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.

Evaluation of NAVA-PAP in premature neonates with apnea of prematurity: minimal backup ventilation and clinically significant events.

Background: Neonates with apnea of prematurity (AOP) clinically deteriorate because continuous positive airway pressure (CPAP) provides inadequate support during apnea. Neurally adjusted ventilatory assist (NAVA) provides proportional ventilator support from the electrical activity of the diaphragm. When the NAVA level is 0 cmH2O/mcV (NAVA-PAP), patients receive CPAP when breathing and backup ventilation when apneic. This study evaluates NAVA-PAP and time spent in backup ventilation. Methods: This was a prospective, two-center, observational study of preterm neonates on NAVA-PAP for AOP. Ventilator data were downloaded after 24 h. The number of clinically significant events (CSEs) was collected. A paired t-test was used to perform statistical analysis. Results: The study was conducted on 28 patients with a gestational age of 25 ± 1.8 weeks and a study age of 28 ± 23 days. The number of CSEs was 4 ± 4.39/24 h. The patients were on NAVA-PAP for approximately 90%/min, switched to backup mode 2.5 ± 1.1 times/min, and spent 10.6 ± 7.2% in backup. Conclusion: Preterm neonates on NAVA-PAP had few CSEs with minimal time in backup ventilation.

Evaluating peak inspiratory pressures and tidal volume in premature neonates on NAVA ventilation.

Neurally adjusted ventilatory assist (NAVA) ventilation allows patients to determine their peak inspiratory pressure and tidal volume on a breath-by-breath basis. Apprehension exists about premature neonates' ability to self-regulate breath size. This study describes peak pressure and tidal volume distribution of neonates on NAVA and non-invasive NAVA. This is a retrospective study of stored ventilator data with exploratory analysis. Summary statistics were calculated. Distributional assessment of peak pressure and tidal volume were evaluated, overall and per NAVA level. Over 1 million breaths were evaluated from 56 subjects. Mean peak pressure was 16.4 ± 6.4 in the NAVA group, and 15.8 ± 6.4 in the NIV-NAVA group (t test, p < 0.001). Mean tidal volume was 3.5 ± 2.7 ml/kg.Conclusion:In neonates on NAVA, most pressures and volumes were within or lower than recommended ranges with pressure-limited or volume-guarantee ventilation. What is known: • Limiting peak inspiratory pressures or tidal volumes are the main strategies to minimize ventilator-induced lung injury in neonates. Neurally adjusted ventilatory assist allows neonates to regulate their own peak inspiratory pressures and tidal volumes on a breath-to-breath basis using neural feedback. What is new: • When neonates chose the size of their breaths based on neural feedback, the majority of peak inspiratory pressures and tidal volumes were within or lower than the recommended peak inspiratory pressure or tidal volume ranges with pressure-limited or volume guarantee ventilation.

Nasal continuous positive airway pressure versus noninvasive NAVA in preterm neonates with apnea of prematurity: a pilot study with a novel approach.

BACKGROUND: Neonates with apnea of prematurity often fail CPAP because it does not provide adequate support during apnea. NAVA provides proportional ventilator support based on electrical activity of the diaphragm. When the NAVA level is 0 cmH20/mcV, the patient receives minimal support above PEEP when breathing and backup ventilation when apneic. This study compares number of clinically significant events on CPAP versus noninvasive NAVA level 0. METHODS: Retrospective study of preterm neonates having apnea of prematurity on nasal CPAP. Patients were then placed on NAVA level 0. The number of events on each mode was collected. Statistics were paired t-test. RESULTS: Seventeen subjects with gestational age 26.1 ± 1.7 weeks, study age 19.5 ± 12.5 days. Events decreased from 17.9 ± 7.8 on CPAP to 10.2 ± 8.1 events on NAVA level 0 (p = 0.00047). CONCLUSIONS: NAVA level 0 reduced the number of clinically significant events compared with CPAP in premature neonates with apnea of prematurity.

Effects of Changes in Apnea Time on the Clinical Status of Neonates on NIV-NAVA.

