Many trials have been carried out to establish the
relative efficacy of various surfactant products in improving clinical
outcome in preterm infants with respiratory distress syndrome (RDS).
Meta-analyses of trials comparing natural and synthetic surfactants
showed a clear reduction in air leaks and suggested improved survival
with natural surfactants . In 2000, Ainsworth, et al. 
reported a higher mortality rate in infants receiving a synthetic
surfactant compared with the natural surfactant. A Cochrane review of
eleven trials demonstrated a significant reduction in the risk of
pneumothorax and mortality rate by use of natural surfactant . Both
natural surfactant extracts and synthetic surfactant extracts were
effective in the treatment and prevention of RDS but natural surfactant
treatment was associated with greater early improvement in the
requirement for ventilatory support.
Prophylactic surfactant administration to infants
judged to be at risk of developing RDS (intubated infants less than
30-32 weeks gestation) demonstrated a decreased incidence of
pneumothorax, pulmonary interstitial emphysema and mortality .
Results suggested that there would be two less cases of pneumothorax and
five less deaths per 100 infants treated with prophylactic surfactant
compared to rescue treatment when surfactant was given within 15 minutes
of birth. This regimen was shown to be as effective as treatment before
the first breath .
In contrast, no difference between early and late
surfactant therapy was observed in a controlled clinical study having a
high rate of antenatal steroid treatment in the study population . In
most of the earlier trials, the rate of antenatal steroid use was low.
The latest Cochrane review of trials comparing early selective treatment
of RDS (within the first two hours of life) to late selective treatment
found evidence of the benefit of early therapy .
Some recent trials focussed on continuous positive
airway pressure (CPAP) treatment and optimal surfactant timing in
extremely low gestational age newborns [8-11]. The Continuous Positive
Airway Pressure or Intubation at Birth (COIN) trial assigned 610 infants
who were born at 25-28 weeks of gestational age to CPAP or intubation
and ventilation at 5 minutes after birth . At 28 days, there was a
lower risk of death or need for oxygen therapy in the CPAP group than in
the intubation group (OR 0.63; 95% CI 0.46 to 0.88; P=0.006). At
36 weeks of gestational age, 33.9% of 307 infants who were assigned to
receive CPAP had died or had bronchopulmonary dysplasia (BPD), as
compared with 38.9% of 303 infants who were assigned to receive
intubation (OR favoring CPAP 0.80; 95% CI, 0.58 to 1.12; P=0.19).
There was little difference in overall mortality. In the CPAP group, 46%
of infants were intubated during the first 5 days, and the use of
surfactant was halved. The incidence of pneumothorax was significantly
increased with 9% in the CPAP as compared with 3% in the intubation
group (P<0.001), but there were no other serious adverse events.
The CPAP group had fewer days of ventilation. Results showed that
primary CPAP treatment with surfactant administration, only if
ventilation is required, was comparable to intubation and immediate
surfactant replacement therapy.
The Surfactant Positive Pressure and Pulse Oximetry
Randomized Trial (SUPPORT) by the NICHD Neonatal Research Network
included infants between 24 and 27 week of gestational age, who were
assigned to intubation and surfactant treatment within 1 hour after
birth or to CPAP treatment, including the possibility of surfactant
administration if intubation criteria were met . Overall, death or
BPD was not significantly different between the study groups. A
significantly lower mortality rate was found in infants who were born
between 24 and 25 weeks and treated with CPAP compared to the same age
group treated with intubation and surfactant therapy (death during
hospitalization: 23.9% vs. 32.1%, P=0.03; death at 36
weeks: 20.0% vs. 29.3%, P=.01). This study demonstrated
that CPAP with subsequent surfactant therapy (if needed) is an
equivalent alternative to intubation and primary surfactant treatment.
The Breathing Outcomes Study, a prospective secondary study to the
SUPPORT trial, assessed respiratory morbidity at 6-month intervals from
hospital discharge to 18-22 months corrected age . Treatment with
early CPAP rather than intubation/surfactant was associated with less
respiratory morbidity defined as wheezing more than twice per week
during the worst 2-week period or cough longer than 3 days without a
A multicentre randomized trial by the Vermont Oxford
Network DRM study group  compared three approaches to the initial
respiratory management of preterm neonates born at 26 to 29 weeks of
gestational age: prophylactic surfactant followed by a period of
mechanical ventilation (prophylactic surfactant); prophylactic
surfactant with rapid extubation to bubble nasal CPAP (intubate-surfactant-extubate)
or initial management with bubble CPAP and selective surfactant
treatment (nCPAP). The primary composite outcome of death or BPD at
corrected 36 weeks of gestational age in 648 infants enrolled at 27
centres did not differ between the groups. In the nCPAP group, 48% were
managed without intubation and ventilation, and 54% without surfactant
treatment. The authors concluded that initial CPAP was a possible and
less invasive and probably even less expensive alternative to surfactant
Prophylactic surfactant followed by nCPAP, and nCPAP
with early selective surfactant therapy were compared in the CURPAP
trial . Of 208 inborn infants born at 25 to 28 weeks of gestational
age, who were not intubated at birth, 105 were randomly assigned to
prophylactic surfactant or nCPAP within 30 minutes of birth.
