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.

Does videolaryngoscopy improve tracheal intubation first attempt success in the NICUs? A report from the NEAR4NEOS.

OBJECTIVE: We hypothesized that videolaryngoscope use for tracheal intubations would differ across NICUs, be associated with higher first attempt success and lower adverse events. STUDY DESIGN: Data from the National Emergency Airway Registry for Neonates (01/2015 to 12/2017) included intubation with direct laryngoscope or videolaryngoscope. Primary outcome was first attempt success. Secondary outcomes were adverse tracheal intubation associated events and severe desaturation. RESULTS: Of 2730 encounters (13 NICUs), 626 (23%) utilized a videolaryngoscope (3% to 64% per site). Videolaryngoscope use was associated with higher first attempt success (p < 0.001), lower adverse tracheal intubation associated events (p < 0.001), but no difference in severe desaturation. After adjustment, videolaryngoscope use was not associated with higher first attempt success (OR:1.18, p = 0.136), but was associated with lower tracheal intubation associated events (OR:0.45, p < 0.001). CONCLUSION: Videolaryngoscope use is variable, not independently associated with higher first attempt success but associated with fewer tracheal intubation associated events.

Sustained Inflation Versus Intermittent Positive Pressure Ventilation for Preterm Infants at Birth: Respiratory Function and Vital Sign Measurements.

OBJECTIVE: To characterize respiratory function monitor (RFM) measurements of sustained inflations and intermittent positive pressure ventilation (IPPV) delivered noninvasively to infants in the Sustained Aeration of Infant Lungs (SAIL) trial and to compare vital sign measurements between treatment arms. STUDY DESIGN: We analyzed RFM data from SAIL participants at 5 trial sites. We assessed tidal volumes, rates of airway obstruction, and mask leak among infants allocated to sustained inflations and IPPV, and we compared pulse rate and oxygen saturation measurements between treatment groups. RESULTS: Among 70 SAIL participants (36 sustained inflations, 34 IPPV) with RFM measurements, 40 (57%) were spontaneously breathing prior to the randomized intervention. The median expiratory tidal volume of sustained inflations administered was 5.3 mL/kg (IQR 1.1-9.2). Significant mask leak occurred in 15% and airway obstruction occurred during 17% of sustained inflations. Among 34 control infants, the median expiratory tidal volume of IPPV inflations was 4.3 mL/kg (IQR 1.3-6.6). Mask leak was present in 3%, and airway obstruction was present in 17% of IPPV inflations. There were no significant differences in pulse rate or oxygen saturation measurements between groups at any point during resuscitation. CONCLUSION: Expiratory tidal volumes of sustained inflations and IPPV inflations administered in the SAIL trial were highly variable in both treatment arms. Vital sign values were similar between groups throughout resuscitation. Sustained inflation as operationalized in the SAIL trial was not superior to IPPV to promote lung aeration after birth in this study subgroup. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02139800.

A multi-centre randomised controlled trial of respiratory function monitoring during stabilisation of very preterm infants at birth.

AIM: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations with an expiratory tidal volume (Vte) within a predefined target range. METHODS: Unmasked, randomised clinical trial conducted October 2013 - May 2019 in 7 neonatal intensive care units in 6 countries. Very preterm infants (24-27 weeks of gestation) receiving PPV at birth were randomised to have a RFM screen visible or not. The primary outcome was the median proportion of inflations during manual PPV (face mask or intubated) within the target range (Vte 4-8 mL/kg). There were 42 other prespecified monitor measurements and clinical outcomes. RESULTS: Among 288 infants randomised (median (IQR) gestational age 26+2 (25+3-27+1) weeks), a total number of 51,352 inflations were analysed. The median (IQR) percentage of inflations within the target range in the RFM visible group was 30.0 (18.0-42.2)% vs 30.2 (14.8-43.1)% in the RFM non-visible group (p = 0.721). There were no differences in other respiratory function measurements, oxygen saturation, heart rate or FiO2. There were no differences in clinical outcomes, except for the incidence of intraventricular haemorrhage (all grades) and/or cystic periventricular leukomalacia (visible RFM: 26.7% vs non-visible RFM: 39.0%; RR 0.71 (0.68-0.97); p = 0.028). CONCLUSION: In very preterm infants receiving PPV at birth, the use of a RFM, compared to no RFM as guidance for tidal volume delivery, did not increase the percentage of inflations in a predefined target range. TRIAL REGISTRATION: Dutch Trial Register NTR4104, clinicaltrials.gov NCT03256578.

Team Stress and Adverse Events during Neonatal Tracheal Intubations: A Report from NEAR4NEOS.

