This document summarizes evidence from randomized controlled trials comparing animal-derived surfactants and synthetic surfactants for treating respiratory distress syndrome in preterm infants. It finds that animal-derived surfactants are generally superior to synthetic surfactants in improving clinical outcomes like reducing oxygen needs and ventilation pressures. Specifically, one trial found poractant alfa was associated with lower mortality compared to the synthetic surfactant pumactant. The document also reviews trials comparing the three major animal-derived surfactants - beractant, calfactant, and poractant alfa - and finds poractant alfa is associated with more rapid improvement and fewer additional doses needed compared to the other surfactants. Differences in

1. Journal of Perinatology (2009) 29, S38–S43
r 2009 Nature Publishing Group All rights reserved. 0743-8346/09 $32
www.nature.com/jp
REVIEW
Animal-derived surfactants: where are we? The evidence from
randomized, controlled clinical trials
R Ramanathan
Division of Neonatal Medicine, Department of Pediatrics, Women’s and Children’s Hospital and Childrens Hospital Los Angeles,
Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Animal-derived surfactants, as well as synthetic surfactants, have been
extensively evaluated in the treatment of respiratory distress syndrome
(RDS) in preterm infants. Three commonly available animal-derived
surfactants in the United States include beractant (BE), calfactant (CA) and
poractant alfa (PA). Multiple comparative studies have been performed
using these three surfactants. Prospective as well as retrospective studies
comparing BE and CA have shown no significant differences in clinical or
economic outcomes. Randomized, controlled clinical trials have shown that
treatment with PA is associated with rapid weaning of oxygen and
ventilatory pressures, fewer additional doses, cost benefits and survival
advantage when compared with BE or CA. Recently, a study using an
administrative database that included over 20 000 preterm infants has
shown a significant decrease in mortality and cost benefits in favor of PA,
when compared with BE or CA. Differences in outcomes between these
animal-derived surfactants may be related to a higher amount of
phospholipids and plasmalogens in PA. To date, animal-derived surfactants
seem to be better than synthetic surfactants during the acute phase of RDS
and in decreasing neonatal mortality. Further studies are needed comparing
animal-derived surfactants with the newer generation of synthetic
surfactants.
Journal of Perinatology (2009) 29, S38–S43; doi:10.1038/jp.2009.31
Keywords: preterm; respiratory distress syndrome; surfactant; animal
derived; synthetic; mortality
Introduction
Significant advances in perinatal care have been achieved over the
past three decades. Despite this, preterm birth rates continue to
increase in the United States.1,2 Respiratory distress syndrome
(RDS) is the leading cause of respiratory insufficiency and is a
major cause of mortality and morbidity in preterm infants.
Incidence of RDS is inversely proportional to gestational age at
birth. Pathophysiology of RDS is characterized by insufficient
Correspondence: Dr R Ramanathan, Division of Neonatal Medicine, Department of
Pediatrics, Women’s and Children’s Hospital and Childrens Hospital Los Angeles, Keck School
of Medicine, University of Southern California, 1240, North Mission Road, Room L-919,
Los Angeles, CA 90033, USA.
E-mail: ramanath@usc.edu
production of a surface-active agent, namely, surfactant. Surfactant
is the first drug developed specifically for treatment of preterm
neonates with RDS. Surfactant therapy has become the standard of
care in the management of RDS. Human surfactant is primarily
composed of dipalmitoylphosphatidylcholine (DPPC) and
surfactant proteins (SP), SP-A, SP-B, SP-C and SP-D. Among these
four surfactant proteins, two hydrophobic proteins, SP-B and SP-C,
play a crucial role in the adsorption and spread of the DPPC at the
air–liquid interphase in the lungs. In addition, an antioxidant
phospholipid, plasmalogen, has been shown to work synergistically
with surfactant-associated hydrophobic proteins in the spreading of
DPPC, thus maintaining lower surface tension and alveolar
stability at the end of expiration.3,4 SP-A and SP-D are lectin
proteins that help to maintain sterility in the lung, whereas SP-B
and SP-C help to maintain stability in the lung. None of the
surfactant preparations contain SP-A or SP-D. Natural, modified
surfactants derived from bovine or porcine lungs contain different
amounts of SP-B, SP-C and plasmalogens. Animal-derived as well
as synthetic surfactants, which are completely devoid of SP-B, SP-C
and plasmalogens, have been extensively evaluated in preterm
infants with RDS. Three animal-derived surfactant preparations
used worldwide include beractant (BE) (Survanta, Abbott
Laboratories Inc., Columbus, OH, USA), calfactant (CA) (Infasurf,
Forest Laboratories, St Louis, MO, USA) and poractant alfa (PA)
(Curosurf, Dey, LP, Napa, CA, USA). Synthetic surfactants that have
been evaluated in comparative trials include colfosceril palmitate
(Exosurf, Research Triangle Park, NC, USA), pumactant (ALEC,
Britannia Pharmaceuticals, Crawley, UK) and lucinactant
(Surfaxin, Discovery Laboratories, Doylestown, PA, USA).
