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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 S301

in the delivery unit.5 The effect of prophylactic giving surfactant treatment. 1) One bolus dose into
natural surfactant on mortality compared with the trachea is easy, seems to work well, but can
rescue treatment is an Odds Ratio of 0.62. This is destabilise the baby. 2) Several bolus doses over
similar to the benet of antenatal steroids which has a few minutes are needed if large volumes of
an OR of 0.60. surfactant are used (Survanta, Exosurf). 3) Moving
the baby to different positions while the small
boluses are given does not improve the effect
EARLY VS DELAYED SELECTIVE of the surfactant and therefore is not necessary.
TREATMENT 4) Through a side port on the endotracheal tube
Although prophylactic treatment is more effective connector may work well and has the big advantage
than rescue treatment, there are trials that have that the endotracheal tube is not disconnected
investigated giving surfactant early (<2 hours after from the ventilator and lung volume lost before
birth) compared with giving it when RDS is the surfactant is given.27 5) Through a dual lumen
well established.23 Two of these trials investigated endotracheal tube seems to work well but most
synthetic surfactants and two natural surfactants. babies are not intubated with such tubes and it is not
The result was that early treatment was more appropriate to reintubate a very premature baby to
effective than delaying it. There are no trials give surfactant.28 6) Slowly, by infusion pump down,
comparing prophylactic with early treatment. The a ne catheter into the trachea does not seem to
message is that surfactant treatment should be given work as well as bolus installation.29 7) Nebulising
to intubated babies straight after intubation or if that surfactant is complicated, wasteful and is not very
is not possible as soon after birth as feasible. effective.

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 This work is in progress and no rm recommenda-
condition deteriorates. This may be because the tions can be made. Alternative strategies that have
exogenous surfactant can be inactivated and been advocated include: a) prophylactic CPAP from
metabolised after it has been instilled in the birth with intubation and surfactant administration
lung. It seems appropriate to give further doses if the baby has worsening RDS measured by
of surfactant to such babies.1 Two RCTs,24,25 of an increasing carbon dioxide level and oxygen
natural surfactant, have compared a single dose requirement, b) intubation of a baby treated with
with multiple doses for the treatment of established CPAP followed by surfactant administration and early
RDS. Multiple doses were associated with a extubation.
reduction in the incidence of pneumothorax. Little The many RCTs of surfactant vs placebo enrolled
difference was shown in other clinical outcomes. ventilated babies and not babies who were being
There is little data to encourage the use of more treated with nasal CPAP. The babies were not
doses.
specically intubated to give the surfactant and so
the results cant be extrapolated to babies treated
WHAT ARE THE CRITERIA FOR with nasal CPAP.
REDOSING WITH SURFACTANT? Although there are trials of intubating babies
treated with surfactant and then extubating them
The criteria for giving repeated doses of surfactant to CPAP again they have several problems that
are not clear. In one study26 retreatment of ventilated mean the results cannot easily be extrapolated. In
infants at an FiO2 > 0.3 was compared with and Verder 1994,30 the small number of babies enrolled
FiO2 > 0.4 at a mean airway pressure of >7 cm H2 O. were relatively mature with gestational ages up to
There were no differences in the main clinical 35 weeks, with an age at entry of about 12 hours,
outcomes. The time interval for redosing has not which is relatively late for surfactant treatment. The
been elucidated. intubation rate in the group treated with CPAP alone
was 85%. This is very high for babies of this
HOW SHOULD SURFACTANT BE gestation and much higher than the rate reported
by other people using CPAP from birth. The rate of
GIVEN? intubation in the surfactant treated group at 43% was
There are a number of different techniques for no better than the rate found by other groups when
S302 C. MORLEY AND P. DAVIS

CPAP is used alone. In Verder 199931 the study to be as effective as larger doses. The only evidence
investigated early vs late intubation and surfactant is that 100 mg is more effective than a 60 mg dose.
treatment. The enrollment criteria were so selective
that it is difcult to extrapolate the results to all babies WHAT ARE THE LONG-TERM EFFECTS
on CPAP.
OF SURFACTANT TREATMENT?
There are considerable practical problems with
intubating a baby who is well on nasal CPAP. It will There are several follow-up studies of treatment
destabilise the baby and will lead to deterioration, with different surfactants.3539 They all show that
albeit transiently in most cases. Surfactant instillation the neurodevelopmental outcome for the surviving
also causes a temporary deterioration. If the baby is babies is similar to the controls. Therefore surfactant
treated with morphine, atropine and suxamethonium saves lives without increasing the rate of handicap.
for intubation this will interfere with the spontaneous
ventilation for many hours and prevent the baby CONCLUSION
being extubated back to CPAP. All this means that
There is good evidence that surfactant treatment
treating babies on CPAP with surfactant is not
should be given to all babies less than 30 weeks
a simple procedure and its use should not be
who are intubated at birth and all babies ventilated
recommended until there is more supporting data.
for RDS as quickly as possible after intubation, as
There is good evidence that even very premature
a single bolus, and if possible without disconnecting
babies can be very successfully treated with nasal
from the ventilator. A second dose may be effective
CPAP without surfactant. This may be in part
after a few hours if the babys respiratory status is not
because positive end expiratory pressure conserves
improving or deteriorating. Only those experienced in
surfactant.
the care of ventilated very premature babies should
give surfactant. Dont intubate babies on nasal CPAP
IS SURFACTANT TREATMENT just to give surfactant.
EFFECTIVE IN MICRO PREMS OR
RELATIVELY MATURE BABIES? THE FUTURE
It has been suggested that surfactant treatment is Although the search for improved surfactants is on-
not appropriate for the smallest premature babies going it will be difcult to prove these produce
less than 25 weeks gestation because there are better outcomes because this would require very
no data to support the treatment of these babies. large trials. An impetus to develop new synthetic
surfactants may come from concerns that natural
However, the data that is available suggests that
surfactants are unsafe from an immunological or
surfactant treatment for babies as small as 500 g
infectious viewpoint.
reduces the complications.32 The data from the Ten
Most of the surfactant trials were done in an
Centre trial of ALEC33 also showed that there were
era when rates of antenatal steroid use were low.
positive effects in the smallest babies.
Because of this and other advances in neonatal care
There are very few babies over 32 weeks
new premature babies have much better outcomes
gestation who develop RDS with complications and
and exogenous surfactant therapy may not play as
so it is difcult to nd data that shows surfactant
critical a role as previously. There is also some
treatment is effective in these babies. In the larger
evidence that intubation and ventilation at birth may
babies, above 1250 g there is good evidence that
contribute to the lung damage. It is possible that
surfactant treatment is effective for those babies who
the outcome will be improved even more by treating
develop RDS.34 However, experience suggests that
vigorous, steroid prepared, premature babies with
surfactant does improve those who need ventilating
nasal CPAP from birth.
for RDS.

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