DOI: 10.1542/peds.

2010-0922
; originally published online January 24, 2011; 2011;127;300 Pediatrics
Jucille Meneses, Vineet Bhandari, Joao Guilherme Alves and Delia Herrmann
Controlled Trial
Noninvasive Ventilation for Respiratory Distress Syndrome: A Randomized

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Noninvasive Ventilation for Respiratory Distress
Syndrome: A Randomized Controlled Trial
WHATS KNOWN ON THIS SUBJECT: Nasal continuous positive
airway pressure (NCPAP) has been the initial respiratory support
for many preterm infants with respiratory distress syndrome (RDS).
Nasal intermittent positive-pressure ventilation (NIPPV) seems to
increase the benecial effects of NCPAP by combining it with
ventilatory inations.
WHAT THIS STUDY ADDS: This study suggests that NIPPV, as an
intial respiratory support for preterm infants with RDS, is
feasible and safe and may have benecial effects, when
compared with NCPAP.
abstract
CONTEXT: Strategies for reducing exposure to endotracheal ventila-
tion through the use of early noninvasive ventilation has proven to be
safe and effective, but the option with the greatest benets needs to be
determined.
OBJECTIVE: To determine, in infants with respiratory distress syn-
drome, if early nasal intermittent positive-pressure ventilation (NIPPV)
compared with nasal continuous positive airway pressure (NCPAP)
decreases the need for mechanical ventilation.
PATIENTS AND METHODS: In this single-center, randomized controlled
trial, infants (gestational ages 26 to 33
6
7 weeks) with respiratory dis-
tress syndrome were randomly assigned to receive early NIPPV or
NCPAP. Surfactant was administered as rescue therapy. The primary
outcome was the need for mechanical ventilation within the rst 72
hours of life.
RESULTS: A total of 200 infants, 100 in each arm, were randomly as-
signed. Rates of the primary outcome did not differ signicantly be-
tween the NIPPV (25%) and NCPAP (34%) groups (relative risk [RR]: 0.71
[95% condence interval (CI): 0.481.14]). In posthoc analysis, from 24
to 72 hours of life, signicantly more infants in the NIPPV group re-
mained extubated compared with those in the NCPAP groups (10 vs
22%; RR: 0.45 [95%CI: 0.220.91]). This difference was also noted in the
group of infants who received surfactant therapy, NIPPV (10.9%), and
NCPAP (27.1%) (RR: 0.40 [95% CI: 0.180.86]).
CONCLUSIONS: Early NIPPV did not decrease the need for mechanical
ventilation compared with NCPAP, overall, in the rst 72 hours of life.
However, further studies to assess the potential benets of noninva-
sive ventilation are warranted, especially for the most vulnerable or
preterm infants. Pediatrics 2011;127:300307
AUTHORS: Jucille Meneses, MD, DM,
a
Vineet Bhandari,
MD, DM,
b
Joao Guilherme Alves, MD, DM,
a
and Delia
Herrmann, MD, DM
c
a
Department of Pediatrics, Instituto de Medicina Integral Prof
Fernando Figueira (IMIP), Recife, Brazil;
b
Department of
Pediatrics, Yale University School of Medicine, New Haven,
Connecticut; and
c
Department of Pediatrics, University of
Alagoas, Maceio, Brazil
KEY WORDS
respiratory distress syndrome, preterm infant, noninvasive
ventilation
ABBREVIATIONS
ETTendotracheal tube
MVmechanical ventilation
BPDbronchopulmonary dysplasia
NCPAPnasal continuous positive airway pressure
RDSrespiratory distress syndrome
PPVpositive-pressure ventilation
NIPPVnasal intermittent positive-pressure ventilation
SNIPPVsynchronized nasal intermittent positive-pressure
ventilation
RCTrandomized controlled trial
BWbirth weight
PDApatent ductus arteriosus
RRrelative risk
CIcondence interval
This trial has been registered at www.clinicaltrials.gov (identi-
er NCT00821119).
www.pediatrics.org/cgi/doi/10.1542/peds.2010-0922
doi:10.1542/peds.2010-0922
Accepted for publication Nov 17, 2010
Address correspondence to Jucille Meneses, MD, MS, Rua Dom
Jose Lopes 955, Apt 1801, PE 51021-370, Recife, Brazil. E-mail:
jmeneses@elogica.com.br
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2011 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.
