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MCC 260101

REVIEW

CURRENT
OPINION NAVA and PAVþ for lung and diaphragm protection
Katerina Vaporidi

Purpose of review
Complications of mechanical ventilation, such as ventilator-induced lung injury (VILI) and ventilator-induced
diaphragmatic dysfunction (VIDD), adversely affect the outcome of critically ill patients. Although mostly
studied during control ventilation, it is increasingly appreciated that VILI and VIDD also occur during
assisted ventilation. Hence, current research focuses on identifying ways to monitor and deliver protective
ventilation in assisted modes. This review describes the operating principles of proportional modes of assist,
their implications for lung and diaphragm protective ventilation, and the supporting clinical data.
Recent findings
Proportional modes of assist, proportional assist ventilation, PAV, and neurally adjusted ventilatory assist,
NAVA, deliver a pressure assist that is proportional to the patient’s effort, enabling ventilation to be better
controlled by the patient’s brain. This control underlies the potential of proportional modes to avoid over-
assist and under-assist, improve patient–ventilator interaction, and provide protective ventilation. Indeed, in
clinical studies, proportional modes have been associated with reduced asynchronies, enhanced
diaphragmatic recovery, and limitation of excessive tidal volume. Additionally, proportional modes
facilitate better monitoring of the delivery of protective assisted ventilation.
Summary
Physiological rationale and clinical data suggest a potential role for proportional modes of assist in
providing and monitoring lung and diaphragm protective ventilation.
Keywords
assisted ventilation, driving pressure, ventilator-induced diaphragmatic dysfunction, ventilator-induced lung injury

INTRODUCTION alveolar wall, hyaline membrane formation, heter-

Positive pressure mechanical ventilation has been used
as a life-saving intervention for patients with acute
respiratory failure for over 70 years [1]. Over the past
20 years, extensive experimental research [2–5] and
landmark clinical studies highlighted the injurious
effects of mechanical ventilation, first on the lung
parenchyma (ventilator-induced lung injury, VILI),
and, more recently, on the diaphragm (ventilator-
induced diaphragmatic dysfunction, VIDD) [6–8].
The means to implement protective mechanical venti-
lation, for both the lung and the diaphragm are cur-
rently major topics in intensive care medicine research
agenda [9]. This review will focus on the potential
role of proportional modes of assist, neurally adjusted
ventilatory assist, NAVA, and proportional assist
ventilation, PAV, in providing protective ventilation.
LUNG AND DIAPHRAGM INJURY
ASSOCIATED WITH ASSISTED
MECHANICAL VENTILATION
Mechanical ventilation promotes lung injury by
over-stretching the alveoli [2]. Disruptions of
ogenous distribution, local and systemic inflamma-
tion are the main characteristics of VILI [2]. Clinical
studies in patients under passive ventilation have
shown that avoiding excessive lung stress by limit-
ing tidal volume and maintaining alveoli open
using PEEP can protect from VILI [6,10,11]. Yet,
lung over-stretch and injury during mechanical
ventilation may occur independently of the venti-
latory mode, and thus VILI should be of concern
not only during controlled but also during assisted
ventilation [12,13].
Although the risk for VILI in patients under
assisted ventilation is presumably less than in pas-
sively ventilated patients, as assisted ventilation
is often used during recovery, and spontaneous
Department of Intensive Care, School of Medicine, University of Crete,
Heraklio, Greece
Correspondence to Katerina Vaporidi, MD, PhD, Department of Intensive
Care, University of Crete, School of Medicine, office 8A4, Heraklio,
Greece. Tel: +30 2810394729; e-mail: vaporidi@uoc.gr
Curr Opin Crit Care 2019, 25:000–000
DOI:10.1097/MCC.0000000000000684

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Respiratory system
KEY POINTS
Proportional modes of assist have the potential to provide lung
and diaphragm-protective ventilation (video abstract, http://
links.lww.com/COCC/A31) by several mechanisms:
 Avoiding diaphragmatic atrophy from over-assist as
tidal volume is not delivered in the absence of patient
effort.
 Permit the function of the protective mechanisms of
control of breathing that limit effort to avoid lung
over-stretch.
 Enable monitoring of driving pressure.
 Minimize injury and prolongation of ventilation
associated with asynchronies.
breathing improves lung mechanics, it is by no
means negligible. It is increasingly recognized that
spontaneous breathing in the presence of preexist-
ing lung injury may induce VILI, and the term
patient self-inflicted lung injury has been proposed
to describe the phenomenon [12,13]. Experimental
data indicate that, in injured lungs, spontaneous
effort may result in regional overstretch as a result of
volume redistribution (pendelluft), and uneven
transmission of negative intrathoracic pressure
[14,15]. Clinical studies have shown an association
between high tidal volume and failure of noninva-
sive ventilation [16], and improved outcome with
use of neuromuscular blockers in early ARDS [17],
suggesting that strenuous spontaneous efforts dur-
ing mechanical ventilation may promote VILI. It is,
therefore, important to provide protective ventila-
tion both in control and in assisted modes. Hence,
similarly to control modes, there is a need to moni-
tor and manage lung distending pressures during
assisted ventilation.
