Impact of Neurally Adjusted Ventilatory Assist Management on Neurodevelopmental Outcomes in Extremely Preterm Infants

Impact of Neurally Adjusted Ventilatory Assist Management on Neurodevelopmental Outcomes in Extremely Preterm Infants | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Pulmonology This is a preprint and has not been peer reviewed. Data may be preliminary. 26 April 2025 V1 Latest version Share on Impact of Neurally Adjusted Ventilatory Assist Management on Neurodevelopmental Outcomes in Extremely Preterm Infants Authors : Tomoko Saito 0009-0005-2279-9356 [email protected] , Tomoyuki Shimokaze 0000-0001-8490-475X , Yoshinori Inagaki , Takahiro Noguchi , Jun Shibasaki , and Katsuaki Toyoshima Authors Info & Affiliations https://doi.org/10.22541/au.174563475.56547412/v1 Published Pediatric Pulmonology Version of record Peer review timeline 344 views 197 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Introduction: Neurally Adjusted Ventilatory Assist (NAVA) improves patient–ventilator synchrony using diaphragmatic electrical activity. However, its long-term impact on neurodevelopment in extremely preterm infants remains unclear. This study examined the association between NAVA management and neurodevelopmental outcomes. Methods: We retrospectively compared infants born at ≤27 weeks’ gestation who were admitted before (2016–2017, n=38) and after (2019–2021, n=44) NAVA implementation. The primary outcome was the developmental quotient (DQ) at 18 months, assessed using the Kyoto Scale of Psychological Development. Results: Comparing the pre- and post-implementation groups: median gestational age, 25.5 vs. 25.9 weeks (p=0.67); postmenstrual age at extubation, 30.6 vs. 32.1 weeks (p<0.001); NAVA use, 0% vs. 91%; and high-frequency oscillatory ventilation use, 74% vs. 46% (p=0.013). No significant differences were observed between the groups in corticosteroid use, bronchopulmonary dysplasia incidence, postmenstrual age at discharge, or home oxygen therapy. At 18 months, DQ scores were as follows in the pre- and post-implementation groups: Full Scale (83 vs. 89; p=0.32), Gross Motor (81 vs. 86; p=0.45), Cognitive/Adaptive (83 vs. 90; p=0.56), and Language/Social (71 vs. 88; p=0.109). Modified Checklist for Autism in Toddlers score was 3 in both groups (p=0.86). Multivariable analysis revealed that NAVA use (adjusted odds ratio [aOR] 2.99, 95% confidence interval [CI]: 1.14–7.81) and gestational age (aOR 1.59, 95% CI: 1.08–2.33) were associated with Full Scale DQ ≥85; whereas sex and birth weight standard deviation were not. Conclusion: Despite the prolonged tracheal intubation period, NAVA management was associated with improved neurodevelopment outcomes at 18 months. Impact of Neurally Adjusted Ventilatory Assist Management on Neurodevelopmental Outcomes in Extremely Preterm Infants Tomoko Saito, MD, PhD, Tomoyuki Shimokaze, MD, PhD, Yoshinori Inagaki, MD, Takahiro Noguchi, MD, Jun Shibasaki, MD, Katsuaki Toyoshima, MD, PhD Department of Neonatology, Kanagawa Children’s Medical Center, Yokohama, Kanagawa, Japan. Correspondence to Tomoko Saito, [email protected] Department of Neonatology, Kanagawa Children’s Medical Center 2-138-4 Mutsukawa, Minami-ku, Yokohama, 232-8555, Japan Phone: +81-45-711-2351, Fax: +81-45-721-3324 Funding information: No funding was received for this study. Keywords: corticosteroid, neonate, bronchopulmonary dysplasia, mechanical ventilation, NAVA, NICU Running head: NAVA and Neurodevelopment in Preterm Infants Abstract (249 words) Introduction: Neurally Adjusted Ventilatory Assist (NAVA) improves patient–ventilator synchrony using diaphragmatic electrical activity. However, its long-term impact on neurodevelopment in extremely preterm infants remains unclear. This study examined the association between NAVA management and neurodevelopmental outcomes. Methods: We retrospectively compared infants born at ≤27 weeks’ gestation who were admitted before (2016–2017, n=38) and after (2019–2021, n=44) NAVA implementation. The primary outcome was the developmental quotient (DQ) at 18 months, assessed using the Kyoto Scale of Psychological Development. Results: Comparing the pre- and post-implementation groups: median gestational age, 25.5 vs. 25.9 weeks (p=0.67); postmenstrual age at extubation, 30.6 vs. 32.1 weeks (p<0.001); NAVA use, 0% vs. 91%; and high-frequency oscillatory ventilation use, 74% vs. 46% (p=0.013). No significant differences were observed between the groups in corticosteroid use, bronchopulmonary dysplasia incidence, postmenstrual age at discharge, or home oxygen therapy. At 18 months, DQ scores were as