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Use of surfactant therapy

Article · January 2011

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Henry L Halliday David G Sweet

Queen's University Belfast University of West London
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REVI EW ARTICLE © 2011 SNL All rights reserved

Surfactant therapy in 2011

Surfactant therapy has revolutionised neonatal respiratory care since its introduction in the
1980s and is now recommended routinely early in the course of respiratory distress syndrome.
Recent guidelines have attempted to achieve a balance between the role of surfactant therapy,
which requires at least a short period of mechanical ventilation, and a more conservative
approach using continuous positive airway pressure alone. In this review current
recommendations for optimising the use of surfactant are described.

David G Sweet
MD, FRCPCH
Consultant Neonatologist, Royal Maternity
R ecent published guidelines from the
United States, Canada and Europe
outline expert opinion on how surfactant
Controlled trials and these have been
subjected to 29 Cochrane systematic
reviews. Twelve different surfactant
Hospital, Belfast, Northern Ireland therapy should be used in babies with preparations have been used in clinical
david.sweet@belfasttrust.hscni.net respiratory distress syndrome (RDS) in the trials4, with timing of first administration
current era1-3. The common theme is that in trials ranging from immediate
Henry L Halliday surfactant replacement therapy, if it is prophylaxis in the delivery room to
MD, FRCPE, FRCP, FRCPH going to be used, should be used as early as intervention when babies are at least six to
Consultant Neonatologist, Perinatal possible and at present natural (animal eight hours old5, and the number of doses
Medicine, Department of Child Health, derived rather than synthetic) surfactants ranging from one to four6. Despite all of
Queen’s University Belfast, Northern Ireland
are the treatments of choice. This comes this evidence, it is still sometimes difficult
with the caveat that as often as possible we in individual cases to decide when best to
should try and manage babies without intervene with surfactant, particularly in
resorting to intubation and mechanical babies who are apparently managing on
ventilation by maximising the use of CPAP early in the course of RDS. The aim
continuous positive airway pressure of this review is to summarise where we
(CPAP). A summary of recommendations are now with surfactant therapy, and the
for surfactant therapy from the 2010 reasoning behind some of the 2010
European Guidelines is shown in TABLE 1. European recommendations.
Surfactant replacement therapy is one of
Keywords the most intensively studied interventions Which surfactant is best?
in medicine. There are now 185 There are several different types of
surfactant replacement therapy; randomised controlled trials of surfactant surfactant preparation licensed for use in
respiratory distress syndrome; preterm
therapy in the Cochrane Register of babies with RDS. These include synthetic
baby; continuous positive airway
pressure; mechanical ventilation
Type of surfactant Natural better than synthetic
Key points
Sweet D.G., Halliday H.L. Use of surfactant Prophylaxis Under 26 weeks’ gestation, or if needing intubation
therapy in 2011. Infant 2011; 7(3): x-x. Timing of first rescue dose Develop individual protocols for when to intervene as RDS
1. Surfactant therapy plays an important progresses based on oxygen requirements and gestational age
role in the management of babies with
RDS. Dose 200mg/kg better than 100mg/kg for rescue therapy if using
2. If surfactant therapy is needed then the poractant alfa. Otherwise use 100mg/kg
earlier it is given the better, including
prophylaxis for some very high risk Ventilation vs CPAP Use CPAP in preference. Extubate to CPAP as early as possible
babies. after surfactant. Consider INSURE technique for babies on
3. If babies with RDS can be managed CPAP who require surfactant
with CPAP alone then surfactant may Second and third doses Give second and occasionally third doses of surfactant if
not be needed. ongoing evidence of RDS such as persistent requirement for
4. Surfactant can also be used in babies on mechanical ventilation and supplemental oxygen
CPAP without resorting to prolonged
mechanical ventilation. TABLE 1 Summary of 2010 European recommendations for surfactant therapy.
5. More than one dose may be needed. Key: RDS=respiratory distress syndrome; CPAP=continuous positive airway pressure;
INSURE=INtubation, SURfactant and Extubation to CPAP .