Mechanical ventilation can induce injury not
only in the lungs but also in the diaphragm by an
entirely different process. Resting is not normal for
the diaphragm, and studies have shown that disuse
atrophy of the diaphragm begins soon after initia-
tion of passive mechanical ventilation [7]. Dia-
phragmatic atrophy progresses over time of
inactivity (passive ventilation) [18,19]. Recent stud-
ies have confirmed the clinical significance of dia-
phragmatic atrophy, showing that it is associated
with the need for prolonged mechanical ventilation
and ICU stay [8,20,21]. It has recently been shown
that, similarly to passive ventilation, spontaneous
breathing with high level of assist can result in
diaphragmatic atrophy, highlighting that the mere
presence of spontaneous effort during assisted
ventilation does not protect from VIDD [22,23].
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Therefore, we need to focus on ways to identify
and prevent diaphragmatic atrophy during assisted
&
ventilation [24 ,25].
The proportional modes of ventilatory assist, hav-
ing some fundamental differences from the conven-
tional modes of assist (such as pressure support and
assist volume) in their principles of operation, may
facilitate in providing protective assisted ventilation.
PROPORTIONAL MODES OF ASSIST,
PRINCIPLES OF OPERATION
During assisted ventilation, both the patient and the
ventilator contribute to the pressure required to
overcome the elastic and resistive load during tidal
breathing, according to the equation of motion:
Pmus þ Pvent ¼ V0  R þ V  E þ PEE, where Pmus is the
pressure generated by the patient’s respiratory
muscles, Pvent is the pressure provided by the venti-
lator, V0 and V are the instantaneous flow and
volume, respectively, R and E are the resistance
and elastance of the respiratory system, and PEE is
the elastic recoil pressure at end-expiration [26]. The
defining characteristic of proportional modes, PAV
and NAVA, is that the ventilator-delivered pressure
is adjusted throughout inspiration proportionally to
patient’s effort [26].
In PAV, the ventilator software calculates ela-
stance and resistance using brief end-inspiratory
occlusions performed randomly every few breaths
[27,28] For pressure delivery, the ventilator moni-
tors inspiratory flow and volume and generates
pressure, which is, at any time during inspiration,
the sum of instantaneous flow and volume multi-
plied by an operator-selected gain factor (% assist).
Thus, the ventilator delivers a pressure proportional
to the flow and volume generated by the patient’s
effort, and the operator defines the percentage of
‘unloading’, that is the fraction of total pressure
required for ventilation that will be delivered by
the ventilator [26–28].
In NAVA, the ventilator analyzes the diaphrag-
matic electromyographic (EMG) signal, obtained by
a dedicated nasogastric tube equipped with a series
of EMG electrodes positioned across the diaphragm
[29]. The Pvent delivered is proportional to the EMG
signal (the operator sets the ratio of Pvent in cmH2O
per mV of EMG signal) [26,29]. The triggering vari-
able is the EMG signal in NAVA, and the traditional
flow criterion in PAV. The pressure delivery ends
(cycling off criterion), in NAVA when the EMG
signal subsides, and in PAV when flow decreases
to a preset value (following a decrease in patient’s
effort) [26].
The main difference between proportional and
conventional modes of assist is the relationship
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NAVA and PAVR for lung and diaphragm protection Vaporidi
FIGURE 1. Schematic representation of the relationship
between patient effort and tidal volume in unassisted
spontaneous breathing and different modes of assist: assist-
volume (without backup rate, AVC), pressure support (PS),
proportional modes (Proportional).
between patient effort and tidal volume (VT), Fig. 1
&&
[30,31,32 ]. During unassisted (spontaneous)
breathing, VT increases relatively linearly with
increasing effort. In assist-volume control (AVC)
independent of patient effort, VT is preset, thus
the Pmus–VT relationship is a horizontal line. Pres-
sure support causes a parallel upward shift of the
spontaneous, unassisted Pmus–VT line, as a constant
pressure is added to Pmus. Proportional modes
increase the slope of Pmus–VT, because the pressure
added by the ventilator to Pmus is not constant, but
increases with increasing Pmus. This difference
underlies the physiological basis of the protective
role of proportional modes against lung and dia-
phragm injury, as discussed below.
