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ObjectiveTo 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.DesignSingle-arm, non-randomised, feasibility trial.SettingThree centres in the Children’s Hospital of Philadelphia neonatal care network.PatientsTwelve preterm infants of postmenstrual age 27–35 weeks, postnatal age >24 hours, and receiving a fraction of inspired oxygen (FiO2) >0.25 on CPAP of 4–7 cm H2O.InterventionsWe 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 measuresWithin-subject change in V′/Q′ mismatch between baseline and best CPAP levels.ResultsThere 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 H2O.ConclusionsNon-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 numberNCT02983825.

Introduction Lung biopsy is infrequently utilized in the population of infants with severe bronchopulmonary dysplasia (BPD). Yet, its presentation may overlap with other infant diffuse lung diseases, including those within the spectrum of childhood interstitial lung diseases (chILD). Lung biopsy might differentiate between these entities, or discern those with an extremely poor prognosis. Both might alter the clinical management of a subset of infants diagnosed with BPD. Methods In this tertiary referral center, we drew on a retrospective cohort of 306 preterm infants with severe BPD. Of these, nine underwent lung biopsy between 2012 and 2017. Our aim was to assess the indication of lung biopsy, the prior clinical history, safety of the procedure, and describe the biopsy findings. Finally, we considered management decisions in relation to the biopsy results in these patients. Results The average gestational age and birth weight of the 9 patients were 30±3 (range 27-34) weeks and 1421±571 (range 611-2140) grams. All infants had serial echocardiograms to assess for pulmonary hypertension, genetic testing, and computed tomography angiography (CTA) prior to biopsy. All patients showed moderate to severe alveolar simplification and 8 had some degree of pulmonary interstitial glycogenosis (PIG) ranging from focal to diffuse. Following biopsy, 2 infants with findings of PIG received high dose systemic steroids and 2 separate infants had care redirected. Conclusion In our cohort, lung biopsy was safe and well tolerated. Findings from lung biopsy may aid decision making in selected patients when used as a part of a step-wise diagnostic algorithm.

ObjectiveSurvival rates of extremely premature infants are rising, but changes in neurodevelopmental impairment (NDI) rates are unclear. Our objective was to perform a systematic review of intrainstitutional variability of NDI over time.DesignSystematic review and meta-analysis.Data sourcesOvid MEDLINE, Embase, PubMed, Cochrane Library and Google Scholar.Study selectionStudy eligibility: (1) at least two discrete cohorts of infants born Main outcomeChange in NDI rates. Quality, validity and bias were assessed using Grading of Recommendations, Assessment, Development, and Evaluation and Quality in Prognosis Studies guidelines.ResultsOf 203 publications, 15 were eligible, including 13 229 infants. At the first time point, average NDI rate across study groups weighted by sample size was 41.0% (95% CI 34.0% to 48.0%). The average change in NDI between time points was −3.3% (95% CI −8·8% to 2.2%). For each added week of gestation at birth, the rate of NDI declined by 9.7% (95% CI 6.2% to 13.3%). Most studies exhibited moderate–severe bias in at least one domain, especially attrition rates.ConclusionsWhen comparing discrete same-centre cohorts over time, there was no significant change in NDI rates in infants born

Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia.We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity.A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively.In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).

Extreme prematurity is associated with an increased risk to develop bronchopulmonary dysplasia (BPD). Severe BPD is associated with a significant long-term burden for the affected infant, families and society. Currently there are limited prevention and treatment options. Regenerative approaches using mesenchymal stromal cells (MSC) are associated with promising benefits in animal experiments. First clinical studies, using MSC in humans, suggest safety. To accelerate the process of bench to bed-side development of MSC-based therapies, a global and collaborative approach is needed that includes all key stakeholders. Results of a workshop that was held during the Pediatric Academic Societies meeting in 2019 are summarized. A roadmap is provided discussing next steps of bringing MSC-based interventions into clinical practice.

