Noninvasive neurally adjusted ventilatory assist versus nasal continuous positive airway pressure for preterm respiratory support: a systematic review

Introduction

Preterm infants frequently require invasive mechanical ventilation (MV) shortly after birth to ensure adequate alveolar ventilation and gas exchange. However, accumulating evidence has demonstrated that prolonged MV in preterm infants is closely associated with ventilator-induced lung injury (VILI) and airway inflammation (1,2), and contributes to an elevated risk of ventilator-associated pneumonia, mortality, and neurological impairments (3). Consequently, the adoption of non-invasive respiratory support modalities or early extubation is recommended to minimize the risk of lung injury and optimize neonatal outcomes.

Nasal continuous positive airway pressure (NCPAP) serves as a standard noninvasive modality for supporting respiration in premature infants during the postnatal transition period (4). By maintaining airway patency and preserving alveolar function and functional residual capacity, NCPAP mitigates the risk of lung overdistension while enhancing lung compliance and oxygenation (4). Consequently, NCPAP reduces the requirement for supplemental oxygen and lowers the incidence of pulmonary complications (5). Despite its efficacy in preventing extubation failure among preterm infants, the failure rate associated with NCPAP remains substantial, ranging from 25% to 35% in this population (6-8).

Conventional neonatal MV typically employs time- or flow-triggered cycling between inspiration and expiration, which may inadequately align with the neurophysiological demands of preterm infants (4). In contrast, noninvasive neurally adjusted ventilatory assist (NIV-NAVA) represents an advanced ventilation strategy that leverages neural triggers to enhance breathing synchrony (9). This modality utilizes an esophageal catheter to continuously monitor the electrical activity of the diaphragm (Edi), from which it calculates the average electrical activity of the diaphragm (AEdi)—a real-time parameter that modulates ventilator support (10). By dynamically adapting to the infant’s respiratory efforts, NIV-NAVA enables greater autonomy in regulating ventilation parameters, including breath initiation, termination, volume, rate, and peak pressure (11,12). Theoretically, this personalized approach more effectively matches neonatal respiratory demands compared to conventional modalities, positioning NIV-NAVA as a promising intervention for neonatal respiratory failure (13).

Recent clinical investigations have reported several advantages of NIV-NAVA over NCPAP as primary respiratory support, including reduced treatment failure rates, higher extubation success, shorter durations of MV, and improved patient-ventilator synchrony (14-18). However, these findings are constrained by small sample sizes and heterogeneous study designs. Moreover, the long-term safety profile of NIV-NAVA relative to NCPAP remains incompletely characterized, particularly regarding potential associations with bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP). Further large-scale, randomized trials are urgently needed to clarify these uncertainties and establish evidence-based guidelines for clinical implementation.

In recognition of the current evidence landscape, a meta-analysis was deemed inappropriate for this systematic review. This methodological choice was primarily necessitated by the limited availability of adequately powered randomized controlled trials (RCTs) and substantial inter-study heterogeneity. To preserve the validity of findings and avoid misleading conclusions arising from data pooling, we confined our analysis to a qualitative synthesis of eligible studies. This approach ensures transparency in evidence appraisal while acknowledging the inherent variability in the current literature.

The purpose of this systematic review is to compare and evaluate the safety and efficacy of NIV-NAVA and NCPAP as primary or post-extubation ventilation modes for preterm infants. By analyzing existing literature, we hope to provide insights that can aid healthcare professionals in making informed decisions on the most appropriate mode of respiratory support for preterm infants, based on their unique clinical needs and circumstances. We present the article in accordance with the PRISMA reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-23-36/rc).

Methods

This review was performed according to a predefined protocol, which was developed in line with the recommendations for systematic reviews. The study protocol can be accessed online (https://www.crd.york.ac.uk/prospero/export_details_pdf.php). Registration: CRD42023421604 (PROSPERO).