300 MENESES et al
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Noninvasive ventilation, ventilatory
support that does not use an invasive
articial airway such as an endotra-
cheal tube (ETT), has been increasingly
used to reduce mechanical ventilation
(MV) in preterm infants and subse-
quently lower the incidence of bron-
chopulmonary dysplasia (BPD).
1,2
Nasal continuous positive airway
pressure (NCPAP) has been the initial
respiratory support for preterm in-
fants with respiratory distress syn-
drome (RDS) and has become an es-
tablished practice in many centers.
3,4
Studies have revealed benecial ef-
fects when combining early surfactant
treatment by transient intubation (the
intubation, surfactant treatment, and
extubation [INSURE] approach) fol-
lowed by NCPAP to further reduce the
risk of invasive ventilation
58
while
demonstrating a trend toward a lower
incidence of BPD.
79
However, not all in-
fants who are given early NCPAP can be
successfully managed, and studies
have revealed failure rates that range
from 25% to 50%,
2,8,1012
which has en-
couraged the use of nasal intermittent
positive-pressure ventilation (NIPPV)
to reduce these failure rates.
NIPPV is noninvasive ventilation that in-
creases the benecial effects of NCPAP
by combining it with ventilatory ina-
tions and, therefore, decreasing the
need for ETT ventilation.
13,14
It can be
used in a synchronized (SNIPPV) or
nonsynchronized manner to supple-
ment the infants own breathing ef-
forts.
15
Kiciman et al
16
found reduced
thoracoabdominal motion asynchrony
during SNIPPV when compared with
NCPAP. Aghai et al
17
revealed that
SNIPPV decreases the work of breath-
ing in preterm infants. SNIPPV in-
creased tidal volume and minute vol-
ume when compared with NCPAP.
18
Trials have found that NIPPV decreases
the rate of extubation failure, without
adverse gastrointestinal complica-
tions, in preterm infants when com-
pared with NCPAP.
1921
The initiation of MV in the rst days of a
preterm infant is a major factor for
BPD and ventilator-associated morbid-
ities.
22,23
Two randomized controlled
trials (RCTs) have revealed that early
NIPPV reduced the need for endotra-
cheal intubation within the rst 72
hours of life when compared with
NCPAP. Kugelman et al
24
found a signi-
cant difference in the total cohort (11
of 43 [25%] in the NIPPV group and 20
of 41 [49%) in the NCPAP group; P
.04) and a similar trend in infants with
a birth weight (BW) of 1500 g (6 of 19
[31%] and 13 of 21 [62%], respectively;
P .06). They also reported that fail-
ure of NIPPV was associated with
lower BW. Subsequently, Sai Sunil
Kishore et al
25
demonstrated that the
need for MV at 48 hours was signi-
cantly less among the infants in the
NIPPV group (13.5% vs 35.9%).
We conducted a single-center, pro-
spective RCT using standardized proto-
cols for intubation and surfactant
therapy. The primary outcome of the
study was to assess the need for intu-
bation within the rst 72 hours of life
after random assignment to early
NIPPV or NCPAP.
METHODS
Subjects
This single-center RCT was conducted
from August 2007 to September 2009
at the Instituto de Medicina Integral
Prof Fernando Figueira in an inborn
tertiary NICU and approved by the insti-
tutional research ethics committee.
Preterm infants were eligible if gesta-
tional age was 26 to 33
6
7 weeks and
there was clinical evidence of respira-
tory distress. Small for gestational age
was classied according to Alexander
et al.
26
Parental written informed con-
sent was required before delivery of
the potentially eligible infants. Infants
were excluded for any of the following
reasons: major congenital anomalies;
presence of cardiovascular instability;
intubation at admission to the NICU;
consent not provided or refused; or un-
availability of a ventilator. Infants were
resuscitated according to Neonatal Re-
suscitation Program guidelines.
