Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome 

Cover Sheet

Short title: Natural vs synthetic surfactant
Reviewer(s): Soll RF

Date of most recent amendment: 24/02/1999
Date of most recent substantive amendment: 22/02/1999
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
 

Acknowledgements
Dr. Soll would like to acknowledge N. Moreland for preparation of the manuscript.

Potential conflict of interest
Dr. R. Soll has acted as a paid consultant and invited speaker for several of the pharmaceutical companies which manufacture surfactant preparations (Abbott Laboratories, Ross Laboratories, Chiesi Pharmaceuticals, Dey Laboratories, Burroughs Wellcome).  Dr. Soll is the principal investigator or co-principal investigator of two of the randomized controlled trials cited in this review.

Abstract

Objective

To compare the effect of synthetic surfactant to natural surfactant in premature infants with established respiratory distress syndrome.

Search strategy

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

Selection criteria

Randomized controlled trials comparing administration of synthetic surfactants to administration of natural surfactant extracts in premature infants with respiratory distress syndrome were considered for this review.

Data collection & analysis

Data regarding clinical outcomes including pneumothorax, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (all intraventricular hemorrhage and severe intraventricular hemorrhage), chronic lung disease, retinopathy of prematurity, and mortality were excerpted by the primary reviewer (R. Soll).  Data analysis was conducted according to the standards of the Neonatal Cochrane Review Group.

Main results

The meta-analysis supports a significant reduction in the risk of pneumothorax (typical relative risk 0.68, 95% CI 0.56, 0.83; typical risk difference -0.04 95% CI -0.06, -0.02).  No disadvantages to natural surfactant extract treatment are noted regarding other outcomes.  A trend towards reduced mortality is noted in association with natural surfactant extract treatment.

Conclusions

Both natural surfactant extracts and synthetic surfactant extracts are effective in the treatment of established respiratory distress syndrome.  Comparative trials demonstrate greater early improvement in the requirement for ventilatory support and fewer pneumothoraces associated with natural surfactant extract treatment.  On clinical grounds, natural surfactant extracts would seem to be the more desirable choice.

Background

Randomized controlled trials have demonstrated the effectiveness of surfactant therapy in the treatment of infants with established respiratory distress syndrome.  Surfactant administration decreases the severity of respiratory distress, decreases the frequency of pneumothorax, increases survival without chronic lung disease, and decreases mortality (Soll 1992).  Surfactant preparations  are now widely used and have been credited with recent improvements in overall infant mortality (Horbar 1992, Schwartz 1994).  A wide variety of surfactant preparations have been developed and tested.  These include synthetic surfactants and surfactants derived from animal sources.  Although clinical trials have demonstrated that both synthetic surfactants and natural surfactant preparations are effective, comparison in animal models has suggested that there may be greater efficacy of natural surfactant products, perhaps due to the protein content of natural surfactant  (Tooley 1987).

Clinical trials which compared a natural surfactant extract to synthetic surfactant in the treatment of established respiratory distress syndrome have been included in this systematic review.  This review updates the existing review of Natural surfactant extract vs synthetic surfactant in the treatment of established respiratory distress syndrome which was published in the Cochrane Library Issue 3, 1997 (Soll 1997). 

Objectives

To compare the effect of synthetic surfactant to natural surfactant in premature infants with established respiratory distress syndrome. 

Materials and Methods

Criteria for considering studies for this review

Types of studies
Randomized controlled clinical trials comparing administration of synthetic surfactants to administration of natural surfactant extracts in premature infants with respiratory distress syndrome were considered for this review.

Types of participants
Premature infants with established respiratory distress syndrome.

Types of intervention
Infants were randomly allocated to receive either the synthetic surfactant Exosurf Neonatal, or natural surfactant extract.

Types of outcome measures
Clinical outcomes from the studies included pneumothorax, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage (all intraventricular hemorrhage and severe intraventricular hemorrhage), chronic lung disease, retinopathy of prematurity, and mortality.

Search strategy for identification of studies

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.

Methods of the review

For each included trial, information was collected about the method of randomization, blinding, drug intervention, stratification, and whether or not the trial was single or multi-centered.  Information regarding trial participants included birthweight or gestational age, postnatal age, and disease severity.
Information on clinical outcomes was analyzed including the incidence of pneumothorax, patent ductus arteriosus, intraventricular hemorrhage (any intraventricular hemorrhage and severe intraventricular hemorrhage, grades 3 or 4), chronic lung disease, and mortality.

