Prophylactic or Early Selective Surfactant Combined
With nCPAP in Very Preterm Infants
WHAT’S KNOWN ON THIS SUBJECT: Prophylactic surfactant and
delivery room nCPAP are beneficial practices to reduce lung
injury in preterm infants. A brief intubation for surfactant
administration in preterm infants on nCPAP reduces the need for
MV when used early in respiratory distress syndrome.
WHAT THIS STUDY ADDS: In spontaneously breathing preterm
newborns who are treated with nCPAP, prophylactic surfactant
given within 30 minutes of birth is not superior to early selective
surfactant in terms of requirement of MV in the first 5 days of
life.
abstract
OBJECTIVE: Early surfactant followed by extubation to nasal continu-
ous positive airway pressure (nCPAP) compared with later surfactant
and mechanical ventilation (MV) reduce the need for MV, air leaks, and
bronchopulmonary dysplasia. This randomized, controlled trial inves-
tigated whether prophylactic surfactant followed by nCPAP compared
with early nCPAP application with early selective surfactant would re-
duce the need for MV in the first 5 days of life.
METHODS: A total of 208 inborn infants who were born at 25 to 28
weeks’ gestation and were not intubated at birth were randomly as-
signed to prophylactic surfactant or nCPAP within 30 minutes of birth.
Outcomes were assessed within the first 5 days of life and until death
or discharge of the infants from hospital.
RESULTS: Thirty-three (31.4%) infants in the prophylactic surfactant
group needed MV in the first 5 days of life compared with 34 (33.0%) in
the nCPAP group (risk ratio: 0.95 [95% confidence interval: 0.64 –1.41];
P ! .80). Death and type of survival at 28 days of life and 36 weeks’
postmenstrual age and incidence of main morbidities of prematurity
(secondary outcomes) were similar in the 2 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 36 weeks’ postmenstrual age.
CONCLUSIONS: Prophylactic surfactant was not superior to nCPAP and
early selective surfactant in decreasing the need for MV in the first 5
days of life and the incidence of main morbidities of prematurity in
spontaneously breathing very preterm infants on nCPAP. Pediatrics
2010;125:e1402–e1409
e1402 SANDRI et al
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AUTHORS: Fabrizio Sandri, MD,a Richard Plavka, MD,b
Gina Ancora, MD,c Umberto Simeoni, MD,d Zbyněk
Stranak, MD,e Stefano Martinelli, MD,f Fabio Mosca, MD,g
José Nona, MD,h Merran Thomson, MD,i Henrik Verder,
MD,j Laura Fabbri, PhD,k and Henry Halliday, MD,l for the
CURPAP Study Group
aDipartimento Materno-Infantile, Ospedale Maggiore, Bologna,
Italy; bDepartment of Obstetrics and Gynaecology, General
Faculty Hospital, Prague, Czech Republic; cDipartimento della
Salute della Donna, del Bambino e dell’Adolescente, Ospedale S.
Orsola Malpighi, Bologna, Italy; dDepartment of Neonatology,
Assistance Publique, Hôpitaux de Marseille, Marseille, France;
eDepartment of Pediatrics, Maternity Hospital, Podoli, Prague,
Czech Republic; fDipartimento Materno-Infantile, Ospedale
Niguarda Ca Granda, Milan, Italy; gDipartimento Materno-
Infantile, Ospedale Maggiore Policlinico, Mangiagalli e Regina
Elena-Fondazione IRCCS-Università di Milano, Milan, Italy;
hDepartment of Pediatrics, Maternidade Dr Alfredo Da Costa,
Lisbon, Portugal; iDepartment of Pediatrics, Queen Charlotte’s
and Chelsea Hospital, London, England; jDepartment of
Pediatrics, Holbaek Hospital, University of Copenhagen,
Copenhagen, Denmark; kNeonatology Clinical Unit, Chiesi
Farmaceutici SpA, Parma, Italy; and lDepartment of Child Health,
Royal Maternity Hospital, Belfast, Northern Ireland
KEY WORDS
nCPAP, preterm newborn, surfactant, respiratory distress
syndrome, mechanical ventilation, bronchopulmonary dysplasia
ABBREVIATIONS
MV—mechanical ventilation
BPD— bronchopulmonary dysplasia
RDS—respiratory distress syndrome
RCT—randomized, controlled trial
nCPAP—nasal continuous positive airway pressure
InSurE—intubation-surfactant-extubation
GA— gestational age
FIO2—fraction of inspired oxygen
RR—risk ratio
CI— confidence interval
This trial has been registered at www.clinicaltrials.gov
(identifier NCT00501982).
