Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8

Contents lists available at ScienceDirect

Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Review

Nasal intermittent positive pressure ventilation in preterm infants:

Equipment, evidence, and synchronization
Louise S. Owen a, b, c, *, Brett J. Manley a, b
a
Neonatal Services and Newborn Research Centre, The Royal Women's Hospital, Parkville, Australia
b
Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, Australia
c
Murdoch Childrens Research Institute, Parkville, Australia

s u m m a r y
Keywords: The use of nasal intermittent positive pressure ventilation (NIPPV) as respiratory support for preterm
Premature infant infants is well established. Evidence from randomized trials indicates that NIPPV is advantageous over
Neonatal intensive care
continuous positive airway pressure (CPAP) as post-extubation support, albeit with varied outcomes
Continuous positive airway pressure
Respiratory distress syndrome
between NIPPV techniques. Randomized data comparing NIPPV with CPAP as primary support, and for
Newborn the treatment of apnea, are conflicting. Intrepretation of outcomes is limited by the multiple techniques
and devices used to generate and deliver NIPPV. This review discusses the potential mechanisms of
action of NIPPV in preterm infants, the evidence from clinical trials, and summarizes recommendations
for practice.
© 2016 Elsevier Ltd. All rights reserved.

1. Introduction mandatory ventilation [2]; or NI-PSV: non-invasive pressure sup-

NIPPV has been used as a form of non-invasive respiratory
support in newborn infants since the 1970s [1]; however, uncer-
tainty remains regarding its mechanism of action, and how best to
apply it and in which infants.
This review evaluates the evidence currently available to assess
whether NIPPV should be used, and under which clinical circum-
stances. It examine hows NIPPV may be applied, with particular
reference as to whether or not NIPPV should be synchronized
(sNIPPV) with spontaneous breathing.
port ventilation [3].
Bi-level CPAP is often included under the umbrella of NIPPV.
This mode also combines CPAP with intermittent pressure in-
creases via a nasal interface, but describes alternating high and low
levels of CPAP. Throughout both levels the infant breathes inde-
pendently. Bi-level CPAP has also been called nasal BiPAP [4] and
biphasic nasal CPAP [5].
3. Generating and delivering NIPPV

2. Terminology and techniques 3.1. Pressure

“NIPPV” is an umbrella term for multiple techniques combining
the application of positive distending pressure (continuous positive
airway pressure: CPAP) with intermittent pressure increases
applied at the nose, without an endotracheal tube. The various
abbreviations used to describe NIPPV in the literature reflect
whether synchronization was attempted, and the ventilation
strategy applied, e.g. N-SIMV: nasal synchronized intermittent
* Corresponding author. Address: Newborn Research Centre, The Royal Women's
Hospital, Level 7, 20 Flemington Road, Parkville, Victoria 3052, Australia. Tel.: þ613
8345 3766; fax: þ613 8345 3789.
E-mail address: louise.owen@thewomens.org.au (L.S. Owen).
In theory, any ventilator can be used to generate non-
synchronized (ns)NIPPV and many have been used in published
studies [6e9]. However, the most cited ventilator in the NIPPV
literature, and one of very few that have been used to provide
sNIPPV, is the Infant Star (Infrasonics Inc., San Diego, CA, USA).
However, this ventilator is no longer in production and conse-
quently its use has almost ceased. Some manufacturers are intro-
ducing ventilators with incorporated synchronization mechanisms,
two of which have been used in published NIPPV studies: Giulia
(Giulia Neonatal Nasal Ventilator, Ginevri Medical Technologies,
Rome, Italy [10e12]) and Sophie (Fritz Stephan Medizintechnik
GmbH, Gackenbach, Germany [13]).

