Seminars in Fetal & Neonatal Medicine xxx (2016) 1e7

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Seminars in Fetal & Neonatal Medicine

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Review

Physiology of non-invasive respiratory support

Stamatia Alexiou a, *, Howard B. Panitch b
a
Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
b
The Perelman School of Medicine at The University of Pennsylvania, Division of Pulmonary Medicine, The Children's Hospital of Philadelphia,
Philadelphia, PA, USA

s u m m a r y
Keywords: Non-invasive ventilation (NIV) is used in neonates to treat extrathoracic and intrathoracic airway
Nasal continuous positive airway pressure obstruction, parenchymal lung disease and disorders of control of breathing. Avoidance of airway
Prematurity
intubation is associated with a reduction in the incidence of chronic lung disease among preterm infants
Respiratory distress syndrome
Lung mechanics
with respiratory distress syndrome. Use of nasal continuous positive airway pressure (nCPAP) may help
establish and maintain functional residual capacity (FRC), decrease respiratory work, and improve gas
exchange. Other modes of non-invasive ventilation, which include heated humidified high-flow nasal
cannula therapy (HHHFNC), nasal intermittent mandatory ventilation (NIMV), non-invasive pressure
support ventilation (NI-PSV), and bi-level CPAP (SiPAP™), have also been shown to provide additional
benefit in improving breathing patterns, reducing work of breathing, and increasing gas exchange when
compared with nCPAP. Newer modes, such as neurally adjusted ventilatory assist (NAVA), hold the
promise of improving patienteventilator synchrony and so might ultimately improve outcomes for
preterm infants with respiratory distress.
© 2016 Elsevier Ltd. All rights reserved.

1. Introduction Several subsequent medium-to-large randomized controlled

Non-invasive ventilation (NIV) is used in neonates to treat
extrathoracic and central intrathoracic airway obstruction, to
prevent respiratory failure in infants with apnea of prematurity,
and to correct existing respiratory failure in infants with respiratory
distress syndrome (RDS). In this latter group, NIV has been used in
an effort to prevent initial airway intubation and to maintain
alveolar recruitment after extubation. The trend towards favoring
the use of NIV over invasive ventilation in preterm neonates with
RDS arose from the findings of a survey of respiratory care practices
at eight tertiary care centers, in which one center had a much lower
incidence of bronchopulmonary dysplasia (BPD) among its preterm
survivors than any of the other centers [1]. There were several
differences in care at that center compared with the others,
including the early institution of nasal continuous positive airway
pressure (nCPAP) in all preterm infants with signs of respiratory
distress.
* Corresponding author. Address: 11059 Colket Translational Research Building,
3501 Civic Center Boulevard, Philadelphia, PA 19104, USA. Tel.: þ1 215 590 3749;
fax: þ1 215 590 3500.
E-mail address: alexiouS1@email.chop.edu (S. Alexiou).
trials compared nCPAP to invasive mechanical ventilation for
prevention of BPD or death and showed no advantage [2e4]. Three
meta-analyses of these studies, however, demonstrated a small
advantage of nCPAP for prevention of the composite of BPD and/or
death [5e7]. A recent comparison of nasal intermittent positive
pressure ventilation (NIPPV) to invasive conventional mechanical
ventilation (CMV) also failed to detect a difference between the two
in the prevention of death or development of BPD [8]. There are
differences in the way that positive pressure is delivered to the
airways between NIPPV and CMV. Here we describe the physiologic
effects of non-invasive positive airway pressure and we discuss
similarities and important differences between nCPAP and the
other currently available non-invasive techniques.
