3. REVIEW ARTICLES
Surfactant replacement therapy has
become the standard of care for preterm infants with surfactant deficiency
and respiratory distress syndrome
(RDS). Multiple randomized controlled
trials (RCTs) and meta-analyses of
those trials established the benefits of
surfactant in improving survival rates
and reducing the incidence of pneumothorax.1–4 The trials also showed
better efficacy of animal-derived surfactants, compared with non–proteincontaining synthetic surfactants.2 Although several animal-derived surfactants are available, beractant, poractant alfa, and calfactant are the 3
most-commonly used, animal-derived
surfactants throughout the world.
Less-commonly used, animal-derived
surfactants include bovine lipid surfactant (in Canada), bovactant (in some European countries), surfactant-TA (in Japan),
Surfacen (in Cuba), and Newfacten (in
Korea).
These animal-derived surfactants differ in their composition (amounts of
phospholipids, surfactant-associated
proteins B and C, and plasmalogens),
viscosity, and volume of administration, which might affect their clinical
efficacy and ease of administration.
Beractant is a minced bovine lung extract that has added lipids (colfosceril
palmitate, palmitic acid, and tripalmitin) to standardize its composition and
to make it similar to other natural
lung surfactants. It contains smaller
amounts of phospholipids, surfactantassociated protein B, and plasmalogen, compared with calfactant, which
is a lavage preparation from bovine
lung. Poractant alfa is a surfactant
that is derived from minced porcine
lungs, subjected to chloroform/methanol extraction, and further purified
through liquid-gel chromatography. As
a result, it contains the largest
amounts of phospholipids distributed
in the smallest volumes, as well as the
largest amount of plasmalogen.5 Many
PEDIATRICS Volume 128, Number 6, December 2011
retrospective studies and RCTs have
been published to compare the clinical
efficacies of animal-derived surfactants; however, controversy remains
regarding the animal-derived surfactant with superior clinical efficacy. Because of the small size of most of the
RCTs, the 2008 American Academy of
Pediatrics recommendation states, “it
is unclear whether significant differences in clinical outcomes exist among
the available animal-derived surfactant products.”6 We conducted this systematic review with the objective of
comparing the efficacy of a porcine
surfactant (poractant alfa) with that of
commonly used bovine surfactants
(beractant and calfactant), with respect to clinical outcomes for preterm
infants with RDS or at risk of RDS.
METHODS
trolled Trials (all years). We used the
following key words: “pulmonary
surfactant,” “surfactant treatment,”
“poractant alfa,” “calfactant,” and
“beractant.” For Medline, we limited
our search to human studies and to
studies involving all infants from birth
to 23 months. We applied the Cochrane
sensitivity-maximizing and Cochrane
sensitivity- and precision-maximizing
strategies as our special search
strategies.7
We also searched the abstract archives of the Society of Pediatric Research annual meetings (2000 –2009),
the Food and Drug Administration
database, and the clinicaltrials.gov
Web site. Finally, we hand-searched
the references cited in the studies
identified through our electronic
search and in review articles on surfactant therapy.
Eligibility Criteria
We included studies in this review if
they were RCTs (published as complete articles or as abstracts) that
compared porcine surfactant (poractant alfa) versus bovine surfactant (beractant and/or calfactant) for preterm
infants who were at risk for RDS or had
clinical and/or radiologic evidence of
RDS. To be included, each study had to
report Ն1 of the clinical outcomes
listed below. We excluded quasirandomized studies for this review. We
did not restrict studies according to
language, type of administration strategy (prophylaxis or rescue treatment),
or dosage of surfactant.
Study Selection
All of the studies retrieved through the
search strategies described above
were imported to an electronic bibliographic management program (Refworks [ProQuest, Ann Arbor, MI]), and
duplicates were removed. We reviewed the titles and abstracts (where
available) of the remaining articles
and excluded those that were not relevant to our topic and those that did not
meet the eligibility criteria. The fulltext versions were obtained for the relevant articles that could be included in
the systematic review.
Data-Collection Process
Information Sources
We used broad search strategies to
identify eligible studies. We conducted
a systematic literature search in December 2010, using the methods of the
Cochrane Collaboration for Systematic
Reviews of Interventions.7 The databases searched included Medline
(1980 to December 2010) and the
Cochrane Central Register of Con-
Data from included trials were extracted, on standard data collection
forms, independently by 3 reviewers.
