PAEDIATRIC RESPIRATORY REVIEWS (2004) 5(Suppl A), S299S304

Surfactant treatment for premature lung

disorders: A review of best practices in 2002*
Colin Morley and Peter Davis

Neonatal Department, Royal Womens Hospital, 132 Grattan Street, Melbourne, VIC 3053,
Australia

TYPES OF SURFACTANT use of antenatal steroids was very low, on average

about 30%. Antenatal steroid treatment is now used
The inaccurately labelled natural surfactants that
in well over 80% of very premature deliveries.
are currently used to treat infants include: Surfac-
This treatment has a profound effect on RDS
tant TA, Survanta, Infasurf, Alveofact, BLES and
and its complications and so may ameliorate the
Curosurf. Although derived from animal lungs they
effects of surfactant treatment. If increasing rates
are highly engineered and manipulated. Surfac-
of antenatal steroids lead to fewer babies with
tant TA and Survanta are basically lipid extracts of
surfactant deciency and RDS then the benet:risk
bovine lung mince. Dipalmitoylphosphatidylcholine
ratio of surfactant treatment may have changed.
(DPPC), tripalmitin and palmitic acid are added to
Most trials had highly selected groups of babies
improve the surface properties. Infasurf, Alveofact
and often excluded babies with other complicating
and BLES are bovine lung washes subjected to chlo-
problems so the results of the trials may not
roform/methanol extraction. Curosurf is porcine lung
represent the babies we now want to treat. Examples
mince submitted to chloroform/methanol extraction
are: the randomised European multicentre trial of
and then puried by liquidgel chromatography.
Curosurf7 which only enrolled ventilated babies
The articial surfactants are: Exosurf which is
with birth weights between 700 g and 2000 g who
made from DPPC, hexadecanol, and tyloxapol.
received their surfactant treatment between 2 and 15
Pumactant (ALEC), which is made from DPPC 70%
hours and an FiO2 > 0.6 and had no complicating
and phosphatidylglycerol 30%. Both of these are no
disease. This only represents about 10% of babies
longer being marketed in Europe and the USA.
with RDS and so the results should not be
There are two other synthetic surfactants under
extrapolated to all babies with RDS. The American
development: KL4 (sinapultide) and rSPC (Venti-
trial of Survanta8 only enrolled babies between
cute). At present, there are no randomised controlled
3 and 6 hours after birth with birth weights between
trials (RCTs) of these new products in premature
750 and 1750 g, who had RDS, needed ventilation
babies.
with an FiO2 > 0.4 with an arterial oxygen tension
>80 mm Hg, had a normal blood pressure, a blood
INTERPRETING THE TRIALS glucose above 2.1 mmol/L, and no seizures.
Many trials emphasise only short-term outcomes,
When considering the data available in the RCTs
i.e., a fall in FiO2 or airway pressure in the rst few
one needs to be cautious about whether the results
hours after treatment. Although interesting these are
are now applicable to current babies. The following
relatively unimportant compared with the effects on
trial characteristics need to be considered: The
survival and long term out come.
RCTs were largely done in the 1980s when there
were far fewer very premature babies than are
cared for in the 2000s. In most of the trials the ACUTE EFFECTS OF SURFACTANT
TREATMENT
* Correspondence to: Prof. Colin Morley. Tel.: +61-(3)-9344-2524;
E-mail: morleyc@cryptic.rch.unimelb.edu.au The acute benets of surfactant treatment include

* This review draws heavily on material published in the Cochrane Library, particularly the work of Prof. Roger Soll.16

1526-0542/$ see front matter 2004 Elsevier Science Ltd. All rights reserved.
S300 C. MORLEY AND P. DAVIS

Table 1 WHICH IS THE BEST NATURAL

Main effects of surfactant therapy on major outcomes in a meta-
analysis of the 35 RCTs of surfactant vs placebo
SURFACTANT?
