Short title: Prophylactic synthetic surfactant
Reviewer(s): Soll RF
Date of most recent amendment: 20/02/1998
Date of most recent substantive amendment: 26/01/1998
Date next stage expected: / /
Contact
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
Telephone1: +1-802-656-2392
Telephone2:
Facsimile: +1-802-656-2077
E-mail: rsoll@salus.med.uvm.edu
Sources of support for the review
Neonatal Collaborative Review Group, NIH Contract N01-MD-6-3253,
USA
Acknowledgements
I would like to thank Nancy Moreland for preparation of the
manuscript.
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-Welcome).
To assess the effect of prophylactic administration of synthetic surfactant in preterm newborns at risk for developing respiratory distress syndrome (RDS).
Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactant; limits: age groups, newborn infants; publication type, clinical trial), previous reviews including cross-references, abstracts, conference and symposia proceedings, expert informants, and journal hand searching in the English language.
Randomized, controlled trials which compared the effect of prophylactic synthetic surfactant administered to high risk preterm newborns at or shortly after birth in order to prevent respiratory distress syndrome and other complications of prematurity.
Data regarding clinical outcomes including the incidence of pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (any grade and severe intraventricular hemorrhage), bronchopulmonary dysplasia, mortality, bronchopulmonary dysplasia or death, retinopathy of prematurity (any retinopathy, and retinopathy stages 3-4) mortality to one year of age, and 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.
Studies of prophylactic administration of synthetic surfactant note a variable improvement in the respiratory status and a decrease in respiratory distress syndrome in infants who receive prophylactic synthetic surfactant. The meta-analysis supports a decrease in the risk of pneumothorax (typical relative risk 0.67, 95% CI 0.50, 0.90; typical risk difference -0.05, 95% CI -0.09, -0.02), a decrease in the risk of pulmonary interstitial emphysema (typical relative risk 0.68, 95% CI 0.50, 0.93; typical risk difference -0.06, 95% CI -0.11, -0.01), and a decrease in risk of neonatal mortality (typical relative risk 0.70, 95% CI 0.58, 0.85; typical risk difference -0.07, 95% CI -0.11, -0.03). No differences were seen in the risk of intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity and cerebral palsy. The meta-analysis supports an increase in the risk of patent ductus arteriosus associated with prophylactic synthetic surfactant administration (typical relative risk 1.11, 95% CI 1.00, 1.22; typical risk difference 0.05, 95% CI 0.00,0.10), and an increase in the risk of pulmonary hemorrhage (typical relative risk 3.28, 95% CI 1.50, 7.16; typical risk difference 0.03, 95% CI 0.01, 0.05).
Prophylactic intratracheal administration of synthetic surfactant to infants judged to be at risk of developing respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who receive prophylactic synthetic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, and a decreased risk of neonatal mortality. Infants who receive prophylactic synthetic surfactant have an increased risk of developing patent ductus arteriosus and pulmonary hemorrhage.
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), phosphatidylethanolamine, 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 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, in part, 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 have 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, neutrolipids, 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 discussed, 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 at high risk of developing respiratory distress syndrome. In these studies, infants were randomized to receive surfactant or control treatment immediately after delivery, prior to the onset of respiratory symptoms. Investigators hoped to decrease the incidence of respiratory distress syndrome and other complications associated with prematurity.
The following analysis is a systematic review of the seven randomized controlled trials which compare the prophylactic administration of synthetic surfactant extract to control treatment in preterm infants at risk of developing RDS. Results of some of these analyses were previously published in 'Effective Care of the Newborn Infant' (Soll 1992).
To assess the effect of prophylactic administration of synthetic surfactant in preterm infants at risk of developing respiratory distress syndrome (RDS).
Types of studies
Randomized controlled trials comparing prophylactic synthetic
surfactant administration (surfactant given prior to the first
breath or immediately after delivery room intubation and stabilization)
to control treatment.
Types of participants
Premature infants with or without evidence of surfactant deficiency.
Types of intervention
Infants randomized to receive prophylactic synthetic surfactant
administration (pre-ventilatory or post-ventilatory) versus control
treatment (intratracheal administration of normal saline or air
placebo). Studies utilized a variety of synthetic surfactant products
including DPPC/high density lipoprotein (Halliday 1984), powdered
DPPC and phosphatidylglycerol (Wilkinson 1985), dipalmitoylphosphatidylcholine
and phosphatidylglycerol in saline (Ten Centre Study 1987), and
Exosurf Neonatal (dipalmitoylphosphatidylcholine, hexadecanol,
and tyloxapol) (Bose 1990, Phibbs 1991, Corbet 1991, and Stevenson
1992).