27
Study Intervention
Randomization was performed by
using random-number, computer-
generated protocol, and sequentially
numbered sealed opaque envelopes
that contained the group assignments
were prepared. Infants from multiple
births were randomly assigned indi-
vidually. When the infant was admitted
to the NICU and had fullled the entry
criteria, the envelope was opened and
the allocated treatment, NCPAP or
NIPPV, was started immediately.
We used a time-cycled, pressure-
limited, and continuous-ow neonatal
ventilator (Inter Neo, Intermed Inc, Sao
Paulo, Brazil) for infants assigned to
the NIPPV group, in the nonsynchro-
nized mode. The initial settings were:
frequency of 20 to 30 breaths per
minute, peak inspiratory pressure of
15 to 20 cm H
2
O, peak end expiratory
pressure of 4 to 6 cm H
2
O, inspiratory
time of 0.4 to 0.5 seconds, and a ow
rate of 8 to 10 L/minute. Infants ran-
domly assigned to the NCPAP group
were initiated on a pressure of 5 to 6
cm H
2
O and a ow of 8 to 10 L/minute
by an underwater seal (Bubble CPAP
system [Intermed Inc]). Short binasal
prongs were used, and settings were
adjusted to target a pulse oxygen sat-
uration between 88% to 92%.
The diagnosis and severity of RDS were
based on clinical signs along with Keros
and Makinens radiologic classication.
28
Infants were maintained in their allo-
cated treatment at least during the
rst 72 hours, because crossover was
not allowed. Surfactant (Curosurf
[Chiesi Pharmaceuticals, Parma, It-
aly]) was administered, 100 mg/kg per
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dose, as a rescue treatment by the
INSURE (intubation, surfactant treat-
ment, and extubation) approach if in-
fants needed invasive MV or if they
were on noninvasive ventilation that
required a fraction of inspired oxygen
of 0.50 to maintain the targeted sat-
uration of 88%to 92%. We gave a sec-
ond dose if the infants needed a frac-
tion of inspired oxygen of 0.40 to
maintain the targeted saturation. If in-
fants were intubated for surfactant in
the rst 72 hours, they were extubated
to their allocated mode. Subjects were
weaned from NIPPV or NCPAP accord-
ing to our standard nursery practice.
After 72 hours of life, infants in the
NIPPV group could be weaned to NCPAP
and later to nasal cannula. Infants in
the NCPAP group were also weaned to
nasal cannula. Prophylactic methyl-
xanthines were used in all infants.
Primary and Secondary Outcomes
The primary outcome was to assess
the need for intubation within the rst
72 hours of life in the 2 groups. The
criteria for failure were met by at
least 1 of the following: pH 7.20
and PaCO
2
60 mm Hg; recurrent ap-
nea with 3 episodes per hour asso-
ciated with bradycardia; a single
episode of apnea that required bag-
and-mask ventilation; and a PaO
2

50 mm Hg with a fraction of inspired
oxygen of 0.5.
The secondary outcomes concerning
respiratory support were total dura-
tion on ETT ventilation, total duration
on NCPAP, total duration on supple-
mental oxygen, incidence of pneumo-
thorax, and BPD. BPD was dened ac-
cording to the National Institutes of
Health consensus denition.
29
Other
outcomes included incidence of patent
ductus arteriosus (PDA), necrotizing
enterocolitis, intraventricular hemor-
rhage grades 3 and 4, retinopathy of
prematurity stage 3, time to full
feeds, and length of hospital stay. PDA
was conrmed by echocardiography,
and intraventricular hemorrhage was
dened by using the Papile classica-
tion.
30
Necrotizing enterocolitis was
classied according to Bells classi-
cation, as modied by Kliegman and
Walsh,
31
at stage II or greater. Retinop-
athy of prematurity was dened ac-
cording to the international classica-
tion of retinopathy of prematurity.
32
Full feeds were dened as feeds that
reached 130 to 150 mL/kg per day.
