jobe AH. Decreased surfactant dose-response after delayed administration to preterm rabbits. American Journal of Respiratory & Critical Care Medicine 1995;152:113-20.

Sinclair 1992

Sinclair J, Bracken M. Effective Care of the Newborn. Oxford University Press, 1992.

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:e1588-95.

Sinkin 1998

Sinkin RA, Kramer BM, Merzbach JL, Myers GJ, Brooks JG, Palumbo DR, et al. School-age follow-up of prophylactic versus rescue surfactant trial: pulmonary, neurodevelopmental, and educational outcomes. Pediatrics 1998;101:E11.

Soll 1992

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

Soll 1997

Soll RF, Ozek 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 2000

Soll RF. Synthetic surfactant for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD001149. DOI: 10.1002/14651858.CD001149.

Soll 2001a

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

Soll 2009

Soll R, Ozek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000141. DOI: 10.1002/14651858.CD000141.pub2.

Soll 2010

Soll R, Ozek E. Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD001079. DOI: 10.1002/14651858.CD001079.pub2.

Stevens 2007

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

Tan 2012

Tan K, Lai NM, Sharma A. Surfactant for bacterial pneumonia in late preterm and term infants. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD008155. DOI: 10.1002/14651858.CD008155.pub2.

Vaucher 1993

Vaucher YE, Harker L, Merritt TA, Hallman M, Gist K, Bejar R, et al. Outcome at twelve months of adjusted age in very low birth weight infants with lung immaturity: a randomized, placebo-controlled trial of human surfactant. Journal of Pediatrics 1993;122:126-32.

Wright 1997

Wright JL, Sun JP, Churg A. Site of methacholine reactivity in the peripheral airways: analysis using lung explants. American Journal of Physiology 1997;272:L68-72. [Other: PubMed PMID: 9038904]

Yost 2000

Yost CC, Soll RF. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD001456. DOI: 10.1002/14651858.CD001456.

Other published versions of this review

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.

Soll 2001b

Soll RF, Morley CJ. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD000510. DOI: 10.1002/14651858.CD000510. [Other: PubMed PMID: 11405966]

Classification pending references

  • None noted.

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Data and analyses

1 Prophylactic surfactant vs. treatment of established respiratory distress in preterm infants

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

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Neonatal mortality 10 4507 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.76, 1.04]
1.1.1 Studies without routine application of CPAP 8 2761 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.56, 0.85]
1.1.2 Studies with routine application of CPAP 2 1746 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.97, 1.58]
1.2 Mortality at 36 weeks PMA or prior to hospital discharge 5 1458 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.63, 1.00]
1.2.1 Studies without routine application of CPAP 4 1030 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.56, 0.93]
1.2.2 Studies with routine application of CPAP 1 428 Risk Ratio (M-H, Fixed, 95% CI) 1.76 [0.79, 3.94]
1.3 Bronchopulmonary dysplasia (oxygen requirement at 28 to 30 days of age) 10 3191 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.91, 1.14]
1.3.1 Studies without routine application of CPAP 9 2789 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.81, 1.11]
1.3.2 Studies with routine application of CPAP 1 402 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.99, 1.36]
1.4 Bronchopulmonary dysplasia or death at 28 to 30 days of age 8 3033 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.81, 0.98]
1.4.1 Studies without routine application of CPAP 7 2613 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.73, 0.92]
1.4.2 Studies with routine application of CPAP 1 420 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.96, 1.31]
1.5 Chronic lung disease 6 2070 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [1.00, 1.28]
1.5.1 Studies without routine application of CPAP 4 558 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [0.77, 2.17]
1.5.2 Studies with routine application of CPAP 2 1512 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.99, 1.26]
1.6 Chronic lung disease or death 3 1866 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [1.02, 1.25]
1.6.1 Studies without routine application of CPAP 1 122 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.67, 2.49]
1.6.2 Studies with routine application of CPAP 2 1744 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [1.02, 1.24]
1.7 Any air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) 9 4076 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.71, 1.04]
1.7.1 Studies without routine application of CPAP 8 2760 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.63, 0.98]
1.7.2 Studies with routine application of CPAP 1 1316 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.73, 1.60]
1.8 Pneumothorax 8 3094 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.56, 1.04]
1.8.1 Studies without routine application of CPAP 7 2663 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.53, 1.05]
1.8.2 Studies with routine application of CPAP 1 431 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.39, 2.01]
1.9 Pulmonary interstitial emphysema 6 2185 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.53, 1.02]
1.9.1 Studies without routine application of CPAP 6 2185 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.53, 1.02]
1.10 Any pulmonary hemorrhage 4 2023 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.49, 2.22]
1.10.1 Studies without routine application of CPAP 3 1592 Risk Ratio (M-H, Fixed, 95% CI) 0.73 [0.28, 1.87]
1.10.2 Studies with routine application of CPAP 1 431 Risk Ratio (M-H, Fixed, 95% CI) 2.12 [0.54, 8.39]
1.11 Patent ductus arteriosus 8 3093 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.89, 1.08]
1.11.1 Studies without routine application of CPAP 7 2663 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.88, 1.10]
1.11.2 Studies with routine application of CPAP 1 430 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.79, 1.20]
1.12 Sepsis 6 2438 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.64, 1.08]
1.12.1 Studies without routine application of CPAP 5 2013 Risk Ratio (M-H, Fixed, 95% CI) 0.68 [0.51, 0.92]
1.12.2 Studies with routine application of CPAP 1 425 Risk Ratio (M-H, Fixed, 95% CI) 1.70 [0.96, 3.03]
1.13 Necrotizing enterocolitis 8 4237 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.73, 1.10]
1.13.1 Studies without routine application of CPAP 6 2516 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.76, 1.44]
1.13.2 Studies with routine application of CPAP 2 1721 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.60, 1.04]
1.14 Intraventricular hemorrhage (in infants receiving cranial ultrasound) 10 3105 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.82, 1.00]
1.14.1 Studies without routine application of CPAP 9 2684 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.81, 0.99]
1.14.2 Studies with routine application of CPAP 1 421 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.73, 1.50]
1.15 Severe intraventricular hemorrhage 10 4347 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.74, 1.04]
1.15.1 Studies without routine application of CPAP 8 2656 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.70, 1.08]
1.15.2 Studies with routine application of CPAP 2 1691 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.67, 1.16]
1.16 Retinopathy of prematurity (in infants screened) 7 3401 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.85, 1.20]
1.16.1 Studies without routine application of CPAP 5 2042 Risk Ratio (M-H, Fixed, 95% CI) 1.34 [0.92, 1.94]
1.16.2 Studies with routine application of CPAP 2 1359 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.75, 1.11]
1.17 Retinopathy of prematurity, Stage 2 or more 5 2738 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.73, 1.28]
1.17.1 Studies without routine application of CPAP 3 1379 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.46, 2.04]
1.17.2 Studies without routine application of CPAP 2 1359 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.72, 1.30]
1.18 Periventricular Leukomalacia 5 2000 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.75, 2.01]
1.18.1 Studies without routine application of CPAP 4 1604 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.76, 2.16]
1.18.2 Studies with routine application of CPAP 1 396 Risk Ratio (M-H, Fixed, 95% CI) 0.72 [0.12, 4.28]

