Journal Pre-proof

Novel forms of ventilation in neonates: neurally adjusted ventilatory

assist and proportional assist ventilation

RL McKinney , L Wallström , SE Courtney , R Sindelar

PII: S0146-0005(24)00015-6
DOI: https://doi.org/10.1016/j.semperi.2024.151889
Reference: YSPER 151889

To appear in: Seminars in Perinatology

Please cite this article as: RL McKinney , L Wallström , SE Courtney , R Sindelar , Novel forms of
ventilation in neonates: neurally adjusted ventilatory assist and proportional assist ventilation, Semi-
nars in Perinatology (2024), doi: https://doi.org/10.1016/j.semperi.2024.151889

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 Novel forms of ventilation in neonates: neurally adjusted ventilatory assist and

proportional assist ventilation

McKinney RL1#, Wallström L2, Courtney SE3, Sindelar R2

1
Alpert Medical School of Brown University, Providence, Rhode Island
2
Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
3
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR

#
Corresponding author: Associate Professor Robin McKinney, MD

Address: 593 Eddy Street, Providence, RI 02906

Email: robin.mckinney@lifespan.org

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Disclosure: The authors report no potential conflicts of interest (Authors please confirm

complete and correct).

ABSTRACT

Patient-triggered modes of ventilation are currently the standard of practice in the care of term

and preterm infants. Maintaining spontaneous breathing during mechanical ventilation

promotes earlier weaning and possibly reduces ventilator-induced diaphragmatic dysfunction.

A further development of assisted ventilation provides support in proportion to the respiratory

effort and enables the patient to have full control of their ventilatory cycle. In this paper we

will review the literature on two of these modes of ventilation: neurally adjusted ventilatory

assist (NAVA) and proportional assist ventilation (PAV), propose future studies and suggest

clinical applications of these modes.

INTRODUCTION

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 Mechanical ventilation has been used for decades in preterm infants to provide

respiratory support in patients with respiratory insufficiency. There are multiple modes of

conventional ventilation in neonates, which mainly use a flow trigger to synchronize the

ventilator with the patient’s spontaneous breathing effort. Synchronization is important

because asynchrony can cause volutrauma [1, 2], fluctuations in cerebral blood flow with risk

of intraventricular haemorrhage (IVH) [3, 4], respiratory distress, and suboptimal ventilation

and oxygenation [5]. Synchronized intermittent mandatory ventilation (SIMV) and assist

control (A/C) ventilation are the two most widely used modes of conventional mechanical

ventilation. In SIMV a user-selected number of breaths is supported by mechanical inflations,

while the rest are either unsupported or augmented with a flow-cycled, pressure-controlled

amount of pressure, known as pressure support (PS). In A/C all spontaneous breaths are

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supported, resulting in more even tidal volume. Synchronization has been shown to reduce the

work of breathing compared with intermittent mandatory ventilation, with A/C having been

shown to unload the diaphragmatic workload more than SIMV [6]. Trigger systems that detect

flow (or pressure) changes are adversely affected by leak around uncuffed endotracheal tubes

and can lead to asynchrony with the mechanical inflations due to insufficient sensitivity or

delayed trigger response, and consequently lead to missed spontaneous breaths, triggering on

expiration, or inappropriate triggering (auto-cycling) due to artefactual signals [7].

Neurally adjusted ventilatory assist (NAVA) and proportional assist ventilation (PAV)

are two novel modes of ventilation that use the diaphragmatic electrical activity (Edi) and the

airflow changes detected by a pneumotachograph (PNT), respectively, to adjust the inflation

pressure continuously in response to the ongoing breathing effort of the patient. Thus, the

patient controls the support of the ventilator throughout the respiratory cycle and defines both

the peak inflation pressure and inspiratory time. The focus of this review is the physiology,

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limitations and evidence behind the proposed benefits of these modes of ventilation as applied

in neonates.

NEURALLY ADJUSTED VENTILATORY ASSIST

Neurally adjusted ventilatory assist (NAVA) uses the electrical activity of the diaphragm

(Edi) to regulate the applied ventilator pressure. The Edi signal, registered by a nasogastric tube

with nine electrodes (Edi catheter) and placed near the diaphragm, is used to trigger inflation

and to determine the level of inflation pressure throughout the cycle (Figure 1) [8-10]. Stronger

inspiratory effort leads to more engagement of the diaphragm and larger electrical activity as

sensed by the Edi catheter, triggering inflation pressures in proportion to the measured voltage

amplified by the user-selected NAVA level (cmH2O/µV) above the set positive end-expiratory