Types of outcome measures
Data for the following clinical outcomes is included in the
meta-analysis:
1) Pneumothorax
2) Pulmonary interstitial emphysema
3) Patent ductus arteriosus
4) Necrotizing enterocolitis
5) Intraventricular hemorrhage
6) Severe intraventricular hemorrhage (grade III-IV)
7) Bronchopulmonary dysplasia
8) Retinopathy of prematurity
9) Severe retinopathy of prematurity, Stage 3-4
10) Neonatal mortality
11) Mortality prior to hospital discharge
12) Bronchopulmonary dysplasia or death
13) Mortality at one year of age
14) Not assessed at follow-up
15) Cerebral palsy
16) Moderate/severe cerebral palsy
Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: pulmonary surfactant; limits: age groups, newborn infants: publication type, clinical trial), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal hand searching in the English language.
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 gestational age criteria, birthweight criteria, and other inclusion or exclusion criteria was noted. Information on clinical outcomes was analyzed including pneumothorax, pulmonary interstitial emphysema, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (any intraventricular hemorrhage and severe intraventricular hemorrhage), bronchopulmonary dysplasia, retinopathy of prematurity (any retinopathy and severe retinopathy, Stages 3-4), neonatal mortality, mortality prior to hospital discharge, bronchopulmonary dysplasia or death, mortality at one year of age, assessment at follow-up and cerebral palsy (any cerebral palsy and moderate/severe cerebral palsy).
Studies included in this review: Halliday (1984), Wilkinson (1985), Ten Centre Study (1987), Bose (1990), Phibbs (1991), Corbet (1991), Stevenson (1992). Details of each study are given in the 'Characteristics of Included Studies' table and references.
Halliday (1984) tested a surfactant composed of a saline suspension of DPPC and high density lipoprotein (HDL). In previous in vitro studies, this surfactant demonstrated the ability to adsorb and spread rapidly. The investigators studied 100 infants between 25 and 33 weeks gestation. Infants were randomized to receive either intratracheal DPPC/HDL or manual ventilation with air. Infants enrolled in this trial were followed for initial complications of prematurity and seen at two years of age to evaluate growth and development (Halliday 1986).
A synthetic surfactant composed of DPPC and PG has been tested in the United Kingdom. Morley (1981) first studied a dry synthetic mixture of DPPC/PG. The infants studied were 34 weeks gestation or less and required resuscitation in the delivery suite. Twenty-two infants were given DPPC/PG via the endotracheal tube. The comparison group consisted of infants of similar gestational age, resuscitated in the delivery room without the investigators present at the delivery (33 infants). Treated infants required less ventilatory support initially, but no sustained improvement was noted. No deaths were noted in the treatment group, whereas eight control infants died. The results of this clinical experience with dry powdered DPPC/PG have not been corroborated in other studies. Wilkinson (1985) conducted a randomized controlled trial with DPPC/PG in both the prevention and treatment of respiratory distress syndrome in infants 31 weeks gestation or less. Infants given prophylactic dry DPPC/PG did not better than untreated controls.
The Ten Centre Collaborative Study (1987) used a saline suspension of DPPC and PG called artificial lung expanding compound (ALEC). The Ten Centre Study randomized 328 infants between 25 and 29 weeks gestation to either ALEC or 1 ml of saline. This trial was an extension of a trial that originally enrolled infants in Cambridge and Nottingham and was expanded to include infants at eight other centers. Partial results are also reported by Morley (1988). Treatment was administered in the delivery room by injecting the surfactant suspension into the hypopharynx of the infant. In those infants who failed to breathe spontaneously, intubation and resuscitation were followed by a retreatment via the endotracheal tube. Infants who remained intubated could be given up to two more doses during the first 24 hours of life. No immediate benefit of surfactant treatment was reported. Treated infants demonstrated a significant decrease in severe intracranial hemorrhage and neonatal mortality. Infants from this trial who were born in Cambridge were followed at nine and 18 months (Morley 1990).
The most widely tested of the complex synthetic surfactant products is Exosurf Neonatal (Burroughs Wellcome). Exosurf Neonatal is composed primarily of DPPC, but also contains hexadecanol (an alcohol) and tyloxapol (a non-ionic surfactant). Hexadecanol and tyloxapol are not found in naturally occurring surfactant and have been added to aid in the spread and dispersion of the surfactant. Exosurf Neonatal has been successfully tested in animal models (Tooley 1987). The effects of Exosurf Neonatal in animal models is significantly better than saline control, but not equivalent to treatment with a crude natural surfactant extract.