IntroductionLow pressure nasal continuous positive airway pressure (nCPAP) has long been the mainstay of non-invasive respiratory support for preterm neonates, at a constant distending pressure of 5–8 cmH2O. When traditional nCPAP pressures are insufficient, other modes including nasal intermittent positive pressure ventilation (NIPPV) are used. In recent years, high nCPAP pressures (≥9 cmH2O) have also emerged as an alternative. However, the comparative benefits and risks of these modalities remain unknown.Methods and analysisIn this multicentre pilot randomised controlled trial, infants Ethics and disseminationThe trial has been approved by the respective research ethics boards at each institution (McMaster Children’s Hospital: Hamilton integrated REB approval #2113; Royal Alexandra Hospital: Health Research Ethics Board approval ID Pro00090244; Westmead Hospital: Human Research Ethics Committee approval ID 2022/ETH01343). Written, informed consent will be obtained from all parents/guardians prior to study enrolment. The findings of this pilot study will be disseminated via presentations at national and international conferences and via publication in a peer-reviewed journal. Social media platforms including Twitter will also be used to generate awareness.Trial registration numberNCT03512158.

In 2019, 2.4 million neonates (infants

BACKGROUND: 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. OBJECTIVES: To assess the effects of 'low' (≤ 5 cm H(2)O) versus 'moderate‐high' (> 5 cm H(2)O) initial nasal CPAP pressure levels in preterm infants receiving CPAP either: 1) for initial respiratory support after birth and neonatal resuscitation or 2) following mechanical ventilation and endotracheal extubation. SEARCH METHODS: 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. SELECTION CRITERIA: We included RCTs, quasi‐RCTs, cluster‐RCTs and cross‐over RCTs randomizing preterm infants of gestational age < 37 weeks or birth weight < 2500 grams within the first 28 days of life to different nasal CPAP levels. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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(2) = 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. 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.

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 .

Introduction: Approximately, one in ten infants is born preterm or requires hospitalization at birth. These complications at birth have long-term consequences that can extend into childhood and adulthood. Timely detection of developmental delay through surveillance could enable tailored support for these babies and their families. However, the possibilities for follow-up are limited, especially in middle- and low-income countries, and the tools to do so are either not available or too expensive. A standardized and core set of outcomes for neonates, with feasible tools for evaluation and follow-up, could result in improving quality, enhance shared decision-making, and enable global benchmarking. Methods: The International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group, which was comprised of 14 health-care professionals (HCP) and 6 patient representatives in the field of neonatal care. An outcome set was developed using a three-round modified Delphi process, and it was endorsed through a patient representative-validation survey and an HCP survey. Results: A literature review revealed 1,076 articles and 26 registries which were screened for meaningful outcomes, patient-reported outcome measures, clinical measures, and case mix variables. This resulted in a neonatal set with 21 core outcomes covering three domains (physical, social, and mental functioning) and 14 tools to assess these outcomes at three timepoints. Discussion: This set can be implemented globally and it will allow comparison of outcomes across different settings and countries. The transparent consensus-driven development process which involved stakeholders and professionals from all over the world ensures global relevance.