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pressure (PEEP) [11, 12]. Compared to other triggering devices, Edi is a relatively stable signal

that has minimal trigger delay and is unaffected by movement or airflow artefacts [13]. The

ventilator displays the maximal Edi and the minimal Edi, the former being the maximal

diaphragmatic electrical activity reached at peak inspiration [14], and the latter being the

diaphragmatic electrical activity at end-expiration (or the tonic diaphragm activity),

representing the activity at functional residual capacity (FRC) [10]. Peak inflation pressure

(PIP) is calculated as:

PIP (cmH2O) = NAVA level (cmH2O/µV) X (Edi max – Edi min [µV]) + PEEP (cmH2O)

The clinical application of NAVA has been studied both in preterm and term newborn

infants and compared to different patient triggered modalities, but no long term randomized

controlled trials (RCTs) have been performed. In multiple small short-term cross-over studies

in infants with respiratory distress syndrome (RDS) or evolving bronchopulmonary dysplasia

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(BPD), NAVA has been shown to reduce the peak inflation pressure (PIP), the fraction of

inspiratory oxygen, and the work of breathing compared with other conventional flow- or

pressure-triggered ventilation modes [15-26]. Theoretically this should be a more lung

protective strategy with less chance of volutrauma, barotrauma and formation of reactive

oxygen species implicated in pulmonary complications of preterm birth. Because NAVA was

first developed for adult patients, the concern has been that very premature infants with

immature respiratory control will poorly regulate their own PIPs and tidal volumes (VT). The

paper by Protain et al [26] attempts to put to rest this concern, but their findings that about 50

% of tidal volumes were less than 2mL/kg are implausible with conventional ventilation. The

use of proximal (ventilator end of the circuit) measurement and reliance on the circuit

compensation feature that does not function well in small infants with uncuffed endotracheal

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tubes, the reported VT is clearly inaccurate. The concern is that none of the published studies

looked at long term outcomes, and a Cochrane Review from 2017 found the predefined

objectives of primary or rescue treatment with NAVA in reducing BPD, mortality, or morbidity

(IVH, periventricular leukomalacia [PVL] or pneumothorax), were met in only one out of 17

selected studies. It was thus not considered as a fully validated mode of ventilation [18, 27].

This review illustrates the current lack of good clinical data regarding the safety clinical

efficacy of NAVA. However, NAVA has been shown to be potentially clinically useful as a

weaning modality, especially in larger, more mature infants. A multi-centre review of current

clinical practice showed it was successfully used as a weaning mode of ventilation in 67% of

infants with severe BPD (sBPD) [28].

NAVA’s greatest potential benefit, the ability to optimize patient-ventilator synchrony

and comfort, is also the hardest to measure. With conventional flow triggered ventilation in

older preterm infant sedation is often needed to allow them to synchronize and tolerate being

intubated. By allowing the patient to control their own ventilation without wasted breaths or

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asynchrony, less sedation can potentially be used with NAVA. A retrospective trial of infants

with sBPD showed a reduced need for sedation in infants who transitioned to NAVA [29, 30].

Less sedation improves the ability to participate in developmentally appropriate activities,

which could lead to better neurological and developmental outcomes. Currently long-term

neurodevelopmental outcome data on infants ventilated with NAVA are lacking.

As in all applications of patient triggered ventilatory assistance, NAVA is dependent on

spontaneous breathing effort. The respiratory control of premature infants is immature and the

response to changes in CO2 and O2 are inconsistent. The reduced capacity to compensate for

changes in gas exchange puts them at risk of developing respiratory acidosis. Because of this, it

is difficult to base changes to the proportional assist ventilation during NAVA (and PAV) using

a single set of variables. In this patient population, it is important to adjust the ventilator

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settings and the alarm settings, depending on the observed ventilatory and maturational status

of each individual infant. Because the respiratory activity is driven by both pH and PCO2,

clinicians must not focus solely on PCO2 targets but rather evaluate the patient’s respiratory

drive in the context of pH. Further, it is possible to over-assist the patient by increasing the

NAVA level. This can unload the respiratory muscles excessively and diminish CO2-induced

breathing activity, and thus reduce Edi and VT [14, 31]. NAVA-capable ventilators also have a

simultaneous flow (or pressure) triggered pressure support ventilation mode in addition to the

backup mode in case of inadequate Edi signal. However, this pneumatically (flow or pressure)

triggered mode might interfere with the Edi signal if inadvertent auto-triggering occurs.

Therefore, it is prudent to inactivate this option in favour of the more rapidly responsive and

less artefact-prone Edi signal and rely on backup ventilation in case of apnea or poor Edi

signal. Additionally, if too high PIPs are set for the backup ventilation, this might both reduce

the CO2-induced respiratory drive and increase the inspiratory inhibitory reflex, thereby

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reducing adequate spontaneous breathing activity and preventing the patient going back to

NAVA mode.

