Date of most recent amendment: 26/05/1998
Date of most recent substantive amendment: 22/05/1998
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
Telephone 1: +1-802-656-2392
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 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).
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).
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.
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.
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.
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).
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).
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
Study Identifier: Robillard 1964
Reason for Exclusion: Surfactant and route of administration
inadequate
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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.
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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)