OBJECTIVE: To measure within-subject changes in ventilation/perfusion (V'/Q') mismatch in response to a protocol of individualised nasal continuous positive airway pressure (CPAP) level selection.

DESIGN: Single-arm, non-randomised, feasibility trial.

SETTING: Three centres in the Children's Hospital of Philadelphia neonatal care network.

PATIENTS: Twelve preterm infants of postmenstrual age 27-35 weeks, postnatal age >24 hours, and receiving a fraction of inspired oxygen (FiO) >0.25 on CPAP of 4-7 cm HO.

INTERVENTIONS: We applied a protocol of stepwise CPAP level changes, with the overall direction and magnitude guided by individual responses in V'/Q' mismatch, as determined by the degree of right shift (kilopascals, kPa) in a non-invasive gas exchange model. Best CPAP level was defined as the final pressure level at which V'/Q' improved by more than 5%.

MAIN OUTCOME MEASURES: Within-subject change in V'/Q' mismatch between baseline and best CPAP levels.

RESULTS: There was a median (IQR) within-subject reduction in V'/Q' mismatch of 1.2 (0-3.2) kPa between baseline and best CPAP levels, p=0.02. Best CPAP was observed at a median (range) absolute level of 7 (5-8) cm HO.

CONCLUSIONS: Non-invasive measures of V'/Q' mismatch may be a useful approach for identifying individualised CPAP levels in preterm infants. The results of our feasibility study should be interpreted cautiously and replication in larger studies evaluating the impact of this approach on clinical outcomes is needed.

TRIAL REGISTRATION NUMBER: NCT02983825.

OBJECTIVE: To measure within-subject changes in ventilation/perfusion (V'/Q') mismatch in response to a protocol of individualised nasal continuous positive airway pressure (CPAP) level selection.

DESIGN: Single-arm, non-randomised, feasibility trial.

SETTING: Three centres in the Children's Hospital of Philadelphia neonatal care network.

PATIENTS: Twelve preterm infants of postmenstrual age 27-35 weeks, postnatal age >24 hours, and receiving a fraction of inspired oxygen (FiO) >0.25 on CPAP of 4-7 cm HO.

INTERVENTIONS: We applied a protocol of stepwise CPAP level changes, with the overall direction and magnitude guided by individual responses in V'/Q' mismatch, as determined by the degree of right shift (kilopascals, kPa) in a non-invasive gas exchange model. Best CPAP level was defined as the final pressure level at which V'/Q' improved by more than 5%.

MAIN OUTCOME MEASURES: Within-subject change in V'/Q' mismatch between baseline and best CPAP levels.

RESULTS: There was a median (IQR) within-subject reduction in V'/Q' mismatch of 1.2 (0-3.2) kPa between baseline and best CPAP levels, p=0.02. Best CPAP was observed at a median (range) absolute level of 7 (5-8) cm HO.

CONCLUSIONS: Non-invasive measures of V'/Q' mismatch may be a useful approach for identifying individualised CPAP levels in preterm infants. The results of our feasibility study should be interpreted cautiously and replication in larger studies evaluating the impact of this approach on clinical outcomes is needed.

TRIAL REGISTRATION NUMBER: NCT02983825.

<p><strong>BACKGROUND: </strong>Preterm infants are at risk of lung atelectasis due to various anatomical and physiological immaturities, placing them at high risk of respiratory failure and associated harms. Nasal continuous positive airway pressure (CPAP) is a positive pressure applied to the airways via the nares. It helps prevent atelectasis and supports adequate gas exchange in spontaneously breathing infants. Nasal CPAP is used in the care of preterm infants around the world. Despite its common use, the appropriate pressure levels to apply during nasal CPAP use remain uncertain.</p>

<p><strong>OBJECTIVES: </strong>To assess the effects of 'low' (≤ 5 cm HO) versus 'moderate-high' (&gt; 5 cm HO) initial nasal CPAP pressure levels in preterm&nbsp;infants receiving CPAP either: 1) for initial respiratory support after birth and neonatal resuscitation or 2) following mechanical ventilation and endotracheal extubation.</p>

<p><strong>SEARCH METHODS: </strong>We ran a comprehensive search on 6 November 2020 in the following databases: CENTRAL via CRS Web and MEDLINE via Ovid. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-randomized trials.</p>

<p><strong>SELECTION CRITERIA: </strong>We included RCTs, quasi-RCTs, cluster-RCTs and cross-over RCTs randomizing preterm infants of gestational age &lt; 37 weeks or birth weight &lt; 2500 grams within the first 28 days of life to different nasal CPAP levels.</p>

<p><strong>DATA COLLECTION AND ANALYSIS: </strong>We used the standard methods of Cochrane Neonatal to collect and analyze data. We used the GRADE approach to assess the certainty of the evidence for the prespecified primary outcomes.</p>