2. Effects of non-invasive ventilation
Avoiding airway intubation reduces the risk for laryngeal and
tracheal mucosal injury. When the larynx is not compromised by
the presence of an endotracheal or tracheostomy tube, an infant
may slow and reduce expiratory flow by partially adducting the
vocal cords. This laryngeal “braking” is one method that neonates
normally use to maintain functional residual capacity (FRC) above
the volume that would otherwise result from the greater inward

http://dx.doi.org/10.1016/j.siny.2016.02.007
1744-165X/© 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Alexiou S, Panitch HB, Physiology of non-invasive respiratory support, Seminars in Fetal & Neonatal Medicine
(2016), http://dx.doi.org/10.1016/j.siny.2016.02.007
2 S. Alexiou, H.B. Panitch / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e7
recoil of the lungs relative to the outward recoil of the chest wall
[9,10]. In addition, application of NIPPV may cause laryngeal
adduction during inspiration in newborn lambs via vagally medi-
ated bronchopulmonary receptors [11]. This laryngeal constriction,
which was not present with the application of CPAP but which
increased with increasing tidal volumes, could represent a protec-
tive mechanism to prevent lung overdistension. It could, however,
also limit the utility of NIV by diminishing the size of delivered tidal
volumes and add to patienteventilator dys-synchrony due to
inspiratory laryngeal obstruction.
The absence of an endotracheal tube and preservation of
laryngeal function may also reduce the risk for nosocomial pneu-
monia and sepsis. There is some suggestion that endotracheal tube-
associated airway colonization with Gram-negative bacteria creates
a moderate risk for bloodstream infections in mechanically venti-
lated neonates [12]. The same study also demonstrated an associ-
ation between the presence of Gram-negative bacteria recovered
from the airway and severe BPD. Whether avoidance of endotra-
cheal intubation alone reduces the risk for BPD remains to be
determined.
Although laryngeal and tracheal injury may be avoided with
non-invasive techniques, damage to facial structures and even
intracranial lesions reported after the earliest uses of nCPAP and
NIPPV have been ascribed to the interfaces and fixation devices
used to deliver positive pressure non-invasively. In older devices,
early application of CPAP or NIPPV via an oronasal mask secured by
a Velcro strap across the occiput in neonates <1501 g was associ-
ated with flattening of the skull at the occiput and with intra-
cerebellar hemorrhages [13]. A mesh netting fixation device was
used to overcome this problem [14], but lack of access to the in-
fant’s oropharynx for suctioning, gastric distension, and nasal
obstruction from displacement of the mask remained as problems
with the use of oronasal masks [15]. Subsequently, nasal prong
systems of various lengths were described that overcame some of
the problems of oronasal masks or headboxes [16e18]. Fixation
devices now employ a bonnet to avoid cranial vault deformation,
but displacement of interfaces may still be problematic. Short bi-
nasal prongs have been shown to be superior to single-prong sys-
tems in terms of ameliorating symptoms of respiratory failure or
need for reintubation [19]. This is likely the result of reduced
resistance through the bi-nasal system [20], as well as avoidance of
leak from the contralateral nostril, both of which lead to better
pressure transmission to the airways. Nevertheless, injury to the
philtrum, columella, and nasal septum as well as circumferential
dilation of the nares and snubbing of the tip of the nose have been
described with bi-nasal prong systems [21e26]. Nasal masks have
also been used to deliver positive pressure to the airways of
neonates, but these have a rate of skin injury similar to that of bi-
nasal prongs [26].
Intestinal distension has also been described as a complication
of either nCPAP or NIPPV use in neonates. In older studies,
gastrointestinal perforation [27] and benign diffuse intestinal
distension [28] were associated with nCPAP or NIPPV use. Perfo-
rations were more widely found in those infants who had experi-
enced perinatal asphyxia, and it was speculated that increased
intraluminal pressure from aerophagia damaged a bowel wall
already compromised by relative ischemia [27]. The resting pres-
sure of the upper esophageal sphincter (UES) has not been reported
in sick neonates, but among healthy infants it was 28.9 ± 10 cmH2O
[29]. It is conceivable that the threshold UES opening pressure in a
neonate with respiratory distress is frequently surmounted by the
positive pressures applied through the nose, leading to aerophagia
and gaseous distension of the bowel. Among anesthetized children
aged <1 year, gastric insufflation occurred during facemask pres-
sure control ventilation with inspiratory pressures of 15 cmH2O in
Please cite this article in press as: Alexiou S, Panitch HB, Physiology of non-invasive respiratory support, Seminars in Fetal & Neonatal Medicine
(2016), http://dx.doi.org/10.1016/j.siny.2016.02.007
50%, with some experiencing gastric insufflation with pressures as
low as 10 cmH2O [30]. Importantly, most neonates tolerate appli-
cation of nCPAP or NIPPV with few gastrointestinal complications,
and even those with significant bowel distension do not routinely
have coexisting feeding intolerance [28]. The excessive intestinal
distension described in some of the earlier studies of neonatal NIV
may not be as great a problem with the advent of newer nCPAP and
NIPPV systems: for instance, it was not listed as a complication
among 1009 extremely low birth weight infants in a recent NIPPV
trial [31].