Statistical Analysis
On the basis of previous data from our
NICU, 40% to 45% of our preterm in-
fants administered early NCPAP and
rescue surfactant treatment for RDS
needed intubation and MV within the
rst 72 hours of life. We estimated a
20% absolute reduction in the need to
use ETT ventilation with the early use of
NIPPV. A sample size of 100 infants per
group was calculated with a power of
80% and an error rate of 5%.
Categorical variables were compared
by using
2
or Fishers test, as needed.
Students t test was used for continu-
ous variables with a normal distribu-
tion, and for skewed distribution,
Mann-Whitneys test was used. The
analysis was performed according to
the intention-to-treat principle.
RESULTS
In total, 423 infants were assessed for
eligibility and 223 were excluded. Of
these infants, 64 were excluded be-
cause of clinical conditions that did not
meet the eligibility criteria. Consent
was not obtained for 82 eligible infants
(the mother was admitted in labor and
there was a lack of time before deliv-
ery, the consent formwas not found, or
the study members were not aware
of the admission or were unable to
reach the parents in the appropriate
time). Fourteen parents refused con-
sent, and 63 infants were eligible but
did not get randomly assigned be-
cause there was no ventilator avail-
able in the NICU and, hence, were
placed on bubble CPAP. As a result, 100
infants were randomly assigned to early
NCPAP and 100 to early NIPPV (Fig 1).
Table 1 lists the demographic and clin-
ical characteristics of both groups.
The high proportion of small for gesta-
tional age (40.5%) is reective of a low-
income population with a high incidence
of pregnancy-induced hypertension
(36%). Infants who received PPV in the
delivery roomwere equally distributed
among the groups (NCPAP, 35%; NIPPV,
32%). Eighteen (9%) all the infants
were intubated for resuscitation and
then extubated on admission to the
NICU; 10 were randomly assigned to
NCPAP and 8 to NIPPV.
The rates of the primary outcome did
not differ signicantly between the
NIPPV and NCPAP groups (relative risk
[RR]: 0.71 [95% condence interval
(CI): 0.481.14]) (Table 2) or in the sub-
group of infants who received surfac-
tant therapy (Table 3).
In the posthoc subgroup analysis of
the primary outcome, a signicant dif-
ference was found between the NIPPV
and NCPAP groups during the period
from 24 to 72 hours (RR: 0.45 [95% CI:
0.220.91]), which was also present in
the group of infants who received sur-
factant, NIPPV, and NCPAP (RR: 0.40
[95% CI: 0.180.86]).
Infants with a BW of 1000 g had a
signicantly decreased failure rate in
the NIPPV group when compared with
those in the NCPAP group (P .03), but
no difference between the groups was
found in infants with a BW of 1000 g
(P .65).
In the NCPAP group, 36 infants never
got intubated and 30 never got surfac-
tant; 18 (18%) never got intubated or
received surfactant. In the NIPPV
group, 42 never got intubated and 27
never received surfactant; 19 (19%)
never got intubated or received surfac-
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tant. We found no difference between
the groups.
In this study, noninvasive ventilation
failed for 59 infants in the rst 72
hours, and it failed for 27 (45.7%) of
them in the rst 24 hours. PPV was
given to 9 of 27 (33.3%) infants (by self-
inating bag and mask for 3 infants
and with an ETT for the other 6 infants).
These 6 infants were extubated in the
delivery room after recovery and then
admitted to the NICU; 3 infants were
randomly assigned to the CPAP group
and 3 to the NIPPV group. All 27 infants
received surfactant therapy, 19 (70%)
required 2 doses, 18 (65%) had RDS
classied as moderate, and the mean
time to ETT intubation was 12.3 6.8
hours, which suggests an initially
more severe form of respiratory dis-
ease. Five of the 27 infants (18.5%) had
early sepsis.
In the NIPPV group (n 100), noninva-
sive ventilation failed for 25 infants in
the rst 72 hours, and 75 infants were
able to be weaned to NCPAP. However,
33 of 75 (44%) infants later needed MV
at median day of life 13. A total of 58
infants needed MV in the NIPPV group,
45 (77%) because of recurrent/signi-
cant apneic episodes.
