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Synthetic surfactant treatment for preterm infants with respiratory distress syndrome

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Authors

Soll RF

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


Dates

Date of most recent amendment: 26/05/1998
Date of most recent substantive amendment: 22/05/1998
Date next stage expected: / /

Contact reviewer

Dr Roger F. Soll

Associate Professor of Pediatrics
Department of Pediatrics
University of Vermont College of Medicine
A-121 Medical Alumni Building
Burlington
VT USA
05405-0068
Telephone 1: +1-802-656-2392
Facsimile: +1-802-656-2077

E-mail: rsoll@salus.med.uvm.edu

Sources of support

Neonatal Collaborative Review Group, NIH Contract #N01-MD-6-3253, USA

Acknowledgements

I would like to thank Nancy Moreland for preparation of this manuscript.

Potential conflict of interest

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).

Abstract

Objective

To assess the effect of intratracheal administration of synthetic surfactant in premature newborns with established respiratory distress syndrome (RDS).

Search strategy

Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactants; limits: age groups, newborn infant; publication types, clinical trial), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal handsearching in the English language.

Selection criteria

Randomized controlled trials which compared the effect of synthetic surfactant treatment to routine management in the treatment of preterm infants with respiratory distress syndrome.

Data collection & analysis

Data regarding clinical outcome including the incidence of pneumothorax, pulmonary interstitial emphysema, pulmonary hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, apnea of prematurity, intraventricular hemorrhage (any grade, and severe intraventricular hemorrhage), bronchopulmonary dysplasia, neonatal mortality, bronchopulmonary dysplasia or death, retinopathy of prematurity (any retinopathy, and retinopathy greater than Stage 3), mortality at hospital discharge, mortality to one year of age, and cerebral palsy (any, and moderate/severe cerebral palsy) was excerpted from the report of the clinical trials by the reviewer. Data were analyzed according to the standards of the Cochrane Neonatal Review Group.

Main results

Six randomized controlled trials of synthetic surfactant treatment of established respiratory distress syndrome were identified. Five of the studies used Exosurf Neonatal (a synthetic surfactant composed of dipalmitoylphosphatidylcholine, hexadecanol and tyloxapol); one small study utilized a mixture of dipalmitoylphosphatidylcholine (DPPC) and phosphatidylglycerol (PG). Treatment with intratracheal Exosurf Neonatal in premature infants with established respiratory distress syndrome improves pulmonary gas exchange and decreases the requirement for ventilatory support. In individual trials, the use of Exosurf Neonatal resulted in a statistically significant reduction in pneumothorax, patent ductus arteriosus, bronchopulmonary dysplasia (BPD), BPD or death at 28 days, and mortality. Similar results are seen when these large trials of Exosurf Neonatal are analyzed in conjunction with the smaller trial of dry powdered DPPC and phosphatidylglycerol (PG). The meta-analysis supports a decrease in the risk of pneumothorax (typical relative risk 0.64, 95% CI 0.55, 0.76, typical risk difference -0.09, 95% CI -0.12, -0.06), a decrease in the risk of pulmonary interstitial emphysema (typical relative risk 0.62, 95% CI 0.54, 0.71, typical risk difference -0.12, 95% CI -0.16, -0.09), a decrease in the risk of patent ductus arteriosus (typical relative risk 0.90, 95% CI 0.84, 0.97; typical risk difference -0.06 95% CI -0.10, -0.02), a decrease in the risk of intraventricular hemorrhage (typical relative risk 0.88, 95% CI 0.77, 0.99; typical risk difference -0.04, 95% CI -0.08, -0.00), a decrease in the risk of bronchopulmonary dysplasia (typical relative risk 0.75, 95% CI 0.61, 0.92; typical risk difference -0.04, 95% CI -0.06, -0.01), a decrease in the risk of neonatal mortality (typical relative risk 0.73, 95% CI 0.61, 0.88; typical risk difference -0.05, 95% CI -0.07, -0.02), a decrease in the risk of bronchopulmonary dysplasia or death at 28 days (typical relative risk 0.73, 95% CI 0.65, 0.83; typical risk difference -0.06, 95% CI -0.11, -0.05), a decrease in the risk of mortality prior to hospital discharge (typical relative risk 0.79, 95% CI 0.68, 0.92; typical risk difference -0.05, 95% CI -0.07, -0.02) and a decrease in the risk of mortality during the first year of life (typical relative risk 0.80, 95% CI 0.69, 0.94; typical risk difference -0.04, 95% CI -0.07, -0.01). Treatment with synthetic surfactant increases the risk of apnea of prematurity (typical relative risk 1.20, 95% CI 1.09, 1.31; typical risk difference 0.08, 95% CI 0.04, 0.12).

Conclusions

Intratracheal administration of synthetic surfactant to infants with established respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who are treated with synthetic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, a decreased risk of intraventricular hemorrhage, a decreased risk of bronchopulmonary dysplasia, a decreased risk of neonatal mortality, a decreased risk of mortality prior to hospital discharge and at 1 year of age. Infants who receive synthetic surfactant treatment for established RDS have an increased risk of apnea of prematurity.

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Background

Respiratory Distress Syndrome (RDS) is caused by a deficiency or dysfunction of pulmonary surfactant. Surfactant lines the alveolar surface and prevents atelectasis at end expiration. Pulmonary surfactant is predominantly dipalmitoylphosphatidylcholine with lesser amounts of other phospholipids including phosphatidylglycerol (PG), phosphatydylethanolamine, and phosphatidylinositol. Pulmonary surfactant also contains neutral lipids and distinct surfactant proteins. The physiologic function of surfactant includes the ability to lower surface tension, as well as the ability to rapidly adsorb, spread, and reform a monolayer in the the dynamic conditions associated with the respiratory cycle (Jobe 1993).

