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Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome

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Authors

Roger Soll1, Eren Özek2

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


1Division of Neonatal-Perinatal Medicine, University of Vermont, Burlington, USA [top]
2Pediatrics / Division of Neonatology, Maramara University Medical Center, Istanbul, Turkey [top]

Citation example: Soll R, Özek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 1999, Issue 2. Art. No.: CD000141. DOI: 10.1002/14651858.CD000141.

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: 10 November 2008
Date of Search: 30 June 2008
Next Stage Expected: 10 November 2010
Protocol First Published: Not specified
Review First Published: Issue 2, 1999
Last Citation Issue: Issue 2, 1999

What's new

Date / Event Description
11 November 2008
Updated

This review updates the existing review of "Multiple versus single dose natural surfactant extract for severe respiratory distress syndrome", published in the Cochrane Library, Issue 3, 1997 (Soll 1997b).

There has been a change in the title and scope of the review. The title has been changed to "Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome".

In keeping with the change in the scope of the review, the study of Corbet 1995 has been added.

11 November 2008
New citation: conclusions not changed

Substantive update

26 February 2008
Amended

Converted to new review format.

History

Date / Event Description
16 February 1999
New citation: conclusions changed

Substantive amendment

Abstract

Background

Randomized controlled trials have demonstrated the efficacy of surfactant therapy in the treatment of infants at risk for or having respiratory distress syndrome (RDS). Due to surfactant inactivation, multiple doses of surfactant may lead to improved outcome.

Objectives

To determine the effect of multiple doses of exogenous surfactant compared to single doses of exogenous surfactant on mortality and complications of prematurity in premature infants at risk for or having respiratory distress syndrome.

Search methods

For the initial search in 1999, searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactant; limits: age groups, newborn infant; publication type, clinical trials), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal hand searching in the English language.

In June 2008, the searches were updated including Medline, Cinhal and Embase using similar terms as the original search.

Selection criteria

Randomized controlled trials comparing a policy of multiple doses of surfactant to a policy of single doses of surfactant extract in premature infants at risk for or having respiratory distress syndrome were considered for this review.

Data collection and analysis

Data on clinical outcomes including pneumothorax, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (all intraventricular hemorrhage and severe intraventricular hemorrhage), bronchopulmonary dysplasia, retinopathy of prematurity, and mortality were excerpted by the both reviewers (R. Soll; E. Özek). For this update additional data were sought on pulmonary hemorrhage, periventricular leukomalacia, neurodevelopmental follow-up, rehospitalization for pulmonary reasons, and reactive airway disease. Data were analyzed according to the standards of the Cochrane Neonatal Review Group.

Results

Three trials were identified that met study criteria. Two studies were randomized controlled trials of multiple vs. single dose animal derived surfactant extract in infants with established respiratory distress syndrome. Meta-analysis of these trials suggests a reduction in the risk of pneumothorax (typical relative risk 0.51, 95% CI 0.30, 0.88; typical risk difference-0.09, 95% CI -0.15, -0.02) and a trend towards a reduction in the risk of mortality (typical relative risk 0.63, 95% CI 0.39, 1.02; typical risk difference -0.07, 95% CI -0.14, 00.00).

One study of multiple vs. single dose synthetic surfactant in infants at high risk of respiratory distress syndrome was identified. This study reported a decrease in NEC (relative risk 0.20, 95% CI 0.08, 0.51; risk difference-0.05, 95% CI -0.07, -0.02) and mortality (relative risk 0.56, 95% CI 0.39, 0.81; risk difference-0.07, 95% CI -0.12, -0.03)

No data on long-term neurological or pulmonary outcome were reported.

No complications associated with multiple dose treatment were reported in the identified trials.

Authors' conclusions

In infants with established respiratory distress, a policy of multiple doses of animal derived surfactant extract resulted in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of pneumothorax and a trend toward improved survival.

In infants at high risk of respiratory distress, a policy of multiple doses of synthetic surfactant resulted in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of NEC and decreased mortality.

The ability to give multiple doses of surfactant to infants with ongoing respiratory insufficiency leads to improved clinical outcome and appears to be the most effective treatment policy.

Plain language summary

Multiple vs. single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome

Multiple doses of surfactant have more benefit than a single dose.