www.pediatrics.org/cgi/doi/10.1542/peds.2009-2131
doi:10.1542/peds.2009-2131
Accepted for publication Jan 25, 2010
Address correspondence to Fabrizio Sandri, MD, Ospedale
Maggiore, Via Dell’Ospedale 2, 40100 Bologna, Italy. E-mail:
f.sandri@ausl.bologna.it
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2010 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: Dr Fabbri is the head of the
Neonatology Clinical Department of and Dr Halliday has served
as a consultant to Chiesi Farmaceutici; the other authors have
no financial relationships relevant to this article to disclose.

Respiratory distress syndrome con-
tributes to mortality and morbidity in
very preterm infants and with mechan-
ical ventilation (MV) is a major deter-
minant of bronchopulmonary dysplasia
(BPD). Surfactant treatment changes
the natural history of respiratory dis-
tress syndrome (RDS), resulting in a
30% to 65% relative reduction in risk
for pneumothorax and up to a 40% rel-
ative reduction in neonatal mortality;
adverse events are infrequent and
long-term follow-up studies are reas-
suring.1 Randomized, controlled trials
(RCTs) have demonstrated that pro-
phylactic or early surfactant therapy
compared with delayed rescue surfac-
tant treatment results in improved
outcomes for preterm infants at high
risk.2
Nasal continuous positive airway pres-
sure (nCPAP) is an important first-line
form of respiratory support in new-
borns and is used as an alternative to
intubation and MV in extremely pre-
term infants.3,4 Observational and co-
hort studies have shown that nCPAP
followed by intubation, surfactant ad-
ministration, and MV only if nCPAP fail-
ure criteria are reached reduce the
need for MV. Furthermore, a reduced
incidence of BPD without increased
mortality has been reported.5–8 Few
RCTs have compared intubation and
MV with early nCPAP or different types
of nCPAP and did not highlight signifi-
cant differences.9–11
A brief intubation for surfactant ad-
ministration in newborns on nCPAP,
the intubation-surfactant-extubation
(InSurE) method,12,13 has also been in-
vestigated and resulted in a reduced
need for MV in the first week of life
when used early in RDS14–17; however,
the vast majority of these studies in-
cluded a low number of extremely pre-
term infants. Prophylactic surfactant
and delivery room nCPAP to maintain
functional residual volume have been
identified as potentially beneficial
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practices that, if adopted for extremely
preterm infants, could reduce lung in-
jury18; however, no RCTs have yet com-
pared prophylactic surfactant with
early nCPAP, especially in extremely
preterm infants at high risk for devel-
oping RDS. In fact, the recently pub-
lished Continuous Positive Airway
Pressure or Intubation at Birth (COIN)
trial compared the use of nCPAP
shortly after birth with intubation and
MV; in both groups, surfactant was
given only to mechanically ventilated
patients with high oxygen require-
ment, and there was no immediate ex-
tubation to nCPAP.11
An international randomized con-
trolled trial to evaluate the efficacy of
combining prophylactic surfactant
and early nasal continuous positive
airway pressure in very preterm in-
fants (CURPAP study) was designed to
compare the administration of prophy-
lactic surfactant followed by nCPAP
with early nCPAP followed by early se-
lective surfactant. The primary end
point was the need for MV in the first 5
days of life.