Data collected included study design,
study interventions, number of subjects in each arm, prenatal corticosteroid use, infant and maternal
demographic characteristics, inclusion and exclusion criteria, primary
and secondary outcomes, and vari-
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4. ables used to assess study quality
(see below). Discrepancies between
the 3 reviewers were resolved
through discussion.
surgically ligated cases had been
treated medically as well, although
this might underestimate the true incidence of PDA).
Data Items
Risk of Bias in Individual Studies
The primary outcome measure was
the incidence of oxygen requirements
at a postmenstrual age of 36 weeks,
which was labeled either bronchopulmonary dysplasia (BPD) or chronic
lung disease (CLD) in the articles. The
incidence was calculated from data for
all enrolled infants in each study. Secondary outcomes related to respiratory care were pulmonary air leaks
(including pneumothorax and/or pulmonary interstitial emphysema), pulmonary hemorrhage (defined as the
presence of bright red blood in the endotracheal tube, with rapid deterioration of the patient’s clinical status),
mean airway pressure (MAP) used
during mechanical ventilation (described as the median and interquartile range in the first 6 hours), duration
of mechanical ventilation, fraction of
inspired oxygen (FIO2) (described as
the median value in the first 6 hours),
duration of supplemental oxygen treatment, and the need for surfactant redosing. Secondary outcomes related
to complications of prematurity included the incidences of sepsis (defined as positive blood culture results), necrotizing enterocolitis, patent
ductus arteriosus (PDA) (diagnosed on
the basis of clinical signs, with or without echocardiographic findings), retinopathy of prematurity (ROP),8 and
intraventricular hemorrhage (IVH)
(classified according to the system described by Papile et al9), length of hospital stay, and death before hospital
discharge. We included pneumothorax, pulmonary interstitial emphysema, and unspecified air leaks under
the term pulmonary air leaks. With respect to PDA, we included only data for
clinical PDA cases and those treated
medically (with the assumption that
The Cochrane Risk of Bias tool7 was
used to assess the methodologic
quality of the included studies. Three
independent reviewers evaluated the
validity and design characteristics of
each study for significant sources of
bias, which included adequacy of
random sequence generation, allocation concealment, and blinding for
interventions and outcome assessment and use of intention-to-treat
analysis. Each item was assessed as
yes (low risk of bias), no (high risk of
bias), or unclear (investigators were
unable to determine, on the basis of
available data). Discrepancies between the 3 reviewers were resolved
through discussion.
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SINGH et al
Summary Measures and Synthesis
of Results
The analysis was performed with Review Manager 5.0 (Nordic Cochrane
Centre, Copenhagen, Denmark), by using a fixed-effect model to obtain relative risks (RRs) and 95% confidence
intervals (CIs) for dichotomous variables and weighted mean differences
and 95% CIs for continuous variables.
We assessed data through qualitative
analysis if noncomparable measurement units were used in different studies. We planned to perform analyses by
pooling the data for different surfactants irrespective of the dosages used
and then performing subgroup analyses on the basis of different dosages
for the porcine and bovine surfactants.
Significant heterogeneity was considered to be present if the I2 statistic was
Ͼ50%, which suggests caution in interpretation of the results of the
meta-analysis.
RESULTS
Studies Analyzed
Our Medline and Cochrane Central
Register of Controlled Trials searches
retrieved 758 articles (after removal of
duplicates). After a review of the titles
and abstracts, we excluded 615 articles that were not relevant to our research question, 44 articles that were
reviews on surfactants, and 92 articles
that did not meet study design or inclusion criteria or did not report Ն1
of the aforementioned outcomes. We
obtained full-text versions for the remaining 7 studies for complete
review.10–16
After review of the full-text versions, 2
studies were excluded; 1 of the articles12 discussed the effects of surfactant on PDA as a follow-up article after
publication of the original article,11
and the other study13 did not use true
randomization (interventions were allocated on the basis of whether the patient’s admission code was an odd or
even number) and had poor allocation
concealment. Additional searches of
the Society of Pediatric Research abstract archives, the US Food and Drug
Administration database, and the clinicaltrials.gov Web site and hand
searches of the references from studies and review articles identified
through the searches described above
did not yield any other study eligible
for inclusion.