Surfactant is essential to normal lung function in babies. Respiratory distress syndrome (RDS) is caused by a lack of, or dysfunction in, surfactant. A variety of surfactants (ranging for synthetic to animal derived) have been manufactured and are given to babies at risk for or having RDS. This review of trials found that multiple doses, rather than a single dose, further improved babies' outcomes. Multiple doses decreased the need for mechanical ventilation (machine-assisted breathing). In trials using animal derived surfactant in babies with RDS, multiple dose treatment lowered the risk of lung complications and there was a trend towards lowering the risk of death as well. In infants at high risk of respiratory distress, a policy of multiple doses of synthetic surfactant resulted in greater improvements regarding oxygenation and ventilatory requirements, a decreased risk of intestinal injury (necrotizing enterocolitis) and decreased mortality.

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Background

Randomized controlled trials have demonstrated the effectiveness of surfactant therapy in the treatment of infants at risk for or having respiratory distress syndrome. Surfactant administration decreases the severity of respiratory distress, decreases the frequency of pneumothorax, increases survival without chronic lung disease and decreases mortality (Soll 1992). In general, the initial trials of surfactant replacement therapy evaluated the effect of single doses of surfactant. In these studies, surfactant treatment resulted in rapid and dramatic improvements in oxygenation and ventilatory requirement. However, in many of the single dose studies, the clinical impact was less than anticipated. Fujiwara 1988 and Charon 1989 described the response of infants treated with single doses of surfactant. Both authors described a group of neonates that responded only transiently to surfactant therapy. The possibility of surfactant inhibition or inactivation has led investigators to attempt multiple dose therapy.

Multiple reviews have addressed the use of animal derived surfactant preparations or synthetic surfactant preparations in the prevention or treatment of respiratory distress syndrome (Soll 1997a; Soll 1998a; Soll 1998b). Reviews have also addressed the benefits of preventive or early treatment and the benefits of different specific surfactant products (Yost 1999; Soll 2001a; Soll 2001b; Pfister 2007; Stevens 2007). For this review, randomized controlled trials comparing a policy of multiple doses of surfactant to a policy of single doses of surfactant extract in premature infants at risk for or having respiratory distress syndrome were considered.

Objectives

To determine the effect of multiple doses of exogenous surfactant compared to a single dose of exogenous surfactant on mortality and complications of prematurity in premature infants at risk for or having respiratory distress syndrome.

Secondary objectives include subgroup analyses according to:

  • treatment strategy
  • surfactant preparation [synthetic surfactant (non-protein containing), protein containing synthetic surfactant, animal derived surfactant extract)
  • gestational age

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Methods

Criteria for considering studies for this review

Types of studies

Randomized, controlled clinical trials comparing a policy of multiple doses of exogenous surfactant to a policy of a single dose of exogenous surfactant in premature infants at risk for or having respiratory distress syndrome were considered for this review.

Types of participants

Participants will include:

  • premature infants (< 30 weeks gestation or < 1250g) at risk for respiratory distress syndrome
  • premature infants with established respiratory distress syndrome requiring assisted ventilation

Types of interventions

Infants were randomly allocated to receive either a single dose of an exogenous surfactant or multiple doses of an exogenous surfactant for the prevention or treatment of RDS. Exogenous surfactant preparations were classified as:

  • synthetic surfactant (non-protein containing)
  • protein containing synthetic surfactant
  • animal derived surfactant extract

Types of outcome measures

Clinical outcomes included initial improvement in oxygenation and need for ventilatory support as well as complications of prematurity including: pneumothorax, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (all intraventricular hemorrhage and severe intraventricular hemorrhage), chronic lung disease, retinopathy of prematurity and mortality. For this update additional data were sought on pulmonary hemorrhage, periventricular leukomalacia, neurodevelopmental follow-up, and rehospitalization for pulmonary reasons and reactive airway disease.

Search methods for identification of studies

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

  1. Published manuscripts: Search included Pubmed (1966 to June 2008), Cinhal, and EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 1. 2008). All languages were included. Search terms: {surfactant OR pulmonary surfactant}, limited to humans and further limited to the age group of newborn infants (infant, newborn) and type of publication (clinical trial). From the resulting studies randomized controlled studies that fulfill the inclusion criteria were selected. The bibliography cited in each publication obtained was searched in order to identify additional relevant articles.
  2. Published abstracts: The abstracts of the Society for Pediatric Research (USA) (published in Pediatric Research) for the years 1985 to 2008 were searched by hand using the following key words: {surfactant OR pulmonary surfactant} AND {respiratory distress syndrome}.

