Application of neurally adjusted ventilatory assist (NAVA): a narrative review

Introduction

The breathing process encompasses lung ventilation and gas exchange, with inhalation being an active process driven by nerve signals originating from the medulla oblongata, prompting muscle contraction, chest cavity expansion, and a reduction in lung pressure, allowing air to enter the lungs. In contrast, quiet exhalation is a passive process. However, in certain specific circumstances, such as during surgery, respiratory failure, respiratory muscle weakness, paralysis, airway obstruction, or cardiopulmonary resuscitation, patients may face challenges in independent breathing and therefore require assistance from a ventilator.

Mechanical ventilation (MV) is commonly used in the management of respiratory dysfunction in the intensive care unit (ICU), with ventilation modes including synchronized intermittent mandatory ventilation (SIMV), controlled intermittent mandatory ventilation (CIMV), continuous positive airway pressure (CPAP), and pressure support ventilation (PSV). Each ventilation mode has its unique clinical applications to meet the needs of different patients and optimize ventilation efficacy.

Various ventilation strategies possess distinct benefits and drawbacks, influencing both patient comfort and the efficacy of ventilation. PSV (1) is frequently utilized; however, it can result in a misalignment between the patient and the ventilator, potentially leading to discomfort and exhaustion. Since its introduction in 1999, a novel mode of respiratory assistance referred to as NAVA has progressively garnered interest and attained United States Food and Drug Administration (FDA) approval in 2007, thereby offering additional alternatives for MV. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-835/rc).

Methods

We searched Medline via PubMed from inception to December 31, 2024. Keywords included “NAVA”, “neurally adjusted ventilatory assist”, “diaphragm electrical activity (E_Adi)”, “patient-ventilator synchrony”, “E_Adi”, “over-assistance”, “weaning”, “liberate”, “sedation”, “neurogenic ventilation efficiency”, “neuromuscular efficiency”, and “NAVA level”. This study is a narrative review. It does not assess the quality or the risk of bias of the included literature. Inclusion criteria focused on studies involving NAVA, published in peer-reviewed journals and available in English. The search strategy is detailed in Table 1.

Principle of NAVA ventilator

The diaphragm, located at the thoracic cavity’s base, contracts due to phrenic nerve impulses affecting muscle fibers (Figure 1), with contraction strength depending on activated motor units linked to neural activity intensity (2). As the main respiratory muscle, its function impacts both respiratory pumping and the connection between the respiratory center and lung ventilation, influencing patient respiratory performance.

Figure 1 Differences in the initiation methods between NAVA and traditional ventilation modes. The diagram shows the main differences between the NAVA mode and traditional ventilation modes in terms of triggering mechanisms. Neural impulses from the central nervous system are transmitted to the phrenic nerve, prompting the diaphragm to undergo mechanical contraction. The changes in electrical signals triggered by mechanical contraction are key to initiating NAVA ventilation, marking the beginning of MV. In traditional ventilation modes, after the diaphragm contracts, changes in airflow, pressure, and volume occur, which subsequently activate the ventilator’s assistive function through pneumatic signals. E_Adi, diaphragm electrical activity; MV, mechanical ventilation; NAVA, neurally adjusted ventilatory assist.

The diaphragm electrical activity (E_Adi) employs electrophysiological methodologies to assess and quantify the diaphragm’s electrical signals, represented in microvolt (µV). The capture of E_Adi signals is facilitated by a catheter that comprises eight bipolar microelectrodes. The catheter, containing eight bipolar microelectrodes, is introduced through the esophagus and positioned at the gastroesophageal junction where the phrenic nerve trunk meets the diaphragm (3) (Figure 2). As the diaphragm fibers undergo contraction, these electrodes continuously gather the electrical signals generated by the diaphragm. The E_Adi signal represents the spatial and temporal aggregation of diaphragmatic electrical potentials (4). The electrical signals are processed by a computer and displayed as E_Adi waveforms on a ventilator with the necessary interface. Its primary function is to monitor diaphragmatic activity and reflect the output from the respiratory center. When the E_Adi signal exceeds the doctor-set threshold, the ventilator begins ventilation. The ventilation pressure is proportional to the intensity of the E_Adi signal, with the proportionality constant determined by the NAVA level (NAVAL), which is also set by the doctor. When the E_Adi signal drops below the threshold, the ventilator switches to exhalation mode. Additionally, if the E_Adi signal becomes unstable and the apnea lasts longer than the preset threshold, the system switches to backup ventilation to ensure patient safety.

Figure 2 A schematic diagram of the NAVA application. (I) shows a tracheal intubation connected to a ventilator for respiratory support, and the ventilator mode is NAVA; (II) shows a NAVA catheter with eight microelectrode arrays mounted on the tip; and (III) shows a magnified schematic diagram of the electrode arrays on the tip of the NAVA catheter. NAVA, neurally adjusted ventilatory assist.

E_Adi monitoring enables a quantitative evaluation of the intensity and frequency of neural activity associated with diaphragm contractions (5,6). It primarily encompasses two fundamental metrics: the minimum E_Adi value (E_Adi min, represent the spontaneous tonic activity of the diaphragm) and the peak E_Adi value (E_Adi peak, indicative of the amplitude of electrical activity linked to inspiratory efforts) (7). These metrics provide insights into the contraction strength of the diaphragm as well as the central respiratory drive during the act of breathing (8). Studies have demonstrated a notable linear relationship between the E_Adi values in both adults and children and the pressure produced by the diaphragm (9,10).