3. Physiologic effects of non-invasive respiratory support
In older children and adults, resting lung volume, or functional
residual capacity (FRC), is passively determined, as the balance of
two opposing forces e between the inward recoil of the lung and
the outward recoil of the chest wall. In infants, however, the chest
wall is more compliant [32] favoring the inward recoil of the lung. If
left to the passive balance of these forces, end-expiratory lung
volume would be proportionally lower in infants compared with
that of older children and adults. Airway closure would also occur
during normal exhalation [33] leading to ventilationeperfusion
mismatch and hypoxemia. To prevent this, infants utilize several
maneuvers to maintain FRC above the passively determined end-
expiratory lung volume. These include laryngeal braking [9,34],
contraction of inspiratory muscles during exhalation to decrease
expiratory air flow [10], and a reduced exhalation time. Together,
these prevent emptying of lung units, thereby causing breath
stacking or dynamic hyperinflation [35].
The disparity between chest wall and lung compliances is
heightened in neonates with surfactant deficiency or parenchymal
lung disease. Under normal circumstances, the horizontal attitude
of the neonate's ribs along with the circular shape of the neonatal
thorax result in a much smaller contribution of rib cage expansion
to tidal volume compared with the abdominal (diaphragmatic)
contribution [36]. Instead, intercostal muscle contraction serves to
stabilize the chest wall and prevent the loss of tidal volume that
would result from inward movement of the thorax with diaphragm
contraction. The excessively negative intrathoracic pressure needed
to expand poorly compliant lungs in surfactant-deficient neonates
can easily overcome this thoracic preservation of tidal volume. The
clinical manifestation of this is reflected in severe sternal and
intercostal retractions. To compensate for the loss of thoracic vol-
ume, diaphragmatic displacement doubles to maintain an adequate
tidal volume [37]. The neonatal diaphragm and intercostal muscles
contain fewer type I muscle fibers than are found in older infants,
thus increasing the risk of muscle fatigue [38]. In addition, the
lower lung compliance exaggerates the discrepancy between that
of the lung and chest wall compliances, further reducing FRC and
compromising gas exchange [39e44]. These disadvantages make it
difficult for neonates to overcome increased respiratory loads,
rendering them susceptible to atelectasis and respiratory failure
[32].
3.1. Physiology of continuous positive airway pressure
Application of CPAP improves lung compliance and uniformity
of ventilation by preventing de-recruitment of alveoli and collapse
of small airways during exhalation in the surfactant-deficient lung
[45]. Following reversal of atelectasis, previously constricted blood
vessels dilate, leading to an increase in pulmonary blood flow. This
improves ventilationeperfusion matching, decreases intra-
pulmonary shunting, and lowers the PaCO2 [46e48]. Animal
models have also shown that CPAP can improve type II pneumocyte
function and conserve surfactant by reducing the protein leak
 S. Alexiou, H.B. Panitch / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e7
associated with atelectasis [49]. Use of CPAP may also improve
central intrathoracic airway function [50]. It maintains airway
patency in those infants with abnormally collapsible central
airways either by redistributing the intraluminal pressure gradient
or by increasing lung volume [51,52]. In the extrathoracic airway,
CPAP increases the pharyngeal cross-sectional area and decreases
resistance.
Treatment with CPAP also affects control of breathing. Preterm
neonates are at risk for apnea, which may result from an imma-
ture central drive, upper airway obstruction, or an increase in
respiratory load. CPAP reduces obstruction of the extrathoracic
airway by serving as a stent to maintain airway patency. The
maintenance of airway patency with nCPAP is most likely a
passive phenomenon, since genioglossus electromyographic ac-
tivity decreases in response to the pharyngeal distension that
results from CPAP application during sleep in healthy adults [53].