Data collection and analysis

We used the standard methods of the Cochrane Collaboration as described in the Cochrane Collaboration Handbook and the specific recommendations of the Neonatal Review Group.

Selection process:

We included randomized controlled trials fulfilling the selection criteria described in the previous section. Both review authors separately selected the studies for inclusion. Any disagreements were resolved by discussion.

Criteria for assessing the methodological quality of the studies:

We used the standard method of the Cochrane Neonatal Review Group. We assessed the methodological quality of the studies by assessing the risk for four types of bias (selection, performance, attrition and detection). Both review authors separately assessed each study. Any disagreements were resolved by discussion.

Data extraction and entry:

Both review authors separately extracted, assessed and coded all data for each study, using a form that was designed specifically for this review. We replaced any standard error of the mean by the corresponding standard deviation. Any disagreements were resolved by discussion. For each study, final data will be entered into RevMan by one review author (RS) and then checked by a second review author (EO).

Statistical analyses:

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

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Results

Description of studies

The review includes the following studies: Corbet 1995; Dunn 1990; Speer 1992. The methods of randomization, description of participants, description of interventions, and outcomes reported are summarized in the Table of Characteristics of Included Studies.

Studies with animal derived surfactant extract:

Dunn 1990: Dunn and coworkers studied premature infants within a gestational age of 30 - 36 weeks. Included infants had respiratory distress syndrome requiring assisted ventilation and supplemental oxygen. Enrollment occurred before six hours of age. Seventy-five infants were randomly assigned to either control (air placebo), a single dose of bovine lung surfactant extract (100 mg/kg) or multiple doses of bovine lung surfactant extract (100 mg/kg). Infants assigned to the multiple dose group could receive up to three additional doses as indicated during the first 72 hours of life.

Speer 1992: Speer and coworkers conducted a randomized multicenter trial to determine whether the beneficial effects of a single dose of Curosurf (200 mg/kg) in infants with severe respiratory distress syndrome could be enhanced by using multiple doses of surfactant. Preterm neonates (birth weight 700 to 2000 g) with severe respiratory distress syndrome requiring artificial ventilation and a fraction of inspired oxygen greater than or equal to 0.6 were randomized into two groups at an age of 2 to 15 hours (single dose: n = 176, multiple doses: n = 167). Both groups received Curosurf (200 mg/kg) immediately after randomization. In neonates randomized to receive multiple dose treatment, two additional doses of Curosurf (100 mg/kg each) were instilled into the airways (12 and 24 hours after the initial dose) provided that the infant still needed artificial ventilation with a fraction of inspired oxygen greater than 0.21.

Studies with synthetic surfactant:

Corbet 1995: Corbet and coworkers conducted a double-blind, randomized clinical trial at 33 US centers comparing one vs. three prophylactic doses of synthetic surfactant in inborn infants with a birth weight of 700 to 1100 g. All 826 infants received an initial prophylactic dose of synthetic surfactant (Exosurf Neonatal) within 30 minutes of birth. Subsequently 410 infants received two doses of placebo (air) 12 and 24 hours later, and 416 infants received two additional doses of surfactant.

Study outcomes included initial clinical improvement (measurements of oxygenation and ventilatory support) as well as complications of prematurity including pneumothorax, patent ductus arteriosus, pulmonary hemorrhage, necrotizing enterocolitis, sepsis, intraventricular hemorrhage, bronchopulmonary dysplasia, and mortality. This review focuses on clinical outcomes described in these three studies.

Risk of bias in included studies

Only randomized clinical trials that compared multiple doses of exogenous surfactant to single doses of exogenous surfactant in premature infants at risk for or having respiratory distress syndrome were included in the analysis.

Trials comparing various other dosage strategies are not included in this review.

All three studies used of sealed, opaque envelopes for randomization. In the study of Dunn 1990, randomization was stratified by gestational age, exposure to antenatal steroids, and the infant's gender. Speer 1992 stratified infants by birthweight. In the study of Corbet 1995, randomization used stratification by gestational age and the infant's gender.

Dunn 1990 attempted to minimize bias by having staff not involved with the care of the patient administer surfactant. Speer 1992 made no attempt to conceal treatment assignment. Corbet 1995 attempted to minimize bias by having a "drug administration team" (staff not involved with the care of the patient) administer any subsequent surfactant doses.