The first attempts to utilize synthetic surfactants occurred in the 1960s. Investigators attempted to aerosolize dipalmitoylphosphatidylcholine (DPPC) to infants with established respiratory distress syndrome (Robillard 1964, Chu 1967). These investigators could not demonstrate any beneficial effect of surfactant replacement. The poor results were due to an incomplete understanding of what constitutes pulmonary surfactant. The first successful animal model of surfactant replacement therapy was conducted by Enhorning and coworkers (1972). Enhorning administered a crude, natural surfactant extract obtained from lavage of the lungs of mature rabbits directly into the trachea of immature rabbits. Improvement in lung compliance and alveolar expansion was noted. Success in animal models led to widespread clinical trials of surfactant therapy in the newborn.

A wide variety of surfactant products has been formulated and studied in clinical trials. These include synthetic surfactants and natural surfactant extracts. Natural surfactant extracts are derived from animal or human sources. Currently used synthetic surfactants are complex combinations of dipalmitoylphosphatidylcholine and other phospholipids, neutral lipids, lipoprotein, or alcohols. Components of synthetic surfactants are not directly obtained from the extraction of surfactant from animal lung.

The original trials of DPPC alone are not included in this review, since neither the surfactant nor the route of administration are considered adequate. Included trials all used complex synthetic surfactants in an attempt to treat infants with established respiratory distress syndrome. In these studies, infants requiring assisted ventilation with clinical and radiographic evidence of respiratory distress syndrome were randomized to receive intratracheal synthetic surfactant or control treatment. Investigators hoped to decrease the need for cardiorespiratory support and the incidence of complications associated with prematurity.

The following analysis is a systematic review of six randomized controlled trials which compare synthetic surfactant administration in infants with established respiratory distress syndrome to control treatment. Results of some of these analyses were previously published in "Effective Care of the Newborn Infant" (Soll, 1992).

Objectives

To assess the effect of intratracheal synthetic surfactant treatment in infants with established respiratory distress syndrome (RDS).

Materials and Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials comparing intratracheal synthetic surfactant treatment of established respiratory distress syndrome to control treatment.

Types of participants

Neonates with clinical and radiologic evidence of respiratory distress syndrome requiring assisted ventilation.

Types of intervention

Infants randomized to receive synthetic surfactant treatment versus control treatment (intratracheal administration of air placebo). Five studies utilized Exosurf Neonatal (dipalmitoylphosphatidylcholine, hexadecanol, and tyloxapol) (Phibbs 1991, Long 1991, US Exosurf 1991, Smyth 1995, McMillan 1995). Wilkinson (1985) used dry powdered DPPC and phosphatidylglycerol.

Types of outcome measures

Data for the following clinical outcomes are included in the meta-analysis: 1) pneumothorax, 2) pulmonary interstitial emphysema, 3) pulmonary hemorrhage, 4) patent ductus arteriosus, 5) necrotizing enterocolitis, 6) apnea of prematurity, 7) intraventricular hemorrhage, 8) severe intraventricular hemorrhage (Grade III or PVED), 9) bronchopulmonary dysplasia, 10) retinopathy of prematurity, 11) severe retinopathy of prematurity (greater than stage 3), 12) neonatal mortality, 13) mortality prior to hospital discharge, 14) bronchopulmonary dysplasia or death, 15) mortality at 1 year of age, 16) not assessed at follow-up, 17) cerebral palsy, 18) moderate/severe cerebral palsy.

Search strategy for identification of studies

Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactants; limits: age groups, newborn infant; publication types, clinical trial), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal handsearching in the English language.

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Methods of the review

For each included study, information was collected regarding the method of randomization, blinding, drug intervention, stratification, and whether the trial was single or multicenter. Information regarding trial participants including birthweight criteria, and other inclusion or exclusion criteria was noted. Information on clinical outcome was analyzed including pneumothorax, pulmonary interstitial emphysema, pulmonary hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, apnea of prematurity, intraventricular hemorrhage (any intraventricular hemorrhage and severe intraventricular hemorrhage), bronchopulmonary dysplasia, retinopathy of prematurity (any retinopathy and severe retinopathy greater than Stage 3), neonatal mortality, mortality prior to hospital discharge, bronchopulmonary dysplasia or death, mortality at 1 year of age, assessment at follow-up, and cerebral palsy (any cerebral palsy and moderate/severe cerebral palsy).

Description of studies

Studies included in this review: Wilkinson (1985), Phibbs (1991), Long (1991), US Exosurf Study (1991), Smyth (1995), and McMillan (1995). Details of each study are given in the "Characteristics of Included Studies" table and references.

Wilkinson (1985) evaluated the use of dry DPPC/PG in a small, randomized controlled trial. Infants of 31 weeks' gestation or less who did not require intubation in the delivery room (and therefore were not enrolled in the prevention study) were enrolled if they subsequently developed respiratory distress syndrome requiring assisted ventilation and demonstrated an immature lecithin/sphingomyelin ratio. Neither immediate nor long-term benefit could be demonstrated with treatment.

With the exception of Wilkinson (1985), all other trials of synthetic surfactant treatment utilized Exosurf Neonatal. Phibbs (1991) studied the effect of a single dose of Exosurf Neonatal in infants weighing 650 grams or more who had RDS requiring assisted ventilation and supplemental oxygen greater than 40%. Requirements for ventilatory support decreased significantly during the 72 hours after treatment. No other clinical benefit was noted.