Five eligible studies were included in
the final analysis. Tables 1, 2, and 3
summarize the characteristics and
quality assessments of these studies.10,11,14–16 Three of the studies were
conducted in the United States,11,14,15 1
each was conducted in Germany16 and
Greece.10 A total of 529 infants were
enrolled in these 5 studies. Most of the
studies were small RCTs except for 1
study,15 which contributed 55% of the
pooled sample size for the metaanalysis. The studies were comparable
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5. REVIEW ARTICLES
TABLE 1 Characteristics of Included RCTs
N
Control
(Beractant), n
Gestational Age,
Mean Ϯ SD, wk
Birth Weight,
Mean Ϯ SD, g
Male, %
Prenatal Steroid
Use, %
73
53
293
58
52
Speer et al16
Baroutis10
Ramanathan et al15
Malloy et al14
Fujii et al11
Intervention
(Poractant), n
33
27
195
29
25
40
26
98
29
27
28.8 Ϯ 2.22
28.9 Ϯ 0.81
28.7 Ϯ 1.73
29.4 Ϯ 3.24
27.2 Ϯ 2.44
1088 Ϯ 239
1207 Ϯ 392
1161 Ϯ 265
1401 Ϯ 616
917 Ϯ 254
45.2
49
59
46.6
61.5
39.7
28.3
80.9
74.1
98
TABLE 2 Details of Included RCTs
Inclusion Criteria
Surfactant
Primary Outcome Studied
Speer et al,16 multicenter
(Germany)
BW of 700–1500 g with RDS;
ventilated with FIO2 of Ն0.4;
surfactant within 1–24 h of life
Poractant, 200 mg/kg, or beractant, 100
mg/kg (repeat dose up to maximum of
400 mg/kg)
Baroutis,10 1 perinatal
center (Greece)
BW of Ͻ2000 g and GA of Ͻ32 wk
with RDS; ventilated with FIO2 of
Ն0.3; surfactant within 4 h of life
BW of 750–1750 g and GA of Ͻ35 wk
with RDS; intubated and
ventilated with FIO2 of Ͼ0.3;
surfactant within 6 h of life
Alveofact, 100 mg/kg, poractant, 100 mg/kg,
or beractant, 100 mg/kg
Ramanathan et al,15
multicenter (United
States)
Malloy et al,14 1 perinatal
center (United States)
GA of Ͻ37 wk with RDS
Fujii et al,11 2 perinatal
centers (United
States)
GA of 240⁄7 to 296⁄7 wk; surfactant and
ventilation soon after birth (Ͻ6
h); randomization immediately
before delivery
Poractant, 100 mg/kg, poractant, 200 mg/
kg, or beractant, 100 mg/kg
Poractant, 200 mg/kg, or beractant, 100
mg/kg (repeat dose up to maximum of
400 mg/kg)
Poractant, 200 mg/kg, or beractant, 100
mg/kg
Effects of 2 treatment regimens on gas
exchange, ventilator requirements,
and 28-d outcomes for infants with
RDS
Comparison of clinical outcomes with 3
surfactant regimens
Evaluation of effectiveness of 100 mg/
kg dose of poractant by comparing
onset of clinical response with those
for 200 mg/kg poractant and 100
mg/kg beractant
FIO2 requirement in first 48 h after first
dose of surfactant
Short-term treatment efficacy of 2
commonly used surfactants
BW indicates birth weight; GA, gestational age.
TABLE 3 Quality Assessment of Included Trials
Speer et al16
Adequate method of
randomization
Concealment of
allocation
Blinding of
intervention
Blinding of outcome
assessors
Complete follow-up
monitoring
Malloy et al14
Fujii et al11
Yes
Yes
Yes, random number
Yes
Yes, opaque sealed
envelopes
No
Yes, opaque sealed
envelopes
No
Yes, sealed envelopes
Yes, sealed envelopes
No
No
Yes, computer-generated
(block)
Yes, sealed opaque
envelopes
No
No
No
Yes
Yes
Unclear
Yes
Yes
Yes
Yes
Yes
with respect to the birth weights, gestational ages, and genders of the subjects included except for the study by
Fujii et al,11 which included extremely
premature infants. Wide variation in
prenatal corticosteroid use was noted
among the different studies (rates varied from 28% to 98%). These studies
performed well in quality assessments
for randomization and allocation concealment but suffered from perforPEDIATRICS Volume 128, Number 6, December 2011
Baroutis10
Ramanathan et al15
mance bias resulting from lack of
blinding for interventions and outcome assessments.