OBJECTIVE: This study aimed to examine the association between team stress level and adverse tracheal intubation (TI)-associated events during neonatal intubations. STUDY DESIGN: TIs from 10 academic neonatal intensive care units were analyzed. Team stress level was rated immediately after TI using a 7-point Likert scale (1 = high stress). Associations among team stress, adverse TI-associated events, and TI characteristics were evaluated. RESULT: In this study, 208 of 2,009 TIs (10%) had high stress levels (score < 4). Oxygenation failure, hemodynamic instability, and family presence were associated with high stress level. Video laryngoscopy and premedication were associated with lower stress levels. High stress level TIs were associated with adverse TI-associated event rates (31 vs. 16%, p < 0.001), which remained significant after adjusting for potential confounders including patient, provider, and practice factors associated with high stress (odds ratio: 1.90, 96% confidence interval: 1.36-2.67, p < 0.001). CONCLUSION: High team stress levels during TI were more frequently reported among TIs with adverse events.

Association between Policy Changes for Oxygen Saturation Alarm Settings and Neonatal Morbidity and Mortality in Infants Born Very Preterm.

OBJECTIVE: To determine the impact of policy changes for pulse oximetry oxygen saturation (SpO2) alarm limits on neonatal mortality and morbidity among infants born very preterm. STUDY DESIGN: This was a retrospective cohort study of infants born very preterm in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants were classified based on treatment at a hospital with an SpO2 alarm policy change and study epoch (before vs after policy change). We used a generalized linear mixed model to determine the effect of hospital group and epoch on the primary outcomes of mortality and severe retinopathy of prematurity (ROP) and secondary outcomes of necrotizing enterocolitis, bronchopulmonary dysplasia, and any ROP. RESULTS: There were 3809 infants in 10 hospitals with an SpO2 alarm policy change and 3685 infants in 9 hospitals without a policy change. The nature of most policy changes was to narrow the SpO2 alarm settings. Mortality was lower in hospitals without a policy change (aOR 0.63; 95% CI 0.50-0.80) but did not differ between epochs in policy change hospitals. The odds of bronchopulmonary dysplasia were greater for hospitals with a policy change (aOR 1.65; 95% CI 1.36-2.00) but did not differ for hospitals without a policy change. Severe ROP and necrotizing enterocolitis did not differ between epochs for either group. The adjusted odds of any ROP were lower in recent years in both hospital groups. CONCLUSIONS: Changing SpO2 alarm policies was not associated with reduced mortality or increased severe ROP among infants born very preterm.

Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial.

Importance: Preterm infants must establish regular respirations at delivery. Sustained inflations may establish lung volume faster than short inflations. Objective: To determine whether a ventilation strategy including sustained inflations, compared with standard intermittent positive pressure ventilation, reduces bronchopulmonary dysplasia (BPD) or death at 36 weeks' postmenstrual age without harm in extremely preterm infants. Design, Setting, and Participants: Unmasked, randomized clinical trial (August 2014 to September 2017, with follow-up to February 15, 2018) conducted in 18 neonatal intensive care units in 9 countries. Preterm infants 23 to 26 weeks' gestational age requiring resuscitation with inadequate respiratory effort or bradycardia were enrolled. Planned enrollment was 600 infants. The trial was stopped after enrolling 426 infants, following a prespecified review of adverse outcomes. Interventions: The experimental intervention was up to 2 sustained inflations at maximal peak pressure of 25 cm H2O for 15 seconds using a T-piece and mask (n = 215); standard resuscitation was intermittent positive pressure ventilation (n = 211). Main Outcome and Measures: The primary outcome was the rate of BPD or death at 36 weeks' postmenstrual age. There were 27 prespecified secondary efficacy outcomes and 7 safety outcomes, including death at less than 48 hours. Results: Among 460 infants randomized (mean [SD] gestational age, 25.30 [0.97] weeks; 50.2% female), 426 infants (92.6%) completed the trial. In the sustained inflation group, 137 infants (63.7%) died or survived with BPD vs 125 infants (59.2%) in the standard resuscitation group (adjusted risk difference [aRD], 4.7% [95% CI, -3.8% to 13.1%]; P = .29). Death at less than 48 hours of age occurred in 16 infants (7.4%) in the sustained inflation group vs 3 infants (1.4%) in the standard resuscitation group (aRD, 5.6% [95% CI, 2.1% to 9.1%]; P = .002). Blinded adjudication detected an imbalance of rates of early death possibly attributable to resuscitation (sustained inflation: 11/16; standard resuscitation: 1/3). Of 27 secondary efficacy outcomes assessed by 36 weeks' postmenstrual age, 26 showed no significant difference between groups. Conclusions and Relevance: Among extremely preterm infants requiring resuscitation at birth, a ventilation strategy involving 2 sustained inflations, compared with standard intermittent positive pressure ventilation, did not reduce the risk of BPD or death at 36 weeks' postmenstrual age. These findings do not support the use of ventilation with sustained inflations among extremely preterm infants, although early termination of the trial limits definitive conclusions. Trial Registration: clinicaltrials.gov Identifier: NCT02139800.

