Randomised crossover trial of Neurally Adjusted Ventilatory Assist (NAVA) for Neonates with Congenital diaphragmatic hernias: the NAN-C study

Randomised crossover trial of Neurally Adjusted Ventilatory Assist (NAVA) for Neonates with Congenital diaphragmatic hernias: the NAN-C study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Randomised crossover trial of Neurally Adjusted Ventilatory Assist (NAVA) for Neonates with Congenital diaphragmatic hernias: the NAN-C study Sandeep Shetty, Allan Jenkinson, Grace Poole, Theodore Dassios, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8703181/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Apr, 2026 Read the published version in European Journal of Pediatrics → Version 1 posted 9 You are reading this latest preprint version Abstract Background Retrospective studies comparing NAVA to assist control ventilation (ACV) in neonates with congenital diaphragmatic hernia (CDH) have shown that ventilatory mode may improve respiratory parameters. Objectives To determine if infants with CDH studied post-operatively had a lower oxygenation index (OI) on NAVA compared to ACV. Methods This dual-centre randomised cross-over trial compared post-operative NAVA with ACV in infants with CDH. Infants were randomised to receive either NAVA or ACV first in a 1:1 ratio for a four hour period. At the end of each four hour period, blood gas analysis was performed and the OI calculated. The inspired oxygen concentration (FiO 2 ), the peak inflation (PIP) and mean airway pressure (MAP) were averaged from the last five minutes on each mode. Results Eleven infants were randomised. Nine infants completed the trial. with median gestational age of 38 (range 34.6–39.3) weeks and median postnatal age of 7 (range 5–36) days. Eight had left sided CDH, six had patch repair and two had thoracoscopic repair. The mean OI after four hours on NAVA was 3.9 compared to 5.9 on ACV (p = 0.008). The Peak Edi (6.05 versus 9.86 µV, p = 0.028), PIP (17 versus 22 cm H 2 O, p = 0.017) and MAP (8.7 versus 11.1 cm H 2 O, p = 0.008), expiratory tidal volume (5.06 versus 9.86 mls/kg, p = 0.043) were lower on NAVA versus ACV. Two infants were randomised, but the trial was stopped due to a low Edi signal. Conclusion NAVA compared to ACV improved oxygenation postoperatively in infants with CDH. On NAVA, infants had superior (lower) oxygen indices, peak Edi, expiratory tidal volume and peak and mean airway pressures. Neurally adjusted ventilatory assist NAVA prematurity bronchopulmonary dysplasia BPD Figures Figure 1 Figure 2 Key notes This study reports infants with CDH studied on four hours each of NAVA and assist controlled ventilation. On NAVA, infants had superior (lower) oxygen indices, lower peak Edi, expiratory tidal volume, peak and mean airway pressures Introduction Congenital diaphragmatic hernia (CDH) occurs due to an incomplete fusion of the diaphragm during fetal development, enabling abdominal viscera to herniate into the thoracic cavity 1 . Herniation may disrupt development of the lung and associated vasculature, resulting in pulmonary hypoplasia and pulmonary hypertension 2 . Neonates typically undergo surgical reduction in the first few days after birth 1 . The ventilation-perfusion mismatch often seen in infants with CDH can make the post-operative ventilation of this population challenging. The use of mechanical ventilation (MV) is the standard care for babies with CDH in neonatal intensive care units (NICU) across the UK 3 . The use of MV in this patient group, however, can injure the hypoplastic and contralateral lung, termed ventilator-associated lung injury (VALI) 4 . The optimal mode of ventilation to prevent VALI in neonates with CDH remains unclear 5 . NAVA may trigger ventilatory support earlier in the respiratory cycle compared to pressure-triggered ventilatory methods (PTV), where the infant must initiate a sufficient change in pressure or flow to trigger ventilatory support 6 . Several small studies have demonstrated that NAVA improves patient-ventilatory asynchrony due to reduced trigger delays and auto or double triggering 7 . In the CDH population, it has been hypothesised that a structurally abnormal diaphragm may impede Edi signal detection and negate the benefits of NAVA. In a retrospective 1:2 matched case-control study, however, there was no significant difference in the Edi signal between infants with CDH ventilated with NAVA and those without 8 . In a retrospective cohort study, five out of seven infants that underwent a surgical patch repair for CDH had active Edi signals 7 . Several small studies have suggested NAVA is superior compared to assist control ventilation. A retrospective cohort analysis of 15 CDH neonates supported with 72 hours of NAVA showed reductions in the peak inspiratory pressure (PIP), mean-airway pressure (MAP) and resulted in less sedative-medication use 9 . Another retrospective cohort of 12 infants in a single centre had d improvements in oxygenation index (OI) on NAVA, compared to pressure-support modes 10 . While results from retrospective analysis have been promising, to our knowledge there has been no prospective crossover trial investigating NAVA in infants with CDH. Our objective was to determine if in neonates with CDH, NAVA would result in a better OI, compared to ACV. The secondary objective was to determine if there were differences in other clinically important outcomes including sedative medication use. Methods Trial design NAN-C was a dual-centre, randomised, open-label cross-over trial designed with a superiority framework. It was carried out in two neonatal intensive care units (NICUs) in the UK, St George’s University NHS Foundation Trust (SGH) and Kings College Hospital NHS Foundation Trust (KCH). NAN-C was granted a favourable ethical opinion by the West of Scotland Research Ethics Committee (REC). NAN-C was prospectively registered on ClinicalTrials.gov NCT05839340 on May2023 11 . The study included neonates born with CDH. Eligible infants were identified by the researchers following discussion with the clinical team. Parents of participants meeting the screening inclusion criteria were approached to give consent for their infant’s participation. Infants were studied post-operatively. At SGH, CDH infants were routinely ventilated using ACV on Servo-n ventilator (named ‘Pressure Control (PC)’ on the Servo-n ventilator, Maquet Critical Care, Solna, Sweden) which also offers the NAVA mode of ventilation. At King’s College NHS Foundation Trust, infants were routinely ventilated using ACV on the SLE 6000 ventilator (software versions 4.3; SLE Ltd., South Croydon, UK). Hence, at KCH infants were transferred from the SLE 6000 to the Servo-n ventilator for the study and entered into a ventilatory support tolerance trial (VSTT). During the VSTT infants were ventilated on ACV using the Servo-n ventilator ( named ‘Pressure Control (PC)’ on the Servo-n ventilator, Maquet Critical Care, Solna, Sweden ) for one hour. During the VSTT, the positive end-expiratory pressure (PEEP) was kept between 4-5cm H 2 O and inflation time at 0.36-0.4s. The fraction of inspired oxygen concentration (FiO 2 ) was adjusted with the aim of maintaining oxygen saturations between 85 and 95%. At this stage, infants requiring an FiO 2 greater than 80% to maintain their oxygen saturation or requiring nitric oxide were excluded. If the infant passed the VSTT, they entered the study. At both sites they were randomised to receive either ACV or NAVA for the first four-hours on the Servo-n ventilator. Following a 20-minute stabilisation period, they then received the second mode of ventilation (Figure-1). At the end of the trial, infants received the routine standard of care. The same ventilator settings and backup rate were used. In particular, the positive end expiratory pressure (PEEP) was kept at 4–5 cmH 2 O as had been used prior to the study and the inflation time was set, as previously, at 0.36 to 0.4 seconds. The apnoea time was set at two seconds and the upper pressure limit at least 5 cm H 2 O higher than the baseline settings but did not exceed 30 cm H 2 O. A six or eight French, 50 cm, Edi catheter was inserted and correct positioning confirmed as per the instructions of the manufacturer using the Edi catheter positioning guide function on the ventilator (Magnet Servo-n User Manual Version 4.6). The guide function displays the retrocardiac echocardiograph. Correct positioning was when the P waves and QRS complexes were visible in the uppermost leads and then decreased in size until the P waves disappeared in the lowest lead. Coloured highlighting of the central two leads appeared once the catheter was