Search strategy

We carried out a comprehensive literature search up to May 1, 2025, across multiple databases including the Cochrane Library, MEDLINE, Embase, CINAHL, Web of Science, CNKI, and Wangfang. The search strategy combined keywords with Medical Subject Headings (MeSH) terms. Key search terms included “preterm infant”, “premature infant”, “neonatal prematurity”, “Noninvasive neurally adjusted ventilatory assist”, “NIV-NAVA”, “Interactive Ventilatory Support”, “Proportional Assist Ventilation”, “nCPAP Ventilation”, and “Nasal Continuous Positive Airway Pressure”.

In addition to electronic database searches, we manually reviewed clinical trial registries, conference proceedings, and reference lists of included studies. We also employed the “related articles” feature in PubMed and the “related records” function in Web of Science to identify additional relevant studies. All searches were restricted to articles published in English or Chinese. The search strategy of PubMed in Appendix 1.

Inclusion and exclusion criteria

Inclusion criteria

We included RCTs and high-quality observational studies that compared the efficacy of NIV-NAVA and NCPAP as primary or post-extubation respiratory support for preterm infants. Literature retrieval adhered to the PICO framework:

• P (participants): the participants of this study were limited to preterm infants who were born before 37 weeks of completed gestational age or less than 259 days since the first day of the woman’s last menstrual period, as defined by the World Health Organization.
• I (intervention): NIV-NAVA was used as primary or post-extubation respiratory support for preterm infants in the experimental group.
• C (comparison): NCPAP was used as primary or post-extubation respiratory support for preterm infants in the controlled group.
• O (outcomes):
  • Primary outcomes included: treatment failure and reintubation rate.
    • Reintubation rate: the proportion of infants who require reintubation (placement of an endotracheal tube) within 72 hours following planned extubation, expressed as a percentage of the total number of extubated infants in the study population.
    • Treatment failure: failure of primary modality (NIV-NAVA vs. NCPAP) requiring change or escalation to an alternative mode of respiratory support.
  • Secondary outcomes included: FIO₂, incidence of apnea, duration of NIV, administration of pulmonary surfactant, the rates of NEC, ROP, BPD, intraventricular hemorrhage (IVH), apnea, pneumothoraces.
    • NEC defined according to modified Bell’s criteria (stage 2 to 3) during hospitalization (19).
    • BPD: the diagnostic criteria and grading for BPD are based on the standards proposed by the U.S. National Institute of Child Health and Human Development in June 2000 (20).
    • ROP: all stages and severe (stage 3 or greater) during hospitalisation (21).

Study design: RCTs or high-quality observational studies.

Exclusion criteria

Studies were excluded if they met any of the following criteria:

• Duplicate publications.
• Inability to extract or calculate effect sizes for primary outcomes.
• Insufficient data on participant characteristics or intervention details.

Data extraction and synthesis

To ensure the accuracy and reliability of the review, literature screening and data extraction were performed independently by two investigators (N.X and R.Y.). Any discrepancies encountered during this process were resolved through discussion or, if necessary, by consultation with a third senior investigator (C.S.). For studies with missing information, the original authors were contacted via email to request additional data.

The literature screening process consisted of two phases: (I) initial screening of titles and abstracts to exclude obviously irrelevant records, followed by (II) a full-text assessment of the remaining articles against the eligibility criteria.

Data extracted from the included studies encompassed the following items: first author, year of publication, study design, primary outcomes, and secondary outcomes. Additionally, we also extracted data on the effects of NIV-NAVA versus NCPAP when used as initial respiratory support or post-extubation respiratory support on the following critical outcomes: treatment failure, reintubation rate, FiO₂ requirements, incidence of apnea, duration of NIV, need for pulmonary surfactant administration, and the incidence rates of major neonatal morbidities including NEC, ROP, BPD, IVH, apnea, and pneumothoraces. Given the substantial heterogeneity in interventions and outcome measures across the included studies, the results were synthesized narratively rather than quantitatively (meta-analysis).

Quality appraisal

Quality appraisal for randomized studies was performed using the revised Cochrane Risk of Bias tool (22,23). The quality assessment included seven aspects (random sequence generation, allocation concealment, blinding of participants or personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias), with each aspect rated as low, high, or unclear in the risk of bias. We used Review Manager (RevMan) software 5.3 to provide risk of bias graphs and summaries. Quality appraisal for observational studies was performed using the Newcastle-Ottawa-Scale (NOS) (24), which evaluates from three dimensions: comparability between groups, selection of study subjects, and measurement of exposure factors. The total score is 9 points, and studies with a score of 7 or higher are included. Two reviewers working independently rated the studies, and a final decision was reached by consensus with a senior author.