Extremely low birth weight (ELBW) infants are at risk for end-organ hypoxia and ischemia. Regional tissue oxygenation of the brain and gut as monitored with near-infrared spectroscopy (NIRS) may change with postnatal age, but normal ranges are not well defined.A prospective study of ELBW preterm infants utilized NIRS monitoring to assess changes in cerebral and mesenteric saturation (Csat and Msat) over the first week after birth. This secondary study of a multicenter trial comparing hemoglobin transfusion thresholds assessed cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE) and relationships with perinatal variables.In 124 infants, both Csat and Msat declined over the first week, with a corresponding increase in oxygen extraction. With lower gestational age, lower birth weight, and 5-min Apgar score ≤5, there was a greater increase in oxygen extraction in the brain compared to the gut. Infants managed with a lower hemoglobin transfusion threshold receiving ≥2 transfusions in the first week had the lowest Csat and highest cFTOE (p 0.001).Brain oxygen extraction preferentially increased in more immature and anemic preterm infants. NIRS monitoring may enhance understanding of cerebral and mesenteric oxygenation patterns and inform future protective strategies in the preterm ELBW population.Simultaneous monitoring of cerebral and mesenteric tissue saturation demonstrates the balance of oxygenation between preterm brain and gut and may inform protective strategies. Over the first week, oxygen saturation of the brain and gut declines as oxygen extraction increases. A low hemoglobin transfusion threshold is associated with lower cerebral saturation and higher cerebral oxygen extraction compared to a high hemoglobin transfusion threshold, although this did not translate into clinically relevant differences in the TOP trial primary outcome. Greater oxygen extraction by the brain compared to the gut occurs with lower gestational age, lower birth weight, and 5-min Apgar score ≤5.

Rationale: Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, and do not adequately predict childhood morbidity. Objectives: To determine which of 18 prespecified, revised definitions of bronchopulmonary dysplasia that variably define disease 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. Methods: We assessed infants born at less than 32 weeks of gestation between 2011 and 2015 at 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Measurements and Main Results: Of 2,677 infants, 683 (26%) died or developed serious respiratory morbidity. The diagnostic criteria that best predicted this outcome defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks’ postmenstrual age, regardless of prior or current oxygen therapy: no bronchopulmonary dysplasia, no support (n = 773); grade 1, nasal cannula ≤2 L/min (n = 1,038); grade 2, nasal cannula >2 L/min or noninvasive 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. Conclusions: The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support administered at 36 weeks’ postmenstrual age, regardless of supplemental oxygen use.

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.

Rationale Infants with severe bronchopulmonary dysplasia (sBPD) and airway obstruction may develop dynamic hyperinflation and intrinsic positive end-expiratory pressure (PEEPi ), which impairs patient/ventilator synchrony. Objectives To determine if PEEPi is present in infants with sBPD during spontaneous breathing and if adjusting ventilator PEEP improves patient/ventilator synchrony and comfort. Methods Interventional study in infants with sBPD. PEEPi measured by esophageal pressure (Pes) and pneumotachometer, during pressure-supported breaths. PEEP i defined as the difference between Pes at start of the inspiratory effort minus Pes at onset of inspiratory flow. The set PEEP was adjusted to minimize PEEP i . "Best PEEP" was the setting with minimal wasted efforts (WE), an inspiratory effort seen on the Pes waveform without a corresponding ventilator breath. FiO 2 and SpO 2 measured pre- and post-PEEP adjustment. Sedation requirements evaluated 72 hours preprocedure and postprocedure. Results Twelve infants were assessed (gestational age, 24.9 ± 1.4 weeks; study age, 48.8 ± 1.5 weeks, postmenstrual age). Mean baseline ventilator PEEP was 16.4 cm H2 O (14-20 cm H 2 O). Eight infants required an increase, one, a reduction, and three, no change in the set PEEP. For the eight infants requiring an increase in set PEEP, there was an 18.9% reduction in WE and a reduction in FiO 2 (0.084 ± 0.058) requirements in the subsequent 24 hours. Conditional sedation was reduced in five infants postprocedure. No adverse events occurred during testing. Conclusion PEEPi is measurable in infants with sBPD with concurrent esophageal manometry and flow-time tracings without the need for pharmacological paralysis. In those with PEEP i , increasing ventilator PEEP to offset PEEP i improves synchrony.