The effects of CPAP on respiratory drive are not completely un-
derstood. CPAP has been shown to alter the HeringeBreuer
inflation reflex by allowing infants to adjust to increased respi-
ratory loads [54]. Further, it was suggested that CPAP improved
apnea through constant nasopharyngeal stimulation [55], pre-
sumably through activation of laryngeal afferent mechanorecep-
tors [56]. In addition, lower rib cage distortion has been shown to
inhibit inspiration through stimulation of the intercostal phrenic
inhibitory reflex [57]. Through its ability to stabilize the chest
wall, CPAP can suppress this reflex. Clinically however, nCPAP was
shown to improve obstructive but not central apneas in neonates
[58]. Another suggested mechanism by which CPAP prevents
apneas includes a reduction in the number of sleep disturbances
caused by airway obstructions [47]. Importantly, whereas CPAP
can alter lung and chest wall mechanics and reduce a neonate's
work of breathing, it does not help an infant maintain ventilation
during apneic episodes.
3.2. Physiology of non-invasive positive pressure ventilation
The goal of NIPPV is to provide greater ventilatory support over
that achieved with nCPAP, or to reduce respiratory work. In addi-
tion to supplying a baseline supra-atmospheric pressure
throughout exhalation, NIPPV also periodically provides a positive
pressure above baseline and can maintain alveolar ventilation
during apneic episodes. This causes an increase in mean airway
pressure above that developed with nCPAP, and so can improve
oxygenation by maintaining alveolar recruitment. The higher
pressures above CPAP can also enhance tidal volumes, improving
CO2 elimination. Pressure-controlled breaths are either machine-
triggered (non-synchronized) or patient-triggered (synchronized).
Synchronized NIPPV (nSIPPV), when compared with nCPAP, aug-
ments tidal volume (Vt) while simultaneously reducing inspiratory
work, as reflected in esophageal pressure measurements [48]. In
addition, minute ventilation (VE) increased and transcutaneous CO2
(TcCO2) values decreased, even though the respiratory rate was
lower when infants were supported with nSIPPV. In contrast, using
a device that employed respiratory inductance plethysmography
and abdominal wall motion to trigger and cycle positive pressure
breaths in a pressure support mode, Ali et al. found no difference in
Vt or VE between preterm neonates supported with either nCPAP or
non-invasive pressure support ventilation (NI-PSV) [46]. In a post-
hoc analysis, however, those infants with TcCO2 55 mmHg
demonstrated an increase in Vt and VE when supported with NI-
PSV whereas those with TcCO2 <55 mmHg did not. All subjects
generated lower esophageal pressures, suggesting unloading of
respiratory muscles, and less thoracoabdominal asynchrony in
NI-PSV mode compared with nCPAP [46].
Please cite this article in press as: Alexiou S, Panitch HB, Physiology of non-invasive respiratory support, Seminars in Fetal & Neonatal Medicine
(2016), http://dx.doi.org/10.1016/j.siny.2016.02.007
3
There are potential problems associated with nCPAP or NIPPV
support beyond those related to interfaces. Whereas the goal of
nCPAP and NIPPV is to provide enough distending pressure to
optimize alveolar recruitment, there is always the risk of over-
distending lung units and decreasing lung compliance. A reduction
in lung compliance may lead to a decrease in Vt and consequently
to an increase in PCO2 and dead-space ventilation. These forms of
support, just like invasive ventilation, apply positive pressure to the
respiratory system and so may cause complications such as pneu-
mothorax, pulmonary interstitial emphysema, or pneumo-
mediastinum [59]. In a large randomized controlled clinical trial in
25e28-week gestation newborns treated with either nCPAP or
intubation with mechanical ventilation, there was a 9% incidence of
pneumothorax in the nCPAP group compared with 3% in the intu-
bated group [3]. In contrast, a similar randomized controlled trial in
24e27-week gestation newborns found no difference in pneumo-
thorax between those treated with nCPAP and intubation [4]. Lung
overdistention also increases intrathoracic pressure, which may
reduce venous return to the heart and lower cardiac output [60], or
delay venous return from the head and increase intracranial pres-
sure [61].