Four large multicenter trials studied the effect of multiple doses of Exosurf Neonatal in the treatment of respiratory distress syndrome (Long 1991, US Exosurf Study 1991, McMillan 1995, Smyth 1995). These trials evaluated a wide range of infants with severe respiratory distress syndrome. The US Exosurf Study (1991) and McMillan (1995) (the Canadian Exosurf Neonatal Study Group) evaluated very low birthweight infants with respiratory distress syndrome (birthweight criteria: US Exosurf Study 700-1350 grams, McMillan/Canadian Exosurf Study 750-1249 grams). Infants were enrolled if they had respiratory distress syndrome requiring assisted ventilation, an arterial/alveolar ratio < 0.22, and were between 2 and 24 hours of age. Both trials reported significant improvement in respiratory status during the first week of life. The US Exosurf Trial (1991) reported a decrease in mortality in surfactant treated infants. In both studies, a significant decrease in the incidence of pneumothorax and BPD or death at 28 days of age was noted.

Larger infants with respiratory distress syndrome were studied by the combined American and Canadian Exosurf Neonatal Study Group (1991). Entry criteria were similar to the other Exosurf treatment studies, except infants with birthweight >1250 grams were enrolled. Surfactant treated infants had significant improvement in respiratory status as well as improvement in long-term clinical outcome. A significant reduction in pneumothorax, intraventricular hemorrhage, bronchopulmonary dysplasia, and neonatal death was noted. As previously described in the smaller infants, an increase in apnea of prematurity was reported.

Smyth (1995) has reported on extremely low birthweight infants weighing 500-749 grams who met entry criteria similar to the other Exosurf treatment studies. No clinical improvement was associated with treatment.

Methodological quality of included studies

Randomized controlled trials which compared the effect of intratracheal synthetic surfactant treatment to control treatment (sham air treatment) in infants with established respiratory distress syndrome are included in the analysis. Specific methodologic issues regarding the six studies are discussed below:

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

BLINDING OF TREATMENT: Investigators attempted to blind treatment. Most studies relied on a drug administration team to administer the randomly allocated treatment. Individuals in this drug administration team were not responsible for ongoing care of the infant or for study evaluation.

BLINDING OF OUTCOME ASSESSMENT: Investigators who were not involved with treatment assessed study outcomes.

EXCLUSION AFTER RANDOMIZATION: Minimal exclusions were noted after randomization. All the trials report on the short term (in hospital) outcomes of virtually all randomized infants. However, long term follow-up for neurodevelopmental status (including evaluation for cerebral palsy) ranges from 84% to 100% of survivors.

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Results

Treatment of premature infants with established respiratory distress syndrome using complex synthetic surfactants (Exosurf Neonatal) leads to an improvement in oxygenation and ventilatory requirement. Synthetic surfactant treatment of premature infants with established respiratory distress syndrome has the following clinical impact:

PNEUMOTHORAX: Five of the randomized controlled trials reported on the incidence of pneumothorax. Long (1991), McMillan (1995), and the US Exosurf Study (1991) all demonstrated a decrease in the risk of pneumothorax associated with synthetic surfactant treatment. The typical estimate from the meta-analysis of all five trials suggests that synthetic surfactant extract treatment will lead to a significant reduction in the risk of pneumothorax (typical relative risk 0.64, 95% CI 0.55, 0.76; typical risk difference -0.09, 95% CI -0.12, -0.06).

PULMONARY INTERSTITIAL EMPHYSEMA: Four of the randomized controlled trials reported on the incidence of pulmonary interstitial emphysema. Long (1991), McMillan (1995), and the US Exosurf Study (1991) all reported a decrease in the risk of pulmonary interstitial emphysema associated with synthetic surfactant treatment. The typical estimate from the meta-analysis suggests that synthetic surfactant treatment will lead to a significant reduction in the risk of pulmonary interstitial emphysema (typical relative risk 0.62, 95% CI 0.54, 0.71, typical risk difference -0.12, 95% CI -0.16, -0.09).

PULMONARY HEMORRHAGE: Five of the randomized controlled trials reported on pulmonary hemorrhage. None of the individual trials reported a difference in the risk of pulmonary hemorrhage. The typical estimate from the meta-analysis suggests no effect of synthetic surfactant treatment on the risk of pulmonary hemorrhage (typical relative risk 1.44, 95% CI 0.68, 3.05; typical risk difference 0.00, 95% CI -0.00, 0.01).

PATENT DUCTUS ARTERIOSUS: Five of the randomized controlled trials reported on the incidence of patent ductus arteriosus associated with synthetic surfactant treatment. Long (1991) demonstrated a decrease in the risk of patent ductus arteriosus (relative risk 0.84, 95% CI 0.75, 0.95; risk difference -0.08, 95% CI -0.14, -0.03). The US Exosurf Study (1991) reported a trend towards decreased risk of patent ductus arteriosus. The typical estimate from the meta-analysis suggests that synthetic surfactant treatment of infants with established respiratory distress syndrome will lead to a significant reduction in the risk of patent ductus arteriosus (typical relative risk 0.90, 95% CI 0.84, 0.97; typical risk difference -0.06, 95% CI -0.10, -0.02).

NECROTIZING ENTEROCOLITIS: Five the randomized controlled trials reported on the incidence of necrotizing enterocolitis. None of the individual trials reported a difference in the risk of necrotizing enterocolitis and the typical estimate from the meta-analysis supports no difference in the risk of necrotizing enterocolitis (typical relative risk 1.32, 95% CI 0.76, 2.29; typical risk difference 0.01, 95% CI -0.01, 0.02).

APNEA OF PREMATURITY: Four trials reported on the risk of apnea of prematurity. The trials of Long (1991) and the US Exosurf Study (1991) both reported an increased risk of apnea of prematurity associated with synthetic surfactant treatment. The typical estimate from the meta-analysis suggests an increase in the risk of apnea of prematurity associated with synthetic surfactant treatment (typical relative risk 1.20, 95% CI 1.09, 1.31; typical risk difference 0.08, 95% CI 0.04, 0.12).

