Multiple versus single dose natural surfactant extract for severe neonatal
respiratory distress syndrome
Cover Sheet
Short title: Multiple v. single dose surfactant
Reviewer(s): Soll RF
Date of most recent amendment: 22/02/1999
Date of most recent substantive amendment: 16/02/1999
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 has acted as the principal investigator
or co-investigator of several of the randomized controlled trials of surfactant
preparations (trials not included in this review).
Abstract
Objective
To compare the effect of multiple doses of natural surfactant extract to
single doses of natural surfactant extract 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 trials), 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 a policy of multiple doses of natural
surfactant extract to a policy of single doses of natural surfactant extract
in premature infants with respiratory distress syndrome were considered
for this review.
Data collection & analysis
Data on 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 were analyzed according to the standards
of the Neonatal Cochrane Review Group.
Main results
Two randomized controlled trials of multiple vs. single dose natural surfactant
extract in infants with established respiratory distress syndrome were
identified. Meta-analysis of these trials suggests a reduction in
the risk of pneumothorax (typical relative risk 0.51, 95% CI 0.30, 0.88;
typical risk difference-0.09, 95% CI -0.15, -0.02) and a trend towards
a reduction in mortality (typical relative risk 0.63, 95% CI 0.39, 1.02;
typical risk difference -0.07, 95% CI -0.14, 00.00). No complications
associated with multiple dose treatment are reported in the identified
trials.
Conclusions
In infants with established respiratory distress, a policy of multiple
doses of natural surfactant extract results in greater improvements regarding
oxygenation and ventilatory requirements, a decreased risk of pneumothorax
and a trend toward improved survival. The ability to give multiple
doses of surfactant to infants with ongoing respiratory insufficiency leads
to improved clinical outcome and appears to be the most effective treatment
policy.
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). In general,
the initial trials of surfactant replacement therapy evaluated the effect
of single doses of surfactant. In these studies, surfactant treatment
resulted in rapid and dramatic improvements in oxygenation and ventilatory
requirement. However, in many of the single dose studies, the clinical
impact was less than anticipated. Fujiwara (1988) and Charon (1989)
describe the response of infants treated with single doses of surfactant.
Both authors describe a group of neonates responded only transiently to
surfactant therapy. The possibility of surfactant inhibition or inactivation
has led investigators to attempt multiple dose therapy.
Clinical trials which compare a policy of multiple doses of natural
surfactant extract to a policy of single doses of natural surfactant extract
in infants with established respiratory distress syndrome are included
in the following review. This review updates the existing review
of Multiple v. single dose natural surfactant extract for severe RDS, published
in the Cochrane Library, Issue 3, 1997.
Objectives
To compare the effect of multiple doses of natural surfactant extract to
single doses of natural surfactant extract 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 a policy of multiple
doses of natural surfactant extract to a policy of single doses of natural
surfactant extract in premature infants with respiratory distress syndrome
were considered for this review.
Types of participants
Premature infants with established respiratory distress syndrome requiring
assisted ventilation.
Types of intervention
Infants were randomly allocated to receive either single doses of a
natural surfactant extract or multiple doses of natural surfactant extract.
Types of outcome measures
Clinical outcomes included initial improvement in oxygenation and need
for ventilatory support as well as complications of prematurity including:
pneumothorax, patent ductus arteriosus, necrotizing enterocolitis, intraventricular
hemorrhage (all intraventricular hemorrhage and severe intraventricular
hemorrhage), chronic lung disease, retinopathy of prematurity and mortality.
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
infant; publication type, clinical trials), previous reviews including
cross references, abstracts, conference and symposia proceedings, expert
informants, and journal hand searching in the English language.
Methods of the review
For each included trial, information was collected regarding the method
of randomization, blinding, drug intervention, stratification, and
whether the trial was single or multicentered. 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 0-4), chronic lung disease, and mortality.
Description of studies
The review includes the following studies: Dunn (1990) and Speer
(1992). The methods of randomization, description of participants,
description of interventions, and outcomes reported are summarized in the
Table of Characteristics of Included Studies. Dunn (1990) included
premature infants within the gestational age range of 30-36 weeks.
Infants had respiratory distress syndrome requiring assisted ventilation
and supplemental oxygen. Enrollment occurred before 6 hours of age.
Infants were randomly assigned to either control (air placebo), a single
dose of bovine lung surfactant extract (100 mg/kg) or multiple doses of
bovine lung surfactant extract (100 mg/kg). Infants assigned to the
multiple dose group could receive up to 4 doses during the first 72 hours
of life. Speer (1992) enrolled premature infants with a birthweight
ranging between 700-2000 gms. Enrolled infants had respiratory distress
syndrome requiring assisted ventilation and supplemental oxygen of greater
than or equal to 60%. Infants ranged between 2 to 15 hours of age
at enrollment. Infants were randomly assigned to either a single
dose of Curosurf (100 mg/kg) or multiple doses of Curosurf (100 mg/kg x
3 doses). The multiple dose group received additional doses of Curosurf
at 12 and 24 hours after the initial dose if the infant remained on assisted
ventilation.