Effects of interventions

COMPARISON 1: Multiple vs. single doses of exogenous surfactant for the prevention or treatment of respiratory distress syndrome

Dunn 1990 administered multiple doses to 70% of the infants randomized to multiple dose policy. Speer 1992 administered multiple doses to 65% of infants randomized to a multiple dose policy. The percentage of infant's receiving multiple doses in the study of Corbet 1995 is unclear.

All three studies demonstrated more sustained improvement in oxygenation and decreased requirement for ventilatory support in the group of infants allowed to receive multiple doses of exogenous surfactant. Other clinically important outcomes are detailed below:

Pneumothorax (Outcome 1.1):

Animal derived surfactant extract: Both trials reported on the outcome pneumothorax. Speer 1992 reported a reduction in the incidence of pneumothorax in the multiple dose group (9% vs. 18%, relative risk 0.49, 95%CI 0.28, 0.88; risk difference -0.09, 95%CI -0.15, -0.02). The meta-analysis supports a decreased risk of pneumothorax associated with multiple dose surfactant therapy (typical relative risk 0.42, 95% CI 0.35, 0.52; typical risk difference -0.18, 95% CI -0.22, -0.14).

Synthetic surfactant: Corbet 1995 did not report a statistically significant reduction in the risk of pneumothorax (relative risk 0.82, 95% CI 0.57, 1.17).

Pulmonary Hemorrhage (Outcome 1.2):

Animal derived surfactant extract: Only Speer 1992 reported on the outcome pulmonary hemorrhage.There was no statistically significant difference in the risk of pulmonary hemorrhage in the multiple dose group (relative risk 0.79, 95%CI 0.18, 3.48; risk difference -0.00, 95%CI -0.03, 0.03).

Synthetic surfactant: Corbet 1995 did not report a statistically significant difference in the risk of pulmonary hemorrhage (relative risk 1.24, 95% CI 0.69, 2.24).

Patent Ductus Arteriosus (Outcome 1.3):

Animal derived surfactant extract: Both Dunn 1990 and Speer 1992 reported on the outcome Patent Ductus Arteriosus (PDA). Neither study reported a reduction in Patent Ductus Arteriosus. The meta-analysis does not support a decreased in the risk of Patent Ductus Arteriosus associated with multiple dose surfactant therapy (typical relative risk 1.12, 95% CI 0.93, 1.36; typical risk difference -0.18, 95% CI -0.22, -0.14).

Synthetic surfactant: Corbet 1995 did not report a statistically significant reduction in the risk of Patent Ductus Arteriosus (relative risk 1.02, 95% CI 0.90, 1.14).

Necrotizing Eneterocolitis (Outcome 1.4):

Animal derived surfactant extract: Only Speer 1992 reported on the outcome necrotizing enterocolitis.There was a trend towards a decrease in the risk of necrotizing enterocolitis in the multiple dose group (relative risk 0.10, 95%CI 0.01, 1.72; risk difference -0.03, 95%CI -0.06, 0.00).

Synthetic surfactant: Corbet 1995 reported a statistically significant difference in the risk of necrotizing enterocolitis (relative risk 0.20, 95% CI 0.08, 0.51; risk difference -0.05, 95%CI -0.06, -0.02).

Bacterial sepsis (Outcome 1.5):

Animal derived surfactant extract: Only Speer 1992 reported on the outcome bacterial sepsis.There was a trend towards a decrease in the risk of bacterial sepsis in the multiple dose group (relative risk 0.66, 95%CI 0.41, 1.08; risk difference -0.07, 95%CI -0.15, 0.01).

Synthetic surfactant: Corbet 1995 reported no statistically significant difference in the risk of bacterial sepsis (relative risk 0.20, 95% CI 0.08, 0.51; risk difference -0.03, 95%CI -0.09, 0.03).

Intraventricular hemorrhage (Outcome 1.6):

Animal derived surfactant extract: Both Dunn 1990 and Speer 1992 reported on Intraventricular hemorrhage (IVH). Neither study reported a reduction in IVH overall. The meta-analysis does not support a decreased in the risk of Intraventricular hemorrhage associated with multiple dose surfactant therapy (typical relative risk 0.98, 95% CI 0.77, 1.25; typical risk difference -0.01, 95% CI -0.10, 0.09).