http://dx.doi.org/10.1016/j.siny.2016.01.003
1744-165X/© 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Owen LS, Manley BJ, Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence,
and synchronization, Seminars in Fetal & Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.01.003
2 L.S. Owen, B.J. Manley / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8
The set pressures and rates used during ventilator-generated
NIPPV are usually similar to peri-extubation endotracheal ventila-
tion settings (peak pressures 14e24 cmH2O and positive end
expiratory pressure (PEEP) 3e6 cmH2O) [7e9,14e17]. Typically,
peak pressure duration is short (<0.5 s) with a range of 10e60
cycles/min [7e9,14e17].
There are few devices capable of delivering biphasic CPAP to
newborns. The flow-driver “SiPAP” and its predecessor the Infant
Flow Driver Advance e IFDa (both Care Fusion, Yorba Linda, CA,
USA) were developed to deliver CPAP and biphasic CPAP. At least
one new device designed to deliver these modes is available, but is
yet to be clinically evaluated: Medin CNO (Medical Innovations
GmbH, Puchheim, Germany). Biphasic CPAP uses lower set pres-
sures and lower rates than traditional ventilator-generated NIPPV,
partly due to limitations within the delivery devices, and partly
because there is no intent to mimic or fit in with spontaneous
breathing patterns.
Both the SiPAP and IFDa devices have a maximum deliverable
pressure of 11 cmH2O in the biphasic mode, except under certain
circumstances. Studies using biphasic CPAP describe longer high-
pressure duration (0.5e1.0 s), cycle rates of 10e30/min and 3e4
cmH2O differences between high (typically 8e9 cmH2O) and low
(typically 4e6 cmH2O) CPAP pressure settings [5,18e22].
Additionally, SiPAP and IFDa can be set to deliver traditional
NIPPV patterns with shorter, more frequent high-pressure in-
tervals. In this setting synchronization may be desired, and in
synchronized mode SiPAP can deliver peak pressure of 15 cmH2O.
Some studies have used the SiPAP in this way [23,24].
Whether these devices and strategies should be considered
different modes of support or simply a spectrum of NIPPV is un-
clear. However, for the purpose of this review, NIPPV is considered
to have high-pressure duration 0.5 s, and biphasic CPAP >0.5 s.
3.2. Patient interface
NIPPV and biphasic CPAP studies have mostly used short
binasal prongs as the patient interface. Binasal prongs have been
shown to reduce re-intubation rates during CPAP, in comparison
to single nasal prongs [25]. Several NIPPV studies have used
binasal nasopharyngeal prongs [6,8,15,26,27]; however, two
groups have reported abdominal distension with these longer
prongs [8,26]. Recently, nasal cannulae have been used to deliver
NIPPV in a lung model [28]. However, the NIPPV pressure trans-
mission was greatly attenuated by the small diameter nasal
cannulae, compared with traditional CPAP prongs. There have
been no studies using NIPPV delivered via nasal mask, nor direct
comparisons between interfaces during NIPPV or biphasic CPAP.
With all interfaces there are likely to be large and variable leaks
from the nose and mouth, which may limit the effectiveness of the
applied pressures.
4. How are NIPPV and biphasic CPAP thought to work?
4.1. NIPPV: pressure and volume
It has been suggested that NIPPV pressure changes micro-recruit
alveoli and improves functional residual capacity (FRC) [16,29,30],
but no clinical trials support these theories. Nasal intermittent
positive pressure ventilation is so called because it was initially
presumed that pressure changes delivered into the nose would
translate into lung inflations. However, observational data have
shown that during NIPPV the delivered peak pressure is variable
and often substantially below the set peak pressure [31,32], likely
related to leak. These observations measured intra-prong pressure,
not intra-thoracic pressure, which is likely to be lower still, and
Please cite this article in press as: Owen LS, Manley BJ, Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence,
and synchronization, Seminars in Fetal & Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.01.003
more variable [28] due to pressure loss across different prongs [33].
However, these observations have demonstrated slightly higher
delivered mean airway pressures (MAP) during NIPPV than CPAP
alone: this in itself may be enough to account for the apparent
advantages of NIPPV [31,34]. Most studies comparing CPAP with
NIPPV have not aligned MAP between study groups and therefore
the variable is unaccounted for. One study directly examining MAP
found no difference in oxygenation, carbon dioxide (CO2) levels or
respiratory rate (RR) between nsNIPPV and CPAP delivered at
NIPPV-MAP level [35]; tidal volume (VT) and desaturation events
were better during MAP-level CPAP.
So do applied NIPPV pressures translate to lung volume change?
NIPPV may slightly increase end expiratory lung volume, compared
with CPAP [23], although this also could be due to increased MAP.
However, data have demonstrated that during nsNIPPV the ma-
jority of pressure peaks occur during spontaneous expiration and
have no effect on VT [11,36]. When pressure peaks occur during
spontaneous inspiration those volumes increase by ~15% [36]. This
suggests that timing of pressure change is important to confer
volume change. One group has demonstrated higher VT during
sNIPPV (NIPPV pressures 12/3 cmH2O, compared with CPAP 3
cmH2O), reporting 40% higher volumes during sNIPPV [11]. In this
study infants were enrolled immediately after extubation, and very
low PEEP was used in the CPAP group. Other similar studies
enrolled infants already stable on CPAP, used higher PEEPs, and
failed to demonstrate VT difference between CPAP and sNIPPV
[3,23,37,38]. A study that directly compared sNIPPV (~90% of
pressure peaks delivered during inspiration) with nsNIPPV (~20% of
pressure peaks during delivered during inspiration) found no dif-
ference in VT between modes [37].
NIPPV pressure peaks may not effectively reach the lungs during
central (non-obstructive) apnea [10,36]. Data have demonstrated
that during 95% of central apneas no NIPPV pressure changes
produced lung volume change (Fig. 1), possibly due to obstructive
components of central apnea [39]. In 5% of central apneas NIPPV
pressures produced VT change one-quarter the volume of sponta-
neous breaths [36]
Therefore, it does not seem likely that pressure or volume
change are the prime mechanisms of action during NIPPV.
4.2. NIPPV: gas exchange
Given the limited pressure and volume effects of NIPPV it could
be anticipated that there would be minimal effect on gas exchange.
Of six studies investigating oxygenation and CO2 clearance, two
reported lower CO2 during NIPPV [11,40], one reported lower ox-
ygen saturation (by 1%) during NIPPV [41], and the remainder (all
using sNIPPV) found no difference in either parameter [3,10,37].
Infants in all six studies were adequately supported with CPAP at
study entry, potentially limiting any difference in these parameters.
In contrast, Huang et al.'s study enrolled infants shortly after
extubation and found improved oxygen and CO2 levels during
sNIPPV, compared with nsNIPPV [13].
4.3. NIPPV: work of breathing
Five studies investigating work of breathing (WOB) during
sNIPPV found reduced WOB compared with CPAP [3,11,13,37,38]; a
sixth reported improved thoraco-abdominal synchrony [2]. Two
direct comparisons of sNIPPV with nsNIPPV found that sNIPPV
improved thoraco-abdominal synchrony [37] and reduced WOB
[13,37]. Less WOB may seem of small benefit, but over a prolonged
period may influence need for intubation or re-intubation, or fre-
quency of apnea.
 L.S. Owen, B.J. Manley / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8 3

Fig. 1. Nasal intermittent positive pressure ventilation (NIPPV) pressure (upper), spontaneous breathing and apnea recorded by a Graseby capsule and respiratory inductance
plethysmography (RIP; center), and oxygen saturation (lower) during central apnea, with no lung volume change observed during apnea. (Reproduced from Owen LS, Morley CJ,
Dawson JA, Davis PG. Effects of non-synchronised nasal intermittent positive pressure ventilation on spontaneous breathing in preterm infants. Archs Dis Child Fetal Neonatal Ed
2011;96:F422e8 with permission from BMJ Publishing Group Ltd.)

4.4. NIPPV: other mechanisms
Other possible actions include pharyngeal inflation, triggering of
Head's paradoxical reflex [15,30,32,42], and amelioration of apneic
events [36,42]. Animal studies have demonstrated active glottal
closure during the majority of central apneas in premature lambs
[43], preserving lung volume, and possibly limiting apnea-related
desaturation [44], an effect which has been reported in preterm
infants [36,42]. A crossover study comparing two modes of nsNIPPV
(ventilator and flow-driver) with two modes of CPAP (flow-driver
and “bubble CPAP”) found no difference in apnea number between
modes [41]. However, another crossover study comparing nsNIPPV
with sNIPPV and with CPAP [10] found fewer desaturations and
central apneas during sNIPPV than during other modes.
and 88% in Brazil [47] in 2009. Surveys have not distinguished
between NIPPV and biphasic CPAP. The devices, and consequently
the settings, vary between countries; in Brazil, ventilator-generated
NIPPV was almost exclusively used, whereas the UK and Ireland
predominantly used flow drivers (e.g. SiPAP). Typical pressure
settings during ventilator-generated NIPPV were 20/5 cmH2O [47],
compared with 10/5 cmH2O using SiPAP [45]. Reported cycle rates
averaged 20e30/min and high-pressure duration was consistently
<0.5s with both devices. All three published surveys cited >90%
usage of short binasal prongs to deliver NIPPV, but also up to 50%
nasal mask use [45]; nasopharyngeal prongs were used in a small
minority [47].

