Seminars in Fetal & Neonatal Medicine xxx (2016) 1e8
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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
Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, Australia
c
Murdoch Childrens Research Institute, Parkville, Australia
b
s u m m a r y
Keywords:
Premature infant
Neonatal intensive care
Continuous positive airway pressure
Respiratory distress syndrome
Newborn
The use of nasal intermittent positive pressure ventilation (NIPPV) as respiratory support for preterm
infants is well established. Evidence from randomized trials indicates that NIPPV is advantageous over
continuous positive airway pressure (CPAP) as post-extubation support, albeit with varied outcomes
between NIPPV techniques. Randomized data comparing NIPPV with CPAP as primary support, and for
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
NIPPV has been used as a form of non-invasive respiratory
support in newborn infants since the 1970s [1]; however, uncertainty 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 circumstances. It examine hows NIPPV may be applied, with particular
reference as to whether or not NIPPV should be synchronized
(sNIPPV) with spontaneous breathing.
2. Terminology and techniques
“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).
mandatory ventilation [2]; or NI-PSV: non-invasive pressure support ventilation [3].
Bi-level CPAP is often included under the umbrella of NIPPV.
This mode also combines CPAP with intermittent pressure increases via a nasal interface, but describes alternating high and low
levels of CPAP. Throughout both levels the infant breathes independently. Bi-level CPAP has also been called nasal BiPAP [4] and
biphasic nasal CPAP [5].
3. Generating and delivering NIPPV
3.1. Pressure
In theory, any ventilator can be used to generate nonsynchronized (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 consequently its use has almost ceased. Some manufacturers are introducing 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
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The set pressures and rates used during ventilator-generated
NIPPV are usually similar to peri-extubation endotracheal ventilation 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 pressures 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 highpressure 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 intervals. 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 unclear. 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 transmission 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
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 majority 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 difference 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 spontaneous 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 oxygen 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 frequency of apnea.
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
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.
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 unstable 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 reported 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 proinflammatory 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]
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
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
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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 thoracoabdominal 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 desaturations and bradycardias with sNIPPV than with nsNIPPV. However, 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 reported 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).
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 plethysmography (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 initiation 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 proportional pressure support [61]. Non-invasive NAVA in children provides 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?
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]. Synchronization 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 infants, 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
Although devices are available, data suggest that synchronization 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 using 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 synchronized 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 CPAPdriver-generated NIPPV, and between sNIPPV and nsNIPPV
No randomized controlled trials (RCTs) have directly examined
differences between ventilator-generated and flow-drivergenerated NIPPV, nor between sNIPPV and nsNIPPV. A subanalysis of the 497 infants randomized to receive NIPPV in Kirpalani et al.'s trial [65] reported on the 241 infants who received mainly
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
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Fig. 2. Biphasic continuous positive airway pressure delivered by SiPAP (top), spontaneous breathing recorded by respiratory inductance plethysmography (center) and spontaneous 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 SiPAPgenerated 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 flowdriver 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% confidence 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 protocol 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 ventilatorgenerated group received sNIPPV, whereas 40% of the flow-driver
group received sNIPPV. There was no statistically significant difference 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 respiratory 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
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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 prescribed 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 synchronized, 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 comparison 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 noninvasive 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].
Pressure and lung volume change do not appear to be predominant mechanisms of action during NIPPV, and it has been hard
to delineate benefits of NIPPV in infants who are already established 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 evidence 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.
7.8. Biphasic CPAP vs CPAP as primary respiratory support
9. Conclusion and research agenda
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.
Few studies have examined long-term effects of NIPPV, or the
relative benefits of sNIPPV versus nsNIPPV. Currently, ventilatorgenerated 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 ‘synchronized nasal pressure support’ would more accurately reflect
the techniques.
Future NIPPV research should include:
8. Summary and practice points
NIPPV includes a spectrum of support, from low-pressure, lowrate, 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.
detailed comparisons of NIPPV devices, techniques, and synchronization systems;
studies assessing the impact of NIPPV while correcting for MAP;
adequately designed studies examining long-term outcomes
following NIPPV;
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
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.
[20]
[21]
[22]
Funding sources
[23]
None.
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