Description of studies

The review includes the following studies:  Alvarado (1993), Horbar (1993), Pearlman (1993), Seghal (1994), Hudak (1996), Vermont Oxford Neonatal Network (1996) and Modanlou (1997).  Various entry criteria were utilized.  The trials of Alvarado (1993), Horbar (1993), Vermont Oxford Neonatal Network (1996), and Modanlou (1997) all studied infants with birthweight <1500 grams.  The studies of Hudak (1996), and Pearlman (1993) studied premature infants without a specific birthweight limitation.  Seghal (1994) studied infants between birthweights 600-1750 grams.  All studies required that the infants be on assisted ventilation and have respiratory distress syndrome.  A variety of criteria for oxygen requirement at entry were used.  Alvarado (1993) required that infants be in supplemental oxygen >40%.  The study of Horbar (1993) and the Vermont Oxford Neonatal Network (1996) required that infants be in supplemental oxygen >30%.  Hudak (1996) and Modanlou (1997) required that infants demonstrate an arterial/alveolar oxygen ratio of less than or equal to 0.22.  This corresponds to being in approximately 40% supplemental oxygen.  A variety of age criteria were set out by investigators.  Age at entry varied from 6 hours of age (Horbar 1993, Vermont Oxford Neonatal Network 1996) to 72 hours of age (Hudak 1996).

In all of the included studies, the synthetic surfactant was Exosurf Neonatal, a synthetic surfactant containing colfosceril palmitate, cetyl alcohol and tyloxapol.  In all but Hudak's study (1996), the natural surfactant extract tested was Survanta, a modified bovine surfactant extract.  Hudak  (1996) studied the bovine surfactant, Infasurf.  Infasurf is obtained from the lavage of calf lung.  Unlike Survanta, no supplemental lipids are added to this formulation.

Study outcomes included initial clinical improvement as well as a variety of  complications of prematurity including pneumothorax, patent ductus arteriosus, pulmonary hemorrhage, necrotizing enterocolitis, intraventricular hemorrhage, chronic lung disease, and mortality.  This analysis focuses on clinical outcomes described in these studies.

Methodological quality of included studies

Only randomized  clinical trials which compared the effects of synthetic surfactant to natural surfactant extract in premature infants with established respiratory distress syndrome were included in the analysis.  Fifteen potentially relevant trials were identified.  Eight trials were excluded from the final analysis.  The studies of Cotton (1992),  Rolands (1993), and Stenson (1994) were excluded because they were not randomized trials.  Grauaug (1994), Choukroun (1994), Bassiouny (1997) and Murdoch (1998) do not present relevant clinical outcomes for inclusion in the analysis.  Hudak (1997) reports a comparison of Infasurf and Exosurf Neonatal in the context of prophylactic surfactant administration.  The remaining seven studies were either random or quasi-random in treatment assignment and reported on at least one relevant clinical outcome.

The methods of randomization were specified in 6 of the studies.  Horbar (1993) used randomization lists at study center pharmacies.  Hudak (1996), Seghal (1994), and Vermont Oxford Neonatal Network (1996) all used sealed envelopes opened by the clinical investigators.  Modanlou (1997) used shuffled color-coded cards. Pearlman (1993) used a quasi-randomized strategy allowing for alternate month treatment.  The randomization methods used by Alvarado (1993) are not specified.

In the trials of Alvarado (1993) and Hudak (1996) investigators administering surfactant treatment were unaware of treatment assignment.  In the other trials, treatment concealment was not attempted. 

Results

Each of the studies comparing natural surfactant extract to synthetic surfactant reported greater improvement in immediate need for respiratory support associated with treatment with natural surfactant extract.  Several studies reported more significant differences between the preparations.  Alvarado (1993) reported fewer days on mechanical ventilation, fewer days on supplemental oxygen, and fewer days of hospitalization associated with treatment with natural surfactant extract.  Hudak (1996) and the Vermont Oxford Neonatal Network (1996) reported a decreased incidence of pneumothorax associated with natural surfactant extract treatment.

In the meta-analysis, natural surfactant is designated the experimental therapy and synthetic surfactant the control therapy.