6. Synchronization during NIPPV

4.5. Biphasic CPAP
Few studies have examined potential mechanisms of action
during biphasic CPAP. Theories include higher upper CPAP level
leading to higher MAP and improved oxygenation [21], alternating
CPAP levels resulting in increased FRC [20,21], recruitment of un-
stable alveoli [20], and decreased WOB [5].
One study reported no differences in oxygenation, RR or CO2
levels between biphasic CPAP and CPAP [19], whereas another re-
ported higher oxygen levels, lower RR and CO2 levels during biphasic
CPAP, although the differences were very small [21]. There are no
reported differences in heart rate, apneas, desaturations [19], or pro-
inflammatory cytokines [20] between CPAP and biphasic CPAP.
5. How do clinicians apply NIPPV and biphasic CPAP?
NIPPV is widely used to treat preterm infants, with reported
rates ranging from 48% in the UK (2006) [45] to 71% in Ireland [46]
6.1. Animal and adult studies
Extrapolation of the use of synchronization during endotracheal
ventilation to synchronize NIPPV seems logical, but does it work?
Does the interposition of the larynx reduce our ability to deliver
effective synchronized pressure changes?
Animal studies have shown that applying positive pressure at
the nose results in laryngeal narrowing and consequently reduced
lung inflation [48]. Physiological studies have shown that if applied
pressures reach the upper airway, glottic function is unaltered, but
if pressures reach the lower airways the broncho-pulmonary
pressure receptors initiate glottal narrowing [49]. Adult studies
have shown that NIPPV applied at increasing ventilatory settings
results in increasing glottal narrowing, obstructive apnea, and
reduced tidal volume [50,51]. Potential consequences of applying
pressure to a closed glottis include ineffective respiratory support,
excessive upper airway pressure, and gastric distention. This

Please cite this article in press as: Owen LS, Manley BJ, Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence,
and synchronization, Seminars in Fetal & Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.01.003
4 L.S. Owen, B.J. Manley / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8
information questions whether synchronization during neonatal
NIPPV would be effective.
During biphasic CPAP, high pressure duration is typically
0.5e1 s, compared with typical spontaneous inspiration of 0.3 s in
preterm infants [52], therefore synchronization with spontaneous
breathing is not targeted.
6.2. Direct comparisons between sNIPPV and nsNIPPV in preterm
infants
Few studies have made direct comparisons between NIPPV
modes. Chang et al. [37] compared sNIPPV and nsNIPPV at 20 and
40 cycles/min and found no differences in VT, minute ventilation,
RR, oxygenation, CO2 level, desaturation events, or thoraco-
abdominal synchrony. Inspiratory WOB was reduced during
sNIPPV, especially when more cycles per minute were
synchronized.
Gizzi et al. [10] reported fewer central apneas and total desa-
turations and bradycardias with sNIPPV than with nsNIPPV. How-
ever, infants in the nsNIPPV group received 20 pressure cycles per
minute whereas those in the sNIPPV group had all spontaneous
breaths supported (mean RR: 57). This is likely to have produced a
higher MAP during sNIPPV (although this is not reported) and may
account for some of the difference seen. Huang et al. [13], who
reported decreased WOB, RR, CO2, and improved oxygenation re-
ported a difference in MAP (8.6 cmH2O sNIPPV, versus 7.9 cmH2O
nsNIPPV) despite delivering nsNIPPV at 40 cycles/min; during
sNIPPV infants were supported for all spontaneous breath (mean
RR 70).
6.3. Practicalities of applying synchronization during neonatal
NIPPV
Synchronization with spontaneous breathing during neonatal
endotracheal ventilation either uses a pneumatic pressure trigger
or a flow sensor, which may be more sensitive [53]. Synchroniza-
tion during NIPPV is challenging due to the large and variable leaks
[54] of mouth opening and variable nasal prongs fit in the nares.
Normal onset of inspiration commences with glottal abduction,
followed by diaphragmatic contraction. However, in preterm in-
fants, typically one-third of breaths, and up to 60%, commence with
diaphragmatic contraction followed by glottal abduction [55].
Therefore, deciding which event to detect in order to react rapidly
to the onset of inspiration is unclear.
Airway flow detection may be a way of ensuring that the glottis
is open before pressure is applied, but the most commonly cited
method of NIPPV synchronization is the Graseby capsule (GC). This
is a small polythene foam-filled disk, which is cheap, lightweight,
disposable and unaffected by air leak. The capsule is affixed to the
anterior abdominal wall below the xiphisternum; compression or
distortion of the capsule is detected by a pneumatic transducer. Its
accuracy is limited by position and fixation [56], and by movement
artifact, although data regarding its accuracy during NIPPV suggest
that it correctly detects the onset of inspiration about 90% of the
time [37]. The GC was the synchronization device for the Infant Star
ventilator, now out of production, but which was used in most of
the randomized studies evaluating sNIPPV [14e16,57]. Stephan
ventilators (Fritz Stephan, Gackenbach, Germany) now incorporate
software using the GC signal during non-invasive support, and
initial reports of its reliability are encouraging [13,58].
The SiPAP flow-driver can be used to deliver sNIPPV, albeit with
relatively low peak pressures. Bench top and clinical data using
SiPAP suggest that the GC rapidly and accurately detects breaths,
resulting in initiation of increased air flow within 30 ms [56,59].
However, at higher spontaneous breath rates and the SiPAP
Please cite this article in press as: Owen LS, Manley BJ, Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence,
and synchronization, Seminars in Fetal & Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.01.003
responded less consistently to GC signals 50e75% of the time [56,60]
(Fig. 2), delivering lower, more variable pressures [59]. Thus far, one
randomized study has used SiPAP to deliver sNIPPV in this way [24].
One group has consistently reported success using a nasal flow
trigger [10e12], reporting initiation of air flow within 65 ms, and
accurate triggering in >90% of breaths [11]. However, the device
(Giulia neonatal nasal ventilator) is not widely available, and others
have not been able to successfully use other nasal flow triggers
during NIPPV [42]. Kugelman et al. used the pressure trigger device
within the SLE2000 ventilator (Specialized Laboratory Equipment
Ltd, South Croydon, UK) for NIPPV synchronization [7], which was
thought to be successful, although acknowledging that appropriate
triggering could not be verified. Respiratory inductance plethys-
mography (RIP) has been used to synchronize NIPPV [3] but is not
currently commercially available. A study of surface sensors found
that, compared with esophageal pressure change to indicate initi-
ation of inspiration, abdominal RIP detected inspiration 53 ms
earlier, a GC 13 ms after, and a chest RIP band 103 ms after the
esophageal pressure change [58]. This correlates with Stern et al.
who found that the GC responded before the sum of RIP chest and
abdominal bands [56]. Recently, a diaphragmatic electromyogram
e neurally adjusted ventilator assist (NAVA) e has offered the
possibility of providing inspiratory synchronization plus propor-
tional pressure support [61]. Non-invasive NAVA in children pro-
vides better synchronization than pneumatic triggers [62];
however, it is invasive and costly, requires practice to accurately
place the sensor [63], and there are few data on neonatal outcomes
[64].
6.4. Is synchronization being used clinically?
Although devices are available, data suggest that synchroniza-
tion is not always locally available, or used. In the UK [45], 77% of
nurseries using NIPPV reported attempting synchronization using
the GC and SiPAP, whereas in Brazil 1% used this method, 45% used
ventilator pressure triggers, and the remainder did not attempt
synchronization [47]. Researchers are not always successful in us-
ing synchronization; Mediema et al. [23] reported that in 22 infants
where synchronization was attempted using the GC and SiPAP, so
few breaths were correctly triggered that analysis was not possible.
Courtney reported that attempts at synchronization using flow
triggering were also unsuccessful [42]. The considerable cost of
specialized equipment required to synchronize NIPPV could limit
its uptake, even if proven beneficial.
7. Randomized trials of NIPPV and biphasic CPAP
7.1. Comparisons with CPAP
Kirpalani published the largest NIPPV trial, studying NIPPV as
primary (49%) and post-extubation support (51%), either synchro-
nized or not, and using any NIPPV delivery device [65]. The trial
randomized 1009 infants at <30 weeks of gestation, to NIPPV or
CPAP. There were no differences in primary (combined outcome of
death or moderate/severe bronchopulmonary dysplasia, BPD) or
secondary outcomes between groups.
7.2. Direct comparisons between ventilator-generated and CPAP-
driver-generated NIPPV, and between sNIPPV and nsNIPPV
No randomized controlled trials (RCTs) have directly examined
differences between ventilator-generated and flow-driver-
generated NIPPV, nor between sNIPPV and nsNIPPV. A sub-
analysis of the 497 infants randomized to receive NIPPV in Kirpa-
lani et al.'s trial [65] reported on the 241 infants who received mainly
 L.S. Owen, B.J. Manley / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8 5