Assessment of the certainty of evidence

We assessed the certainty of evidence for each outcome using the GRADE approach, which classifies evidence as high, moderate, low, or very low based on study limitations, inconsistency, indirectness, imprecision, and publication bias. Two reviewers (R.Y. and D.L.) independently rated the certainty of evidence. Disagreements were resolved through discussion or, if necessary, by consulting a third reviewer (H.Z.).

Results

Our literature search identified 190 articles, 11 of which were excluded as duplicate publications. Following initial screening of titles and abstracts, 171 articles deemed clearly irrelevant were eliminated. A full-text review of the remaining articles led to the exclusion of one additional study for failing to meet the predefined outcome criteria. Ultimately, five RCTs (14,15,17,25,26) and two retrospective studies (16,18) were included in this systematic review. The study selection process is illustrated in Figure 1. Key characteristics of the included studies, such as study population, sample size in each reported group, study design, intervention measures, outcomes, and the gestational age and birth weight of preterm infants, are summarized in (Table 1). A comparison of key outcome measures—including treatment failure rate, reintubation rate, and other relevant endpoints—between the NIV-NAVA and NCPAP groups, both when applied as initial respiratory support and as post-extubation support, is provided in (Tables 2,3).

Figure 1 PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only.

Effect of NIV-NAVA and NCPAP as primary respiratory support for premature infants

Treatment failure

Three RCTs evaluated the efficacy of neurally adjusted ventilatory assist (NIV-NAVA) versus NCPAP as primary respiratory support for reducing noninvasive ventilation failure among preterm infants. Collectively, these studies demonstrated no significant difference in treatment failure rates between NIV-NAVA and NCPAP.

Yagui et al. (14) randomized 123 preterm infants to NCPAP (n=64) or NIV-NAVA (n=59), defining treatment failure as endotracheal intubation and invasive MV within 72 hours of life based on predefined criteria. The failure rate was 15.6% (10/64) in the NCPAP group and 20.3% (12/59) in the NIV-NAVA group (P=0.65), with all infants transitioning to invasive MV upon failure. Kallio et al. (15) randomized 40 preterm infants to NIV-NAVA (n=20) or NCPAP (n=20), where failure was defined by criteria including FiO₂ ≥0.4, excessive work of breathing, frequent apnea, or requirement for surfactant therapy. Failure occurred in 35% (7/20) of infants in the NIV-NAVA group and 50% (10/20) in the NCPAP group (P=0.36), with all treatment failures undergoing endotracheal intubation and invasive ventilation. Lee et al. (25) assigned 20 preterm infants to NIV-NAVA (n=10) or NCPAP (n=10), requiring intubation for failure criteria such as persistent high FiO₂, pH <7.25, or frequent apnea with bradycardia. The failure rate was 30% (3/10) in the NIV-NAVA group and 40% (4/10) in the NCPAP group (P>0.99), with all infants converted to invasive MV via endotracheal intubation and administered surfactant in cases of treatment failure.

In summary, these RCTs consistently showed no significant benefit of NIV-NAVA over NCPAP in reducing noninvasive ventilation failure, though specific failure criteria and sample sizes varied across studies.

FIO₂

A total of 40 preterm infants (gestational age 28+0 to 36+6 weeks) with respiratory distress requiring CPAP and supplemental oxygen (FiO₂ >0.23) were randomized to receive either NIV-NAVA or CPAP (15). At study enrollment, the mean FiO₂ was 0.29 in both groups. After 12 hours of treatment, FiO₂ decreased to 0.26±0.07 in the NIV-NAVA group and 0.26±0.04 in the CPAP group, with a mean difference of 0.006 [95% confidence interval (CI): −0.4 to 0.5] and no statistically significant between-group difference throughout the course of noninvasive ventilation (P=0.80). A notable subgroup finding was that NIV-NAVA patients who did not require surfactant therapy demonstrated a rapid reduction in oxygen requirements. However, this phenomenon was not observed in those needing surfactant administration, and it did not translate to an overall difference in the duration of oxygen supplementation between the two groups (median 35.8 vs. 53.9 hours, P=0.76).

