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>Furosemide is a diuretic drug used to increase urine flow in order to reduce the amount of salt and water in the body. It is commonly utilized to treat preterm infants with chronic lung disease of prematurity. There is a need for a simple and reliable quantitation of furosemide in human urine. We have developed and validated an ultra-high performance liquid chromatography-tandem mass spectrometry method for furosemide quantitation in human urine with an assay range of 0.100-50.0&nbsp;μg/ml. Sample preparation involved solid-phase extraction with 10&nbsp;μl of urine. Intra-day accuracies and precisions for the quality control samples were 94.5-106 and 1.86-10.2%, respectively, while inter-day accuracies and precision were 99.2-102 and 3.38-7.41%, respectively. Recovery for furosemide had an average of 23.8%, with an average matrix effect of 101%. Furosemide was stable in human urine under the assay conditions. Stability for furosemide was shown at 1&nbsp;week (room temperature, 4, -20 and -78°C), 6&nbsp;months (-78°C), and through three freeze-thaw cycles. This robust assay demonstrates accurate and precise quantitation of furosemide in a small volume (10&nbsp;μl) of human urine. It is currently being implemented in an ongoing pediatric clinical study.</p>

<p><strong>OBJECTIVE: </strong>Furosemide renal clearance is slow after very preterm (VP) birth and increases with postnatal maturation. We compared furosemide dose frequency and total daily dose between postmenstrual age (PMA) groups in VP infants.</p>

<p><strong>STUDY DESIGN: </strong>Observational cohort study of VP infants exposed to a repeated-dose course of furosemide in Pediatrix neonatal intensive care units (NICU) from 1997 to 2016.</p>

<p><strong>RESULTS: </strong>We identified 6565 furosemide courses among 4638 infants. There were no statistically significant differences between PMA groups on the odds of receiving more frequent furosemide dosing. Furosemide courses initiated at &lt;28 weeks PMA were associated with a higher total daily dose than those initiated at a later PMA.</p>

<p><strong>CONCLUSIONS: </strong>Furosemide dosing practices in the NICU are similar across PMA groups, despite maturational changes in drug disposition. Research is needed to identify and test rational dosing strategies across the PMA spectrum for this commonly used but unproven pharmacotherapy.</p>

<p><strong>BACKGROUND: </strong>Timely development of early motor skills is essential for later skill development in multiple domains. Infants with severe bronchopulmonary dysplasia (BPD) have significant risk for developmental delays. Early motor skill development in this population has not been described. The aim of the present study was to characterize motor skill acquisition at 3 and 6 months corrected age (CA) and assess trajectories of skill development over this time period in infants with severe BPD.</p>

<p><strong>METHODS: </strong>We performed a single-center, retrospective descriptive study. Motor skills were categorized as present and normal, present but atypical, or absent at 3 and 6 months CA. Logistic regression was used to identify clinical characteristics associated with negative trajectories of skill acquisition.</p>

<p><strong>RESULTS: </strong>Data were available for 232 infants and 187 infants at 3 and 6 months CA, respectively. Ten motor skills were present and normal in 5-44%(range) of subjects at 3 months. Nineteen motor skills were present and normal in 1-63%(range) of subjects at 6 months. Significant postural asymmetry was noted throughout the study period. Loss of skills and worsening asymmetries over time were common. Exposure to sedating medications was significantly associated with poor development.</p>

<p><strong>CONCLUSION: </strong>We report delays in motor skill acquisition and postural asymmetries in infants with severe BPD at both 3 and 6 months CA. The association between sedating medications and poor development suggests that efforts to limit these exposures may lead to improved development. Targeted interventions to facilitate early motor development may improve outcomes of this high-risk population.</p>

<p><strong>OBJECTIVE: </strong>Create a prioritization framework for value-based improvement in neonatal care.</p>

<p><strong>STUDY DESIGN: </strong>A retrospective cohort study of very low birth weight (&lt;1500 g) and/or very preterm (&lt;32 weeks) infants discharged between 2012 and 2019 using the Pediatric Health Information System Database. Resource use was compared across hospitals and adjusted for patient-level differences. A prioritization score was created combining cost, patient exposure, and inter-hospital variability to rank resource categories.</p>

<p><strong>RESULTS: </strong>Resource categories with the greatest cost, patient exposure, and inter-hospital variability were parenteral nutrition, hematology (lab testing), and anticoagulation (for central venous access and therapy), respectively. Based on our prioritization score, parenteral nutrition was identified as the highest priority overall.</p>

<p><strong>CONCLUSIONS: </strong>We report the development of a prioritization score for potential value-based improvement in neonatal care. Our findings suggest that parenteral nutrition, central venous access, and high-volume laboratory and imaging modalities should be priorities for future comparative effectiveness and quality improvement efforts.</p>

<p><strong>OBJECTIVE: </strong>To evaluate the association between chronic diuretic exposures and enteral electrolyte use in infants developing severe bronchopulmonary dysplasia (sBPD).</p>

<p><strong>STUDY DESIGN: </strong>Retrospective longitudinal cohort study in infants admitted to United States children's hospitals. We identified diuretic exposures and measured enteral NaCl and KCl use during pre-defined exposure risk-interval days. We used mixed-effects logistic regression to model the association between diuretic exposures and electrolyte use.</p>

<p><strong>RESULTS: </strong>We identified 442,341 subject-days in 3252 infants. All common diuretic classes and class combinations were associated with increased NaCl and KCl use. Thiazide monotherapy was associated with greater electrolyte use than loop monotherapy. The addition of potassium-sparing diuretics was associated with a limited reduction in KCl use compared to thiazide monotherapy.</p>

<p><strong>CONCLUSIONS: </strong>Chronic diuretic exposures are associated with increased NaCl and KCl use. Presumptions about the relative impact of different diuretic classes on electrolyte derangements may be inaccurate and require further study.</p>

<p><strong>OBJECTIVE: </strong>To rank clinician-driven tests and treatments (CTTs) by their total cost during the birth hospitalization for preterm infants.</p>

<p><strong>STUDY DESIGN: </strong>Retrospective cohort of very low birth weight (&lt;1500 g) and/or very preterm (&lt;32 weeks) subjects admitted to US children's hospital Neonatal Intensive Care Units (2012-2018). CTTs were defined as pharmaceutical, laboratory and imaging services and ranked by total cost.</p>

<p><strong>RESULTS: </strong>24,099 infants from 51 hospitals were included. Parenteral nutrition ($85M, 32% of pharmacy costs), blood gas analysis ($34M, 29% of laboratory costs), and chest radiographs ($18M, 31% of imaging costs) were the costliest CTTs overall. More than half of CTT-related costs occurred during 10% of hospital days.</p>

<p><strong>CONCLUSIONS: </strong>The majority of CTT-related costs were from commonly used tests and treatments. Targeted efforts to improve value in neonatal care may benefit most from focusing on reducing unnecessary utilization of common tests and treatments, rather than infrequently used ones.</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>