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.

Study protocol for a randomized controlled trial of Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation: the PROMIZING study.

BACKGROUND: Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mechanical ventilation mode that delivers assistance to breathe in proportion to the patient's effort. The proportional assistance, called the gain, can be adjusted by the clinician to maintain the patient's respiratory effort or workload within a normal range. Short-term and physiological benefits of this mode compared to pressure support ventilation (PSV) include better patient-ventilator synchrony and a more physiological response to changes in ventilatory demand. METHODS: The objective of this multi-centre randomized controlled trial (RCT) is to determine if, for patients with acute respiratory failure, ventilation with PAV+ will result in a shorter time to successful extubation than with PSV. This multi-centre open-label clinical trial plans to involve approximately 20 sites in several continents. Once eligibility is determined, patients must tolerate a short-term PSV trial and either (1) not meet general weaning criteria or (2) fail a 2-min Zero Continuous Positive Airway Pressure (CPAP) Trial using the rapid shallow breathing index, or (3) fail a spontaneous breathing trial (SBT), in this sequence. Then, participants in this study will be randomized to either PSV or PAV+ in a 1:1 ratio. PAV+ will be set according to a target of muscular pressure. The weaning process will be identical in the two arms. Time to liberation will be the primary outcome; ventilator-free days and other outcomes will be measured. DISCUSSION: Meta-analyses comparing PAV+ to PSV suggest PAV+ may benefit patients and decrease healthcare costs but no powered study to date has targeted the difficult to wean patient population most likely to benefit from the intervention, or used consistent timing for the implementation of PAV+. Our enrolment strategy, primary outcome measure, and liberation approaches may be useful for studying mechanical ventilation and weaning and can offer important results for patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02447692 . Prospectively registered on May 19, 2015.

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.

Proportional assist ventilation feasibility in the early stage of respiratory failure: a prospective randomized multicenter trial.

BACKGROUND: Proportional assist ventilation (PAV+) is an assisted ventilator mode usually applied during weaning. We aimed to determine the feasibility of using PAV+ in the early phase of acute respiratory failure compared to volume-assist control ventilation (V-ACV) in order to shorten the length of mechanical ventilation (MV). METHODS: We conducted a prospective randomized trial comparing high-assistance PAV+ (gain 80%) vs. V-ACV in four university hospital Intensive Care Units. Patients were included based on a previous pilot trial. Length of MV was the main objective. Secondary objectives were length of stay (LOS) in ICU/hospital, and ICU/hospital/60-day mortality. Statistics - Mann-Whitney U Test and Fisher's Exact Test. RESULTS: We could not find differences in length of MV or any of the analyzed variables between the 52 patients with PAV+ and 50 patients with V-ACV. The high PAV+ failure rate (42%) was attributed to excessive sedation, high respiratory rate, and high respiratory effort. CONCLUSIONS: The use of high-assistance PAV+ in the early phase of MV does not present benefits compared to V-ACV. The high rate of PAV+ failure reinforces the need for sedative optimization, learning curve, and better patient selection.

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.

Non-invasive neurally adjusted ventilatory assist versus nasal intermittent positive-pressure ventilation in preterm infants born before 30 weeks' gestation.

BACKGROUND: Non-invasive neurally adjusted ventilatory assist (NIV-NAVA), a mode of non-invasive ventilation (NIV) controlled by diaphragmatic electrical activity, may be superior to other NIV as a respiratory support after extubation in preterm infants, but no report has compared NIV-NAVA with other NIV methods. We evaluated the effectiveness and adverse effects of NIV-NAVA after extubation in preterm infants <30 weeks of gestation. METHODS: This retrospective study involved patients who were born before 30 weeks of gestation. We mainly used NIV-NAVA or nasal intermittent positive-pressure ventilation (NIPPV) for preterm infants as the NIV after extubation and compared these two groups. The primary outcome was treatment failure. The secondary outcomes were extubation failure and adverse events. Treatment failure was defined as a change of NIV (NIPPV was switched to NIV-NAVA, or NIV-NAVA was switched to NIPPV) or reintubation ≤7 days after extubation. RESULTS: Fifteen patients were in the NIV-NAVA group, and 19 were in the NIPPV group. The gestational age of the NIV-NAVA group was younger than that of the NIPPV group (25.7 ± 2.4 weeks vs 27.3 ± 1.8 weeks). Treatment failure occurred in six cases (40%) in the NIV-NAVA group and in nine cases (47.4%) in the NIPPV group, and no significant difference was demonstrated. No significant difference in adverse events was noted. CONCLUSIONS: NIV-NAVA has advantages compared with NIPPV as the NIV for premature infants after extubation. NIV-NAVA can also be used safely without a significant difference in the rate of complications compared with NIPPV.