Collectively, these data indicate that NIV-NAVA did not provide a statistically significant benefit over CPAP in reducing FiO₂ or improving overall oxygen requirements in preterm infants with respiratory distress, despite a transient improvement in a specific subgroup of NIV-NAVA.

Incidence of apnea

Two RCTs examined the effects of immediate NIV-NAVA vs. NCPAP on apnea incidence in preterm infants, with divergent results potentially explained by methodological variations (14,25). Lee et al. (25) studied 20 preterm infants focusing on neural apnea—defined as a flat Edi signal lasting ≥5 seconds. Result demonstrated NIV-NAVA significantly reduced apnea frequency versus NCPAP during the first two postnatal hours (3.0±0.7 and 6.2±1.4 vs. 10.8±4.2 and 29.1±12.2 episodes/hour, respectively; P=0.046). In contrast, Yagui et al. (14) analyzed 123 very low birth weight infants using clinical apnea, defined as recurrent episodes requiring intervention (≥2 PPV or >3 tactile-stimulated episodes/hour). NCPAP showed a non-significant trend toward lower apnea incidence (34.5% vs. 48%, P=0.82), with comparable caffeine use between groups (P=0.76).

Key differences in apnea definitions (neural vs. clinical) and study populations may account for these contrasting findings.

Duration of non-invasive ventilation

Two RCTs compared immediate NIV-NAVA versus NCPAP for preterm infants’ NIV duration, reporting numerical but statistically insignificant differences (14,25). Yagui et al. (14) defined NIV duration as the total support time until weaning or intubation. NCPAP showed a longer duration (147±181 vs. 127±137 hours, P=0.72), potentially attributable to heterogeneous respiratory distress severity, though Minimal Invasive Surfactant Therapy use was balanced between groups (P>0.99). In contrast, Lee et al. (25) measured NIV duration as total hospital days, finding shorter duration with NCPAP (median 25.5 vs. 35.5 days, P=0.91), possibly reflecting transitional physiology post-intervention.

These discrepancies may stem from divergent definitions (hours vs. days) and initiation protocols (≤48 hours post-birth vs. immediate). Neither modality consistently reduced NIV duration, suggesting that outcomes are influenced more by patient-specific factors than ventilation mode.

Pulmonary surfactant administration

None of the three included RCTs demonstrated a statistically significant difference in surfactant requirement between preterm infants managed with NIV-NAVA and those receiving NCPAP.A nuanced divergence in treatment patterns was observed. Kallio et al. reported comparable overall surfactant use (NIV-NAVA: 7 vs. CPAP: 10, P=0.34), but identified a trend toward more frequent multiple dosing in the NIV-NAVA group (6 vs. 3 patients), whereas single-dose administration predominated in the CPAP group (7 vs. 1). This trend (P=0.09) suggests that NIV-NAVA failure may correlate with greater respiratory severity, necessitating intensified surfactant treatment—consistent with the prolonged invasive ventilation observed in this subgroup. In contrast, Yagui et al. found no difference in surfactant utilization via MIST (NCPAP: 29.7% vs. NIV-NAVA: 28.8%, P>0.99) or time to first dose (9.45±11.75 vs. 14.34±11.8 hours, P=0.20), indicating that NIV-NAVA did not reduce surfactant need when used as initial respiratory support. The pilot physiological study by Lee et al., though underpowered, also showed no difference in surfactant use (30% vs. 40%, P>0.99).

In summary, aggregated evidence indicates that NIV-NAVA does not reduce the incidence or alter the timing of surfactant therapy compared to NCPAP. The suggestive association between NIV-NAVA failure and increased surfactant dosing warrants validation in larger trials.