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 REVI EW ARTICLE

(protein-free) surfactants and natural allowable cumulative dose (600mg/kg vs determine if an individual baby is at risk of
surfactants (derived from animal lungs) 300mg/kg) of poractant alfa would result developing severe RDS. The 2010
and both types of surfactant showed in improved survival or reduction of European Consensus Guideline suggests a
benefit compared with placebo. Natural bronchopulmonary dysplasia (BPD). policy of selective prophylaxis for some
surfactants contain surfactant proteins Babies treated with 200mg/kg showed a babies at very high risk of RDS, with very
which enable them to work more quickly more sustained improvement in early rescue surfactant for the remainder of
although it was not initially clear if this was oxygenation and fewer of them required a extremely preterm babies, and avoiding
an advantage. Direct comparative trials of second dose (69% vs 77%). However these intubation for surfactant in the ‘more
synthetic versus natural surfactants took early improvements did not appear to mature’ preterm babies if it is considered
place during the 1990s and 11 have been influence the primary outcome which was likely that CPAP will suffice. However even
subjected to a Cochrane systematic review, death or oxygen dependency at 28 days since this 2010 guideline further important
with the meta-analysis showing improved (51% each group) and death before studies have been published which provide
outcomes if natural surfactants are used7. discharge (23.5% vs 25 %)10. The authors additional information to address this
Natural surfactants result in fewer concluded that the lower dose regimen was question.
pneumothoraces and a reduction in equally effective as the higher and should It is clear that if surfactant is used for
mortality (typical relative risk 0.87, 95% CI be employed as it is more cost effective. established RDS in ventilated babies then it
0.76 to 0.98). In the UK, the older synthetic It must be borne in mind that this study is more effective when given earlier rather
surfactants Exosurf® and Pumactant® are was performed in an era when exposure to than waiting until babies require higher
no longer on the market. antenatal steroids was only 17%, the amounts of supplemental oxygen5.
In recent years attempts have been made surfactant was given as relatively late rescue Similarly prophylactic administration of
to produce improved synthetic surfactants therapy and CPAP was not as widely used. surfactant has been shown to be superior
by the addition of peptides which mimic Nowadays, in the era of non-invasive to rescue therapy. Meta-analysis of eight
the actions of natural surfactant proteins. respiratory support the issue of whether trials during the 1990s using natural
The rationale for doing this is that different surfactant doses can influence surfactants showed a 39% reduction in
synthetic surfactants have highly management has been re-explored. neonatal mortality if babies less than 32
reproducible compositions and can be Pharmacokinetic studies using carbon-13 weeks are treated within 15 minutes after
produced in large quantities; they may labelled poractant alfa show that a higher birth compared with treatment a few hours
reduce potential risk for immune reactions initial dose of surfactant results in a later14. There was also a reduction in
to animal proteins or transmission of significantly longer half-life11 and this is pneumothorax and pulmonary interstitial
infections and may be more acceptable to mirrored by observed clinical differences, emphysema. However almost 50% more
some cultures on religious grounds. The including better oxygenation and less need infants received surfactant when being
synthetic surfactant that has been studied for subsequent redosing in babies who treated prophylactically, suggesting that
the most is lucinactant, a surfactant receive the higher dose11,12. The difference is many of them may not have required
preparation containing phospholipids and likely to be due to recycling of degraded surfactant. There was no reduction in BPD
a high concentration of a synthetic peptide surfactant components. in the Cochrane meta-analysis14, however
(KL4 peptide) that resembles one of the Several clinical studies have compared separate individual patient analysis of the
domains of surfactant protein B. the recommended dose of 200mg/kg three trials in which poractant alfa was
Comparative studies confirmed that poractant alfa with the recommended dose used showed a significant reduction in the
lucinactant was better than one of the of 100mg/kg of beractant. Individually the risk of oxygen dependency at 28 days of
older synthetic surfactants, but not studies are small, but the higher dose of age [adjusted odds ratio 0.54 (95% CI 0.34
superior to existing natural surfactant surfactant resulted in more rapid to 0.86)]15. Of the studies included in the
preparations and the product has not yet improvement in oxygenation. Meta- Cochrane meta-analysis, the earliest
been licensed for use in newborns8,9. analysis of combined survival data from median time of administration in the
328 babies in these studies suggest a rescue surfactant group was one and a half
What dose should be used? reduction in mortality favouring 200mg/kg hours after birth.
The doses of surfactant we use today come of poractant alfa13. The use of antenatal steroids and CPAP
directly from the original surfactant studies for respiratory support was much lower 20
from the 1980s, and these doses were When should surfactant be given? years ago when these studies were
usually chosen pragmatically based partly The issue of timing of surfactant therapy undertaken. Many babies included in these
on the volume of surfactant that could be continues to cause debate. In an ideal trials would not nowadays be considered
tolerated. The early studies of poractant world surfactant replacement would only eligible for surfactant, particularly if they
alfa used 100mg/kg or 200mg/kg (1.25- be used for babies with surfactant had received the benefit of antenatal
2.5mL/kg) and for beractant used deficiency who require mechanical steroids and were managing well on CPAP.
100mg/kg (4mL/kg) and these are still the ventilation. The difficulty is that the There was a strong argument to try and
doses used today. Early small dose finding evidence until recently has directed determine which babies really require
studies suggested better outcomes with clinicians towards the earliest possible surfactant prophylaxis if antenatal steroids
higher initial doses of surfactant. In the administration of surfactant in order to and CPAP are used. Units adopting policies
early 1990s an attempt was made to improve survival, although we know that of more aggressive CPAP use seemed to
determine if a higher starting dose intubation and ventilation may be harmful have reduced rates of BPD with no
(200mg/kg vs 100mg/kg) and maximum and there is no reliable predictive test to increase in mortality16, but it is only very