Natural vs synthetic-surfactant studies
Fourteen trials comparing animal-derived surfactants with
synthetic surfactants have been published (Table 1).5–18 To date,
treatment with animal-derived surfactant preparations has been
shown to result in better clinical response during the acute phase
of RDS as evidenced by rapid weaning of inspired oxygen, mean
airway pressure and lower air leaks when compared with treatment

2. Animal-derived surfactants
R Ramanathan
S39
Table 1 Summary of 14 trials comparing animal-derived surfactants with synthetic surfactants for RDS in preterm infants
Trials (n ¼ 14)
Surfactant
Horbar et al.5
Beractant vs colfosceril
palmitate
Beractant vs colfosceril
palmitate
Beractant vs colfosceril
palmitate
Beractant vs colfosceril
palmitate
Beractant vs colfosceril
palmitate
Calfactant vs colfosceril
palmitate
Calfactant vs colfosceril
palmitate
Beractant vs colfosceril
palmitate
Beractant vs colfosceril
palmitate
Poractant alfa vs colfosceril
palmitate
Poractant alfa vs colfosceril
palmitate
Poractant alfa vs pumactant
Alvarado et al.6
Pearlman et al.7
Sehgal et al.8
VON9
Hudak et al.10
Hudak et al.11
Modanlou
et al.12
da Costa et al.13
Rollins et al.14
Kukkonen
et al.15
Ainsworth
et al.16
Moya et al.17
Sinha et al.18
Lucinactant vs colfosceril
palmitote vs beractant
Lucinactant vs poractant alfa
Number of
patients
Type
Patients
Results
617
Treatment
500–1500 g
Beractant: lower 0–72 h FiO2 and MAP
66
Treatment
<1500 g
Beractant: decreased duration of PPV, O2, LOS
121
Treatment
No differences in any outcomes
41
Treatment
Any with
RDS
600–1750 g
No differences in any outcomes
1296
Treatment
501–1500 g
Beractant: lower FiO2 at 72 h, lower 0–72 h MAP, fewer air leaks
1126
Treatment
All with RDS
Calfactant: lower 0–72 h FiO2 and MAP, fewer air leaks
846
Prophylaxis
<29 weeks
122
Treatment
<1500 g
Calfactant: less RDS, lower 0–72 h FiO2 and MAP, fewer air leaks,
more intraventricular hemorrhage
Beractant: lower FiO2, MAP and OI
89
Treatment
66
Treatment
<37 weeks,
1000 g
All with RDS
Poractant alfa: lower FiO2, and improved a/A ratio
228
Treatment
All with RDS
Poractant alfa: lower FiO2, and MAP
212
Treatment
<30 weeks
1294
Prophylaxis
600–1250 g
252
Prophylaxis
600–1250 g
Poractant alfa: decreased mortality (trial stopped after interim
analysis)
Lucinactant more effective than colfosceril palmitate and similar to
beractant
Non-inferiority trial, early trial closure, original sample size 496, no
differences in any outcomes
No difference
Abbreviations: RDS, respiratory distress syndrome; FiO2, fraction of inspired oxygen; MAP, mean airway pressure; PPV, positive pressure ventilation; LOS, length of stay; OI, oxygenation index.
with synthetic preparations. Furthermore, neonatal mortality has
also been shown to be lower among infants treated with a porcinederived surfactant when compared with those treated with
pumactant, a synthetic preparation.16 Ainsworth et al.16 compared
the porcine-derived surfactant, PA, with pumactant. This trial was
stopped by the data and safety monitoring committee, because
mortality assumed greater importance than the primary outcome.
