Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.

BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

Fecal microbiota and volatile metabolome pattern alterations precede late-onset meningitis in preterm neonates.

OBJECTIVE: The fecal microbiota and metabolome are hypothesized to be altered before late-onset neonatal meningitis (LOM), in analogy to late-onset sepsis (LOS). The present study aimed to identify fecal microbiota composition and volatile metabolomics preceding LOM. METHODS: Cases and gestational age-matched controls were selected from a prospective, longitudinal preterm cohort study (born <30 weeks' gestation) at nine neonatal intensive care units. The microbial composition (16S rRNA sequencing) and volatile metabolome (gas chromatography-ion mobility spectrometry (GC-IMS) and GC-time-of-flight-mass spectrometry (GC-TOF-MS)), were analyzed in fecal samples 1-10 days pre-LOM. RESULTS: Of 1397 included infants, 21 were diagnosed with LOM (1.5%), and 19 with concomitant LOS (90%). Random Forest classification and MaAsLin2 analysis found similar microbiota features contribute to the discrimination of fecal pre-LOM samples versus controls. A Random Forest model based on six microbiota features accurately predicts LOM 1-3 days before diagnosis with an area under the curve (AUC) of 0.88 (n=147). Pattern recognition analysis by GC-IMS revealed an AUC of 0.70-0.76 (P<0.05) in the three days pre-LOM (n=92). No single discriminative metabolites were identified by GC-TOF-MS (n=66). CONCLUSION: Infants with LOM could be accurately discriminated from controls based on preclinical microbiota composition, while alterations in the volatile metabolome were moderately associated with preclinical LOM.

Effect of Systemic Hydrocortisone on Brain Abnormalities and Regional Brain Volumes in Ventilator-dependent Infants Born Preterm: Substudy of the SToP-BPD Study.

OBJECTIVE: To evaluate whether a high cumulative dose of systemic hydrocortisone affects brain development compared with placebo when initiated between 7 and 14 days after birth in ventilated infants born preterm. STUDY DESIGN: A double-blind, placebo-controlled, randomized trial was conducted in 16 neonatal intensive care units among infants born at <30 weeks of gestation or with a birth weight of <1250 g who were ventilator-dependent in the second week after birth. Three centers performed MRI at term-equivalent age. Brain injury was assessed on MRI using the Kidokoro scoring system and compared between the 2 treatment groups. Both total and regional brain volumes were calculated using an automatic segmentation method and compared using multivariable regression analysis adjusted for baseline variables. RESULTS: From the 3 centers, 78 infants participated in the study and 59 had acceptable MRI scans (hydrocortisone group, n = 31; placebo group, n = 28). Analyses of the median global brain abnormality score of the Kidokoro score showed no difference between the hydrocortisone and placebo groups (median, 7; IQR, 5-9 vs median, 8, IQR, 4-10, respectively; P = .92). In 39 infants, brain tissue volumes were measured, showing no differences in the adjusted mean total brain tissue volumes, at 352 ± 32 mL in the hydrocortisone group and 364 ± 51 mL in the placebo group (P = .80). CONCLUSIONS: Systemic hydrocortisone started in the second week after birth in ventilator-dependent infants born very preterm was not found to be associated with significant differences in brain development compared with placebo treatment. TRIAL REGISTRATION: The SToP-BPD study was registered with the Netherlands Trial Register (NTR2768; registered on 17 February 2011; https://www.trialregister.nl/trial/2640) and the European Union Clinical Trials Register (EudraCT, 2010-023777-19; registered on 2 November 2010; https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023777-19/NL).

Effects of postnatal corticosteroids on lung development in newborn animals. A systematic review.