in the correct place. Once correct positioning was confirmed, the catheter was securely attached to the infant’s face using an adhesive dressing. Infants were then randomised to receive either ACV or NAVA first for four hours and then to receive the alternative mode for the subsequent four hours. The order in which the infants received the two modes was randomised between each baby using a sequential opaque sealed envelope system. Before the infant was changed to NAVA mode, the NAVA level was adjusted so that the displayed pressure waveform on NAVA closely matched the actual pressure waveform on the baseline settings, aiming for the peak Edi to be between 5 and 15 µV as per the recommendations of the manufacturer. The baseline ventilator settings were used to determine the backup settings to be used on NAVA in the absence of an Edi signal. The FiO 2 was adjusted with the aim of maintaining oxygen saturations between 85 and 95%, as the target outlined in the CDH Euro Consortium 2015 1 . At the end of each four hour, arterial or capillary blood gas analysis was performed and the oxygenation index (OI) calculated as the inspired oxygen concentration (FiO 2 ) x mean airway pressure (MAP) × 100/paO 2 . The FiO 2 , the PIP, MAP, tidal volume and respiratory system compliance were recorded from the ventilator displays and averaged from the last five minutes of each four-hour period. The data were downloaded into excel via a USB stick. Sample size The planned sample size was 18 infants, as this would allow detection of a difference in oxygenation index between the two modes of one standard deviation, with 80% power and 5% significance. An interim analysis was planned to take place halfway through, i.e. after nine patients had completed the study. Studies with proportional assist ventilation (PAV), a ventilation mode which also provides tailored support throughout the infant’s inspiratory cycle, demonstrated the OI on PAV was better in all patients than on ACV 12 , 13 . Similarly, mean OI after one hour on NAVA was better than ACV 14 . In order to preserve the type I error at 5%, the interim analysis was conducted at 0.01 with the final analysis conducted using 0.04. This gave an overall type 1 error rate (significance level) of 5% [(1–0.01) × (1–0.04) = 0.95 = 1–0.05]. If the interim analysis showed p < 0.01, then the trial was to stop, and the final analyses conducted using the nine patients treated to that point. Statistical analysis The results were positively skewed. Differences between ventilatory modes were assessed for statistical significance using the paired Wilcoxon signed-rank test using IBM SPPS statistical software, V.29 (IBM Corporation, USA). Geometric means and 95% confidence intervals were calculated manually in Excel for descriptive purposes. The ratio of geometric means and the corresponding 95% confidence intervals are presented descriptively and can be interpreted as the percentage difference between NAVA and ACV. To assess whether the order of ventilation influenced the magnitude of OI change, the differences in OI (NAVA – ACV) were compared between infants who received NAVA first versus ACV first using the Mann–Whitney U test. Results Two randomised infants were withdrawn during VSTT due to persistently low Edi signals. Both infants had severe left-sided congenital diaphragmatic hernia, with pre-FETO observed-to-expected lung-to-head ratios (O/E LHR) of 13% and 15%, respectively. Both were male and underwent FETO at 26 weeks’ gestation. Gestational age at birth was 38.6 and 34.1 weeks, with corrected ages at the time of study of 39.6 and 36.4 weeks, respectively. Intraoperative findings demonstrated diaphragmatic agenesis in both cases: one infant had a type C defect (anteromedial and posteromedial rim present, with absent anterolateral and posterolateral rims), while the second had a type D defect, characterised by a completely deficient diaphragm and hiatus. Both infants had liver herniation. At the interim analysis, the comparison of oxygenation index (OI) on NAVA versus ACV was statistically significant. OI was lower on NAVA for all infants (Tables 1.1 and 1.2, Fig. 2 ). The nine infants, six males and three females, had a median gestational age of 38 weeks (range 34.6–39.3) and median birthweight of 3 kg (range 2.1–3.9). Infants were studied at a median postnatal age of 7 days (range 5–33). The median O/E LHR ratio was 46 (range 30–81). Eight infants had left-sided CDH; six underwent patch repair and two underwent thoracoscopic repair. Two infants underwent a FETO procedure at 26 weeks of gestation, with balloon deflation prior to birth. None of the infants had received antenatal steroids. Only one infant, born at 34 weeks received two doses of surfactant. Six infants received sedation, morphine infusion at maximum of 10 mcg/kg/hr; the concentration remained the same in both modes of ventilation and did not affect the Edi signal. Five infants were studied first on NAVA and four on ACV. There was no evidence that the order of ventilation affected the size of the OI difference (p = 0.66). Table 1.1 Characteristics and Oxygenation Index on ACV vs NAVA Gas FiO₂ OI-ACV OI-NAVA First mode GA (wks) PNA (d) Hosp Patch O/E LHR FETO Art 0.35 3.7 2.8 NAVA 38.3 6 SGH N 44 N Art 0.33 6.8 5.5 NAVA 39.9 6 SGH Y 46 N Art 0.23 7.4 2.7 PC 38.7 5 SGH N 40 N Cap 0.29 6.9 6.6 NAVA 38.6 14 KCH Y 46 Y Art 0.30 3.3 1.6 PC 39.4 8 KCH Y 50 N Art 0.35 6.8 6.7 NAVA 39.3 33 KCH Y 37 N Cap 0.26 4.7 4.3 PC 38.0 7 SGH Y 81 N Cap 0.21 5.9 3.9 NAVA 39.9 7 KCH Y 30 Y Art 0.25 7.6 3.0 PC 39.3 5 SGH N 80 N Abbreviations: GA gestational age; PNA postnatal age; O/E LHR observed-to-expected lung-to-head ratio; SGH St George’s Hospital; KCH King’s College Hospital. The ratio of geometric means for OI, calculated manually for descriptive purposes, was 0.66 (NAVA/ACV), representing a descriptive 34% lower OI on NAVA compared with ACV (Table 1.2 ). Peak inspiratory pressure (PIP, p = 0.017) and mean airway pressure (MAP, p = 0.008) were significantly lower on NAVA. Peak electrical activity of the diaphragm (Peak Edi, p = 0.028) and expiratory tidal volume (p = 0.043) were also lower on NAVA. There were no significant differences between modes for FiO₂ (p = 0.672), compliance (p = 0.345), respiratory rate (p = 0.889) and oxygen saturation (p = 0.564). Table 1.2 Results by ventilatory mode The results are presented as the geometric mean (range) for each mode, the ratio of geometric means between the two modes and the corresponding 95% CI Mean PC Mean NAVA Ratio of geometric means (NAVA/ACV) 95% confidence interval for ratio P value Oxygenation index 5.9 (3.3–7.6) 3.9 (1.6–6.7) 0.66 0.50–0.90 0.008 Peak inspiratory pressure (cmH 2 O) 22 (14–28) 17 (8–26) 0.77 0.62–0.91 0.017 Mean airway pressure) (cmH 2 O) 11.05 (8–15) 8.65 (8–13) 0.78 0.68–0.89 0.008 FiO 2 0.28 (0.22–0.35) 0.26 (0.21–0.36) 0.93 0.81–1.08 0.672 Peak Edi (µV) 9.86 (1.2–27.0) 6.05 (1.4–16.7) 0.61 0.44–0.95 0.028 Expiratory tidal volume (ml/kg) 6.60 (5.21–7.9) 5.06 (4-5.98) 0.76 0.67–0.90 0.043 Compliance (ml/cmH 2 O) 1.31 (0.60–1.90) 1.46 (0.64–2.32) 1.11 0.84–1.49 0.345 Respiratory rate (breaths/min) 50.38 (40–64) 50.32 (42–65) 0.99 0.89–1.14 0.889 Oxygen saturations (%) 97 (94–99) 97 (94–99) 1.00 1.0–1.01 0.564 Discussion In this prospective randomised crossover trial, in infants who completed the study NAVA was associated with a significantly lower OI compared with ACV in post-operative neonates with congenital diaphragmatic hernia (CDH). This improvement was observed consistently in all infants who completed the study and was accompanied by significantly lower peak inspiratory pressure (PIP) and mean airway pressure (MAP), suggesting more efficient oxygenation at lower ventilatory pressures. Two infants with severe left sided CDH did not progress beyond the VSTT due to low Edi suggesting reduced diaphragmatic signal associated with severe diaphragmatic agenesis. Beck et al showed that NAVA improves neuromechanical efficiency by unloading the diaphragm while maintaining spontaneous respiratory drive, as evidenced by reduced Edi amplitude without suppression of breathing effort 15 . Similar reductions in diaphragmatic effort during NAVA have been demonstrated in neonates and children using oesophageal pressure–Edi relationships, supporting the concept that lower Edi during NAVA reflects effective unloading rather than diaphragmatic dysfunction 16 , 17 . Our finding of lower peak Edi on NAVA is consistent with these observations and suggests improved diaphragm–ventilator coupling in infants with CDH. NAVA delivers breath-by-breath proportional assistance, which may be particularly advantageous in CDH, where respiratory