Surfactant was administered for treatment of established RDS and not for prophylaxis in all included studies. The studies compared poractant alfa with
beractant; no studies compared poractant alfa with calfactant. The dose of beractant was 100 mg/kg for both the ini-
tial and repeat administrations in all of
the studies. The initial dose of beractant
was compared against a high initial dose
(200 mg/kg) of poractant alfa in 4 studies11,14–16 and against a low initial dose
(100 mg/kg) of poractant alfa in 2 studies.10,15 One of the studies15 had 2 arms
for poractant alfa treatment, one with
a 200 mg/kg dose and the other with a
100 mg/kg dose. Subsequent doses of
poractant alfa were all at 100 mg/kg.
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6. TABLE 4 Pooled Estimates for Poractant Versus Beractant
Outcome
Poractant at 100 mg/kg or 200 mg/kg
vs Beractant at 100 mg/kg
BPD
Pulmonary hemorrhage
Pulmonary air leak
Redosing
Death
Sepsis
Necrotizing enterocolitis
PDA
Severe ROP
Severe IVH
0.98 (0.75 to 1.29)
1.06 (0.46 to 2.44)
0.67 (0.35 to 1.35)
0.71 (0.57 to 0.88)a
0.51 (0.30 to 0.89)a
1.69 (0.88 to 3.24)b
1.05 (0.50 to 2.18)
0.84 (0.68 to 1.05)b
1.16 (0.57 to 2.36)b
0.89 (0.49 to 1.61)
Duration of oxygen treatment
Duration of ventilation
Length of hospital stay
Ϫ5.02 (Ϫ7.44 to Ϫ2.68)b,c
Ϫ5.57 (Ϫ6.60 to Ϫ4.55)b,c
Ϫ26.32 (Ϫ36.57 to Ϫ16.07)b,c
Poractant at 200 mg/kg vs
Beractant at 100 mg/kg
RR (95% CI)
0.99 (0.74 to 1.33)
0.76 (0.32 to 1.81)
0.52 (0.22 to 1.22)
0.64 (0.53 to 0.83)a
0.29 (0.12 to 0.66)a
1.69 (0.88 to 3.24)b
1.03 (0.43 to 2.48)
0.86 (0.68 to 1.08)b
1.16 (0.57 to 2.36)b
0.69 (0.36 to 1.31)
Weighted mean difference (95% CI)
Ϫ2.0 (Ϫ8.42 to 4.42)
Ϫ2.0 (Ϫ7.19 to 3.19)
Ϫ9.90 (Ϫ29.96 to 9.16)
Poractant at 100 mg/kg vs
Beractant at 100 mg/kg
0.96 (0.66 to 1.41)
1.23 (0.39 to 3.88)
1.00 (0.41 to 2.41)
0.81 (0.59 to 1.11)
0.89 (0.46 to 1.74)
1.00 (0.36 to 2.76)
0.84 (0.61 to 1.15)
1.15 (0.58 to 2.31)
Ϫ4.98 (Ϫ7.44 to Ϫ2.52)b,c
Ϫ5.61 (Ϫ6.64 to Ϫ4.57)b,c
Ϫ33 (Ϫ45.16 to Ϫ20.84)c
P Ͻ .05.
Significant test of heterogeneity.
c P Ͻ .0001.
a
b
Results of Meta-analyses
Oxygen Requirements at a
Postmenstrual Age of 36 Weeks
Each study reported the incidence of
oxygen requirements at a postmenstrual age of 36 weeks (either as BPD
or as CLD) for all enrolled infants. The
meta-analysis did not show a significant difference between the infants
treated with poractant alfa and those
treated with beractant (RR: 0.98 [95%
CI: 0.75–1.29]; P ϭ .89; I2 ϭ 0%). The
result remained insignificant even
when the analysis was restricted to
studies that used a 200 mg/kg dose of
poractant alfa or a 100 mg/kg dose of
poractant alfa in comparison with beractant (Table 4).
Respiratory Support
The effects of the type of surfactant on
MAP and FIO2 were assessed qualitatively because of differences in the use
of reporting metrics among the studies. Two studies showed significant differences in MAP values, favoring poractant alfa,11,16 whereas 1 study did
not find any difference between the 2
groups with respect to this outcome.15
The difference in the effects of surfactants on MAP was observed for the
first 24 hours by Speer et al16 and for
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SINGH et al
72 hours by Fujii et al,11 favoring poractant alfa, whereas no difference was
observed in the first 6 hours by Ramanathan et al.15
both ventilation and oxygen treatment
(I2 Ͼ 75%).