Fig. 2. Biphasic continuous positive airway pressure delivered by SiPAP (top), spontaneous breathing recorded by respiratory inductance plethysmography (center) and sponta-
neous breathing as recorded by the Graseby capsule component of SiPAP (lower). When respiratory rate (RR) is high (84/min) SiPAP responds to alternate spontaneous breaths.
When RR falls to 55/min all breaths are responded to, and delivered pressures are higher. (Reproduced from Owen LS, Morley CJ, Davis PG. Effects of synchronisation during SiPAP-
generated nasal intermittent positive pressure ventilation (NIPPV) in preterm infants. Archs Dis Child Fetal Neonatal Ed 2015;100:F24e30 with permission from BMJ Publishing
Group Ltd.).

ventilator-generated NIPPV, and the 215 who received mainly flow-
driver NIPPV [66]. It is not specified whether those on flow-driver
NIPPV received biphasic CPAP or traditional NIPPV. No differences
were seen in the composite primary outcome (death or BPD), but
there was significantly higher mortality [odds ratio: 5.01; 95% con-
fidence interval (CI): 1.74, 14.4] in the flow-driver NIPPV group. Data
were not given for set pressures in the trial, though the study pro-
tocol recommended pressures that would result in higher pressures
in the ventilator-generated NIPPV group e this could potentially
have affected the outcome. The recent Cochrane review [67], which
included seven additional studies in the analysis of NIPPV by device,
for the outcome of extubation failure, reported relative risk 0.64
(95% CI: 0.44, 0.95) favoring ventilator-generated NIPPV.
The same sub-analysis examined mode of NIPPV. For infants
where sufficient data were available (n ¼ 410), 102 received mostly
sNIPPV and 308 mostly nsNIPPV. Less than 10% of the ventilator-
generated group received sNIPPV, whereas 40% of the flow-driver
group received sNIPPV. There was no statistically significant dif-
ference in the combined primary outcome between synchronized
and non-synchronized groups (33.3% vs 38.6%, P ¼ 0.33) [66].
7.3. NIPPV vs CPAP as primary respiratory support
Five trials have compared nsNIPPV with CPAP as primary res-
piratory support after birth [8,9,17,40,68]. Four allowed INSURE
(INtubation-SURfactant-Extubation) within both groups [8,9,17,68].
Two studies reported less need for mechanical ventilation (MV)
within 48 h in the nsNIPPV groups [8,9], whereas three reported no
difference in need for MV at four [40], 48 [68], and 72 h of age [17].
Sub-analysis of Kirpalani et al.'s trial also found no difference in
death/BPD between NIPPV and CPAP in the subgroup receiving
primary non-invasive support [65].
Two trials examined sNIPPV compared with CPAP as primary
support; neither allowed INSURE. Kugelman et al. [7] (using
ventilator-generated NIPPV) reported less need for MV in the
sNIPPV group (25% vs 49%, P ¼ 0.04). Wood [24] (using the SiPAP),
reported no difference in need for MV between groups (13.3% vs
11.7%, P ¼ 0.78) [24]. A recent meta-analysis, including one sNIPPV
[7] and two nsNIPPV primary support studies [8,17] demonstrated a
relative risk reduction for intubation <72 h in the NIPPV group
(0.60; 95% CI: 0.43, 0.83) [69].
7.4. NIPPV vs CPAP for the treatment of apnea
Two RCTs compared nsNIPPV with CPAP for the treatment of
apnea of prematurity. One reported no benefit of nsNIPPV over
CPAP [32], whereas the other found a greater reduction in apneic
events in the nsNIPPV group [70]. Meta-analysis concluded that
NIPPV may enhance the effects of CPAP in severe apnea but more
data are required [71].