METHODS
Study Design
This was a phase IV international, mul-
ticenter, open-label, RCT approved by
independent ethics committees in ac-
cordance with requirements of each
participating country. It was con-
ducted in accordance with good clini-
cal practice guidelines and all applica-
ble regulatory rules under the guiding
principles of the Declaration of Hel-
sinki. Inborn infants with gestational
ages (GAs) from 25 weeks 0 days and
28 weeks 6 days were included. Exclu-
sion criteria were severe birth as-
phyxia or a 5-minute Apgar score "3,
endotracheal intubation for resuscita-
tion or insufficient respiratory drive,
known genetic disorders, potentially
life-threatening conditions unrelated
to prematurity, and premature rup-
ARTICLES
ture of membranes for #3 weeks.
Written informed consent was ob-
tained before delivery.
Randomization
Eligible infants were randomly assigned
immediately after birth by using a cen-
tral interactive voice response system.
Randomization was stratified by GA at
birth into 2 strata: 25 to 26 weeks and
27 to 28 weeks. Infants were assigned
to 1 of 2 treatment groups within 1 of
the 2 strata in a 1:1 ratio. The block size
for the randomization within each
stratum was 4. The randomization de-
sign ensured that, in the case of twins,
both siblings were allocated to the
same treatment group.
Study Intervention
Positive pressure with the system in
use in each delivery room (flow-
dependent bag or T-piece system) was
used to stabilize newborns in both
groups after birth. When infants ful-
filled all entry criteria, they were ran-
domly assigned by using the interac-
tive voice response system and the
allocated treatment was begun within
30 minutes of birth.
Infants who were randomly assigned
to prophylactic surfactant were intu-
bated for administration of a dose
of poractant alfa (Curosurf [Chiesi
Farmaceutici, Parma, Italy]) of 200 mg/
kg. The tube position was confirmed by
auscultation. During surfactant admin-
istration, infants were manually venti-
lated to facilitate surfactant distribu-
tion and then extubated to nCPAP as
soon as possible within 1 hour if respi-
ratory drive was present. In the ab-
sence of good respiratory drive, MV
was started. Infants who were extu-
bated to nCPAP after surfactant were
eligible for MV if nCPAP failure oc-
curred (nCPAP failure criteria are de-
fined in detail in the next section).
Infants who were assigned to nCPAP
were stabilized on nCPAP alone. In the
e1403
event of nCPAP failure and after obtain-
ing a chest radiograph, early selective
surfactant was administered in a dose
of 200 mg/kg. Thereafter, infants were
treated as in the prophylactic surfac-
tant group.
During stabilization and transport to
the NICU, any CPAP device was allowed
according to the practice of each in-
vestigative site; in the NICU, nCPAP was
given through nasal prongs/mask us-
ing a flow-dependent system (the In-
fant Flow System was preferred) with
an initial pressure of 6 to 7 cm H2O, in
both groups. A second dose and addi-
tional doses of surfactant of 100 mg/kg
could be administered to infants who
were on MV.
Continuous monitoring by pulse oxim-
etry was performed; fraction of in-
spired oxygen (FIO2), clinical outcomes
(usual complications of prematurity),
nCPAP, and MV pressures were re-
corded at regular intervals. The clini-
cal risk index for babies score19 was
assessed. Concomitant medications
were recorded for 5 days after initial
treatment. Adverse events and clinical
outcomes were assessed until the end
of study, at death, or at discharge from
hospital.
Definition of nCPAP Failure
Infants who met !1 of the following
criteria were defined as nCPAP fail-
ures: FIO2 #0.4 on nCPAP to maintain
oxygen saturation of 85% to 92% for at
least 30 minutes unless rapid clinical
deterioration occurred, apnea defined
as #4 episodes of apnea per hour or
#2 episodes of apnea per hour when
ventilation with bag and mask was re-
quired, respiratory acidosis defined as
PCO2 #65 mm Hg (8.5 kPa), and pH
"7.2 on arterial or capillary blood gas
sample.
Indication for Termination of MV
The decision to extubate and place on
nCPAP was considered when there
e1404 SANDRI et al
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was good respiratory drive, FIO2 re-
quirement was "0.4 to maintain pulse
oximetry readings (85%–92%), ventila-
tor pressures were relatively low (ie,
mean airways pressure "7 and "8
cm H2O in conventional mechanical
and high-frequency oscillatory ventila-
tion, respectively), capillary or arterial
PCO2 was "65 mm Hg (8.5 kPa), and pH
was !7.2.