drive and mechanics can fluctuate substantially in the post-operative period. Concerns have previously been raised that structural abnormalities of the diaphragm in CDH, particularly following patch repair, might impair the detection or reliability of the Edi signal and limit the utility of NAVA. However, both our findings and prior retrospective studies suggest that clinically usable Edi signals are achievable in the majority of CDH infants, including those undergoing patch repair 5 , 8 , 18 . In our cohort, NAVA was feasible in nine of eleven infants studied, supporting its applicability in this population. This is despite infants receiving sedation at the same dose throughout the study, which did not influence the results. Previous CDH studies of NAVA have largely been retrospective and observational. Kallio et al. reported reductions in PIP, MAP, and sedative exposure in CDH infants supported with NAVA 19 , while Gentili et al. demonstrated the feasibility of NAVA during weaning in a small cohort 20 . In addition, Amin and Arca reported the successful use of non-invasive NAVA following CDH repair in a retrospective series, supporting feasibility across the post-operative respiratory care pathway, although this was reported in abstract form only 18 . Our study extends these findings by providing prospective, randomised crossover data, thereby reducing confounding related to disease severity and inter-patient variability. Unlike earlier retrospective reports, our trial demonstrates that improvements in oxygenation occur rapidly and consistently within hours of initiating NAVA, supporting a direct physiological effect rather than delayed clinical improvement. This study has limitations. The sample size was small, and the trial was stopped early following a statistically significant interim analysis, which may overestimate treatment effects. The short exposure period limits conclusions regarding long-term outcomes such as duration of ventilation or chronic lung disease. Nonetheless, the crossover design strengthens internal validity by allowing each infant to act as their own control; there was no evidence that the order of ventilation influenced the magnitude of OI change. As the same ventilator was used for each mode, the significant differences demonstrated are due to the differences in the modes, rather than differences in the ventilator performance. The infants included had a wide range of severity including patch repair, prematurity and range of postnatal age when repaired, yet we saw a positive effect of NAVA in all infants. We used capillary blood samples to calculate the OIs in three patients. We used the same method for both ventilation modes the end of each of the four hour periods, thus the use of capillary blood sampling did not bias our results. The infants were all clinically stable when assessed and none were seriously ill, had shock, hypotension or peripheral vasoconstriction at the time of assessment 21 . Thus, we feel it was appropriate to calculate the OIs from the capillary blood samples. In conclusion, NAVA significantly improved oxygenation despite lower airway pressures in post-operative neonates with CDH. Larger multicentre trials are required to determine whether these short-term physiological benefits translate into improved long-term clinical outcomes. Abbreviations ACV — Assist-Control Ventilation CDH — Congenital Diaphragmatic Hernia Edi — Electrical activity of the diaphragm FETO — Fetoscopic Endoluminal Tracheal Occlusion FiO₂ — Fraction of inspired oxygen MAP — Mean Airway Pressure MV — Mechanical Ventilation NAVA — Neurally Adjusted Ventilatory Assist NICU — Neonatal Intensive Care Unit O/E LHR — Observed-to-Expected Lung-to-Head Ratio OI — Oxygenation Index PAV — Proportional Assist Ventilation PC — Pressure Control PEEP — Positive End-Expiratory Pressure PIP — Peak Inspiratory Pressure PTV — Pressure-Triggered Ventilation VALI — Ventilator-Associated Lung Injury VSTT — Ventilatory Support Tolerance Trial Declarations Acknowledgements : We thank the clinical team at St George’s and King’s College Hospital neonatal unit for the support of the consultant and nursing staff with the ongoing research studies. Competing interests: Dr Shetty was previously a member of the Medical Advisory Board for Maquet Critical Care AB and has received honoraria from Getinge for speaking at webinars and conferences. Professor Greenough has held grants and honoraria for lecturing from ventilator companies. They were not involved in the study design, data collection, data analysis or production of the manuscript. Funding: AJ is supported by a KMRT/KCHC PhD studentship Author contributions: AG, SS, CH, GP designed the study. SS and AJ collected the data. SS, AG and AJ designed the statistical analysis and analysed the data. SS drafted the first manuscript. All authors were involved in the preparation of the manuscript and approved the final manuscript as submitted. Ethics approval: West of Scotland Research Ethics Committee (REC) in accordance with the Declaration of Helsinki. Consent to participate: Infants whose parents gave informed written consent were recruited. References Snoek KG, Reiss IK, Greenough A, et al. Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update. Neonatology. 2016;110(1):66-74. Montalva L, Antounians L, Zani A. Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling. Pediatr Res. May 2019;85(6):754-768. Keszler M. Mechanical ventilation strategies. Semin Fetal Neonatal Med. Aug 2017;22(4):267-274. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. Nov 28 2013;369(22):2126-2136. Lecomte F, Brander L, Jalde F, et al. Physiological response to increasing levels of neurally adjusted ventilatory assist (NAVA). Respir Physiol Neurobiol. Apr 30 2009;166(2):117-124. Rossor TE, Hunt KA, Shetty S, Greenough A. Neurally adjusted ventilatory assist compared to other forms of triggered ventilation for neonatal respiratory support. Cochrane Database Syst Rev. Oct 27 2017;10(10):CD012251. Bordessoule A, Emeriaud G, Morneau S, Jouvet P, Beck J. Neurally adjusted ventilatory assist improves patient-ventilator interaction in infants as compared with conventional ventilation. Pediatr Res. Aug 2012;72(2):194-202. Alander M, Peltoniemi O, Pokka T, Kontiokari T. Comparison of pressure-, flow-, and NAVA-triggering in pediatric and neonatal ventilatory care. Pediatr Pulmonol. Jan 2012;47(1):76-83. Kurland Y, Gurung K, Pallotto EK, et al. Neurally adjusted ventilatory assist in neonates with congenital diaphragmatic hernia. J Perinatol. Aug 2021;41(8):1910-1915. 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. Sep 2016;175(9):1175-1183. Poole G, Harris C, Shetty S, Dassios T, Jenkinson A, Greenough A. Correction: Study protocol for a randomised cross-over trial of Neurally adjusted ventilatory Assist for Neonates with Congenital diaphragmatic hernias: the NAN-C study. Trials. Feb 7 2024;25(1):109. Bhat P, Patel DS, Hannam S, et al. Crossover study of proportional assist versus assist control ventilation. Arch Dis Child Fetal Neonatal Ed. Jan 2015;100(1):F35-38. Shetty S, Bhat P, Hickey A, Peacock JL, Milner AD, Greenough A. Proportional assist versus assist control ventilation in premature infants. Eur J Pediatr. Jan 2016;175(1):57-61. Shetty S, Hunt K, Peacock J, Ali K, Greenough A. Crossover study of assist control ventilation and neurally adjusted ventilatory assist. Eur J Pediatr. Apr 2017;176(4):509-513. Beck J, Sinderby C. [Clinical application of neurally adjusted ventilatory assist]. Zhonghua Nei Ke Za Zhi. Jun 2011;50(6):449-452. Stein H, Firestone K. Application of neurally adjusted ventilatory assist in neonates. Semin Fetal Neonatal Med. Feb 2014;19(1):60-69. Firestone KS, Fisher S, Reddy S, White DB, Stein HM. Effect of changing NAVA levels on peak inspiratory pressures and electrical activity of the diaphragm in premature neonates. J Perinatol. Aug 2015;35(8):612-616. Amin R, Arca MJ. Feasibility of Non-invasive Neurally Adjusted Ventilator Assist After Congenital Diaphragmatic Hernia Repair. J Pediatr Surg. Mar 2019;54(3):434-438. Kallio M, Peltoniemi O, Anttila E, Pokka T, Kontiokari T. Neurally adjusted ventilatory assist (NAVA) in pediatric intensive care--a randomized controlled trial. Pediatr Pulmonol. Jan 2015;50(1):55-62. Gentili A, Masciopinto F, Mondardini MC, Ansaloni S, Reggiani ML, Baroncini S. Neurally adjusted ventilatory assist in weaning of neonates affected by congenital diaphragmatic hernia. J Matern Fetal Neonatal Med. Apr 2013;26(6):598-602. McLain BI, Evans J, Dear PR. Comparison of capillary and arterial blood gas measurements in neonates. Arch Dis Child. Jul 1988;63(7 Spec No):743-747. Additional