BACKGROUND: Postnatal systemic corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids. Animal studies may provide valuable information on these variable effects. This systematic review summarizes the effects of postnatal systemic corticosteroids on lung development in newborn animals. METHODS: A systematic search was performed in PubMed and Embase in December 2022. The protocol was published on PROSPERO (CRD42021177701). RESULTS: Of the 202 eligible studies, 51 were included. Only newborn rodent studies met the inclusion criteria. Most studies used dexamethasone (98%). There was huge heterogeneity in study outcome measures and corticosteroid treatment regimens. Reporting of study quality indicators was mediocre and risk of bias was unclear due to poor reporting of study methodology. Meta-analysis showed that postnatal corticosteroids caused a decrease in body weight as well as persistent alveolar simplification. Subgroup analyses revealed that healthy animals were most affected. CONCLUSION: In newborn rodents, postnatal systemic corticosteroids have a persistent negative effect on body weight and lung development. There was huge heterogeneity in experimental models, mediocre study quality, unclear risk of bias, and very small subgroups for meta-analysis which limited firm conclusions. IMPACT: Postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids while the underlying mechanism of this variable effect is unknown. This is the first systematic review and meta-analysis of preclinical newborn animal studies reviewing the effect of postnatal systemic corticosteroids on lung development. In newborn rodent models, postnatal corticosteroids have a persistent negative effect on body weight and lung alveolarization, especially in healthy animals.

Diaphragmatic electromyography in infants: an overview of possible clinical applications.

Preterm infants often experience breathing instability and a hampered lung function. Therefore, these infants receive cardiorespiratory monitoring and respiratory support. However, the current respiratory monitoring technique may be unreliable for especially obstructive apnea detection and classification and it does not provide insight in breathing effort. The latter makes the selection of the adequate mode and level of respiratory support difficult. Electromyography of the diaphragm (dEMG) has the potential of monitoring heart rate (HR) and respiratory rate (RR), and it provides additional information on breathing effort. This review summarizes the available evidence on the clinical potential of dEMG to provide cardiorespiratory monitoring, to synchronize patient-ventilator interaction, and to optimize the mode and level of respiratory support in the individual newborn infant. We also try to identify gaps in knowledge and future developments needed to ensure widespread implementation in clinical practice. IMPACT: Preterm infants require cardiorespiratory monitoring and respiratory support due to breathing instability and a hampered lung function. The current respiratory monitoring technique may provide unreliable measurements and does not provide insight in breathing effort, which makes the selection of the optimal respiratory support settings difficult. Measuring diaphragm activity could improve cardiorespiratory monitoring by providing insight in breathing effort and could potentially have an important role in individualizing respiratory support in newborn infants.

The role of nutritional interventions in the prevention and treatment of chronic lung disease of prematurity.

Chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Nutrition may affect incidence and severity of BPD. In this context, the Section on Nutrition, Gastroenterology and Metabolism, the Pulmonary Section of the European Society for Paediatric Research (ESPR) and SPR have joined forces to review the current knowledge on nutritional issues related to BPD. The aim of this narrative review is to discuss the clinical implications for nutritional practice. Nutrient deficiencies may influence pathogenesis of BPD. Adequate nutrition and growth can play a crucial role in the prevention of and recovery from BPD. Optimal nutrition strategy is an important principle, especially in the early postnatal period. As optimal energy intake in infants at risk of BPD or with evolving BPD is not yet defined, further research with well-designed studies on nutritional strategies for preterm infants with BPD is urgently needed. IMPACT: Based on current evidence it seems reasonable to recommend that BPD diagnosed infants should receive an energy supply ranging from 120 to 150 Kcal/kg/d. Exclusive MOM feed with adequate fortification should be encouraged as this is associated with a significant reduction in the risk of BPD. Suboptimal nutritional delivery is often seen in preterm infants with BPD compared to controls.

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

AIMS: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. METHODS: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. RESULTS: Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. CONCLUSION: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Predictive Performance of a Gentamicin Pharmacokinetic Model in Term Neonates with Perinatal Asphyxia Undergoing Controlled Therapeutic Hypothermia.