Primary and Secondary Outcomes
The primary outcome was need for MV
within the first 5 days of life. Infants in
both groups were considered to have
reached the primary outcome when
they could not be extubated within 1
hour after surfactant administration
or when they met the nCPAP failure cri-
teria after extubation. The secondary
outcomes were death, survival in room
air, survival with oxygen, and survival
on respiratory support at 28 days of
life and at 36 weeks’ postmenstrual
age; incidence of BPD by using criteria
proposed by the National Institute of
Child Health and Human Development/
National Heart, Lung, and Blood Institute/
Office of Rare Diseases Workshop20;
air leaks; pulmonary hemorrhage; in-
traventricular hemorrhage21; patent
ductus arteriosus defined echocardio-
graphically; retinopathy of prematurity
by stage of severity22; necrotizing en-
terocolitis defined as stage 2 or higher
as per modified Bell criteria23; cystic
periventricular leukomalacia24; sepsis
defined as a positive blood culture or
suggestive clinical and laboratory find-
ings leading to treatment with antibiot-
ics for at least 7 days despite absence
of a positive blood culture; duration of
hospitalization; total duration of MV;
and use of systemic postnatal ste-
roids. Requirement for surfactant
(need for early selective in the nCPAP
arm and additional doses in both
groups) was also recorded. All out-
comes were assessed until death or
discharge from hospital.
Statistical Analysis
By using data from participating cen-
ters, it was estimated that 50% of in-
fants of 25 to 28 weeks’ GA would re-
quire MV. We calculated a sample size
on the basis that prophylactic surfac-
tant would reduce this outcome to
30%. With 80% power and a 2-sided sig-
nificance level of .05, 93 infants would
be needed in each group. Assuming a
dropout rate of 12%, 104 infants per
group were needed, giving a total sam-
ple size of 208 participants, ignoring
nonindependence of twins. The analy-
sis was performed according to the
intention-to-treat principle.
For the primary efficacy analysis, we
used the Cochran-Mantel-Haenszel
(CMH) test, which adjusts for stratifi-
cation factors of GA and center. Risk
ratios (RRs), 95% confidence intervals
(CIs), and P values are reported. The
influence of including twins in the pri-
mary analysis as independent obser-
vations was assessed by using 2 sensi-
tivity analyses. The primary analysis
was repeated when (1) 1 infant from
each set of twins was removed at ran-
dom from the analysis and (2) all twins
were removed from the analysis popu-
lation. A logistic regression analysis
was performed on the primary analy-
sis by using a number of covariates,
including treatment, stratum, gender,
race, type of delivery, birth weight, pre-
natal steroids, and twin birth.
For the secondary analyses, propor-
tional data were analyzed by using the
Cochran-Mantel-Haenszel test and con-
tinuous data by using an analysis of
covariance. Overall differences be-
tween treatment groups and associ-
ated 95% CIs are reported. An analysis
of normality of data was also per-
formed, and for data not normally dis-
tributed, a suitable transformation
was performed. When there were no
suitable transformations, data were
analyzed by using the Wilcoxon Rank-
sum test and the median difference be-
 ARTICLES

group were FIO2 #0.4 in 6 of 33, apneic

episodes or absence of respiratory
drive in 23 of 33, and respiratory aci-
dosis in 6 of 33. In the nCPAP group,
these were FIO2 #0.4 in 25 of 34, apneic
episodes or absence of respiratory
drive in 19 of 34, and respiratory aci-
dosis in 13 of 34. Exploratory logistic
regression by using the primary out-
come as a function of covariates
showed that need for MV in the first 5
days was inversely related to birth
weight (P ! .001) and significantly
greater in boys compared with girls
(P ! .046). These covariates were in-
cluded in the final model via stepwise
progression. The adjusted odds ratio
for the treatment allocation was 1.02
FIGURE 1 (95% CI: 0.55–1.88; P ! .95).
Number of infants who were eligible for the study and randomly assigned to treatment groups.

