The Diaphragmatic Initiated Ventilatory Assist (DIVA) trial: study protocol for a randomized controlled trial comparing rates of extubation failure in extremely premature infants undergoing extubation to non-invasive neurally adjusted ventilatory assist versus non-synchronized nasal intermittent positive pressure ventilation.

BACKGROUND: Invasive mechanical ventilation contributes to bronchopulmonary dysplasia (BPD), the most common complication of prematurity and the leading respiratory cause of childhood morbidity. Non-invasive ventilation (NIV) may limit invasive ventilation exposure and can be either synchronized or non-synchronized (NS). Pooled data suggest synchronized forms may be superior. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) delivers NIV synchronized to the neural signal for breathing, which is detected with a specialized catheter. The DIVA (Diaphragmatic Initiated Ventilatory Assist) trial aims to determine in infants born 240/7-276/7 weeks' gestation undergoing extubation whether NIV-NAVA compared to non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV) reduces the incidence of extubation failure within 5 days of extubation. METHODS: This is a prospective, unblinded, pragmatic, multicenter phase III randomized clinical trial. Inclusion criteria are preterm infants 24-276/7 weeks gestational age who were intubated within the first 7 days of life for at least 12 h and are undergoing extubation in the first 28 postnatal days. All sites will enter an initial run-in phase, where all infants are allocated to NIV-NAVA, and an independent technical committee assesses site performance. Subsequently, all enrolled infants are randomized to NIV-NAVA or NS-NIPPV at extubation. The primary outcome is extubation failure within 5 days of extubation, defined as any of the following: (1) rise in FiO2 at least 20% from pre-extubation for > 2 h, (2) pH ≤ 7.20 or pCO2 ≥ 70 mmHg; (3) > 1 apnea requiring positive pressure ventilation (PPV) or ≥ 6 apneas requiring stimulation within 6 h; (4) emergent intubation for cardiovascular instability or surgery. Our sample size of 478 provides 90% power to detect a 15% absolute reduction in the primary outcome. Enrolled infants will be followed for safety and secondary outcomes through 36 weeks' postmenstrual age, discharge, death, or transfer. DISCUSSION: The DIVA trial is the first large multicenter trial designed to assess the impact of NIV-NAVA on relevant clinical outcomes for preterm infants. The DIVA trial design incorporates input from clinical NAVA experts and includes innovative features, such as a run-in phase, to ensure consistent technical performance across sites. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , trial identifier NCT05446272 , registered July 6, 2022.

Resultados de la ventilación asistida ajustada neuronalmente no invasiva y la presión positiva continua nasal en recién nacidos prematuros: revisión sistemática y metanálisis / Outcomes of noninvasive neurally adjusted ventilatory assist and nasal continuous positive airway pressure in preterm infants: a systematic review and meta-analysis

Introducción: los beneficios de la ventilación asistida ajustada neuronalmente (NAVA) en los recién nacidos prematuros son inciertos. El objetivo de este estudio fue explorar si la NAVA no invasiva (NIV) era más beneficiosa para los recién nacidos prematuros que la presión positiva continua nasal (NCPAP). Diseño del estudio: metanálisis de tres ensayos clínicos: dos ensayos controlados aleatorizados y un estudio de grupos cruzados. Se comparó la NAVA-NIV con la NCPAP y se informó sobre el fracaso del tratamiento, la mortalidad y los eventos adversos como resultados principales. Resultados: tres estudios con 173 pacientes (89 recibieron NAVA-NIV) cumplieron los criterios de inclusión en este metanálisis. No se observaron diferencias en el fracaso del tratamiento entre la NAVA-NIV y la NCPAP (razón de riesgos [RR] = 1,09; intervalo de confianza [IC] del 95 % = 0,65-1,84; diferencia de riesgos = 0,02; IC95% = -0,10-0,14; I2 = 33 %; P = 0,23). De manera similar, no hubo diferencias en la mortalidad (RR = 1,52; IC95% = 0,51-4,52; no aplica heterogeneidad). En comparación con la NCPAP, la NAVA-NIV redujo significativamente el uso de cafeína (RR = 0,85; IC 95% = 0,74-0,98; I2 = 71 %; P = 0,03). Conclusiones: en comparación con la NCPAP, no hay evidencia suficiente para sacar una conclusión sobre los beneficios o daños de la NAVA-NIV en los recién nacidos prematuros. Los hallazgos de esta revisión deben confirmarse en ensayos clínicos con una metodología rigurosa y potencia adecuada