Neural breathing patterns in preterm newborns supported with non-invasive neurally adjusted ventilatory assist.

OBJECTIVE: To characterize the neural breathing pattern in preterm infants supported with non-invasive neurally adjusted ventilatory assist (NIV-NAVA). STUDY DESIGN: Single-center prospective observational study. The electrical activity of the diaphragm (EAdi) was periodically recorded in 30-second series with the Edi catheter and the Servo-n software (Maquet, Solna, Sweden) in preterm infants supported with NIV-NAVA. The EAdiPeak, EAdiMin, EAdiTonic, EAdiPhasic, neural inspiratory, and expiratory times (nTi and nTe) and the neural respiratory rate (nRR) were calculated. EAdi curves were generated by Excel for visual examination and classified according to the predominant pattern. RESULTS: 291 observations were analyzed in 19 patients with a mean GA of 27.3 weeks (range 24-36 weeks), birth weight 1028 g (510-2945 g), and a median (IQR) postnatal age of 18 days (4-27 days). The distribution of respiratory patterns was phasic without tonic activity 61.9%, phasic with basal tonic activity 18.6, tonic burst 3.8%, central apnea 7.9%, and mixed pattern 7.9%. In addition, 12% of the records showed apneas of >10 seconds, and 50.2% one or more "sighs", defined as breaths with an EAdiPeak and/or nTi greater than twice the average EAdiPeak and/or nTi of the recording. Neural times were measurable in 252 observations. The nTi was, median (IQR): 279 ms (253-285 ms), the nTe 764 ms (642-925 ms), and the nRR 63 bpm (51-70), with a great intra and inter-subjects variability. CONCLUSIONS: The neural breathing patterns in preterm infants supported with NIV-NAVA are quite variable and are characterized by the presence of significant tonic activity. Central apneas and sighs are common in this group of patients. The nTi seems to be shorter than the mechanical Ti commonly used in assisted ventilation.

Proportional assist ventilation versus pressure support ventilation in weaning ventilation: a pilot randomised controlled trial.

OBJECTIVE: Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mode of ventilation that provides assistance in proportion to patient effort. This may have physiological and clinical advantages when compared with pressure support ventilation (PSV). Our objective was to compare these two modes in patients being weaned from mechanical ventilation. DESIGN: Prospective randomised controlled trial comparing PSV with PAV+. SETTING: University-affiliated, tertiary referral intensive care unit (ICU). PARTICIPANTS: Mechanically ventilated patients on a controlled mode of ventilation for at least 24 hours, who were anticipated to be spontaneously ventilated for at least 48 hours after randomisation. INTERVENTIONS: Nil. MAIN OUTCOME MEASURES: The primary outcome was time to successful liberation from the ventilator after the commencement of a spontaneous mode of ventilation. Secondary outcomes were requirement of rescue (mandatory) ventilation, requirement of sedative drugs, requirement for tracheostomy, re-intubation within 48 hours of extubation, ICU length of stay (LOS), hospital LOS, and ICU and hospital mortality. RESULTS: 50 patients were randomised to either PSV (n = 25) or PAV+ (n = 25). There was no significant difference between the PAV+ and PSV groups in time to successful weaning (84.3 v 135.9 hours, respectively; P = 0.536). Four patients randomised to PAV+ were crossed over to PSV during weaning. There was no significant difference between groups for rescue ventilation, reintubation within 48 hours, tracheostomy, sedatives and analgesics prescribed, and ICU and hospital LOS. ICU mortality was higher in the PSV group (25% v 4 %; P = 0.002). CONCLUSIONS: Both modes of ventilation were comparable in time to liberation from the ventilator.

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.

Prevalence and Prognosis Impact of Patient-Ventilator Asynchrony in Early Phase of Weaning according to Two Detection Methods.

BACKGROUND: Patient-ventilator asynchrony is associated with a poorer outcome. The prevalence and severity of asynchrony during the early phase of weaning has never been specifically described. The authors' first aim was to evaluate the prognosis impact and the factors associated with asynchrony. Their second aim was to compare the prevalence of asynchrony according to two methods of detection: a visual inspection of signals and a computerized method integrating electromyographic activity of the diaphragm. METHODS: This was an ancillary study of a multicenter, randomized controlled trial comparing neurally adjusted ventilatory assist to pressure support ventilation. Asynchrony was quantified at 12, 24, 36, and 48 h after switching from controlled ventilation to a partial mode of ventilatory assistance according to the two methods. An asynchrony index greater than or equal to 10% defined severe asynchrony. RESULTS: A total of 103 patients ventilated for a median duration of 5 days (interquartile range, 3 to 9 days) were included. Whatever the method used for quantification, severe patient-ventilator asynchrony was not associated with an alteration of the outcome. No factor was associated with severe asynchrony. The prevalence of asynchrony was significantly lower when the quantification was based on flow and pressure than when it was based on the electromyographic activity of the diaphragm at 0.3 min (interquartile range, 0.2 to 0.8 min) and 4.7 min (interquartile range, 3.2 to 7.7 min; P < 0.0001), respectively. CONCLUSIONS: During the early phase of weaning in patients receiving a partial ventilatory mode, severe patient-ventilator asynchrony was not associated with adverse clinical outcome, although the prevalence of patient-ventilator asynchrony varies according to the definitions and methods used for detection.