4. CPAP delivery modalities
The devices that generate nCPAP are broadly categorized by
whether they provide constant or variable flow. Constant flow
systems include CPAP generated by a mechanical ventilator and
bubble CPAP systems. Bubble CPAP flow is set by the clinician: gas
flow is increased until bubbling is achieved, whereas air leakage
can be detected by the disappearance of bubbling. The distending
pressure is dependent on the depth to which the expiratory limb of
the circuit is submerged in liquid. Pressure oscillations occur due to
gas bubbling within the liquid, and the magnitude of the oscilla-
tions is dependent on the flow rate. The pressure oscillations mimic
high-frequency oscillatory ventilation and they may contribute to
gas exchange [62]. A premature lamb model evaluating the effect of
bubble versus ventilator-derived CPAP showed that lambs treated
with bubble CPAP rather than ventilator CPAP had less ventilation
inhomogeneity, lower respiratory quotients, and higher PaO2
values at 150 min of life. These findings suggest better volume
recruitment and maintenance of peripheral airway patency with
bubble compared to ventilator CPAP [63]. Increasing the magnitude
and frequency of the bubble oscillations can promote alveolar
recruitment and stabilize the lungs through a phenomenon called
“stochastic resonance,” defined as the ability to enhance a weak
signal by adding “noise” to it. However, others disagree with this
theory and believe that the effects of oscillations applied at the
airway opening become attenuated as they reach alveoli, making it
unlikely that they enhance ventilation [64].
Variable flow CPAP systems utilize fluidic flow-opposition
systems that are modifications of the Benveniste valve [65]. Such
systems direct jets of gas through narrow orifices into the nasal
prongs where the flow decelerates as the tube diameter increases;
this results in an increase in pressure in accordance with the Ber-
noulli principle. If inspiratory flow demand increases, additional
gas is entrained from the expiratory tubing to maintain flow
demand and pressure. On exhalation, the gas jet flips and directs
flow to the expiratory circuit, potentially enhancing patient comfort
[59,65].
Several studies have evaluated different CPAP generating
systems and their effects on physiologic measurements such as
work of breathing, breathing pattern and assessments of gas
exchange. However, device comparisons have been hampered by
use of different nasal interfaces (short bi-nasal and single-nasal
4 S. Alexiou, H.B. Panitch / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e7
prongs, long nasopharyngeal single-prong systems) and hetero-
geneous patient populations [19]. As such, no one CPAP system
has been considered superior to others when outcomes such as
duration of support or extubation failure are used as endpoints.
One recent randomized controlled trial compared variable-flow
to bubble CPAP in preterm infants with respiratory distress
syndrome [66]. Both delivery systems were found to be effective
for post-extubation respiratory support, but, in a secondary
subgroup analysis among the infants who required mechanical
ventilation for 14 days, bubble CPAP decreased the time needed
on support by 50% and reduced the post-extubation failure rate.
No difference was seen among the infants who required >14 days
of mechanical ventilation [66]. This finding has been interpreted
as an endorsement for bubble CPAP use in infants prone to
develop atelectasis, since its oscillations in pressure may better
maintain lung volume recruitment [65]. Such claims, however,
require further investigation. In a more recent study, there was
no benefit between continuous and variable-flow devices in the
prevention of airway intubation in preterm infants within the
first 6 h of life [67].
5. Heated, humidified high-flow nasal cannula therapy
Early reports demonstrated that administration of supplemental
oxygen by standard nasal cannulae could provide end-expiratory
distending pressure and improve breathing patterns in preterm
infants compared to no support [68]. This observation and the
intolerance of nCPAP interfaces in some neonates led to an interest
in using higher gas flow rates through standard nasal cannulae. By
heating and highly humidifying the delivered gas, higher flow rates
can be delivered to patients without drying the proximal airways.
The heat and humidification are integral to the success of the
therapy, as even brief use of gas at room temperature and humidity
in preterm neonates is associated with a decrease in pulmonary
compliance and conductance [69]. Furthermore, by heating the gas
to body temperature and fully saturating it, metabolic demand,
including oxygen consumption and CO2 production, is minimized
[70]. This is one possible mechanism by which high-flow therapy
can reduce ventilatory demand.