INTRAVENTRICULAR HEMORRHAGE: Four of the randomized controlled trials reported on the risk of intraventricular hemorrhage. Long (1991) reported a decrease in the risk of intraventricular hemorrhage associated with synthetic surfactant treatment (relative risk 0.76, 95% CI 0.61, 0.95; risk difference -0.06, 95% CI -0.10, -0.01). The typical estimate from the meta-analysis suggests a decrease in the risk of intraventricular hemorrhage (typical relative risk -0.88, 95 % CI 0.77, 0.99; typical risk difference -0.04, 95 % CI -0.08, -0.00).

SEVERE INTRAVENTRICULAR HEMORRHAGE: Five of the randomized controlled trials reported on the risk of severe intraventricular hemorrhage. None of the individual trials supports a difference in the risk of severe intraventricular hemorrhage and the typical estimate from the meta-analysis suggests no difference in the risk of severe intraventricular hemorrhage (typical relative risk 0.84, 95% CI 0.63, 1.12; typical risk difference -0.01, 95% CI -0.03, 0.01).

BRONCHOPULMONARY DYSPLASIA: Five randomized controlled trials reported on the risk of bronchopulmonary dysplasia. Long (1991) reported a decrease in the risk of bronchopulmonary dysplasia associated with synthetic surfactant treatment ( relative risk 0.49, 95% CI 0.28, 0.86; risk difference -0.03, 95% CI -0.05, -0.01). The typical estimate from the meta-analysis suggests a decrease in the risk of bronchopulmonary dysplasia associated with synthetic surfactant treatment (typical relative risk 0.75, 95% CI 0.61, 0.92; typical risk difference -0.04, 95% CI -0.06, -0.01).

NEONATAL MORTALITY: All six randomized controlled trials reported on the risk of neonatal mortality. Long (1991) and the US Exosurf Study (1991) both reported a decrease in the risk of neonatal mortality associated with synthetic surfactant treatment. The typical estimate from the meta-analysis suggests a decrease in the risk of neonatal mortality associated with synthetic surfactant treatment (typical relative risk 0.73, 95% CI 0.61, 0.88; typical risk difference -0.05, 95% CI -0.07, -0.02).

BRONCHOPULMONARY DYSPLASIA OR DEATH: Four of the randomized controlled trials reported the combined outcome of bronchopulmonary dysplasia or death. Long (1991) and the US Exosurf Study (1991) both reported a decreased risk of bronchopulmonary dysplasia or death at 28 days in infants who received synthetic surfactant treatment. The typical estimate from the meta-analysis suggests a decreased risk of bronchopulmonary dysplasia or death at 28 days in infants who received synthetic surfactant treatment (typical relative risk 0.73, 95% CI 0.65, 0.83; typical risk difference -0.08, 95% CI -0.11, -0.05).

MORTALITY PRIOR TO HOSPITAL DISCHARGE: All six randomized controlled trials reported on the risk of mortality prior to hospital discharge. The US Exosurf study (1991) reported a decreased risk of mortality prior to discharge in infants who received synthetic surfactant treatment (relative risk 0.54, 95% CI 0.37, 0.80; risk difference -0.13, 95% CI -0.21, -0.05). The typical estimate from the meta-analysis suggests a decreased risk of mortality prior to hospital discharge in infants who received synthetic surfactant treatment (typical relative risk 0.79, 95% CI 0.68, 0.92; typical risk difference -0.05, 95% CI -0.07, -0.02).

RETINOPATHY OF PREMATURITY: Three trials reported on retinopathy of prematurity in follow-up evaluation of infants (McMillan 1995, Smyth 1995, US Exosurf 1991). A trend towards a decreased risk of retinopathy of prematurity was noted by Smyth (1995). The meta-analysis evaluates the risk of retinopathy in surviving infants who were examined. The typical estimate from the meta-analysis suggests no difference in the risk of any retinopathy (typical relative risk 0.93, 95% CI 0.80, 1.09; typical risk difference -0.03, 95% CI -0.11, 0.04) or in the risk of severe retinopathy of prematurity (typical relative risk 0.73, 95% CI 0.46, 1.17; typical risk difference -0.03, 95% CI -0.08, 0.02).

MORTALITY AT ONE YEAR: Four of the randomized controlled trials reported on mortality at one year of age. The US Exosurf Study (1991) reported decreased mortality at one year of age in infants who received synthetic surfactant (relative risk 0.57, 95% CI 0.39, 0.82; risk difference -0.13, 95% CI -0.21, -0.05). The typical estimate from the meta-analysis suggests a decreased risk of mortality in infants who received synthetic surfactant treatment (typical relative risk 0.80, 95% CI 0.69, 0.94; typical risk difference -0.04, 95% CI -0.07, -0.01).

FOLLOW-UP EVALUATION: Five of the randomized controlled trials reported on follow-up of infants enrolled in the trials. Wilkinson (1985) briefly notes the incidence of cerebral palsy in the primary report. Follow-up of infants of Long (1991) is reported by Sauve (1995) and Courtney (1995). Follow-up of the infants enrolled in the trial of McMillan (1995) is reported by Saigal (1995) and Courtney (1995). Follow-up of the infants enrolled in the study of Smyth (1995) is reported by Casiro (1995) and Courtney (1995). Infants from the US Exosurf Study (1991) are reported by Gong (1995) and Courtney (1995). Between 84% and 100% of survivors were evaluated in the studies. Completeness of follow-up was similar in the two treatment groups. The US Exosurf Study (1991) reports a decreased risk of cerebral palsy in infants who received synthetic surfactant treatment (relative risk 0.38, 95% CI 0.15, 0.98; risk difference -0.07, 95% CI -0.14, -0.01). The meta-analysis suggests no difference in the risk of cerebral palsy (typical relative risk 0.76, 95% CI 0.55, 1.05; typical risk difference -0.02, 95% CI -0.05, 0.00) or in the risk of moderate to severe cerebral palsy (typical relative risk 0.75 95% CI 0.48, 1.16; typical risk difference -0.01 95% CI -0.04, 0.01).