The meta-analyses support a significant reduction in the risk of pneumothorax (typical relative risk 0.68, 95% CI 0.56, 0.83; typical risk difference -0.04, 95% CI -0.06, -0.02).  No disadvantages to natural surfactant extract treatment are noted in other outcomes.  A trend towards decreased mortality is noted with natural surfactant extract.

Discussion

Synthetic surfactants and natural surfactant extracts have both been proven to be effective in the prevention and treatment of RDS and have become widely available for clinical use.  Although clinical trials have demonstrated that both synthetic surfactants and natural surfactant preparations are effective, comparison in animal models has suggested that there may be greater efficacy of natural surfactant products, perhaps due to the protein content of natural surfactants.  The randomized controlled trials which have been conducted comparing natural surfactant extract to synthetic surfactant have universally demonstrated greater improvement in immediate need for ventilatory support in infants who receive natural surfactant extracts.  The meta-analyses support a significant decrease in pneumothorax associated with natural surfactant extract treatment.  A trend towards increased survival with natural surfactant extract is also noted.  The meta-analyses do not support any deleterious effects of natural surfactant extract treatment. 

Conclusions

Implications for practice

Both natural surfactant extracts and synthetic surfactant extracts are effective in the treatment of established respiratory distress syndrome.  Comparative trials demonstrate greater early improvement in the requirement for ventilatory support and fewer pneumothoraces associated with natural surfactant extract treatment.  On clinical grounds, natural surfactant extracts would seem to be the more desirable choice when compared to currently available synthetic surfactants.

Implications for research

Clinical trials which compare newer synthetic surfactants such as KL4 to available natural surfactant extracts have not as yet been reported.

Characteristics of Included Studies

Study: Alvarado 1993
Method: Randomized
Single center trial
Blinding of randomization:  yes
Blinding of intervention:  can't tell
Complete follow-up:  yes
Blinding of outcome measurement:  can't tell
Participants: Birthweight <1500 grams
Assisted ventilation
Supplemental oxygen >40%
Respiratory distress syndrome
Age <24 hours
Exosurf Neonatal n=33
Survanta n=33
Interventions: Survanta v. Exosurf
Multiple doses
Outcomes: Clinical Improvement
Days on assisted ventilation
Days on supplemental oxygen
Days in hospital
Mortality

Study: Horbar 1993
Method: Randomized
Multicenter trial
Blinding of randomization:  yes
   (randomization lists at study
    center pharmacy)
Blinding of intervention:  no
Complete follow-up:  yes
Blinding of outcome measurement:  no
Stratification by birthweight
Participants: Birthweight 501-1500 grams
Assisted ventilation
Supplemental oxygen >30%
Respiratory distress syndrome
Age <6 hours
Exosurf Neonatal n= 309
Survanta n= 308
Interventions: Survanta v. Exosurf
Multiple doses
Outcomes: PRIMARY:
Death or BPD
Average FiO2, mean airway pressure
SECONDARY:
Complications of prematurity
Complications associated with dosing

Study: Hudak 1996
Method: Randomized
Multicenter trial
Blinding of randomization:  yes
   (sealed envelopes)
Blinding of intervention:  yes
Complete follow-up:  yes
Blinding of outcome measurement:  yes
Participants: Respiratory distress syndrome
Assisted ventilation
a/A ratio  less than or equal to 0.22
Age <72 hours
Exosurf Neonatal n= 508
Infasurf n= 525
Interventions: Infasurf v. Exosurf
Treatment crossover allowed after second dose
Outcomes: PRIMARY:
Pneumothorax
SECONDARY:
Crossover treatment
Mortality
Survival without chronic lung disease
Days on assisted ventilation
Days in oxygen
Days in hospital

Study: Modanlou 1997
Method: Randomized
   (method not specified)
Single center trial
Blinding of randomization:  yes
Blinding of intervention:  no
Complete follow-up:  yes
Blinding of outcome measurement:  no
Participants: Birthweight 500-1500 grams
Premature infants
Assisted ventilation
Respiratory distress syndrome
age less than or equal to 8 hours
a/A ratio less than or equal to 0.22 or supplemental oxygen >0.4
Exosurf Neonatal n= 61
Survanta n= 61
Interventions: Survanta vs. Exosurf
Multiple doses
Outcomes: Average FiO2
Mean airway pressure
Duration of ventilation
Duration of supplemental oxygen
Mortality
Complications of prematurity