NAVA uses the E_Adi signals as the start signal for the ventilator, which has significant advantages over traditional pneumatic signals. This is because it is immune to gas leaks, reducing ventilator response time (11) and improving patient-ventilator synchronization. Furthermore, even at elevated assist levels, the E_Adi signal remains detectable (5), facilitating a relatively precise assessment of the positive end-expiratory pressure (PEEP). This capability contributes to the optimization of breathing patterns and alleviates diaphragmatic strain (12). The unique physiological vulnerability of pediatric patients, the absolute need for high levels of human-machine synchronization, and the urgency of lung protection have become the main battleground for research and application of NAVA technology. NAVA adjusts the ventilator settings for assisted ventilation by monitoring the E_Adi signal. Clinicians have the ability to modify the proportion of assisted ventilation by altering the NAVAL.

Adjustment of NAVALs

The NAVAL representative E_Adi is converted to the pressure ratio coefficient for ventilator support. Clinicians have the ability to modify the proportion of assisted ventilation by altering the NAVAL. The NAVAL is calculated as the product of E_Adi and a user-specified gain factor, with measurement units of cmH₂O/µV. This parameter indicates the patient’s exertion during ventilatory support. At any given NAVAL, the airway pressure (Paw) exhibits variability in response to changes in E_Adi. As NAVAL increases, the ventilator takes on more work. Therefore, NAVAL’s implementation must suit each patient’s unique characteristics. The adjustment of NAVAL aims to achieve optimal respiratory unloading, that is, to achieve the best match between E_Adi and tidal volume (Vt) (neuro-ventilation matching), and to avoid excessive support as the goal. Modifications to NAVAL can be performed by observing parameters including Vt, Paw, and E_Adi measurements (Table 2).

EAdi catheter positioning

Barwing and his research team (32) proposed a formula to predict the optimal catheter position (OPT). This formula is based on the distance, which measures from the nose to the earlobe and then to the xiphoid process (NEX distance). OPT is defined by three criteria: a stable respiratory E_Adi, electrical activity detected by the central wire of the catheter positioning tool, and the absence of P waves in the distal wire. The results showed that, among 25 subjects, the NEX distance predicted OPT in 18 cases, indicating this formula can help clinicians accurately place the E_Adi catheter. However, the generalizability of these findings is limited due to the small sample size. Moreover, the study did not consider related factors affecting catheter placement, including body position, PEEP, and intra-abdominal pressure (IAP).

In clinical practice, the ventilator’s NEX distance formula is used to initially locate the E_Adi catheter position. The catheter can then be precisely adjusted based on the E_Adi waveform. If necessary, the catheter position can be further confirmed by a bedside chest X-ray.

The systematic titration method

The systematic titration method is currently the widely recognized NAVAL titration approach (17,33) (Figure 3). NAVAL is initially set at the lowest point (0.5–1.0 cmH₂O/µV), and the patient achieves stable ventilation. Then, NAVAL is gradually increased in 0.5 cmH₂O/µV increments, with each step maintained for at least 3 minutes to stabilize the E_Adi parameter. As NAVAL is elevated, there is a corresponding rise in Paw and a decline in E_Adi. This phase is identified as the first stage of titration. With further increases in NAVAL, the Paw eventually reaches a critical threshold, entering a plateau phase, during which E_Adi experiences a significant reduction. This scenario characterizes the second stage of titration. The NAVAL value just prior to reaching this critical threshold is regarded as the optimal setting. Consequently, the first stage may indicate that the NAVAL is inadequate to fulfill the patient’s respiratory requirements, whereas the second stage implies a diminished diaphragmatic workload, which could potentially lead to hyperventilation. Ververidis et al. (34) have developed a NAVAL adjustment algorithm model based on systematic titration technology. The model’s results are similar to classical visual assessment methods, but further improvements and validation are needed before clinical application.

Figure 3 The chart shows that the NAVAL increases at a constant rate. As the NAVAL rises, the Paw also increases, while the E_Adi value shows a downward trend. This phase is referred to as the first stage of titration, which is the portion before line A in the illustration. When NAVAL further increases, the Paw reaches a critical threshold and enters a plateau phase, during which the E_Adi value decreases significantly. This phenomenon is regarded as the second stage of titration, which is the portion between lines A and B in the illustration. The transition from the first stage to the second stage of NAVAL is considered the optimal setting. ΔE_Adi, change in E_Adi; ΔPaw, change in Paw; E_Adi, diaphragm electrical activity; NAVA, neurally adjusted ventilatory assist; NAVAL, NAVA level; Paw, airway pressure.

There are distinctions between NAVAL settings in noninvasive ventilation NAVA (NIV-NAVA) after extubation and those during invasive ventilation. The investigation conducted by LoVerde et al. (17) included paired titration trials involving 15 infants. The findings revealed that the implementation of NIV-NAVA led to an elevation in NAVAL while the peak inspiratory pressure (PIP) sustained a high value. Concurrently, the reduction in the E_Adi was relatively minimal. The researchers proposed that when shifting a patient from NAVA mode to NIV-NAVA, an initial increment of NAVAL by 0.5–1.0 cmH₂O/mV is advisable to enhance PIP. Following this adjustment, the NIV-NAVA setting can be systematically decreased to 0 cmH₂O/mV. This strategy has the potential to considerably diminish the incidence of extubation failure as well as the occurrence of clinically significant events.

The system titration technique adjusts NAVAL parameters to match each patient’s physiological thresholds. This strategy enhances patient-ventilator synchronization and reduces asynchronous, making it a recommended approach. However, the method’s complexity and time requirements limit its practical its use in clinical settings.

The PSV method

Moreover, in clinical practice, the PSV mode can be used to set NAVAL. Based on the matching goals, this method can be divided into two types: pressure matching and Vt matching.

The pressure matching method aims to reach the peak Paw (Ppeak) during PSV mode (35). The PSV mode is set with standardized PEEP and Vt (6 mL/kg), which is calculated based on predicted body weight (PBW). After ventilation stabilizes, record Ppeak, then switch to NAVA mode and adjust parameters to match Ppeak to that in PSV mode.