Introduction: The benefits of neurally adjusted ventilatory assist (NAVA) in preterm infants are unclear. This study aimed to explore if noninvasive NAVA is more beneficial for preterm infants than nasal continuous positive airway pressure (NCPAP). Study design: Meta-analysis was performed in three clinical trials comprising two randomized controlled trials and one crossover study. We compared NIV-NAVA and NCPAP and reported treatment failure, mortality, and adverse events as the primary outcomes. Results: Three studies including 173 patients (89 of whom underwent NIV-NAVA) were eligible for this meta-analysis. This review found no difference in treatment failure between NIV-NAVA and NCPAP (RR 1.09, 95% CI 0.65 to 1.84; RD 0.02, 95% CI -0.10-0.14; I2=33%, P=0.23). Similarly, there was no difference in mortality (RR 1.52, 95% CI 0.51-4.52, heterogeneity not applicable). Compared with NCPAP, NIV-NAVA significantly reduced the use of caffeine (RR 0.85, 95% CI 0.74-0.98, I2=71%, P=0.03). Conclusions: Compared with NCPAP, there is insufficient evidence to conclude on the benefits or harm of NIV-NAVA therapy for preterm infants. The findings of this review should be confirmed using methodologically rigorous and adequately powered clinical trials.

Outcomes of noninvasive neurally adjusted ventilatory assist and nasal continuous positive airway pressure in preterm infants: a systematic review and meta-analysis. / Resultados de la ventilación asistida ajustada neuronalmente no invasiva y la presión positiva continua nasal en recién nacidos prematuros: revisión sistemática y metanálisis.

INTRODUCTION: The benefits of neurally adjusted ventilatory assist (NAVA) in preterm infants are unclear. This study aimed to explore if noninvasive NAVA is more beneficial for preterm infants than nasal continuous positive airway pressure (NCPAP). STUDY DESIGN: Meta-analysis was performed in three clinical trials comprising two randomized controlled trials and one crossover study. We compared NIV-NAVA and NCPAP and reported treatment failure, mortality, and adverse events as the primary outcomes. RESULTS: Three studies including 173 patients (89 of whom underwent NIV-NAVA) were eligible for this meta-analysis. This review found no difference in treatment failure between NIVNAVA and NCPAP (RR 1.09, 95% CI 0.65 to 1.84; RD 0.02, 95% CI -0.10-0.14; I2=33%, P=0.23). Similarly, there was no difference in mortality (RR 1.52, 95% CI 0.51-4.52, heterogeneity not applicable). Compared with NCPAP, NIVNAVA significantly reduced the use of caffeine (RR 0.85, 95% CI 0.74-0.98, I2=71%, P=0.03). CONCLUSIONS: Compared with NCPAP, there is insufficient evidence to conclude on the benefits or harm of NIV-NAVA therapy for preterm infants. The findings of this review should be confirmed using methodologically rigorous and adequately powered clinical trials.

Introducción: los beneficios de la ventilación asistida ajustada neuronalmente (NAVA) en los recién nacidos prematuros son inciertos. El objetivo de este estudio fue explorar si la NAVA no invasiva (NIV) era más beneficiosa para los recién nacidos prematuros que la presión positiva continua nasal (NCPAP). Diseño del estudio: metanálisis de tres ensayos clínicos: dos ensayos controlados aleatorizados y un estudio de grupos cruzados. Se comparó la NAVA-NIV con la NCPAP y se informó sobre el fracaso del tratamiento, la mortalidad y los eventos adversos como resultados principales. Resultados: tres estudios con 173 pacientes (89 recibieron NAVA-NIV) cumplieron los criterios de inclusión en este metanálisis. No se observaron diferencias en el fracaso del tratamiento entre la NAVA-NIV y la NCPAP (razón de riesgos [RR] = 1,09; intervalo de confianza [IC] del 95 % = 0,65-1,84; diferencia de riesgos = 0,02; IC95% = -0,10-0,14; I2 = 33 %; P = 0,23). De manera similar, no hubo diferencias en la mortalidad (RR = 1,52; IC95% = 0,51-4,52; no aplica heterogeneidad). En comparación con la NCPAP, la NAVA-NIV redujo significativamente el uso de cafeína (RR = 0,85; IC 95% = 0,74-0,98; I2 = 71 %; P = 0,03). Conclusiones: en comparación con la NCPAP, no hay evidencia suficiente para sacar una conclusión sobre los beneficios o daños de la NAVA-NIV en los recién nacidos prematuros. Los hallazgos de esta revisión deben confirmarse en ensayos clínicos con una metodología rigurosa y potencia adecuada.