Secondary Outcomes
tween treatments and associated P bated after surfactant treatment com- There were no significant differences
value are reported. RRs and 95% CIs pared with 19 of 50 infants who were between groups for any secondary
are reported. intubated for selective surfactant in outcome, even when the 2 GA strata
the nCPAP group; reintubation after ex- were analyzed separately (Tables 3
RESULTS tubation to nCPAP was required for 23 and 4). Median (range) days of hospi-
Study Groups of 95 and for 15 of 31, respectively. The talization were 68 (2–212) in the pro-
Figure 1 shows the number of new- reasons for MV (#1 could be re- phylactic surfactant group and 71 (1–
borns who were assessed for eligibil- corded) in the prophylactic surfactant 202) in the nCPAP group (P ! .66);
ity, the number of eligible newborns,
and the number of newborns who
were randomly assigned to each treat- TABLE 1 Baseline Demographic and Clinical Characteristics of the Patients
ment group. A total of 208 newborns Characteristic Prophylactic Surfactant nCPAP
(N ! 105) (N ! 103)
were enrolled between March 2007
GA, mean $ SD, wk 27.0 $ 1.0 27.00 $ 1.0
and May 2008 in 24 European NICUs. GA 25–26 wk, n (%) 32.0 (30.5) 31.0 (30.0)
The demographic and clinical charac- Antenatal corticosteroids, n (%)
teristics were similar in the 2 groups Complete course 82 (78.1) 81 (78.6)
(Table 1). Incomplete course 19 (18.1) 20 (19.4)
Cesarean delivery, n (%) 75 (71.0) 74 (72.0)
Birth weight, mean $ SD, g 967 $ 221 913 $ 200
Primary Outcome Male gender, n (%) 57 (54.3) 54 (52.4)
Thirty-three (31.4%) infants in the pro- Multiple births, n (%) 33 (31.4) 30 (29.1)
Apgar score at 5 min, median (range) 8 (5–10) 8 (4–10)
phylactic surfactant group needed MV CRIB score, median (range) 1 (0–9) 2 (0–15)
in the first 5 days compared with 34 All data were not statistically different in the 2 study groups. CRIB indicates clinical risk index for babies.
(33.0%) in the nCPAP group (RR: 0.95
[95% CI: 0.64 –1.41]; P ! .80). The pres-
TABLE 2 Primary Outcome: Need for MV Within 5 Days
ence of twins did not influence the re-
GA, n (%) Prophylactic Surfactant nCPAP RR (95% CI)
sults. Primary outcome in the 2 GA
(N ! 105) (N ! 103)
strata was also similar (Table 2).
25–28 wk 6 d 33 (31.4) 34 (33.0) 0.95 (0.64–1.41)
In the prophylactic surfactant group, 25–26 wk 6 d 15 (46.9) 12 (38.7) 1.21 (0.68–2.16)
10 of 105 newborns could not be extu- 27–28 wk 6 d 18 (24.7) 22 (30.6) 0.81 (0.47–1.37)

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TABLE 3 Death and Type of Survival
Outcome 28 d of Age 36 wk Postmenstrual Age
Prophylactic Surfactant, nCPAP, RR (95% CI) Prophylactic Surfactant, nCPAP, RR (95% CI)
n (%) n (%) n (%) n (%)
Survivors in room air 43 (41.0) 32 (31.1) 1.32 (0.91–1.90) 82 (78.1) 81 (78.6) 0.99 (0.86–1.14)
Survivors with oxygen only 11 (10.5) 15 (14.6) 0.72 (0.35–1.49) 5 (4.8) 5 (4.9) 0.98 (0.29–3.29)
Survivors on respiratory 44 (41.9) 47 (45.6) 0.92 (0.67–1.25) 9 (8.6) 6 (5.8) 1.47 (0.54–3.99)
support (MV or nCPAP)
Death
25–28 wk 6 d 7 (6.7) 9 (8.7) 0.76 (0.30–1.97) 9 (8.6) 11 (10.7) 0.80 (0.35–1.86)
25–26 wk 6 d 2 (6.3) 3 (9.7) 0.65 (0.13–3.10) 4 (12.5) 3 (9.7) 1.29 (0.34–4.96)
27–28 wk 6 d 5 (6.8) 6 (8.3) 0.82 (0.27–2.45) 5 (6.8) 8 (11.1) 0.71 (0.20–2.61)

TABLE 4 Secondary Outcomes however, these trials were performed

Outcomes Prophylactic Surfactant nCPAP RR (95% CI) when prenatal steroid use was very
(N ! 105), n (%) (N ! 103), n (%) low (%20%) compared with 96% to
Pneumothorax 7 (6.7) 1 (1.0) 6.82 (0.86–53.75)
98% in our study. The increased use of
Pulmonary interstitial emphysema 3 (2.9) 4 (3.9) 0.74 (0.17–3.21)
Pulmonary hemorrhage 3 (2.9) 2 (1.9) 1.47 (0.25–8.76) prenatal steroids may be 1 of the rea-
Intraventricular hemorrhage grades 3–4 6 (5.7) 8 (7.8) 0.73 (0.27–2.03) sons for not finding a difference be-
