doi:10.1111/jpc.
13500
VIEWPOINT
The fascinating story of surfactant
Henry L Halliday
Department of Child Health, Queen’s University Belfast, Belfast, Northern Ireland
The story of surfactant probably began in 1929 when Kurt von
Neergaard, a German-born Physiologist working in Switzerland
filled a porcine lung with an isotonic gum solution ‘to eliminate
surface tension of the air tissue interfaces’.1 After expanding the
lung with air and liquid, he concluded that ‘a lower surface ten-
sion would be useful for the respiratory mechanism’ and that
‘Surface tension as a force counteracting the first breath of the
newly born should be investigated further’. Unfortunately, von
Neergaard did not follow his own advice and it was Peter Gruen-
wald, a Pathologist working in New York who 18 years later
repeated these experiments with the lungs of stillborn infants.2
Gruenwald stated ‘The resistance to aeration is due to surface ten-
sion which counteracts the entrance of air’ and he showed that
surface active substances reduced the pressure needed for aera-
tion. Of interest Peter Gruenwald later was a teacher of Mary
Ellen Avery who was to play a major role in understanding the
pathogenesis of respiratory distress syndrome (RDS). Prior to that,
in the early 1950s, Richard Pattle in England,3 Charles Macklin in
Canada4 and John Clements at the US Army Chemical Center in
Maryland, USA5 were studying the effects of nerve gases on the
lungs. Each in their own way contributed greatly to understanding
the importance of surfactant. It is remarkable that three men
working on chemical warfare projects in three countries in the
1950s came to similar conclusions independently (see Fig. 1).
Pathogenesis of RDS
The next step was to show that hyaline membrane disease, now
called RDS, was caused by abnormal surface tension in the lungs.
Mary Ellen Avery was a research fellow in Jere Mead’s laboratory
in Boston, with Clement Smith as her clinical supervisor. Mel
was so impressed with Clements’ studies in 1957 that she visited
him in Edgewood to learn about the surface film Wilhelmy bal-
ance and adapt it to study lung extracts from newborn infants
who had died soon after birth. Figure 2 is from the original publi-
cation in 1959, showing surface tension in dynes/cm on the verti-
cal axis plotted against birthweight on the horizontal axis.6
Babies dying of hyaline membrane disease (closed circles) had
mean minimal surface tensions of about 30 dynes/cm compared
with about 8 dynes/cm for those who died of other causes (open
Correspondence: Professor Henry L Halliday, 74 Deramore Park South,
Belfast BT9 5JY, Northern Ireland; email: henry.halliday@doctors.org.uk
Conflict of interest: The author does consulting work for Chiesi Farma-
ceuti, Parma, Italy.
This article is adapted from a presentation at the opening ceremony of
‘The Neonate: An International Symposium for Asia’, Shanghai, March
30 to April 1, 2016.
Journal of Paediatrics and Child Health 53 (2017) 327–332
© 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)
circles). Avery and Mead concluded ‘Hyaline membrane disease
is associated with absence or late appearance of some substances
which in normal subjects render the internal surface capable of
attaining a low surface tension when lung volume is decreased’.
Despite knowledge of the cause of RDS as early as 1959, clini-
cians were reluctant to accept that surfactant deficiency was the
major problem to be overcome and as a result progress to
develop a cure proceeded slowly until a tragic event occurred.
In 1963, President John Fitzgerald Kennedy and his wife Jac-
queline Bouvier Kennedy were involved in a sad chapter of the
history of surfactant. On 7 August 1963, just 4 years after Mead
and Avery’s seminal research on pathogenesis of RDS, Patrick
Bouvier Kennedy, third child of President and Jackie Kennedy
was born at 35 weeks after a placental abruption. Tragically, he
died 2 days later from hyaline membrane disease despite state-of-
the-art care in Boston. An obituary in the New York Times noted
the absence of any specific treatment for hyaline membrane dis-
ease. This event helped focus attention on RDS. Within a year
trials with synthetic surfactants had begun.
The First Clinical Trials with Synthetic
Surfactants
Developmental work on surfactant phospholipids by Marshall
Klaus and his colleagues in San Francisco7 allowed the first trials
with synthetic surfactants to be conducted in Canada and Singa-
pore, with publications in 19648 and 1967.9 Alas, the results were
not good; both studies used nebulised dipalmitoylphosphatidylcho-
line (DPPC) with no apparent beneficial effects. The study of Jac-
queline Chu and colleagues (including John Clements, Marshall
Klaus and Bill Tooley) in Singapore left the authors so disillusioned
that they entitled their paper ‘Neonatal Pulmonary Ischemia’
implying that the underlying cause of RDS was low pulmonary
blood flow rather than surfactant deficiency.9 We now know that
phospholipids on their own lower surface tension in vitro but pro-
teins are necessary for the rapid spreading and adsorption needed
for efficacy in vivo. Also, nebulisation was not an effective method
of delivering surfactant to the lungs. About 2 years later, in 1969,
an important observation in New Zealand was reported.10
Prenatal Corticosteroids
Graham Liggins, an Obstetrician working in Auckland, infused
glucocorticoids into pregnant sheep to try to prevent preterm
labour and by serendipity he noticed that the immature lambs
did not die soon after birth from RDS but survived.10 With his co-
researcher Ross Howie, a Paediatrician, he later performed an
important randomised controlled trial to show that maternal
betamethasone given to women at risk of preterm birth reduced
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Fascinating story of surfactant
rates of RDS and neonatal mortality, at least in part by stimulat-
ing surfactant synthesis. This seminal paper was published in
197211 and it eventually led to acceptance of prenatal corticoster-
oids as a major contribution to improved perinatal care.
Introduction of Natural Surfactants
In the same year, 1972, in Stockholm, Goran Enhorning, another
Obstetrician, and Bengt Robertson, a Paediatric Pathologist,
328
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HL Halliday
Fig. 1 Some of the pioneers of the dis-
covery and understanding of pulmonary
surfactant.
showed that preterm rabbits treated with natural surfactant did
not die soon after birth.12 In 1973, they also showed that pharyn-
geal deposition rather than tracheal instillation of natural surfac-
tant was effective13 in reducing mortality from RDS, but over
40 years later this is still not a recognised method of surfactant
administration.
Tetsuro Fujiwara in the 1970s was working in Forrest
Adams’ laboratory in California14 but before US studies in
humans could begin Fujiwara returned to Japan and in 1980
Fig. 2 Mary Ellen Avery who in 1959,
with Jere Mead, reported high surface
tension in the lungs of babies dying of
respiratory distress syndrome (hyaline
membrane disease).
Journal of Paediatrics and Child Health 53 (2017) 327–332
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HL Halliday Fascinating story of surfactant