BACKGROUND: Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH. METHODS: The external data set contained a subset of neonates included in the prospective observational multicenter PharmaCool Study. Predictive performance was assessed by visually inspecting observed-versus-predicted concentration plots and calculating bias and precision. In addition, simulation-based diagnostics, model refitting, and bootstrap analyses were performed. RESULTS: The external data set included 323 gentamicin concentrations of 39 neonates. Both the model-building and external data set included neonates from multiple centers. The original gentamicin PK model predicted the observed gentamicin concentrations with adequate accuracy and precision during all phases of controlled TH. Model appropriateness was confirmed with prediction-corrected visual predictive checks and normalized prediction distribution error analyses. Model refitting to the merged data set (n = 86 neonates with 935 samples) showed accurate estimation of PK parameters. CONCLUSIONS: The results of this external validation study justify the generalizability of the gentamicin dosing recommendations made in the original study for neonates with perinatal asphyxia undergoing controlled TH (5 mg/kg every 36 or 24 h with gestational age 36-41 and 42 wk, respectively) and its applicability in model-informed precision dosing.

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia.

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T>MIC) (for efficacy purposes and 100% T>4×MIC and 100% T>5×MIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T>MIC during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T>MIC during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T>4×MIC and 100% T>5×MIC are desired.

Neurodevelopmental Outcomes at Two Years' Corrected Age of Very Preterm Infants after Implementation of a Post-Discharge Responsive Parenting Intervention Program (TOP Program).

OBJECTIVE: To compare neurodevelopmental outcomes at 2 years corrected age (CA) between infants born very preterm (VP) who did or did not receive a postdischarge responsive parenting intervention (Transmural developmental support for very preterm infants and their parents [TOP program]) between discharge home and 12 months' CA. STUDY DESIGN: The Systemic Hydrocortisone to Prevent Bronchopulmonary Dysplasia (SToP-BPD) study showed no differences between treatment groups in motor and cognitive development using the Dutch Bayley Scales of Infant Development and behavior using the Child Behavior Checklist at 2 years' CA. During its study period, the TOP program was gradually scaled up nationwide in the same population, providing an opportunity to evaluate the effect of this program on neurodevelopmental outcome, after adjusting for baseline differences. RESULTS: Among 262 surviving VP infants in the SToP-BPD study, 35% received the TOP program. Infants in the TOP group had a significantly lower incidence of a cognitive score <85 (20.3% vs 35.2%; adjusted absolute risk reduction: -14.1% [95% CI: -27.2 to -1.1]; P = .03), and a significantly higher mean cognitive score (96.7 ± 13.8), compared with the non-TOP group (92.0 ± 17.5; crude mean difference: 4.7 [95% CI: 0.3 to 9.2]; P = .03). No significant differences were found on motor scores. For behavior problems, a small but statistically significant effect for anxious/depressive problems was found in the TOP group (50.5 vs 51.2; P = .02). CONCLUSIONS: VP infants supported by the TOP program from discharge until 12 months' CA had better cognitive function at 2 years' CA. This study demonstrates a sustained positive effect of the TOP program in VP infants.

Exhaled Volatile Organic Compounds for Early Prediction of Bronchopulmonary Dysplasia in Infants Born Preterm.

OBJECTIVE(S): To investigate the predictive performances of exhaled breath volatile organic compounds (VOCs) for development of bronchopulmonary dysplasia (BPD) in infants born preterm. METHODS: Exhaled breath was collected from infants born <30 weeks' gestation at days 3 and 7 of life. Ion fragments detected by gas chromatography-mass spectrometry analysis were used to derive and internally validate a VOC prediction model for moderate or severe BPD at 36 weeks of postmenstrual age. We tested the predictive performance of the National Institute of Child Health and Human Development (NICHD) clinical BPD prediction model with and without VOCs. RESULTS: Breath samples were collected from 117 infants (mean gestation 26.8 ± 1.5 weeks). Thirty-three percent of the infants developed moderate or severe BPD. The VOC model showed a c-statistic of 0.89 (95% CI 0.80-0.97) and 0.92 (95% CI 0.84-0.99) for the prediction of BPD at days 3 and 7, respectively. Adding the VOCs to the clinical prediction model in noninvasively supported infants resulted in significant improvement in discriminative power on both days (day 3: c-statistic 0.83 vs 0.92, P value .04; day 7: c-statistic 0.82 vs 0.94, P value .03). CONCLUSIONS: This study showed that VOC profiles in exhaled breath of preterm infants on noninvasive support in the first week of life differ between those developing and not developing BPD. Adding VOCs to a clinical prediction model significantly improved its discriminative performance.