25–26 wk 6 d 3 (9.4) 4 (12.9) 0.73 (0.19–2.75) tween our 2 study groups. Less likely,
27–28 wk 6 d 3 (4.1) 4 (5.6) 0.74 (0.19–2.89)
Patent ductus arteriosus 43 (41.0) 51 (49.5) 0.83 (0.62–1.10) the protective effect of surfactant may
Medically treated 28 (26.7) 35 (34.0) have been masked by the period of MV
Surgically ligated 6 (5.7) 3 (2.9) within 1 hour after the surfactant ad-
Retinopathy of prematurity
Any 30 (28.6) 30 (29.1) 0.98 (0.65–1.48) ministration.26 Although, according to
Stage !2 7 (6.7) 7 (6.8) 0.98 (0.36–2.70) the protocol, extubation was recom-
Necrotizing enterocolitis 7 (6.7) 9 (8.7) 0.76 (0.30–1.90) mended as soon as possible after sur-
Cystic periventricular leukomalacia 3 (2.9) 2 (1.9) 1.47 (0.25–8.76)
Sepsis 45 (42.9) 43 (41.7) 1.02 (0.75–1.40) factant administration, the precise du-
Moderate and severe BPD in survivors ration of intubation was not recorded.
25–28 wk 6 d 14/98 (14.3) 11/94 (11.7) 1.22 (0.58–2.50) Conversely, the limit of 1 hour to per-
25–26 wk 6 d 7/30 (23.3) 7/28 (25.0) 0.93 (0.38–2.30)
27–28 wk 6 d 7/68 (10.3) 4/66 (6.1) 1.70 (0.55–5.30) form the surfactant administration
Use of systemic postnatal 14 (13.3) 11 (10.7) 1.25 (0.59–2.62) procedure in these very preterm new-
corticosteroids borns seemed a good compromise be-
tween speed and safety and reflects
standard clinical practice.27
median (range) hours of mechanical DISCUSSION A systematic review of studies that com-
ventilation were 128.8 (1–1466) and Early nCPAP, surfactant treatment, and pared InSurE with later selective surfac-
132.8 (1–2698) in the 2 study groups, MV are established interventions for tant treatment followed by MV showed
respectively (P ! .33). treatment of neonatal RDS. These a reduced need for MV in newborns
Fifty (48.5%) infants in the nCPAP methods complement each other, al- who were treated with the former ap-
group needed early selective surfac- though the optimal strategy remains proach.27 The authors concluded that
tant at a median age of 240 minutes to be confirmed. Our study shows that, RCTs of prophylactic surfactant adminis-
(range: 10 –5728 minutes). Fourteen in spontaneously breathing preterm tration with rapid extubation compared
(13.3%) infants in the prophylactic sur- newborns who were treated with with later, selective surfactant therapy
factant group needed a second dose of nCPAP, prophylactic surfactant given were needed. A recent retrospective
surfactant compared with 11 (10.6%) within 30 minutes of birth was not su- study showed that the majority of infants
in the nCPAP group (RR: 1.25 [95% CI: perior to early selective surfactant in who were "28 weeks’ GA and were ini-
0.59 –2.62]; P ! .56). Three or more terms of requirement of MV in the first tially intubated, given surfactant, and
doses of surfactant were given to 3 5 days of life. Prophylactic surfactant thereafter placed on nCPAP could be
(2.8%) infants in the prophylactic sur- treatment within 15 minutes of birth maintained on nCPAP alone.28
factant group and to 3 (2.9%) infants in reduced mortality compared with We considered that prophylactic In-
the nCPAP group. later selective surfactant treatment25; SurE needed a randomized trial to de-

e1406 SANDRI et al
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termine whether it offers additional
advantage over the early selective In-
SurE. Our findings suggest that in
spontaneously breathing newborns of
25 to 28 weeks’ GA, it is possible to ini-
tiate nCPAP and treat with surfactant
later only when they show signs of
RDS, which in our population occurred
in 48.5% of cases. The not statistically
significant trend toward a higher re-
quirement of MV in infants who received
prophylactic surfactant compared with
those who received early selective treat-
ment in the lower GA stratum confirms
the validity of this approach also in the
more preterm infants.