Fig. 3 The first report of successful

bovine-derived surfactant treatment of
infants with respiratory distress syndrome.

published in the Lancet the results of administration of
Surfactant-TA to 10 preterm infants.15 These were relatively
mature infants with a mean gestation of 30 weeks and mean
birthweight over 1500 g. Within a short time, mean arterial
oxygen tension had increased from about 45–210 torr and chest
radiographs also improved. Nine of the 10 infants developed a
patent ductus arteriosus and 2 died but natural surfactant
(in this case bovine-derived) was launched as a treatment for
RDS in 198015 (see Fig. 3).
Meanwhile in Belfast, we had developed a synthetic surfactant
containing DPPC and high density lipoprotein and had tested it
prophylactically on 100 preterm babies of less than 34 weeks’
gestation.16 Our results were somewhat disappointing and we
were considering the next steps to take when I met Colin Morley
who had developed his own synthetic surfactant (ALEC or
pumactant) with Alec Bangham in Cambridge.17 He was inter-
ested in our results and helped us analyse the outcome for a sub-
group of infants of 25–29 weeks’ gestation. Figure 4 shows

Fig. 4 Colin Morley who with Alec Bang-

ham developed ALEC (or pumactant) and
results from four UK trials using ALEC and
Turfsurf (two dipalmitoylphosphatidylcholine-
based synthetic surfactants) in babies of
25–29 weeks’ gestation.