Declarations Competing interest reported. Dr Shetty was previously a member of the Medical Advisory Board for Maquet Critical Care AB and has received honoraria from Getinge for speaking at webinars and conferences. Professor Greenough has held grants and honoraria for lecturing from ventilator companies. They were not involved in the study design, data collection, data analysis or production of the manuscript. Cite Share Download PDF Status: Published Journal Publication published 09 Apr, 2026 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 20 Feb, 2026 Reviews received at journal 13 Feb, 2026 Reviewers agreed at journal 13 Feb, 2026 Reviewers agreed at journal 09 Feb, 2026 Reviewers agreed at journal 08 Feb, 2026 Reviewers invited by journal 07 Feb, 2026 Editor assigned by journal 03 Feb, 2026 Submission checks completed at journal 02 Feb, 2026 First submitted to journal 26 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8703181","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":588701519,"identity":"8938f094-a886-4f01-a618-ad5779879220","order_by":0,"name":"Sandeep Shetty","email":"data:image/png;base64,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","orcid":"","institution":"St George's Healthcare NHS Trust","correspondingAuthor":true,"prefix":"","firstName":"Sandeep","middleName":"","lastName":"Shetty","suffix":""},{"id":588701520,"identity":"ab5a4120-adde-488d-9e99-b053c0d2b2c5","order_by":1,"name":"Allan Jenkinson","email":"","orcid":"","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Allan","middleName":"","lastName":"Jenkinson","suffix":""},{"id":588701521,"identity":"36e8326c-7abb-4a3f-a460-144dfa34e137","order_by":2,"name":"Grace Poole","email":"","orcid":"","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Grace","middleName":"","lastName":"Poole","suffix":""},{"id":588701522,"identity":"88b63bf1-c956-4732-9d1f-8b0c58bc1de3","order_by":3,"name":"Theodore Dassios","email":"","orcid":"","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Theodore","middleName":"","lastName":"Dassios","suffix":""},{"id":588701523,"identity":"8f34c4c7-c06c-489c-98c9-9d073844e29e","order_by":4,"name":"Chris Harris","email":"","orcid":"","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Chris","middleName":"","lastName":"Harris","suffix":""},{"id":588701524,"identity":"60483d0d-e5e8-4321-80ca-c3d48c5e4e22","order_by":5,"name":"Anay Kulkarni","email":"","orcid":"","institution":"St George's Healthcare NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"Anay","middleName":"","lastName":"Kulkarni","suffix":""},{"id":588701525,"identity":"085b7210-c111-46ac-b45a-c8aec9671480","order_by":6,"name":"donovan Duffy","email":"","orcid":"","institution":"St George's Healthcare NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"donovan","middleName":"","lastName":"Duffy","suffix":""},{"id":588701526,"identity":"8c02518c-338f-4a0c-a7c8-0baa68dc28fa","order_by":7,"name":"Anne Greenough","email":"","orcid":"","institution":"King's College London","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"","lastName":"Greenough","suffix":""}],"badges":[],"createdAt":"2026-01-26 18:38:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8703181/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8703181/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-026-06888-5","type":"published","date":"2026-04-09T15:58:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102593527,"identity":"35e6d565-cce4-4ff7-8c32-8de514819455","added_by":"auto","created_at":"2026-02-13 11:50:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":33220,"visible":true,"origin":"","legend":"\u003cp\u003eStudy Protocol\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure \u0026nbsp;\u0026nbsp;1. Ventilation Protocol for the NAN-C Trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt \u0026nbsp;\u0026nbsp;King’s College Hospital NHS Foundation Trust (KCH), infants are routinely \u0026nbsp;\u0026nbsp;ventilated using assist control ventilation (ACV) on the SLE 6000 ventilator. \u0026nbsp;\u0026nbsp;If infants meet the eligibility criteria, they will be transferred from ACV \u0026nbsp;\u0026nbsp;on the SLE 6000 to ACV on the servo-n ventilator. Infants will be stabilised \u0026nbsp;\u0026nbsp;on the servo-n-ventilator for one hour in the ventilatory support tolerance \u0026nbsp;\u0026nbsp;trial. If suitable, infants will then be randomised to receive either ACV or \u0026nbsp;\u0026nbsp;neurally adjusted ventilator assist (NAVA) for 4 hours. Following a 20-minute \u0026nbsp;\u0026nbsp;stabilisation period, they will then receive the second mode of ventilation.\u003c/p\u003e\n\u003cp\u003eAt St. \u0026nbsp;\u0026nbsp;George’s University Hospital (SGH) infants are routinely ventilated on ACV on \u0026nbsp;\u0026nbsp;the servo-n ventilator. They will be randomised to either NAVA or ACV on the \u0026nbsp;\u0026nbsp;servo-n ventilator.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8703181/v1/abfa4dbb72673ea7eb9be515.png"},{"id":102593528,"identity":"9a77d6f4-3520-4a90-b575-00a63c0ff3dd","added_by":"auto","created_at":"2026-02-13 11:50:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26124,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual OI data at the end of each mode\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8703181/v1/32ae7d932d0a3bfdc81fc524.png"},{"id":106808856,"identity":"4faf301c-4825-4fc4-bcf3-950ea8447b74","added_by":"auto","created_at":"2026-04-13 16:03:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":695915,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8703181/v1/4edfb1e2-aa7a-4ea0-ac69-ae249dbcac9f.pdf"}],"financialInterests":"Competing interest reported. Dr Shetty was previously a member of the Medical Advisory Board for Maquet Critical Care AB and has received honoraria from Getinge for speaking at webinars and conferences. Professor Greenough has held grants and honoraria for lecturing from ventilator companies. They were not involved in the study design, data collection, data analysis or production of the manuscript.","formattedTitle":"Randomised crossover trial of Neurally Adjusted Ventilatory Assist (NAVA) for Neonates with Congenital diaphragmatic hernias: the NAN-C study","fulltext":[{"header":"Key notes","content":"\u003cul\u003e\n \u003cli\u003eThis study reports infants with CDH studied on four hours each of NAVA and assist controlled ventilation.\u003c/li\u003e\n \u003cli\u003eOn NAVA, infants had superior (lower) oxygen indices, lower peak Edi, expiratory tidal volume, peak and mean airway pressures\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eCongenital diaphragmatic hernia (CDH) occurs due to an incomplete fusion of the diaphragm during fetal development, enabling abdominal viscera to herniate into the thoracic cavity \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Herniation may disrupt development of the lung and associated vasculature, resulting in pulmonary hypoplasia and pulmonary hypertension \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Neonates typically undergo surgical reduction in the first few days after birth\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The ventilation-perfusion mismatch often seen in infants with CDH can make the post-operative ventilation of this population challenging. The use of mechanical ventilation (MV) is the standard care for babies with CDH in neonatal intensive care units (NICU) across the UK \u003csup\u003e3\u003c/sup\u003e. The use of MV in this patient group, however, can injure the hypoplastic and contralateral lung, termed ventilator-associated lung injury (VALI) \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The optimal mode of ventilation to prevent VALI in neonates with CDH remains unclear \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. NAVA may trigger ventilatory support earlier in the respiratory cycle compared to pressure-triggered ventilatory methods (PTV), where the infant must initiate a sufficient change in pressure or flow to trigger ventilatory support \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Several small studies have demonstrated that NAVA improves patient-ventilatory asynchrony due to reduced trigger delays and auto or double triggering \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. In the CDH population, it has been hypothesised that a structurally abnormal diaphragm may impede Edi signal detection and negate the benefits of NAVA. In a retrospective 1:2 matched case-control study, however, there was no significant difference in the Edi signal between infants with CDH ventilated with NAVA and those without \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. In a retrospective cohort study, five out of seven infants that underwent a surgical patch repair for CDH had active Edi signals \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Several small studies have suggested NAVA is superior compared to assist control ventilation. A retrospective cohort analysis of 15 CDH neonates supported with 72 hours of NAVA showed reductions in the peak inspiratory pressure (PIP), mean-airway pressure (MAP) and resulted in less sedative-medication use \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Another retrospective cohort of 12 infants in a single centre had d improvements in oxygenation index (OI) on NAVA, compared to pressure-support modes \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. While results from retrospective analysis have been promising, to our knowledge there has been no prospective crossover trial investigating NAVA in infants with CDH. Our objective was to determine if in neonates with CDH, NAVA would result in a better OI, compared to ACV. The secondary objective was to determine if there were differences in other clinically important outcomes including sedative medication use.