Synthetic surfactant: Corbet (1995) did not report on the overall incidence of Intraventricular hemorrhage.

Severe Intraventricular hemorrhage (Outcome 1.7):

Animal derived surfactant extract: Neither the study of Dunn 1990 or Speer 1992 reported a reduction in the risk of severe intraventricular hemorrhage. The meta-analysis does not support a decreased risk of severe intraventricular hemorrhage associated with multiple dose animal derived surfactant extract therapy (typical relative risk 1.14, 95% CI 0.76, 1.71; typical risk difference -0.18, 95% CI -0.22, -0.14).

Synthetic surfactant: Corbet 1995 did not report a statistically significant reduction in the risk of severe intraventricular hemorrhage (relative risk 0.96, 95% CI 0.72, 1.26).

Bronchopulmonary Dysplasia (Outcome 1.8):

Animal derived surfactant extract: Neither the study of Dunn 1990 or Speer 1992 reported a reduction in the risk of bronchopulmonary dysplasia.The meta-analysis does not support a decreased risk of bronchopulmonary dysplasia associated with multiple dose animal derived surfactant extract therapy (typical relative risk 1.00, 95% CI 0.58, 1.71; typical risk difference 0.00, 95% CI -0.06, 0.06).

Synthetic surfactant: Corbet (1995) did not report a statistically significant reduction in the risk of pneumothorax (relative risk 1.20, 95% CI 0.82, 1.76).

Mortality (Outcome 1.9):

Animal derived surfactant extract: Both trials reported on mortality. Speer 1992 reported a trend towards a reduction in the risk of mortality in the multiple dose group (relative risk 0.63, 95%CI 0.39, 1.02; risk difference -0.08, 95%CI -0.16, 0.00). The meta-analysis supports a decreased risk of mortality associated with multiple dose surfactant therapy (typical relative risk 0.63, 95% CI 0.39, 1.02; typical risk difference -0.07, 95% CI -0.14, 0.00).

Synthetic surfactant: Corbet 1995 reported a statistically significant reduction in the risk of mortality (relative risk 0.56, 95% CI 0.39, 0.81; risk difference -0.07, 95% CI -0.12, -0.03).

Bronchopulmonary Dysplasia or death (Outcome 1.10):

Animal derived surfactant extract: Only Speer 1992 reported on the combined outcome Bronchopulmonary Dysplasia or death.There was no decrease in the risk of Bronchopulmonary Dysplasia or death in the multiple dose group (relative risk 0.80, 95%CI 0.57, 1.11; risk difference -0.07, 95%CI -0.16, 0.03).

Synthetic surfactant: Corbet 1995 reported no statistically significant difference in the risk of Bronchopulmonary Dysplasia or death (relative risk 0.84, 95% CI 0.66, 1.08; risk difference -0.04, 95%CI -0.10, 0.02).

Discussion

Although the initial trials of single dose surfactant therapy demonstrated dramatic results regarding early improvement in oxygenation and ventilatory support, the clinical outcome was not as promising as anticipated. In animal studies, a more sustained response to surfactant therapy could be maintained if animals were given repeated doses of animal derived surfactant extract (Walthers 1985). In retrospective analyses of single dose surfactant therapy studies, it was clear that as many as one-third of the treated infants appeared to relapse after initial therapy (Fujiwara 1988; Charon 1989). The use of repeated dosing was an attractive way to improve and sustain response to surfactant therapy. Two randomized controlled trials reported on the effect of a policy of multiple dose surfactant therapy compared to a policy of single dose therapy with animal derived surfactant extract. Sustained response was reported in the group that received multiple doses of surfactant. The meta-analysis suggests a decreased risk of pneumothorax and a trend toward a decreased risk of mortality.

Corbet 1995 compared one vs. three prophylactic doses of synthetic surfactant in inborn infants with a birth weight of 700 to 1100 g. They demonstrated.a statistically significant reduction in the risk of mortality, in the risk of necrotizing enterocolitis and more sustained improvement in oxygenation and decreased requirement for ventilatory support in the group of infants allowed to receive multiple doses of exogenous surfactant.

Authors' conclusions

Implications for practice

A more sustained response is seen in infants with respiratory distress syndrome who are allowed multiple doses of exogenous surfactant. Meta-analysis suggests improvement in clinical outcomes including decreasing the risk of pneumothorax. The ability to give multiple doses of exogenous surfactant appears to be the most desirable approach to treatment.