Discussion

Six randomized controlled trials were identified which compared synthetic surfactant treatment of established respiratory distress syndrome to control treatment. Five of the randomized controlled trials utilized Exosurf Neonatal (dipalmitoylphosphatidylcholine, tyloxapol and hexadecanol). Only the small study of Wilkinson (1985) utilized dry powdered DPPC and phosphatidylglycerol (PG). Since investigators were treating infants with clinical signs and symptoms of respiratory distress syndrome, a broad range of gestational ages and birthweights are included. Only the study of Smyth (1995) focused on the extreme of very low birthweight (500-749 grams). The five studies of Exosurf Neonatal all enrolled infants prior to 24 hours of age. The larger studies of Exosurf Neonatal allowed for a repeat treatment 12 hours after the initial treatment if the infants remained on assisted ventilation (Long 1991, McMillan 1995, Smyth 1995, US Exosurf 1991). The larger studies of Exosurf Neonatal all report improvement in the immediate respiratory course. In the studies of Exosurf Neonatal, there are reports of improvement in oxygenation and ventilatory requirements in the 48-72 hours after treatment.

The meta-analysis suggests that synthetic surfactant treatment of established respiratory distress syndrome leads to a significant decrease in the risk of pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, bronchopulmonary dysplasia, intraventricular hemorrhage, and mortality. The meta-analysis suggests that for every 100 infants given synthetic surfactant treatment of established respiratory distress syndrome, there will be 9 fewer pneumothoraces, 12 fewer cases of pulmonary interstitial emphysema, 6 fewer cases of significant patent ductus arteriosus, 4 fewer intraventricular hemorrhages, 4 fewer cases of bronchopulmonary dysplasia, and 5 fewer deaths.

Statistical non-homogeneity was noted in the analyses of the impact of synthetic surfactant treatment on pneumothorax, pulmonary interstitial emphysema, and bronchopulmonary dysplasia. The study of Wilkinson (1985) stands out as a uniquely different trial since the infants were not treated with Exosurf Neonatal. However, Wilkinson (1985) only contributed data to the analysis of bronchopulmonary dysplasia and is an extremely small trial, making it doubtful that this study is the source of heterogeneity. More likely the study of Smyth (1995), which included only extremely premature infants, represents the source of heterogeneity. This raises the question of the efficacy of synthetic surfactant in preventing these morbid outcomes in the extremely premature infant.

Individual studies as well as the meta-analysis suggests that there may be an increase in the risk of apnea of prematurity associated with synthetic surfactant treatment. The meta-analysis suggests that for every 100 infants treated with synthetic surfactant for established respiratory distress syndrome, there will be 8 more infants who demonstrate apnea of prematurity. This finding may be due to the increased survival rate and reduced need for assisted ventilation in surfactant treated infants. Unlike the trials of prophylactic synthetic surfactant (Soll 1998), a decrease in the risk of patent ductus arteriosus and no increase in the risk of pulmonary hemorrhage was demonstrated. In animals treated with surfactant products, earlier and more severe shunting through the patent ductus arteriosus has been noted. Pulmonary hemorrhage is thought to occur as a consequence of massive ductal shunting. Although not reported in the randomized controlled trials of synthetic surfactant treatment of established respiratory distress syndrome, pulmonary hemorrhage was addressed retrospectively in analyses by Raju (1993). The risk of pulmonary hemorrhage appears to occur with both synthetic surfactant products and natural surfactant extracts. In clinical practice, pulmonary hemorrhage may be preventable by aggressive treatment of the patent ductus arteriosus and appropriate ventilatory management. No other side effects of synthetic surfactant treatment were reported.

The trials included in this review compared synthetic surfactant treatment of established respiratory distress syndrome with no surfactant treatment. After the demonstration of the efficacy of surfactant in both preventing and treating respiratory distress syndrome, trials were conducted which compared the policies of prophylactic surfactant administration in infants at risk of RDS with selective treatment of infants who develop RDS. These trials were conducted using natural surfactant preparations. In these studies, prophylactic natural surfactant was noted to be superior to late selective treatment of babies with established RDS (Soll 1997a).

Studies have also evaluated the differences between synthetic surfactant and natural surfactant extract. These trials were only done in the context of treating established respiratory distress syndrome. In these studies, the use of natural surfactant extract appears superior in decreasing the risk of pneumothorax and increasing survival (Soll 1997b).

Conclusions

Implications for practice

Synthetic surfactant treatment of infants with established respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who received synthetic surfactant treatment have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, a decreased risk of intraventricular hemorrhage, a decreased risk of bronchopulmonary dysplasia, a decreased risk of neonatal mortality, a decreased risk of mortality prior to hospital discharge and at 1 year of age. Synthetic surfactant treatment of established respiratory distress syndrome may lead to an increase in apnea of prematurity. However, this complication does not overshadow the positive impact on outcome (including reductions in intraventricular hemorrhage, neonatal mortality and late mortality).

Implications for research

Synthetic surfactant treatment of established respiratory distress syndrome has been proven to improve clinical outcome. Further placebo controlled trials of synthetic surfactant are no longer warranted. Trials which compared the prophylactic treatment strategy to treatment of established disease have been tested using natural surfactant extract (see review: Prophylactic Surfactant vs. Treatment with Surfactant). Trials which have compared currently available synthetic surfactant to natural surfactant extract have been conducted. Overview analysis of these trials suggests that natural surfactant extract may be preferred to synthetic surfactant due to the decreased risk of pneumothorax associated with natural surfactant extract treatment (see review: Natural Surfactant Extract vs. Synthetic Surfactant). New formulations of synthetic surfactants, such as KL4, are promising and warrant further evaluation (Cochrane 1996).