The principle of Vt matching is to set NAVAL with Vt as the target (36). The initial PSV level is set to achieve a pressure of 6–8 mL/kg PBW. The respiratory rate (RR) is set to 20–30 bpm. After ventilation is stabilized, the average Vt is recorded. After switching to NAVA mode, adjust NAVAL to maintain Vt close to that during PSV.

Targeting the Ppeak and Vt parameters in PSV mode allows quick completion of the initial setup for NAVA mode. This method is suitable for expedient setups without time titration. However, it requires close monitoring of changes in respiratory dynamics. Studies show (35,36) that 75% of patients who set NAVA using the PSV reference method require secondary adjustments. This high adjustment rate may be due to differences in the driving mechanisms of NAVA and PSV, which can lead to excessive initial support. Because the initial setup only matches Ppeak or Vt without further validation, it may cause asynchronous phenomena such as trigger delays and ineffective triggering.

NAVAL settings during liberation

Another method is to set the optimal NAVAL target at 60% of the maximum E_Adi value during spontaneous breathing and ineffective triggering (37). Following each adjustment of NAVAL, it is essential to assess blood gases and make necessary changes to respiratory settings until a successful spontaneous breathing trial (SBT) is accomplished, ultimately facilitating extubation. This adjustment strategy, aimed at achieving 60% of the maximum E_Adi value, is particularly relevant for patients undergoing liberation. Enhanced respiratory mechanics facilitate a gradual decrease in NAVAL while ensuring sufficient breathing, oxygenation, and alveolar ventilation for successful extubation.

Nonetheless, the research conducted by Brander et al. (33) suggests that the E_Adi value at optimal NAVAL corresponds to 75% of the highest E_Adi value documented at the lowest NAVAL, assuming that the expiratory pressure exceeds PEEP =3 cmH₂O. Consequently, further investigation is needed to validate a more precise and user-friendly method for NAVAL adjustment.

Validating the matching degree through Range90

Chiew et al. (27) proposed a method using Range90 fluctuation measurement to quantify the synergistic relationship between neural impulses and ventilation output. This method provides an objective basis to adjust the level. The width of the 5^th to 95^th percentile range, known as Range90, can be derived by integrating the neural ventilation efficiency (NVE) indicators for each breathing cycle.

Range90=95thVt/∫EAdi−5thVt/∫EAdi[1]

This parameter is tailored to individual patients and serves as an indicator of the overall level of “compatibility” between the ventilator output and the patient’s requirements. A reduced Range90 signifies a superior alignment between Vt and ∫EAdi. Conversely, patients exhibiting a larger Range90 are more prone to experiencing discrepancies between Vt and their effective ventilation. This implies that, irrespective of the patient’s specific ∫EAdi, their ability to synchronize Vt and ∫EAdi is diminished. Furthermore, this approach necessitates alignment with the Ppeak value established by the clinician during the initial settings of the PSV phase.

The titration of NAVA and the apnea trigger time configuration is vital for patient safety, especially in pediatrics. Both studies by Protain et al. (38) and Nam et al. (39) advise against setting NAVAL above 4 cmH₂O/mV to prevent providing excessive respiratory support for preterm infants. Researchers, including Morgan et al. (40), conducted a prospective study on 15 neonates born before 30 weeks, evaluating the effects of 2 vs. 5 seconds apnea durations on ventilation efficacy. Findings indicated that opting for a 2-second apnea duration resulted in an increase in the frequency of backup ventilation from 0.5 to 2.5 instances per minute, while the proportion of time allocated to backup ventilation rose from 2% to 9% per minute. Moreover, the shorter apnea duration revealed notable benefits, as the occurrence of clinically significant events diminished from 7 to 2 times per hour. Currently, NAVA settings focus on the titration process, while other parameters like trigger thresholds and inspiratory apnea duration require further study for more comprehensive guidance for clinical implementation.

Advantages of NAVA ventilator

MV is essential in clinical treatment. However, lack of synchrony between patients and ventilators often causes discomfort and anxiety. This issue is especially pronounced in pediatric patients. This asynchrony places extra on respiratory muscles, potentially extending ventilation duration and raising the risk of ventilator-induced lung injury (VILI) and mortality.

In contrast, NAVA technology monitors E_Adi in real time and enables adaptive ventilation. This method enhances respiratory variability, aligning more closely with human physiology. As a result, NAVA significantly improves synchronization between the patient and MV, reducing respiratory asynchrony. Furthermore, NAVA decreases the risk of overventilation, which increases patient survival rates. At the same time, NAVA reduces the incidence of diaphragm dysfunction and significantly lowers sedative demand in pediatric patients, improving Richmond Agitation-Sedation Scale (RASS) scores in premature infants.

Moreover, during the liberating phase of MV, NAVA demonstrates its advantages. Compared to PSV and CPAP modes, NAVA not only increases the success rate of liberation but also shortens the liberation time, enhances diaphragm function, reduces diaphragm atrophy, and decrease the re-intubation rate in premature infants. NAVA also has potential benefits for patients with congenital diaphragmatic hernia (CDH) and bronchopulmonary dysplasia (BPD). However, improper settings may lead to complications. Therefore, NAVA holds great promise for improving patient comfort and clinical outcomes during MV.

Improving patient-ventilator synchrony

During MV, inadequate interaction and synchronization between the patient and the ventilator can result in discomfort, agitation, and an increased workload for breathing (41). This situation may ultimately jeopardize the patient’s overall prognosis (42,43), potentially resulting in inappropriate extubation, prolonged MV time, and an increased risk of tracheostomy. Pediatric patients have a higher RR and lower strength than adults, making them more prone to patient-ventilator asynchrony (PVA) (44). The phenomena of asynchrony can be classified into several categories depending on the specific phases of the respiratory cycle (45): (I) trigger phase: ineffective triggering, auto-triggering, and delay in triggering; (II) inspiration phase: flow rates that are excessively high or low; and (III) expiration phase: occurrences of double triggering, premature cycling, or delayed cycling.