<p><strong>MAIN RESULTS: </strong>Eleven trials met inclusion criteria of the review. Four trials were parallel-group RCTs reporting our prespecified primary or secondary outcomes. Two trials randomized 316 infants to low versus moderate-high nasal CPAP for initial respiratory support, and two trials randomized 117 infants to low versus moderate-high nasal CPAP following endotracheal extubation. The remaining seven studies were cross-over trials reporting short-term physiological outcomes. The most common potential sources of bias were absent or unclear blinding of personnel and assessors and uncertain selective reporting. Nasal CPAP for initial respiratory support after birth and neonatal resuscitation None of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta-analysis. No trials reported on moderate-severe neurodevelopmental impairment at 18 to 26 months. The remaining five outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcomes of: death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.56 to 1.85; 1 trial, 271 participants); mortality by hospital discharge (RR 1.04, 95% CI 0.51 to 2.12; 1 trial, 271 participants); BPD at 28 days of age (RR 1.10, 95% CI 0.56 to 2.17; 1 trial, 271 participants); BPD at 36 weeks' PMA (RR 0.80, 95% CI 0.25 to 2.57; 1 trial, 271 participants), and treatment failure or need for mechanical ventilation (RR 1.00, 95% CI 0.63 to 1.57; 1 trial, 271 participants). We assessed the certainty of the evidence as very low for all five outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates. Nasal CPAP following mechanical ventilation and endotracheal extubation One of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta-analysis. On the basis of these data, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcome of treatment failure or need for mechanical ventilation (RR 1.52, 95% CI 0.92 to 2.50; 2 trials, 117 participants; I = 17%; risk difference 0.15, 95% CI -0.02 to 0.32; number needed to treat for an additional beneficial outcome 7, 95% CI -50 to 3). We assessed the certainty of the evidence as very low due to risk of bias, inconsistency across the studies, and imprecise effect estimates. No trials reported on moderate-severe neurodevelopmental impairment at 18 to 26 months or BPD at 28 days of age. The remaining three outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcomes of: death or BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants); mortality by hospital discharge (RR 2.94, 95% CI 0.12 to 70.30; 1 trial, 93 participants), and BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants). We assessed the certainty of the evidence as very low for all three outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates.&nbsp; AUTHORS' CONCLUSIONS: There are insufficient data from randomized trials to guide nasal CPAP level selection in preterm infants, whether provided as initial respiratory support or following extubation from invasive mechanical ventilation. We are uncertain as to whether low or moderate-high nasal CPAP levels improve morbidity and mortality in preterm infants. Well-designed trials evaluating this important aspect of a commonly used neonatal therapy are needed.</p>

<p><strong>OBJECTIVES: </strong>To measure between-center variation in loop diuretic use for infants developing severe bronchopulmonary dysplasia (BPD) in United States children's hospitals, and to compare mortality and age at discharge among infants from low versus high use centers.</p>

<p><strong>STUDY DESIGN: </strong>We performed a retrospective cohort study of preterm infants &lt;32 weeks gestational age developing severe BPD. The primary outcome was cumulative loop diuretic use, defined as the proportion of days with exposure between admission and discharge. Infant characteristics associated with loop diuretic use at P &lt; .10 were included in multivariable models to adjust for center differences in case-mix. Hospitals were ranked from lowest to highest in adjusted use, and dichotomized into low or high use centers. We then compared mortality and postmenstrual age at discharge between groups through multivariable analyses.</p>

<p><strong>RESULTS: </strong>We identified 3252 subjects from 43 centers. Significant variation between centers remained despite adjustment for infant characteristics, with use present in an adjusted mean range of 7.3% to 49.4% of days, p &lt; 0.0001. Mortality (adjusted odds ratio 0.98 [95% CI 0.62, 1.53], p = 0.92) and postmenstrual age at discharge (marginal mean [95% CI]: 47.3 [46.8 , 47.9] versus 47.4 [46.9, 47.9] weeks, p = 0.96) were similar in low and high use groups, respectively.</p>

<p><strong>CONCLUSIONS: </strong>Marked variation in loop diuretic use for infants developing severe BPD exists between US children's hospital, without an observed difference on mortality or discharge age. Research to provide evidence-based guidance for this common exposure is needed.</p>

<p><strong>OBJECTIVE: </strong>Compare rates of hypoxaemia during transpyloric and gastric feedings in very preterm infants with severe bronchopulmonary dysplasia.</p>

<p><strong>DESIGN: </strong>N-of-1 multiple crossover trials with individual patient and pooled data analyses.</p>

<p><strong>SETTING: </strong>Level IV intensive care nursery.</p>

<p><strong>PATIENTS: </strong>Infants receiving positive airway pressure between 36 and 55 weeks postmenstrual age were enrolled between December 2014-July 2016.</p>

<p><strong>INTERVENTION: </strong>N-of-1 trial consisting of two blocks, each with a 4-day gastric and 4-day transpyloric feeding period assigned in random order.</p>

<p><strong>MAIN OUTCOME MEASURES: </strong>The primary outcome was the frequency of daily intermittent hypoxaemic events (SpO ≤80% lasting 10-180 s). Secondary outcomes included the daily proportion of time with an SpO ≤80% and mean daily fraction of inspired oxygen.</p>