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Study: Long 1991
Method: Randomized
Multicenter
Blinding of randomization: Yes (opaque, sealed envelopes
Blinding of intervention: Yes (Drug administration team)
Complete Follow-up:
Short term: Yes
Long term: 84%
Blinding of outcome measurement: Yes
Stratification: By birthweight and gender
Long-term follow-up: Sauve 1995, Courtney 1995
Participants: Neonates
Birthweight equal to or >1250 grams (Canada)
Birthweight > 1350 grams (USA)
Respiratory distress syndrome
Assisted ventilation
a/A ratio < 0.22
No proven lung maturity
No major congenital anomaly
No evidence of hydrops fetalis
Age < 24 hours
Infants Randomized:
Exosurf = 614
Control = 623
Interventions: Intratracheal Exosurf Neonatal
(5 mg/kg) or sham treatment (air)
Second dose 12 hours later if infant remained on assisted ventilation
Outcomes: PRIMARY OUTCOME:
Neonatal death or survival with bronchopulmonary dysplasia
SECONDARY OUTCOME
cardiorespiratory support
complications of Prematurity
Notes: Primary outcome (mortality and bronchopulmonary dysplasia) reported based on intention to treat.
Other complications of prematurity reported based on treatment received.

Study: McMillan 1995
Method: Randomized
Multicenter
Blinding of randomization: Yes (opaque, sealed envelopes)
Blinding of intervention: Yes (Drug administration team)
Complete Follow-up:
Short term: Yes
Long term: 93%
Blinding of outcome measurement: Yes
Stratification: Based on birthweight and gender.
Longterm Follow-up: Saigal 1995, Courtney 1995
Participants: Neonates
Birthweight 750-1249 grams
Respiratory distress syndrome
Assisted ventilation
a/A ratio < 0.22
Age 2-24 hours
Infants Randomized:
Exosurf Neonatal = 176
Control = 168
Interventions: Intratracheal Exosurf Neonatal
(5 ml/kg) or sham treatment (air)
Second dose 12 hours later if infant remained on assisted ventilation
Outcomes: PRIMARY OUTCOME:
Survival without bronchopulmonary dysplasia at 28 days
SECONDARY OUTCOME
cardiorespiratory support
complications of prematurity
Notes: Primary outcomes (survival without BPD), BPD and neonatal mortality reported based on intention to treat.
Other complications of prematurity reported based on treatment received.

Study: Phibbs 1991
Method: Randomized
Single Center
Blinding of randomization: Yes (sealed envelopes)
Blinding of intervention: No
Complete Follow-up:
Short term: Yes
Long term: none
Blinding of outcome measurement: No
Stratification: Based on birthweight
Participants: Neonates
Birthweight >650 grams
Clinical diagnosis of hyaline membrane disease
Ventilatory support
for infants 650-1250 grams:
(mean airway pressure equal to or
>7 cm H20)
FiO2 equal to or > 0.4
for infants >1250 grams:
mean airway pressure equal to or
>8 cm H2;
FiO2 equal to or >0.5
Arterial catheter
No major congenital anomaly
No meconium aspiration
Granulocyte count equal to or >1000/mm3
Age 4-24 hours
Infants randomized:
Exosurf = 57
Air placebo = 53
Interventions: Intratracheal Exosurf Neonatal (5ml/kg) given in 4 aliquots or sham treatment (air)
Outcomes: Incidence of major complications:
chronic lung disease
patent ductus arteriosus
intracranial hemorrhage
mortality
ventilatory requirements
Notes: 110 infants randomized
6 excluded from analysis
(4 treated, 2 control)

Study: Smyth 1995
Method: Randomized
Multicenter
Blinding of randomization: Yes (opaque, sealed envelopes)
Blinding of intervention: Yes (drug administration team)
Complete Follow-up:
Short term: Yes
Long term: 96%
Blinding of outcome measurement: Yes
Stratification: Based on birthweight and gender
Long-term follow up: Casiro 1995, Courtney 1995
Participants: Neonates
Birthweight 500-749 grams
Respiratory distress syndrome
Assisted ventilation
a/A ratio < 0.22
Age 2-24 hours
Infants randomized:
Exosurf Neonatal = 115
Control = 109
Interventions: Intratracheal Exosurf Neonatal
(5 ml/kg) or sham treatment (air)
Second dose 12 hours later if infant remained on assisted ventilation
Outcomes: PRIMARY OUTCOME:
Neonatal mortality
bronchopulmonary dysplasia
survival at 28 days without BPD
SECONDARY OUTCOMES
cardiorespiratory support
complications of prematurity
Notes: Primary outcome (neonatal mortality, BPD, survival without BPD) reported based on intention to treat.
Other complications of prematurity reported based on treatment received.

Study: US Exosurf 1991
Method: Randomized
Multicenter
Blinding of Randomization: Yes (Opaque sealed envelopes)
Blinding of Intervention: Yes (Drug Administration Team)
Complete Follow-up:
Short term: Yes
Long term: 80%
Blinding of Outcome Measurement: Yes
Stratification: Based on birthweight and gender
Long term follow-up:
Gong 1995
Courtney 1995
Participants: Neonates
Birthweight 700-1350 grams, inclusive
Respiratory Distress Syndrome
Assisted ventilation
a/A ratio < 0.22
No proven lung maturity
No major congenital anomaly
No evidence of hydrops fetalis
No positive gram stain
Age 2-24 hours
Infants randomized:
Exosurf Neonatal = 206
Control = 213
Interventions: Intratracheal Exosurf Neonatal
( 5 ml/kg) or sham treatment (air)
via side port adapter in 2 aliquots. Second dose 12 hours later if infant remained on assisted ventilation.
Outcomes: PRIMARY OUTCOME:
Neonatal death or survival with
bronchopulmonary dysplasia
SECONDARY OUTCOME:
cardiorespiratory support
complications of prematurity
Notes: Primary outcome (mortality and bronchopulmonary dysplasia) reported based on intention to treat. Unclear whether other complications of prematurity reported as intention to treat or treatment received.