Implications for research

Multiple clinical trials have compared a variety of dosing issues including timing of treatment (prophylactic administration of surfactant vs. treatment of established respiratory distress syndrome); a variety of high dose and low dose regimens, and single v. multiple doses (discussed in this analysis). Specific criteria for repeat doses and timing of repeat doses could be refined in future studies.

Acknowledgements

Drs. Soll and Özek would like to acknowledge the help of Susan Hayward in preparation of the manuscript.

Contributions of authors

Dr Roger Soll wrote the original review. Dr. Eren Özek planned the modifications of the review for the update. Both review authors reviewed the search strategy, reviewed the output from the search, selected studies, excerpted data on clinical outcomes, and helped draft the manuscript.

Declarations of interest

Dr. R. Soll has acted as a paid 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. Soll has acted as the principal investigator or co-investigator of several of the randomized controlled trials of surfactant preparations (trials not included in this review).

Dr. E. Ozek has been a speaker at educational programs sponsored by Abbott Laboratories, a manufacturer of surfactant products.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Corbet 1995

Methods

Randomized controlled
Multicenter
Blinding of Randomization: Yes
Blinding of Intervention: Yes
Complete Follow-up: Yes
Blinding of Outcome Measurement: Yes

Participants

Birth weight 700-1100g

Interventions

All infants received initial prophylactic dose of synthetic surfactant within 30 minutes of birth

Subsequent management: two additional doses of synthetic surfactant (Exosurf Neonatal) or placebo

Outcomes

PRIMARY:
a/A ratio
SECONDARY:
Ventilatory Requirement
Complications of Prematurity

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

Dunn 1990

Methods

Randomized controlled
Single center
Blinding of Randomization: Yes
Blinding of Intervention: Yes
Complete Follow-up: Yes
Blinding of Outcome Measurement: Yes
Stratification: gestational age,
Antenatal steroids, Sex

Participants

Premature infants
Gestational age 30-36 wks
Respiratory distress syndrome
Assisted ventilation
Supplemental oxygen
Age < 6 hrs

Interventions

Control (air placebo) vs single dose
Bovine lung surfactant extract
(100 mg/kg) vs multiple dose
(max 4 doses)
Bovine lung surfactant extract
(100 mg/kg)
Retreatment allowed
in multiple dose group
during first 72 hrs of life
(max 4 doses)

Outcomes

PRIMARY:
a/A ratio
SECONDARY:
Ventilatory Requirement
Complications of Prematurity

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

Speer 1992

Methods

Randomized
Multicenter trial
Blinding of Randomization: Yes
Blinding of Intervention: No
Complete Follow-up: Yes
Blinding of Outcome Measurement: No
Stratified by birthweight

Participants

Premature infants
Birthweight 700-2000 grams
Respiratory distress syndrome
Assisted ventilation
Supplemental oxygen equal to or greater than 60%
Age 2-15 hrs

Interventions

Single dose Curosurf (100 mg/kg) vs. Multiple dose Curosurf
(100 mg/kg) x 3 doses
Multiple dose group received additional doses of Curosurf
at 12 and 24 hours after initial dose
if on assisted ventilation

Outcomes

PRIMARY:
Bronchopulmonary dysplasia or death
SECONDARY:
Ventilatory requirements
Oxygenation
Complications of Prematurity

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

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References to studies

Included studies

Corbet 1995

Corbet A, Gerdes J, Long W, Avila E, Puri A, Rosenberg A, Edwards K, Cook L. Double-blind randomized trial of one versus three prophylactic doses of synthetic surfactant in 826 neonates weighing 700 to 1000 grams: effects on mortality rate. Journal of Pediatrics 1995;126:969-78.

Dunn 1990

Dunn MS, Shennan AT, Possmayer F. Single- vs multiple- dose surfactant replacement therapy in neonates of 30 to 36 weeks' gestation with respiratory distress syndrome. Pediatrics 1990;86:564-71.

Speer 1992

Speer CP, Robertson B, Curstedt T, Halliday HL [see article for full collaborative authorship]. Randomized European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: single vs multiple doses of Curosurf. Pediatrics 1992;89:13-20.