Nearly one-third of infants in our study
required MV in the first 5 days of life, in
both study groups. This rate is lower
than the estimated 50% at the time our
trial began and is also lower com-
pared with the COIN trial,11 which re-
ported a need for endotracheal intuba-
tion and MV in 46% of infants who were
of 25 to 28 weeks’ GA and randomly
assigned to receive nCPAP at birth;
however, in that study and in the
CURPAP participating centers in the
pretrial period, extubation after sur-
factant instillation was not planned or
standardized. Actually, in the CURPAP
trial, 50 (48.5%) of 103 infants in the
nCPAP group were intubated to receive
surfactant, but MV was required only
in 34 (33%) of 103 because 16 (15.5%)
of 103 were successfully extubated
and avoided MV within 5 days of life. In
summary, our results show that nearly
one-third of infants who were intu-
bated for surfactant administration
can be successfully extubated to
nCPAP at these low GAs.
The main reasons for MV were increas-
ing oxygen requirement and apnea. In
this study, MV after surfactant instilla-
tion was started when FIO2 require-
ment was #0.4. Some NICUs use a
more conservative approach, starting
MV at an FIO2 value of #0.6. Moreover,
other, recent ventilatory strategies,
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such as nasal intermittent positive
pressure ventilation or bilevel CPAP,
were not allowed in this study.
Whether these approaches could have
further reduced the need for MV in our
group of infants of 25 to 28 weeks’ GA
remains an open issue that needs ad-
ditional investigation.
Our study showed a very good respira-
tory outcome in the whole population:
78% to 79% of infants, in both arms,
survived without any supplemental ox-
ygen or respiratory support at 36
weeks’ postmenstrual age. The inci-
dences of moderate/severe BPD were
14.3% and 11.7%, respectively, in the
prophylactic surfactant and nCPAP
groups; that is lower than the 30% in-
cidence reported in other studies.29,30
The need for oxygen treatment among
survivors was also lower than in the
COIN trial of a comparable population
treated with a very similar approach11;
however, that study differed from ours
in a number of ways. First, in the nCPAP
group, surfactant was given to infants
who were intubated for MV when they
needed #60% rather than 40% oxygen.
Second, there was no immediate extu-
bation to nCPAP. Third, surfactant was
not administered to all intubated in-
fants, and the proportion of infants
who were treated with surfactant was
lower than in our nCPAP group (38%
vs 48.5%); therefore, the respiratory
management used in our study com-
bining extensive use of nCPAP with ei-
ther prophylactic or early selective
surfactant seems to be both safe and
efficacious in spontaneously breathing
infants of 25 to 28 weeks’ GA.
Previous studies reported an in-
creased incidence of pneumothorax in
nCPAP-treated compared with MV-
treated newborns or no treatment.11,31
The use of prophylactic or early surfac-
tant therapy has been associated with
a decreased risk for pneumothorax.27
In our study, the combination of nCPAP
with prophylactic or early surfactant
ARTICLES
treatment resulted in an overall inci-
dence of pneumothorax of 3.8%; 6 of
the 8 infants who developed pneumo-
thorax were on MV at the time of pneu-
mothorax diagnosis. This incidence is
lower than that reported in other stud-
ies.11,32 In newborns who were allo-
cated to receive nCPAP in the delivery
room, the COIN trial11 reported an inci-
dence of pneumothorax of 9.1% com-
pared with 1.0% in the CURPAP trial.