PREVENTING OVER-ASSISTANCE WITH
PROPORTIONAL MODES
A key feature of the control of breathing system is that
a change in (minute) ventilation is mainly performed
through change of effort/tidal volume, while respira-
tory rate changes only minimally [33,34]. During
assisted ventilation (without backup rate), the respi-
ratory rate is determined by the patient, whereas the
tidal volume is jointly determined by the patient’s
effort, the mode and level of assist, and patient–
ventilator interactions [30,31,33]. An important dif-
ference between proportional and conventional
modes of assist, with paramount implications for
protective ventilation, is the tidal volume provided
in response to patient’s effort (Fig. 1).
Under AVC, once the ventilator is triggered, the
preset VT is delivered, and the resulting minute venti-
lation is the product of this VT and patient’s respiratory
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rate. If this minute ventilation results in a PaCO2 that
is lower than the brain demands, the response of the
&&
control of breathing will be to decrease effort [32 ,33].
Yet, minute ventilation will remain unchanged,
because, as long as the ventilator is triggered, the same
VT is delivered in each breath. Thus, a patient may
appear to maintain spontaneous breathing and nor-
mal blood gases, while, by exerting very little effort,
just adequate to trigger the ventilator, places his/her
diaphragm at risk of disuse atrophy.
Under pressure support, once the ventilator is
triggered, the preset pressure is delivered. In the
absence of any additional patient effort after trig-
gering, the delivered VT depends on respiratory
system mechanics, rising time and cycling off crite-
rion. This VT, known as minimum VT, may be
substantial, if the pressure support is relatively high
and mechanics relatively normal. Therefore, simi-
larly to AVC, if the minute ventilation (product of
minimum VT and patient’s respiratory rate) results
in a PaCO2 that is lower than the brain demands, the
control of breathing system will decrease effort,
potentially to the point that the patient relaxes all
inspiratory muscles after triggering. As a result, in
pressure support, similarly to AVC, a comfortably
breathing patient with normal blood gases, may be
at risk for disuse diaphragmatic atrophy.
The cardinal characteristic of proportional
modes, providing the basis for diaphragm protective
ventilation, is the absence of minimum VT. Under
proportional modes, if the patient relaxes the inspi-
ratory muscles after triggering, the delivered VT will
be close to zero (Fig. 1). Therefore, under propor-
tional modes, patients cannot maintain adequate
ventilation without at least some contraction of the
inspiratory muscles throughout inspiration.
Clinical studies have shown that proportional
modes may facilitate weaning [35–37], and the
prevention or reversal of diaphragmatic atrophy
occurring in control modes, could be a contributing
mechanism. Indeed, a study comparing the change
in diaphragmatic efficiency after controlled
mechanical ventilation between pressure support
and NAVA, showed that NAVA but not pressure
support improved diaphragm function [38].
PREVENTING LUNG OVER-STRETCH WITH
PROPORTIONAL MODES
Normally lung over-stretch is prevented by (a) reflex
mechanisms limiting inspiratory time (Hering–Bre-
uer reflex), and (b) the progressively decreasing abil-
ity of inspiratory muscles to generate pressure at
increasing lung volumes (change in force–length
relationship and decrease of respiratory system com-
pliance) [39,40]. These protective mechanisms can be
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Respiratory system
overridden during mechanical ventilation, especially
with conventional modes. Under AVC, the delivered
volume is completely independent of either the dura-
tion of neural inspiration, or the pressure generated
by the inspiratory muscles (after triggering). Under
pressure support, the duration of mechanical infla-
tion is determined by the preset cycling off criterion
(a value of inspiratory flow), which depends on the
total pressure provided (Pmusþ pressure support), the
rising time and the respiratory system mechanics. As
a result, the neural inspiratory time has limited
impact on the duration of inspiration [41]. Moreover,
a constant, preset pressure, delivered by the ventila-
tor and obviously not affected by lung volume, is
added to the one generated by the patient’s muscles.
Consequently, a decrease of patient’s effort has lim-
ited impact on the delivered volume, as VT depends
on the sum of Pmus and pressure support. Therefore,
under conventional modes of assist, the inherent
mechanisms preventing lung over-stretch are ren-
dered inefficient. On the contrary, proportional
modes of assist allow the unobstructed operation
of these protective mechanisms. First, the duration
of mechanical inflation closely follows patient’s
effort. Hence, if inspiratory time is decreased as a
result of activation of the Hering–Breuer reflex, the
mechanical inspiratory time, and consequently the
delivered tidal volume will be decreased. Addition-
ally, the progressive decrease of patient-generated
pressure at increasing lung volume will be mirrored
by a similar decrease in the pressure provided by the
ventilator. This physiologic rationale is supported by
clinical data: one study examined the effect of appli-
cation of NAVA at increasing levels in healthy vol-
unteers performing maximal lung inflation
maneuvers [42]. This study showed that increasing
NAVA assist was associated with a progressive reduc-
tion of diaphragmatic activity, resulting in minimal
changes in inspiratory capacity. In critically ill ARDS
patients, increasing levels of NAVA assist have been
associated with decreasing patient effort and stable
tidal volume [43]. Moreover, in critically ill patients
during ventilation with PAV, an analysis of the time
course of driving pressure showed that patients were
able to avoid lung over-stretch, as indicated by a
driving pressure below 15 cmH2O, for most (95%)
of the observation period [44 ].
