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

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)