Duration of invasive ventilation

Evidence regarding the impact of NIV-NAVA versus NCPAP on invasive ventilation duration is conflicting. One trial reported prolonged ventilation duration after NIV-NAVA failure (88.4±22.5 vs. 36.8±23.0 hours; P<0.001), suggesting greater illness severity in non-responders (15). Conversely, a larger trial found shorter ventilation courses in the NIV-NAVA group (28.25±34.1 vs. 95.6±45.8 hours; P=0.01), potentially attributable to concomitant use of minimally invasive surfactant therapy (14). A third, underpowered study detected no significant difference (25).

In summary, the observed heterogeneity likely reflects differences in clinical protocols and patient populations. The interaction between non-invasive mode selection and subsequent ventilator duration requires further rigorous evaluation.

Complications

Three RCTs comparing NIV-NAVA and NCPAP in preterm infants found no significant differences in major neonatal complications, despite minor numerical variations. Yagui et al. (14) reported comparable rates of BPD (3.4% vs. 8.1%, P=0.44), IVH (20.4% vs. 12.1%, P=0.34), pneumothorax (3.6% vs. 1.6%, P=0.60), and patent ductus arteriosus (25.4% vs. 26.6%, P>0.99) in very low birth weight infants (≤1,500 g). Kallio et al. (15) similarly found no significant differences in IVH (5% vs. 0%, P>0.99), pneumothorax (10% vs. 10%), or atelectasis (50% vs. 55%, P=0.23). Lee et al. (25) observed equivalent complication rates in infants born at 28–32 weeks, including pneumothorax (10% vs. 0%, P>0.99).

The consistency across studies, despite variations in population gestational age and timing of ventilation initiation, suggests that NIV-NAVA and NCPAP do not differ significantly in their ability to reduce major neonatal complications. Minor numerical discrepancies likely reflect differences in sample size and clinical context, with outcomes more strongly influenced by baseline infant maturity and disease severity than ventilatory modality.

Effectiveness of NIV-NAVA versus NCPAP as post-extubation respiratory support in premature infants

Reintubation

Three studies reported statistically significant reductions in reintubation rates with NIV-NAVA (16-18). Shin et al. (17) conducted a RCT involving preterm infants born at <30 weeks’ gestation, demonstrating that NIV-NAVA was associated with a significantly lower reintubation rate compared to NCPAP (8.6% vs. 28.6%, P=0.031). Similarly, two retrospective studies supported these findings: Yagui et al. (16) observed a marked reduction in reintubation rates in high-risk preterm infants (11.7% in NIV-NAVA vs. 50.0% in NCPAP, P<0.02); Lee et al. (18) reported a comparable trend in very preterm infants (<30 weeks’ gestation), with reintubation rates of 6.3% in the NIV-NAVA group versus 37.5% in the NCPAP group (P=0.041).

Notably, one RCT by Dai et al. (26) found no significant difference in weaning failure rates (a composite outcome including reintubation) between NIV-NAVA and NCPAP (19.44% vs. 16.66%, P>0.05) in preterm infants with respiratory distress syndrome. This inconsistency may be attributed to variations in study populations (e.g., broader gestational age range and differing severity of respiratory distress) and operational definitions of failure.

Collectively, the majority of evidence, particularly from RCTs and targeted retrospective analyses in high-risk preterm populations, indicates that NIV-NAVA reduces the risk of reintubation within 72 hours post-extubation compared to NCPAP, highlighting its potential as a superior post-extubation support strategy in select preterm cohorts.

Patient-ventilator synchrony

In the context of noninvasive respiratory support following extubation in preterm infants, NIV-NAVA exhibits significantly improved patient-ventilator synchrony compared to NCPAP. The study by Dai et al. demonstrated that the NIV-NAVA group had markedly lower rates of ineffective triggering (0.41±0.06 vs. 0.46±0.08 events/min, P<0.05), double triggering (0.43±0.08 vs. 0.55±0.09 events/min, P<0.05), and auto-triggering (0.31±0.07 vs. 0.39±0.06 events/min, P<0.05) (26). Trigger delay was also significantly shorter (86±9 vs. 97±7 ms, P<0.05), resulting in a lower overall incidence of asynchrony (11.11% vs. 33.33%, P<0.05) (26). Complementing these findings, Shin et al. reported physiological evidence through Edi monitoring. Significantly lower peak and swing Edi values were observed in the NIV-NAVA group at 4, 12, and 24 hours post-extubation, indicating reduced respiratory effort and work of breathing.