Objective To assess parents' views of their children's health-related quality of life (HRQoL) and the association between neonatal morbidities and HRQoL in children with severe bronchopulmonary dysplasia (BPD) who survived to 18-36 months of corrected age. Study Design Study population included infants born Results Seventy children (67% male, gestational age 26.1 ± 2.0 weeks, and birth weight 797 ± 318g) were enrolled at 27.1 ± 5.8 months of corrected age. Mean PHY-QoL and PS-QoL were 78.0 ± 21.9 and 75.3 ± 17.9, respectively, both significantly lower than reported means for term and preterm cohorts, with the exception of emotional QoL. Adjusted postnatal composite morbidity score was cumulatively associated with poorer PHY-QoL (P = .002) and poorer PS-QoL (P = .015). Presence of each additional neonatal morbidity was associated with a 4.4-point decrease in PHY-QoL and 2.8-point decrease in PS-QoL. Conclusions In this cohort, parental perceived HRQoL for their child with severe BPD was lower than expected for term and preterm populations. Neonatal morbidities had an additive association with poorer parental assessment of PHY-QoL and PS-QoL. These findings may aid in care of children with severe BPD and their families, both in the intensive care nursery and postdischarge.

The infant mortality rate in USA exceeds that of most other developed nations, ranking 26th among Organisation for Economic Co-operation and Development countries.1 Non-Hispanic black infants in USA die more than twice as often as non-Hispanic white infants (11.4 vs 4.9 per 1000 live births).2 This disparity reflects disparities in preterm birth (PTB) rates, since two-thirds of infant mortality occurs in preterm infants.3 The PTB rate is 52% higher for black (13.8%) than white (9.0%) women. Efforts to reduce PTB and its disparities have failed (figure 1). We propose that racial disparities in PTB are a cumulative biosensor of exposures that vary by race, arising from long-standing inequities. Figure 1 Black-white disparities in preterm birth over 10 years in USA.64 65 RR, relative risk. ### PTB disparities are not due to genetic sequence variation between racial groups While some monogenic diseases track (incompletely) with race, such as sickle cell anaemia and cystic fibrosis, the vast majority of health conditions cannot be mapped to genetic variation between racial groups. Most human genetic variation is found within ancestral groups with only 5%–10% of gene frequencies differing between ancestral groups.4 Nonetheless, different frequencies of single nucleotide polymorphisms (SNPs) by race have led some investigators to search for genetic differences that cause racial disparities in PTB. However, SNPs explain an exceedingly small portion of PTB risk, and are often not replicated.5 6 Some strong evidence supports that disparities in birth outcomes are largely attributable to environmental, as opposed to genetic variation. One example is the phenomenon of erosion of immigrant health over generations. Birth weight (BWT) distributions of infants born to African-born black women and US-born white women nearly overlap, whereas infants born to US-born black women were substantially smaller.7 Indeed in a study of 27 states’ births in 2008, foreign-born black women had significantly lower odds of PTB than US-born black women even …

Background: Premature infants with severe bronchopulmonary dysplasia (sBPD) are at risk of pulmonary hypertension (PH). Serum brain natriuretic peptide (BNP) is used to predict disease severity in adult PH. Its diagnostic utility in sBPD-associated PH is unknown. Objective: The aim of this paper was to determine the accuracy of BNP, against echocardiogram (echo), to diagnose PH in infants born Methods: We conducted a retrospective cohort study of all infants with sBPD with an echo and BNP within a 24-h period, at ≥36 weeks postmenstrual age. PH was defined as: right ventricular pressure >½ systemic blood pressure estimated from tricuspid regurgitant jet or patent ductus arteriosus (PDA) velocity, bidirectional or right-to left-PDA, and/or flat/bowing ventricular septum at end-systole. Receiver-operating characteristic (ROC) curves were constructed to test the diagnostic accuracy of BNP. Results:Of 128 infants, 68 (53%) had echo evidence of PH. BNP was higher among the infants with PH (median [interquartile range]: 127 pg/mL [39–290] vs. 35 [20–76], p < 0.001). The area under the ROC curve for diagnosing PH using BNP was 0.74 (95% CI 0.66–0.83). At an optimal cutpoint of 130 pg/mL, BNP correctly classified the presence or absence of PH in 70% of the infants (specificity: 92, sensitivity: 50%). Conclusions: BNP, relative to concurrent echo, demonstrated moderate accuracy for diagnosing PH in this cohort of preterm infants with sBPD. BNP may help rule in PH in this population but has low utility to rule out the disease.