Four randomized controlled trials have evaluated the use of a single intratracheal prophylactic dose of Exosurf Neonatal in infants at risk of developing RDS (Bose 1990, Phibbs 1991, Corbet 1991, and Stevenson 1992). The results from these studies are favorable, but not consistent. Phibbs and coworkers (1991) studied Exosurf Neonatal in both the prevention and treatment of respiratory distress syndrome. In the prevention trial, 74 infants of birthweight 700-1350 grams were randomized to Exosurf or control treatment. Significant reduction in the requirement for ventilatory support was noted in the 72 hours after treatment. No other substantial clinical benefits were noted. Two large multicenter trials evaluated prophylactic Exosurf Neonatal in a similar population. Bose (1990) and Corbet (1991) studied Exosurf Neonatal in infants with birthweights 700-1350 grams and 700-1100 grams, respectively. Both trials reported early improvement in the need for supplemental oxygen and ventilatory support. In Corbet's study (1991), fewer pneumothoraces were noted in treated infants and mortality was significantly decreased. Bose (1990) did not demonstrate an improvement in overall mortality, but the number of surviving infants without BPD was increased. Stevenson (1992) studied a single dose of prophylactic Exosurf Neonatal in infants with birthweight 500-699 grams. No significant clinical effect is reported in this trial.
Infants enrolled in the Exosurf Neonatal trials were followed at one and two years adjusted age (Corbet 1995, Kraybill 1995, Sell 1995, Walther 1995).
Randomized controlled trials which compared the effect of prophylactic synthetic surfactant administration (synthetic surfactant prior to the first breath or immediately after intubation and stabilization in the delivery room) compared to control treatment (sham air treatment or instillation of normal saline) in premature infants thought to be at risk for developing respiratory distress syndrome are included in the analysis. Specific methodologic issues regarding the seven studies are discussed below:
Randomization:
All included studies allocated assigned treatment by randomization.
In all seven 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 resuscitation team to administer the randomly allocated treatment.
Individuals in this resuscitation team were not responsible for
ongoing care of the infant or for study evaluation.
Blinding of outcome assessment:
Investigators who are not involved with treatment are assigned
to administration of assessment and study outcomes.
Exclusion after randomization:
Minimal exclusions were noted after randomization.
Prophylactic administration of complex synthetic surfactants in preterm infants at risk for developing RDS has a variable effect on oxygenation and ventilatory requirements. Prophylactic administration of synthetic surfactant extract in preterm infants at risk of developing RDS has the following clinical impact:
PNEUMOTHORAX: Six of the randomized controlled trials reported on the incidence of pneumothorax associated with prophylactic synthetic surfactant administration. Corbet (1991) and Stevenson (1992) both reported a decrease in the risk of pneumothorax associated with the administration of synthetic surfactant. The typical estimate from the meta-analysis suggests that prophylactic administration of synthetic surfactant will lead to a significant reduction in the risk of pneumothorax (typical relative risk 0.67, 95% CI 0.50, 0.90; typical risk difference -0.05, 95% CI -0.09, -0.02).
PULMONARY INTERSTITIAL EMPHYSEMA: Only two of the randomized controlled trials reported on the incidence of pulmonary interstitial emphysema. In the trial of Bose (1990) a significant reduction was noted in the risk of pulmonary interstitial emphysema (typical relative risk 0.50, 95% CI 0.27, 0.95; typical risk difference -0.07, 95% CI -0.13, -0.01). The typical estimate from the meta-analysis suggests that prophylactic administration of synthetic surfactant will lead to a significant reduction in the risk of pulmonary interstitial emphysema (typical relative risk 0.68, 95% CI 0.50, 0.93; typical risk difference -0.06, 95% CI -0.11, -0.01).
PATENT DUCTUS ARTERIOSUS: None of the individual trials reported a difference in the risk of patent ductus arteriosus. Typical estimate of the meta-analysis supports a slight increase in the risk of patent ductus arteriosus associated with prophylactic synthetic surfactant administration (typical relative risk 1.11, 95% CI 1.00, 1.22; typical risk difference 0.05, 95% CI 0.00, 0.10).
PULMONARY HEMORRHAGE: Four of the seven studies reported on pulmonary hemorrhage. Stevenson (1992) reported an increase in the risk of pulmonary hemorrhage associated with prophylactic synthetic surfactant administration (typical relative risk 6.17, 95% CI 1.41, 26.91; typical risk difference 0.10, 95% CI 0.03, 0.16). The typical estimate from the meta-analysis suggests that prophylactic administration of synthetic surfactant increases the risk of pulmonary hemorrhage (typical relative risk 3.28, 95% CI 1.50, 7.16; typical risk difference 0.03, 95% CI 0.01, 0.05).