Many investigators have compared the pressure generated in
the nasopharynx or esophagus with heated, humidified high-flow
nasal cannula therapy (HHHFNC) with that generated by nCPAP
[71e73]. The pressure generated is determined not only by the flow
rate, but also by the size of the nasal cannula relative to the nares
and the degree of leak from both the nose and the mouth [68,74].
Thus, pressures might vary considerably depending on body posi-
tion and whether the mouth is kept closed or allowed to be open.
Distending pressure, however, may not be the only way in which
HHHFNC therapy affects ventilation. In an oleic acid lung injury
model, neonatal piglets were supported with either nCPAP or
HHHFNC therapy [75]. Intra-tracheal pressures were similar
between the therapies at the same flow range, but HHHFNC therapy
resulted in a flow-dependent reduction in PaCO2 and increase in
PaO2 up to a threshold determined by the volume of the naso-
pharyngeal dead space. No such relationship was seen with gradual
increases in CPAP from 2 to 6 cmH2O. The authors concluded that
the major effect of HHHFNC therapy on gas exchange was to wash
out the nasopharyngeal dead space, thereby maximizing ventila-
tory efficiency.
Another mechanism by which HHHFNC therapy can help
improve gas exchange relates to a decrease in resistance across the
nasopharynx [70]. High flow rates can match or surpass the
patient's peak inspiratory flow, reducing airway resistance in the
nasopharynx and improving work of breathing. Measures of work
Please cite this article in press as: Alexiou S, Panitch HB, Physiology of non-invasive respiratory support, Seminars in Fetal & Neonatal Medicine
(2016), http://dx.doi.org/10.1016/j.siny.2016.02.007
of breathing in neonates supported with HHHFNC between 3 and
5 L/min were comparable to values obtained when the infants were
supported with 6 cmH2O nCPAP [76]. Esophageal pressures were
lower than those with nCPAP under conditions of the highest
HHHFNC flow, suggesting that factors other than lung distension
improved respiratory mechanics.
Despite the potential advantages of HHHFNC therapy, studies
have failed to show any significant difference in post-extubation
success rates among patients being initially supported with
HHHFNC versus nCPAP [77e79]. One limitation to the use of
HHHFNC is the inter- and intra-subject variability in pressures that
can be generated. The relative size of the nasal cannula to the nares,
and the presence or absence of leak through the mouth add to the
variability of those pressures. With current systems, the absence of
a pressure-limiting valve in the circuit to prevent delivery of
excessive pressures remains a potential concern.
6. Modes of NIPPV support
The modes of NIPPV used in neonates differ somewhat from
those used in older children and adults. At present, there are no
reports of the use of neonatal non-invasive bi-level pressure
support ventilation, where each breath is patient (flow or
pressure)-triggered and flow-cycled. This mode, with or without a
set backup rate of pressure-limited, time-cycled breaths, is usually
called bi-level positive airway pressure (BLPAP) when adminis-
tered to older children and adults. One neonatal study did, how-
ever, examine the effect of non-invasive pressure support
ventilation in preterms, using abdominal motion detected by
respiratory inductance plethysmography for trigger and cycle
signals [46]. However, that equipment is currently not commer-
cially available. The various modes of neonatal NIPPV that have
been described in infants include: nasal intermittent mandatory
ventilation (NIMV), non-invasive pressure support ventilation (NI-
PSV), and bi-level CPAP (SiPAP™). Characteristics of these mo-
dalities are outlined in Table 1.
The systems used to deliver NIPPV are inherently “leaky” and
small preterm infants may not generate an inspiratory pressure or
flow signal at the equipment interface that is large enough for a
ventilator to detect. Thus, alternate signals based on abdominal
movement or diaphragm electrical signals have been used to detect
patient effort for patienteventilator synchronization. Even with
adequate means to detect patient effort, synchronized NIMV (S-
NIMV) has not always resulted in significant increases in Vt or VE
over non-synchronized NIMV [80]. The mode of ventilation used,
however, might have influenced those findings. Chang et al. used
IMV rates of 20 and 40 breaths/min in NIMV and S-NIMV modes,
but respiratory rates of their subjects were routinely higher [80].