Please cite this article in press as: Owen LS, Manley BJ, Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence,
and synchronization, Seminars in Fetal & Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.01.003
6 L.S. Owen, B.J. Manley / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8
7.5. NIPPV vs CPAP as post extubation support
Five RCTs compared sNIPPV with CPAP post extubation: all
showed reduced extubation failure rates with sNIPPV
[11,14e16,72]. Meta-analysis of these studies showed a clinically
important advantage of sNIPPV over CPAP in preventing extubation
failure (relative risk: 0.25; 95% CI: 0.15, 0.41) [67], and in reducing
BPD (0.64; 0.44, 0.95) [67].
Two RCTs compared nsNIPPV with CPAP post extubation.
Khorana et al. [6] reported no difference in re-intubation rates at
seven days; however, the study groups were not well matched.
Kahramaner et al. [73] described 67 preterm infants randomized to
nsNIPPV or CPAP and found that infants receiving nsNIPPV
remained on non-invasive support for longer. However, the pre-
scribed weaning strategy may have contributed to this outcome.
Other outcomes are hard to interpret as 40% of infants in the CPAP
group died. The recently updated Cochrane review examining
NIPPV support post extubation included eight studies, five syn-
chronized, one non-synchronized, one biphasic CPAP and one with
mixed therapies [67], overall these studies provided benefit over
CPAP for extubation success (risk ratio: 0.71), but the impact on BPD
was lost.
7.6. Synchronized NIPPV vs biphasic CPAP as primary support
One RCT has examined sNIPPV (flow-synchronized), in com-
parison with biphasic CPAP in preterm infants [12], mostly
following an INSURE procedure. Infants requiring early intubation
and ventilation were excluded. Pressure settings between groups
were different due to sNIPPV being ventilator-generated and
biphasic CPAP being flow-driver-generated, although the groups
probably had comparable MAP during treatment. No differences
were seen in the primary (duration of support and failure of non-
invasive support) or secondary outcomes.
7.7. Synchronized NIPPV vs nasal high flow (HF) therapy as primary
respiratory support
One study has compared sNIPPV with nasal HF in premature
infants, demonstrating longer duration of support with HF, but no
other differences between groups [74].
7.8. Biphasic CPAP vs CPAP as primary respiratory support
Lista et al. [20] reported on 40 infants randomized to biphasic or
plain CPAP as primary support, with INSURE if required. Primary
outcome assessed inflammatory markers (no difference between
groups), whereas secondary outcomes demonstrated fewer days of
respiratory support and supplemental oxygen in the biphasic
group.
7.9. Biphasic CPAP vs CPAP as post extubation support
One RCT compared biphasic with plain CPAP post extubation.
O'Brien et al. [5] randomized 136 infants <1250 g and found no
difference in successful extubation at seven days. However, the trial
was stopped early due to a change in local practice, and was
therefore underpowered.
8. Summary and practice points
NIPPV includes a spectrum of support, from low-pressure, low-
rate, biphasic CPAP, to high-pressure support fully synchronized
with spontaneous breathing. Devices and preferences for NIPPV
delivery vary around the world, but its use is widespread.
Please cite this article in press as: Owen LS, Manley BJ, Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence,
and synchronization, Seminars in Fetal & Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.01.003
Pressure and lung volume change do not appear to be pre-
dominant mechanisms of action during NIPPV, and it has been hard
to delineate benefits of NIPPV in infants who are already estab-
lished on CPAP. Studies of infants immediately post extubation, or
dependant on NIPPV support may produce different results. The
most consistent findings to date have been reduced WOB and more
extubation success during sNIPPV.
Designing studies to isolate the impact of NIPPV by correcting
for MAP has been difficult, and has made interpretation of many
studies difficult.
Synchronization is complex; synchronizing at the nose is
entirely different from endotracheal synchronization; a very fast
response time is needed as natural inspiration is very short and its
mode of onset is variable. In reality, most clinicians currently do not
provide sNIPPV.
Most RCTs have not been powered to assess long-term outcomes
following NIPPV treatment and the largest appropriately powered
NIPPV trial did not demonstrate long-term benefits. Within this
trial, sub-analysis of techniques (sNIPPV vs nsNIPPV) was
confounded by the fact that ‘better’ ventilator-generated NIPPV was
mostly applied in a ‘less effective’ non-synchronized manner, and
that low-pressure, flow-driver-generated NIPPV was more often
delivered in a synchronized manner. There is no convincing evi-
dence that NIPPV is advantageous over CPAP as primary support;
more than half the trials found no difference in need for MV,
although varying approaches within the studies made it difficult to
interpret the conflicting results. There continue to be very few data
assessing biphasic CPAP, and randomized studies have not shown
benefit of the technique over CPAP.
 Set NIPPV pressures are dictated by the NIPPV delivery device
used.
 NIPPV can reduce extubation failure, most consistently when
synchronized, and delivered by a ventilator.
 The role of NIPPV as primary support is unclear.
 The GC is the most used method of synchronization.
 Other synchronization techniques have potential, particularly
RIP and NAVA.
 When MAP is matched between modes there is little difference
between CPAP, biphasic CPAP, and NIPPV.
9. Conclusion and research agenda
Few studies have examined long-term effects of NIPPV, or the
relative benefits of sNIPPV versus nsNIPPV. Currently, ventilator-
generated NIPPV appears most likely to confer benefit but there
are barriers to assessing whether ventilator-generated sNIPPV is
superior to ventilator-generated nsNIPPV, in terms of practicality