Study outcomes included initial clinical improvement (measurements of
oxygenation and ventilatory support) as well as complications of prematurity
including pneumothorax, patent ductus arteriosus, pulmonary hemorrhage,
necrotizing enterocolitis, intraventricular hemorrhage, chronic lung disease,
and mortality. This review focuses on clinical outcomes described
in these two studies.
The study of Corbet (1995) is not included in this analysis. Corbet
(1995) compared one versus three prophylactic doses of synthetic surfactant
in 826 neonates weighing 700 to 1100 grams. The study is not included
since Corbet (1995) used a synthetic surfactant (Exosurf Neonatal) and
treated infants at risk of developing RDS prophylactically (as opposed
to treatment of established RDS).
Methodological quality of included studies
Only randomized clinical trials which compared multiple doses of natural
surfactant extract to single doses of natural surfactant extract in premature
infants with established respiratory distress syndrome were included in
the analysis.
Trials evaluating single doses of synthetic surfactant vs. multiple
doses of synthetic surfactant are not included in this analysis.
Trials comparing various other dosage strategies are not included in this
review.
The method of randomization for both studies was the use of sealed,
opaque envelopes. In the study of Dunn (1990), randomization used
stratification by gestational age, exposure to antenatal steroids, and
the infant's gender. Speer (1992) stratified infants by birthweight.
Dunn (1990) attempted to minimize bias by having staff not involved
with the care of the patient administer surfactant. Speer (1992)
made no attempt to conceal treatment assignment.
Results
Dunn (1990) administered multiple doses to 70% of the infants randomized
to multiple dose policy. Speer (1992) administered multiple doses
to 65% of infants randomized to a multiple dose policy. Both studies
demonstrated more sustained improvement in oxygenation and decreased requirement
for ventilatory support in the group of infants allowed to receive multiple
doses of natural surfactant extract. Speer (1992) reported a reduction
in the incidence of pneumothorax in the multiple dose group (9% vs. 18%).
The meta-analysis supports a decreased risk of pneumothorax associated
with multiple dose surfactant therapy. No differences in the
risk of patent ductus arteriosus, intraventricular hemorrhage, severe intraventricular
hemorrhage, bronchopulmonary dysplasia, bacterial sepsis are reported in
the individual studies or supported by the meta-analysis. Speer (1992)
reports a trend towards decreased mortality (13% vs. 21%). The meta-analysis
demonstrates a trend towards a decreased risk of mortality.
Discussion
Although the initial trials of single dose surfactant therapy demonstrated
dramatic results regarding early improvement in oxygenation and ventilatory
support, clinical outcome was not as promising as anticipated. In
animal studies, a more sustained response to surfactant therapy could be
maintained if animals were given repeated doses of natural surfactant extract
(Walthers 1985). In retrospective analyses of single dose surfactant
therapy studies, it was clear that as many as one-third of the treated
infants appeared to relapse after initial therapy (Fujiwara 1988, Charon
1989). The use of repeated dosing was an attractive way to improve
and sustain response to surfactant therapy. Two randomized
controlled trials reported on the effect of a policy of multiple dose surfactant
therapy compared to a policy of single dose therapy with natural surfactant
extract. Sustained response is reported in the group that received
multiple doses of surfactant. The meta-analysis suggests a decreased
risk of pneumothorax and a trend toward a decreased risk of mortality.
The study of Corbet (1995) is not included in the review since the approach
to treatment (prophylactic as opposed to treatment of established disease)
and the surfactant preparation (synthetic surfactant as opposed to natural
surfactant extract) are substantially different. Of some interest,
Corbet (1995) also demonstrates significant improvement in clinical outcome
in those infants who received multiple surfactant doses.
Conclusions
Implications for practice
A more sustained response is seen in infants with respiratory distress
syndrome who are allowed multiple doses of natural surfactant extract.
Meta-analysis suggests improvement in clinical outcomes including decreasing
the risk of pneumothorax. The ability to give multiple doses of natural
surfactant extract appears to be the most desirable approach to treatment.
Implications for research
Multiple clinical trials have compared a variety of dosing issues including
timing of treatment (prophylactic administration of surfactant vs. treatment
of established respiratory distress syndrome); a variety of high dose and
low dose regimens, and single v. multiple doses (discussed in this analysis).
Specific criteria for repeat doses and timing of repeat doses could be
refined in future studies.