Thus, many breaths were unsupported and so the contribution of
those breaths to total VE or average Vt could have minimized dif-
ferences. Importantly, in NIMV mode, 56% of the mandatory
breaths were delivered as the subjects were exhaling, whereas
similar patienteventilator dys-synchrony was seen only 5% or 6% of
the time during S-NIMV. When compared to NIMV and nCPAP,
synchronization of positive pressure breaths with patient effort
results in a reduction of spontaneous breathing effort as reflected
by lower esophageal pressure swings [80,81]. This suggests that S-
NIMV is better than either NIMV or nCPAP at respiratory muscle
unloading and reducing work of breathing. Because of the diffi-
culties with signaling and a lack of evidence for the superiority of
S-NIMV over NIMV, non-synchronized IMV is used more frequently
in the USA at present [31].
Non-invasive pressure support ventilation (NI-PSV) works
similarly to its invasive counterpart. The ventilator delivers a
 S. Alexiou, H.B. Panitch / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e7
Table 1
Modalities of nasal intermittent positive pressure ventilation.
Modality Variables set Trigger Cycle
Bi-level Low CPAP, high CPAP, Machine High CPAP is cycled by the Noa
CPAP R, Ti set Ti
NIMV R, PEEP, Ti, PIP or Vt Machine Time
S-NIMV Rate, PEEP, Ti, PIP or Machine or Time
Vt patient
NI-PSV PEEP, PS Patient Patient
CPAP, continuous positive airway pressure; R, rate; Ti, inspiratory time; PEEP, positive end-expiratory pressure; PIP, positive inspiratory pressure; Vt, tidal volume; PS, pressure
support; RIP, respiratory inductance plethysmography.
a
Limited ability to use in a synchronized mode. Not currently available in the USA.
b
Ventilator used is no longer commercially available.
pre-set pressure over the baseline positive pressure in response to
a patient trigger, and the breath cycles to exhalation when the flow
decreases to a specified percentage of peak flow based on the
resistance and compliance of the patient's respiratory system. As
noted, the trigger reported in neonates has relied on abdominal
motion [46]. Other studies have used similar triggering schemes to
provide synchronized support, but the delivered breaths are time-
cycled, making this a form of non-invasive assist/control ventila-
tion [82].
Bi-level CPAP allows the infant to breathe spontaneously at a
baseline CPAP as well as at a second, higher level of CPAP for a
variable time and at a variable rate. This second pressure level
mimics a sigh breath for the infant. The transition between
pressures is slow relative to the infant's inspiratory time, allowing
it to be well tolerated. Alveolar ventilation is dependent on the
infant's spontaneous VE as well as the VE created by the transition
between the two pressures. These “sighs” are not synchronized
with the patient's spontaneous breath; however, patient-
triggered (synchronized) bi-level CPAP is available outside of the
USA. A recent study demonstrated no increase in Vt as a function
of synchronizing bi-level CPAP, and a spontaneous respiratory rate
>55 caused fewer bi-level CPAP breaths to reach their designated
pressure peak [83]. Episodic breathing at the higher CPAP is
intended to recruit alveoli, maintain end-expiratory volume, and
reduce apnea [84]. One study has shown that infants supported
with bi-level CPAP compared to nCPAP required less supple-
mental oxygen, were mechanically ventilated for shorter periods
of time, and were discharged sooner [85]. Bi-level support was
also found to produce a short-term increase in PaO2 and decrease
PaCO2 compared with nCPAP in preterm infants following extu-
bation [86].