The asynchronous index (AI, %) serves as a metric for evaluating the asynchrony rate of ventilators (46). Research has shown that the incidence of asynchrony in adult patients receiving NIV is 43% (47), while invasive ventilation shows an incidence of 21% (48). The pronounced vagal reflex present in neonates and preterm infants may provoke episodes of apnea and periodic breathing. Study reports that the incidence of asynchrony in NIV in children may reach 85.5% (49). This high incidence may result from gas leaks, inappropriate apnea time settings, and the immature neurodevelopment. Research indicates that in pediatric patients undergoing invasive ventilation, around 86% exhibit an AI greater than 10% on the initial day of MV (44). This phenomenon of asynchrony considerably elevates the work of breathing for patients (50), resulting in increased discomfort. Studies have demonstrated that when AI surpasses 10%, there is an associated prolongation of MV duration (10,44), along with an elevated risk for VILI, increased rates of liberation failure, higher tracheostomy rates, and increased mortality during hospitalization (44,51,52).

Consequently, an essential challenge in the clinical use of ventilators is the effective reduction of PVA levels (53). In the context of NIV, leakage is considered an important contributing factor to PVA, which can lead to automatic triggering, delayed cycles, and reduced sensitivity (54). In the context of NIV, leaks are identified as a significant contributor to PVA. NAVA’s assistance level is linked to E_Adi, with signals from the central nervous system detected by the E_Adi catheter, leading to a nearly direct connection between them. Theoretically, gas leakage should not affect the patient’s neural respiratory cycle. Theoretically leaving the patient’s neural respiratory cycle unaffected by ventilator flow leakage. This condition facilitates a high level of synchronization between the patient and the ventilator, which in turn diminishes the frequency of asynchronous events (55). Prior researches have indicated that NAVA can enhance the interaction between patients and ventilators in both invasive and non-invasive settings (56-58), reduce the incidence of asynchronous events, and exhibit a more varied respiratory pattern (49,59-61).

Mally et al. (62) investigated 23 neonates needing invasive MV, finding a significantly lower mismatch index in NAVA compared to conventional modes (18.3%±6.3% vs. 45.8%±9.4%, P<0.05) and a notable decrease in central apnea occurrences (P=0.011). The subjects in the study (62) showed significant variability. The research focused on short-term ventilation lasting only 30 minutes, which complicates the evaluating asynchronous events during prolonged NAVA ventilation. A meta-analysis (58) of 331 adult patients found that in the NAVA cohort significantly reduced AI compared to PSV [mean difference (MD) =−12.82; 95% confidence interval (CI): −21.20 to −4.44]. This finding aligns with the conclusions drawn by Schmidt et al. (26) in an earlier clinical investigation. The rate of PVA with NAVA was lower than with PSV, regardless of assistance level. A study conducted by Spinazzola et al. (63) showed that children with moderate acute respiratory distress syndrome (ARDS) had significantly lower AI during NAVA compared to two PSV periods (NAVA 1.7 vs. PSV1 13.6 vs. PSV2 10, P=0.001), with reduced delays in inspiratory and expiratory triggers using NAVA. Although the study (63) reported the offline outcomes of the children, the short duration limits the makes ability to accurately assess the relationship between NAVA and the offline results. Similarly, a meta-analysis (60) of adults and children found that NIV-NAVA decreases AI and shortens MV duration.

Firestone et al. (64) analyzed 17 preterm infants. The results showed a significant difference in the incidence of clinically significant events (CSE), which are defined by decreased blood oxygen saturation and bradycardia. Specifically, the incidence in the CPAP group was 17.9±7.8 times, while the NAVA group was 10.2±8.1 times, P<0.001. NAVA has demonstrated excellent performance in improving respiratory support, which reduces the dependence on invasive ventilation. Furthermore, a study conducted by Xiao et al. (65) indicated that NAVA excelled over CPAP in enhancing the coordination of ventilation in infants, lowering Ppeak and mean Paw, and displayed improved prognoses throughout the liberating process This advancement may contribute to a diminished reliance on invasive ventilation and decrease the risk of related long-term complications. However, the study (64) has a retrospective design and failed to record the frequency and duration of backup ventilation triggers. Moreover, the study lacks randomization, necessitating prospective research to further validate the results. In comparison to PSV, NAVA exhibits a reduced inspiratory trigger delay time, and an extended synchronization period between neural activity and ventilatory support (66).

Clinical studies on PVA in adult and pediatric patients indicate that NAVA can reduce asynchrony and delay. However, these studies involved a limited number of cases and had a short duration. Further clinical validation is needed in the future.

Avoiding excessive or insufficient assistance from the ventilator

The conventional ventilator mode provides relatively stable support intensity, which limits the recognition of spontaneous breathing and flexibility. This rigidity can ultimately result in either an overabundance or a deficiency of assisted breathing, consequently leading to VILI (67,68). VILI manifests in various forms, including volutrauma, barotrauma, atelectrauma, and biotrauma (inflammation). Sousa et al. (69) utilized a MV pig model of ARDS, the results revealed that mild overdistension correlates with elevated mortality rates. Thus, minimizing lung collapse or establishing a balance between collapse and overdistension may mitigate lung injury.

A fundamental strategy to avert VILI involves the adoption of suitable ventilation settings (70) to prevent excessive or inadequate ventilator assistance. Excessive assistance can lead to the elimination or significant reduction of the patient’s spontaneous inspiratory efforts, inducing disuse atrophy through various cellular mechanisms (71). Conversely, insufficient assistance can impose an excessive load on the diaphragm, initiating acute muscle inflammation and injury (72). This scenario can exacerbate dyspnea, diaphragm fatigue, and self-inflicted lung injury by the patient, particularly in the context of sepsis and systemic inflammation, which heightens muscle fragility (73).