BACKGROUND: Apnea time allows the clinician to set a minimum spontaneous respiratory frequency when using noninvasive neurally-adjusted ventilatory assist (NIV-NAVA). Short apnea times may provide backup ventilation during periods of physiologic variability causing overventilation and suppression of spontaneous respiratory drive. Longer apnea times may allow more spontaneous ventilation but can result in insufficient respiratory support. The purpose of this study was to evaluate various apnea times in neonates on NIV-NAVA. METHODS: This was a 2-center, prospective, 1-factorial, interventional study of neonates <30 weeks gestational age on NIV-NAVA. Clinically important events and ventilator data were recorded for apnea times of 2 s and 5 s for 2 h each. RESULTS: 15 neonates (26 ± 1.6 weeks gestational age, birthweight 893 ± 202 g) were studied. When compared to the 5-s apnea time, the 2-s apnea time showed increased switches into backup ventilation from 0.5 switches/min to 2.5 switches/min (P < .001), and time spent in backup ventilation increased from 2%/min to 9%/min (P < .001). However, clinically important events decreased from 7 clinically important events per hour to 2 clinically important events per hour (P < .001). Measured breathing frequency increased with the 2-s apnea time but spontaneous breathing frequency, FIO2 , peak and minimum electrical activity of the diaphragm, and peak pressure remained unchanged. CONCLUSION: Short apnea times resulted in more switches into backup ventilation and longer time in backup ventilation but promoted clinical stability with fewer clinically important events in neonates ventilated with NIV-NAVA.

Neonatal Resuscitation Program Rolling Refresher: Maintaining Chest Compression Proficiency Through the Use of Simulation-Based Education.

BACKGROUND: Structured training courses have shown to improve patient outcomes; however, guidelines are inconsistently applied in up to 50% of all neonatal resuscitations. This is partly due to the fact that psychomotor skills needed for resuscitation decay within 6 months to a year from the completion of a certification course. Currently, there are no recommendations on how often refresher training should occur to prevent skill decay. PURPOSE: Improve provider proficiency and confidence in the performance of neonatal resuscitation with a focus on chest compression effectiveness. METHODS: The study recruited neonatal intensive care unit providers (n = 25). A simulation-based Neonatal Resuscitation Program (NRP) curriculum was developed and executed. Training sessions were delivered utilizing in situ simulations at varying time intervals. Pre- and postconfidence surveys and practicum skill scores were collected and evaluated by a content expert. Categorical data were summarized by frequency and percentage and tested for distributional equality via Pearson chi-square tests or Fisher exact tests depending on cell sample size distribution. All statistical tests were 2-sided with P < .05 considered statistically significant. RESULTS: Provider overall confidence and rate of chest compressions improved; however, there was no statistically significant difference between groups. Rolling refresher training at varied time intervals did not demonstrate statistically significant differences in chest compression quality among NRP providers. IMPLICATIONS FOR PRACTICE: Rolling refresher training more frequently than every 6 months may not provide added benefit to NRP providers. IMPLICATIONS FOR RESEARCH: Additional research is needed to determine optimal refresher training frequency to prevent skill decay.

Neurally Adjusted Ventilatory Assist for Noninvasive Support in Neonates.

Noninvasive ventilation (NIV) is frequently used in the NICU to avoid intubation or as postextubation support for spontaneously breathing infants experiencing respiratory distress. Neurally adjusted ventilatory assist (NAVA) is used as a mode of noninvasive support in which both the timing and degree of ventilatory assist are controlled by the patient. NIV-NAVA has been successfully used clinically in neonates as a mode of ventilation to prevent intubation, allow early extubation, and as a novel way to deliver nasal continuous positive airway pressure.

Evaluating the Effect of Flow and Interface Type on Pressures Delivered With Bubble CPAP in a Simulated Model.