&
MONITORING PLATEAU AND DRIVING
PRESSURE WITH PROPORTIONAL MODES
Although the physiological protective mechanisms
may be operational in proportional modes, their
efficiency in patients with respiratory failure is
unknown. Experimental data indicate that, in the
presence of lung injury or metabolic acidosis, the
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protective mechanisms may be overridden [45,46].
Thus, particularly in patients with lung injury or high
respiratory drive, it is essential to monitor indices of
lung over-stretch, such as plateau or driving pressure.
It should be noted that, in spontaneously breathing
patients under conventional modes of assist, valid
measurements of plateau and driving pressure are
difficult to obtain. First, as it is not feasible to identify
the end of neural inspiration, and, second, because
awake, spontaneously breathing patients would
sense the airway occlusion, and respond by contract-
ing inspiratory or expiratory muscles, making the
measurement invalid [47]. Of course, invasive mea-
surement of transdiaphragmatic (gastric–esophageal)
pressure can identify the presence of inspiratory/
expiratory muscle activity, and provide detailed
information on lung distending pressures.
In proportional modes, the end of mechanical and
neural inspiration are closely linked, thus facilitating
the measurement of driving pressure, particularly in
the absence of expiratory muscle activity. Addition-
ally, the PAV software makes brief end-inspiratory
occlusions, automatically measuring respiratory sys-
tem compliance and driving pressure [27]. Monitoring
of driving pressure during ventilation with propor-
&
tional modes has been reported recently [44 ,48]. The
feasibility of driving pressure measurement during
NAVA ventilation with manual inspiratory pause
was shown in 12 critically ill patients in the early
postoperative period after lung transplantation [48].
Using PAV, we have shown the feasibility of continu-
ous monitoring of driving pressure during assisted
&
ventilation [44 ]. In this study, in 62 patients recover-
ing from respiratory failure, 10% of patients presented
prolonged periods of high driving pressure. Sustained
high driving pressure occurred exclusively in patients
with low respiratory system compliance, emphasizing
the need to closely monitor patients with significantly
impaired mechanics during assisted ventilation.
Moreover, this study showed a large daily variation
of driving pressure, with a coefficient of variation of
19%, highlighting the need for frequent or continuous
monitoring of lung distending pressures in spontane-
ously breathing patients at risk for VILI.
MINIMIZING PATIENT-VENTILATOR
ASYNCHRONIES WITH PROPORTIONAL
MODES
In spontaneously breathing patients during assisted
ventilation, perfect synchrony between neural and
mechanical breath is difficult to achieve. Asynchro-
nies can occur in all modes of ventilation [49–51],
and can cause lung and diaphragm injury both
directly, as well as indirectly, by prolonging the
duration of mechanical ventilation. Indeed, a strong
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NAVA and PAVR for lung and diaphragm protection Vaporidi
correlation between asynchronies, especially in
clusters, and prolonged mechanical ventilation
has been documented in several studies [50–52].
Certain forms of asynchronies, such as prema-
ture cycling-off and ineffective efforts can cause
diaphragmatic contraction during lengthening
(eccentric contraction), which causes sarcomere dis-
ruption and inflammation [53,54]. Other forms of
asynchronies, such as delayed cycling-off and, more
importantly, double triggering, can result in deliv-
ery of high tidal volume, thus promoting VILI [55].
Several studies have shown that ineffective efforts
and double triggering occur often in pressure sup-
port and AVC [50–52].
Proportional modes, by following more closely
the patient’s ventilatory demands have the poten-
&&
tial to reduce asynchronies [56 ]. Indeed, both PAV
and NAVA have been shown to decrease asynchro-
nies, compared with conventional modes of assist
[37,41,57–61]. Improved patient–ventilator interac-
tion is, therefore, another potential way propor-
tional modes may provide lung and diaphragm
protective ventilation.
CONCLUSION
The recognition of the potential adverse effects of
mechanical ventilation has dramatically changed the
way we approach mechanical ventilation. Providing
optimized, personalized mechanical ventilation,
while preserving spontaneous breathing in critically
ill patients is our next target. Proportional modes of
ventilation are readily available tools, which may
facilitate lung and diaphragm protective ventilation.
Clinical trials are now awaited to better characterize
when and how proportional modes can help prevent
ventilator-induced lung and diaphragm injury.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
The author has received lecture fees from Covidien/Med-
tronic.
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