Study: Pearlman 1993
Method: Quasi randomized
  (alternate month strategy)
Single center trial
Blinding of randomization:  no
Blinding of intervention:  no
Complete follow-up:  yes
Blinding of outcome measurement:  no
Participants: Premature infants
Respiratory distress syndrome
Exosurf Neonatal n= 64
Survanta n= 57
Interventions: Survanta v. Exosurf
Outcomes: Days on assisted ventilation
Pulmonary hemorrhage
Mortality
Complications of prematurity

Study: Sehgal 1994
Method: Randomized
Single center trial
Blinding of randomization:  yes
    (sealed envelopes)
Blinding of intervention:  no
Complete follow-up:  yes
Blinding of outcome measurement:  no
Participants: Birthweight 600-1750 grams
Assisted ventilation
Supplemental oxygen >40%
Respiratory distress syndrome
Age <8 hours
Exosurf Neonatal n= 21
Survanta n= 19
Interventions: Survanta v. Exosurf
Multiple doses
Outcomes: PRIMARY:
Initial response
SECONDARY:
Complications of prematurity

Study: VT Oxford 1996
Method: Randomized
Multicenter trial
Blinding of randomization:  yes
   (Sealed envelopes)
Blinding of intervention:  no
Complete follow-up:  yes
Blinding of outcome measurement:  no
Stratification by birthweight
Participants: Birthweight 501-1500 grams
Assisted ventilation
Supplemental oxygen >30%
Respiratory distress syndrome
Age <6 hours
Exosurf Neonatal n= 644
Survanta n= 652
Interventions: Survanta v. Exosurf
Multiple doses
Outcomes: PRIMARY:
Death or chronic lung disease
SECONDARY:
Complications of prematurity

Characteristics of Excluded Studies

Study Identifier: Bassiouny 1997
Reason for exclusion: No clinical outcomes given.

Study Identifier: Choukroun 1994
Reason for exclusion: No clinical outcomes given.  Assessment limited to changes in pulmonary function.

Study Identifier: Cotton 1992
Reason for exclusion: Not assigned treatment by randomization.

Study Identifier: Grauang 1994
Reason for exclusion: No clinical outcomes given.

Study Identifier: Hudak 1997
Reason for exclusion: Prophylactic surfactant administration.

Study Identifier: Murdoch 1998
Reason for exclusion: No clinical outcomes given.  Assessment limited to changes in cerebral hemodynamics.

Study Identifier: Rollins 1993
Reason for exclusion: Not assigned treatment by randomization.

Study Identifier: Stenson 1994
Reason for exclusion: Not assigned treatment by randomization.

References to Studies

Section 1. References to studies included in this review

Alvarado M, Hingre R, Hakason D, Gross S. Clinical trial of Survanta versus Exosurf in Infants <1500g with respiratory distress syndrome. Pediatr Res 1993;33:314A

Horbar JD, Wright LL, Soll RF, et al. A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. J Pediatr 1993;123:757-66

Hudak ML,  Farrell EE, Rosenberg AA, et al.  A multicenter randomized masked comparison trial of natural versus synthetic surfactant for the treatment of respiratory distress syndrome.  J Pediatr 1996;128:396-406.

Modanlou H, Beharry K, et al:  Comparative efficacy of Exosurf and Survanta surfactants on early clinical course of respiratory distress syndrome and complications of prematurity.  J Perinatol 1997;17:455-60.

Pearlman SA, Leef KH, Stefano JL, et al. A randomized trial comparing Exosurf versus Survanta in the treatment of neonatal RDS. Pediatr Res 1993;33:340A

Sehgal SS, Ewing CK, Richards T and Taeusch HW.  Modified bovine surfactant (Survanta) versus a protein free surfactant (Exosurf) in the treatment of respiratory distress syndrome in preterm infants:  a pilot study.  J Natl Med Assoc 1994;86:46-52.

The Vermont Oxford  Neonatal Network.  A multicenter randomized trial comparing synthetic surfactant with modified bovine surfactant extract in the treatment of neonatal respiratory distress syndrome.  Pediatrics 1996;97:1-6.