NECROTIZING ENTEROCOLITIS: All seven 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 1.11, 95% CI 0.78, 1.59; typical risk difference 0.01, 95% CI -0.02, 0.03).
INTRAVENTRICULAR HEMORRHAGE: Four studies report on the incidence of intraventricular hemorrhage in infants who received prophylactic synthetic surfactant. None of these trials report a difference in the risk of intraventricular hemorrhage and the typical estimate from the meta-analysis supports no difference in the risk of intraventricular hemorrhage (typical relative risk 0.96, 95% CI 0.81, 1.14; typical risk difference -0.01, 95% CI -0.07, 0.04).
SEVERE INTRAVENTRICULAR HEMORRHAGE: Four trials report on the risk of severe intraventricular hemorrhage (IVH grades III or IV). None of the individual trials support a difference in 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 1.01, 95% CI 0.74, 1.37; typical risk difference 0.00, 95% CI -0.04, 0.04).
BRONCHOPULMONARY DYSPLASIA: Four randomized trials reported on the risk of bronchopulmonary dysplasia. No individual trial reported a difference in the risk of bronchopulmonary dysplasia. The typical estimate from the meta-analysis supports no difference in the risk of bronchopulmonary dysplasia (typical relative risk 1.06, 95% CI 0.83 1.36; typical risk difference 0.01, 95% CI -0.04, 0.06).
NEONATAL MORTALITY: All seven randomized controlled trials reported on the risk of neonatal mortality. The Ten Centre Study (1987) and Corbet (1991) report a decrease in the risk of neonatal mortality associated with the prophylactic administration of synthetic surfactant. The typical estimate from the meta-analysis suggests a decrease in the risk of neonatal mortality associated with prophylactic administration of synthetic surfactant (typical relative risk 0.70, 95% CI 0.58 0.85; typical risk difference -0.07, 95% CI -0.11, -0.03).
BRONCHOPULMONARY DYSPLASIA OR DEATH: Four of the randomized controlled trials reported the combined outcome of bronchopulmonary dysplasia or death. Bose (1990) reported a trend towards decreased bronchopulmonary dysplasia or death in infants who received prophylactic synthetic surfactant (typical relative risk 0.72, 95% CI 0.51, 1.02; typical risk difference -0.09, 95% CI -0.18, 0.00). The typical estimate from the meta-analysis suggests a trend towards decreased risk of bronchopulmonary dysplasia or death at 28 days in infants who received prophylactic synthetic surfactant (typical relative risk 0.89, 95% CI 0.77 1.03; typical risk difference -0.04, 95% CI -0.10, 0.01).
MORTALITY PRIOR TO HOSPITAL DISCHARGE: Five of the trials reported on mortality prior to hospital discharge. The Ten Centre Study (1987) reported a decrease in the risk of mortality prior to hospital discharge in those infants who received prophylactic synthetic surfactant (typical relative risk 0.64, 95% CI 0.43, 0.96; typical risk difference -0.11, 95% CI -0.20, -0.01). The typical estimate from the meta-analysis suggests a trend toward decreased risk of mortality prior to hospital discharge in infants who received prophylactic administration of synthetic surfactant (typical relative risk 0.86, 95% CI 0.71, 1.04, typical risk difference -0.05, 95% CI -0.1, 0.02).
RETINOPATHY OF PREMATURITY: Three trials reported on retinopathy of prematurity in follow-up evaluation of infants (Bose 1990, Corbett 1991, Stephenson 1992). None of the studies reported a difference in retinopathy of prematurity or in severe retinopathy of prematurity (retinopathy of prematurity, Stage 3-4). 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 risks of any retinopathy (typical relative risk 0.96, 95% CI 0.86, 1.07; typical risk difference -0.03, 95% CI -0.10, 0.04) or in the risk of severe retinopathy of prematurity (typical relative risk 0.89, 95% CI 0.58, 1.36; typical risk difference -0.01, 95% CI -0.06, 0.03).
MORTALITY AT ONE YEAR OF AGE: Three of the randomized controlled trials reported on survival at one year of age. Corbett (1991) noted decreased mortality in infants who received Exosurf Neonatal (typical relative risk 0.65, 95% CI 0.47, 0.90; typical risk difference -0.11, 95% CI -0.19, -0.03). The typical estimate from the meta-analysis suggests a decreased risk of mortality at one year of age in infants receiving prophylactic synthetic surfactant (typical relative risk 0.83, 95% CI 0.70, 0.98; typical risk difference -0.06, 95% CI -0.11, -0.01).