Ongoing studies

Other references

Additional references

Charon 1989

Charon A, Taeusch HE, Fitzgibbon C, et al. Factors associated with surfactant treatment response in infants with severe respiratory distress syndrome. Pediatrics 1989;83:348-54.

Fujiwara 1988

Fujiwara T, Konishi M, Chida S, et al. Factors affecting response to a single postnatal dose of exogenous surfactant in surfactant treatment of lung disease. In: Jobe A, Taeusch HW, editor(s). Report of the 96th Ross Conference on Pediatric Research. Ohio: Ross Laboratories, 1988.

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.

Soll 1992

Soll RF, McQueen MC. Respiratory distress syndrome. In: Sinclair JC, Bracken M, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:325-58.

Soll 1997a

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

Soll 1998a

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

Soll 1998b

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

Soll 2001a

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

Soll 2001b

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

Stevens 2007

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

Walthers 1985

Walthers FJ, Blaco CE, Houdijk M, Bevers EM. Single versus repetitive doses of natural surfactant as treatment of respiratory distress syndrome in premature lambs. Pediatric Research 1985;19:224-7.

Yost 1999

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

Other published versions of this review

Soll 1997b

Soll RF. Multiple v. single dose natural surfactant extract for severe RDS. Cochrane Database of Systematic Reviews 1997, Issue 3. Art. No.: CD000141. DOI: 10.1002/14651858.CD000141.

Soll 1999

Soll RF. Multiple versus single dose natural surfactant extract for severe neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 1999, Issue 2. Art. No.: CD000141. DOI: 10.1002/14651858.CD000141.

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Data and analyses

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Pneumothorax 3 1220 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.52, 0.94]
1.1.1 Animal derived surfactant extract 2 394 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.30, 0.88]
1.1.2 Synthetic surfactant 1 826 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.57, 1.17]
1.2 Pulmonary Hemorrhage 2 1169 Risk Ratio (M-H, Fixed, 95% CI) 1.17 [0.68, 2.01]
1.2.1 Animal derived surfactant extract 1 343 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.18, 3.48]
1.2.2 Synthetic surfactant 1 826 Risk Ratio (M-H, Fixed, 95% CI) 1.24 [0.69, 2.24]
1.3 Patent ductus arteriosus 3 1169 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.95, 1.16]
1.3.1 Animal derived surfactant extract 2 343 Risk Ratio (M-H, Fixed, 95% CI) 1.12 [0.93, 1.36]
1.3.2 Synthetic surfactant 1 826 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.90, 1.14]
1.4 Necrotizing Enterocolitis 2 1169 Risk Ratio (M-H, Fixed, 95% CI) 0.18 [0.07, 0.44]
1.4.1 Animal derived surfactant extract 1 343 Risk Ratio (M-H, Fixed, 95% CI) 0.10 [0.01, 1.72]
1.4.2 Synthetic surfactant 1 826 Risk Ratio (M-H, Fixed, 95% CI) 0.20 [0.08, 0.51]
1.5 Bacterial sepsis 2 1169 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.70, 1.04]
1.5.1 Animal derived surfactant extract 1 343 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.41, 1.08]
1.5.2 Synthetic surfactant 1 826 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.73, 1.13]
1.6 Intraventricular hemorrhage 2 394 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.77, 1.25]
1.6.1 Animal derived surfactant extract 2 394 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.77, 1.25]
1.7 Severe intraventricular hemorrhage 3 1220 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.72, 1.29]
1.7.1 Animal derived surfactant extract 2 394 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.76, 1.71]
1.7.2 Synthetic surfactant 1 826 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.54, 1.26]
1.8 Bronchopulmonary dysplasia 3 1221 Risk Ratio (M-H, Fixed, 95% CI) 1.13 [0.83, 1.54]
1.8.1 Animal derived surfactant extract 2 394 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.58, 1.71]
1.8.2 Synthetic surfactant 1 827 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.82, 1.76]
1.9 Mortality 3 1220 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.44, 0.78]
1.9.1 Animal derived surfactant extract 2 394 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.39, 1.02]
1.9.2 Synthetic surfactant 1 826 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.39, 0.81]
1.10 BPD or death 2 1170 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.68, 1.01]
1.10.1 Animal derived surfactant extract 1 343 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.57, 1.11]
1.10.2 Synthetic surfactant 1 827 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.66, 1.08]

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This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2009 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.