Prediction Models for Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-Analysis.

OBJECTIVE: To review systematically and assess the accuracy of prediction models for bronchopulmonary dysplasia (BPD) at 36 weeks of postmenstrual age. STUDY DESIGN: Searches were conducted in MEDLINE and EMBASE. Studies published between 1990 and 2022 were included if they developed or validated a prediction model for BPD or the combined outcome death/BPD at 36 weeks in the first 14 days of life in infants born preterm. Data were extracted independently by 2 authors following the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (ie, CHARMS) and PRISMA guidelines. Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool (ie, PROBAST). RESULTS: Sixty-five studies were reviewed, including 158 development and 108 externally validated models. Median c-statistic of 0.84 (range 0.43-1.00) was reported at model development, and 0.77 (range 0.41-0.97) at external validation. All models were rated at high risk of bias, due to limitations in the analysis part. Meta-analysis of the validated models revealed increased c-statistics after the first week of life for both the BPD and death/BPD outcome. CONCLUSIONS: Although BPD prediction models perform satisfactorily, they were all at high risk of bias. Methodologic improvement and complete reporting are needed before they can be considered for use in clinical practice. Future research should aim to validate and update existing models.

Comparison of New Bronchopulmonary Dysplasia Definitions on Long-Term Outcomes in Preterm Infants.

OBJECTIVE: To compare the discriminative performances of the 2018 National Institutes of Health (NIH) and the 2019 Jensen definitions of bronchopulmonary dysplasia (BPD) with the 2001 NIH definition on adverse neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age. STUDY DESIGN: In this single-center retrospective cohort study, outcomes of infants born at <30 weeks of gestational age were collected. The 3 definitions of BPD were compared by adding the different definitions to the National Institute of Child Health and Human Development's outcome prediction model for neurodevelopmental impairment (NDI) or death. Discriminative performance was compared for both outcomes at 2 years and 5 years corrected age by calculating the areas under the receiver operating characteristic curve and z-statistics. RESULTS: The presence of BPD and its severity were determined in 584 infants. There were considerable shifts in BPD grading among the different definitions. At both time points, all BPD definition models had comparable discriminating power for NDI and respiratory morbidity, with one exception. Compared with the 2001 NIH definition, the 2018 NIH definition had less predictive power for the neurologic outcome at 2 years corrected age. CONCLUSIONS: Our comparison of the 3 BPD definitions shows similar discriminative performance on long term neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age.

High-frequency ventilation in preterm infants and neonates.

High-frequency ventilation (HFV) has been used as a respiratory support mode for neonates for over 30 years. HFV is characterized by delivering tidal volumes close to or less than the anatomical dead space. Both animal and clinical studies have shown that HFV can effectively restore lung function, and potentially limit ventilator-induced lung injury, which is considered an important risk factor for developing bronchopulmonary dysplasia (BPD). Knowledge of how HFV works, how it influences cardiorespiratory physiology, and how to apply it in daily clinical practice has proven to be essential for its optimal and safe use. We will present important aspects of gas exchange, lung-protective concepts, clinical use, and possible adverse effects of HFV. We also discuss the study results on the use of HFV in respiratory distress syndrome in preterm infants and respiratory failure in term neonates. IMPACT: Knowledge of how HFV works, how it influences cardiorespiratory physiology, and how to apply it in daily clinical practice has proven to be essential for its optimal and safe use. Therefore, we present important aspects of gas exchange, lung-protective concepts, clinical use, and possible adverse effects of HFV. The use of HFV in daily clinical practice in lung recruitment, determination of the optimal continuous distending pressure and frequency, and typical side effects of HFV are discussed. We also present study results on the use of HFV in respiratory distress syndrome in preterm infants and respiratory failure in term neonates.