Redosing
Four studies reported the effects of the
type of surfactant administration on
FIO2. Three studies showed statistically
significant decreases in FIO2 requirements with poractant alfa, compared
with beractant,14–16 whereas 1 study
did not find any difference between the
2 groups with respect to this outcome.11 Faster weaning of oxygen after
poractant alfa administration was
shown for 6 hours by Ramanathan et
al,15 for 24 hours by Speer et al,16 for 48
hours by Malloy et al,14 and from 12
hours to 72 hours (MAP ϫ FIO2) by Fujii
et al.11
The incidence of redosing was lower in
the group receiving poractant alfa,
compared with the group receiving beractant, with the difference being statistically significant (RR: 0.71 [95% CI:
0.57– 0.88]; P ϭ .002; I2 ϭ 0%). In subgroup analysis, the difference remained significant with poractant alfa
at an initial dose of 200 mg/kg (RR: 0.64
[95% CI: 0.53– 0.83]; P ϭ .0008) but not
with poractant alfa at an initial dose of
100 mg/kg, in comparison with beractant (I2 ϭ 0%).
Although most studies reported durations of ventilation and oxygen treatment, only 2 studies reported the
mean values of these outcomes,10,15
which could be analyzed with Review
Manager. Our analysis showed statistically significant differences in these
outcomes, favoring poractant alfa
(P Ͻ .0001). In the subgroup analysis,
this difference remained significant
only with low-dose poractant alfa
treatment (Table 4). The test of heterogeneity yielded significant results for
In the meta-analysis, a statistically significant decrease in mortality rates
was found, favoring poractant alfa in
comparison with beractant (RR: 0.51
[95% CI: 0.30 – 0.89]; P ϭ .02; I2 ϭ 0%).
In the subgroup analysis, this difference was even more pronounced when
the 200 mg/kg dose of poractant alfa
was compared with beractant (RR:
0.29 [95% CI: 0.12– 0.66]; P ϭ .004) but
was not statistically significant when
the 100 mg/kg dose of poractant alfa
was compared with beractant (RR:
Mortality Rates
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7. REVIEW ARTICLES
0.89 [95% CI: 0.46 –1.74]; P ϭ .74; I2 ϭ
0%) (Table 4).
with low rates of prenatal corticosteroid exposure were excluded.
Secondary Outcomes
DISCUSSION
The length of hospital stay was significantly shorter for infants treated with
poractant alfa, compared with those
treated with beractant (weighted
mean difference: Ϫ26.3 [95% CI: Ϫ36.5
to Ϫ16.07]; P Ͻ .00001) (Table 4). Only
2 studies reported this outcome,10,11
and significant heterogeneity was observed between the study groups (I2 ϭ
75%).
We intended to compare the clinical efficacy of a porcine surfactant (poractant alfa) with the commonly used bovine surfactants (beractant and
calfactant) among preterm infants
with RDS. However, we were able to
compare poractant alfa only against
beractant, because we did not identify
any trials that included a comparison
of poractant alfa against calfactant.
Two studies reported the incidence of
severe ROP (either stage II–IV or requiring photocoagulation therapy),11,14
whereas 1 study reported all cases of
ROP with no mention of staging. 10 In
our review, we included only data from
the 2 studies that reported cases of
severe ROP.11,14 All studies reported
data on severe IVH (grade III or IV),
whereas 1 study also reported on all
cases of IVH in addition to severe IVH.16
In this review, we included only data on
severe IVH. There was no difference in
the incidence of sepsis, necrotizing enterocolitis, PDA, severe ROP, and severe IVH between the 2 types of surfactants (Table 4). The test of
heterogeneity yielded significant results for sepsis, severe ROP, and PDA.
Immediate adverse effects (reflux and
desaturation) were described only by
Speer et al16; therefore, no comparison
could be performed. However, the
rates of pulmonary air leaks and pulmonary hemorrhage were reported in
most of the studies, with no difference
between the 2 types of surfactants.
In this meta-analysis, the incidences of
oxygen requirements at a postmenstrual age of 36 weeks (BPD/CLD) were
31.5% in the poractant alfa group and
29.9% in the beractant group, with the
difference not being statistically significant. The most significant result noted
in our meta-analysis was the effect of
poractant alfa on the rates of death
before hospital discharge, with a RR
reduction of 49%, compared with beractant. Poractant alfa also was noted
to decrease significantly the need for
redosing, to reduce FIO2 requirements
for up to 6 to 48 hours of life, and to
decrease durations of oxygen treatment and mechanical ventilation. It is
important to mention that the observed difference in the effects of surfactants on FIO2 could be attributable to
different ventilation strategies used in
the individual studies, with the exchange of higher MAP values for lower
FIO2 values. Only Fujii et al11 reported
this exchange, and they observed no
difference in FIO2 values between poractant and beractant.