Thirty-three (31.4%) infants in the prophylactic surfactant group (n=103),
needed mechanical ventilation in the first 5 days of life compared with
34 (33.0%) in the nCPAP group (RR 0.95, 95% CI0.64-1.41; P=0.80).
Death and type of survival at 28 days of life and at corrected 36 weeks
of gestational age, and incidence of main morbidities of prematurity
(secondary outcomes) were similar between groups. A total of 78.1% of
infants in the prophylactic surfactant group and 78.6% in the nCPAP
group survived in room air at corrected 36 weeks of gestational age
. In summary, prophylactic surfactant was not superior to nCPAP and
early selective surfactant in decreasing the need for mechanical
ventilation and the other morbidities of prematurity in spontaneously
breathing very preterm infants on nCPAP.
Taking these results together, primary nCPAP
treatment and early surfactant therapy after establishment of
respiratory distress syndrome signs seem to be appropriate for clinical
practice in extremely low gestational age infants.
The Intubation Surfactant Extubation (INSURE)
procedure is discussed as an alternative procedure that may have the
potential to combine the positive effects of surfactant and early CPAP
. Another mode of surfactant administration, via a thin endotracheal
catheter during spontaneous breathing with CPAP, has recently come into
clinical use [14-16]. Results of a multicentre German study showed that
the application of surfactant to spontaneously breathing preterm infants
was feasible, and it reduced the need for subsequent mechanical
ventilation . This effect was even more pronounced in the subgroup
of infants who were stabilized with CPAP after birth. The intervention
group had significantly fewer median days on mechanical ventilation, and
a lower need for oxygen therapy at 28 days compared with the standard
treatment group. The authors recorded no differences in mortality or
serious adverse events between the groups. The main limitations of the
new method were the need for expertise, and a risk of trauma . This
minimally invasive surfactant therapy (MIST) was also successfully
evaluated in eleven preterm infants (25 to 28 weeks of gestational age)
in Australia . The subsequent initiated Collaborative Paired Trials
Investigating Minimally-Invasive Surfactant Therapy (OPTIMIST) trial is
planned to enroll a total of 606 infants from more than 30 centres
worldwide, and is expected to be completed by end-2017 .
Klebermass, et al.  used this less
invasive surfactant administration (LISA) technique in a prospective
cohort of 224 preterm infants (23 to 27 weeks of gestational age), and
compared the results with a historical control group . LISA was well
tolerated by 94% of all infants, and 68% of infants stayed on CPAP on
day 3. The rate of mechanical ventilation was 35% within the first week
and 59% during the entire hospital stay. Compared to historical
controls, significantly higher survival rates and significantly less
intraventricular hemorrhage and cystic periventricular leukomalacia, but
higher rates of patent ductus arteriosus and retinopathy of prematurity
were documented. Experience with the MIST technique used in 44 preterm
infants was recently compared to the INSURE procedure of a historical
control group of 31 infants. It resulted neither in any difference
regarding the rate of intubation and mechanical ventilation during the
first 72 hours, nor secondary respiratory outcomes and relevant
morbidities between the groups . Interestingly, significantly more
babies in the MIST group (35%) compared to the INSURE group (6.5%)
needed a second dose of surfactant.
A meta-narrative review of the efficacy and safety of
minimally invasive surfactant administration using a thin catheter,
aerosolization, a laryngeal mask airway, and pharyngeal administration
in preterm infants with or at risk for respiratory distress syndrome
recently reported on 10 studies (6 randomized and 4 observational),
including 3081 neonates . None of the studies reported any
significant harm with any of the techniques. No statistically
significant reduction in BPD but a potential reduction in the need for
mechanical ventilation within 72 hours of birth when compared with
standard care was observed in eligible studies. The authors concluded
that surfactant administration via a thin catheter might be an
efficacious and potentially safe method.
Guidelines and Recommendations
Updated guidelines of the European Association of
Perinatal Medicine  recommend the early use of CPAP of at least 5-6
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