Characteristics of Included Studies
Study: Dunn 1990
Method: Randomized controlled
Single center
Blinding of Randomization: Yes
Blinding of Intervention: Yes
Complete Follow-up: Yes
Blinding of Outcome Measurement: Yes
Stratification: gestational age,
Antenatal steroids, Sex
Participants: Premature infants
Gestational age 30-36 wks
Respiratory distress syndrome
Assisted ventilation
Supplemental oxygen
Age <6 hrs
Interventions: Control (air placebo) vs single dose
Bovine lung surfactant extract
(100 mg/kg) vs multiple dose
(max 4 doses)
Bovine lung surfactant extract
(100 mg/kg)
Retreatment allowed
in multiple dose group
during first 72 hrs of life
(max 4 doses)
Outcomes: PRIMARY:
a/A ratio
SECONDARY:
Ventilatory Requirement
Complications of Prematurity
Study: Speer 1992
Method: Randomized
Multicenter trial
Blinding of Randomization: Yes
Blinding of Intervention: No
Complete Follow-up: Yes
Blinding of Outcome Measurement: No
Stratified by birthweight
Participants: Premature infants
Birthweight 700-2000 grams
Respiratory distress syndrome
Assisted ventilation
Supplemental oxygen equal to or greater than 60%
Age 2-15 hrs
Interventions: Single dose Curosurf (100 mg/kg) vs. Multiple
dose Curosurf
(100 mg/kg) x 3 doses
Multiple dose group received additional doses of Curosurf
at 12 and 24 hours after initial dose
if on assisted ventilation
Outcomes: PRIMARY:
Bronchopulmonary dysplasia or death
SECONDARY:
Ventilatory requirements
Oxygenation
Complications of Prematurity
Characteristics of Excluded Studies
Study Identifier: Corbet 1995
Reason for exclusion: The study of Corbet (1995) is not included
in the review since the approach to treatment (prophylactic as opposed
to treatment of established disease) and the surfactant preparation (synthetic
surfactant as opposed to natural surfactant extract) are substantially
different.
References to Studies
Section 1. References to studies included in this review
Dunn MS, Shennan AT, Possmayer F. Single- vs multiple- dose surfactant
replacement therapy in neonates of 30 to 36 weeks' gestation with respiratory
distress syndrome. Pediatrics 1990; 86:564-571.
Speer CP, Robertson B, Curstedt T, Halliday HL [see article for full
collaborative authorship]. Randomized European multicenter trial
of surfactant replacement therapy for severe neonatal respiratory distress
syndrome: single vs multiple doses of Curosurf. Pediatrics
1992; 89:13-20.
Section 2. References to studies excluded from this review
Corbet A, Gerdes J, Long W, Avila E, Puri A, Rosenberg A, Edwards K, Cook
L: Double-blind randomized trial of one versus three prophylactic
doses of synthetic surfactant in 826 neonates weighing 700 to 1000 grams:
effects on mortality rate. J Pediatr 1995;126:969-978.
Other References
Section 5. Additional references
Charon A, Taeusch HE, Fitzgibbon C, et al: Factors associated with
surfactant treatment response in infants with severe respiratory distress
syndrome. Pediatrics 1989;83:348-354.
Fujiwara T, Konishi M, Chida S, et al: Factors affecting response
to a single postnatal dose of exogenous surfactant in surfactant treatment
of lung disease. Report of the 96th Ross Conference on Pediatric
Research: A Jobe, H.W. Taeusch (eds). Columbus, Ohio, Ross
Laboratories, 1988.
Soll RF, McQueen MC: Respiratory Distress Syndrome. In Sinclair
J and Bracken M (eds): Effective Care of the Newborn. Oxford
University Press, Oxford, UK, 1992.
Walthers FJ, Blaco CE, Houdijk M, Bevers EM: Single versus repetitive
doses of natural surfactant as treatment of respiratory distress syndrome
in premature lambs. Pediatric Res 1985;19:224-7.
Section 6. Previously published versions of this review
Soll RF. Multiple v. single dose natural surfactant extract for severe
RDS (Cochrane Review). In: The Cochrane Library, Issue 3, 1997.
Oxford: Update Software.
Table of Comparisons
01.00.00 Multiple vs single dose surfactant for severe RDS
01.01.00 Pneumothorax (RR)
01.01.00 Pneumothorax (RD)
01.02.00 Intraventricular hemorrhage (RR)
01.02.00 Intraventricular hemorrhage (RD)
01.03.00 Severe intraventricular hemorrhage (RR)
01.03.00 Severe intraventricular hemorrhage (RD)
01.04.00 Patent ductus arteriosus (RR)
01.04.00 Patent ductus arteriosus (RD)
01.05.00 Bronchopulmonary dysplasia (RR)
01.05.00 Bronchopulmonary dysplasia (RD)
01.06.00 Bacterial sepsis (RR)
01.06.00 Bacterial sepsis (RD)
01.07.00 Mortality (RR)
01.07.00 Mortality (RD)
01.08.00 BPD or death (RR)
01.08.00 BPD or death (RD)