There is no clinical evidence for the superiority of
Surfactant Control Odds ratio NNT a
one surfactant. There are only two trials comparing
Pneumothorax 12.9% 24.3% 0.53 9 natural surfactants (Survanta vs CLSE9 and
Pulmonary interstitial 17.9% 30.3% 0.59 8 Survanta vs Curosurf10 ). These trials are limited
emphysema by their sizes but did not demonstrate clinically
Mortality in hospital 19.8% 25.9% 0.76 16 important differences between the two treatment
28 day mortality 13.6% 19.3% 0.70 18 groups.
a NNT, number of infants needed to treat to prevent one adverse
outcome. WHAT ARE THE ADVERSE EFFECTS OF
SURFACTANT TREATMENT?
improvement in oxygenation. Most trials also showed
a reduction in mean airway pressure. The magnitude Although surfactant treatment is very effective, the
of the effects and rapidity of onset vary depending act of administering the surfactant can cause a
on the type of trial and surfactant. Many of the number of potentially serious problems. These are:
trials also reported an improvement in the chest transient hypoxia and bradycardia, acute airway
X-ray. Table 1 shows the main effects of surfactant obstruction, transient falls in blood pressure, cere-
therapy on major outcomes in a meta-analysis of bral blood ow velocity, cerebral oxyhaemoglobin
the 35 RCTs of surfactant vs placebo. There was concentration, and cerebral activity by amplitude
no effect on bronchopulmonary dysplasia, brain integrated EEG.1117 There is a small increased
haemorrhages, retinopathy of prematurity, or length risk of pulmonary haemorrhage in babies treated
of stay in hospital. with natural surfactants.18 We do not know
whether there will be any long-term effects of
using surfactant manufactured from animal sources.
SHOULD WE USE A NATURAL OR
The real message is that surfactant treatment
SYNTHETIC SURFACTANT? can acutely destabilise a baby and therefore only
As synthetic surfactants are no longer marketed experienced clinicians or neonatal practitioners
in Europe, the USA and Australasia, the choice should administer it.
is easy, only natural surfactants can be used.
However, the Cochrane Review of 10 RCTs with
about 3600 infants shows in Table 2 that in general SHOULD WE GIVE SURFACTANT AT
infants treated with natural surfactants have fewer BIRTH OR TO TREAT ESTABLISHED
pneumothoraces and a slightly reduced mortality RDS?
compared infants treated with synthetic surfactants.
Prophylactic treatment with surfactant means giving
Table 2
it within ten minutes of birth. This aids initial lung
Meta analysis of the ten trials of natural surfactants compared expansion and may reduce lung damage. However,
with synthetic surfactants a reserving treatment for babies with established
disease will reduce the cost of surfactant and expose
Outcome Peto Odds Ratio (95% CI)
fewer infants to any risk of the therapy.
Pneumothorax 0.60 (0.49, 0.73) Rescue treatment with surfactant means giving it
Patent Ductus Arteriosus 0.96 (0.84, 1.11)
when the baby has established RDS. This may be
Sepsis 1.00 (0.87, 1.16)
too late to prevent some of the damage. One of
the frustrations of rescue surfactant treatment is that
Intraventricular haemorrhage 1.14 (1.00, 1.33)
there are no consistent criteria for when it should
Severe intraventricular haemorrhage 1.10 (0.91, 1.33)
be used. Examples of criteria used for giving rescue
Retinopathy of prematurity 0.88 (0.74, 1.03)
surfactant in different studies include: 1) chest X-ray
Bronchopulmonary dysplasia 1.03 (0.89, 1.19)
shows RDS and FiO2 > 0.4, mean airway pressure
Chronic lung disease 1.01 (0.87, 1.18)
more than 7 cm H2 O,19 2) chest X-ray evidence of
Mortality 0.83 (0.70, 0.99)
RDS,20 or 3) FiO2 > 0.6 at 6 to 24 hours,21 4) chest
Chronic lung disease or death 0.95 (0.82, 1.12) X-ray shows RDS and the PaO2 /FiO2 < 150 and the
a From Soll.2
mean airway pressure is more than 7.0 cm H2 O.22
b An odds ratio of less than 1.0 favours natural surfactant. An The evidence is strongly in favour of using
odds ratio of more than 1.0 favours synthetic surfactant. surfactant as early as possible and preferably
SURFACTANT TREATMENT FOR PREMATURE LUNG DISORDERS
in the delivery unit.5 The effect of prophylactic
natural surfactant on mortality compared with
rescue treatment is an Odds Ratio of 0.62. This is
similar to the benet of antenatal steroids which has
an OR of 0.60.