infant VOLUME 7 ISSU E 3 2011 169

REVI EW ARTICLE

recently that the question of delivery room

surfactant versus early initiation of CPAP
has been addressed.
The first of these studies was the COIN
trial17. In this study 610 babies born
between 25 and 28 weeks’ gestation who
were breathing spontaneously but
requiring respiratory support were
randomised to initiation of nCPAP (8cm
H2O) or intubation and mechanical
ventilation in the delivery suite. Babies in
the CPAP arm were not given surfactant
unless they required intubation. Surfactant
therapy was not mandated in the
intubation arm of the trial, with 77% of
intubated babies receiving surfactant
compared with 38% of those initiated on
nCPAP. The primary outcome of death or
BPD was not different between groups
(34% CPAP group vs 39% intubation
group). The early nCPAP group had fewer FIGURE 1 A baby on mechanical ventilation.
days of mechanical ventilation (median 3
vs 4 days; p<0.001) but had a higher
incidence of pneumothorax (9% vs 3%; versus low oxygen saturation targeting) a Surfactant administration,
p<0.001). This study proved that for a total of 1,316 babies born between 24 and ventilation and CPAP
selected population of preterm babies 27 weeks were randomised to receive either
where antenatal steroid use was high Traditionally surfactant administration
intubation and surfactant within one hour
(94%) and who were breathing after five takes place after intubation and at least a
of birth or early initiation of CPAP. There
minutes that initiation of early CPAP short period of mechanical ventilation
was a very high rate of treatment with
would reduce the need for mechanical antenatal steroids. The intended treatment (FIGURE 1) and it is probably these, rather
ventilation and surfactant therapy without allocations were largely successful, with than surfactant per se that are potentially
there being any reduction in survival or surfactant being given 99% of the time in harmful. It is now well established that
increase in BPD. the surfactant group and initiation of prolonged mechanical ventilation can be
There was still concern that managing CPAP in the delivery room 81% of the avoided in some babies who require
preterm babies without early surfactant time for the CPAP group. Thirty three surfactant if the INSURE technique is
exposed them to an increased risk of air percent of the CPAP group never received employed (INtubation, SURfactant and
leak. However as there was no defined surfactant. The CPAP group had a reduced Extubation to CPAP). Six studies
protocol for the administration of total number of days of mechanical undertaken during the 1990s and early
surfactant, this study did not provide ventilation (mean 25 vs 28; p=0.03), a 2000s compared early surfactant and CPAP
evidence for the superiority of CPAP over reduced incidence of steroid therapy for with later surfactant and ventilation. Meta-
early surfactant. BPD (7.2% vs 13.2%; p<0.001) but there analysis shows that babies with RDS
Another important study was CURPAP18 was no significant difference in the managed with a policy of earlier surfactant
in which 208 babies of 25 to 28 weeks’ combined outcome of death or BPD at followed by extubation to CPAP have less
gestation were enrolled if they did not need 36 weeks’ postmenstrual age (48% vs 51%; need for mechanical ventilation (RR 0.67
intubation for stabilisation. Within 30 p=0.3). 95% CI; 0.57-0.79), fewer pneumothoraces
minutes after birth babies were either This study offers a strong argument (RR 0.52 95% CI; 0.28-0.96) and less BPD
initiated on nCPAP or intubated for against routine intubation for prophylactic (RR 0.51 95% CI; 0.26-0.99)20. It was also
prophylactic surfactant followed by surfactant in extremely preterm babies in demonstrated that the earlier the decision
immediate extubation to nCPAP. The the current era of CPAP use. However, one is made to intervene with INSURE the
number needing subsequent intubation cannot assume that this finding should be greater the chance of avoiding ventilation21.
and mechanical ventilation within the first generalised to include babies in whom Avoiding intubation altogether has been
five days of life was similar in both groups. there had been inadequate time for attempted by various methods13 but none
In both groups 78% of babies survived completion of antenatal steroids. Further- is in widespread use today. Intra-amniotic
without BPD showing that prophylactic more, it should be noted that both groups instillation of surfactant in the vicinity of
surfactant was not superior to nCPAP and of infants in the SUPPORT trial remained the fetal mouth and nose is technically
early selective surfactant. on ventilation for a long time (almost four feasible, but the risks of this relatively
The largest study designed to address weeks) compared to those treated in invasive procedure seem to outweigh the
this issue was the SUPPORT trial19. In this Europe or Australia (three or four days) benefits22. Nasopharyngeal and laryngeal
multicentre 2-by-2 factorial study (also and this cannot be explained entirely on mask instillation have also been described
designed to assess the benefits of high the lower gestational age of the former. but more work is needed before these