follows in the pre- and post-implementation groups: Full Scale (83 vs. 89; p=0.32), Gross Motor (81 vs. 86; p=0.45), Cognitive/Adaptive (83 vs. 90; p=0.56), and Language/Social (71 vs. 88; p=0.109). Modified Checklist for Autism in Toddlers score was 3 in both groups (p=0.86). Multivariable analysis revealed that NAVA use (adjusted odds ratio [aOR] 2.99, 95% confidence interval [CI]: 1.14–7.81) and gestational age (aOR 1.59, 95% CI: 1.08–2.33) were associated with Full Scale DQ ≥85; whereas sex and birth weight standard deviation were not. Conclusion: Despite the prolonged tracheal intubation period, NAVA management was associated with improved neurodevelopment outcomes at 18 months. Introduction In preterm infants, invasive mechanical ventilation can provoke inflammatory responses through excessive ventilation volumes and pressures, leading to an increased risk of bronchopulmonary dysplasia (BPD) 1-3 . BPD is a well-recognized risk factor for adverse neurodevelopmental outcomes 4,5 , highlighting the importance of its prevention and management in improving long-term outcomes in this population. Although postnatal corticosteroids are used to reduce the risk of developing BPD, concerns remain regarding their potential neurotoxic effects 6-8 . Consequently, there is growing interest in non-pharmacological strategies for lung protection. Conventional ventilatory modes often fail to achieve optimal patient–ventilator synchrony in preterm infants, potentially increasing the work of breathing and risk of lung injury. Neurally Adjusted Ventilatory Assist (NAVA) is a ventilation mode that uses the electrical activity of the diaphragm (Edi) to synchronize support with spontaneous breathing efforts. NAVA reportedly improves synchrony, reduces peak inspiratory pressure and oxygen demand, and lowers the work of breathing in preterm infants 9-12 . Based on these potential benefits, NAVA was introduced in approximately 20% of NICUs in Japan by 2023 13 , and its use has continued to expand since then. Although NAVA is becoming more commonly used, there is limited evidence on its effect on BPD incidence and long-term neurodevelopmental outcomes 14 . This study evaluated the association between NAVA-based respiratory management and neurodevelopmental outcomes in extremely preterm infants at 18 months corrected age. Materials and Methods This retrospective single-center observational study was conducted in a level III NICU with 51 beds and approximately 400 annual admissions. Eligible participants were infants born at ≤27 weeks of gestation who were admitted to our hospital within 24 hours of birth between January 2016 and December 2021. Exclusion criteria included major congenital anomalies, death before 18 months corrected age, or lack of developmental assessment at 18 months. Infants admitted during the period before (2016–2017) and after NAVA implementation (2019–2021) were assigned to the pre-implementation and post-implementation groups, respectively. The following data were obtained from medical records: birth weight, gestational age, sex, small-for-gestational-age status, 5-minute Apgar score, placental findings, use of antenatal and postnatal corticosteroids, discharge status, and morbidities. Respiratory management protocol All infants born at ≤27 weeks of gestation were intubated at birth and received pulmonary surfactant, followed by ventilation with synchronized intermittent mandatory ventilation (SIMV). Sedation with morphine was routinely administered during the first 72 hours. If ventilator settings needed to be escalated after 72 hours of life, high-frequency oscillatory ventilation (HFOV) was initiated, given its association with a reduced risk of intraventricular hemorrhage. After NAVA implementation, an Edi catheter was inserted and NAVA support initiated once gastrointestinal function was confirmed to be stable. NAVA was not initiated if tracheal extubation was deemed feasible within the first two weeks of life. The criteria for extubation included FiO₂ extubation, the infants received either a high-flow nasal cannula or noninvasive NAVA support. Postnatal corticosteroids were administered for BPD management in infants who required FiO₂ >0.30 for prolonged periods. The initial regimen consisted of hydrocortisone (4 mg/kg/day for 3 days), with a second course considered one week later if clinically indicated. If the response to hydrocortisone was insufficient, dexamethasone (0.2 mg/kg/day for 3 days) was used. NAVA ventilation was delivered using Servo-N (Getinge), while synchronized intermittent mandatory ventilation (SIMV) was administered using either