EARLY VS DELAYED SELECTIVE
TREATMENT
Although prophylactic treatment is more effective
than rescue treatment, there are trials that have
investigated giving surfactant early (<2 hours after
birth) compared with giving it when RDS is
well established.23 Two of these trials investigated
synthetic surfactants and two natural surfactants.
The result was that early treatment was more
effective than delaying it. There are no trials
comparing prophylactic with early treatment. The
message is that surfactant treatment should be given
to intubated babies straight after intubation or if that
is not possible as soon after birth as feasible.
HOW MANY DOSES OF SURFACTANT SHOULD STABLE BABIES TREATED
SHOULD BE USED? WITH NASAL CPAP FROM BIRTH BE
Some babies do not respond very well to one dose, INTUBATED TO GIVE SURFACTANT?
others respond initially and then their respiratory
condition deteriorates. This may be because the
exogenous surfactant can be inactivated and
metabolised after it has been instilled in the
lung. It seems appropriate to give further doses
of surfactant to such babies.1 Two RCTs,24,25 of
natural surfactant, have compared a single dose
with multiple doses for the treatment of established
RDS. Multiple doses were associated with a
reduction in the incidence of pneumothorax. Little
difference was shown in other clinical outcomes.
There is little data to encourage the use of more
doses.
WHAT ARE THE CRITERIA FOR
REDOSING WITH SURFACTANT?
The criteria for giving repeated doses of surfactant
are not clear. In one study26 retreatment of ventilated
infants at an FiO2 > 0.3 was compared with and
FiO2 > 0.4 at a mean airway pressure of >7 cm H2 O.
There were no differences in the main clinical
outcomes. The time interval for redosing has not
been elucidated.
HOW SHOULD SURFACTANT BE
GIVEN?
There are a number of different techniques for
S301
giving surfactant treatment. 1) One bolus dose into
the trachea is easy, seems to work well, but can
destabilise the baby. 2) Several bolus doses over
a few minutes are needed if large volumes of
surfactant are used (Survanta, Exosurf). 3) Moving
the baby to different positions while the small
boluses are given does not improve the effect
of the surfactant and therefore is not necessary.
4) Through a side port on the endotracheal tube
connector may work well and has the big advantage
that the endotracheal tube is not disconnected
from the ventilator and lung volume lost before
the surfactant is given.27 5) Through a dual lumen
endotracheal tube seems to work well but most
babies are not intubated with such tubes and it is not
appropriate to reintubate a very premature baby to
give surfactant.28 6) Slowly, by infusion pump down,
a ne catheter into the trachea does not seem to
work as well as bolus installation.29 7) Nebulising
surfactant is complicated, wasteful and is not very
effective.
This work is in progress and no rm recommenda-
tions can be made. Alternative strategies that have
been advocated include: a) prophylactic CPAP from
birth with intubation and surfactant administration
if the baby has worsening RDS measured by
an increasing carbon dioxide level and oxygen
requirement, b) intubation of a baby treated with
CPAP followed by surfactant administration and early
extubation.
The many RCTs of surfactant vs placebo enrolled
ventilated babies and not babies who were being
treated with nasal CPAP. The babies were not
specically intubated to give the surfactant and so
the results cant be extrapolated to babies treated
with nasal CPAP.
Although there are trials of intubating babies
treated with surfactant and then extubating them
to CPAP again they have several problems that
mean the results cannot easily be extrapolated. In
Verder 1994,30 the small number of babies enrolled
were relatively mature with gestational ages up to
35 weeks, with an age at entry of about 12 hours,
which is relatively late for surfactant treatment. The
intubation rate in the group treated with CPAP alone
was 85%. This is very high for babies of this
gestation and much higher than the rate reported
by other people using CPAP from birth. The rate of
intubation in the surfactant treated group at 43% was
no better than the rate found by other groups when
S302
CPAP is used alone. In Verder 199931 the study
investigated early vs late intubation and surfactant
treatment. The enrollment criteria were so selective
that it is difcult to extrapolate the results to all babies
on CPAP.