170 VOLUME 7 ISSU E 3 2011 infant

 REVI EW ARTICLE

methods can be recommended. Surfactant

nebulisation has also been employed Gestation Gestation 26-27 Gestation 26-27 Gestation Gestation
<26 wk wk – incomplete wk – complete > 27 wk > 30 wk
although lipids are relatively difficult to antenatal steroids antenatal steroids
aerosolise, and most of the surfactant gets
deposited in the ventilator tubing resulting
in the need for very large doses to be
used23. A small pilot study of aerosolised
lucinactant using a vibrating membrane Early CPAP
Consider delivery room surfactant
nebuliser has demonstrated the feasibility if intubation required or if baby Early CPAP Early CPAP
of this method for surfactant treatment of rapidly develops signs of Rescue surfactant Rescue surfactant
Delivery respiratory distress such as if RDS develops if RDS develops
babies on CPAP but more research is room surfactant grunting/recession and FiO2 >30% and FiO2 >40%
needed before it can be recommended24.
Another method of surfactant
FIGURE 2 Suggested protocol for intervention with surfactant based on European Consensus
administration while avoiding ventilation
Guidelines 2010.
has been developed in German neonatal
units in recent years. This technique
involves placement of a fine intratracheal longer periods of mechanical ventilation Gradually clinicians became more
catheter while babies remain rather than CPAP. comfortable, and at its peak surfactant
spontaneously breathing on CPAP25. In a Manufacturers of natural surfactants therapy was used very liberally as
randomised trial of 220 infants of 26 to 28 make specific recommendations regarding prophylaxis in the delivery suite for many
weeks’ gestation 28% of those given re-treatment: beractant (Survanta®) – may babies who perhaps might have managed
surfactant non-invasively by a fine gastric be repeated within 48 hours at intervals of without. More recently the trend has been
tube needed mechanical ventilation at least six hours for four doses; poractant to adopt policies of more ‘selective’
compared to 45% of those treated with alfa (Curosurf®) – 12 hours later for two prophylaxis, with early rescue surfactant
CPAP and rescue surfactant (p<0.05). further doses if still intubated – after for the majority of babies with RDS
Long-term outcomes were not reported prophylaxis may be repeated 6-12 hours (FIGURE 2). This reflects current knowledge
but this may prove to be a promising later although criteria for retreatment are about the potential damaging effects of
not specified. In 2000 a large trial of 1,267 intubation and mechanical ventilation on
technique to reduce the need for
babies who met re-dosing criteria (FiO2 the preterm lung.
intubation and mechanical ventilation in
>0.30) were randomised to receive a
surfactant-treated preterm infants25.
second dose of bovine surfactant or wait References
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172 VOLUME 7 ISSU E 3 2011 infant

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