Adverse effects of small for gestational age differ by gestational week among very preterm infants.

OBJECTIVE: To characterise the excess risk for death, grade 3-4 intraventricular haemorrhage (IVH), bronchopulmonary dysplasia (BPD) and stage 3-5 retinopathy of prematurity independently associated with birth small for gestational age (SGA) among very preterm infants, stratified by completed weeks of gestation. METHODS: Retrospective cohort study using the Optum Neonatal Database. Study infants were born <32 weeks gestation without severe congenital anomalies. SGA was defined as a birth weight <10th percentile. The excess outcome risk independently associated with SGA birth among SGA babies was assessed using adjusted risk differences (aRDs). RESULTS: Of 6708 infants sampled from 717 US hospitals, 743 (11.1%) were SGA. SGA compared with non-SGA infants experienced higher unadjusted rates of each study outcome except grade 3-4 IVH among survivors. The excess risk independently associated with SGA birth varied by outcome and gestational age. The highest aRD for death (0.27; 95% CI 0.13 to 0.40) occurred among infants born at 24 weeks gestation and declined as gestational age increased. In contrast, the peak aRDs for BPD among survivors (0.32; 95% CI 0.20 to 0.44) and the composites of death or BPD (0.35; 95% CI 0.24 to 0.46) and death or major morbidity (0.35; 95% CI 0.24 to 0.45) occurred at 27 weeks gestation. The risk-adjusted probability of dying or developing one or more of the evaluated morbidities among SGA infants was similar to that of non-SGA infants born approximately 2-3 weeks less mature. CONCLUSION: The excess risk for neonatal morbidity and mortality associated with being born SGA varies by adverse outcome and gestational age.

Association Between Video Laryngoscopy and Adverse Tracheal Intubation-Associated Events in the Neonatal Intensive Care Unit.

The effect of video laryngoscopy on adverse events during neonatal tracheal intubation is unknown. In this single site retrospective cohort study, video laryngoscopy was independently associated with decreased risk for adverse events during neonatal intubation.

Association between prophylactic indomethacin and death or bronchopulmonary dysplasia: A systematic review and meta-analysis of observational studies.

The use of prophylactic indomethacin in very preterm infants is controversial. The last randomized controlled trial (RCT) to study this therapy enrolled infants over 20 years ago. More recently, observational studies have investigated the association between exposure to prophylactic indomethacin and neonatal morbidities and mortality. We performed a systematic review and meta-analysis of these studies for the outcomes of death and bronchopulmonary dysplasia (BPD). Two observational studies involving a total of 11,289 very preterm infants were suitable for meta-analysis. The pooled data showed that prophylactic indomethacin was not associated with higher or lower risk-adjusted odds of death or BPD (0.93, 95% CI: 0.76-1.13) and of BPD among survivors (0.94, 95% CI: 0.78-1.12). However, there was a weak association between indomethacin prophylaxis and decreased risk-adjusted odds of mortality (0.81, 95% CI: 0.66-0.98). It is unknown whether this finding resulted from unmeasured confounding, chance, or represents a true benefit. To confirm the hypothesis that prophylactic indomethacin has a small effect on mortality in the current era, a contemporary RCT would need to enroll over 3500 very immature infants at high risk of death.

Car Seat Tolerance Screening in the Neonatal Intensive Care Unit: Failure Rates, Risk Factors, and Adverse Outcomes.

OBJECTIVE: To characterize the epidemiology of Car Seat Tolerance Screening (CSTS) failure and the association between test failure and all-cause 30-day postdischarge mortality or hospital readmission in a large, multicenter cohort of preterm infants receiving neonatal intensive care. STUDY DESIGN: This retrospective cohort study used the prospectively collected Optum Neonatal Database. Study infants were born at <37 weeks of gestation between 2010 and 2016. We identified independent predictors of CSTS failure and calculated the risk-adjusted odds of all-cause 30-day mortality or hospital readmission associated with test failure. RESULTS: Of 7899 infants cared for in 788 hospitals, 334 (4.2%) failed initial CSTS. Greater postmenstrual age at testing and African American race were independently associated with decreased failure risk. Any treatment with an antacid medication, concurrent use of caffeine or supplemental oxygen, and a history of failing a trial off respiratory support were associated with increased failure risk. The mean adjusted post-CSTS duration of hospitalization was 3.1 days longer (95% CI, 2.7-3.6) among the infants who failed the initial screening. Rates of 30-day all-cause mortality or readmission were higher among infants who failed the CSTS (2.4% vs 1.0%; P = .03); however, the difference was not significant after confounder adjustment (OR, 0.38; 95% CI, 0.11-1.31). CONCLUSION: CSTS failure was associated with longer post-test hospitalization but no difference in the risk-adjusted odds for 30-day mortality or hospital readmission. Whether CSTS failure unnecessarily prolongs hospitalization or results in appropriate care that prevents adverse postdischarge outcomes is unknown. Further research is needed to address this knowledge gap.