Before adjusting NAVA settings, it is important to ensure the correct position of the Edi

catheter at the level of the diaphragm as dislodgement poses the greatest problem to correctly

synchronize the ventilator with the patient’s breathing activity (Figure 3) [32]. It is equally

important to evaluate the trends, including the Edi signal, respiratory rate, VT, the time and %

of time in back-up, and the actual and allowed peak pressures. Common problems include Edi

signals being too low or too high (necessitating changes in NAVA level), too much time in

back-up (over-sedation, NAVA level too high, baby getting ill), flattened peak pressure

waveforms (pressure limit too low). Standardized Edi triggering level is usually set at 0.5µV

and is automatically adjusted to changes in the minimal Edi level.

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Non-invasive NAVA

Because it does not depend on a pneumatic trigger and is unaffected by a leak around an

endotracheal tube (ETT) or in an open system (such as non-invasive positive pressure

ventilation [NIPPV]), NAVA is ideally suited for non-invasive ventilation and has a high level

of synchrony [8, 33]. Studies of spontaneously breathing term and mildly preterm infants

without ventilatory assistance have given us some directions as to the normal levels of maximal

and minimal Edi [9, 32].

No long-term studies have been performed with the non-invasive mode of NAVA. Two

recent randomized controlled studies comparing NIV-NAVA with nasal CPAP (nCPAP) during

the early stages of RDS in moderately preterm infants, did not show any benefit in avoiding

and/or time to intubation, except for a shorter duration of mechanical ventilation in the NIV-

NAVA group [34, 35]. Using NIV-NAVA after extubation seems more promising as two small

retrospective studies observed more successful weaning with NIV-NAVA than nCPAP,

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measured as failure within 72 hours of extubation [35-37]. A Cochrane review from 2020

evaluating the safety and effectiveness of NIV-NAVA vs NIPPV included only two studies and

found that there was not enough evidence to draw conclusions on their primary outcomes of

safety and efficacy [38]. Physiologically this makes sense as unlike nCPAP or even NIPPV,

NIV-NAVA will actually provide ventilation and actively reduce the work of breathing.

Treussart et al also showed that NIV-NAVA improved synchronization in extremely premature

infants compared with synchronized intermittent positive airway pressure [39]. An NIH-

sponsored large multicentre trial is currently ongoing, comparing NIV-NAVA to NIPPV in

VLBW infants (ClinicalTrials.gov NCT05446272). The study explores extubation success

using predefined criteria. This study will hopefully give some guidance as to the effectiveness

of NIV-NAVA in this population.

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Beyond the neonatal period NIV-NAVA may have an application in a host of other

pediatric pathologies. In patients with severe bronchiolitis NIV-NAVA has been shown to

improve patient-ventilator synchrony, work of breathing and unload the respiratory muscles

better than nCPAP [40, 41]. This is an attractive application of NIV-NAVA given that NIPPV

does a poor job synchronizing with the patient’s breathing activity, leading to significant

wasted effort and patient ventilator asynchrony [42]. A retrospective review of NIV-NAVA

use in children less than 5 years of age with acute hypoxic respiratory failure was able to

demonstrate a lower rate of intubation in the group that used NIV-NAVA; the majority of the

patients had a viral cause of their respiratory failure [43]. There is a physiological feasibility

for NIV-NAVA providing better oxygenation and ventilation in bronchiolitis as the ventilator

would help unload some of the work of breathing by synchronizing with the breathing activity

of the patient, similarly to how bi-level positive airway pressure (BiPAP) is used in larger

children and adults who are able to generate sufficient negative pressure to trigger and

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synchronize with the ventilator. Without synchronization, non-invasive respiratory support is

no better than nCPAP in unloading the work of breathing.

PROPORTIONAL ASSIST VENTILATION

Similar to NAVA, proportional assist ventilation (PAV) provides support in proportion

to the spontaneous breathing effort, but unlike NAVA, it depends on detection of inspired

airflow by a pneumotachometer (PNT) and thus is susceptible to problems with leak around

uncuffed endotracheal tubes. Its availability is limited to a single European manufacturer and

this modality is not available in North America. The inspired airflow is monitored throughout

the entire respiratory cycle and the assist comes in the form of pressure or flow unloading of

the patient’s spontaneous breaths [44, 45]. This allows the patient full control of the timing of

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each breath, similar to NAVA. PAV performance can be affected by several factors such as:

leaks around uncuffed endotracheal tube (ETT), secretions or water in the pneumotachograph,

and ETT occlusion or malposition. Control of the assisted ventilatory pressure and flow comes

from analysing the airflow through a sensitive laminar PNT that keeps the ∆P/∆V constant to

the pre-set unloading of the total system elastance (Figure 2). The lung elastance (EL) can be

calculated by inverting the effective lung compliance (CL), as measured by the ventilator,

giving EL=1/CL. To unload 75% of EL, set ventilator elastance [EV] at 0.75 x EL or lower the

unloading until good breathing movements are detected. Excessive unloading might lead to

overcompensation of inspiratory pressures to the patient that may inhibit the breathing efforts

and consequently cause the ventilator to revert to the backup mode of flow triggered ventilation

(Figure 3) [46]. The unloading of airway resistance during PAV is less evident as the cross-

sectional area of the lungs related to lung volume (specific airway resistance), is low in

neonates, whereby only compensation for the resistance of the smallest ETTs is usually needed,

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and mainly during inspiration than during expiration to allow for adequate diffusion of gases at

end-inspiration [47, 48].