Section 2.  References to studies excluded from this review

Bassiouny MR, Remo C, Cherian E:  Comparison of the changes in the a/A oxygen ratio after administration of two surfactants for the treatment of neonatal respiratory distress syndrome.  J Trop Pediatr 1997;43:38-41.

Choukroun ML, Llanas B, Apere H, Fayon M, Galperine RI, Guenard H, Demarquez JL:  Pulmonary mechanics in ventilated preterm infants with respiratory distress syndrome after exogenous surfactant administration:  A comparison between two surfactant preparations.  Pediatr Pulmonol 1994;18:273-278.

Cotton RB, Law AB, Lindstrom DP, et al:  Differential effects of synthetic and bovine surfactants on lung volume and oxygenation in premature infants with RDS (Abstract).  Pediatr Res 1992;31:304A.

Grauaug A, Kohan R, Sly P, et al:  Exosurf and Survanta:  Are there advantages of one over the other when used as rescue therapy (Abstract).  Pediatr Res 1994;35:335A.

Hudak ML, Martin DJ, Egan EA, et al:  A multicenter randomized masked comparison trial of synthetic surfactant versus calf lung surfactant extract in the prevention of neonatal respiratory distress syndrome.  Pediatrics 1997;100:39-50.

Murdoch E, Kempley ST:  Randomized trial examining cerebral haemodynamics following artificial or animal surfactant.  Acta Paediatrica 1998;87:411-415.

Rollins M, Jenkins J, Tubman R, et al:  Comparison of clinical responses to natural and synthetic surfactants.  J Perinat Med 1993;21:341-347.

Stenson BJ, Glover RM, Pappy GJ, et al:  Static respiratory compliance in the newborn III.  Early changes after exogenous surfactant treatment.  Arch Dis Child 1994;70:F19-F24.

Section 3.  References to studies awaiting assessment

Peliowski A, Finer NN for the Canadian Surfactant Study Group:  A randomized, blinded, Canadian multicenter trial to compare a bovine surfactant, bLES(R) (b), with a synthetic, Exosurf (E), for the rescue treatment of respiratory distress syndrome (RDS) in premature newborns <=1250 g. Pediatr Res 1998;43:293A.

Section 4.  Ongoing studies

Milligan DWA for the CandA Trial Group:  Randomized comparison between artificial lung expanding compound (ALEC) and Curosurf.

Other References

Section 5.  Additional references

Horbar JD, Wright EC, Onstad L, et al:  Decreased mortality associated with the introduction of surfactant therapy:  An observational study of neonates weighing 601-1300 grams at birth.  Pediatrics 1993;92:191-196.

Schwartz RM, Luby AM, Scanlon JW, Kellogg RJ:  Effect of surfactant on morbidity, mortality and resource use in newborns weighing 500-1500 gr.  N Engl J Med 1994:330:1476-1480.

Soll RF, McQueen MC:  Respiratory Distress Syndrome.  In:  Sinclair JC, Bracken MB, eds Effective Care of the Newborn Infant.  Oxford:  Oxford University Press; 1992:325-358.

Tooley WH, Clements JA, Muramatsu K, et al:  Lung function in prematurely delivered rabbits treated with a synthetic surfactant.  Am Rev Respir Dis 1987;136:651-656.

Section 6.  Previously published versions of this review

Soll RF.  Natural surfactant extract vs synthetic surfactant in the treatment of established respiratory distress syndrome (Cochrane Review).  In:  The Cochrane Library, Issue 3, 1997.  Oxford:  Update Software.

Table of Comparisons

01.00.00 Natural surfactant extract vs synthetic surfactant

01.01.00 Pneumothorax (RR)

01.01.00 Pneumothorax (RD)

01.02.00 Patent ductus arteriosus (RR)

01.02.00 Patent ductus arteriosus (RD)

01.03.00 Intraventricular hemorrhage (RR)

01.03.00 Intraventricular hemorrhage (RD)

01.04.00 Severe intraventricular hemorrhage, grades 3 or 4 (RR)

01.04.00 Severe intraventricular hemorrhage, grades 3 or 4 (RD)

01.05.00 Bronchopulmonary dysplasia (RR)

01.05.00 Bronchopulmonary dysplasia (RD)

01.06.00 Mortality (RR)

01.06.00 Mortality (RD)

01.07.00 Bronchopulmonary dysplasia or mortality (RR)

01.07.00 Bronchopulmonary dysplasia or mortality (RD)