BACKGROUND: Bubble CPAP, used for spontaneously breathing infants to avoid intubation or postextubation support, can be delivered with different interface types. This study compared the effect that interfaces had on CPAP delivery. We hypothesized that there would be no difference between set and measured levels between interface types. METHODS: A validated preterm infant nasal airway model was attached to the ASL 5000 breathing simulator. The simulator was programmed to deliver active breathing of a surfactant-deficient premature infant with breathing frequency at 70 breaths/min inspiratory time of 0.30 s, resistance of 150 cm H2O/L/s, compliance of 0.5 mL/cm H2O, tidal volume of 5 mL, and esophageal pressure of -10 cm H2O. Nasal CPAP prongs, size 4030, newborn and infant RAM cannulas were connected to a nasal airway model and a bubble CPAP system. CPAP levels were set at 4, 5, 6, 7, 8, and 9 cm H2O with flows of 6, 8, and 10 L/min each. Measurements were recorded after 1 min of stabilization. The analysis was performed using SAS 9.4. The Kolmogorov-Smirnov test assessed normality of the data. The Friedman test was used to compare non-normally distributed repeated measures. The Wilcoxon signed-rank test was used to conduct post hoc analysis. All tests were 2-sided, and P values of <.05 were considered as indicating significant differences unless otherwise indicated. RESULTS: At lower set CPAP levels, 4-6 cm H2O, measured CPAP dropped precipitously with the nasal prongs with the highest flow setting. At higher CPAP levels, 7-9 cm H2O measured CPAP concomitantly increased as the flow setting increased. Statistically significant differences in set and measured CPAP occurred for all devices across all CPAP levels, with the measured CPAP less than set for all conditions, P < .001. CONCLUSIONS: Set flow had a profound effect on measured CPAP. The concomitant drop in measured pressure with high and low flows could be attributed to increased resistance to spontaneous breathing or insufficient flow to meet inspiratory demand. Clinicians should be aware of the effect that the interface and flow have on CPAP delivery.

Neonatal respiratory therapist-led rounds can improve staff satisfaction and timeliness of respiratory interventions.

BACKGROUND: Interdisciplinary rounding is used to establish and communicate patient care goals and monitor progress toward goal attainment. This study describes staff satisfaction and process outcomes associated with respiratory therapist (RT)-led interdisciplinary rounds in the neonatal ICU. We hypothesized improved staff satisfaction, execution of orders within 30 min of order entry into the electronic medical record, and communication of accurate and complete data during rounds to the interdisciplinary team. METHODS: Nurses, RTs, nurse practitioners, residents, and attending physicians completed the 13-question survey eliciting demographic information and evaluating staff engagement and professional satisfaction. The survey was anonymous and confidential, and informed consent was implied. Process data were collected for a 10-d period at 2 intervals through direct observation of the rounding process and electronic medical record review. Descriptive statistics reported patient demographics, responses to job satisfaction and engagement survey questions, the number of patients who were visited in daily rounds, the number and type of orders given during rounds, and the number of respiratory orders that were addressed in multidisciplinary teaching rounds rather than during respiratory rounds. The chi-square test was used to determine differences in the proportion of inaccurate and incomplete data communicated during rounds between the 2 data collection periods. The Mann-Whitney U test was used to determine differences in the timeliness of electronic medical record order entry and time to order completion. RESULTS: A 94.8% survey response rate (n = 55) was obtained. Seventy-six percent of participants reported improved communication. Sixty-nine percent of participants reported improved teamwork. Eighty-six percent of orders were implemented immediately after electronic medical record entry. Correct information was provided on 95% and 99.3% of patients (P < .066) and complete information on 93% and 96% of patients (P = .41). CONCLUSIONS: Implementation of respiratory rounds improved staff satisfaction and the timeliness of completing respiratory orders. Spot monitoring at intermittent intervals verified process sustainability.

Standardizing documentation and the clinical approach to apnea of prematurity reduces length of stay, improves staff satisfaction, and decreases hospital cost.