This enhanced synchrony is attributed to the neural triggering mechanism of NIV-NAVA, which utilizes the Edi signal—a direct representation of neural respiratory output—to initiate and cycle ventilation. This approach effectively avoids the trigger failures common with NCPAP, which relies on pneumatic signals susceptible to leak and inconsistent effort.

In summary, NIV-NAVA provides fundamentally improved synchrony by aligning support with the infant’s neural inspiration, thereby reducing asynchrony events and diaphragmatic effort compared to conventional NCPAP.

Duration of non-invasive ventilation

Two studies comparing NIV-NAVA and NCPAP for post-extubation support in preterm infants reported conflicting results regarding NIV duration. Dai et al. (26) found NIV-NAVA significantly reduced median (IQR) support duration [2 (1-3) vs. 5 (3-6) days; P<0.05]. Conversely, Shin et al. (17) observed no significant difference in their RCT of infants <30 weeks’ gestation.

These inconsistencies may reflect population differences (gestational age, disease severity) or varying definitions of NIV duration.

Gas exchange parameters

A synthesis of findings from the four included studies indicates that NIV-NAVA and NCPAP provide comparable gas exchange following extubation in preterm infants (16-18,26). Measurements of arterial blood gases—including PaO₂, carbon dioxide partial pressure of carbon dioxide (PaCO₂), and pH—showed no statistically significant differences between the two modes at the time points assessed across studies (17,26).

The fraction of inspired oxygen (FiO₂) required to maintain target oxygen saturation was also similar between groups, as ventilator settings were adjusted to meet equivalent clinical targets in all studies. One study (26) reported significantly higher oxygenation index (OI) values in the NIV-NAVA group at 12 and 24 hours after treatment compared to the NCPAP group (OI at 24 h: 258.18±40.75 vs. 230.15±43.15, P<0.05), suggesting a potential advantage in oxygenation efficiency. This improvement may be associated with enhanced patient-ventilator synchrony and reduced diaphragmatic work, as supported by lower Edi values observed in NIV-NAVA groups (Shin et al., 2022).

In summary, the examined studies consistently show that NIV-NAVA and NCPAP maintain similar PaO₂, PaCO₂, pH, and FiO₂ levels within target ranges. The improved OI observed with NIV-NAVA in one study suggests a potential benefit in oxygenation efficiency that requires further investigation.

Complications

Four studies compared the effects of NIV-NAVA and NCPAP as post-extubation respiratory support on short- and long-term complications in preterm infants. The findings consistently demonstrated no significant differences in the incidence of major adverse outcomes between the two modalities. Lee et al. (18) observed no significant variations in moderate-to-severe BPD, NEC ≥ stage 2, ROP, IVH ≥ grade 2, or periventricular leukomalacia, suggesting comparable safety profiles between NIV-NAVA and NCPAP. Subsequently, Yagui et al. (16) reported similar rates of BPD, severe IVH (≥ grade III), pneumothorax, and mortality between the two groups. More recently, Shin et al. (17) and Dai et al. (26) further corroborated these findings, with no statistically significant differences in severe BPD, NEC, IVH ≥ grade III, periventricular leukomalacia, or BPD, NEC, and ROP.

Collectively, these findings indicate that NIV-NAVA and NCPAP are associated with similar risks of major complications, including BPD, NEC, ROP, pneumothorax, IVH, and leukomalacia, when used as post-extubation support in preterm infants.

Discussion

Preterm infants frequently require respiratory support shortly after birth to maintain adequate gas exchange, with invasive MV often serving as a life-sustaining intervention. However, prolonged invasive MV is strongly linked to VILI, airway inflammation, and an elevated risk of long-term morbidities such as BPD (1,3). Consequently, minimizing invasive exposure through early transition to noninvasive respiratory support has become a cornerstone of neonatal care (27,28). NIV-NAVA and NCPAP are two widely used modalities, but their comparative efficacy and safety remain subjects of ongoing debate (29,30). In this systematic review, which includes five RCTs (14,15,17,25,26) and two retrospective studies (16,18), we provide a nuanced perspective on the role of NIV-NAVA versus NCPAP in preterm infants. The findings can be stratified by clinical context.