Moderate spontaneous breathing is crucial for critically ill patients on MV. On one side, It helps mitigate diaphragm and respiratory muscle atrophy (74). This aspect is particularly significant as research indicates that muscle atrophy can commence within 18 hours following the initiation of MV and continue to worsen (75,76). Furthermore, higher respiratory variability is associated with higher survival rates and shorter MV duration (77). Conversely, investigators such as Hering et al. (78) discovered that the commencement of spontaneous breathing markedly enhances the perfusion of visceral organs, which significantly influences the prognosis of critically ill patients. Nevertheless, in critical illness scenarios, excessive spontaneous breathing efforts may result in lung injury, particularly effort-dependent lung injury (79). NAVA has exhibited increased respiratory variability across multiple studies (80), which mirrors the respiratory variability observed in healthy individuals (58). A randomized controlled trial conducted by Rolland-Debord et al. (77) established that heightened respiratory variability is positively associated with improved survival rates.

NAVA technology commences the respiratory cycle by detecting electrical activity in the diaphragm. It effectively aligns with the patient’s neural drive to facilitate assisted ventilation. The extent of this assistance is contingent upon the disease stage and the physiological reserve of the respiratory system (81). This adaptability ensures that the ventilator’s support corresponds to the patient’s immediate requirements rather than being predetermined by fixed pressure settings in PSV mode (14). Such a mechanism plays a vital role in achieving “diaphragmatic protective ventilation”. An elevation in the E_Adi signal may suggest insufficient support for the patient, which could stem from factors such as insufficient PEEP, deteriorating conditions, agitation, or the patient’s unpreparedness for MV. Conversely, a reduction in the E_Adi signal may indicate excessive assisted ventilation (82), over-sedation, diaphragm nerve damage, increased IAP, or diminished diaphragmatic drive capacity resulting from prolonged reliance on conventional ventilation. By scrutinizing E_Adi variations, tailored protocols can be established to formulate cycling closure criteria, thereby enhancing the synchronization between the patient and the ventilator (83).

NAVA can safely and effectively alleviate the burden on the respiratory muscle pump during the peak inspiratory phase when compared to PSV. It does not induce cycling closure of ventilatory assistance or cause excessive lung distension (84). Simultaneously, the control of Vt is governed by the patient’s respiratory central command, which mitigates the risks of excessive assisted ventilation and over-distension (85,86), while also reducing the likelihood of ventilator-induced diaphragmatic dysfunction (VIDD) (51,86).

Reduce patients’ sedation needs and improve comfort

MV often causes discomfort and anxiety in patients (87), leading healthcare professionals to use sedatives and analgesics for relief. Nevertheless, the extended use of these medications can lead to a range of adverse effects, including excessive sedation, delirium, and the necessity for prolonged MV (88-90). Extended MV may harm neurological health. Recent research has indicated a relationship between VILI and neurotransmitter imbalances in the hippocampus (91), with further evidence supporting a potential connection between VILI and cognitive deficits (92-94).

Theoretically, the interaction of neural drive and respiratory assistance during deep sedation may be affected by sedatives, potentially harming NAVA more than PSV. Nonetheless, Vaschetto et al. (95) and Kallio et al. (96) studied and found that sedatives reduce the amplitude of the E_Adi signal. Despite this, NAVA can still be successfully initiated and used. Research conducted by Vaschetto et al. (95) and Kallio et al. (96) demonstrates that while sedatives diminish the amplitude of E_Adi signals, fluctuations in E_Adi signaling can still successfully initiate NAVA.

NAVA effectively reduces sedative needs compared to PSV and SIMV, offering advantages for low-dose sedation (97,98). The study by Amigoni et al. (99) examined propofol’s effects on respiratory depression in pediatric patients, showing a 32% average reduction in E_Adi values post-administration. Consequently, ongoing surveillance of E_Adi signals allows precise sedative dosage adjustments without affecting respiratory support.

Hadfield et al. (100) conducted a randomized trial comparing patients in the PSV and NAVA groups. They found similar sedation levels, but the RASS scores in the NAVA group were closer to zero, indicating a better sedation effect.

NAVA is a safe ventilation method for premature infants with BPD in the neonatal ICU (NICU) and may reduce the need for sedatives (101). A retrospective cohort examination conducted by Kurland et al. (102) demonstrated that infants suffering from CDH experienced a notable reduction in their consumption of morphine (P=0.004) and midazolam (P=0.037) following the adoption of NAVA. Administering lower doses of sedatives enhances patient comfort, improves sleep quality, and optimizes regional respiratory support.

Enhancing the success rate of liberation

Liberation is the successful transition from ventilator reliance, involving stopping MV and removing airways. After addressing the causes of respiratory failure, it is crucial to start treatment promptly. Challenges during the liberating process often indicate a higher risk of re-intubation and VILI, increased mortality, and prolonged ICU and hospital stays (103).

NAVA has been shown to enhance the success rate of liberation in patients experiencing difficulties during the liberation process (57,104,105). A randomized trial conducted at a single center by Liu and colleagues (106) firstly revealed that NAVA significantly decreased the liberation duration in comparison to PSV [NAVA n=52; 3.0 (1.2 to 8.0) vs. PSV 7.4 (2.0 to 28.0) days, P=0.039], while also increased the days without MV and the liberation success rate. The study noted that despite shorter liberation time, ICU stay length remained unchanged. Research by Fang et al. (104) shows that children using the NAVA mode can wean off the ventilator earlier than those using CIMV (7.73±2.39 vs. 17.26±3.65 days, P=0.03). Additionally, the NAVA mode reduces the incidence of BPD.