Currently the question of whether to maintain a higher hemoglobin level by transfusing more liberally, as opposed to a more restrictive strategy with lower hemoglobin maintenance levels, has not been answered. We review summarized conclusions of a Cochrane systematic review and meta-analysis of 614 infants in 4 randomized controlled trials (RCT) pooling data. This suggests potential benefits of higher hemoglobin levels, i.e., a possible improved cognition of infants at 18–21 months’ corrected age and a reduction of apnea. However, the data on cognition is hypothesis generating as it derives from a post hoc analysis from a single trial in 451 infants. Moreover, the data on apnea need confirmation in larger trials. The effect of adding data of cognitive 2-year outcomes of 1,744 infants from 2 RCT, which will be reported soon, should expand our understanding. This new data will need to be integrated with the older generation of RCTs but also with emerging suggestions from observational data on potential risks of blood transfusions. We discuss some of these warnings from observational studies. Finally, we ask whether we are ready to individualize blood transfusion to physiological measures made in individual infants, and we point to some current difficulties hindering this step.

Currently the question of whether to maintain a higher hemoglobin level by transfusing more liberally, as opposed to a more restrictive strategy with lower hemoglobin maintenance levels, has not been answered. We review summarized conclusions of a Cochrane systematic review and meta-analysis of 614 infants in 4 randomized controlled trials (RCT) pooling data. This suggests potential benefits of higher hemoglobin levels, i.e., a possible improved cognition of infants at 18-21 months' corrected age and a reduction of apnea. However, the data on cognition is hypothesis generating as it derives from a post hoc analysis from a single trial in 451 infants. Moreover, the data on apnea need confirmation in larger trials. The effect of adding data of cognitive 2-year outcomes of 1,744 infants from 2 RCT, which will be reported soon, should expand our understanding. This new data will need to be integrated with the older generation of RCTs but also with emerging suggestions from observational data on potential risks of blood transfusions. We discuss some of these warnings from observational studies. Finally, we ask whether we are ready to individualize blood transfusion to physiological measures made in individual infants, and we point to some current difficulties hindering this step.

OBJECTIVES Overnight physician staffing in the ICU has been recommended by the Society of Critical Care Medicine and the Leapfrog Consortium. We conducted a survey to review practice in the current era and to compare this with results from a 2006 survey. DESIGN Cross-sectional survey. SETTING Canadian adult ICUs. PARTICIPANTS ICU directors. INTERVENTIONS None. MEASUREMENT AND MAIN RESULTS A 29-question survey was sent to ICU directors describing overnight staffing by residents, fellows, nurse practitioners, and staff physicians, as well as duty duration, clinical responsibilities, and unit characteristics. We established contact with 122 ICU directors, of whom 107 (88%) responded. Of the 107 units, 60 (56%) had overnight in-house physicians. Compared with ICUs without overnight in-house physician coverage, ICUs with in-house physicians were in larger hospitals (p < 0.0001), had more beds (p < 0.0001), had more ventilated patients (p < 0.0001), and had more admissions (p < 0.0001). Overnight in-house physicians were first year residents (R1) in 20 of 60 (33%), second to fifth year residents (R2-R5) in 46 of 60 (77%), and Critical Care Medicine trainees in 19 of 60 (32%). Advanced practice nurses provided overnight coverage in four of 107 ICUs (4%). The most senior in-house physician was a staff physician in 12 of 60 ICUs (20%), a Critical Care Medicine trainee in 14 of 60 (23%), and a resident (R2-R5) in 20 of 60 (33%). The duration of overnight duty was on average 20-24 hours in 22 of 46 units (48%) with R2-R5 residents and 14 of 19 units (74%) covered by Critical Care Medicine trainees. CONCLUSIONS Variability of in-house overnight physician presence in Canadian adult ICUs is linked to therapeutic complexity and unit characteristics and has not changed significantly over the decade since our 2006 survey. Additional evidence about patient and resident outcomes would better inform decisions to revise physician scheduling in Canadian ICUs.