To test the effects of prenatal corticosteroid exposure, a sensitivity analysis
was performed with the exclusion of
studies that reported Ͻ50% prenatal
corticosteroid exposure. The differences remained significant for deaths
and redosing, favoring poractant alfa
(100 mg/kg or 200 mg/kg), compared
with beractant, when the 2 studies10,16
In the subgroup analysis, significant
reductions in mortality rates (70% RR
reduction) and the need for redosing
(36% RR reduction) were observed
with poractant alfa at 200 mg/kg but
not with poractant alfa at 100 mg/kg,
compared with beractant. The differences in mortality rates and the need
for redosing favoring poractant alfa
PEDIATRICS Volume 128, Number 6, December 2011
remained significant even when the
studies with low levels of prenatal corticosteroid exposure were excluded
from the analysis. Significant differences were noted for duration of ventilation, duration of oxygen treatment,
and length of stay with poractant alfa
at 100 mg/kg but not with poractant
alfa at 200 mg/kg, compared with beractant; however, these findings must
be interpreted with caution because of
the presence of significant heterogeneity. The heterogeneity might be attributable to considerable variations
in the results for these outcomes
among the studies, with 1 study reporting significant differences10 and others
showing no effect.11,15
The results of our systematic review
and meta-analysis are in agreement
with the findings of other reviews on
this subject. Five reviews that compared animal-derived surfactants5,17–20
were identified during our search;
however, none was a systematic review. A meta-analysis by Fox and Sothinathan17 showed a reduced need for
redosing, better short-term oxygenation, and reduced risk of death with
poractant alfa, compared with beractant; however, only 3 RCTs10,15,16 were
included in the meta-analysis. A review
of 4 studies10,14–16 by Ramanathan20 reported a similar survival advantage,
reduced need for redosing, and cost
benefit in favor of poractant alfa, compared with beractant. Moya and Maturana19 also reviewed those 4 studies
comparing poractant alfa and beractant10,14–16 and commented on decreased oxygen requirements favoring
poractant, compared with beractant.
However, that review did not include a
meta-analysis of data for any outcomes. Halliday21 performed a metaanalysis of 6 comparisons between poractant alfa and beractant10,14–16,22 (2
arms of the study by Ramanathan et
al15 were considered separate comparisons) and showed significant re-
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e1593
8. ductions in mortality rates and the
need for redosing with poractant alfa,
similar to our meta-analysis. That review did not address surfactant effects
on other outcomes.
Although some of the results of our
meta-analysis were statistically and
clinically significant, they should be interpreted cautiously because of the
following limitations. Only 7 of the 92
relevant articles on surfactant identified in the search were considered sufficiently rigorous to be included in the
meta-analysis, because of a narrow,
specific, research question for this
systematic review. Studies included in
the meta-analysis were of comparatively small size except for 1 study,15
which contributed the most to the
weighted average of the summary
treatment effect. All of the studies
were at risk of performance bias resulting from lack of blinding for both
the interventions and the outcome assessments. Another limitation of this
review is that all of the studies used
surfactant for treatment rather than
for prophylaxis for RDS; therefore, our
results do not necessarily apply to prophylactic use of surfactant. The included studies analyzed clinical outcomes only until hospital discharge
and did not examine long-term outcomes such as neurodevelopmental
outcomes. Finally, this systematic review did not intend to include uncommonly used bovine surfactants (eg, bovactant, surfactant-TA, and bovine lipid
surfactant) in the comparison with
porcine surfactant.
Despite these limitations, this metaanalysis differs from other reviews in
that it includes the largest number of
RCTs comparing poractant alfa and beractant, with a fairly large cumulative
sample size. The superior outcomes
noted in this meta-analysis with poractant alfa, compared with beractant,
particularly with respect to reductions
in mortality rates, the need for redosing, and initial respiratory support,
might be attributable to differences in
the biochemical and biophysical properties of poractant alfa itself or to the
initial higher dose (200 mg/kg) used.
The higher dose of poractant alfa, with
greater contents of phospholipids and
surfactant-associated proteins B and
C, might have resulted in greater improvements in lung function and hence
better outcomes. Because the low
dose of poractant alfa (100 mg/kg) did
not have the same effects on mortality
and redosing rates as did the high
dose of poractant alfa, it seems that
the greater concentrations of phospholipids and surfactant proteins in a
given volume might be responsible for
the observed superior effects when
high-dose poractant alfa is compared
with beractant at the dosage volumes
recommended by the manufacturers.