Glucocorticoid signature of preterm infants developing bronchopulmonary dysplasia.

BACKGROUND: Systemic inflammation plays a key role in the development of bronchopulmonary dysplasia (BPD). Cortisol is known to dampen inflammation. However, adrenal function following preterm birth is characterized by insufficient cortisol levels for the degree of inflammation, and a relative abundancy of cortisol precursors. We investigated whether this pattern could contribute to the development of BPD in preterm infants born <30 weeks of gestation. METHODS: Cortisol, cortisone, 17-OH progesterone (17-OHP) and 11-deoxycortisol were measured in serum obtained at postnatal days 1, 3, 7, 14 and 28, using liquid-chromatography-tandem-mass-spectrometry. The presence of BPD was ascertained at 36 weeks postmenstrual age. RESULTS: Sixty-five infants were included for analysis, of whom 32 (49%) developed BPD. Preterm infants developing BPD, as compared to those without BPD, had higher levels of 17-OHP, 11-deoxycortisol and cortisone relative to cortisol in their first week of life, but not at birth or beyond day 7. CONCLUSION: Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in their first week of life than infants without BPD. These findings suggest that BPD is preceded by an activated hypothalamus-pituitary-adrenal axis that could not meet the high cortisol demands, which may predispose to inflammation and BPD. IMPACT: Relative adrenal insufficiency is common in the first weeks after preterm birth, resulting in insufficient cortisol production for the degree of inflammation and a relative abundance of cortisol precursors; Whether this pattern contributes to the development of bronchopulmonary dysplasia (BPD) is not fully elucidated, since most studies focused on cortisol levels; Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in the first week of life, suggestive of a hypothalamus-pituitary-adrenal-axis activation during BPD development which cannot meet the high cortisol demands in tissues; This glucocorticoid pattern is likely to dispose to inflammation and BPD.

Bronchopulmonary dysplasia is not related to neurofilament light for neuroaxonal damage in preterm infants.

BACKGROUND: Neurofilament light (NfL) has been identified as a biomarker for neuroaxonal damage in preterm infants, but its relation with bronchopulmonary dysplasia (BPD) has not been established. We hypothesized that BPD is associated with increased NfL levels at an early stage, indicative of early neuroaxonal damage. METHODS: We included preterm infants born <30 weeks of gestation for assessment of NfL levels from cord blood and blood obtained at postnatal days 3, 7, 14, and 28. We used linear regression analysis to compare NfL levels between infants with moderate/severe BPD and infants with no/mild BPD, and linear mixed model analysis to compare the effect of time on NfL levels between groups. RESULTS: Sixty-seven infants with a gestational age (GA) of 27 ± 1.3 weeks were included for analysis, of whom 19 (28%) developed moderate/severe BPD. Although NfL levels were higher at every time point in infants with BPD, statistical significance was lost after adjustment for GA, small for gestational age (SGA) and intraventricular hemorrhage (IVH). Groups did not differ in NfL change over time. CONCLUSIONS: The positive association between BPD and NfL in the first weeks of life could be explained by GA, SGA and IVH rather than by development of BPD. IMPACT: Neurofilament light chain (NfL) is a known biomarker for neuroaxonal damage. Biomarkers for brain damage during the first weeks of life in preterm infants developing BPD are lacking. NfL levels obtained during the first weeks of life did not differ between infants with and without BPD in analyses adjusted for GA, SGA, and IVH.

Effort and work-of-breathing parameters strongly correlate with increased resistance in an animal model.