There have been many animal studies of PAV, but only a few small cohorts of neonates

focusing mainly on the feasibility of this mode [49, 50]. Clinical studies have shown short-

term benefits in neonates with acute RDS and evolving BPD in terms of maintaining stable gas

exchange and lower oxygenation index at lower mean airway pressures, compared to other

modes of patient triggered ventilations [51-54], but no long term RCTs have been performed to

evaluate outcomes such as the development of BPD and/or duration of mechanical ventilation.

Similar to NAVA, the facilitated spontaneous breathing coupled with a lower MAP with non-

inferior oxygenation theoretically should lead to a mode of ventilation with less risk of

barotrauma and ventilator-induced lung injury in the immediate neonatal period. During the

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weaning phase of long-term mechanically ventilated infants it may provide more support and

lead to less injury, but long-term studies are needed to test its clinical effectiveness and safety.

The use of PAV as a weaning modality is limited by the fact that there is no non-invasive form

of PAV because the PNT cannot not correctly measure the volumes and pressures in an open

system to adequately unload the elastance. Despite being clinically available for over twenty

years, PAV has not gained widespread acceptance. It remains an attractive concept, but there is

an absence of convincing evidence surrounding clinically important outcomes. Additionally,

the technique is not easy to understand or use in clinical practice. Thus, despite the

attractiveness of the theory of PAV there does not appear to be a compelling reason to make the

effort to master the technique, especially in preterm infants with immature respiratory control.

CONCLUSION

The concept of allowing the patient to control the amount of support provided by the ventilator

is very attractive and available with both NAVA and PAV. NAVA has the additional

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advantage of a diaphragmatic trigger that is not affected by endotracheal leak and has an

instantaneous response time. The limitations of both modalities are that they are positive

feedback loops that assume the patient’s respiratory drive is intact and that the effort is

appropriate. A theoretical advantage of PAV over NAVA is that PAV tries to adjust the elastic

properties of the lung to an estimated normal compliance, thereby enabling the ventilator-lung

system to work at an optimal lung condition and thereby promote an unloaded breathing effort

during inhalation, whereas NAVA adjusts its assistance proportionally solely to the ongoing

weak or strong breathing effort. Under these assumptions, the ventilator compensates for either

poor lung compliance for the former or weak muscles for the latter to provide an adequate tidal

volume. It should be noted that each modality is available only on a single manufacturer

platform and PAV is not currently available in the USA.

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There is some evidence to suggest that both modes of ventilation, provide protection from

ventilator induced respiratory weakness and diaphragmatic atrophy by promoting spontaneous

breathing [55]. An animal model suggested that NAVA could be beneficial in preventing

diaphragm atrophy and other authors have noted the theoretical protection afforded by assisted

modes of ventilation though definitive evidence is lacking [56, 57]. Given the limited evidence

that both PAV and NAVA improve oxygenation and reduce the work or breathing it makes

sense that they would be useful as weaning modalities that allow the patient to be reconditioned

and prepare for successful extubation while slowly removing artificial ventilator support but

doing so in proportion to the needs of the patient.

However, there is potential for unintended consequences when techniques that employ a

positive feedback algorithm and give the patient full control of ventilator function are applied

to extremely low birth weight infants with their immature respiratory centres. These babies

have a great deal of periodic breathing, frequent apnea and intermittent excessive inspiratory

efforts when disturbed, all of which are potentially amplified by the positive feedback

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mechanism. There is an urgent need for adequately powered randomized trials that evaluate

important long-term outcomes, such as IVH, BPD, and neurodevelopment, all of which are

relevant to patients born extremely premature.

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FIGURES, FIGURE LEGENDS AND TABLES

Figure 1. EAdi catheter electrodes (red/black) detecting the electrical activity of the
diaphragm (orange/white), triggering continuous inspiratory pressure support (green),
and detecting airflow changes by a pneumotachograph (grey)

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Figure 2. Airway pressure (Paw) and esophageal pressure (Peso) during PAV with 10ms
servo control

Figure 3. Example of optimal and overcompensated elastic unloading during PAV

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