CONCLUSIONS
Our systematic review and metaanalysis provide evidence that highdose poractant alfa may result in superior short-term clinical outcomes,
compared with beractant, when used
for the treatment of preterm infants
with established RDS. Cost analyses
comparing poractant alfa versus beractant23 and poractant alfa versus
calfactant24 showed significant cost
savings with poractant alfa even when
it was used at a dose twice the dose of
beractant.
No conclusions can be drawn regarding the effects of these 2 surfactants
when they are used prophylactically.
Future research should focus on understanding what specific biochemical
and biophysical aspects of one surfactant confer superiority over others
and should address the issue of outcome advantages with dose-equivalent
concentrations of poractant alfa and
beractant with a large sample of premature infants at greatest risk.
ACKNOWLEDGMENT
We thank Dr Gautham Suresh for his helpful editorial review and comments.
REFERENCES
1. Soll RF. Prophylactic synthetic surfactant
for preventing morbidity and mortality in
preterm infants. Cochrane Database Syst
Rev. 2000;(2):CD001079
2. Soll R, Blanco F. Natural surfactant extract
versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2001;(2):CD000144
3. Soll R. Synthetic surfactant for respiratory
distress syndrome in preterm infants. Cochrane Database Syst Rev. 2000;(2):
CD001149
4. Soll R, Ozek E. Multiple versus single doses
of exogenous surfactant for the prevention
or treatment of neonatal respiratory distress syndrome. Cochrane Database Syst
Rev. 2009;(1):CD000141
e1594
SINGH et al
5. Ramanathan R. Animal-derived surfactants:
where are we? The evidence from randomized, controlled clinical trials. J Perinatol.
2009;29(suppl 2):S38 –S43
6. Engle WA; American Academy of Pediatrics,
Committee on Fetus and Newborn.
Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Pediatrics. 2008;121(2):419 – 432
7. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6. Chichester, United Kingdom:
Wiley; 2006
8. International Committee for Classification
of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Pediatrics. 1984;74(1):127–133
9. Papile LA, Burstein J, Burstein R, Koffler H.
Incidence and evolution of subependymal
and intraventricular hemorrhage: a study
of infants with birth weights less than 1,500
gm. J Pediatr. 1978;92(4):529 –534
10. Baroutis G. Comparison of treatment regimens of natural surfactant preparations in
neonatal respiratory distress syndrome.
Eur J Pediatr. 2004;163(2):127–128
11. Fujii A, Patel S, Allen R, Doros G, Guo C, Testa
S. Poractant alfa and beractant treatment
of very premature infants with respiratory
distress syndrome. J Perinatol. 2010;
30(10):665– 670
12. Fujii A, Allen R, Doros G, O’Brien S. Patent
ductus arteriosus hemodynamics in very
premature infants treated with poractant
Downloaded from pediatrics.aappublications.org at Health Internetwork on September 19, 2012
9. REVIEW ARTICLES
alfa or beractant for respiratory distress
syndrome. J Perinatol. 2010;30(10):
671– 676
13. Gharehbaghi MM, Sakha SH, Ghojazadeh M,
Firoozi F. Complications among premature
neonates treated with beractant and poractant alfa. Indian J Pediatr. 2010;77(7):
751–754
14. Malloy CA, Nicoski P, Muraskas JK. A randomized trial comparing beractant and poractant treatment in neonatal respiratory
distress syndrome. Acta Paediatr. 2005;
94(6):779 –784
15. Ramanathan R, Rasmussen MR, Gerstmann
DR, Finer N, Sekar K; North American Study
Group. A randomized, multicenter masked
comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the
treatment of respiratory distress syndrome in preterm infants. Am J Perinatol.
2004;21(3):109 –119
PEDIATRICS Volume 128, Number 6, December 2011
16. Speer CP, Gefeller O, Groneck P, et al. Randomised clinical trial of two treatment regimens of natural surfactant preparations in
neonatal respiratory distress syndrome.
Arch Dis Child Fetal Neonatal Ed. 1995;72(1):
F8 –F13
17. Fox GF, Sothinathan U. The choice of surfactant for treatment of respiratory distress
syndrome in preterm infants: a review of
the evidence. Infant. 2005;1(1):8 –12
18. Halliday HL. Recent clinical trials of surfactant treatment for neonates. Biol Neonate.
2006;89(4):323–329
19. Moya F, Maturana A. Animal-derived surfactants versus past and current synthetic
surfactants: current status. Clin Perinatol.