Mortality was significantly lower (14.1 vs 31%, P ¼ 0.006; odds
ratio 0.37; 95% confidence interval [0.18, 0.76]) in the PA-treated
infants. This difference was sustained after adjusting for gestational
age, birth weight, gender, center, plurality and use of antenatal
steroids. This was the first randomized, controlled trial that showed
a survival advantage for an animal-derived surfactant preparation
over that for a synthetic surfactant. However, survival advantage
was a secondary endpoint in this trial. The incidence of
bronchopulmonary dysplasia was not different with either
animal-derived or synthetic surfactants. In the only trial17 that
compared two different synthetic preparations, bronchopulmonary
dysplasia was significantly lower with lucinactant therapy when
compared with colfosceril palmitate. In this prophylaxis trial, BE
was included as a reference arm. A total of 1294 preterm infants,
weighing 600 to 1250 g, were included; 509 infants received
colfosceril palmitate, 527 received lucinactant and 258 infants
received BE, within 20 to 30 min of birth. Even though the trial
was designed as a prophylaxis trial, investigators allowed up to
30 min for administration of surfactants. This is because of the fact
that lucinactant is a gel at both room and body temperature, and
had to be warmed in a special warming cradle to 44 1C for 15 min.
In all earlier, randomized, controlled prophylaxis trials, surfactant
was typically administered within 10 to 15 min of birth. In the true
sense, this trial17 is an early rescue trial. Furthermore, comparison
of outcomes between BE and lucinactant was of secondary interest,
and this trial was not powered to detect efficacy against BE. Despite
these limitations, there were no differences in the 14 variables that
Journal of Perinatology

3. Animal-derived surfactants
R Ramanathan
S40
Table 2 Composition of animal-derived surfactant preparations
Surfactant
Preparation/Composition
Beractant
Calfactant
Poractant alfa
Minced bovine lung extract+DPPC+palmitic acid+tripalmitin
Bovine lung lavage+DPPC+cholesterol
Minced porcine lung extract (Liquid gel chromatography)
Phospholipids
(%)a
Plasmalogens
(mol%)b
SP-B
(mg per mM PL)
SP-C
(mg per mM PL)
84
95
99
1.5
NA
3.8
0–1.3
5.4
2–3.7
1–20
8.1
5–11.6
Abbreviations: DPPC, dipalmitoylphosphatidylcholine; SP-B, surfactant protein B; SP-C, surfactant protein-C; NA, not available.
a
Adapted from Dargaville et al.21
b
Adapted from Taeush et al.22 and Rudiger et al.23
were analyzed in this study between BE and lucinactant. In the
second trial,18 designed as a non-inferiority trial, comparing
lucinactant with PA, no differences were found in 16 outcome
variables analyzed between lucinactant- and PA-treated infants.
There were several methodological problems with this trial. This
study was stopped early because of slow recruitment after enrolling
only 50.8% of the original sample size (252 out of 496 patients);
mortality data chosen to assess non-inferiority was from a
placebo-controlled treatment trial published 18 years before this
trial; and the dose of PA used was not the dose used in the
placebo-controlled trial. Survival at 1 year of corrected age was not
different among the BE-treated group; 178/258 infants (69%)
compared with 479/643 (75%) in the two trials17,18 with
lucinactant treatment.19 Similarly, survival at 1 year of corrected
age among the PA-treated group was 97/124 infants (78%)
compared with 479/643 (75%) in the two trials17,18 treated with
lucinactant.19 In a clinical report published in 2008,20 the
American Academy of Pediatrics and the Committee of the Fetus
and Newborn (COFN) issued the following statement: ‘FMore
analysis is needed before the findings from lucinactant studies can
be generalized because of questions about early trial closure and
limited statistical power. Moreover, the metabolic fate of
lucinactant and its component chemicals and potential risks
introduced by the requirement to convert the lucinactant gel into
liquid by using a special warming cradle immediately before
instillation need additional study.’20 In summary, results from
randomized, controlled clinical trials show the superiority of
animal-derived surfactant preparations over the synthetic
surfactants that have been studied. At the time of this writing, there
are no approved synthetic surfactants available for clinical use.
Animal-derived vs animal-derived surfactant studies
Animal-derived surfactant preparations have been extensively
evaluated for the treatment of RDS in preterm infants.
Animal-derived surfactants differ in their source, method of
preparation, composition, viscosity, dosing volume, phospholipid
content, percentage of plasmalogens and amount of SP-B and
SP-C21–23 (Table 2). Minced as well as lavage preparations from
Journal of Perinatology
bovine or porcine lungs are the three commonly used surfactants
worldwide. BE is a minced bovine lung extract that contains lower
amounts of phospholipids, plasmalogen and SP-B, compared with
CA, which is a lavage preparation from bovine lungs. CA contains a
higher amount of SP-B and phospholipids than does BE.