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eTrial design NAN-C was a dual-centre, randomised, open-label cross-over trial designed with a superiority framework. It was carried out in two neonatal intensive care units (NICUs) in the UK, St George\u0026rsquo;s University NHS Foundation Trust (SGH) and Kings College Hospital NHS Foundation Trust (KCH). NAN-C was granted a favourable ethical opinion by the West of Scotland Research Ethics Committee (REC). NAN-C was prospectively registered on ClinicalTrials.gov NCT05839340 on May2023 \u003csup\u003e11\u003c/sup\u003e. The study included neonates born with CDH. Eligible infants were identified by the researchers following discussion with the clinical team. Parents of participants meeting the screening inclusion criteria were approached to give consent for their infant\u0026rsquo;s participation. Infants were studied post-operatively.\u003c/p\u003e \u003cp\u003eAt SGH, CDH infants were routinely ventilated using ACV on Servo-n ventilator (named \u0026lsquo;Pressure Control (PC)\u0026rsquo; on the Servo-n ventilator, Maquet Critical Care, Solna, Sweden) which also offers the NAVA mode of ventilation. At King\u0026rsquo;s College NHS Foundation Trust, infants were routinely ventilated using ACV on the SLE 6000 ventilator (software versions 4.3; SLE Ltd., South Croydon, UK). Hence, at KCH infants were transferred from the SLE 6000 to the Servo-n ventilator for the study and entered into a ventilatory support tolerance trial (VSTT). During the VSTT infants were ventilated on ACV using the Servo-n ventilator (\u003cem\u003enamed \u0026lsquo;Pressure Control (PC)\u0026rsquo; on the Servo-n ventilator, Maquet Critical Care, Solna, Sweden\u003c/em\u003e) for one hour. During the VSTT, the positive end-expiratory pressure (PEEP) was kept between 4-5cm H\u003csub\u003e2\u003c/sub\u003eO and inflation time at 0.36-0.4s. The fraction of inspired oxygen concentration (FiO\u003csub\u003e2\u003c/sub\u003e) was adjusted with the aim of maintaining oxygen saturations between 85 and 95%. At this stage, infants requiring an FiO\u003csub\u003e2\u003c/sub\u003e greater than 80% to maintain their oxygen saturation or requiring nitric oxide were excluded. If the infant passed the VSTT, they entered the study. At both sites they were randomised to receive either ACV or NAVA for the first four-hours on the Servo-n ventilator. Following a 20-minute stabilisation period, they then received the second mode of ventilation (Figure-1). At the end of the trial, infants received the routine standard of care.\u003c/p\u003e \u003cp\u003eThe same ventilator settings and backup rate were used. In particular, the positive end expiratory pressure (PEEP) was kept at 4\u0026ndash;5 cmH\u003csub\u003e2\u003c/sub\u003eO as had been used prior to the study and the inflation time was set, as previously, at 0.36 to 0.4 seconds. The apnoea time was set at two seconds and the upper pressure limit at least 5 cm H\u003csub\u003e2\u003c/sub\u003eO higher than the baseline settings but did not exceed 30 cm H\u003csub\u003e2\u003c/sub\u003eO. A six or eight French, 50 cm, Edi catheter was inserted and correct positioning confirmed as per the instructions of the manufacturer using the Edi catheter positioning guide function on the ventilator (Magnet Servo-n User Manual Version 4.6). The guide function displays the retrocardiac echocardiograph. Correct positioning was when the P waves and QRS complexes were visible in the uppermost leads and then decreased in size until the P waves disappeared in the lowest lead. Coloured highlighting of the central two leads appeared once the catheter was in the correct place. Once correct positioning was confirmed, the catheter was securely attached to the infant\u0026rsquo;s face using an adhesive dressing. Infants were then randomised to receive either ACV or NAVA first for four hours and then to receive the alternative mode for the subsequent four hours. The order in which the infants received the two modes was randomised between each baby using a sequential opaque sealed envelope system. Before the infant was changed to NAVA mode, the NAVA level was adjusted so that the displayed pressure waveform on NAVA closely matched the actual pressure waveform on the baseline settings, aiming for the peak Edi to be between 5 and 15 \u0026micro;V as per the recommendations of the manufacturer. The baseline ventilator settings were used to determine the backup settings to be used on NAVA in the absence of an Edi signal. The FiO\u003csub\u003e2\u003c/sub\u003e was adjusted with the aim of maintaining oxygen saturations between 85 and 95%, as the target outlined in the CDH Euro Consortium 2015\u003csup\u003e1\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAt the end of each four hour, arterial or capillary blood gas analysis was performed and the oxygenation index (OI) calculated as the inspired oxygen concentration (FiO\u003csub\u003e2\u003c/sub\u003e) x mean airway pressure (MAP) \u0026times; 100/paO\u003csub\u003e2\u003c/sub\u003e. The FiO\u003csub\u003e2\u003c/sub\u003e, the PIP, MAP, tidal volume and respiratory system compliance were recorded from the ventilator displays and averaged from the last five minutes of each four-hour period. The data were downloaded into excel via a USB stick.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThe planned sample size was 18 infants, as this would allow detection of a difference in oxygenation index between the two modes of one standard deviation, with 80% power and 5% significance. An interim analysis was planned to take place halfway through, i.e. after nine patients had completed the study. Studies with proportional assist ventilation (PAV), a ventilation mode which also provides tailored support throughout the infant\u0026rsquo;s inspiratory cycle, demonstrated the OI on PAV was better in all patients than on ACV \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Similarly, mean OI after one hour on NAVA was better than ACV \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. In order to preserve the type I error at 5%, the interim analysis was conducted at 0.01 with the final analysis conducted using 0.04. This gave an overall type 1 error rate (significance level) of 5% [(1\u0026ndash;0.01) \u0026times; (1\u0026ndash;0.04)\u0026thinsp;=\u0026thinsp;0.95\u0026thinsp;=\u0026thinsp;1\u0026ndash;0.05]. If the interim analysis showed p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, then the trial was to stop, and the final analyses conducted using the nine patients treated to that point.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe results were positively skewed. Differences between ventilatory modes were assessed for statistical significance using the paired Wilcoxon signed-rank test using IBM SPPS statistical software, V.29 (IBM Corporation, USA). Geometric means and 95% confidence intervals were calculated manually in Excel for descriptive purposes. The ratio of geometric means and the corresponding 95% confidence intervals are presented descriptively and can be interpreted as the percentage difference between NAVA and ACV. To assess whether the order of ventilation influenced the magnitude of OI change, the differences in OI (NAVA \u0026ndash; ACV) were compared between infants who received NAVA first versus ACV first using the Mann\u0026ndash;Whitney U test.