Neurally adjusted ventilatory assist mitigates ventilator-induced diaphragm injury in rabbits.

BACKGROUND: Ventilator-induced diaphragmatic dysfunction is a serious complication associated with higher ICU mortality, prolonged mechanical ventilation, and unsuccessful withdrawal from mechanical ventilation. Although neurally adjusted ventilatory assist (NAVA) could be associated with lower patient-ventilator asynchrony compared with conventional ventilation, its effects on diaphragmatic dysfunction have not yet been well elucidated. METHODS: Twenty Japanese white rabbits were randomly divided into four groups, (1) no ventilation, (2) controlled mechanical ventilation (CMV) with continuous neuromuscular blockade, (3) NAVA, and (4) pressure support ventilation (PSV). Ventilated rabbits had lung injury induced, and mechanical ventilation was continued for 12 h. Respiratory waveforms were continuously recorded, and the asynchronous events measured. Subsequently, the animals were euthanized, and diaphragm and lung tissue were removed, and stained with Hematoxylin-Eosin to evaluate the extent of lung injury. The myofiber cross-sectional area of the diaphragm was evaluated under the adenosine triphosphatase staining, sarcomere disruptions by electron microscopy, apoptotic cell numbers by the TUNEL method, and quantitative analysis of Caspase-3 mRNA expression by real-time polymerase chain reaction. RESULTS: Physiological index, respiratory parameters, and histologic lung injury were not significantly different among the CMV, NAVA, and PSV. NAVA had lower asynchronous events than PSV (median [interquartile range], NAVA, 1.1 [0-2.2], PSV, 6.8 [3.8-10.0], p = 0.023). No differences were seen in the cross-sectional areas of myofibers between NAVA and PSV, but those of Type 1, 2A, and 2B fibers were lower in CMV compared with NAVA. The area fraction of sarcomere disruptions was lower in NAVA than PSV (NAVA vs PSV; 1.6 [1.5-2.8] vs 3.6 [2.7-4.3], p < 0.001). The proportion of apoptotic cells was lower in NAVA group than in PSV (NAVA vs PSV; 3.5 [2.5-6.4] vs 12.1 [8.9-18.1], p < 0.001). There was a tendency in the decreased expression levels of Caspase-3 mRNA in NAVA groups. Asynchrony Index was a mediator in the relationship between NAVA and sarcomere disruptions. CONCLUSIONS: Preservation of spontaneous breathing using either PSV or NAVA can preserve the cross sectional area of the diaphragm to prevent atrophy. However, NAVA may be superior to PSV in preventing sarcomere injury and apoptosis of myofibrotic cells of the diaphragm, and this effect may be mediated by patient-ventilator asynchrony.

Nasal continuous positive airway pressure (NCPAP) or noninvasive neurally adjusted ventilatory assist (NIV-NAVA) for preterm infants with respiratory distress after birth: A randomized controlled trial.