BACKGROUND: Apnea of prematurity, a common disorder, can severely compromise an infant's condition unless correctly diagnosed and treated. Infants with a history of apnea of prematurity can be discharged home but then be rehospitalized for an apneic event, an apparent life-threatening event, or sudden infant death syndrome. The definition of a clinically significant cardiopulmonary event, such events' documentation, and the treatment approach were standardized, and discharge criteria were refined. METHODS: A prospective, single-center comparison was conducted between a group of premature infants before and after implementation of the standard approach. Data were collected prospectively from August 1, 2005, through July 21, 2006, for the prestandard-approach group and from August 1, 2006, through September 16, 2007, for the standard-approach group. RESULTS: Twenty-two (35%) of the 63 infants in the prestandard-approach group experienced discharge delays because of poor documentation, whereby the clinician could not determine the safety of discharge. This resulted in 59 additional hospital days (mean length-of-stay [LOS] increase, 5.7 days). The standard-approach group of 72 infants experienced no discharge delays and no additional hospital days, and LOS decreased (all p < .0001). Annual charges were reduced by more than $58,000 in avoiding unnecessary hospital days. Readmission to the hospital for apnea of prematurity occurred for 5 (7.9%) of the prestandard-approach group but none of the standard-approach group (p = .0203). Overall compliance with the standardization process has been maintained at > or = 96%. CONCLUSION: Implementation of a standard approach to the definition of apnea of prematurity and its treatment and documentation decreases LOS and reduces cost.

Application of neurally adjusted ventilatory assist in neonates.

Neurally adjusted ventilatory assist (NAVA) uses the electrical activity of the diaphragm (Edi) as a neural trigger to synchronize mechanical ventilatory breaths with the patient's neural respiratory drive. Using this signal enables the ventilator to proportionally support the patient's instantaneous drive on a breath-by-breath basis. Synchrony can be achieved even in the presence of significant air leaks, which make this an attractive choice for invasive and non-invasive ventilation of the neonate. This paper describes the Edi signal, neuroventilatory coupling, and patient-ventilator synchrony including the functional concept of NAVA. Safety features, NAVA terminology, and clinical application of NAVA to unload respiratory musculature are presented. The use of the Edi signal as a respiratory vital sign for conventional ventilation is discussed. The results of animal and adult studies are briefly summarized and detailed descriptions of all NAVA-related research in pediatric and neonatal patients are provided. Further studies are needed to determine whether NAVA will have significant impact on the overall outcomes of neonates.

Synchronized mechanical ventilation using electrical activity of the diaphragm in neonates.

The electrical activity of the diaphragm (Edi) is measured by a specialized nasogastric/orogastric tube positioned in the esophagus at the level of the crural diaphragm. Neurally adjusted ventilatory assist (NAVA) uses the Edi signal as a neural trigger and intrabreath controller to synchronize mechanical ventilatory breaths with the patient's respiratory drive and to proportionally support the patient's respiratory efforts on a breath-by-breath basis. NAVA improves patient-ventilator interaction and synchrony even in the presence of large air leaks, and might therefore be an optimal option for noninvasive ventilation in neonates.

Theory-guided design and synthesis of multichromophore dendrimers: an analysis of the electro-optic effect.

Extensive experimental and theoretical study suggests that interchromophore electrostatic interactions are among the most severe impediments to the induction and stability of large electro-optic coefficients in electric-field-poled organic materials. In this report, multichromophore-containing dendritic materials have been investigated as a means to minimize unwanted attenuation of nonlinear optical (electro-optic) activity at high chromophore loading. The dendritic molecular architectures employed were designed to provide optimized molecular scaffolding for electric-field-induced molecular reorientation. Design parameters were based upon past experimental results in conjunction with statistical and quantum mechanical modeling. The electro-optic behavior of these materials was evaluated through experimental and theoretical analysis. Experimental data collected from the dendrimer structures depict a reasonably linear relationship between chromophore number density (N) and electro-optic activity (r(33)) demonstrating a deviation from the dipolar frustration that typically limits r(33) in conventional chromophore/polymer composite materials. The observed linear dependence holds at higher chromophore densities than those that have been found to be practical in systems of organic NLO chromophores dispersed in polymer hosts. Theoretical analysis of these results using Monte Carlo modeling reproduces the experimentally observed trends confirming linear dependence of electro-optic activity on N in the dendrimer materials. These results provide new insight into the ordering behavior of EO dendrimers and demonstrate that the frequently observed asymptotic dependence of electro-optic activity on chromophore number density may be overcome through rational design.

Antiparallel-aligned neutral-ground-state and zwitterionic chromophores as a nonlinear optical material.