There are considerable practical problems with
intubating a baby who is well on nasal CPAP. It will
destabilise the baby and will lead to deterioration,
albeit transiently in most cases. Surfactant instillation
also causes a temporary deterioration. If the baby is
treated with morphine, atropine and suxamethonium
for intubation this will interfere with the spontaneous
ventilation for many hours and prevent the baby
being extubated back to CPAP. All this means that
treating babies on CPAP with surfactant is not
a simple procedure and its use should not be
recommended until there is more supporting data.
There is good evidence that even very premature
babies can be very successfully treated with nasal
CPAP without surfactant. This may be in part
because positive end expiratory pressure conserves
surfactant.
IS SURFACTANT TREATMENT
EFFECTIVE IN MICRO PREMS OR
RELATIVELY MATURE BABIES?
It has been suggested that surfactant treatment is
not appropriate for the smallest premature babies
less than 25 weeks gestation because there are
no data to support the treatment of these babies.
However, the data that is available suggests that
surfactant treatment for babies as small as 500 g
reduces the complications.32 The data from the Ten
Centre trial of ALEC33 also showed that there were
positive effects in the smallest babies.
There are very few babies over 32 weeks
gestation who develop RDS with complications and
so it is difcult to nd data that shows surfactant
treatment is effective in these babies. In the larger
babies, above 1250 g there is good evidence that
surfactant treatment is effective for those babies who
develop RDS.34 However, experience suggests that
surfactant does improve those who need ventilating
for RDS.
SHOULD THE DOSE OF SURFACTANT
BE RELATED TO THE SIZE OF THE
BABY?
Several manufacturers recommend the dose is
adjusted for the size of the baby. This seems obvious
but there is no good data to support the idea. Also
there is very little data about the optimal dose to use
for different babies. Approximately 100 mg/kg seems
C. MORLEY AND P. DAVIS
to be as effective as larger doses. The only evidence
is that 100 mg is more effective than a 60 mg dose.
WHAT ARE THE LONG-TERM EFFECTS
OF SURFACTANT TREATMENT?
There are several follow-up studies of treatment
with different surfactants.3539 They all show that
the neurodevelopmental outcome for the surviving
babies is similar to the controls. Therefore surfactant
saves lives without increasing the rate of handicap.
CONCLUSION
There is good evidence that surfactant treatment
should be given to all babies less than 30 weeks
who are intubated at birth and all babies ventilated
for RDS as quickly as possible after intubation, as
a single bolus, and if possible without disconnecting
from the ventilator. A second dose may be effective
after a few hours if the babys respiratory status is not
improving or deteriorating. Only those experienced in
the care of ventilated very premature babies should
give surfactant. Dont intubate babies on nasal CPAP
just to give surfactant.
THE FUTURE
Although the search for improved surfactants is on-
going it will be difcult to prove these produce
better outcomes because this would require very
large trials. An impetus to develop new synthetic
surfactants may come from concerns that natural
surfactants are unsafe from an immunological or
infectious viewpoint.
Most of the surfactant trials were done in an
era when rates of antenatal steroid use were low.
Because of this and other advances in neonatal care
new premature babies have much better outcomes
and exogenous surfactant therapy may not play as
critical a role as previously. There is also some
evidence that intubation and ventilation at birth may
contribute to the lung damage. It is possible that
the outcome will be improved even more by treating
vigorous, steroid prepared, premature babies with
nasal CPAP from birth.
REFERENCES
1. Soll RF. Multiple versus single dose natural surfactant extract
for severe neonatal respiratory distress syndrome [review].
Cochrane Database of Systematic Reviews [computer le]
2001; CD000141.
2. Soll RF. Natural surfactant extract versus synthetic surfactant
for neonatal respiratory distress syndrome [review]. Cochrane
Database of Systematic Reviews (computer le] 2001;
CD000144.
3. Soll RF. Surfactant treatment of the very preterm infant
[review]. Biol Neonate 1998; 74(suppl 1): 3542.