FOLLOW-UP EVALUATION: Five of the randomized controlled trials reported on follow-up of infants enrolled in the trials. Follow-up from the Ten Centre Study Group (1987) is partially reported by Morley and coworkers (1990). The trials of Bose (1990), Corbett (1991), Stevenson (1992), and Halliday (1984) all reported follow-up on infants at 1-2 years of age. Between 80% and 99% of survivors were evaluated in the studies. Somewhat fewer infants who received surfactant failed to return for follow-up evaluation (typical relative risk 0.63, 95% CI 0.48, 0.82; typical risk difference -0.10, 95% CI -0.15, -0.04). The meta-analysis suggests no difference in the rates of cerebral palsy at 1-2 years of age (typical relative risk 0.93, 95% CI 0.64, 1.33; typical risk difference -0.01, 95% CI -0.07, 0.04). The risk of being severely affected with cerebral palsy is also unchanged by prophylactic synthetic surfactant administration (relative risk 0.92, 95% CI 0.53, 1.59; typical risk difference -0.01, 95% CI -0.05, 0.03).
Seven randomized controlled trials were identified which compared prophylactic administration of synthetic surfactant to control treatment. Studies used a variety of synthetic surfactants including artificial lung expanding compound, (dipalmitoylphosphatidylcholine and phosphatidylglycerol), dipalmitoylphosphatidylcholine and high density lipoprotein, and Exosurf Neonatal (dipalmitoylphosphatidylcholine, toloxapol, and hexadecanol). The majority of studies evaluated infants 30 weeks gestation or less; however, Halliday (1984) studied infants as old as 33 weeks gestation and Stevenson (1992) focused on the extremely premature infants (birthweight 500-699 grams). All studies excluded infants with known lung maturity, but no study required screening for pulmonary immaturity prior to entry into the study. Infants could be enrolled regardless of exposure to antenatal steroids. Only the Ten Centre Study (1987) allowed for multiple surfactant treatments.
Synthetic surfactant had an inconsistent effect on the immediate respiratory course. Only in the studies of Exosurf Neonatal are there reports of improvement in oxygenation and ventilatory requirements in the 48-72 hours after treatment.
The meta-analysis suggests that prophylactic administration of synthetic surfactant leads to a significant decrease in the risk of pneumothorax, pulmonary interstitial emphysema, and neonatal mortality. The meta-analysis suggests that for every 100 infants treated prophylactically, there will be five fewer pneumothoraces, six fewer cases of pulmonary interstitital emphysema, and seven fewer neonatal deaths. No impact is noted on the incidence of intraventricular hemorrhage or severe intraventricular hemorrhage.
Although no individual study reported an increase in the incidence of hemodynamically significant patent ductus arteriosus, the meta-analysis suggests that there is an increase in the risk of patent ductus arteriosus associated with prophylactic synthetic surfactant administration. This risk is of marginal statistical significance. In animals treated with surfactant products, earlier and more severe shunting through the patent ductus arteriosus has been noted. Of interest, the investigators in the trials using Exosurf Neonatal reported an increased incidence in pulmonary hemorrhage. This increased risk of pulmonary hemorrhage is supported by the meta-analysis. Pulmonary hemorrhage is thought to be hemorrhagic pulmonary edema secondary to massive ductal shunting. Although not reported in the randomized controlled trials of other surfactant products, this outcome 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 ductus arteriosus and appropriate ventilatory management. No other side effects of synthetic surfactant treatment were reported.
The trials included in this review compared prophylatic synthetic surfactant with no surfactant treatment. After the demonstration of the efficacy of surfactant in preventing and treating respiratory distress syndrome, trials were conducted which compared the policies of prophylactic surfactant administration in babies at risk of RDS with selective treatment of babies 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 1997b).
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.
Prophylactic administration of synthetic surfactant extract to infants judged to be at risk for developing respiratory distress syndrome has been demonstrated to improve clinical outcome. Infants who receive prophylactic synthetic surfactant have a decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema, and a decreased risk of neonatal mortality. No impact is noted on intraventricular hemorrhage (any hemorrhage or severe intraventricular hemorrhage), necrotizing enterocolitis, bronchopulmonary dysplasia, or retinopathy of prematurity. Prophylactic synthetic surfactant may lead to an increase in the incidence of patent ductus arteriosus and pulmonary hemorrhage. However, these complications did not overshadow the impact on overall outcome (neonatal mortality or late mortality).