Journal of Paediatrics and Child Health 53 (2017) 327–332 329

© 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)

Fascinating story of surfactant
neonatal mortality in four studies – the old and new Cambridge
studies, the Belfast and the Nottingham – surfactant treated
infants had lower death rates than controls in all four trials. In
our study we had only 36 infants of 25–29 weeks’ gestation so
our trial was under-powered to show a difference in this
important sub-group.16 Colin suggested that I should contact
Bengt Robertson in Stockholm and compare our surfactant
with a natural product.
330
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HL Halliday
Fig. 5 Bengt Robertson (RO) and Tore
Curstedt (CU) at Lake Geneva – the crea-
tors of the porcine surfactant – Curosurf,
also known as poractant alfa.
Origin of Curosurf in Stockholm
Meanwhile in Stockholm, Bengt Robertson with his expertise in
in vitro and in vivo testing of surfactants had teamed up with Tore
Curstedt, a Clinical Chemist, with an interest in isolation of phos-
pholipids and proteins.18 Together they produced a porcine sur-
factant which they named after themselves – Curstedt –
Robertson surfactant or Curosurf for short. This surfactant was
Fig. 6 November 1984 in Stockholm
comparing Turfsurf and Curosurf in vitro
and in vivo.
Journal of Paediatrics and Child Health 53 (2017) 327–332