In the NCPAP group (n 100), noninva-
sive ventilation failed for 34 infants in
the rst 72 hours, and 66 infants were
able stay on NCPAP. However, 30 of 66
(45%) infants later needed MV at me-
dian day of life 12. A total of 64 infants
in the NCPAP group needed MV, 55
(86%) because of recurrent apnea that
did not respond to a trial of NIPPV.
The overall rate of BPD was the same in
both groups (Table 2). Of the 20 infants
with BPD in the NCPAP group, 16 sur-
vived (80%), whereas in the NIPPV
group, 18 of 22 infants with BPD sur-
vived (85.7%); this result was not sig-
nicantly different (P .88). In this
study, 4 of 80 (5%) infants in the NCPAP
group and 9 of 83 (10.8%) infants in the
NIPPV group had moderate or severe
BPD, but this was not signicant (P
.16). In the NCPAP group, 57 of 74 (77%)
survived with no BPD, which was simi-
lar to results for the NIPPV group (61 of
78 [78%]; P .86).
No signicant differences were noted
between the 2 treatment groups for
the other secondary respiratory out-
comes (Table 2). All other clinical out-
comes were not different among the 2
treatment groups (Table 4).
DISCUSSION
In this single-center randomized trial,
we found a reduced need for ETT intu-
bation and MV overall within the rst
72 hours in the NIPPV group (25%)
when compared with NCPAP (34%)
Assessed for eligibility (N = 423)
Excluded (n = 223)
Did not meet inclusion criteria (n = 64)
Parents declined to participate (n = 14)
Consent not obtained (n = 82)
Had consent but ventilator unavailable (n = 63)
Randomly assigned
(n = 200)
Allocated to NCPAP (n = 100)
Received allocated intervention (n = 100)
Lost to follow-up (n = 0)
Allocated to NIPPV (n = 100)
Received allocated intervention (n = 100)
Lost to follow-up (n = 0)
Analyzed (n = 100) Analyzed (n = 100)
E
n
r
o
l
l
m
e
n
t
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o
n
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i
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FIGURE 1
Flowchart of the participants.
TABLE 1 Demographic and Clinical Data in the Study Groups
Characteristic NCPAP (N 100) NIPPV (N 100)
Pregnancy-induced hypertension, n (%) 37 (37) 35 (35)
Antenatal steroids, any, n (%) 76 (76) 72 (72)
Cesarean deliveries, n (%) 59 (59) 50 (50)
Multiple births, n (%) 16 (16) 17 (17)
Male gender, n (%) 49 (49) 51 (51)
Delivery-room resuscitation (need for PPV), n (%) 35 (35) 32 (32)
Apgar score at 1 min, median (IQR) 7 (29) 7 (29)
Apgar score at 5 min, median (IQR) 8 (410) 8 (510)
Gestational age, mean SD, wk 30.1 2.3 29 1.6
BW, mean SD, g 1151 289 1112 252
SGA, n (%) 42 (42) 39 (39)
RDS, n (%)
Mild 77 (77) 78 (78)
Moderate 23 (23) 22 (22)
None of the differences between groups were signicant. IQR indicates interquartile range; SGA, small for gestational age
(below the 10th centile).
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(not signicant). Although this nding
could mean that there was actually no
difference with the 2 approaches, the
effect could have been masked be-
cause of sample size or affected by
other factors (see below). In an at-
tempt to better understand the rea-
sons for success/failure using the
nasal-ventilation approach over the
rst 72 hours, we conducted a posthoc
subgroup analysis. During the period
from 24 to 72 hours, a signicant de-
crease was found in the NIPPV group
when compared with infants randomly
assigned to NCPAP. This nding was
similar in the group of infants who re-
quired surfactant.
In this cohort of 59 infants for whom
noninvasive ventilation failed in the
rst 72 hours of life, it failed for 27
(47.5%) of them in the rst 24 hours.