Prophylactic synthetic surfactant has been proven to improve clinical outcome. Further placebo controlled trials of prophylactic synthetic surfactant are no longer warranted. The impact of prophylactic natural surfactant extract administration was reviewed by Soll 1997a (Prophylactic Administration of Natural Surfactant Extract). Trials which compared the prophylactic treatment strategy to treatment of established disease have been conducted using natural surfactant extract (Soll 1997b: Prophylactic Surfactant vs. Treatment with Surfactant).
Study: Bose 1990
Method: Randomized
Multicenter
Blinding of randomization: yes
Blinding of intervention: Attempted (infants treated in screened
area by special drug administration team who did not participate
in subsequent care)
Complete follow-up: yes
Blinding of outcome measurement: yes
Stratification by birthweight (700-1000g, 1001-1350g) and gender
Long-term follow-up:
Corbet (1995), Kraybill (1995) 80% of survivors evaluated
Participants: Premature infants
Inborn
Birthweight 700-1350 grams
No proven lung maturity
No fetal anomaly or chromosomal abnormality
No fetal growth retardation
No evidence of hydrops fetalis
No proven chorioamnionitis
No maternal heroin addiction
Infants randomized:
Exosurf = 192
Air Placebo = 193
Interventions: Intubation and intratracheal administration
of Exosurf Neonatal (5ml/kg) as soon after birth as possible or
intubation and sham air treatment
Outcomes: PRIMARY OUTCOME:
Survival at 28 days of age without bronchopulmonary dysplasia
SECONDARY OUTCOMES:
Ventilatory requirements
Respiratory distress syndrome
Complications of prematurity
FOLLOW-UP:
Assessed at 1 and 2 years adjusted age
Notes: Evaluation of BPD, neonatal mortality does not include
infants with congenital malformation or congenital pneumonia
Study: Corbet 1991
Method: Randomized
Multicenter study
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: yes (staff not involved in clinical
care administered assigned treatment in screened area
Complete follow-up: yes
Blinding of outcome measures: yes
Stratification based on gestational age and gender
Long-term follow-up:
Corbet (1995), Sell (1995): 82% of survivors evaluated
Participants: Premature infants
Birthweight 700-1100 grams
No proven lung maturity
No major congenital malformation
No fetal growth retardation
No evidence of hydrops fetalis
No purulent amnionitis
No maternal heroin addition
Infants randomized:
Exosurf = 224
Air Placebo = 222
Interventions: Intratracheal Exosurf Neonatal (5ml/kg)
or sham treatment (air) in delivery room within 30 minutes after
birth
Outcomes: PRIMARY OUTCOME:
Survival at age 28 days without bronchopulmonary dysplasia
SECONDARY OUTCOMES:
Respiratory distress, mortality, complications of prematurity
FOLLOW-UP:
Assessed at 1 year adjusted age
Notes: Evaluation of BPD, neonatal mortality does not include
infants with congenital malformation or congenital pneumonia
Study: Halliday 1984
Method: Randomized
Single Center
Blinding of Randomization: yes (sealed envelope)
Complete follow-up: no
Blinding of outcome measurement: yes
Blinding of Intervention: attempted (separate staff involved in
treatment administration)
Long-term follow-up:
Halliday (1986) 99% of survivors evaluated
Participants: Premature infants
Gestational age 25-33 weeks
No evidence of lung maturity
No major congenital anomalies
Infants randomized:
DPPC/HDL = 49
Control = 51
Interventions: Intratracheal administration of dipalmitdylphosphatidylcholine
30mg/
High-density lipoprotein 3 mg in 5 ml saline vs. manual ventilation
Outcomes: Respiratory Distress Syndrome
Complications of prematurity
FOLLOW-UP:
Assessed at 2 years
Study: Phibbs 1991
Method: Randomized
Single center
Blinding of randomization: yes (sealed envelopes)
Stratification based on gestational age and gender
Blinding of intervention: no
Complete follow-up: yes
Blinding of outcome measures: no
Participants: Premature infants
Gestational age <34 weeks
Birthweight 700-1350 grams
No major congenital anomaly
Infants randomized:
Exosurf = 38
Air Placebo = 39
Interventions: Intratracheal Exosurf Neonatal (5 ml/kg)
or sham treatment (air) in delivery room after intubation and
minimal ventilation
Outcomes: PRIMARY OUTCOME:
Respiratory Distress Syndrome
Ventiltory requirements
SECONDARY OUTCOMES:
Complications of prematurity
Complications of mortality
Notes: Infants with congenital malformations excluded from
all analyses (2 treatment, 1 control)
Study: Stevenson 1992
Method: Randomized
Multicenter
Blinding of randomization: Yes (sealed envelopes)
Blinding of intervention: Attempted (treatment administered by
a separate dosing team in a screened area)
Complete follow-up: yes
Blinding of outcome measurement: yes
Stratification by Birthweight: (500-599g, 600-699g) and gender
Long-term follow-up:
Corbet (1995), Walther (1995): 83% of survivors evaluated
Participants: Premature infants
Inborn
Birthweight 500-699 grams
No proven lung maturity
No major congenital malformation
No fetal growth retardation
No evidence of hydrops fetalis
No purulent amnionitis
No maternal heroin addiction
Infants randomized:
Exosurf = 109
Air Placebo = 106
Interventions: Intratracheal Exosurf Neonatal (5ml/kg)
or sham treatment (air) in delivery room shortly after birth
Outcomes: PRIMARY OUTCOME:
Neonatal mortality
SECONDARY OUTCOMES:
Ventilatory requirements
Death due to RDS
Bronchopulmonary dysplasia
Complications of prematurity
FOLLOW-UP:
Assessed at 1 year adjusted age
Notes: Primary analysis reported as intention to treat
(BPD, mortality), other outcomes reported based on treatment administered
Study: Ten Centre 1987
Method: Randomized
Multicenter
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: can't tell
Complete follow-up: yes
Blinding of outcome measurement: yes
Stratification by gestational age (25-26 weeks, 27-29 weeks)
Long-term follow-up:
Morley (1990): % survivors followed unclear
Participants: Premature infants
Inborn
Gestational age 25-29 weeks
Infants randomized:
ALEC = 164
Saline = 164
Interventions: Artificial lung expanding compound (dipalmitdylphosphatidylcholine
and phosphatidylglycerol in saline) vs. saline administered in
the pharynx if intubated, a second dose was given third and fourth
doses were given if intubated at 1 and 14 hours of age
Outcomes: PRIMARY OUTCOME:
Mortality
SECONDARY OUTCOME:
Respiratory Distress Syndrome
Complications of prematurity
FOLLOW-UP:
Assessed at 9 and 18 months
Notes: Randomized infants: 328
Ineligible: 20
Total evaluated:
ALEC = 159
Saline = 149
Study: Wilkinson 1985
Method: Randomized
Single Center
Blinding of randomization: yes (sealed envelopes)
Blinding of intervention: yes
Complete follow-up: yes
Blinding of outcome measurement: yes
Stratification based on gender
Participants: Premature infants
Gestational age <31 weeks
Intubated in delivery room
Infants randomized:
DPPC/PG = 16
Control = 16
Interventions: Intratracheal administration of dry powdered
dipalmitoylphosphatidylcholine and phosphatidylglycerol vs. routine
resuscitation
Outcomes: Requirement for respiratory support
Complications of respiratory distress syndrome
Study Identifier: Chu 1967
Reason for exclusion: Utilized ineffective surfactant prepartion
(DPPC alone) and ineffective mode of delivery
Study Identifier: Milner 1984
Reason for exclusion: Reports respiratory compliance only
Study Identifier:Morley 1981
Reason for exclusion: Treatment allocation not random
Study Identifier: Morley 1988
Reason for exclusion: Infants less than 30 weeks gestation
included in Ten Centre Study
Study Identifier: Morley 1991
Reason for exclusion: Reports respiratory compliance only
Study Identifier: Robillard 1964
Reason for exclusion: Utilized ineffective surfactant prepartion
(DPPC alone) and ineffective mode of delivery
Bose C, Corbet A, Bose G, Garcia-Prats J, Lombardy L, Wold D, Donlon D, Long W. Improved outcome at 28 days of age for very low birthweight infants treated with a single dose of a synthetic surfactant. J Pediatr 1990;117:947-953.
Corbet A, Long W, Schumacher R, et al. Double-blind developmental evaluation at one year corrected age of 597 premature infants with birthweights from 500 to 1350 grams enrolled in three placebo controlled trials of prophylactic synthetic surfactant. J Pediatr 1995;126:S5-12.
Kraybill EN, Bose C, Corbet A, Garcia-Prats J, Asbill D, Edwards K, Long W. Double-blind evaluation of developmental and health status to age 2 years of infants weighing 700 to 1350 grams treated prophylactically at birth with a single dose of synthetic surfactant or air placebo. J Pediatr 1995;126:S33-42.