Research conducted by Lee et al. (107) demonstrated that among preterm infants (<30 weeks gestation) undergoing NIV-NAVA as a sequential intervention after extubation, an extubation failure rate of 6.3% was observed within 72 hours. In contrast, that of 37.5% (P=0.041) was observed in preterm infants receiving NIV-CPAP. Furthermore, recent studies (107-110) have suggested that the sequential application of NIV-NAVA following extubation may significantly decrease the re-intubation rate in preterm neonates. A South Korean study (111) also suggests early NAVA initiation aids quicker liberation from ventilation in preterm infants, but further research is needed to confirm this.

The role of the diaphragm is a critical element that influences the prognosis of individuals who are on MV. Research has indicated that VIDD is markedly linked to challenges in liberation and adverse clinical outcomes (112). From a pathophysiological standpoint, NAVA effectively reduces diaphragm atrophy from inactivity (113), aiding in VIDD prevention and liberation. In a study utilizing diaphragmatic ultrasound assessment, it was observed that the diaphragmatic excursion (DE) in preterm infants undergoing NIV-NAVA was significantly greater when compared to those receiving noninvasive positive pressure ventilation (NIPPV) (4.7±1.5 vs. 3.5±0.9 mm, P=0.007) (114). An elevated DE measurement reflects enhanced diaphragmatic functionality, suggesting an increased likelihood of successful liberation (115). It is worth noting that in a randomized controlled trial (116), researchers found that the DE performance in the NAVA group was superior to that in the conventional MV mode group (P=0.01). However, the incidence of VIDD between the two groups did not show a significant difference. Furthermore, diminished diaphragmatic endurance and sleep disturbances resulting from delirium also constitute risk factors complicating the liberating process (117). A meta-analysis conducted by Andersen et al. (118) revealed that NAVA can improve sleep quality in patients undergoing assisted ventilation, thereby alleviating sleep deprivation.

CDH is a congenital defect causing pulmonary hypoplasia and hypertension, significantly increasing mortality and respiratory complications (119). Initially, NIV-NAVA was deemed inappropriate for individuals suffering from CDH, primarily due to alterations in the diaphragm associated with the condition. Nonetheless, existing literatures suggest that NAVA may enhance the synchronization between patients and mechanical ventilators, effectively limit Paws, avert excessive lung distension, and improve the efficiency of gas exchange. These improvements may contribute to a reduction in the alveolar-arterial oxygen partial pressure difference (A-aDO₂) in CDH patients, thereby underscoring its prospective advantages (120). Among infants with BPD who are liberated using NAVA, the success rate can reach up to 67% (121).

Nonetheless, in patients with an immature respiratory center who show significant periodic breathing, incorrect settings of NAVA can result in lung collapse (atelectasis) and/or excessive inflation (lung volume injury) (122). This factor is key in distinguishing NAVA use in pediatrics and adults.

Analyzing the advantages of E_Adi signal

In addition to the applications mentioned above in NAVA, continuous monitoring of E_Adi can also provide more information for clinicians.

The changes in E_Adi waveforms may enhance clinicians’ ability to identify asynchronous events (123), thereby increasing the synchronization rate of patients’ spontaneous ventilation. Such spontaneous ventilation can mitigate the risk of VILI (113). However, the E_Adi signal acquired via a nasogastric tube is limited to assessing diaphragmatic activity. Therefore, it can be effectively combined with surface electromyography (EMG) of the extra-diaphragmatic respiratory muscles to provide a holistic evaluation of neural respiratory drive (124).

The indicators from E_Adi signals provide valuable insights into various breathing patterns, respiratory drive, ventilation needs, patient-ventilator dynamics. Furthermore, these indicators can assist in evaluating the level of sedation and the probability of effective liberation (Table 3).

The E_Adi signal plays a crucial role in forecasting both the liberating process and successful extubation (125). Initial investigations have indicated that alterations in the E_Adi signal can provide earlier predictions of SBT failures compared to conventional metrics (126). A study by Parrilla-Gómez et al. (127) found elevated E_Adi levels in patients with extubation failure, with E_Adi over 30 µV during SBT predicting failure at 92% sensitivity and 67% specificity. This research further validated that E_Adi serves as an independent determinant of extubation failure. In a prospective intervention study (97), the investigators extubated neonates based on E_Adi peak measurements, with no adverse events. Additionally, in adult subjects undergoing an SBT (128), the neuro-excursion efficiency (NEE) parameter emerged as the most reliable predictor when the pressure support (PS) was maintained at 10 cmH₂O, while the variation in neural discharge per minute during the initial minute of SBT initiation was identified as the best predictor throughout the SBT. These outcomes underscore the significance of monitoring E_Adi to detect potential respiratory complications that may be challenging to recognize clinically.

NVE (129) is characterized as the ratio of Vt to the integrated E_Adi during inhalation (Vt/E_Adi, mL/µV) across a single respiratory cycle. This metric is utilized to evaluate the Vt in relation to the inspiratory demand of each breath for an individual patient, thereby indicating the capacity of respiratory muscles to transform the E_Adi signal into Vt. An elevation in NVE signifies that the patient is capable of producing a greater Vt in response to a particular respiratory drive. NVE encapsulates essential elements that affect volume production, including respiratory drive, diaphragm performance, and respiratory workload. Prior research has demonstrated that NVE serves as an effective indicator for assessing the degree of unloading experienced by respiratory muscles (130). Moreover, NVE holds potential as a significant tool for forecasting the readiness of patients for extubation.

Neuromuscular efficiency (NME) (131) is characterized as the ratio of the change in Paw (ΔPaw) to the E_Adi at the point of end-expiratory occlusion. This metric provides insight into the pressure produced per µV of the E_Adi signal, as well as the diaphragm’s efficiency in response to specific electrical activity. Consequently, it indicates the diaphragm’s ability to convert the E_Adi signal into inspiratory pressure. NME is crucial for adjusting ventilatory support, helping evaluate inspiratory effort with each breath (132) and reducing diaphragm dysfunction from improper ventilator assistance.