OBJECTIVES: To compare rates of treatment failure between the use of nasal continuous positive airway pressure (NCPAP) and noninvasive neurally adjusted ventilatory assist (NIV-NAVA) in infants with respiratory distress after birth. METHODS: A randomized, unblinded, double-center trial was conducted in infants with birth weights (BWs) less than or equal to 1500 g and respiratory distress receiving noninvasive respiratory support for less than or equal to 48 hours of life; some infants were initially treated with minimally invasive surfactant therapy as the standard of care. PRIMARY OUTCOME: need for endotracheal intubation with use of mechanical ventilation (MV) at less than or equal to 72 hours of life using prespecified failure criteria. SECONDARY OUTCOMES: use of surfactant, duration of noninvasive support, duration of MV, bronchopulmonary dysplasia (BPD) and death. RESULTS: A total of 123 infants were included (NCPAP group = 64 and NIV-NAVA group = 59). Population characteristics were similar between groups. No difference in the primary outcome was observed: NCPAP = 10 (15.6%) and NIV-NAVA = 12 (20.3%), P = .65. Groups were also similar in the use of surfactant (19 vs 17), duration of noninvasive support (147 ± 181 hours vs 127 ± 137 hours), BPD incidence and death. However, duration of MV was significantly longer in NCPAP group (95.6 ± 45.8 hours vs 28.25 ± 34.1 hour), P = .01. CONCLUSION: In infants with respiratory distress after birth, no differences in treatment failures were observed between NIV-NAVA and NCPAP. These results require further evaluation in a larger study.

Utilization of Neurally Adjusted Ventilatory Assist (NAVA) Mode in Infants and Children Undergoing Congenital Heart Surgery: A Retrospective Review.

We assessed the feasibility and the impact of NAVA compared to conventional modes of mechanical ventilation in ventilatory and gas exchange parameters in post-operative children with congenital heart disease. Infants and children (age < 18 years) that underwent congenital heart surgery were enrolled. Patients were ventilated with conventional synchronized intermittent mechanical ventilation (SIMV) and subsequently transitioned to NAVA during their cardiovascular intensive care unit (CVICU) stay. The ventilatory and gas exchange parameters for the 24 h pre- and post-transition to NAVA were compared. Additional parameters assessed included pain scores and sedation requirements. Eighty-one patients met inclusion criteria with a median age of 21 days (interquartile range 13 days-2 months). The majority of patients enrolled (75.3%) had complex congenital heart disease with high surgical severity scores. The transition to NAVA was tolerated by all patients without complications. The mean peak inspiratory pressure (PIP) was 1.8 cm H2O lower (p < 0.001) and mean airway pressure (Paw) was 0.5 cm H2O lower (p = 0.009) on NAVA compared to conventional modes of mechanical ventilation. There was no significant difference in patients' respiratory rate, tidal volume, arterial pH, pCO2, and lactate levels between the two modes of ventilation. There was a decreased sedation requirement during the time of NAVA ventilation. Comfort scores did not differ significantly with ventilator mode change. We concluded that NAVA is safe and well-tolerated mode of mechanical ventilation for our cohort of patients after congenital heart surgery. Compared to conventional ventilation there was a statistically significant decrease in PIP and Paw on NAVA.

Feasibility of Non-invasive Neurally Adjusted Ventilator Assist After Congenital Diaphragmatic Hernia Repair.

BACKGROUND: The use of neurally adjusted ventilator assist (NAVA) in congenital diaphragmatic hernia (CDH) patients has been historically deemed unwise, since the trigger for breaths is the electromyographic activity of the diaphragmatic muscle. We report on our NAVA experience in CDH patients. METHODS: We performed an IRB-approved retrospective review of newborns from 1/1/2012-1/1/2017 at a Level I Children's Surgery Center undergoing CDH repair. Data obtained included demographics, defect type and repair, respiratory support, and outcomes. RESULTS: Seven infants with CDH were placed on noninvasive-NAVA (NIV-NAVA) after extubation. All seven patients underwent open transabdominal repair, with five requiring patch repair. All survived to discharge, and one year after birth. When we compared this group to a contemporary cohort of patients who also underwent CDH repair, we found no significant differences in birth weight, postmenstrual age, or gender. However, there was a significantly higher need for inhaled nitric oxide (p = 0.002), high frequency oscillatory ventilation (p = 0.016), and extracorporeal membranous oxygenation support (p = 0.045) in the NIV-NAVA cohort. CONCLUSION: This is the first report of NIV-NAVA being successfully utilized as an adjunct to wean infants from conventional ventilation after CDH repair, even in those who require patch repair or with more significant disease severity. LEVELS OF EVIDENCE: III- Retrospective Comparative Study.

Neurally adjusted ventilatory assist compared to other forms of triggered ventilation for neonatal respiratory support.