Plasmalogen content in CA is not known. A lung lavage
preparation from bovine lungs, used in Germany, namely, SF-RI1
(alveofact), contains the lowest amount of plasmalogens. Poractant
alfa is a minced porcine surfactant that undergoes an additional
step, liquid gel chromatography. As a result, PA contains only polar
lipids and is more concentrated than the other animal-derived
surfactants. In addition, PA contains the highest amount of
plasmalogens. Higher plasmalogen content in the tracheal
aspirates from preterm infants has been associated with a lower
incidence of bronchopulmonary dysplasia.24 Eight randomized,
controlled clinical trials25–30 and two retrospective studies31,32
comparing the three natural surfactants have been reported. Four
of the eight trials compared BE with CA25,26 and the remaining
four trials27–30 compared BE with PA (Table 3). There are no
prospective studies published comparing CA with PA.
Randomized trials comparing BE with CA
In the four studies comparing BE with CA,25,26 treatment with CA
was associated with a faster response during the acute phase of
RDS in the rescue trial published in 1997. In the prophylaxis trial25
comparing CA with BE published by the same investigators,
mortality in infants <600 g in birth weight was significantly
higher in the CA group when compared with that in the BE group
(63 vs 26%, P ¼ 0.007). Overall mortality in the prevention trial
was 8% in the BE group and 14% in the CA group (Figure 1). In
the rescue trial,25 mortality rates were 17% and 18% in the BE- and
CA-treated groups, respectively (Figure 1). There were no
significant differences in the percentage of infants requiring two or
more surfactant doses in both these trials (Figure 2). In the
remaining two large, but incomplete trials published in 2005,
involving a total of 2110 preterm infants, no differences in
mortality, need for additional doses, bronchopulmonary dysplasia
or any other outcomes were shown.26 Inadequate sample size from

4. Animal-derived surfactants
R Ramanathan
S41
Table 3 Summary of eight comparative trials among animal-derived surfactants in preterm infants with respiratory distress syndrome
Eight trials
Surfactant
Bloom et al.25
Beractant vs calfactant
Bloom et al.25
Bloom et al.26
Beractant vs calfactant
Beractant vs calfactant
608
Rescue
749/2000 Prophy
<2000 g
23–29 weeks
Bloom et al.26
Beractant vs calfactant
1361/2080 Rescue
401–2000 g
Speer et al.27
Baroutis et al.28
Beractant vs poractant alfa
Beractant vs poractant alfa vs
SF RI1
Beractant vs poractant alfa
Beractant vs poractant alfa
Ramanathan et al.29
Malloy et al.30
Number
374
Prophy or
Rescue
Patient Characteristics Results
Prophy
<1250 g
No differences in any variables; increased mortality with
calfactant in <600 g (63 vs 29%)
Calfactant: lower average 0–72 h FiO2 and MAP
Early trial closure; original sample size 2000; Infants alive
with BPD 34 vs 33%; no differences in any outcomes
Early trial closure; original sample size 2080; infants alive
with BPD 31 vs 31%; no differences in any outcomes
Poractant alfa: lower FiO2, PIP and MAP at 12–24 h
Poractant alfa: fewer days on O2 and PPV; decreased LOS
73
80
Rescue
Rescue
700–1500 g
<2000 g
293
58
Rescue
Rescue
750–1750 g
<37 weeks with RDS
Poractant alfa: lower FiO2, fewer doses, decreased mortality
Poractant alfa: lower FiO2 up to 48 h; fewer doses; lower
volume of surfactant given; fewer PDA
Abbreviations: Prophy, prophylaxis; FiO2, fraction of inspired oxygen; MAP, mean airway pressure; PIP, peak inspiratory pressure; PPV, positive pressure ventilation; LOS, length of stay;
OI, oxygenation index; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; RDS, respiratory distress syndrome.
80
25
Mortality (%)
20
15
10
*
5
*
PA
70
% of Infants > 2 doses
PA
BE
CA
BE
60
CA
50
40
30
*
20
10
0
#25 #25 #26 #26 #27 #28 #29 #30 #31 #32
(P)
(P)
*
0
#25 (P)
#25
#26 (P)
#26
#29
#30^
Figure 1 Mortality differences among the three animal-derived surfactants
reported in 10 studies between 1995 and 2007. Abbreviations: PA, poractant alfa;
BE, beractant; CA, calfactant; #references; (P), prophylaxis; *P<0.05.