HL Halliday
Fig. 7 Rapid clearing of the chest radiograph soon after surfactant
administration.
unique in that, apart from being produced from pig rather than
cow lungs, it went through an additional preparation step of liq-
uid gel chromatography leaving only polar lipids and SP-B and
SP-C with a phospholipid concentration of 80 mg/mL18
(see Fig. 5).
I spent November 1984 in Stockholm comparing our synthetic
surfactant Turfsurf with Curosurf, both in vitro and in Bengt’s 27-
day fetal rabbit model. The 27-day fetal rabbits were given surfac-
tant or saline and ventilated using a multiple chamber, constant
pressure whole body plethysmograph developed by Burkhard
Lachmann and Bengt Robertson and later modified by Bo Sun
(see Fig. 6).
Curosurf was clearly better than Turfsurf in treating experi-
mental RDS.19 Whilst I was in Stockholm, I also witnessed the
treatment with Curosurf of very preterm twins who had severe
RDS, and the white creamy mixture literally turned these blue
babies pink within minutes. The chest x-ray also dramatically
improved within a very short time from a white-out to almost
clear lung fields20 (see Fig. 7).
First Clinical Trials with Curosurf
This led us to design and undertake the first randomised con-
trolled trial of Curosurf, made exclusively in Stockholm by Tore
Curstedt and not by a drug company at that time. We rando-
mised preterm infants with severe RDS (mean inspired oxygen
80%) and mean age 10 hours to treatment with a single dose of
200 mg/kg Curosurf or treatment with mechanical ventilation
alone (control group). We found significant reductions in pulmo-
nary air leaks, neonatal mortality and death or bronchopulmon-
ary dysplasia (BPD) in treated infants.21
Subsequent trials studied single versus multiple doses, early
versus late surfactant treatment, use of CPAP and surfactant and
comparisons with other surfactant preparations.22,23 For the first
few studies in the 1980s and 1990s mortality fell from 50% in
controls to 30% with single dose treatment to about 10% with
multiple doses, but remember this was late rescue treatment
more than 30 years ago, a far cry from today’s practice.
Journal of Paediatrics and Child Health 53 (2017) 327–332
© 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)
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Fascinating story of surfactant
Other Surfactants Used in Clinical Trials
Many surfactant preparations have been used in clinical trials
including: the original protein-free synthetic surfactants – pumac-
tant (ALEC), colfosceril palmitate (Exosurf ) and the Belfast sur-
factant (Turfsurf ) which was never commercially produced; the
natural (minced lung extract) surfactants – Surfactant-TA
(Fujiwara’s surfactant), beractant (Survanta) – the north Ameri-
can version of Surfactant-TA with added DPPC, tripalmitin and
palmitic acid and poractant alfa (Curosurf ); and the natural (lung
lavage extract) surfactants – calf lung surfactant extract or bLES
used in Canada, calfactant (Infasurf ) in the USA and bovactant
(Alveofact) used in parts of Europe. Amniotic fluid extract was a
very interesting surfactant studied by Allen Merritt and Mikko
Hallman – it contained some SP-A in addition to SP-B and SP-C
and appeared to be very effective.22 However, it was withdrawn
from clinical use once the risk of HIV contamination became
apparent. Some new synthetic surfactants containing protein
analogues, including CHF5633, have recently been studied.18
Surfactant was the first drug developed solely for treatment of
neonates; a major breakthrough in neonatal medicine in the past
35 years. Surfactant reduced both neonatal mortality and pulmo-
nary air leaks by about 50%. Its introduction was also associated
with a 6% reduction in infant mortality in the USA. Prophylactic
or very early treatment with a natural surfactant seemed to give
the best results for very preterm infants although recent trials
suggest early CPAP is also effective. Follow-up studies showed no
increase in adverse neuro-developmental or pulmonary sequelae.
Guidelines for Surfactant Treatment
Currently, three surfactant preparations are licensed for use in
Europe: beractant, bovactant and poractant alfa whereas there
are four in the USA: beractant, calfactant, lucinactant and porac-
tant alfa. All but lucinactant are derived from animal lungs.24
Recently, guidelines for surfactant treatment have been updated
in Europe24 and the USA.25 The present indications for surfactant
therapy may be summarised as: treatment of RDS; prophylaxis of
RDS, although early CPAP is probably just as effective in most
cases; surfactant may help in meconium aspiration syndrome
(MAS)26 or neonatal pneumonia,25 improving oxygenation and
reducing need for extracorporeal membrane oxygenation; other
indications are largely experimental.
Conclusions and Future Developments
Not all our problems in neonatology have been solved and those
continuing include – prevention and management of chronic
lung disease or BPD, determining the limits of viability for opti-
mal survival without significant disability, providing appropriate
neonatal care in the developing world and finally putting the
patient (and family) first in all our care decisions.
What does the future hold? New generation synthetic surfac-
tants with protein analogues which are cheaper to produce and
more resistant to inactivation will continue to be developed and
tested in preterm babies.18 As inactivation of surfactant may be a
key feature in pathogenesis of neonatal pneumonia, MAS and
adult RDS, these new surfactants may have a role in their man-
agement. Nebulisation and/or atomisation will continue to be
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Fascinating story of surfactant
developed as means of non-invasive administration of surfactant,
and drug delivery directly to the lungs using surfactant may
become commonplace and an effective way of reducing BPD.
The fascinating story of surfactant also involved names such as
Charles Cochrane, Ted Egan, Lou Gluck, Mikko Hallman, Sam
Hawgood, Alan Jobe, Walker Long, Allen Merritt, Bob Notter,
Michael Obladen, Rod Phibbs, Fred Possmayer, Ola Saugstad,
Don Shapiro, Barry Smith, Roger Soll, Christian Speer, Bo Sun,
Bill Taeusch, Jeff Whitsett and many others. Although only the
latter part of this story occurred during my clinical lifetime it was
an honour to have been involved in some small way. The story,
however, is not over as we enter the era of altering the survival
of preterm infants into survival without long-term disabilities.
Acknowledgement
The author would like to thank Tore Curstedt from the Karo-
linska Institute, Stockholm who provided material for some of
the figures reproduced in this viewpoint article.
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