BACKGROUND: Effective synchronisation of infant respiratory effort with mechanical ventilation may allow adequate gas exchange to occur at lower peak airway pressures, potentially reducing barotrauma and volutrauma and development of air leaks and bronchopulmonary dysplasia. During neurally adjusted ventilatory assist ventilation (NAVA), respiratory support is initiated upon detection of an electrical signal from the diaphragm muscle, and pressure is provided in proportion to and synchronous with electrical activity of the diaphragm (EADi). Compared to other modes of triggered ventilation, this may provide advantages in improving synchrony. OBJECTIVES: Primary• To determine whether NAVA, when used as a primary or rescue mode of ventilation, results in reduced rates of bronchopulmonary dysplasia (BPD) or death among term and preterm newborn infants compared to other forms of triggered ventilation• To assess the safety of NAVA by determining whether it leads to greater risk of intraventricular haemorrhage (IVH), periventricular leukomalacia, or air leaks when compared to other forms of triggered ventilation Secondary• To determine whether benefits of NAVA differ by gestational age (term or preterm)• To determine whether outcomes of cross-over trials performed during the first two weeks of life include peak pressure requirements, episodes of hypocarbia or hypercarbia, oxygenation index, and the work of breathing SEARCH METHODS: We performed searches of the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cohrane Library; MEDLINE via Ovid SP (January 1966 to March 2017); Embase via Ovid SP (January 1980 to March 2017); the Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCO host (1982 to March 2017); and the Web of Science (1985 to 2017). We searched abstracts from annual meetings of the Pediatric Academic Societies (PAS) (2000 to 2016); meetings of the European Society of Pediatric Research (published in Pediatric Research); and meetings of the Perinatal Society of Australia and New Zealand (PSANZ) (2005 to 2016). We also searched clinical trials databases to March 2017. SELECTION CRITERIA: We included randomised and quasi-randomised clinical trials including cross-over trials comparing NAVA with other modes of triggered ventilation (assist control ventilation (ACV),synchronous intermittent mandatory ventilation plus pressure support (SIMV ± PS), pressure support ventilation (PSV), or proportional assist ventilation (PAV)) used in neonates. DATA COLLECTION AND ANALYSIS: Primary outcomes of interest from randomised controlled trials were all-cause mortality, bronchopulmonary dysplasia (BPD; defined as oxygen requirement at 28 days), and a combined outcome of all-cause mortality or BPD. Secondary outcomes were duration of mechanical ventilation, incidence of air leak, incidence of IVH or periventricular leukomalacia, and survival with an oxygen requirement at 36 weeks' postmenstrual age.Outcomes of interest from cross-over trials were maximum fraction of inspired oxygen, mean peak inspiratory pressure, episodes of hypocarbia, and episodes of hypercarbia measured across the time period of each arm of the cross-over. We planned to assess work of breathing; oxygenation index, and thoraco-abdominal asynchrony at the end of the time period of each arm of the cross-over study. MAIN RESULTS: We included one randomised controlled study comparing NAVA versus patient-triggered time-cycled pressure-limited ventilation. This study found no significant difference in duration of mechanical ventilation, nor in rates of BPD, pneumothorax, or IVH. AUTHORS' CONCLUSIONS: Risks and benefits of NAVA compared to other forms of ventilation for neonates are uncertain. Well-designed trials are required to evaluate this new form of triggered ventilation.

Neurally adjusted ventilatory assist for infants under prolonged ventilation.

BACKGROUND: Severe bronchopulmonary dysplasia often leads to prolonged mechanical ventilation lasting several months. Cyanotic episodes frequently occur in these patients, necessitating long-term sedation and/or intermittent muscle paralysis. Neurally adjusted ventilatory assist (NAVA) might provide precisely the amount of support that these patients need without sedation. METHODS: We reviewed the medical records of preterm infants who underwent tracheostomy and required mechanical ventilation for >6 months during a period of 6 years. We compared two groups of patients: those supported with NAVA for ≥2 months versus those supported by pneumatically triggered assist methods. We also evaluated any change after NAVA use in the NAVA group. RESULTS: Among 14 prematurely born patients who received prolonged ventilation, nine were supported with NAVA and five were supported using other ventilator modes. Duration of continuous sedation was significantly shorter and the bolus use of sedatives was also significantly lower in the NAVA group than in the pneumatically triggered assist group. In addition, the NAVA group received a lower dose of dexamethasone than the pneumatically triggered assist group. Compared with before NAVA, the frequency of cyanotic episodes and of the bolus sedatives was significantly decreased after implementation of NAVA. CONCLUSIONS: For infants on prolonged mechanical ventilation, NAVA could reduce cyanotic episodes and the need for sedatives and dexamethasone. NAVA may be superior to pneumatically triggered modes in terms of the minimization of patient-ventilator dyssynchrony while delivering appropriate respiratory support in premature infants with tracheostomy.