SURFACTANT TREATMENT FOR PREMATURE LUNG DISORDERS
4. Soll RF. Synthetic surfactant for respiratory distress syndrome
in preterm infants [review]. Cochrane Database of Systematic
Reviews [computer le] 2001; CD001149.
5. Soll RF, Morley CJ. Prophylactic versus selective use of
surfactant for preventing morbidity and mortality in preterm
infants [review]. Cochrane Database of Systematic Reviews
[computer le] 2001; CD000510.
6. Suresh G, Soll RF. Current surfactant use in premature infants.
In: Wiswell T, Donn SM, eds., Clinics in Perinatology, Me-
chanical Ventilation and Exogenous Surfactant Update 28(3).
Philadelphia: WB Saunders, 2001: pp. 671694.
7. Collaborative European Multicenter Study Group. Surfactant
replacement therapy for severe neonatal respiratory distress
syndrome: An international randomized clinical trial.
Pediatrics 1988; 82: 683691.
8. Horbar JD, Soll RF, Sutherland JM, et al. A multicenter
randomized, placebo-controlled trial of surfactant therapy for
respiratory distress syndrome. N Engl J Med 1989; 320:
959965.
9. Bloom BT, Kattwinkel J, Hall RT, et al. Comparison of Infasurf
(Calf Lung Surfactant Extract) to Survanta (Beractant) in the
treatment and prevention of respiratory distress syndrome.
Pediatrics 1997; 100: 3138.
10. Speer CP, Gefeller O, Groneck P, et al. Randomised trial of
two treatment regimes of natural surfactant preparations in
neonatal respiratory distress syndrome. Arch Dis Child Fetal
Neonatal Ed 1995; 72: F8F13.
11. Liechty K, Donovan E, Purohit D, et al. Reduction of neonatal
mortality after multiple doses of bovine surfactant in low
birth weight neonates with respiratory distress syndrome.
Pediatrics 1991; 88: 1928.
12. Zola EM, Overbach AM, Gunkel JH, et al. Treatment inves-
tigational new drug experience with Survanta (Beractant).
Pediatrics 1993; 91: 546551.
13. Hamdan AH, Shaw NJ. Changes in pulmonary artery pressure
during the acute phase of respiratory distress syndrome
treated with three different types of surfactant. Pediatr
Pulmonol 1998; 25: 191195.
14. Sitler CG, Turnage CS, McFadden BE, et al. Pump admin-
istration of exogenous surfactant: effects on oxygenation,
heart rate, and chest wall movement of premature infants.
J Perinatol 1993; 13: 197200.
15. Cowan F, Whitelaw A, Wertheim D, et al. Cerebral blood ow
velocity changes after rapid administration of surfactant. Arch
Dis Child 1991; 66: 11051109.
16. Edwards AD, McCormick DC, Roth SC, et al. Cerebral
hemodynamic effects of treatment with modied natural
surfactant investigated by near infrared spectroscopy. Pediatr
Res 1992; 32: 532536.
17. Hellstrom-Westas L, Bell AH, Skov L, et al. Cerebroelectrical
depression following surfactant treatment in preterm
neonates. Pediatrics 1992; 89: 643647
18. Raju TN, Langenberg P. Pulmonary haemorrhage and
exogenous surfactant therapy. A metaanalysis. J Pediatr
1993; 123: 603610.
19. Kendig JW, Notter RH, Cox C, et al. A comparison of surfactant
as immediate prophylaxis and as rescue therapy in newborns
of less than 30 weeks gestation. N Engl J Med 1991; 324:
865871.
20. Dunn MS, Shennan AT, Zayack D, Possmeyer F. Bovine
surfactant replacement therapy in neonates of less than
30 weeks gestation a randomised controlled trial of
prophylaxis versus treatment. Pediatrics 1991; 87: 377386.
21. Egberts JE, de Winter P, Sedin G, et al. Comparison of
prophylaxis and rescue treatment with Curosurf in neonates
less than 30 weeks gestation: a randomised trial. Pediatrics
1993; 92: 768774.
S303
22. Walti H, Paris-Llado J, Breart G, Couchard M, French
Collaborative Multicentre Study Group. Porcine surfactant
replacement therapy in newborns of 2531 weeks gestation:
a randomised, multicentre trial of prophylaxis versus rescue
with multiple low doses. Acta Paediatr 1995; 84: 913921.