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTwo randomised infants were withdrawn during VSTT due to persistently low Edi signals. Both infants had severe left-sided congenital diaphragmatic hernia, with pre-FETO observed-to-expected lung-to-head ratios (O/E LHR) of 13% and 15%, respectively. Both were male and underwent FETO at 26 weeks\u0026rsquo; gestation. Gestational age at birth was 38.6 and 34.1 weeks, with corrected ages at the time of study of 39.6 and 36.4 weeks, respectively. Intraoperative findings demonstrated diaphragmatic agenesis in both cases: one infant had a type C defect (anteromedial and posteromedial rim present, with absent anterolateral and posterolateral rims), while the second had a type D defect, characterised by a completely deficient diaphragm and hiatus. Both infants had liver herniation.\u003c/p\u003e\n\u003cp\u003eAt the interim analysis, the comparison of oxygenation index (OI) on NAVA versus ACV was statistically significant. OI was lower on NAVA for all infants (Tables \u003cspan class=\"InternalRef\"\u003e1.1\u003c/span\u003e and 1.2, Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The nine infants, six males and three females, had a median gestational age of 38 weeks (range 34.6\u0026ndash;39.3) and median birthweight of 3 kg (range 2.1\u0026ndash;3.9). Infants were studied at a median postnatal age of 7 days (range 5\u0026ndash;33). The median O/E LHR ratio was 46 (range 30\u0026ndash;81). Eight infants had left-sided CDH; six underwent patch repair and two underwent thoracoscopic repair. Two infants underwent a FETO procedure at 26 weeks of gestation, with balloon deflation prior to birth. None of the infants had received antenatal steroids. Only one infant, born at 34 weeks received two doses of surfactant. Six infants received sedation, morphine infusion at maximum of 10 mcg/kg/hr; the concentration remained the same in both modes of ventilation and did not affect the Edi signal. Five infants were studied first on NAVA and four on ACV. There was no evidence that the order of ventilation affected the size of the OI difference (p\u0026thinsp;=\u0026thinsp;0.66).\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1.1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics and Oxygenation Index on ACV vs NAVA\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGas\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFiO₂\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOI-ACV\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOI-NAVA\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFirst mode\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGA (wks)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePNA (d)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHosp\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePatch\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eO/E LHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFETO\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNAVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSGH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNAVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSGH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSGH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCap\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNAVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKCH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKCH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNAVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKCH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCap\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSGH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCap\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNAVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKCH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eArt\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e39.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSGH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"11\"\u003eAbbreviations: GA gestational age; PNA postnatal age; O/E LHR observed-to-expected lung-to-head ratio; SGH St George\u0026rsquo;s Hospital; KCH King\u0026rsquo;s College Hospital.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003eThe ratio of geometric means for OI, calculated manually for descriptive purposes, was 0.66 (NAVA/ACV), representing a descriptive 34% lower OI on NAVA compared with ACV (Table \u003cspan class=\"InternalRef\"\u003e1.2\u003c/span\u003e). Peak inspiratory pressure (PIP, p\u0026thinsp;=\u0026thinsp;0.017) and mean airway pressure (MAP, p\u0026thinsp;=\u0026thinsp;0.008) were significantly lower on NAVA. Peak electrical activity of the diaphragm (Peak Edi, p\u0026thinsp;=\u0026thinsp;0.028) and expiratory tidal volume (p\u0026thinsp;=\u0026thinsp;0.043) were also lower on NAVA. There were no significant differences between modes for FiO₂ (p\u0026thinsp;=\u0026thinsp;0.672), compliance (p\u0026thinsp;=\u0026thinsp;0.345), respiratory rate (p\u0026thinsp;=\u0026thinsp;0.889) and oxygen saturation (p\u0026thinsp;=\u0026thinsp;0.564).\u003c/p\u003e\n\u003ctable id=\"Tab2\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1.2\u0026nbsp;\u003cstrong\u003eResults by ventilatory mode\u003c/strong\u003e\u0026nbsp;\u003cbr\u003eThe results are presented as the geometric mean (range) for each mode, the ratio of geometric means between the two modes and the corresponding 95% CI\u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean PC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean NAVA\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRatio of geometric means (NAVA/ACV)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% confidence interval for ratio\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOxygenation index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.9\u003c/p\u003e\n \u003cp\u003e(3.3\u0026ndash;7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9\u003c/p\u003e\n \u003cp\u003e(1.6\u0026ndash;6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.50\u0026ndash;0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeak inspiratory pressure (cmH\u003csub\u003e2\u003c/sub\u003eO)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003cp\u003e(14\u0026ndash;28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e(8\u0026ndash;26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.62\u0026ndash;0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean airway pressure) (cmH\u003csub\u003e2\u003c/sub\u003eO)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.05\u003c/p\u003e\n \u003cp\u003e(8\u0026ndash;15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.65\u003c/p\u003e\n \u003cp\u003e(8\u0026ndash;13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.68\u0026ndash;0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003cp\u003e(0.22\u0026ndash;0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003cp\u003e(0.21\u0026ndash;0.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.81\u0026ndash;1.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.672\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeak Edi (\u0026micro;V)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.86\u003c/p\u003e\n \u003cp\u003e(1.2\u0026ndash;27.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.05\u003c/p\u003e\n \u003cp\u003e(1.4\u0026ndash;16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.44\u0026ndash;0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExpiratory tidal volume (ml/kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.60\u003c/p\u003e\n \u003cp\u003e(5.21\u0026ndash;7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.06\u003c/p\u003e\n \u003cp\u003e(4-5.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.67\u0026ndash;0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCompliance (ml/cmH\u003csub\u003e2\u003c/sub\u003eO)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.31\u003c/p\u003e\n \u003cp\u003e(0.60\u0026ndash;1.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.46\u003c/p\u003e\n \u003cp\u003e(0.64\u0026ndash;2.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.84\u0026ndash;1.