The rst 24 hours of life is a crucial
period for preterm infants with RDS,
and most of themwill respond to respi-
ratory support and surfactant therapy.
Yet, 20% of preterm infants are con-
sidered poor responders.
33,34
In addi-
tion, there is a group of sick infants
with major risk factors such as: resus-
citation in the delivery room, severe
form of respiratory disease, presence
of chorioamnionitis, and early sepsis.
These factors may Contribute to a
more progressive respiratory failure
that requires invasive MV.
35,36
The 27
infants for whom noninvasive ventila-
tion failed in the rst 24 hours had ini-
tially a more severe respiratory
course because they required more
aggressive care in the delivery room
and more respiratory support and
doses of surfactant and, subsequently,
had an early need for ETT ventilation
and MV. It is possible that such infants
are more prone to early atelectasis,
which could not be overcome by in-
creased ventilator settings, which re-
sults in failure of NIPPV and reintuba-
tion, as was recently suggested.
13
In a recent RCT, Moretti et al
37
demon-
strated that more infants were suc-
cessfully extubated to SNIPPV when
compared with NCPAP (94% vs 61%).
The main causes of extubation failure
in the NCPAP group were respiratory
acidosis and apneic episodes adding
TABLE 2 Respiratory Support and BPD Outcome in the Study Groups
Outcome NCPAP
(N 100)
NIPPV
(N 100)
RR With NIPPV
(95% CI)
Adjusted
P
Failure of NIV at 72 h, n (%) 34 (34) 25 (25) 0.70 (0.481.14) .16
Failure of NIV in the rst 24 h, n (%) 12 (12) 15 (15) 1.25 (0.612.53) .53
Failure of NIV at 2448 h, n (%) 12 (12) 5 (5) 0.41 (0.151.13) .08
Failure of NIV at 4872 h, n (%) 10 (10) 5 (5) 0.50 (0.171.41) .19
Failure of NIV at 2472 h, n (%) 22 (22) 10 (10) 0.45 (0.220.91) .02
Failure of NIV, n/N (%)
Infants 1000 g 9/37 (24) 11/38 (29) 1.19 (0.552.53) .65
Infants 1000 g 25/63 (39) 14/62 (22) 0.56 (0.320.98) .04
Need for MV, n (%) 64 (64) 58 (58) 0.90 (0.721.13) .38
Total time on MV, median (IQR), d 5 (138) 7 (173) .14
Total time of NCPAP, mean SD, d 9.4 8.9 9.6 6.8 .65
Total time of nasal cannula, mean SD, d 6.1 7 6.8 0.4 .46
Total time of oxygen, mean SD, d 20.4 16 23.6 22.6 .97
BPD, n/N (%)
a
20/80 (25) 22/83 (26.5) 1.06 (0.621.78) .82
Mild
a
16/80 (20) 13/83 (15.6) 0.78 (0.401.52) .46
Moderate
a
1/80 (1.2) 3/83 (7.2) 2.89 (0.3027.2) .32
Severe
a
3/80 (3.7) 6/83 (7.2) 1.90 (0.497.40) .34
NIV indicates noninvasive ventilation; IQR, interquartile range.
a
Denominator survivors to 36 weeks postmenstrual age.
TABLE 3 Respiratory Support and BPD Outcome in the Study Groups of Infants Who Received
Surfactant
Outcome NCPAP (N 70) NIPPV (N 70) RR With NIPPV
(95% CI)
Adjusted
P
Failure of NIV at 72 h, n (%) 31 (44.2) 23 (31.5) 0.71 (0.461.09) .11
Failure of NIV in the rst 24 h, n (%) 12 (17.1) 15 (20.5) 1.19 (0.602.37) .60
Failure of NIV at 2448 h, n (%) 11 (15.7) 4 (5.4) 0.34 (0.111.04) .05
Failure of NIV at 4872 h, n (%) 8 (11.4) 4 (5.4) 0.48 (0.151.54) .22
Failure of NIV at 2472 h, n (%) 19 (27.1) 8 (10.9) 0.40 (0.180.86) .01
Dose of surfactant, median (IQR) 1 (12) 1 (12) .29
Surfactant rescue doses, n (%) 29 (41.4) 24 (32.8) 0.79 (0.511.22) .29
Time of surfactant, median (IQR), h 3 (136) 3 (144) .82
BPD, n/N (%)
a
15/55 (27.3) 19/60 (31.7) 1.16 (0.652.05) .60
NIV indicates noninvasive ventilation; IQR, interquartile range.
a
Denominator survivors to 36 weeks postmenstrual age.