The SERVE-HF safety notice in clinical practice - experiences of a tertiary sleep center.

BACKGROUND: In May 2015, the results of the SERVE-HF trial - addressing adaptive servoventilation (ASV) in chronic congestive heart failure (CHF) patients with central sleep apnea (CSA) - prompted a field safety notice. It was recommended to identify CHF patients treated with ASV and to advise the discontinuation of the treatment. We aimed to analyze the identification process and effect of ASV discontinuation on affected patients. METHODS: 126 patients treated with ASV on May 13th, 2015 at our institution were retrospectively analyzed. Treatment decisions, effect of ASV discontinuation and clinical course were followed for a year. Patients on ASV with CHF were compared to those without CHF. RESULTS: The risk criteria of the safety notice were fulfilled by 10.3% of patients (13/126). Additional echocardiographies were performed in 38%. ASV was discontinued in 93% of patients without adverse events (emergency hospitalization in n = 1). CSA reappeared immediately. Day- or nighttime symptoms were reported by 61%. Symptomatic patients were started on alternative treatments. CHF and non-CHF patients differed in cardiac function and type of SDB. CHF patients had shorter overall treatment duration. Compliance to ASV was similar in both groups with a median usage of 412 min (269; 495)/night in the CHF group and 414.5 min (347; 480) in the non-CHF group. CONCLUSION: Identification of patients "at risk" is feasible but outcome of discontinuation of ASV cannot be evaluated based on these data. ASV withdrawal in patients with stable chronic CHF and CSA leads to an immediate return of sleep disordered breathing. Symptomatic patients may ask for alternative treatment options.

Non-invasive ventilation with intelligent volume-assured pressure support versus pressure-controlled ventilation: effects on the respiratory event rate and sleep quality in COPD with chronic hypercapnia.

BACKGROUND: COPD patients who develop chronic hypercapnic respiratory failure have a poor prognosis. Treatment of choice, especially the best form of ventilation, is not well known. OBJECTIVES: This study compared the effects of pressure-controlled (spontaneous timed [ST]) non-invasive ventilation (NIV) and NIV with intelligent volume-assured pressure support (IVAPS) in chronic hypercapnic COPD patients regarding the effects on alveolar ventilation, adverse patient/ventilator interactions and sleep quality. METHODS: This prospective, single-center, crossover study randomized patients to one night of NIV using ST then one night with the IVAPS function activated, or vice versa. Patients were monitored using polysomnography (PSG) and transcutaneous carbon dioxide pressure (PtcCO2) measurement. Patients rated their subjective experience (total score, 0-45; lower scores indicate better acceptability). RESULTS: Fourteen patients were included (4 females, age 59.4±8.9 years). The total number of respiratory events was low, and similar under pressure-controlled (5.4±6.7) and IVAPS (8.3±10.2) conditions (P=0.064). There were also no clinically relevant differences in PtcCO2 between pressure-controlled and IVAPS NIV (52.9±6.2 versus 49.1±6.4 mmHg). Respiratory rate was lower under IVAPS overall; between-group differences reached statistical significance during wakefulness and non-rapid eye movement sleep. Ventilation pressures were 2.6 cmH2O higher under IVAPS versus pressure-controlled ventilation, resulting in a 20.1 mL increase in breathing volume. Sleep efficiency was slightly higher under pressure-controlled ventilation versus IVAPS. Respiratory arousals were uncommon (24.4/h [pressure-controlled] versus 25.4/h [IVAPS]). Overall patient assessment scores were similar, although there was a trend toward less discomfort during IVAPS. CONCLUSION: Our results show that IVAPS NIV allows application of higher nocturnal ventilation pressures versus ST without affecting sleep quality or inducing ventilation- associated events.

Feasibility and physiological effects of noninvasive neurally adjusted ventilatory assist in preterm infants.