23. Yost CC, Soll RF. Early versus delayed selective surfactant
treatment for neonatal respiratory distress syndrome [review].
Cochrane Database of Systematic Reviews [computer le]
2001; CD001456.
24. Dunn MS, Shennan AT, Possmayer F. Single- versus
multiple-dose surfactant replacement therapy for neonates of
30 to 36 weeks gestation with respiratory distress syndrome.
Pediatrics 1990; 86: 564571.
25. Speer CP, Robertson B, Curstedt T, et al. Randomized
European multicenter trial of surfactant replacement therapy
for severe neonatal respiratory distress syndrome: Single
versus multiple doses of Curosurf. Pediatrics 1992; 89:
1320.
26. Kattwinkel J, Bloom BT, Delmore P, et al. High versus
low threshold surfactant retreatment for neonatal respiratory
distress syndrome. Pediatrics 2000; 106: 282288.
27. Zola EM, Gunkel JH, Chan KK, et al. Comparison of three
dosing procedures for administration of bovine surfactant. J
Pediatr 1993; 122: 453459.
28. Soler A, Fernandez-Ruanova B, Lopez H, et al. A randomized
comparison of surfactant dosing via a dual-lumen
endotracheal tube in respiratory distress syndrome. The
Spanish Surfactant Collaborative Group. Pediatrics 1998;
101: E4.
29. Segerer H, van Gelder W, Angenent FW, et al. Pulmonary
distribution and efcacy of exogenous surfactant in lung-
lavaged rabbits are inuenced by the instillation technique.
Pediatr Res 1993; 34: 490494.
30. Verder H, Robertson B, Griesen G, Ebbesen F, Albertsen P,
Lundstrom K, Jacobsen T, The DanishSwedish multicentre
study group. Surfactant therapy and nasal continuous positive
airway pressure for newborns with respiratory distress
syndrome. N Engl J Med 1994; 331: 10515.
31. Verder H, Albertsen P, Ebbesen F, Griesen G, Robertson B,
Bertelsen A, Agertoft L, Djernes B, Nathan E, Reinholdt J.
Nasal continuous positive airway pressure and early
surfactant therapy for respiratory distress syndrome in
newborns of less than 30 weeks gestation. Pediatrics 1999;
103(2).
32. American Exosurf Neonatal Study Group 1. Controlled
trial of a single dose of synthetic surfactant at birth in
premature infants weighing 500 to 699 grams. J Pediatr 1992;
120(suppl): S3S12.
33. Ten Centre Study Group. Ten centre trial of articial surfactant
(articial lung expanding compound) in very premature
babies. BMJ 1987; 294: 991996.
34. Long W, Corbet A, Cotton R, et al. A controlled trial of synthetic
surfactant in infants weighing 1250 g or more with respiratory
distress syndrome. N Engl J Med 1991; 325: 16961703.
35. Morley CJ, Morley, R. Follow up of premature babies treated
with articial surfactant (ALEC). Arch Dis Child 1990; 65:
667669.
36. Survanta Multidose Study Group. Two-year follow-up of infants
treated for neonatal respiratory distress syndrome with bovine
surfactant. J Pediatr 1994; 124: 962967.
37. Collaborative European Multicentre Study Group. A 2-year
follow-up of babies enrolled in a European multicentre trial of
porcine surfactant replacement for severe neonatal respiratory
distress syndrome. Eur J Pediatr 1992; 151: 372376.
38. Dunn MS, Shennan AT, Hoskins EM, et al. Two year follow-
up of infants enrolled in a randomised trial of surfactant
S304 C. MORLEY AND P. DAVIS

replacement therapy for prevention of neonatal respiratory porcine surfactant replacement for severe neonatal respiratory
distress syndrome. Pediatrics 1998; 82: 543547. distress syndrome: Collaborative European Multicentre Study
39. Robertson B, Curstedt T, Tubman R, et al. A two year follow- Group. Eur J Pediatr 1992; 151: 372376.
up of babies enrolled in a European multicentre trial of