Suporte ventilatório ao nascer e associação com doenças respiratórias aos seis anos: Coorte de Nascimentos de Pelotas, Rio Grande do Sul, Brasil, 2004 / Soporte ventilatorio en el período neonatal y enfermedades respiratorias en los seis primeros años de vida: Cohorte de Nacimientos de Pelotas, Rio Grande do Sul, Brasil, 2004 / Neonatal ventilatory support and respiratory diseases in children up to six years of age: the 2004 Pelotas (Brazil) Birth Cohort study

O objetivo do estudo foi avaliar a associação entre suporte ventilatório no período neonatal e doenças respiratórias até os seis anos de idade. Estudo de coorte de nascimentos de base populacional. A exposição principal foi o suporte ventilatório ao nascimento, definido como o uso de pressão contínua positiva nasal (CPAPn) e/ou ventilação mecânica (VM) por mais de três horas, desde o momento da hospitalização ao nascimento até os 28 dias. Os desfechos foram chiado no peito nos últimos 12 meses, diagnóstico médico de asma alguma vez na vida e episódio de pneumonia ocorrido até os seis anos de idade. Foram realizadas análises brutas e ajustadas para potenciais variáveis de confusão, usando regressão de Poisson. Foram analisadas 3.624 crianças. O uso de CPAPn e VM ou unicamente VM esteve associado com maior frequência de diagnóstico médico de asma, mesmo após ajuste para características maternas e das crianças (RP = 2,24; IC95%: 1,27-3,99). Os resultados do presente estudo alertam para as complicações respiratórias, em médio prazo, decorrentes do suporte ventilatório realizado no período neonatal.

El objetivo del estudio fue evaluar la asociación entre el soporte ventilatorio durante el período neonatal y las enfermedades respiratorias durante los seis primeros años de vida. Se trata de un estudio de cohorte de nacimiento con base poblacional. La exposición principal, soporte ventilatorio al nacimiento, fue definida como el uso de presión positiva nasal (CPAPn) y/o ventilación mecánica (VM) durante más de tres horas, desde la hospitalización al nacimiento, hasta los 28 días de vida. Los resultados analizados fueron: broncoespasmo en los últimos doce meses, diagnóstico médico de asma - realizado alguna vez en la vida- y episodio de neumonía ocurrido hasta los seis años de edad. Se realizaron análisis brutos y ajustados para potenciales variables de confusión, usando la regresión de Poisson. Fueron estudiados 3.624 niños. El uso de soporte ventilatorio estuvo asociado con una mayor frecuencia de diagnóstico médico de asma, incluso tras ajustar las características maternas y de los niños (RP = 2,24; IC95%: 1,27-3,99). Los resultados alertan sobre las complicaciones respiratorias a medio plazo tras el soporte ventilatorio realizado en el período neonatal.

The study's objective was to evaluate the association between neonatal ventilatory support and the subsequent occurrence of respiratory diseases in children up to six years of age. This was a population-based birth cohort study. The main exposure was ventilatory support at birth, defined as the use of nasal continuous positive airway pressure (NCPAP) and/or mechanical ventilation (MV) for more than three hours from the time of hospitalization at birth until the first 28 days of life. Outcomes were: chest wheezing in the twelve months prior to the follow-up interview, medical diagnosis of asthma any time in the child´s life, and occurrence of pneumonia up to six years of age. Crude and adjusted analyses for potential confounding variables were performed using Poisson regression. 3,624 children were analyzed. NCPAP plus MV or MV alone was associated with higher frequency of medical diagnosis of asthma, even after adjusting for maternal and child characteristics (PR = 2.24; 95%CI: 1.27-3.99). The results highlight medium-term respiratory complications associated with neonatal ventilatory support.