OBJECTIVES: To evaluate the survival and neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants at 18 to 26 months with early hypoxemic respiratory failure (HRF). We also assessed whether African American infants with early HRF had improved outcomes after exposure to inhaled nitric oxide (iNO). METHODS: ELBW infants ≤1000 g and gestational age ≤26 weeks with maximal oxygen ≥60% on either day 1 or day 3 were labeled as “early HRF” and born between 2007 and 2015 in the Neonatal Research Network were included. Using a propensity score regression model, we analyzed outcomes and effects of exposure to iNO overall and separately by race. RESULTS: Among 7639 ELBW infants born ≤26 weeks, 22.7% had early HRF. Early HRF was associated with a mortality of 51.3%. The incidence of moderate-severe NDI among survivors was 41.2% at 18 to 26 months. Mortality among infants treated with iNO was 59.4%. Female sex (adjusted odds ratio [aOR]: 2.4, 95% confidence interval [CI]: 1.8–3.3), birth weight ≥720 g (aOR: 2.3, 95% CI: 1.7–3.1) and complete course of antenatal steroids (aOR: 1.6, 95% CI: 1.1–2.2) were associated with intact survival. African American infants had a similar incidence of early HRF (21.7% vs 23.3%) but lower exposure to iNO (16.4% vs 21.6%). Among infants with HRF exposed to iNO, intact survival (no death or NDI) was not significantly different between African American and other races (aOR: 1.5, 95% CI: 0.6–3.6). CONCLUSIONS: Early HRF in infants ≤26 weeks’ gestation is associated with high mortality and NDI at 18 to 26 months. Use of iNO did not decrease mortality or NDI. Outcomes following iNO exposure were not different in African American infants.

Importance Most preterm infants require respiratory support to establish lung aeration after birth. Intermittent positive pressure ventilation and continuous positive airway pressure are standard therapies. An initial sustained inflation (inflation time >5 seconds) is a widely practiced alternative strategy. Objective To conduct a systematic review and meta-analysis of sustained inflation vs intermittent positive pressure ventilation and continuous positive airway pressure for the prevention of hospital mortality and morbidity for preterm infants. Data Sources MEDLINE (through PubMed), Embase, the Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Central Register of Controlled Trials were searched through June 24, 2019. Study Selection Randomized clinical trials of preterm infants born at less than 37 weeks’ gestation that compared sustained inflation (inflation time >5 seconds) vs standard resuscitation with either intermittent positive pressure ventilation or continuous positive airway pressure were included. Studies including other cointerventions were excluded. Data Extraction and Synthesis Two reviewers assessed the risk of bias of included studies. Meta-analysis of pooled outcome data used a fixed-effects model specific to rarer events. Subgroups were based on gestational age and study design (rescue vs prophylactic sustained inflation). Main Outcomes and Measures Death before hospital discharge. Results Nine studies recruiting 1406 infants met inclusion criteria. Death before hospital discharge occurred in 85 of 736 infants (11.5%) treated with sustained inflation and 62 of 670 infants (9.3%) who received standard therapy for a risk difference of 3.6% (95% CI, −0.7% to 7.9%). Although analysis of the primary outcome identified important heterogeneity based on gestational age subgroups, the 95% CI for the risk difference included 0 for each individual gestational age subgroup. There was no difference in the primary outcome between subgroups based on study design. Sustained inflation was associated with increased risk of death in the first 2 days after birth (risk difference, 3.1%; 95% CI, 0.9%-5.3%). No differences in the risk of other secondary outcomes were identified. The quality-of-evidence assessment was low owing to risk of bias and imprecision. Conclusions and Relevance There was no difference in the risk of the primary outcome of death before hospital discharge, and there was no evidence of efficacy for sustained inflation to prevent secondary outcomes. These findings do not support the routine use of sustained inflation for preterm infants after birth.