Study: Wilkinson 1985
Method: Randomized
Single center
Blinding of randomization: Yes (sealed envelope)
Blinding of intervention: Yes
Complete Follow-up:
Short term: Yes
Long term: 100%
Blinding of outcome measurement: Yes
Stratification: Based on gender
Participants: Premature infants
Gestational age < 31 weeks
Respiratory distress syndrome (clinical and radiologic evidence)
Assisted ventilation
L/S ratio < 1.8
Not enrolled in delivery room study
Infants Randomized:
DPPC/PG = 12
Control = 12
Interventions: Intratracheal administration
of dry powered dipalmitoylphosphatidylcholine and phosphatidylglycerol via modified resuscitation bag vs. manual ventilation with modified resuscitation bag.
Outcomes: cardiorespiratory variables
requirement for respiratory support
complications of prematurity

Characteristics of excluded studies

Study Identifier: Chu 1967
Reason for Exclusion: Surfactant and route of administration inadequate

Study Identifier: Robillard 1964
Reason for Exclusion: Surfactant and route of administration inadequate

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References to studies

Included studies

Section 1. References to studies included in this review

Courtney SE, Long W, McMillan A, Walter D, Thompson T, Sauve R, Conway B, Bard H: Double-blind 1 year follow-up of 1540 infants with respiratory distress syndrome randomized to rescue treatment with two doses of synthetic surfactant or air in four clinical trials. J Pediatr 1995;126:543-52.

Long W, Corbet A, Cotton R, Courtney S, McGuiness G, Walter D, Watts J, Smyth J, Bard H, Chernick V, American Exosurf Neonatal Study Group 1, and the Canadian Exosurf Neonatal Study Group. A controlled trial of synthetic surfactant in infants weighing 1250 g or more with respiratory distress syndrome. N Engl J Med 1991, 325:1696-1703.

Sauve R, Long W, Vincer M, Bard M, Derletri D, Stevenson D, Pauly T, Robertson C: Outcome at 1-year adjusted age of 957 infants weighing more than 1250 grams with respiratory distress syndrome randomized to receive synthetic surfactant or air placebo. J Pediatr 1995;126:575-580.

Courtney SE, Long W, McMillan A, Walter D, Thompson T, Sauve R, Conway B, Bard H: Double-blind 1 year follow-up of 1540 infants with respiratory distress syndrome randomized to rescue treatment with two doses of synthetic surfactant or air in four clinical trials. J Pediatr 1995;126:543-52.

McMillan D, Chernick V, Finer N, Schiff D, Bard H, Watts J, Krzeski R, Long W and The Canadian Exosurf Neonatal Study group. Effects of two rescue doses of synthetic surfactant in 344 infants with respiratory distress syndrome weighing 750 to 1249 grams: A double-blind placebo controlled multicenter Canadian trial. J Pediatr 1995;126:590-598.

Saigal S Robertson C, Sankaran K, Bingham W, Casiro O, MacMurray B, Whitfield M, Long W. One year outcome in 232 premature infants with birthweights of 750 to 1249 grams and respiratory distress syndrome randomized to rescue treatment with two doses of synthetic surfactant or air placebo. J Pediatr 1995; 126: 561-7.

Phibbs RH, Ballard RA, Clements JA, Heilbron DC, Phibbs CS, Schlueter MA Sniderman SH, Tooley WH, Wakeley A. Initial clinical trial of Exosurf, a protein-free synthetic surfactant, for the prophylaxis and early treatment of hyaline membrane disease. Pediatrics 1991, 88:1-9.

Casiro O, Bingham W, MacMurray B, Whitfield M, Saigal S, Vincer M, Long W: One year follow-up of 89 infants with birth weights of 500 to 749 grams and respiratory distress syndrome randomized to two rescue doses of synthetic surfactant or air placebo. J Pediatr 1995; 126:553-60.

Courtney SE, Long W, McMillan A, Walter D, Thompson T, Sauve R, Conway B, Bard H: Double-blind 1 year follow-up of 1540 infants with respiratory distress syndrome randomized to rescue treatment with two doses of synthetic surfactant or air in four clinical trials. J Pediatr 1995;126:543-52.

Smyth J, Allen A, MacMurray B, Peliowski A, Sankaran K, Volbert F, Shukla A, Long W. Canadian Exosurf Neonatal Study Group. Double-blind, randomized, placebo controlled Canadian multicenter trial of two doses of synthetic surfactant or air placebo in 224 infants weighing 500-749 grams with respiratory distress syndrome. J Pediatr 1995;126:581-9.

Courtney SE, Long W, McMillan A, Walter D, Thompson T, Sauve R, Conway B, Bard H: Double-blind 1 year follow-up of 1540 infants with respiratory distress syndrome randomized to rescue treatment with two doses of synthetic surfactant or air in four clinical trials. J Pediatr 1995;126:543-52.

Gong A, Anday E, Boros S, Bucciarelli R, Burchfield D, Zucker J, Long W: One year follow-up evaluation of 260 premature infants with respiratory distress syndrome and birthweights of 700 to 1350 grams randomized to 2 rescue doses of synthetic surfactant or air placebo. J Pediatr 1995;126:568-74.

Long WA, Thompson T, Sundell H, Schumacher R, Volberg F, Guthrie R, American Exosurf Neonatal Study Group. Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700- to 1350-gram infants with respiratory distress syndrome. J Pediatr 1991, 118:595-605.