and cost. Encouragingly, there is little evidence of harm during
NIPPV, with no increase in abdominal adverse events, in contrast to
early fears with the technique [75].
What is the best name for all the NIPPV techniques? We
have virtually no supporting evidence of ‘ventilation’; perhaps
‘non-invasive pressure support’, ‘nasal pressure support’ or ‘syn-
chronized nasal pressure support’ would more accurately reflect
the techniques.
Future NIPPV research should include:
 detailed comparisons of NIPPV devices, techniques, and syn-
chronization systems;
 studies assessing the impact of NIPPV while correcting for MAP;
 adequately designed studies examining long-term outcomes
following NIPPV;
 L.S. Owen, B.J. Manley / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8
 investigating how available NIPPV techniques can be integrated
into a holistic BPD prevention strategy in high-risk infants.
Conflict of interest statement
None declared.
Funding sources
None.
References
[1] Helmrath TA, Hodson WA, Oliver Jr TK. Positive pressure ventilation in the
newborn infant: the use of a face mask. J Pediatr 1970;76:202e7.
[2] Kiciman NM, Andreasson B, Bernstein G, Mannino FL, Rich W, Henderson C,
et al. Thoracoabdominal motion in newborns during ventilation delivered by
endotracheal tube or nasal prongs. Pediatr Pulmonol 1998;25(3):175e81.
[3] Ali N, Claure N, Alegria X, D'Ugard C, Organero R, Bancalari E. Effects of non-
invasive pressure support ventilation (NI-PSV) on ventilation and respiratory
effort in very low birth weight infants. Pediatr Pulmonol 2007;42:704e10.
[4] Migliori C, Cavazza A, Motta M, Bottino R, Chirico G. Early use of nasal-BiPAP
in two infants with congenital central hypoventilation syndrome. Acta Pae-
diatr 2003;92:823e6.
[5] O'Brien K, Campbell C, Brown L, Wenger L, Shah V. Infant flow biphasic nasal
continuous positive airway pressure (BP- NCPAP) vs. infant flow NCPAP for
the facilitation of extubation in infants' 1,250 grams: a randomized
controlled trial. BMC Pediatr 2012;12:43.
[6] Khorana M, Paradeevisut H, Sangtawesin V, Kanjanapatanakul W, Chotigeat U,
Ayutthaya JK. A randomized trial of non-synchronized nasopharyngeal
intermittent mandatory ventilation (nsNIMV) vs. nasal continuous positive
airway pressure (NCPAP) in the prevention of extubation failure in pre-term
<1,500 grams. J Med Assoc Thai 2008;91(Suppl. 3):S136e42.
[7] Kugelman A, Feferkorn I, Riskin A, Chistyakov I, Kaufman B, Bader D. Nasal
intermittent mandatory ventilation versus nasal continuous positive airway
pressure for respiratory distress syndrome: a randomized, controlled, pro-
spective study. J Pediatr 2007;150:521e6. 26 e1.
[8] Sai Sunil Kishore M, Dutta S, Kumar P. Early nasal intermittent positive
pressure ventilation versus continuous positive airway pressure for respira-
tory distress syndrome. Acta Paediatr 2009;98:1412e5.
[9] Shi Y, Tang S, Zhao J, Shen J. A prospective, randomized, controlled study of
NIPPV versus nCPAP in preterm and term infants with respiratory distress
syndrome. Pediatr Pulmonol 2014;49:673e8.
[10] Gizzi C, Montecchia F, Panetta V, Castellano C, Mariani C, Campelli M, et al. Is
synchronised NIPPV more effective than NIPPV and NCPAP in treating apnoea
of prematurity (AOP)? A randomised cross-over trial. Arch Dis Child Fetal
Neonatal Ed 2015;100(1):F17e23 [Epub 2014/10/17].
[11] Moretti C, Gizzi C, Papoff P, Lampariello S, Capoferri M, Calcagnini G, et al.
Comparing the effects of nasal synchronized intermittent positive pressure
ventilation (nSIPPV) and nasal continuous positive airway pressure (nCPAP)
after extubation in very low birth weight infants. Early Hum Dev
1999;56(2e3):167e77.
[12] Salvo V, Lista G, Lupo E, Ricotti A, Zimmermann LJ, Gavilanes AW, et al.
Noninvasive ventilation strategies for early treatment of RDS in preterm in-
fants: an RCT. Pediatrics 2015;135(3):444e51 [Epub 2015/02/11].
[13] Huang L, Mendler MR, Waitz M, Schmid M, Hassan MA, Hummler HD. Effects
of synchronization during noninvasive intermittent mandatory ventilation in
preterm infants with respiratory distress syndrome immediately after extu-
bation. Neonatology 2015;108:108e14.
[14] Barrington KJ, Bull D, Finer NN. Randomized trial of nasal synchronized
intermittent mandatory ventilation compared with continuous positive
airway pressure after extubation of very low birth weight infants. Pediatrics
2001;107:638e41.
[15] Friedlich P, Lecart C, Posen R, Ramicone E, Chan L, Ramanathan R.
A randomized trial of nasopharyngeal-synchronized intermittent mandatory
ventilation versus nasopharyngeal continuous positive airway pressure in
very low birth weight infants after extubation. J Perinatol 1999;19(6 Pt 1):
413e8.
[16] Khalaf MN, Brodsky N, Hurley J, Bhandari V. A prospective randomized,
controlled trial comparing synchronized nasal intermittent positive pressure
ventilation versus nasal continuous positive airway pressure as modes of
extubation. Pediatrics 2001;108:13e7.
[17] Meneses J, Bhandari V, Alves JG, Herrmann D. Noninvasive ventilation for
respiratory distress syndrome: a randomized controlled trial. Pediatrics
2011;127:300e7.
[18] Ancora G, Maranella E, Grandi S, Pierantoni L, Guglielmi M, Faldella G. Role of
bilevel positive airway pressure in the management of preterm newborns
who have received surfactant. Acta Paediatr 2010;99:1807e11.
[19] Lampland AL, Plumm B, Worwa C, Meyers P, Mammel MC. Bi-level CPAP does
not improve gas exchange when compared with conventional CPAP for the
Please cite this article in press as: Owen LS, Manley BJ, Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence,
and synchronization, Seminars in Fetal & Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.01.003
7
treatment of neonates recovering from respiratory distress syndrome. Archs
Dis Child Fetal Neonatal Ed 2015;100:F31e4.
[20] Lista G, Castoldi F, Fontana P, Daniele I, Cavigioli F, Rossi S, et al. Nasal
continuous positive airway pressure (CPAP) versus bi-level nasal CPAP in
preterm babies with respiratory distress syndrome: a randomised control