ObjectiveTo identify sociodemographic and clinical factors associated with withholding or withdrawing life-sustaining treatment (WWLST) for extremely low gestational age neonates.DesignObservational study of prospectively collected registry data from 19 National Institute of Child Health and Human Development Neonatal Research Network centres on neonates born at 22–28 weeks gestation who died >12 hours through 120 days of age during 2011–2016. Sociodemographic and clinical factors were compared between infants who died following WWLST and without WWLST.ResultsOf 1168 deaths, 67.1% occurred following WWLST. Withdrawal of assisted ventilation (97.4%) was the primary modality. WWLST rates were inversely proportional to gestational age. Life-sustaining treatment was withheld or withdrawn more often for non-Hispanic white infants than for non-Hispanic black infants (72.7% vs 60.4%; 95% CI 1.00 to 1.92) or Hispanic infants (72.7% vs 67.2%; 95% CI 1.32 to 3.72). WWLST rates varied across centres (38.6–92.6%; pConclusionsAmong infants who died, WWLST rates varied widely across centres and were associated with gestational age, race, ethnicity, necrotiing enterocolitis, and severe brain injury. Further exploration is needed into how race, centre, and approaches to care of infants with necrotiing enterocolitis and severe brain injury influence WWLST.

Continuous positive airway pressure (CPAP), noninvasive intermittent positive pressure ventilation (NIPPV), heated humidified high flow nasal cannula (HHFNC), and noninvasive high-frequency ventilation (nHFV) are modes of noninvasive respiratory support (NRS) used in clinical practice. We describe results of an umbrella review, conducted using standard methods for meta-analysis, of the association between NRS use and bronchopulmonary dysplasia (BPD). The use of CPAP with or without intubated surfactant and extubate (INSURE) procedure reduced the risk of BPD compared to mechanical ventilation (risk difference (RD), –0.06; confidence interval (CI) –0.11 to –0.01; number needed to treat (NNT), 17). Synchronized-NIPPV as initial or post extubation support reduced the risk of BPD compared to CPAP (RD, –0.11; CI, –0.19 to –0.04; NNT, 9 and RD, –0.15; CI, –0.28 to –0.02; NNT, 7, respectively. Nonsynchronized-NIPPV reduced BPD risk when used post extubation support compared to CPAP (RD, –0.12; CI, –0.22 to –0.01; NNT 8).

Background: It is unknown whether observational studies comparing laparotomy versus peritoneal drainage for surgical treatment of necrotizing enterocolitis (NEC) in preterm infants differ from rand...

OBJECTIVES: This study tested the hypothesis that longer duration of any type of respiratory support is associated with an increased rate of death or neurodevelopmental impairment (NDI) at 18–22 months. METHODS: Retrospective cohort study using the Generic Database of NICHD Neonatal Research Network from 2006 to 2010. Infants were born at

Aim To assess in children with severe bronchopulmonary dysplasia at a corrected age of 18-36 months: (i) Neonatal follow-up clinic attendance rates; (ii) Parent-identified reasons for difficulty attending neonatal follow-up. Methods Mixed methods study utilising semi-structured phone interviews with parents of infants eligible for follow-up with severe bronchopulmonary dysplasia (defined as gestational age 2 L nasal cannula at 36 weeks post-menstrual age) at 18-36 months corrected age. Questions addressed barriers to neonatal follow-up attendance. Enrolment continued to saturation (no new themes emerging). Results A total of 58 infants (69% male) were enrolled. Infants were 26 ± 2.1 weeks gestational age and birth weight 794 ± 262 g. At 28 ± 5.8 months corrected age, 26% had never attended neonatal follow-up clinic, 16% stopped attending before discharge, 5% were discharged, and 53% were still followed. Longer travel distance from home to follow-up clinic was associated with poorer attendance. Parent-generated items related to neonatal follow-up barriers were coded into four themes: Logistics, Time, Perceptions and Emotional Stress. Conclusion Despite high risk of developmental delay in infants with severe bronchopulmonary dysplasia, neonatal follow-up rates are suboptimal. Careful review of parent-identified barriers could be utilised to develop targeted strategies to improve neonatal follow-up attendance in this high-risk population.