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.345\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRespiratory rate (breaths/min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.38\u003c/p\u003e\n \u003cp\u003e(40\u0026ndash;64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50.32\u003c/p\u003e\n \u003cp\u003e(42\u0026ndash;65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.89\u0026ndash;1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.889\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOxygen saturations (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003cp\u003e(94\u0026ndash;99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003cp\u003e(94\u0026ndash;99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.0\u0026ndash;1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.564\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this prospective randomised crossover trial, in infants who completed the study NAVA was associated with a significantly lower OI compared with ACV in post-operative neonates with congenital diaphragmatic hernia (CDH). This improvement was observed consistently in all infants who completed the study and was accompanied by significantly lower peak inspiratory pressure (PIP) and mean airway pressure (MAP), suggesting more efficient oxygenation at lower ventilatory pressures. Two infants with severe left sided CDH did not progress beyond the VSTT due to low Edi suggesting reduced diaphragmatic signal associated with severe diaphragmatic agenesis.\u003c/p\u003e \u003cp\u003eBeck et al showed that NAVA improves neuromechanical efficiency by unloading the diaphragm while maintaining spontaneous respiratory drive, as evidenced by reduced Edi amplitude without suppression of breathing effort \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Similar reductions in diaphragmatic effort during NAVA have been demonstrated in neonates and children using oesophageal pressure\u0026ndash;Edi relationships, supporting the concept that lower Edi during NAVA reflects effective unloading rather than diaphragmatic dysfunction \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Our finding of lower peak Edi on NAVA is consistent with these observations and suggests improved diaphragm\u0026ndash;ventilator coupling in infants with CDH. NAVA delivers breath-by-breath proportional assistance, which may be particularly advantageous in CDH, where respiratory drive and mechanics can fluctuate substantially in the post-operative period.\u003c/p\u003e \u003cp\u003eConcerns have previously been raised that structural abnormalities of the diaphragm in CDH, particularly following patch repair, might impair the detection or reliability of the Edi signal and limit the utility of NAVA. However, both our findings and prior retrospective studies suggest that clinically usable Edi signals are achievable in the majority of CDH infants, including those undergoing patch repair \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. In our cohort, NAVA was feasible in nine of eleven infants studied, supporting its applicability in this population. This is despite infants receiving sedation at the same dose throughout the study, which did not influence the results.\u003c/p\u003e \u003cp\u003ePrevious CDH studies of NAVA have largely been retrospective and observational. Kallio et al. reported reductions in PIP, MAP, and sedative exposure in CDH infants supported with NAVA \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, while Gentili et al. demonstrated the feasibility of NAVA during weaning in a small cohort \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In addition, Amin and Arca reported the successful use of non-invasive NAVA following CDH repair in a retrospective series, supporting feasibility across the post-operative respiratory care pathway, although this was reported in abstract form only \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Our study extends these findings by providing prospective, randomised crossover data, thereby reducing confounding related to disease severity and inter-patient variability. Unlike earlier retrospective reports, our trial demonstrates that improvements in oxygenation occur rapidly and consistently within hours of initiating NAVA, supporting a direct physiological effect rather than delayed clinical improvement.\u003c/p\u003e \u003cp\u003eThis study has limitations. The sample size was small, and the trial was stopped early following a statistically significant interim analysis, which may overestimate treatment effects. The short exposure period limits conclusions regarding long-term outcomes such as duration of ventilation or chronic lung disease. Nonetheless, the crossover design strengthens internal validity by allowing each infant to act as their own control; there was no evidence that the order of ventilation influenced the magnitude of OI change. As the same ventilator was used for each mode, the significant differences demonstrated are due to the differences in the modes, rather than differences in the ventilator performance. The infants included had a wide range of severity including patch repair, prematurity and range of postnatal age when repaired, yet we saw a positive effect of NAVA in all infants. We used capillary blood samples to calculate the OIs in three patients. We used the same method for both ventilation modes the end of each of the four hour periods, thus the use of capillary blood sampling did not bias our results. The infants were all clinically stable when assessed and none were seriously ill, had shock, hypotension or peripheral vasoconstriction at the time of assessment \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Thus, we feel it was appropriate to calculate the OIs from the capillary blood samples.\u003c/p\u003e \u003cp\u003eIn conclusion, NAVA significantly improved oxygenation despite lower airway pressures in post-operative neonates with CDH. Larger multicentre trials are required to determine whether these short-term physiological benefits translate into improved long-term clinical outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACV \u0026mdash; Assist-Control Ventilation\u003c/p\u003e\n\u003cp\u003eCDH \u0026mdash; Congenital Diaphragmatic Hernia\u003c/p\u003e\n\u003cp\u003eEdi \u0026mdash; Electrical activity of the diaphragm\u003c/p\u003e\n\u003cp\u003eFETO \u0026mdash; Fetoscopic Endoluminal Tracheal Occlusion\u003c/p\u003e\n\u003cp\u003eFiO₂ \u0026mdash; Fraction of inspired oxygen\u003c/p\u003e\n\u003cp\u003eMAP \u0026mdash; Mean Airway Pressure\u003c/p\u003e\n\u003cp\u003eMV \u0026mdash; Mechanical Ventilation\u003c/p\u003e\n\u003cp\u003eNAVA \u0026mdash; Neurally Adjusted Ventilatory Assist\u003c/p\u003e\n\u003cp\u003eNICU \u0026mdash; Neonatal Intensive Care Unit\u003c/p\u003e\n\u003cp\u003eO/E LHR \u0026mdash; Observed-to-Expected Lung-to-Head Ratio\u003c/p\u003e\n\u003cp\u003eOI \u0026mdash; Oxygenation Index\u003c/p\u003e\n\u003cp\u003ePAV \u0026mdash; Proportional Assist Ventilation\u003c/p\u003e\n\u003cp\u003ePC \u0026mdash; Pressure Control\u003c/p\u003e\n\u003cp\u003ePEEP \u0026mdash; Positive End-Expiratory Pressure\u003c/p\u003e\n\u003cp\u003ePIP \u0026mdash; Peak Inspiratory Pressure\u003c/p\u003e\n\u003cp\u003ePTV \u0026mdash; Pressure-Triggered Ventilation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVALI \u0026mdash; Ventilator-Associated Lung Injury\u003c/p\u003e\n\u003cp\u003eVSTT \u0026mdash; Ventilatory Support Tolerance Trial\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: We thank the clinical team at St George\u0026rsquo;s and King\u0026rsquo;s College Hospital neonatal unit for the support of the consultant and nursing staff with the ongoing research studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e Dr Shetty was previously a member of the Medical Advisory Board for Maquet Critical Care AB and has received honoraria from Getinge for speaking at webinars and conferences. Professor Greenough has held grants and honoraria for lecturing from ventilator companies. They were not involved in the study design, data collection, data analysis or production of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eAJ is supported by a KMRT/KCHC PhD studentship\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eAG, SS, CH, GP designed the study. SS and AJ collected the data. SS, AG and AJ designed the statistical analysis and analysed the data. SS drafted the first manuscript. All authors were involved in the preparation of the manuscript and approved the final manuscript as submitted.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eWest of Scotland Research Ethics Committee (REC) in accordance with the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u0026nbsp;\u003c/strong\u003eInfants whose parents gave informed written consent were recruited.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSnoek KG, Reiss IK, Greenough A, et al. Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update. \u003cem\u003eNeonatology. \u003c/em\u003e2016;110(1):66-74.\u003c/li\u003e\n\u003cli\u003eMontalva L, Antounians L, Zani A. Pulmonary hypertension secondary to congenital diaphragmatic hernia: factors and pathways involved in pulmonary vascular remodeling. \u003cem\u003ePediatr Res. \u003c/em\u003eMay 2019;85(6):754-768.