The NeuroSync index (133) assesses the synchronization of the neuro-respiratory cycle with the respiratory cycle controlled by the ventilator by analyzing the ventilator pressure in conjunction with the E_Adi waveform. This approach enables objective assessment of the patient’s neuro-respiratory patterns and ventilator performance, allowing adjustments to enhance their synergy. Optimizing their temporal alignment improves lung expansion pressure and ventilation effectiveness. It should be noted that extremely low or undetectable E_Adi signals do not mean that the patient has not activated other inspiratory muscles besides the diaphragm. It is important to emphasize that the NeuroSync index does not exhibit sensitivity to variations in respiratory patterns that may arise due to aging or pathological conditions. For instance, in a newborn with a neural inspiratory duration of 300 ms, a trigger delay of 100 ms could lead to an excessive error margin of 33%. Furthermore, this index is relevant not only for patients undergoing invasive ventilation but also for those receiving NIV (134), as it operates based on E_Adi catheter monitoring, which is independent of pneumatic signals.

Patients undergoing bilateral lung transplantation frequently encounter injuries to the phrenic nerve, which can result in dysfunction of the diaphragm. Furthermore, the denervation of the vagus nerve may disrupt the regulation of ventilation. A study conducted by researchers, including Grasselli et al. (135) revealed that 63% of the subjects exhibited notable alterations in the stability of E_Adi. When the level of NAVAL was elevated to 150% of the baseline, the PIP rose by 8.7 cmH₂O in comparison to PEEP. Concurrently, the maximum value of E_Adi decreased by 10.1 mV. This observation suggests that, despite a reduction in E_Adi activity, the effectiveness of ventilation has enhanced with the increase in NAVAL, alongside a modest increase in Vt. This further substantiates the viability of implementing NAVA at an early stage following bilateral lung transplantation.

In a cohort study involving 24 neonates, Gurumahan and his team (136) established that the minimum and maximum reference ranges for the E_Adi are 1–5 and 3–17 µV, respectively. This observation aligns with findings from several prior studies (6,137). The researchers indicated that in an ICU setting, a breathing amplitude of at least 5 µV per breath may be adequate to avert diaphragmatic disuse atrophy (138). Nonetheless, considerable individual variability exists in E_Adi signals, leading to the primary use of recordings to evaluate alterations in respiratory drive within the same patient. The reference range provided by existing literature is of limited value due to sample size and selection constraints, necessitating larger-scale multicenter trials in the future to establish applicable values.

Disadvantages of NAVA ventilator

Certain limitations of NAVA are associated with its triggering mechanisms as well as the population to which it is applicable.

There are two key points before using NAVA. First, the E_Adi catheter must be accurately placed and the E_Adi signal calibrated. The proper placement of the catheter electrode is the first step in implementing NAVA ventilation. Research shows that cardiac activity significantly increases the risk of artifacts (131), so the catheter depth can be adjusted using bedside chest X-rays or E_Adi waveforms. The catheter depth can be moved within ±5 cm without affecting the normal operation of NAVA. We speculate this is related to the longitudinal arrangement of the electrodes. Even if the catheter is far from the diaphragm, some electrodes may still be close to the diaphragm surface. Additionally, the patient’s physiological responses or behaviors may also cause changes in catheter position (139). For example, swallowing or hiccupping can trigger contractions of the esophageal muscles, leading to temporary displacement of the catheter and producing transient E_Adi artifacts. Changes in the patient’s position can similarly affect electrode contact, leading to signal drift or interference, which is particularly common in premature infants. If the ventilator does not detect the E_Adi signal or if the patient has no spontaneous breathing, NAVA will default to backup ventilation mode to maintain the patient’s ventilation.

Second, the NAVAL should be adjusted. Elevated NAVALs may provoke erratic periodic breathing patterns (140), resulting in apnea and discomfort for the patient (31,71). Additionally, several studies propose a link between NAVA and the occurrence of double triggering (51,141). This phenomenon is thought to be associated with the biphasic characteristics of the E_Adi signal, which arises when the inspiratory phase of the ventilator is shorter than the patient’s neural inspiratory phase, consequently leading to the occurrence of two successive cycles and an increase in patient discomfort (71). Therefore, close observation is needed to prevent excessive ventilation or lung injury caused by MV.

The initiation mechanism of NAVA is based on the observation of diaphragmatic electrical activity. While research indicates that sedative agents can diminish the amplitude of E_Adi signals (31), this does not restrict the utilization of NAVA (105,106). The assessment of E_Adi signals is subject to various influencing factor (32), such as catheter positioning, sedation depth, and the administration of muscle relaxants. Furthermore, artifacts in E_Adi signals can affect the interpretation of ventilator software signals. Artifacts can be classified into two categories: mechanical artifacts and electrical artifacts. Mechanical artifacts arise from fluctuations in intrathoracic pressure resulting from cardiac contraction and relaxation, as well as minor shifts in the E_Adi catheter’s position relative to the diaphragm (13,142). Electrical artifacts (143,144) results from the combined effects of cardiac activity and extracorporeal devices. The frequency of cardiac activity mainly lie within the 0–15 Hz range, while those of electromyographic activity fall within 20–250 Hz. In patients with arrhythmias or weakened diaphragm function, the frequency components of these two signals may overlap, which makes distinguishing between them difficult. Extracorporeal devices, such as intra-aortic balloon catheters, cardiac pacemakers, and external heating systems, can cause distortion of the E_Adi signal. This artifact may lead to a time delay between physiological inspiration and the onset of E_Adi inspiratory, which can negatively affect clinical decision-making.