Objective To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants. Study design Previously generated GWA data from the Neonatal Research Network9s anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1.2 million single-nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. p Values and false discovery rates (FDRs) were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p −5 . Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points. Results Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10 −8 ); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram-positive sepsis), RALA, IMMP2L (Gram-negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram-negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and interleukin-1-associated receptor kinase 2 (p values Conclusions No SNPs met genome-wide significance in this cohort of extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified.

Objective To describe the pharmacokinetics and pharmacodynamics of milrinone in infants with persistent pulmonary hypertension of the newborn (PPHN) and to explore the impact of age on milrinone disposition. Design Randomized, open label pilot study. Setting Multicenter; level 3 and level 4 neonatal intensive care units. Patients Six infants ≥34 weeks' gestational age and Intervention Intravenous milrinone lactate in one of two dosing regimens: (1) low dose, 20 mcg/kg bolus followed by 0.2 mcg/kg/minute, and (2) standard dose, 50 mcg/kg bolus followed by 0.5 mcg/kg/minute. Measurements and Main Results The final structural model was a two-compartment disposition model with interindividual variability estimated on clearance (CL). The estimated value of CL is 7.65 mL/minute/3.4 kg (3.05 mL/minute/kg). The addition of age improved the precision of the CL estimate, and CL increased with chronological age in days. The oxygenation index was highly variable within each participant and improved with time. There were no observed safety concerns in either dosing group. Conclusion The CL of milrinone in newborns with PPHN is reduced and increases with age. In this pilot study, we did not see significant pharmacodynamic or safety effects associated with drug exposure.

This article explores the validity of the Sustained Aeration Inflation for Infant Lungs (SAIL) randomized controlled clinical trial. The SAIL trial enrolled 460 infants out of a planned 600, but the trial was stopped early for harm. We ask here, whether there were any threats to validity in the trial as conducted. We then explore what design elements of the trial could have been improved upon. Finally, we consider what the implications are for future trials in this arena. Clinical Trial Registration: www.clinicaltrials.gov, Identifier: NCT02139800.

Objectives To compare the number of intermittent hypoxia events before and after packed red blood cell (pRBC) and non-pRBC transfusions in very low birth weight infants, and to compare the time spent with saturations of ≤85% before and after transfusions in the same population. Study design This prospective observational study was conducted from April 2014 to August 2017. It included 92 transfusions (81 pRBC, 11 non-pRBC) from 41 very low birth weight infants between 230/7 and 286/7 weeks of gestation. The primary outcome was number of intermittent hypoxia events. Secondary outcomes included the percent time of Peripheral capillary oxygen saturation (SpO2)of ≤85%, ≤80%, and ≤75%. A mixed ANOVA model was used to examine the relationship between event rate and covariates. Results The mean number of intermittent hypoxia events per hour decreased from 5.27 ± 5.02 events per hour before pRBC transfusion to 3.61 ± 3.17 per hour after pRBC transfusions (P Conclusions In very low birth weight infants with a hematocrit of 20%-42%, pRBC transfusions are associated with decreased frequency of intermittent hypoxia. No such diminution of intermittent hypoxia events was observed in infants who had received a non-pRBC transfusion. This finding suggests that the observed beneficial effects of RBC transfusions on apnea and its clinical manifestations of intermittent hypoxia are mediated through an enhanced oxygen carrying capacity.