\u003c/li\u003e\n\u003cli\u003eKeszler M. Mechanical ventilation strategies. \u003cem\u003eSemin Fetal Neonatal Med. \u003c/em\u003eAug 2017;22(4):267-274.\u003c/li\u003e\n\u003cli\u003eSlutsky AS, Ranieri VM. Ventilator-induced lung injury. \u003cem\u003eN Engl J Med. \u003c/em\u003eNov 28 2013;369(22):2126-2136.\u003c/li\u003e\n\u003cli\u003eLecomte F, Brander L, Jalde F, et al. Physiological response to increasing levels of neurally adjusted ventilatory assist (NAVA). \u003cem\u003eRespir Physiol Neurobiol. \u003c/em\u003eApr 30 2009;166(2):117-124.\u003c/li\u003e\n\u003cli\u003eRossor TE, Hunt KA, Shetty S, Greenough A. Neurally adjusted ventilatory assist compared to other forms of triggered ventilation for neonatal respiratory support. \u003cem\u003eCochrane Database Syst Rev. \u003c/em\u003eOct 27 2017;10(10):CD012251.\u003c/li\u003e\n\u003cli\u003eBordessoule A, Emeriaud G, Morneau S, Jouvet P, Beck J. Neurally adjusted ventilatory assist improves patient-ventilator interaction in infants as compared with conventional ventilation. \u003cem\u003ePediatr Res. \u003c/em\u003eAug 2012;72(2):194-202.\u003c/li\u003e\n\u003cli\u003eAlander M, Peltoniemi O, Pokka T, Kontiokari T. Comparison of pressure-, flow-, and NAVA-triggering in pediatric and neonatal ventilatory care. \u003cem\u003ePediatr Pulmonol. \u003c/em\u003eJan 2012;47(1):76-83.\u003c/li\u003e\n\u003cli\u003eKurland Y, Gurung K, Pallotto EK, et al. Neurally adjusted ventilatory assist in neonates with congenital diaphragmatic hernia. \u003cem\u003eJ Perinatol. \u003c/em\u003eAug 2021;41(8):1910-1915.\u003c/li\u003e\n\u003cli\u003eKallio M, Koskela U, Peltoniemi O, et al. Neurally adjusted ventilatory assist (NAVA) in preterm newborn infants with respiratory distress syndrome-a randomized controlled trial. \u003cem\u003eEur J Pediatr. \u003c/em\u003eSep 2016;175(9):1175-1183.\u003c/li\u003e\n\u003cli\u003ePoole G, Harris C, Shetty S, Dassios T, Jenkinson A, Greenough A. Correction: Study protocol for a randomised cross-over trial of Neurally adjusted ventilatory Assist for Neonates with Congenital diaphragmatic hernias: the NAN-C study. \u003cem\u003eTrials. \u003c/em\u003eFeb 7 2024;25(1):109.\u003c/li\u003e\n\u003cli\u003eBhat P, Patel DS, Hannam S, et al. Crossover study of proportional assist versus assist control ventilation. \u003cem\u003eArch Dis Child Fetal Neonatal Ed. \u003c/em\u003eJan 2015;100(1):F35-38.\u003c/li\u003e\n\u003cli\u003eShetty S, Bhat P, Hickey A, Peacock JL, Milner AD, Greenough A. Proportional assist versus assist control ventilation in premature infants. \u003cem\u003eEur J Pediatr. \u003c/em\u003eJan 2016;175(1):57-61.\u003c/li\u003e\n\u003cli\u003eShetty S, Hunt K, Peacock J, Ali K, Greenough A. Crossover study of assist control ventilation and neurally adjusted ventilatory assist. \u003cem\u003eEur J Pediatr. \u003c/em\u003eApr 2017;176(4):509-513.\u003c/li\u003e\n\u003cli\u003eBeck J, Sinderby C. [Clinical application of neurally adjusted ventilatory assist]. \u003cem\u003eZhonghua Nei Ke Za Zhi. \u003c/em\u003eJun 2011;50(6):449-452.\u003c/li\u003e\n\u003cli\u003eStein H, Firestone K. Application of neurally adjusted ventilatory assist in neonates. \u003cem\u003eSemin Fetal Neonatal Med. \u003c/em\u003eFeb 2014;19(1):60-69.\u003c/li\u003e\n\u003cli\u003eFirestone KS, Fisher S, Reddy S, White DB, Stein HM. Effect of changing NAVA levels on peak inspiratory pressures and electrical activity of the diaphragm in premature neonates. \u003cem\u003eJ Perinatol. \u003c/em\u003eAug 2015;35(8):612-616.\u003c/li\u003e\n\u003cli\u003eAmin R, Arca MJ. Feasibility of Non-invasive Neurally Adjusted Ventilator Assist After Congenital Diaphragmatic Hernia Repair. \u003cem\u003eJ Pediatr Surg. \u003c/em\u003eMar 2019;54(3):434-438.\u003c/li\u003e\n\u003cli\u003eKallio M, Peltoniemi O, Anttila E, Pokka T, Kontiokari T. Neurally adjusted ventilatory assist (NAVA) in pediatric intensive care--a randomized controlled trial. \u003cem\u003ePediatr Pulmonol. \u003c/em\u003eJan 2015;50(1):55-62.\u003c/li\u003e\n\u003cli\u003eGentili A, Masciopinto F, Mondardini MC, Ansaloni S, Reggiani ML, Baroncini S. Neurally adjusted ventilatory assist in weaning of neonates affected by congenital diaphragmatic hernia. \u003cem\u003eJ Matern Fetal Neonatal Med. \u003c/em\u003eApr 2013;26(6):598-602.\u003c/li\u003e\n\u003cli\u003eMcLain BI, Evans J, Dear PR. Comparison of capillary and arterial blood gas measurements in neonates. \u003cem\u003eArch Dis Child. \u003c/em\u003eJul 1988;63(7 Spec No):743-747.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Neurally adjusted ventilatory assist, NAVA, prematurity, bronchopulmonary dysplasia, BPD","lastPublishedDoi":"10.21203/rs.3.rs-8703181/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8703181/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRetrospective studies comparing NAVA to assist control ventilation (ACV) in neonates with congenital diaphragmatic hernia (CDH) have shown that ventilatory mode may improve respiratory parameters.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eTo determine if infants with CDH studied post-operatively had a lower oxygenation index (OI) on NAVA compared to ACV.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis dual-centre randomised cross-over trial compared post-operative NAVA with ACV in infants with CDH. Infants were randomised to receive either NAVA or ACV first in a 1:1 ratio for a four hour period. At the end of each four hour period, blood gas analysis was performed and the OI calculated. The inspired oxygen concentration (FiO\u003csub\u003e2\u003c/sub\u003e), the peak inflation (PIP) and mean airway pressure (MAP) were averaged from the last five minutes on each mode.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eEleven infants were randomised. Nine infants completed the trial. with median gestational age of 38 (range 34.6\u0026ndash;39.3) weeks and median postnatal age of 7 (range 5\u0026ndash;36) days. Eight had left sided CDH, six had patch repair and two had thoracoscopic repair. The mean OI after four hours on NAVA was 3.9 compared to 5.9 on ACV (p\u0026thinsp;=\u0026thinsp;0.008). The Peak Edi (6.05 versus 9.86 \u0026micro;V, p\u0026thinsp;=\u0026thinsp;0.028), PIP (17 versus 22 cm H\u003csub\u003e2\u003c/sub\u003eO, p\u0026thinsp;=\u0026thinsp;0.017) and MAP (8.7 versus 11.1 cm H\u003csub\u003e2\u003c/sub\u003eO, p\u0026thinsp;=\u0026thinsp;0.008), expiratory tidal volume (5.06 versus 9.86 mls/kg, p\u0026thinsp;=\u0026thinsp;0.043) were lower on NAVA versus ACV. Two infants were randomised, but the trial was stopped due to a low Edi signal.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eNAVA compared to ACV improved oxygenation postoperatively in infants with CDH. On NAVA, infants had superior (lower) oxygen indices, peak Edi, expiratory tidal volume and peak and mean airway pressures.\u003c/p\u003e","manuscriptTitle":"Randomised crossover trial of Neurally Adjusted Ventilatory Assist (NAVA) for Neonates with Congenital diaphragmatic hernias: the NAN-C study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-13 11:50:19","doi":"10.21203/rs.3.rs-8703181/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-20T22:13:07+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-13T18:04:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"82852859151448781456441587688048009724","date":"2026-02-13T14:23:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"104841777772619382780210054964501513749","date":"2026-02-10T04:55:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93944861014960963140631166761127999206","date":"2026-02-08T23:40:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-07T23:20:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-03T20:07:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-03T03:36:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2026-01-26T18:29:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"85957c87-af3b-4621-b275-52446f0b0d43","owner":[],"postedDate":"February 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T16:01:02+00:00","versionOfRecord":{"articleIdentity":"rs-8703181","link":"https://doi.org/10.1007/s00431-026-06888-5","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2026-04-09 15:58:09","publishedOnDateReadable":"April 9th, 2026"},"versionCreatedAt":"2026-02-13 11:50:19","video":"","vorDoi":"10.1007/s00431-026-06888-5","vorDoiUrl":"https://doi.org/10.1007/s00431-026-06888-5","workflowStages":[]},"version":"v1","identity":"rs-8703181","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8703181","identity":"rs-8703181","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}