Primary respiratory support

As the primary respiratory support modality, current clinical evidence indicates that NIV-NAVA does not demonstrate significant advantages over NCPAP in reducing treatment failure rates. Three RCTs (14,15,25) reported comparable treatment failure rates, none of which reached statistical significance. This clinical observation aligns with the findings that NIV-NAVA neither significantly reduced oxygen requirements (FiO₂) at 12 hours post-extubation nor shortened the overall duration of oxygen therapy (15). A meta-analysis of three RCTs including 183 neonates further confirms this, showing that the endotracheal intubation rate was 25% in the NIV-NAVA group and 26% in the NCPAP group [relative risk (RR) 0.91, 95% CI: 0.56–1.48], with no statistically significant difference (31). The European Guidelines on the Management of Neonatal Respiratory Distress Syndrome (32) continue to recommend NCPAP as the first-line non-invasive respiratory support for preterm infants with respiratory distress syndrome, based on current evidence, while noting that NIV-NAVA still requires more clinical research data for validation. This recommendation is highly consistent with the main findings of this study—that NIV-NAVA has not yet demonstrated clear clinical advantages as a primary respiratory support modality.

Compared to chest movements and airflow measures or bradycardia and desaturations to identify apnea (33,34), Edi signal is a direct and reliable method. In this review, the observations regarding apnea present an interesting dichotomy: NIV-NAVA significantly reduced the incidence of neural apnea within the first 2 hours after birth (25), but this advantage was not replicated in clinical apnea metrics (14). Fewer neural apneic episodes during NIV-NAVA compared to NCPAP may indicate that NIV-NAVA stimulates respiratory drive or that the reduction of apneic episodes is caused by an accomplished higher mean airway pressure compared to NCPAP. This discrepancy may stem from their distinct pathophysiological definitions—neural apnea reflects central respiratory drive dysfunction, whereas clinical apnea refers to overt apnea events requiring clinical intervention. The potential mechanisms by which NIV-NAVA reduces neural apnea may include improved patient-ventilator synchrony through Edi-triggered technology or maintenance of higher mean airway pressure levels. However, the precise clinical significance of these findings requires further investigation.

Post-extubation support

NIV-NAVA demonstrates superior clinical efficacy in post-extubation respiratory support. Three clinical studies—comprising one RCT (17) and two retrospective cohort analyses (16,18)—consistently reported significantly lower 72-hour reintubation rates with NIV-NAVA compared to NCPAP (P<0.05 for all studies). These findings were further supported by a meta-analysis conducted by Kuitunen et al. (31), which pooled data from two RCTs and demonstrated a statistically significant reduction in reintubation risk with NIV-NAVA versus conventional NCPAP/nasal intermittent positive pressure ventilation (RR 0.29, 95% CI: 0.10–0.81].

The physiological advantages of NIV-NAVA may underlie its clinical benefits. In the RCT by Shin et al. (17), NIV-NAVA recipients exhibited significantly lower peak electrical activity of Edi and reduced Edi swing (both P<0.01), indicating improved respiratory muscle unloading. Latremouille et al. (35) further characterized NIV-NAVA’s unique pressure dynamics, demonstrating its ability to maintain higher mean airway pressures while achieving lower peak inspiratory pressures compared to conventional modalities. This pressure profile promotes effective alveolar recruitment while minimizing barotrauma risk—a particularly advantageous feature for preterm infants transitioning from invasive MV, who frequently present with diaphragmatic fatigue and respiratory pattern instability.

Current evidence presents some inconsistencies regarding ventilation duration outcomes. While Dai et al. (26) reported significantly shorter duration of NIV support with NIV-NAVA, Shin et al. (17) found no significant between-group differences. This discrepancy may be attributable to: (I) heterogeneous gestational age distributions across study populations, and (II) variations in operational definitions of ventilation duration. Similarly, while Shin et al. (17) documented reduced FiO₂ requirements at 12 and 24 hours post-extubation in the NIV-NAVA group, this effect was not replicated in Dai et al.’s study (26). These collective findings suggest that baseline respiratory disease severity may serve as an important effect modifier of NIV-NAVA’s therapeutic efficacy.

