First name
Nicolas
Middle name
A
Last name
Bamat

Title

Use of ventilation/perfusion mismatch to guide individualised CPAP level selection in preterm infants: a feasibility trial.

Year of Publication

2022

Date Published

09/2022

ISSN Number

1468-2052

Abstract

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.

DOI

10.1136/archdischild-2022-324474

Alternate Title

Arch Dis Child Fetal Neonatal Ed

PMID

36104165

Title

Development, validation, and implementation of an UHPLC-MS/MS method for the quantitation of furosemide in infant urine samples.

Year of Publication

2022

Number of Pages

e5262

Date Published

2022 Mar

ISSN Number

1099-0801

Abstract

<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>

DOI

10.1002/bmc.5262

Alternate Title

Biomed Chromatogr

PMID

34648199

Title

Association between postmenstrual age and furosemide dosing practices in very preterm infants.

Year of Publication

2022

Date Published

2022 Jan 24

ISSN Number

1476-5543

Abstract

<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>

DOI

10.1038/s41372-022-01320-w

Alternate Title

J Perinatol

PMID

35075306

Title

Early motor development in infants with moderate or severe bronchopulmonary dysplasia.

Year of Publication

2021

Date Published

2021 Oct 12

ISSN Number

1878-4429

Abstract

<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>

DOI

10.3233/NPM-210750

Alternate Title

J Neonatal Perinatal Med

PMID

34657851

Title

Prioritization framework for improving the value of care for very low birth weight and very preterm infants.

Year of Publication

2021

Date Published

2021 Jun 01

ISSN Number

1476-5543

Abstract

<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>

DOI

10.1038/s41372-021-01114-6

Alternate Title

J Perinatol

PMID

34075201

Title

The association between diuretic class exposures and enteral electrolyte use in infants developing grade 2 or 3 bronchopulmonary dysplasia in United States children's hospitals.

Year of Publication

2021

Date Published

2021 Jan 28

ISSN Number

1476-5543

Abstract

<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>

DOI

10.1038/s41372-021-00924-y

Alternate Title

J Perinatol

PMID

33510422

Title

Cost of clinician-driven tests and treatments in very low birth weight and/or very preterm infants.

Year of Publication

2020

Date Published

2020 Dec 02

ISSN Number

1476-5543

Abstract

<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>

DOI

10.1038/s41372-020-00879-6

Alternate Title

J Perinatol

PMID

33268831

Title

Loop Diuretics in Severe Bronchopulmonary Dysplasia: Cumulative Use and Associations with Mortality and Age at Discharge.

Year of Publication

2020

Date Published

2020 Nov 02

ISSN Number

1097-6833

Abstract

<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>

DOI

10.1016/j.jpeds.2020.10.073

Alternate Title

J Pediatr

PMID

33152371

Title

Protocol adherence rates in superiority and noninferiority randomized clinical trials published in high impact medical journals.

Year of Publication

2020

Number of Pages

1740774520941428

Date Published

2020 Jul 15

ISSN Number

1740-7753

Abstract

<p><strong>BACKGROUND/AIMS: </strong>Noninferiority clinical trials are susceptible to false confirmation of noninferiority when the intention-to-treat principle is applied in the setting of incomplete trial protocol adherence. The risk increases as protocol adherence rates decrease. The objective of this study was to compare protocol adherence and hypothesis confirmation between superiority and noninferiority randomized clinical trials published in three high impact medical journals. We hypothesized that noninferiority trials have lower protocol adherence and greater hypothesis confirmation.</p>

<p><strong>METHODS: </strong>We conducted an observational study using published clinical trial data. We searched PubMed for active control, two-arm parallel group randomized clinical trials published in JAMA: The Journal of the American Medical Association, The New England Journal of Medicine, and The Lancet between 2007 and 2017. The primary exposure was trial type, superiority versus noninferiority, as determined by the hypothesis testing framework of the primary trial outcome. The primary outcome was trial protocol adherence rate, defined as the number of randomized subjects receiving the allocated intervention as described by the trial protocol and followed to primary outcome ascertainment (numerator), over the total number of subjects randomized (denominator). Hypothesis confirmation was defined as affirmation of noninferiority or the alternative hypothesis for noninferiority and superiority trials, respectively.</p>

<p><strong>RESULTS: </strong>Among 120 superiority and 120 noninferiority trials, median and interquartile protocol adherence rates were 91.5 [81.4-96.7] and 89.8 [83.6-95.2], respectively; = 0.47. Hypothesis confirmation was observed in 107/120 (89.2%) of noninferiority and 64/120 (53.3%) of superiority trials, risk difference (95% confidence interval): 35.8 (25.3-46.3), &lt; 0.001.</p>

<p><strong>CONCLUSION: </strong>Protocol adherence rates are similar between superiority and noninferiority trials published in three high impact medical journals. Despite this, we observed greater hypothesis confirmation among noninferiority trials. We speculate that publication bias, lenient noninferiority margins and other sources of bias may contribute to this finding. Further study is needed to identify the reasons for this observed difference.</p>

DOI

10.1177/1740774520941428

Alternate Title

Clin Trials

PMID

32666826

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