BackgroundNoninvasive neurally adjusted ventilator assist (NIV-NAVA) was introduced to our clinical practice via a pilot and a randomized observational study to assess its safety, feasibility, and short-term physiological effects.MethodsThe pilot protocol applied NIV-NAVA to 11 infants on nasal CPAP, high-flow nasal cannula, or nasal intermittent mandatory ventilation (NIMV), in multiple 2- to 4-h periods of NIV-NAVA for comparison. This provided the necessary data to design a randomized, controlled observational crossover study in eight additional infants to compare the physiological effects of NIV-NAVA with NIMV during 2-h steady-state conditions. We recorded the peak inspiratory pressure (PIP), FiO2, Edi, oxygen saturations (histogram analysis), transcutaneous PCO2, and movement with an Acoustic Respiratory Movement Sensor.ResultsThe NAVA catheter was used for 81 patient days without complications. NIV-NAVA produced significant reductions (as a percentage of measurements on NIMV) in the following: PIP, 13%; FiO2, 13%; frequency of desaturations, 42%; length of desaturations, 32%; and phasic Edi, 19%. Infant movement and caretaker movement were reduced by 42% and 27%, respectively. Neural inspiratory time was increased by 39 ms on NIV-NAVA, possibly due to Head's paradoxical reflex.ConclusionNIV-NAVA was a safe, alternative mode of noninvasive support that produced beneficial short-term physiological effects, especially compared with NIMV.

Influences of Duration of Inspiratory Effort, Respiratory Mechanics, and Ventilator Type on Asynchrony With Pressure Support and Proportional Assist Ventilation.

BACKGROUND: Pressure support ventilation (PSV) is often associated with patient-ventilator asynchrony. Proportional assist ventilation (PAV) offers inspiratory assistance proportional to patient effort, minimizing patient-ventilator asynchrony. The objective of this study was to evaluate the influence of respiratory mechanics and patient effort on patient-ventilator asynchrony during PSV and PAV plus (PAV+). METHODS: We used a mechanical lung simulator and studied 3 respiratory mechanics profiles (normal, obstructive, and restrictive), with variations in the duration of inspiratory effort: 0.5, 1.0, 1.5, and 2.0 s. The Auto-Trak system was studied in ventilators when available. Outcome measures included inspiratory trigger delay, expiratory trigger asynchrony, and tidal volume (VT). RESULTS: Inspiratory trigger delay was greater in the obstructive respiratory mechanics profile and greatest with a effort of 2.0 s (160 ms); cycling asynchrony, particularly delayed cycling, was common in the obstructive profile, whereas the restrictive profile was associated with premature cycling. In comparison with PSV, PAV+ improved patient-ventilator synchrony, with a shorter triggering delay (28 ms vs 116 ms) and no cycling asynchrony in the restrictive profile. VT was lower with PAV+ than with PSV (630 mL vs 837 mL), as it was with the single-limb circuit ventilator (570 mL vs 837 mL). PAV+ mode was associated with longer cycling delays than were the other ventilation modes, especially for the obstructive profile and higher effort values. Auto-Trak eliminated automatic triggering. CONCLUSIONS: Mechanical ventilation asynchrony was influenced by effort, respiratory mechanics, ventilator type, and ventilation mode. In PSV mode, delayed cycling was associated with shorter effort in obstructive respiratory mechanics profiles, whereas premature cycling was more common with longer effort and a restrictive profile. PAV+ prevented premature cycling but not delayed cycling, especially in obstructive respiratory mechanics profiles, and it was associated with a lower VT.

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.

Neurally adjusted ventilatory assist in patients with acute respiratory failure: study protocol for a randomized controlled trial.

BACKGROUND: Patient-ventilator asynchrony is a common problem in mechanically ventilated patients with acute respiratory failure. It is assumed that asynchronies worsen lung function and prolong the duration of mechanical ventilation (MV). Neurally Adjusted Ventilatory Assist (NAVA) is a novel approach to MV based on neural respiratory center output that is able to trigger, cycle, and regulate the ventilatory cycle. We hypothesized that the use of NAVA compared to conventional lung-protective MV will result in a reduction of the duration of MV. It is further hypothesized that NAVA compared to conventional lung-protective MV will result in a decrease in the length of ICU and hospital stay, and mortality. METHODS/DESIGN: This is a prospective, multicenter, randomized controlled trial in 306 mechanically ventilated patients with acute respiratory failure from several etiologies. Only patients ventilated for less than 5 days, and who are expected to require prolonged MV for an additional 72 h or more and are able to breathe spontaneously, will be considered for enrollment. Eligible patients will be randomly allocated to two ventilatory arms: (1) conventional lung-protective MV (n = 153) and conventional lung-protective MV with NAVA (n = 153). Primary outcome is the number of ventilator-free days, defined as days alive and free from MV at day 28 after endotracheal intubation. Secondary outcomes are total length of MV, and ICU and hospital mortality. DISCUSSION: This is the first randomized clinical trial examining, on a multicenter scale, the beneficial effects of NAVA in reducing the dependency on MV of patients with acute respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov website ( NCT01730794 ). Registered on 15 November 2012.