2 Prophylactic surfactant vs. treatment of established respiratory distress in preterm infants less than 30 weeks gestation

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

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Neonatal mortality 9 3259 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.78, 1.07]
2.1.1 Studies without routine application of CPAP 7 1513 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.58, 0.88]
2.1.2 Studies with routine application of CPAP 2 1746 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.97, 1.58]
2.2 Bronchopulmonary dysplasia (oxygen requirement at 28 to 30 days of age) 8 1915 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.95, 1.21]
2.2.1 Studies without routine application of CPAP 7 1513 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.87, 1.20]
2.2.2 Studies with routine application of CPAP 1 402 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.99, 1.36]
2.3 Bronchopulmonary dysplasia or death at 28 to 30 days of age 7 1785 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.85, 1.02]
2.3.1 Studies without routine application of CPAP 6 1365 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.76, 0.97]
2.3.2 Studies with routine application of CPAP 1 420 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.96, 1.31]
2.4 Chronic lung disease 6 2070 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [1.00, 1.28]
2.4.1 Studies without routine application of CPAP 4 558 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [0.77, 2.17]
2.4.2 Studies with routine application of CPAP 2 1512 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.99, 1.26]
2.5 Chronic lung disease or death 3 1866 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [1.02, 1.25]
2.5.1 Studies without routine application of CPAP 1 122 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.67, 2.49]
2.5.2 Studies with routine application of CPAP 2 1744 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [1.02, 1.24]

3 Prophylactic surfactant vs. treatment of established respiratory distress in preterm infants who have mostly received steroids

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

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Neonatal mortality 3 1868 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.97, 1.55]
3.1.1 Studies without routine application of CPAP 1 122 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.45, 2.63]
3.1.2 Studies with routine application of CPAP 2 1746 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.97, 1.58]
3.2 Bronchopulmonary dysplasia (oxygen requirement at 28 to 30 days of age) 2 528 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [1.06, 1.43]
3.2.1 Studies without routine application of CPAP 1 108 Risk Ratio (M-H, Fixed, 95% CI) 2.14 [1.32, 3.49]
3.2.2 Studies with routine application of CPAP 1 420 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.96, 1.31]
3.3 Bronchopulmonary dysplasia or death at 28 to 30 days of age 2 552 Risk Ratio (M-H, Fixed, 95% CI) 1.54 [1.09, 2.18]
3.3.1 Studies without routine application of CPAP 1 122 Risk Ratio (M-H, Fixed, 95% CI) 1.61 [1.12, 2.31]
3.3.2 Studies with routine application of CPAP 1 430 Risk Ratio (M-H, Fixed, 95% CI) 1.32 [0.53, 3.28]
3.4 Chronic lung disease 3 1642 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.98, 1.26]
3.4.1 Studies without routine application of CPAP 1 106 Risk Ratio (M-H, Fixed, 95% CI) 1.75 [0.54, 5.63]
3.4.2 Studies with routine application of CPAP 2 1536 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.97, 1.25]
3.5 Chronic lung disease or death 3 1868 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.99, 1.56]
3.5.1 Studies without routine application of CPAP 1 122 Risk Ratio (M-H, Fixed, 95% CI) 1.29 [0.67, 2.49]
3.5.2 Studies with routine application of CPAP 2 1746 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.97, 1.58]

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Figures

  • None noted.

Sources of support

Internal sources

  • Pontificia Universidad Javeriana, Colombia
  • Support the time dedicated by Dr. Maria Rojas

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.

Feedback

  • None noted.

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2012 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.