BACKGROUND: Effort of Breathing (EOB) calculations may be a reliable alternative to Work of Breathing (WOB) calculations in which Respiratory Inductance Plethysmography (RIP) replaces spirometry. We sought to compare EOB and WOB measurements in a nonhuman primate model of increasing extrathoracic inspiratory resistance simulating upper airway obstruction (UAO). METHODS: RIP, spirometry, and esophageal manometry were measured in spontaneously breathing, intubated Rhesus monkeys utilizing 11 calibrated resistors randomly applied for 2-min. EOB was calculated breath-by-breath as Pressure Rate Product (PRP) and Pressure Time Product (PTP). WOB was calculated from the Pressure-Volume curve based on spirometry (WOBSPIR) or RIP flow (WOBRIP). RESULTS: WOB, PRP and PTP showed similar linear increases when exposed to higher levels of resistive loads. When comparing WOBSPIR to WOBRIP, a similar strong correlation was seen for both signals as resistance increased and there were no statistically significant differences. CONCLUSION: EOB and WOB parameters utilizing esophageal manometry and RIP, independent of spirometry, showed a strong correlation as a function of increasing inspiratory resistance in nonhuman primates. This allows several potential monitoring possibilities for non-invasively ventilated patients or situations where spirometry is not available. IMPACT: EOB and WOB parameters showed a strong correlation as a function of increasing inspiratory resistance in nonhuman primates. There was a strong correlation between spirometry-based WOB versus RIP-based WOB. To date, it has remained untested as to whether EOB is a reliable alternative for WOB and if RIP can replace spirometry in these measurements. Our results enable additional potential monitoring possibilities for non-invasively ventilated patients or situations where spirometry is not available. Where spirometry is not available, there is no need to apply a facemask post extubation to a spontaneously breathing, non-intubated infant to make objective EOB measurements.

Curriculum and assessment tool for less invasive surfactant administration: an international Delphi consensus study.

BACKGROUND: Training and assessment of operator competence for the less invasive surfactant administration (LISA) procedure vary. This study aimed to obtain international expert consensus on LISA training (LISA curriculum (LISA-CUR)) and assessment (LISA assessment tool (LISA-AT)). METHODS: From February to July 2022, an international three-round Delphi process gathered opinions from LISA experts (researchers, curriculum developers, and clinical educators) on a list of items to be included in a LISA-CUR and LISA-AT (Round 1). The experts rated the importance of each item (Round 2). Items supported by more than 80% consensus were included. All experts were asked to approve or reject the final LISA-CUR and LISA-AT (Round 3). RESULTS: A total of 153 experts from 14 countries participated in Round 1, and the response rate for Rounds 2 and 3 was >80%. Round 1 identified 44 items for LISA-CUR and 22 for LISA-AT. Round 2 excluded 15 items for the LISA-CUR and 7 items for the LISA-AT. Round 3 resulted in a strong consensus (99-100%) for the final 29 items for the LISA-CUR and 15 items for the LISA-AT. CONCLUSIONS: This Delphi process established an international consensus on a training curriculum and content evidence for the assessment of LISA competence. IMPACT: This international consensus-based expert statement provides content on a curriculum for the less invasive surfactant administration procedure (LISA-CUR) that may be partnered with existing evidence-based strategies to optimize and standardize LISA training in the future. This international consensus-based expert statement also provides content on an assessment tool for the LISA procedure (LISA-AT) that can help to evaluate competence in LISA operators. The proposed LISA-AT enables standardized, continuous feedback and assessment until achieving proficiency.

Time to first passage of meconium and defecation frequency preceding necrotizing enterocolitis in preterm infants: a case-control study.

Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality in preterm infants. Early recognition and treatment of NEC are critical to improving outcomes. Enteric nervous system (ENS) immaturity has been proposed as a key factor in NEC pathophysiology. Gastrointestinal dysmotility is associated with ENS immaturity and may serve as a predictive factor for the development of NEC. In this case-control study, preterm infants (gestational age (GA) < 30 weeks) were included in two level-IV neonatal intensive care units. Infants with NEC in the first month of life were 1:3 matched to controls based on GA (± 3 days). Odds ratios for NEC development were analyzed by logistic regression for time to first passage of meconium (TFPM), duration of meconial stool, and mean daily defecation frequency over the 72 h preceding clinical NEC onset (DF < T0). A total of 39 NEC cases and 117 matched controls (median GA 27 + 4 weeks) were included. Median TFPM was comparable in cases and controls (36 h [IQR 13-65] vs. 30 h [IQR 9-66], p = 0.83). In 21% of both cases and controls, TFPM was ≥ 72 h (p = 0.87). Duration of meconial stool and DF < T0 were comparable in the NEC and control group (median 4 and 3, resp. in both groups). Odds of NEC were not significantly associated with TFPM, duration of meconial stools, and DF < T0 (adjusted odds ratio [95% confidence interval]: 1.00 [0.99-1.03], 1.16 [0.86-1.55] and 0.97 [0.72-1.31], resp.). CONCLUSION: In this cohort, no association was found between TFPM, duration of meconium stool, and DF < T0 and the development of NEC. WHAT IS KNOWN: • Necrotizing enterocolitis (NEC) is a life-threatening acute intestinal inflammatory disease of the young preterm infant. Early clinical risk factors for NEC have been investigated in order to facilitate early diagnosis and treatment. • Signs of disrupted gastrointestinal mobility, such as gastric retention and paralytic ileus, have been established to support the diagnosis of NEC. Nevertheless, defecation patterns have insufficiently been studied in relation to the disease. WHAT IS NEW: • Defecation patterns in the three days preceding NEC did not differ from gestational age-matched controls of corresponding postnatal age. Additionally, the first passage of meconium and the duration of meconium passage were comparable between cases and controls. Currently, defecation patterns are not useful as early warning signs for NEC. It remains to be elucidated whether these parameters are different based on the location of intestinal necrosis.

(Un)warranted variation in local hospital protocols for neonatal referral to the pediatrician: An explorative study in the Netherlands.

BACKGROUND: Studies indicate unwarranted variation in a wide range of neonatal care practices, contributing to preventable morbidity and mortality. Unwarranted variation is the result of complex interactions and multiple determinants. One of the determinants contributing to unwarranted variation in care may be variation in local hospital protocols. The purpose of this study was to examine variation in the content of obstetric and neonatal protocols for six common indications for neonatal referral to the pediatrician: large for gestational age/macrosomia, small for gestational age/fetal growth restriction, meconium-stained amniotic fluid, vacuum extraction, forceps extraction, and cesarean birth. METHODS: We conducted a nationwide cross-sectional study examining protocols for neonatal referral to the pediatrician in the obstetric and neonatal departments of all Dutch hospitals. Variation in protocols was analyzed between regions, between neonatal and obstetrics departments located in the same hospital, and within neonatal and obstetrics departments. RESULTS: There was considerable variation in protocols between regions, between neonatal and obstetrics departments, and within neonatal and obstetrics departments. The results of this study showed considerable variation in recommendations for type of referral, admission, screening/diagnostic tests, treatment, and discharge. Furthermore, results generally showed lower referral thresholds in neonatal departments compared with obstetric departments, and higher referral thresholds in the eastern region of the Netherlands. We also found variation in local hospital protocols, which could not be explained by population characteristics but which may be explained by varying recommendations in existing national and international guidelines and/or lack of adherence to these guidelines. CONCLUSIONS: To reduce unwarranted variation in local protocols, evidence-based, multidisciplinary guidelines should be developed in the Netherlands. Further research addressing knowledge gaps is needed to inform these guidelines. Attention should be paid to the implementation of evidence, and only where evidence is lacking or inconclusive should agreements be based on multidisciplinary consensus. Where protocols deviate from evidence-based guidelines because of specific local circumstances, clearer, more transparent justifications should be made. Uniformity in guidance will offer clear standards for care evaluation and provide opportunities to reduce inappropriate care.