7. Neurally adjusted ventilatory assist
During spontaneous breathing, a respiratory signal originating
in the brainstem travels via the phrenic nerve to the diaphragm,
causing electrical excitation of the diaphragm. The diaphragm
contracts and produces negative pressure within the chest,
causing lung expansion and ventilation. Central and peripheral
chemoreceptors as well as pulmonary stretch receptors provide
feedback to adjust respiratory drive. One of the limitations of
non-invasive ventilation is that the level of applied support
cannot be regulated proportionally to the patient’s effort with
each breath [87]. The need for improved patienteventilator
synchrony has led to the development of neurally adjusted
ventilatory assist (NAVA). Originally available as an invasive mode
of ventilatory support, it can now be applied non-invasively
(NIV-NAVA) through nasal prongs, a mask, or a nasopharyngeal
tube. NIV-NAVA has been used successfully in preterm infants
recovering from RDS [88]. In supplying either invasive or non-
Please cite this article in press as: Alexiou S, Panitch HB, Physiology of non-invasive respiratory support, Seminars in Fetal & Neonatal Medicine
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5
Synchronized? Comments
Trigger synchrony is possible when using a Graseby capsule [82,83].
Breaths are time cycled.
No e
Yes Trigger synchrony is possible when using abdominal capsule.
Yesb Breaths can be triggered and cycled using RIP [46]
invasive support, NAVA utilizes the electrical activity of the dia-
phragm (EAdi) as determined by the patient’s respiratory drive as
a trigger to synchronize and adjust the magnitude of mechani-
cally supported spontaneous breaths [89]. A specialized naso-
gastric catheter, containing eight to ten bipolar electrodes, is
positioned in the lower esophagus at the level of the crural dia-
phragm to measure the EAdi signal.
NAVA has the advantage of triggering and delivering a peak
inspiratory pressure that is directly proportional to the EAdi [88].
The breath is cycled when the electrical activity decreases by 30% to
70%. This allows the patient to determine peak inspiratory pressure,
inspiratory and expiratory time, and respiratory rate [87]. For each
breath, the peak pressure is determined by the formula:
Peak pressure ¼ NAVA level (cmH2O/mV)  EAdi (peak  min)
(mV) þ PEEP (cmH2O).
The NAVA level determines how much work the patient does
compared to the ventilator: as the level increases, the workload is
transferred from the respiratory muscles to the ventilator. The level
should be initially set so that the peak pressure delivered is similar
to that from conventional ventilation. The level reaches a “break-
point” when optimal respiratory muscle unloading has been
attained. Any further increase in the NAVA level will result in a
decrease in the EAdi peak, suggesting a decrease in respiratory
drive due to overventilation. NAVA is presently the only mode of
ventilation that allows effective triggering even in the presence of
large air leaks (~75%) [88,90]. Despite multiple studies showing
improved patienteventilator synchrony [88,91,92], it cannot be
used in patients whose respiratory drive is unable to produce a
robust and steady EAdi signal and it may be inappropriate for
extreme preterms, those with sepsis, and those with neurologic
injury [90]. Prospective studies are needed to determine if the use
of NAVA has any effect on clinical outcomes or the incidence of BPD
in preterm infants.
8. Conclusion
Non-invasive ventilation has been shown to be an effective
strategy for reducing respiratory distress in neonates by optimizing
pulmonary mechanics, improving ventilation and oxygenation, and
reducing work of breathing. Despite the multiple choices available
to clinicians, no single mode is clearly superior over the others.
Newer modes, such as NAVA, are designed to improve synchroni-
zation, which has the potential to enhance the benefits of
non-invasive ventilation. Whereas the initial goal is to avoid intu-
bation in an effort to prevent ventilator-induced lung injury,
long-term studies are needed to determine the effectiveness of
non-invasive ventilation for reducing bronchopulmonary dysplasia
and improving neurodevelopmental outcomes.
6 S. Alexiou, H.B. Panitch / Seminars in Fetal & Neonatal Medicine xxx (2016) 1e7
Practice points
 The respiratory physiologic derangements of premature
birth are well understood; the various aspects of me-
chanical ventilatory support are directed to correct them.
 Use of NIV can ameliorate respiratory distress, prevent
intubation, and reduce the risk of post-extubation failure
by optimizing pulmonary mechanics, reducing metabolic
demand, and improving gas exchange.
 One of the biggest challenges of non-invasive positive
pressure ventilation is the ability to maintain patient
eventilator synchrony. Newer modes such as NAVA may
overcome these limitations, but need further testing.
Research directions
 Methods to improve patienteventilator synchrony.
 Randomized trials to determine relative superiority of
various modes of NIPPV.
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