The earlier administration of surfac-
tant and the lower rate of mechani-
cally ventilated infants in the CURPAP
compared with the COIN trial could
explain this difference. In fact, in the
CURPAP trial, the median age for surfac-
tant administration in the nCPAP group
was 4.0 hours compared with 6.6 hours
for intubation in the COIN trial, and the
rate of mechanically ventilated new-
borns was 33% compared with 46%.
Infants who were treated with prophy-
lactic surfactant tended to have a
higher rate of pneumothorax com-
pared with the nCPAP group (6.7% vs
1.0%), although this difference was not
statistically significant. A recent study
that investigated risk factors for pneu-
mothorax concluded that only factors
that were present on the day of pulmo-
nary air leak were independently asso-
ciated with this outcome.32 In our pop-
ulation, only 2 infants developed a
pneumothorax on the day of random-
ization, suggesting that treatment allo-
cation did not influence this outcome;
however, we cannot exclude that in
some infants who were in the prophy-
lactic surfactant group and had more
compliant lungs, the administration of
surfactant coupled with positive pres-
sure ventilation through an endotra-
cheal tube may have induced pulmonary
damage, eventually leading to air leaks.
The incidences of other complications
related to prematurity were not signif-
icantly different between the 2 treat-
ment groups and did not differ sub-
stantially from those of the COIN trial.11
e1407
The relatively high frequency of sepsis
in our population could be attributed
to the broad criteria used to define it.
The durations of MV and hospitaliza-
tion were almost identical in the 2
study groups and in line with previous
results.11 Also, the use of additional
doses of surfactant after the first pro-
phylactic or early selective dose did not
differ significantly between the groups.
CONCLUSIONS
The main implication for clinical
practice of this study is that nCPAP
should be started soon after birth in
spontaneously breathing infants of
25 to 28 weeks’ GA and early selective
surfactant should be given once
signs of respiratory distress have
developed. With this strategy, #50%
of infants will need only nCPAP, 48.5%
will need intubation and surfactant,
and nearly one-third will need MV in
the first 5 days of life. These results
are particularly reliable, because
nearly 85% of eligible newborns
were randomly assigned.
These conclusions can be applied to
a population of infants who are born
between GAs of 25 weeks 0 days and
28 weeks 6 days and do not require
intubation at birth, representing the
majority of infants who were as-
sessed for eligibility in our study.
Moreover, the use of prenatal ste-
roids was very high in our study, and
it is possible that in other settings
the results might be different.
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ACKNOWLEDGMENTS
This study was funded by Chiesi Farma-
ceutici SpA (Parma, Italy).
Participating investigators and study
centers are listed according to the
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Republic: Z. Stranak, I. Berka, J. Meli-
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e1409
 Prophylactic or Early Selective Surfactant Combined With nCPAP in Very
Preterm Infants
Fabrizio Sandri, Richard Plavka, Gina Ancora, Umberto Simeoni, Zbynek Stranak,
Stefano Martinelli, Fabio Mosca, José Nona, Merran Thomson, Henrik Verder, Laura
Fabbri, Henry Halliday and for the CURPAP Study Group
Pediatrics 2010;125;e1402; originally published online May 3, 2010;
DOI: 10.1542/peds.2009-2131
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/125/6/e1402.full.
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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 Prophylactic or Early Selective Surfactant Combined With nCPAP in Very
Preterm Infants
Fabrizio Sandri, Richard Plavka, Gina Ancora, Umberto Simeoni, Zbynek Stranak,
Stefano Martinelli, Fabio Mosca, José Nona, Merran Thomson, Henrik Verder, Laura
Fabbri, Henry Halliday and for the CURPAP Study Group
Pediatrics 2010;125;e1402; originally published online May 3, 2010;
DOI: 10.1542/peds.2009-2131

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/125/6/e1402.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Dahlgren Medical Library on March 10, 2015