Servo-N or VN500 (Dräger), and high-frequency oscillatory ventilation (HFOV) was provided with VN500. BPD severity was assessed at 36 and 40 weeks of postmenstrual age using the Jensen classification 15 . Total corticosteroid exposure was calculated by converting the dexamethasone doses to their hydrocortisone equivalents 16 . Neurodevelopmental assessment Neurodevelopment was assessed at 18 months corrected age by a certified psychologist using the Kyoto Scale of Psychological Development (KSPD), a standardized developmental test designed for Japanese children 17 . The KSPD evaluates the developmental quotient (DQ) across three domains: postural–motor, cognitive–adaptive, and language–social. The overall DQ is calculated as the average of these three scores. The KSPD demonstrated strong internal consistency with a split-half reliability coefficient of 0.875 for the overall DQ score. Although developed in Japan, the concurrent validity of the KSPD has been supported by strong correlations with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), indicating that the KSPD provides comparable assessments of developmental functions 17 . In this study, a DQ score ≥85 was considered indicative of normal development, based on the standard classification used in the KSPD follow-up protocols. In addition, the Japanese version of the Modified Checklist for Autism in Toddlers (M-CHAT) was administered simultaneously to screen for autism spectrum disorder (ASD). The M-CHAT is a parent-completed questionnaire widely used to assess ASD risk in infants and toddlers aged 18 to 30 months 18 . Outcomes The primary outcome was overall DQ score at 18 months corrected age. DQ scores were compared between the pre- and post-implementation groups. Additionally, we examined the association between NAVA use and normal development (defined as DQ ≥ 85). Statistical analysis Continuous variables were summarized using medians and interquartile ranges, while categorical variables were expressed as counts with percentages. The Mann–Whitney U and chi-square tests were used to compare continuous and categorical variables, respectively. To identify factors associated with normal development (DQ ≥ 85), we built a logistic regression model including covariates known or suspected to influence neurodevelopment: gestational age, sex, birth weight standard deviation (SD), and NAVA use. We limited the number of independent variables to avoid overfitting and assessed multicollinearity among the covariates. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) modified for biostatistical analysis. Statistical significance was set at p < 0.05. Ethical considerations The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Kanagawa Children’s Medical Center (approval number: 139-7). Due to the retrospective nature of the study and the use of anonymized data, we adopted an opt-out system and posted a summary of the study on the website of the hospital. The ethics committee waived the requirement for individual informed consent. Results Patient background characteristics (Figure 1） During the study period, 104 infants born at ≤27 weeks of gestation were admitted to our hospital. After excluding five infants with major congenital anomalies, 48 and 50 infants were assigned to the pre-implementation and post-implementation groups, respectively. Among them, two infants died in the pre-implementation period, and one infant died in the post-implementation period. Additionally, eight and five infants were excluded from the study due to relocation or lack of neurodevelopmental assessment at 18 months corrected age, respectively. As a result, 38 and 44 infants remained in the pre-implementation and post-implementation groups, respectively. Respiratory management, morbidity, and discharge status (Figure 2 and Table 1) The frequency of HFOV use decreased after NAVA implementation. In the post-implementation group, 91% of infants were managed with NAVA. Among these, NAVA was used for a median of 49% of the days on invasive mechanical ventilation. The median proportion of days on HFOV decreased from 61% to 0% in the post-implementation group. Furthermore, the median postmenstrual age at tracheal extubation was later following NAVA implementation. No significant differences were observed between the two groups in terms of postnatal corticosteroid use after the first week of life, BPD severity at 36 and 40 weeks of corrected age, weight gain z-score from birth to 40 weeks, head circumference at 40 weeks, postmenstrual age at discharge, use of home oxygen therapy, or the incidence of in-hospital