trial. Arch Dis Child Fetal Neonatal Ed 2010;95(2):F85e9 [Epub 2009/12/02].
[21] Migliori C, Motta M, Angeli A, Chirico G. Nasal bilevel vs. continuous positive
airway pressure in preterm infants. Pediatr Pulmonol 2005;40:426e30.
[22] Ricotti A, Salvo V, Zimmermann LJ, Gavilanes AW, Barberi I, Lista G, et al. N-
SIPPV versus bi-level N-CPAP for early treatment of respiratory distress syn-
drome in preterm infants. J Maternal-Fetal Neonat Med 2013;26(13):1346e51
[Epub 2013/03/16].
[23] Miedema M, van der Burg PS, Beuger S, de Jongh FH, Frerichs I, van Kaam AH.
Effect of nasal continuous and biphasic positive airway pressure on lung
volume in preterm infants. J Pediatr 2013;162:691e7.
[24] Wood FE, Gupta S, Tin W, Sinha S. Randomised controlled trial of synchron-
ised intermittent positive airway support versus continuous positive airway
pressure as a primary mode of respiratory support in preterm infants with
respiratory distress syndrome. Pediatric Academic Society. Washington DC,
USA: platform presentation, abstact no. 3500.8. 2013.
[25] De Paoli AG, Davis PG, Faber B, Morley CJ. Devices and pressure sources for
administration of nasal continuous positive airway pressure (NCPAP) in pre-
term neonates. Cochrane Database Syst Rev 2008;(1):CD002977.
[26] Jackson JK, Vellucci J, Johnson P, Kilbride HW. Evidence-based approach to
change in clinical practice: introduction of expanded nasal continuous posi-
tive airway pressure use in an intensive care nursery. Pediatrics 2003;111(4 Pt
2):e542e7.
[27] Ramanathan R, Sekar KC, Rasmussen M, Bhatia J, Soll RF. Nasal intermittent
positive pressure ventilation after surfactant treatment for respiratory
distress syndrome in preterm infants <30 weeks' gestation: a randomized,
controlled trial. J Perinatol 2012;32:336e43.
[28] Mukerji A, Belik J. Neonatal nasal intermittent positive pressure ventilation
efficacy and lung pressure transmission. J Perinatol 2015;35:716e9.
[29] Hutchison AA, Bignall S. Non-invasive positive pressure ventilation in the
preterm neonate: reducing endotrauma and the incidence of broncho-
pulmonary dysplasia. Archs Dis Child Fetal Neonatal Ed 2008;93:F64e8.
[30] Owen LS, Morley CJ, Davis PG. Neonatal nasal intermittent positive pressure
ventilation: what do we know in 2007? Archs Dis Child Fetal Neonatal Ed
2007;92:F414e8.
[31] Owen LS, Morley CJ, Davis PG. Pressure variation during ventilator generated
nasal intermittent positive pressure ventilation in preterm infants. Archs Dis
Child Fetal Neonatal Ed 2010;95:F359e64.
[32] Ryan CA, Finer NN, Peters KL. Nasal intermittent positive-pressure ventilation
offers no advantages over nasal continuous positive airway pressure in apnea
of prematurity. Am J Dis Child 1989;143:1196e8.
[33] De Paoli AG, Lau R, Davis PG, Morley CJ. Pharyngeal pressure in preterm in-
fants receiving nasal continuous positive airway pressure. Arch Dis Child Fetal
Neonatal Ed 2005;90:F79e81.
[34] Owen LS, Morley CJ, Davis PG. Do the pressure changes of neonatal non-
synchronised NIPPV (NS nasal intermittent positive pressure ventilation)
confer advantages over CPAP, or are high CPAP pressures as effective? Pediatr
Res 2011;96:F422e8.
[35] Owen LS, Morley CJ, Davis PG. Do the pressure changes of neonatal non-
synchronised NIPPV confer advantages over CPAP, or are high CPAP pres-
sures as effective? Pediatr Res 2011;70(Suppl. 5(November)). Abstract.
[36] Owen LS, Morley CJ, Dawson JA, Davis PG. Effects of non-synchronised nasal
intermittent positive pressure ventilation on spontaneous breathing in pre-
term infants. Archs Dis Child Fetal Neonatal Ed 2011;96:F422e8.
[37] Chang HY, Claure N, D'Ugard C, Torres J, Nwajei P, Bancalari E. Effects of
synchronization during nasal ventilation in clinically stable preterm infants.
Pediatr Res 2011;69:84e9.
[38] Aghai ZH, Saslow JG, Nakhla T, Milcarek B, Hart J, Lawrysh-Plunkett R, et al.
Synchronized nasal intermittent positive pressure ventilation (SNIPPV) de-
creases work of breathing (WOB) in premature infants with respiratory
distress syndrome (RDS) compared to nasal continuous positive airway
pressure (NCPAP). Pediatr Pulmonol 2006;41(9):875e81.
[39] Lemke RP, Idiong N, Al-Saedi S, Kwiatkowski K, Cates DB, Rigatto H. Evidence
of a critical period of airway instability during central apneas in preterm in-
fants. Am J Respir Crit Care Med 1998;157:470e4.
[40] Bisceglia M, Belcastro A, Poerio V, Raimondi F, Mesuraca L, Crugliano C, et al. A
comparison of nasal intermittent versus continuous positive pressure delivery
for the treatment of moderate respiratory syndrome in preterm neonates.
Minerva Pediatr 2007;59(2):91e5.
[41] Pantalitschka T, Sievers J, Urschitz MS, Herberts T, Reher C, Poets CF. Rando-
mised crossover trial of four nasal respiratory support systems for apnoea of
prematurity in very low birthweight infants. Archs Dis Child Fetal Neonatal Ed
2009;94:245e8.
[42] Courtney SE, Barrington KJ. Continuous positive airway pressure and nonin-
vasive ventilation. Clin Perinatol 2007;34:73e92. vi.
[43] Renolleau S, Letourneau P, Niyonsenga T, Praud JP, Gagne B. Thyroarytenoid
muscle electrical activity during spontaneous apneas in preterm lambs. Am J
Respir Crit Care Med 1999;159(5 Pt 1):1396e404.
[44] Reix P, Arsenault J, Dome V, Fortier PH, Lafond JR, Moreau-Bussiere F, et al.
Active glottal closure during central apneas limits oxygen desaturation in
premature lambs. J Appl Physiol 2003;94(5):1949e54 [Epub 2003/01/14].
8 L.S. Owen, B.J. Manley / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8
[45] Owen LS, Morley CJ, Davis PG. Neonatal nasal intermittent positive pressure
ventilation: a survey of practice in England. Archs Dis Child Fetal Neonatal Ed
2008;93:F148e50.
[46] Kieran EA, Walsh H, O'Donnell CP. Survey of nasal continuous positive airways
pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV)
use in Irish newborn nurseries. Archs Dis Child Fetal Neonatal Ed 2011;96:
F156.
[47] de Medeiros SK, Carvalho WB, Soriano CF. Practices of use of nasal intermit-
tent positive pressure ventilation (NIPPV) in neonatology in northeastern
Brazil. J Pediatr (Rio J) 2012;88:48e53.