<p><strong>RESULTS: </strong>Of 15 infants, 13 completed the trial and 2 stopped early for transient worsening in respiratory status during gastric feedings. In the intention-to-treat analyses, transpyloric feedings resulted in increased rates of intermittent hypoxaemia in five infants, greater time per day in hypoxaemia in three infants and more supplemental oxygen use in three infants. One infant received more supplemental oxygen during gastric feedings. The remaining study outcomes were similar between the feeding routes in all other infants. Pooling all data, transpyloric feedings resulted in a higher frequency of intermittent hypoxaemic events (median 7.5/day (IQR 1-23.5) vs 3/day (1-11); adjusted incidence rate ratio 1.8, 95% CI 1.3 to 2.5) and a greater proportion of daily hypoxaemia time (median 0.8% (IQR 0.1-2.3) vs 0.4% (0.07-1.8); adjusted mean difference 1.6, 95% CI 1.1 to 2.5).</p>

<p><strong>CONCLUSIONS: </strong>Transpyloric compared with gastric feedings modestly increased rates of hypoxaemia among study participants.</p>

<p><strong>TRIAL REGISTRATION NUMBER: </strong>NCT02142621.</p>

<p>Reducing the risk of primary noninvasive ventilation failure in extremely low birthweight infants is linked to reducing bronchopulmonary dysplasia. In a secondary analysis of randomized data, we identified that failure rates and time to failure were similar for nasal intermittent positive pressure ventilation vs nasal continuous positive airway pressure.</p>

<p>Differences in preterm birth rates between black and white women are the largest contributor to racial disparities in infant mortality. In today's age of precision medicine, analysis of the genome, epigenome, metabolome, and microbiome has generated interest in determining whether these biomarkers can help explain racial disparities. We propose that there are pitfalls as well as opportunities when using precision medicine analyses to interrogate disparities in health. To conclude that racial disparities in complex conditions are genetic in origin ignores robust evidence that social and environmental factors that track with race are major contributors to disparities. Biomarkers measured in omic assays that may be more environmentally responsive than genomics, such as the epigenome or metabolome, may be on the causal pathway of race and preterm birth, but omic observational studies suffer from the same limitations as traditional cohort studies. Confounding can lead to false conclusions about the causal relationship between omics and preterm birth. Methodological strategies (including stratification and causal mediation analyses) may help to ensure that associations between biomarkers and exposures, as well as between biomarkers and outcomes, are valid signals. These epidemiologic strategies present opportunities to assess whether precision medicine biomarkers can uncover biology underlying perinatal health disparities.</p>

<p><strong>OBJECTIVE: </strong>To identify the number of cumulative medication exposures and most frequently used medications in infants with severe BPD.</p>

<p><strong>STUDY DESIGN: </strong>We performed a retrospective cohort study in infants with severe BPD admitted to United States children's hospitals. We measured cumulative medication exposures in individual subjects and between-center variation after adjustment for infant characteristics. We then identified the specific medications and therapeutic classes with the highest rates of use.</p>

<p><strong>RESULTS: </strong>In 3252 subjects across 43 hospitals, we identified a median (interquartile range) of 30 (17-45) cumulative medication exposures per infant. The adjusted mean number of medication exposures varied between centers (p &lt; 0.0001), with a range of 22-50. Diuretics and furosemide were the most frequently prescribed therapeutic class and specific medication for the management of severe BPD.</p>

<p><strong>CONCLUSIONS: </strong>Infants with severe BPD are exposed to alarming number of medications of unclear efficacy and safety, with marked variation between center.</p>

<p><strong>RATIONALE: </strong>Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, nor adequately predict childhood morbidity.</p>

<p><strong>OBJECTIVE: </strong>To determine which of 18 pre-specified, revised definitions of bronchopulmonary dysplasia, that variably define disease presence and severity according to the level of respiratory support and supplemental oxygen administered at 36 weeks postmenstrual age, best predicts death or serious respiratory morbidity through 18-26 months corrected age.</p>

<p><strong>METHODS: </strong>We assessed infants born &lt;32 weeks' gestation between 2011-2015 at 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network.</p>

<p><strong>RESULTS: </strong>Of 2677 infants, 683 (26%) died or developed serious respiratory morbidity. The criteria that best predicted this outcome defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks postmenstrual age, irrespective of prior or current oxygen therapy: no bronchopulmonary dysplasia, no support (n=773); grade 1, nasal cannula ≤2L/min (n=1038); grade 2, nasal cannula &gt;2L/min or non-invasive positive airway pressure (n=617); and grade 3, invasive mechanical ventilation (n=249). These criteria correctly predicted death or serious respiratory morbidity in 81% of study infants. Rates of this outcome increased stepwise from 10% among infants without bronchopulmonary dysplasia to 77% among those with grade 3 disease. A similar gradient (33%-79%) was observed for death or neurodevelopmental impairment.</p>

<p><strong>CONCLUSIONS: </strong>The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support at 36 weeks postmenstrual age, irrespective of supplemental oxygen use. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial License 4.0 (http://creativecommons.org/licenses/by-nc/4.0/).</p>