complications. Neurodevelopmental outcomes at 18 months corrected age (Tables 2 and 3) No significant differences were observed between the two groups in terms of overall DQ scores on outcomes. Multivariable logistic regression analysis revealed that both NAVA use and gestational age were significantly associated with normal development, whereas birth weight SD and sex were not. Discussion This retrospective study evaluated the impact of a NAVA-based respiratory strategy on neurodevelopmental outcomes in extremely preterm infants. Although the duration of tracheal intubation was prolonged following NAVA implementation, the need for postnatal corticosteroids did not increase, and NAVA use was significantly associated with a higher likelihood of normal neurodevelopment (DQ ≥ 85) at 18 months corrected age. After NAVA implementation, approximately 90% of the infants were managed with NAVA. The longer duration of tracheal intubation observed during this period may reflect the broader use of NAVA. Since NAVA enables real-time visualization of Edi 19 , clinicians may have been more cautious when deciding to perform tracheal extubation, particularly when spontaneous breathing appeared unstable. The longer intubation period after the introduction of NAVA may not simply reflect a poorer prognosis, but rather a tailored and individualized extubation process based on each infant’s respiratory stability. Additionally, NAVA use is associated with a reduced need for sedation compared to other modes of ventilation 20 . Infants managed with NAVA may have experienced greater comfort and less distress, potentially diminishing the urgency to expedite weaning from mechanical ventilation. Prolonged tracheal intubation period was linked to reduced brain volume and impaired psychomotor development 4,5,21 . However, in the present study, despite a longer duration of tracheal intubation, NAVA use was positively associated with normal developmental outcomes. These findings are consistent with previous studies by Piatek et al., which reported that extended tracheal intubation with NAVA was not associated with adverse brain MRI findings or poorer cognitive function at 2 years corrected age in extremely preterm infants 22,23 . Moreover, the Canadian Oxygen Trial post-hoc analysis indicated that intermittent hypoxemia in extremely preterm infants is associated with later death or disability 24 . Prolonged mechanical ventilation with NAVA until the stabilization of spontaneous breathing may help prevent intermittent hypoxemia, and the improved patient–ventilator synchrony characteristics of NAVA may contribute positively to neurodevelopmental outcomes. This study has some limitations. First, this was a retrospective single-center analysis conducted in a setting with a low incidence of intraventricular hemorrhage and periventricular leukomalacia, which may limit the generalizability of the findings. Second, neurodevelopmental outcomes were assessed only at 18 months corrected age, and extended follow-up through school age is warranted. Third, although prolonged tracheal intubation may affect infant comfort, it must be weighed against the risks of hypoxemia and bradycardia after tracheal extubation. In conclusion, although the duration of intubation was prolonged following the introduction of NAVA, its use was associated with a higher likelihood of normal neurodevelopment at 18 months corrected age. These findings suggest that prolonged intubation may not be detrimental to neurodevelopment when managed appropriately with NAVA. This challenges the conventional emphasis on early tracheal extubation and highlights the importance of optimizing the quality of respiratory support rather than prioritizing its duration. Further studies are required to evaluate the long-term neurodevelopmental effects of NAVA in extremely preterm infants. Acknowledgements We would like to thank Editage (www.editage.jp) for English language editing. Conflict of Interest The authors have no acknowledgments to declare. References 1. Isayama T, Iwami H, McDonald S, Beyene J. Association of Noninvasive Ventilation Strategies With Mortality and Bronchopulmonary Dysplasia Among Preterm Infants: A Systematic Review and Meta-analysis. JAMA. 2016;316(6):611-624.2. Dou C, Yu YH, Zhuo QC, et al. Longer duration of initial invasive mechanical ventilation is still a crucial risk factor for moderate-to-severe bronchopulmonary dysplasia in very preterm infants: a multicentrer prospective study. World J Pediatr. 