Figure 2 Infants requiring>2 doses in the six comparative trials reported from
1997 to 2005. Abbreviations: PA, poractant alfa; BE, beractant; CA, calfactant;
#references; (P), prophylaxis; ^, mean doses; *P<0.05.
early trial closures prevented the investigators from accepting or
rejecting null hypotheses. Sample sizes were calculated to show a
difference of 6% in the primary outcome of infants alive at
36 weeks post-menstrual age and not receiving supplemental
oxygen. Prophylaxis study was stopped after enrolling 749 of the
2000 infants in the original sample size and the rescue trial was
also stopped after enrolling 1361 of 2080 infants. Overall mortality
rates in the prophylaxis trial were 12% and 13%, and 10% and 11%
in the treatment trial in the BE- and CA-treated groups, respectively
(Figure 1). There were no significant differences in the percentage
of infants requiring two or more surfactant doses in both these
trials, similar to the earlier comparative trials published 8 years
before these two studies (Figure 2). In summary, there were no
differences in mortality or dosing requirements reported in the four
trials comparing BE with CA.
Randomized trials comparing BE with PA
Four randomized, controlled clinical treatment trials comparing BE
with PA have been published.27–30 Three of the four trials used
200 mg per kg of PA for the first dose and subsequent doses were
given at 100 mg kgÀ1. In the study by Baroutis et al.,28 three
animal-derived surfactants (BE, PA and SF RI1) were compared
and these investigators used 100 mg kgÀ1 for the initial as well as
for subsequent doses in all three surfactant groups. All four trials
showed a faster weaning of supplemental oxygen in the PA-treated
group when compared with treatment with BE. In the trial by
Ramanathan et al.,29 infants were randomized to 100 or
200 mg kgÀ1 for the initial dose of PA and 100 mg kgÀ1 for the
initial dose of BE. All infants received 100 mg kgÀ1 of PA or BE
for subsequent doses. The prespecified mortality at 36 weeks
post-menstrual age among preterm infants p32 weeks was
Journal of Perinatology

5. Animal-derived surfactants
R Ramanathan
S42
significantly lower in the 200 mg per kg PA-treated group
compared with that in the BE-treated group (3% vs 11%,
P ¼ 0.034; OR 0.26, 95% CI 0.07, 0.98) (Figure 1). When mortality
results from two of the four studies27,29 were combined in a
meta-analysis, mortality was significantly lower in the PA-treated
group when compared with that in the BE-treated group
(OR 0.35, 95% CI 0.13, 0.92).33 Need for additional doses were also
significantly lower in the PA-treated group when compared with
that in the BE-treated group in two of the four trials29,30
(Figure 2). In summary, results from randomized, controlled
clinical trials comparing animal-derived surfactants show survival
advantage, decreased need for additional doses and cost benefits in
favor of PA when compared with BE. There were no differences
observed in any of the trials comparing BE with CA.
produce a synthetic surfactant that closely mimic the various
components, including plasmalogens that are present in
animal-derived surfactants, may be needed to achieve outcomes
that are equivalent to or better than animal-derived surfactants.
Disclosure
R Ramanathan is a paid consultant for Dey, LP, but holds
no equity. This paper was based on a talk presented at the
Evidence vs Experience in Neonatal Practices Fifth Annual CME
Conference that was supported by an unrestricted educational grant
from Dey, LP.
References
Retrospective studies comparing BE, CA and PA
Results from two retrospective studies have been published or
presented. Clark et al.31 published a retrospective study using data
extracted from their administrative database. This study was
primarily carried out to address the potential for a Type I error in
the prospective randomized trial published in 1997.25 A total of
5169 records were studied and 300 infants were of <600 g birth
weight. The differences in mortality reported earlier from the
randomized, controlled trial in a subgroup of patients of <600 g
body weight25 were not observed in this retrospective study. In the
second retrospective study that compared mortality differences from
a large national database in the United States among preterm
infants treated with BE, CA or PA, Ramanathan et al.32 reported a
significantly lower mortality among infants treated with PA when
compared with that among those treated with BE or CA. They
evaluated data from 13 234 preterm neonates treated with
one of the three animal-derived surfactant preparations. Adjusted,
all-cause mortality among preterm infants was significantly lower
in the PA-treated group (6.08%) when compared with that among
BE- (8.12%) or CA (8.44%)-treated neonates (P<0.0001 for both).
In preterm infants <34 weeks, mortality rate was lower in the
PA-treated group (7.5%) when compared with that in the
BE- (9.6%) or CA (9.6%) (P<0.0001 for both) -treated group.
In summary, evidence from randomized controlled clinical
trials, as well as retrospective studies, has shown that there are
differences in mortality and dosing requirements among preterm
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