[48] Praud JP, Samson N, Moreau-Bussiere F. Laryngeal function and nasal venti-
latory support in the neonatal period. Paediatr Respir Rev 2006;7(Suppl. 1):
S180e2.
[49] Roy B, Samson N, Moreau-Bussiere F, Ouimet A, Dorion D, Mayer S, et al.
Mechanisms of active laryngeal closure during noninvasive intermittent
positive pressure ventilation in nonsedated lambs. J Appl Physiol
2008;105(5):1406e12 [Epub 2008/08/16].
[50] Jounieaux V, Aubert G, Dury M, Delguste P, Rodenstein DO. Effects of nasal
positive-pressure hyperventilation on the glottis in normal sleeping subjects.
J Appl Physiol 1995;79:186e93.
[51] Jounieaux V, Aubert G, Dury M, Delguste P, Rodenstein DO. Effects of nasal
positive-pressure hyperventilation on the glottis in normal awake subjects.
J Appl Physiol 1995;79:176e85.
[52] South M, Morley CJ. Monitoring spontaneous respiration in the ventilated
neonate. Archs Dis Child 1986;61:291e4.
[53] Dimitriou G, Greenough A, Laubscher B, Yamaguchi N. Comparison of airway
pressure-triggered and airflow-triggered ventilation in very immature infants.
Acta Paediatr 1998;87:1256e60.
[54] Fischer HS, Roehr CC, Proquitte H, Hammer H, Wauer RR, Schmalisch G. Is
volume and leak monitoring feasible during nasopharyngeal continuous
positive airway pressure in neonates? Intensive Care Med 2009;35:1934e41.
[55] Eichenwald EC, Howell 3rd RG, Kosch PC, Ungarelli RA, Lindsey J, Stark R.
Developmental changes in sequential activation of laryngeal abductor muscle
and diaphragm in infants. J Appl Physiol 1992;73:1425e31.
[56] Stern DJ, Weisner MD, Courtney SE. Synchronized neonatal non-invasive
ventilation e a pilot study: the Graseby capsule with bi-level NCPAP.
Pediatr Pulmonol 2014;49:659e64.
[57] Bhandari V, Gavino RG, Nedrelow JH, Pallela P, Salvador A, Ehrenkranz RA,
et al. A randomized controlled trial of synchronized nasal intermittent posi-
tive pressure ventilation in RDS. J Perinatol 2007;27(11):697e703.
[58] Anonymous. External respiratory signals in spontaneously breathing preterm
infants. European Society of Paediatric Research, 2012, Istanbul, Turkey. Archs
Dis Child 2012;97(Suppl. 2):A509.
[59] Owen LS, Morley CJ, Davis PG. Effects of synchronisation during SiPAP-
generated nasal intermittent positive pressure ventilation (NIPPV) in pre-
term infants. Archs Dis Child Fetal Neonatal Ed 2015;100:F24e30.
[60] Owen LS, Morley CJ, Davis PG. Bench-top accuracy of SiPAP-generated nasal
intermittent positive pressure ventilation. Acta Paediatr 2013;102:e385e8.
[61] Beck J, Reilly M, Grasselli G, Mirabella L, Slutsky AS, Dunn MS, et al. Patient-
ventilator interaction during neurally adjusted ventilatory assist in low birth
weight infants. Pediatr Res 2009;65(6):663e8 [Epub 2009/02/17].
Please cite this article in press as: Owen LS, Manley BJ, Nasal intermittent positive pressure ventilation in preterm infants: Equipment, evidence,
and synchronization, Seminars in Fetal & Neonatal Medicine (2016), http://dx.doi.org/10.1016/j.siny.2016.01.003
[62] Vignaux L, Grazioli S, Piquilloud L, Bochaton N, Karam O, Levy-Jamet Y, et al.
Patient-ventilator asynchrony during noninvasive pressure support ventila-
tion and neurally adjusted ventilatory assist in infants and children. Pediatric
Crit Care Med 2013;14(8):e357e64 [Epub 2013/07/19].
[63] Duyndam A, Bol BS, Kroon A, Tibboel D, Ista E. Neurally adjusted ventilatory
assist: assessing the comfort and feasibility of use in neonates and children.
Nurs Crit Care 2013;18:86e92.
[64] Stein H, Firestone K. Application of neurally adjusted ventilatory assist in
neonates. Semin Fetal Neonatal Med 2014;19:60e9.
[65] Kirpalani H, Millar D, Lemyre B, Yoder BA, Chiu A, Roberts RS. A trial
comparing noninvasive ventilation strategies in preterm infants. N Engl J Med
2013;369:611e20.
[66] Millar D, Lemyre B, Kirpalani H, Chiu A, Yoder BA, Roberts RS. A comparison of
bilevel and ventilator-delivered non-invasive respiratory support. Archs Dis
Child Fetal Neonatal Ed 2016;101:21e5.
[67] Lemyre B, Davis PG, De Paoli AG, Kirpalani H. Nasal intermittent positive
pressure ventilation (NIPPV) versus nasal continuous positive airway pressure
(NCPAP) for preterm neonates after extubation. Cochrane Database Syst Rev
2014;(9):CD003212.
[68] Armanian AM, Badiee Z, Heidari G, Feizi A, Salehimehr N. Initial treatment of
respiratory distress syndrome with nasal intermittent mandatory ventilation
versus nasal continuous positive airway pressure: a randomized controlled
trial. Int J Prev Med 2014;5:1543e51.
[69] Meneses J, Bhandari V, Alves JG. Nasal intermittent positive-pressure venti-
lation vs nasal continuous positive airway pressure for preterm infants with
respiratory distress syndrome: a systematic review and meta-analysis. Archs
Pediatr Adolesc Med 2012;166:372e6.
[70] Lin C, Wang S, Lin Y, Yeh T. Efficacy of nasal intermittent positive pressure
ventilation in treating apnea of prematurity. Pediatr Pulmonol 1998;26:
349e53.
[71] Lemyre B, Davis PG, De Paoli AG. Nasal intermittent positive pressure venti-
lation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for
apnea of prematurity. Cochrane Database Syst Rev 2000;(3):CD002272.
[72] Gao WW, Tan SZ, Chen YB, Zhang Y, Wang Y. Randomized trial of nasal
synchronized intermittent mandatory ventilation compared with nasal
continuous positive airway pressure in preterm infants with respiratory
distress syndrome [in Chinese]. Zhongguo Dang Dai Er Ke Za Zhi 2010;12:
524e6.
[73] Kahramaner Z, Erdemir A, Turkoglu E, Cosar H, Sutcuoglu S, Ozer EA. Un-
synchronized nasal intermittent positive pressure versus nasal continuous
positive airway pressure in preterm infants after extubation. J Maternal Fetal
Neonatal Med 2014;27:926e9.
[74] Kugelman A, Riskin A, Said W, Shoris I, Mor F, Bader D. A randomized pilot
study comparing heated humidified high-flow nasal cannulae with NIPPV for
RDS. Pediatr Pulmonol 2015;50:576e83.
[75] Garland JS, Nelson DB, Rice T, Neu J. Increased risk of gastrointestinal perfo-
rations in neonates mechanically ventilated with either face mask or nasal
prongs. Pediatrics 1985;76:406e10.