Corbet A, Bucciarelli R, Goldman S, Mammel M, Wold D, Long W, US Exosurf Pediatric Study Group 1. Decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: a multicenter controlled trial. J Pediatr 1991;118:277-284.
Corbet A, Long W, Schumacher R, et al. Double-blind developmental evaluation at one year corrected age of 597 premature infants with birthweights from 500 to 1350 grams enrolled in three placebo controlled trials of prophylactic synthetic surfactant. J Pediatr 1995;126:S5-12.
Sell M, Cotton R, Hirata T, Guthrie R, Leblanc M, Mammel M, Long W. One year follow-up of 273 infants with birthweights of 700 to 1100 grams after prophylactic treatment of respiratory distress syndrome with synthetic surfactant or air placebo. J Pediatr 1995;126:S20-25.
Halliday HL, McClure G, Reid MM. Growth and development two years after artificial surfactant replacement at birth. Early Hum Dev 1986;13:323-327.
Halliday HL, Reid MM, Meban C, McClure G, Lappin TRJ, Thomas PS. Controlled trial of artificial surfactant to prevent respiratory distress syndrome. Lancet 1984;1:476-478.
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.
Stevenson D, Walther F, Long W, Sell M, Pauly T, Gong A, Easa D, Pramanik A, LeBlanc M, Anday E, Dhanireddy R, Burchfield D, Corbet A, American Exosurf Neonatal Study Group 1. Controlled trial of a single dose of synthetic surfactant at birth in premature infants weighing 500 to 699 grams. J Pediatr 1992;120:S3-S12.
Walther FJ, Mullett M, Schumacher R, Sundell H, Easa D, Long W. One year follow-up of 66 premature infants weighing 500 to 699 grams treated with a single dose of synthetic surfactant or air placebo at birth: results of a double-blind trial. J Pediatr 1995;126:S13-19.
Morley CJ, Morley R: Follow-up of premature babies treated with artificial surfactant (ALEC). Arch Dis Child 1990;65:667-669.
Ten Centre Study Group. Ten centre trial of artificial surfactant (artificial lung expanding compound) in very premature babies. Br Med J 1987;294:991-996.
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.
Chu J, Clements JA, Cotten EK, Klaus MH, Sweet AY, Tooley WH. Neonatal Pulmonary Ischemia. Pediatrics 1967;40(suppl):709-782.
Milner AD, Vyas H, Hopkin IE. Effect of exogenous surfactant on total respiratory system compliance. Arch Dis Child 1984;59:369-371.
Morley CJ, Bangham AD, Miller N, Davis JA. Dry artificial surfactant and its effect on very premature babies. Lancet 1981; I:64-68.
Morley CJ, Greenough A, Miller NG, Bangham AD, Pool J, Wood S, South M, Davis JA, Vyas H. Randomized trial of artificial surfactant (ALEC) gien at birth to babies from 23 to 34 weeks gestation. Early Hum Dev 1988;17:41-54.
Morley CJ, Greenough A. Respiratory compliance in premature babies treated with artificial surfactant (ALEC). Arch Dis Child 1991;68:467-471.
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.
Enhorning G, Robertson B. Lung expansion in the premature rabbit fetus after tracheal deposition of surfactant. Pediatrics 1972;50:58-66.
Jobe AH. Pulmonary surfactant therapy. N Engl J Med 1993;328:861-868.
Raju TN, Langenberg P. Pulmonary hemorrhage and exogenous surfactant. J Pediatr 1993;123:603-610.
Soll RF. Prophylactic administration of natural surfactant extract. 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, 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, 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.
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.
01.00.00 Prophylactic synthetic surfactant
01.01.00 Pneumothorax
01.02.00 Intraventricular hemorrhage
01.03.00 Bronchopulmonary dysplasia
01.04.00 Neonatal mortality
01.05.00 Mortality prior to hospital discharge
01.06.00 BPD or death at 28 days
01.07.00 Patent ductus arteriosus
01.08.00 Pulmonary interstitial emphysema
01.09.00 Necrotizing enterocolitis
01.10.00 Severe intraventricular hemorrhage
01.11.00 Pulmonary hemorrhage
01.12.00 Cerebral palsy, 1-2 years
01.13.00 Cerebral palsy, moderate/severe
01.14.00 Retinopathy of prematurity
01.15.00 Severe retinopathy of prematurity
01.16.00 Mortality at 1 year
01.17.00 Survivors not assessed at follow-up