2023;19(6):577-585.3. Söderström F, Ågren J, Sindelar R. Early extubation is associated with shorter duration of mechanical ventilation and lower incidence of bronchopulmonary dysplasia. Early Hum Dev. 2021;163:105467.4. Guillot M, Guo T, Ufkes S, et al. Mechanical Ventilation Duration, Brainstem Development, and Neurodevelopment in Children Born Preterm: A Prospective Cohort Study. J Pediatr. 2020;226:87-95.e83.5. Vliegenthart RJS, van Kaam AH, Aarnoudse-Moens CSH, van Wassenaer AG, Onland W. Duration of mechanical ventilation and neurodevelopment in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2019;104(6):F631-f635.6. Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev. 2021;10(10):Cd001146.7. Douglas E, Hodgson KA, Olsen JE, et al. Postnatal corticosteroids and developmental outcomes in extremely preterm or extremely low birth weight infants: The Victorian Infant Collaborative Study 2016-17 cohort. Acta Paediatr. 2023;112(6):1226-1232.8. Taniguchi A, Nishida K, Suzuki T, et al. Total Hydrocortisone Dosage in the Neonatal Period May Be Related to Low Developmental Quotient in Extremely Low Birth Weight Infants: A Retrospective Cohort Study. Neonatology. 2024;121(2):195-202.9. Lee J, Kim HS, Sohn JA, et al. Randomized crossover study of neurally adjusted ventilatory assist in preterm infants. J Pediatr. 2012;161(5):808-813.10. Oda A, Parikka V, Lehtonen L, Azimi S, Porres I, Soukka H. Neurally adjusted ventilatory assist in ventilated very preterm infants: A crossover study. Pediatr Pulmonol. 2021;56(12):3857-3862.11. Rosterman JL, Pallotto EK, Truog WE, et al. The impact of neurally adjusted ventilatory assist mode on respiratory severity score and energy expenditure in infants: a randomized crossover trial. J Perinatol. 2018;38(1):59-63.12. Kallio M, Koskela U, Peltoniemi O, et al. Neurally adjusted ventilatory assist (NAVA) in preterm newborn infants with respiratory distress syndrome-a randomized controlled trial. Eur J Pediatr. 2016;175(9):1175-1183.13. Tanaka K, Hayashi R, Ariyama Y, Takahashi N, Namba F. Management of bronchopulmonary dysplasia in Japan: A nationwide survey. Early Hum Dev. 2023;186:105867.14. Lefevere J, van Delft B, Decaluwe W, Derriks F, Cools F. Neurally adjusted ventilatory assist in preterm infants: A systematic review and meta-analysis. Pediatr Pulmonol. 2024;59(7):1862-1870.15. Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019;200(6):751-759.16. B.C.Knollmann LLB. Chapter 50: Adrenocorticotropic Hormone, Adrenal Steroids, and the Adrenal Cortex. In: Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 14th Edition. . MCGRAW-HILL EDUCATION; 2023.17. Kono Y, Yonemoto N, Kusuda S, et al. Developmental assessment of VLBW infants at 18 months of age: A comparison study between KSPD and Bayley III. Brain Dev. 2016;38(4):377-385.18. Koyama T, Inokuchi E, Inada N, et al. Utility of the Japanese version of the Checklist for Autism in Toddlers for predicting pervasive developmental disorders at age 2. Psychiatry Clin Neurosci. 2010;64(3):330-332.19. Sinderby C, Navalesi P, Beck J, et al. Neural control of mechanical ventilation in respiratory failure. Nat Med. 1999;5(12):1433-1436.20. 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Supplementary Material File (figure_legends.docx) Download 15.68 KB File (table_nava_20250423.docx) Download 25.34 KB Information & Authors Information Version history V1 Version 1 26 April 2025 Peer review timeline Published Pediatric Pulmonology Version of Record 15 Oct 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Pulmonology Keywords bronchopulmonary dysplasia corticosteroid mechanical ventilation nava nicu Authors Affiliations Tomoko Saito 0009-0005-2279-9356 [email protected] Kanagawa Kenritsu Kodomo Iryo Center Masuika View all articles by this author Tomoyuki Shimokaze 0000-0001-8490-475X Kanagawa Kenritsu Kodomo Iryo Center Masuika View all articles by this author Yoshinori Inagaki Kanagawa Kenritsu Kodomo Iryo Center Masuika View all articles by this author Takahiro Noguchi Kanagawa Kenritsu Kodomo Iryo Center Masuika View all articles by this author Jun Shibasaki Kanagawa Kenritsu Kodomo Iryo Center Masuika View all articles by this author Katsuaki Toyoshima Kanagawa Kenritsu Kodomo Iryo Center Masuika View all articles by this author Metrics & Citations Metrics Article Usage 344 views 197 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Tomoko Saito, Tomoyuki Shimokaze, Yoshinori Inagaki, et al. Impact of Neurally Adjusted Ventilatory Assist Management on Neurodevelopmental Outcomes in Extremely Preterm Infants. Authorea . 26 April 2025. DOI: https://doi.org/10.22541/au.174563475.56547412/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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