TABLE 4 Neonatal Outcomes in the Study Groups
Outcome NCPAP
(N 100)
NIPPV
(N 100)
RR With NIPPV
(95% CI)
Adjusted
P
Pneumothorax, n (%) 5 (5) 3 (3) 0.60 (0.142.44) .47
PDA, n (%) 29 (29) 25 (25) 0.86 (0.541.36) .52
PDA, indomethacin, n (%) 24 (24) 16 (16) 0.66 (0.371.17) .16
PDA, ligation, n (%) 6 (6) 4 (4) 0.66 (0.190.29) .51
NEC, n (%) 9 (9) 5 (5) 0.55 (0.191.50) .27
IVH, grades 3 and 4, n/N (%)
a
6/75 (8) 6/73 (8.2) 1.02 (0.343.00) .96
ROP stage 3, n/N (%)
b
8/71 (11.2) 10/64 (15.6) 1.38 (0.583.20) .45
Time to full feeds, mean SD, d 18.3 8.1 17.9 9.9 .49
Duration of hospitalization, mean SD, d 53.9 19.15 55.9 20.5 .45
Survival to discharge, n (%) 74 (74) 78 (78) 1.05 (0.901.23) .50
Survival with no BPD, n/N (%) 57/74 (77) 61/78 (78) 1.01 (0.851.20) .86
NEC indicates necrotizing enterocolitis; IVH, intraventricular hemorrhage; ROP, retinopathy of prematurity.
a
Denominator infants submitted to cranial ultrasound scans.
b
Denominator infants submitted to examination by ophthalmologist.
304 MENESES et al
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up to 75% of the cases, which were not
present in the SNIPPV group. The au-
thors suggested that the most impor-
tant effect of SNIPPV might be that of
stimulating breathing. We believe that
the results of our subgroup analysis,
during the period from 24 to 72 hours,
provide clinically relevant information,
because during the rst few days of
life and especially after the rst 24
hours, when the preterm infant is re-
solving RDS, this apparent advantage
of NIPPV over NCPAP in stimulating
breathing to avoid apnea and hyper-
capnia could play an important role in
avoiding failure of noninvasive ventila-
tion. In addition, we speculate that the
relative success of NIPPV over NCPAP
after 24 hours could be a result of im-
proved pulmonary mechanics, which
results in better alveolar recruitment,
after elimination of those infants with
worse lung function in the rst 24
hours.
Another interesting result was that
among infants with a BW of 1000 g,
NIPPV failure was signicantly lower
when compared with NCPAP, which in-
dicates a more effective approach in
reducing the need for ETT ventilation in
this subgroup of patients. For this
group of infants, we speculate that im-
proved pulmonary mechanics caused
by their relatively larger size contrib-
uted to better alveolar recruitment.
However, caution needs to be main-
tained when interpreting these re-
sults, because the number of infants
with a BWof 1000 g, and especially of
750 g, was small.
A lower incidence of BPD in infants
treated initially with NCPAP when com-
pared with MV has been reported.
22,23
However, 2 multicenter RCTs have not
found a decrease in BPDwhen compar-
ing these 2 ventilatory strategies. The
Continuous Positive Airway Pressure
or Intubation at Birth (COIN) trial found
the outcome of oxygen dependency at
28 days of age lower in the NCPAP
group, although this was not seen at 36
weeks postmenstrual age.
38
The more
recent Surfactant, Positive Pressure
and Pulse Oximetry Randomized Trial
(SUPPORT) revealed no difference in
the primary outcome of death or BPD
between infants assigned to early
NCPAP or early surfactant and MV.