In some newborns, the application of ventilatory support can result in diaphragmatic stretching, leading to the generation of electrical activity signals. This phenomenon is known as the Hering-Breuer paradox reflex (145), which encompasses both inflation and deflation reflexes. A notable constraint of the NIV-NAVA technology is its inability to precisely identify spontaneous breaths arising from the Hering-Breuer paradox reflex. This reflex is initiated when the passive stretching of the diaphragm by the delivery of gas by the ventilator activates the inspiratory activity. The refractory period between signals from the inspiratory motor neurons is increased to prevent overdistention of the lungs. This results in a delay in the onset of the subsequent inspiration and an extension of expiration, leading to a decrease in both breathing rate and Vt.

Selecting the right patient cohort for NAVA in clinical settings is crucial. The process of generating the E_Adi signal consists of three main phases: first, the activation of the respiratory center; next, the conduction of electrical signals through the phrenic nerve nucleus, the phrenic nerve itself, and the neuromuscular junction; and finally, the stimulation of the diaphragm’s muscle fibers. The efficacy of NAVA is clearly dependent on the proper functioning of the respiratory center, the phrenic nerve, and the diaphragm muscle fibers. Any disruption in the transmission of signals from the respiratory center to the diaphragm can hinder the production of the E_Adi signal.

In practice, changes in phrenic nerve conduction can cause E_Adi signals to inaccurately reflect inspiratory effort, making them unsuitable for triggering respiratory support (Table 4). For example, a partial neuromuscular blockade can enhance central respiratory drive, while simultaneously causing a significant decrease in the E_Adi signal (P<0.001) (146). By evaluating variations in diaphragmatic pressure (i.e., transdiaphragmatic pressure) and computing the ratio of pressure changes to E_Adi, one can establish a measure of phrenic mechanical coupling (147), which indicates the diaphragmatic pressure generated per µV of E_Adi. If a patient displays diaphragmatic dysfunction, this can lead to a decoupling of the phrenic nerve (148), resulting in a scenario where the E_Adi signal fails to accurately reflect central respiratory drive. It is imperative for patients undergoing NAVA ventilation to retain an intact neuromuscular transmission capacity (9); however, the efficacy of NAVA might be limited in patients with CDH due to insufficient signal generation. Furthermore, the existence of pleural effusion may negatively impact the reliability of the E_Adi signal (149). In cases involving patients such as premature infants, whose respiratory centers are still developing, caution should be exercised when implementing NAVA, as this could lead to frequent backup ventilation and the risk of lung injury (125). Therefore, in formulating NAVA treatment approaches, it is essential to conduct a comprehensive assessment of the patient’s diaphragmatic functionality and overall neuromuscular transmission capability.

Currently, robust clinical research evidence is lacking to substantiate a notable enhancement in critical clinical outcomes for patients utilizing the NAVA mode (60,150). NAVA does not significantly correlate with improved clinical outcomes when compared to modes such as PSV and adaptive support ventilation (ASV) (151-154). The clinical endpoints assessed in these studies encompass NIV failure rates, duration of MV, ICU length of stay, mortality rates, necessity for tracheostomy, and the prevention of respiratory failure exacerbation. An observational study (155) analyzed 91 patients using NIV via NAVA mode compared to matched cohorts of 134 and 202 patients using PSV. Following adjustments for confounding variables, the investigation revealed no significant impact of the NAVA mode on intubation rates in NIV-NAVA patients, NIV duration, or 90-day mortality when juxtaposed with PSV. A large randomized controlled trial (153) contrasted PSV and NAVA during NIV in a cohort of 100 patients diagnosed with new-onset acute respiratory failure (ARF). In the aggregate population, this study did not show any significant differences between NAVA and PSV concerning NIV failure rates (30% vs. 32%, P=0.83). Additionally, there was no meaningful disparity in the 28-day mortality rates (18% vs. 34%, P=0.07). An increasing number of studies focus on the immediate benefits of NAVA in patients, especially in pediatric trials, but the adult requires more research.

The clinical use of NAVA is affected by factors like accessibility, cost, and technology. Patients must independently incur the costs of the E_Adi catheter, as medical insurance may not cover these expenses. Furthermore, the NAVA modality requires frequent electrode catheter repositioning, raising costs, and necessitates specialized ventilators, limiting its use in healthcare facilities. Clinical research (156) identifies “technical challenges” as a significant limitation of the NAVA approach, while “insufficient clinical expertise” is recognized as the principal obstacle to its broader adoption. Consequently, although NAVA offers innovative insights into the monitoring of diaphragmatic electrical activity, healthcare professionals must exercise caution in exploring methodologies and interpreting findings, ensuring a thorough consideration of the patient’s physiological and pathological context.

Conclusions

NAVA implementation depends on monitoring diaphragmatic electrical activity. This approach aligns with physiological characteristics and improves coordination between the ventilator and patient. It reduces the asynchrony index and sedatives. Furthermore, NAVA promotes spontaneous breathing, prevents diaphragmatic atrophy, and increases weaning success. Although short-term clinical benefits have been confirmed, more cases are needed to further investigates its long-term effects.

Accurate positioning of the NAVA catheter is fundamental for monitoring E_Adi. Typically, catheter position is estimated by measuring the distance from the nose through the earlobe to the xiphoid process, then adjusted according to the E_Adi waveform. Factors such as patient positioning, PEEP, and IAP may displace the catheter, affecting signal stability and necessitating frequent position checks. Furthermore, the NAVA titration process is complex and time-consuming, requiring simplification of operational procedures and the establishment of standardized protocols and reference values.

NAVA requires intact neural pathways and diaphragmatic function, limiting its use in patients with diaphragmatic developmental disorders. It may be ineffective for immature pediatric respiratory systems and carries a risk of double triggering, further restricting its application in these patients. Moreover, contraindications for NAVA remain unclearly defined; thus, more clinical research across diverse diseases is necessary to define its indications and contraindications.

Acknowledgments

None.

Footnote

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