The Association between Positive Tracheal Aspirate Cultures and Adverse Pulmonary Outcomes in Preterm Infants with Severe Bronchopulmonary Dysplasia.

Objective Bacterial colonization of the airway may contribute to the development of bronchopulmonary dysplasia. Whether airway colonization increases risk for later adverse respiratory outcomes is less clear. We described tracheal aspirate culture results obtained from preterm infants receiving mechanical ventilation at 36 weeks postmenstrual age (PMA) and evaluated the association between bacteria type and the risk for prolonged supplemental oxygen use. Study Design We conducted a retrospective, single-center cohort study comparing infants (1) with and without a tracheal aspirate culture that grew a Gram-negative rod (GNR) and (2) with and without a culture that grew a Gram-positive cocci (GPC). Results Among 121 infants, 65 (53.7%) and 51 (42.2%) had a tracheal aspirate culture that grew a potentially pathogenic GNR and GPC prior to 36 weeks PMA, respectively. GNR were associated with increased risk for death or use of supplemental oxygen at discharge (adjusted odds ratio [aOR], 6.2; 95% confidence interval [CI], 1.8-21.1), and use of supplemental oxygen at discharge among survivors (aOR, 5.5; 95% CI, 1.6-19.0). GPC did not affect the risk for any study outcomes. Conclusion GNR but not GPC in the airways of preterm infants receiving mechanical ventilation at 36 weeks PMA is associated with increased risk for prolonged supplemental oxygen use.

Sustained Lung Inflation: Physiology and Practice.

Lung aeration is the most critical task newborns must accomplish after birth. Almost all extremely preterm infants require respiratory support during this process, but the best method to promote lung aeration in preterm infants is unknown. The current standard practice is intermittent positive pressure ventilation with positive end-expiratory pressure. Sustained inflation is a promising alternative strategy for lung liquid clearance and aeration. Here we review the physiologic rationale for sustained inflation and the available clinical evidence for sustained inflation in preterm infants.

Evidence-Based Pharmacologic Therapies for Prevention of Bronchopulmonary Dysplasia: Application of the Grading of Recommendations Assessment, Development, and Evaluation Methodology.

Bronchopulmonary dysplasia (BPD) is the most common chronic complication of extreme preterm birth. The authors applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to pharmacologic therapies found to prevent BPD. Caffeine and vitamin A are the only medications shown in high-quality studies to prevent BPD without the risk of clinically important adverse effects. Dexamethasone is effective for the prevention of BPD; but for many infants, the increased risks of hypertrophic cardiomyopathy, gastrointestinal perforation, and cerebral palsy outweigh this benefit. Several medications are currently under investigation for the prevention of BPD, but few are novel agents.

Sustained Aeration of Infant Lungs (SAIL) trial: study protocol for a randomized controlled trial.

BACKGROUND: Extremely preterm infants require assistance recruiting the lung to establish a functional residual capacity after birth. Sustained inflation (SI) combined with positive end expiratory pressure (PEEP) may be a superior method of aerating the lung compared with intermittent positive pressure ventilation (IPPV) with PEEP in extremely preterm infants. The Sustained Aeration of Infant Lungs (SAIL) trial was designed to study this question. METHODS/DESIGN: This multisite prospective randomized controlled unblinded trial will recruit 600 infants of 23 to 26 weeks gestational age who require respiratory support at birth. Infants in both arms will be treated with PEEP 5 to 7 cm H2O throughout the resuscitation. The study intervention consists of performing an initial SI (20 cm H20 for 15 seconds) followed by a second SI (25 cm H2O for 15 seconds), and then PEEP with or without IPPV, as needed. The control group will be treated with initial IPPV with PEEP. The primary outcome is the combined endpoint of bronchopulmonary dysplasia or death at 36 weeks post-menstrual age. TRIAL REGISTRATION: www.clinicaltrials.gov , Trial identifier NCT02139800 , Registered 13 May 2014.