Efficient noncentrosymmetric arrangement of nonlinear optical (NLO) chromophores with high first-order hyperpolarizability (beta) for increased electro-optical (EO) efficiency has proven challenging as strong dipolar interactions between the chromophores encourage antiparallel alignment, attenuating the macroscopic EO effect. This work explores a novel approach to simultaneously achieve large beta values while providing an adjustable dipole moment by linking a strong neutral-ground-state (NGS) NLO chromophore with positive beta to a zwitterionic (ZWI) chromophore with negative beta in an antiparallel fashion. It is proposed that the overall beta of such a structure will be the sum of the absolute values of the two types of chromophores while the dipole moment will be the difference. Molecules 1-3 were synthesized to test the feasibility of this approach. Molecular dynamics calculations and NMR data supported that the NGS chromophore component and the ZWI chromophore component self-assemble to an antiparallel conformation in chloroform. Calculations showed that the dipole moment of 1 is close to the difference of the two component chromophores. Hyper-Rayleigh scattering (HRS) studies confirmed that the first hyperpolarizability of 1 is close to the sum of the two component chromophores. These results support the idea that an antiparallel-aligned neutral-ground-state chromophore and a zwitterionic chromophore can simultaneously achieve an increase in beta and a decrease of the dipole moment.

Linear and nonlinear optical properties of a macrocyclic trichromophore bundle with parallel-aligned dipole moments.

A macrocyclic trichromophore bundle 1 with parallel-aligned dipole moments has been synthesized to study the influence of aggregation and orientation of a nonlinear optical (NLO) chromophore on its optical properties. The linear and nonlinear optical properties of 1 and a single chromophore standard 2 have been studied by UV-vis absorption, fluorescence, solvatochromic spectrometry, and hyper-Rayleigh scattering (HRS). Reduced first-order hyperpolarizability beta, hypsochromic shift, enhanced solvatochromic shifts, and fluorescence quenching for individual chromophores were observed when 1 was compared with 2. Analysis of the data showed that the transition dipole moment changes only slightly when the chromophores are parallel aligned in the bundle architecture. However, the apparent hyperpolarizability of the individual chromophores decreased significantly by about 20%. The reduction in beta for the individual chromophores in 1 is largely due to the hypsochromic shift, i.e., excitation energy increase of the interband (charge-transfer) energy gap and the reduced difference between the ground-state and excited-state dipole moments. The hypsochromic shift and fluorescence quenching are consistent with exciton theory. Possible reasons for the enhanced solvatochromic shift are discussed.

Systematic study of the structure-property relationship of a series of ferrocenyl nonlinear optical chromophores.

A series of novel nonlinear optical (NLO) chromophores 1-4 incorporating the ferrocenyl (Fc) group as an electron donor and 2-dicyanomethylene-3-cyano-4-methyl-2,5-dihydrofuran (TCF) derivatives as electron acceptors are presented. The use of a constant Fc donor and varied acceptors and bridges makes it possible to systematically determine the contribution of the conjugated bridge and the acceptor strength to chromophore nonlinear optical activity. The X-ray crystal structures of all four chromophores allow for the systematic investigation of the structure-property relationship for this class of molecules. For example, the crystal structures reveal that both cyclopentadienyl groups in the ferrocenyl donor contribute to the electron donating ability. The first-order hyperpolarizabilities beta of these chromophores, measured by hyper-Rayleigh scattering (HRS) relative to p-nitroaniline are reported. These beta values are compared to those calculated by density functional theory (DFT). The excellent agreement between the theoretical and experimental beta values demonstrates that a linear relation exists between the hyperpolarizability and the bond length alternation. An electrooptic coefficient, r(33), of approximately 25 pm/V at 1300 nm, for compound 4, incorporated into a polymer matrix, is competitive with organic chromophores. Moreover, this r(33) is more than 30 times larger than the previously reported value for an organometallic chromophore in a poled polymer matrix. This work not only underscores the potential for Fc donor moieties, which have been underutilized, but also demonstrates that experimental characterization and theoretical simulations are now congruent, viable methods for assessing potential performance of NLO materials.