Safety and complications

Current evidence indicates comparable rates of major complications between NIV-NAVA and NCPAP, whether applied as primary respiratory support or post-extubation therapy. Multiple studies (14,15,17,18,25) showed no significant differences in BPD, NEC, ROP, IVH, or pneumothorax incidence. Xu et al.’s meta-analysis (28) reinforced this conclusion, revealing no statistical differences in pneumothorax (RR 1.38, 95% CI: 0.33–5.83), IVH (RR 1.79, 95% CI: 0.77–4.18), or BPD (RR 0.43, 95% CI: 0.09–2.15) between modalities. Notably, Gupta et al. (36) reported zero Edi catheter-related adverse events, providing robust evidence for NIV-NAVA’s clinical safety.

Mechanistic and clinical implications

NIV-NAVA’s theoretical advantage lies in its ability to synchronize ventilation with the infant’s neural respiratory drive via Edi monitoring, potentially reducing asynchrony and respiratory effort (9,11). This is supported by findings of lower Edi-derived work of breathing in post-extubation NIV-NAVA recipients (17). However, in primary support, this mechanistic benefit did not translate to reduced treatment failure, possibly because early postnatal respiratory instability is driven more by lung immaturity than asynchrony. As stated in the European Neonatal Respiratory Distress Syndrome Management Guidelines (32), surfactant deficiency is a major factor in early-onset respiratory distress in preterm infants, overshadowing the potential benefits of improved synchrony provided by NIV-NAVA.

The post-extubation setting may better exploit NIV-NAVA’s strengths: preterm infants recovering from invasive MV often struggle with diaphragmatic fatigue and irregular respiratory patterns, where synchronized support could prevent decompensation. The higher reintubation rates with NCPAP in this context (16-18) underscore the value of targeted synchrony in maintaining respiratory stability. Latremouille et al. (35) also found that NIV-NAVA was associated with increased respiratory variability, which is a marker of adaptive respiratory control and has been linked to better extubation outcomes.

Future directions

First, large-scale, multicenter RCTs are required to validate the efficacy and safety of NIV-NAVA in providing respiratory support for preterm infants.

Second, additional research is needed to optimize NIV-NAVA parameter settings for different subgroups of preterm infants. This involves exploring the optimal NAVA level, positive end-expiratory pressure (PEEP) settings, and inspiratory-expiratory ratio based on factors such as birth weight, gestational age, and the severity of respiratory distress.

Third, cost-effectiveness analyses are of crucial importance, particularly in low- and middle-income countries. These analyses should not only take into account the direct costs of Edi catheters and dedicated ventilators but also evaluate the potential cost savings arising from reduced reintubation rates, shortened hospital stays, and improved long-term outcomes.

Conclusions

NIV-NAVA emerges as a valuable post-extubation support modality, reducing reintubation rates and respiratory effort in preterm infants, without increasing complications. As primary support, it offers no consistent advantage over NCPAP in reducing treatment failure but may benefit select subgroups. Clinicians should consider NIV-NAVA as a preferred post-extubation strategy, particularly in high-risk preterm infants, while awaiting larger trials to confirm its role in primary respiratory support.

Acknowledgments

We would like to thank the patients, their families and the staff involved in the study for their cooperation.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-23-36/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-23-36/prf

Funding: This research was supported by Key Program of the Xiamen Medical and Health (No. 3502Z20234013), Fujian Provincial Health Commission science and technology plan project (No. 2022TG027), Xiamen Natural Science Foundation Project (No. 3502Z202373137), The Innovation and Entrepreneurship Project for High-level Talents in Medical and Health Fields of Quanzhou Science and Technology Bureau (2023C014YR), Construction of Clinical Key Discipline in Xiamen Children’s Hospital (XE2022-YNPY-A03), Xiamen Medical and Health Guidance Project (3502Z20224ZD1272).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-23-36/coif). The authors have no conflicts of interest to declare.

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