39
Bhandari et al evaluated SNIPPV and
surfactant therapy, compared with
continued ETT MV, and found a signi-
cantly lower primary outcome of BPD/
death in the SNIPPV group.
40
From a
recent trial, Ramanathan et al
41
also
reported a signicant reduction in
physiologic and clinical BPD in the
NIPPV group. Results of these studies
suggest that NIPPV seems to be fea-
sible and effective and results in a
lower incidence of BPD when com-
pared with MV.
The impact of NCPAP compared with
SNIPPV on the incidence of BPD was
evaluated in a large retrospective
study in infants with a birthweight
equaling 1250 g. In the subgroup of
those born at 500 to 750 g, SNIPPV was
associated with a signicant lower in-
cidence of BPD (P .01), as well as the
composite outcome BPD/death (P
.01), when compared with NCPAP.
42
Kugelman et al
24
also found a substan-
tial decrease in the incidence of BPD in
the NIPPV group among the subgroup
of infants born at 1500 g (5% vs 33%;
P .04) when compared with NCPAP.
As we pointed out previously,
43
in addi-
tion to the lower rate of ETT found in
the NIPPV group in this study, higher
tolerance to initial ventilatory settings
and early extubation from MV might
have helped decrease the incidence of
BPD in this group.
We did not nd a difference in the inci-
dence or severity of BPD or the com-
bined outcome of survival without BPD
for infants in the NIPPV versus NCPAP
groups. An important nding was that
there were no gastrointestinal compli-
cations. The incidence of necrotizing
enterocolitis as well as the time to full
feeds was the same in both groups.
Other authors have reported the same
ndings, which emphasizes the safety
of NIPPV.
24,25,4042
This study has some limitations. The
rst limitation concerns potential se-
lection bias; consent was not obtained
for 82 infants, which accounts for 20%
of the eligible infants. This result is
similar to that of the Surfactant Posi-
tive Airway Pressure and Pulse Oxime-
try Randomized Trial, in which the au-
thors found that 5 families needed
to be antenatally identied and
screened for every 1 infant enrolled
successfully in the study.
39
In this
study, 63 infants (15% of the eligible
population) were excluded because
of the unavailability of a ventilator
(ventilators were used for both MV
and NIPPV), which became a practi-
cal limitation to provide NIPPV.
Another limitation of this single-center
study was that the difference found in
failure of noninvasive ventilation in the
NCPAP arm (34%) was lower than that
used for the calculation of our sample
size (40%45%), which was based on
our historical rate. We believe that
multiple factors contributed this dif-
ference: exclusion of infants of 26
weeks gestation; increased antenatal
steroid use; earlier administration of
surfactant; and enhanced use of
NCPAP over time. Per our study de-
sign, we allowed crossover of infants
to other modes of respiratory sup-
port after 72 hours. It is possible that
a longer duration of NIPPV in the rst
postnatal week may have additional
benets.
The strengths of the study include the
RCT design and the use of consistent
standardized protocols established in
our NICU. Given that the majority of the
NICUs do not have access to SNIPPV,
the use of NIPPV and bubble CPAP is
clinically relevant.
ARTICLES
PEDIATRICS Volume 127, Number 2, February 2011 305
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CONCLUSIONS
Our study results suggest that NIPPV is
feasible and safe and may have bene-
cial effects when compared with NC-
PAP, especially for infants with a BW of
1000 g. Further multicenter RCTs
with adequate power, targeted to in-
fants with a BWof 1000 g, are needed
to assess if NIPPV and/or NCPAP as the
rst (soon after birth) or primary (ie,
after a brief intubation and early sur-
factant administration) mode of nonin-
vasive respiratory support can affect
BPD and long-term outcomes.
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DOI: 10.1542/peds.2010-0922
; originally published online January 24, 2011; 2011;127;300 Pediatrics
Jucille Meneses, Vineet Bhandari, Joao Guilherme Alves and Delia Herrmann
Controlled Trial
Noninvasive Ventilation for Respiratory Distress Syndrome: A Randomized

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