2007;34(1):145–177
20. Ramanathan R. Choosing a right surfactant
for respiratory distress syndrome treatment. Neonatology. 2009;95(1):1–5
21. Halliday HL. Surfactants: past, present and
future. J Perinatol. 2008;28(suppl 1):
S47–S56
22. Halahakoon W. A Study of Cerebral Function
Following Surfactant Treatment for Respiratory Distress Syndrome [MD thesis]. Belfast, Northern Ireland: Queen’s University;
1999
23. Marsh W, Smeeding J, York JM, Ramanathan R, Sekar K. A cost minimization comparison of two surfactants— beractant
and poractant alfa— based upon prospectively designed, comparative clinical trial
data. J Pediatr Pharmacol Ther. 2004;9:
117–125
24. Gerdes JS, Seiberlich W, Sivieri EM, et al. An
open-label comparison of calfactant and
poractant alfa administration traits and impact on neonatal intensive care unit resources. J Pediatr Pharmacol Ther. 2006;
11(2):92–100
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e1595
![Efficacy of Porcine Versus Bovine Surfactants for
Preterm Newborns With Respiratory Distress
Syndrome: Systematic Review and Meta-analysis
abstract
AUTHORS: Neetu Singh, MD,a Kristy L. Hawley, MPH,b and
Kristin Viswanathan, MPHc
OBJECTIVE: To compare the efficacy of a porcine surfactant (poractant
alfa) versus bovine surfactants (beractant and calfactant) with respect to clinical outcomes among preterm infants with respiratory
distress syndrome.
aDepartment of Pediatrics, Dartmouth Hitchcock Medical Center,
Lebanon, New Hampshire; bSchool of Medicine and Health
Sciences, George Washington University, Washington, DC; and
cBoard of Health Sciences Policy, Institute of Medicine, National
Academy of Sciences, Derwood, Maryland
METHODS: A search of major electronic databases, including Medline
(1980 –2010) and the Cochrane Central Register of Controlled Trials,
for randomized controlled trials that compared poractant alfa versus
beractant and/or calfactant among preterm infants with respiratory
distress syndrome who required intubation and surfactant treatment
was performed. The primary outcome was oxygen requirement at a
postmenstrual age of 36 weeks.
KEY WORDS
pulmonary surfactant, poractant alfa, calfactant, beractant
RESULTS: Five randomized controlled trials involving 529 infants compared poractant alfa versus beractant for rescue treatment. No trials
studied surfactant prophylaxis, and none compared poractant alfa versus calfactant. The incidences of oxygen dependence at a postmenstrual age of 36 weeks were similar for poractant alfa and beractant.
Infants treated with poractant alfa at 100 mg/kg (low dose) or 200
mg/kg (high dose) exhibited statistically significant reductions in
deaths (relative risk: 0.51 [95% confidence interval: 0.30 – 0.89]), the
need for redosing (relative risk: 0.71 [95% confidence interval: 0.57–
0.88]), oxygen requirements, duration of oxygen treatment, and duration of mechanical ventilation. The test of heterogeneity yielded positive results for the latter 2 outcomes. The difference remained
statistically significant for deaths and the need for redosing with highdose poractant alfa but not for low dose poractant alfa.
ABBREVIATIONS
RDS—respiratory distress syndrome
BPD—bronchopulmonary dysplasia
CLD—chronic lung disease
RCT—randomized controlled trial
RR—relative risk
CI—confidence interval
FIO2—fraction of inspired oxygen
MAP—mean airway pressure
PDA—patent ductus arteriosus
ROP—retinopathy of prematurity
IVH—intraventricular hemorrhage
www.pediatrics.org/cgi/doi/10.1542/peds.2011-1395
doi:10.1542/peds.2011-1395
Accepted for publication Aug 15, 2011
Address correspondence to Neetu Singh, MD, Department of
Neonatology, Dartmouth Hitchcock Medical Center, 1 Medical
Center Dr, Lebanon, NH 03756. E-mail: neetu.singh@hitchcock.
org
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2011 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
CONCLUSIONS: There were significant reductions in deaths and the
need for redosing with high-dose poractant alfa but not low-dose poractant alfa, compared with beractant. Pediatrics 2011;128:
e1588–e1595
e1588
SINGH et al
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