Wilkinson AR, Jenkins PA, Jeffrey JA. Two controlled trials of dry artificial surfactant: early effects and later outcome in babies with surfactant deficiency. Lancet 1985, 2:287-291.

Section 2. References to studies excluded from this review

Chu J, Clements JA, Cotten E, Klaus MH, Sweet AY, Tooley WH. Neonatal pulmonary ischemia. Pediatrics 1967;40(suppl):709-782.

Robillard E, Alarie Y, Dagenais-Perusse P, Baril E, Guilbeault A. Micro-aerosol administration of synthetic dipalmitoyl lecithin in the respiratory distress syndrome: A preliminary report. Can Med Assoc J 1964;90:55-57.

Other references

Section 5. Additional references

Cochrane CG, Revak SD, Merritt TA, Heldt GP, Hallman M, Dunningham MD, Easa D, Pramanik A, Edwards DK, Alberts MS: The efficacy and safety of KL4 surfactant in preterm infants with respiratory distress syndrome. Am J Resp Crit Care Med 1996;153:404-410.

Dechant KL, Faulds D. Colfosceril palmitate. A review of the therapeutic efficacy and clinical tolerability of a synthetic surfactant preparation (Exosurf Neonatal) in neonatal respiratory distress syndrome. Drugs 1991;42:877-94.

Enhorning G, Robertson B. Lung expansion in the premature rabbit fetus after tracheal deposition of surfactant. Pediatrics 1992;50:58-66.

Jobe AH. Pulmonary surfactant therapy. N Engl J Med 1993; 328:861-8.

Raju TN, Langenberg P. Pulmonary hemorrhage and exogenous surfactant. J Pediatr 1993; 123:603-610.

Soll RF, McQueen MC. Respiratory Distress Syndrome. In: Sinclair J, Bracken M (eds) Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:325-58.

Soll RF, Morley CJ. Prophylactic surfactant vs treatment with surfactant. In: Sinclair JC, Bracken MB, Soll RF, Horbar JD (eds) Neonatal Module of The Cochrane Database of Systematic Reviews, [updated 02 December 1997]. Available in the Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration; Issue 1. Oxford: Update Software 1998. Updated quarterly.

Soll RF. Natural surfactant extract vs. synthetic surfactant in the treatment of established respiratory distress syndrome. In: Sinclair JC, Bracken MB, Soll RF, Horbar JD (eds) Neonatal Module of The Cochrane Database of Systematic Reviews, [updated 02 December 1997]. Available in the Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration; Issue 1. Oxford: Update Software 1998. Updated quarterly.

Soll RF: Prophylactic Synthetic Surfactant in Preterm Infants (Cochrane Review). In: The Cochrane Library, Issue 2. Oxford: Update Software; 1998. Updated Quarterly.

Tooley WH, Clements JA, Maramatsu K, Brown CL, Schlueter MA. Lung function in prematurely delivered rabbits treated with a synthetic surfactant. Am Rev Respir Dis 1987; 136:651-656.

Van Houten J, Long W, Mullett M, Finer N, Derleth D, McMurray B, Pelinowski A, Walker D, Wold D, Sankaran K. Pulmonary hemorrhage in premature infants after treatment with synthetic surfactant: an autopsy evaluation. J Pediatr 1992;120:S40-S44.

Section 6. Previously published versions of this review

Soll RF, McQueen MC. Respiratory Distress syndrome. Chapter 15 in Effective Care of the Newborn Infant. eds. JC Sinclair and MB Bracken, Oxford University Press, Oxford, pp 325-358.

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Table of Comparisons

01.00.00 Synthetic surfactant vs control

01.01.00 Pneumothorax (RR)

01.01.00 Pneumothorax (RD)

01.02.00 Pulmonary interstitial emphysema (RR)

01.02.00 Pulmonary interstitial emphysema (RD)

01.03.00 Pulmonary hemorrhage (RR)

01.03.00 Pulmonary hemorrhage (RD)

01.04.00 Patent ductus arteriosus (RR)

01.04.00 Patent ductus arteriosus (RD)

01.05.00 Necrotizing enterocolitis (RR)

01.05.00 Necrotizing enterocolitis (RD)

01.06.00 Apnea of prematurity (RR)

01.06.00 Apnea of prematurity (RD)

01.07.00 Intraventricular hemorrhage (RR)

01.07.00 Intraventricular hemorrhage (RD)

01.08.00 Severe IVH (RR)

01.08.00 Severe IVH (RD)

01.09.00 Bronchopulmonary dysplasia (RR)

01.09.00 Bronchopulmonary dysplasia (RD)

01.10.00 Neonatal mortality (RR)

01.10.00 Neonatal mortality (RD)

01.11.00 BPD or death at 28 days (RR)

01.11.00 BPD or death at 28 days (RD)

01.12.00 Retinopathy of prematurity in survivors examined (RR)

01.12.00 Retinopathy of prematurity in survivors examined (RD)

01.13.00 Severe retinopathy of prematurity in survivors examined (RR)

01.13.00 Severe retinopathy of prematurity in survivors examined (RD)

01.14.00 Mortality prior to hospital discharge (RR)

01.14.00 Mortality prior to hospital discharge (RD)

01.15.00 Mortality at 1 year (RR)

01.15.00 Mortality at 1 year (RD)

01.16.00 Lost to follow-up (RR)

01.16.00 Lost to follow-up (RD)

01.17.00 Cerebral palsy in survivors examined (RR)

01.17.00 Cerebral palsy in survivors examined (RD)

01.18.00 Moderate - severe cerebral palsy in survivors examined (RR)

01.18.00 Moderate - severe cerebral palsy in survivors examined (RD)