Use of nontidal high-frequency oscillatory ventilation (HFOV) while the lungs are expanded by an imposed airway pressure (P(aw)) in neonates is increasingly based on evidence of decreased risk of ...lung injury. However, an objective method to optimize P(aw) is lacking. We measured lung volume changes (deltaV(L)t) via respiratory inductance plethysmography over a range of P(aw) settings in five piglets before and after lung lavage. These multiple deltaV(L)(t) were then simultaneously fit by an exponential rise to maximum model, deltaV(L)(t, P(aw)) = deltaV(L,max). (1 - e(-(t/tau))), where deltaV(L,max) was a sigmoidal function of P(aw) and tau varied with lung volume. Postlavage, the effective compliance (C(EFF) = deltaV(L,max)/P(aw)) was generally decreased, whereas tau increased, indicating a slower paced volume recruitment. Model-derived C(EFF)-deltaV(L,max) relationships were altered substantially after lavage and were sigmoidal with a bell-shaped derivative function. The maximum of its derivative corresponded to a favorable (or optimal) deltaV(L)/P(aw) where the maximal increase in compliance is achieved. In conclusion, C(EFF)-deltaV(L,max) data available from respiratory inductance plethysmography provided important insight to changes in lung mechanics. These also provided a basis of an objective method (1) to optimize P(aw) during HFOV and (2) to assess the efficacy of treatments and progression/regression of underlying disease in neonates managed with HFOV.
Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood.
To describe the use of opioids ...and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age.
This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020.
Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay.
Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III).
There were 936 EP infants (448 48% female infants; 611 65% White infants; mean SD gestational age, 181 8 days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median interquartile range motor score, 85 73-97 vs 97 91-107). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure.
In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age.
Many premature infants with respiratory failure are deficient in surfactant, but the relationship to occurrence of bronchopulmonary dysplasia (BPD) is uncertain.
Tracheal aspirates were collected ...from 209 treated and control infants enrolled at 7-14 days in the Trial of Late Surfactant. The content of phospholipid, surfactant protein B, and total protein were determined in large aggregate (active) surfactant.
At 24 h, surfactant treatment transiently increased surfactant protein B content (70%, p < 0.01), but did not affect recovered airway surfactant or total protein/phospholipid. The level of recovered surfactant during dosing was directly associated with content of surfactant protein B (r = 0.50, p < 0.00001) and inversely related to total protein (r = 0.39, p < 0.0001). For all infants, occurrence of BPD was associated with lower levels of recovered large aggregate surfactant, higher protein content, and lower SP-B levels. Tracheal aspirates with lower amounts of recovered surfactant had an increased proportion of small vesicle (inactive) surfactant.
We conclude that many intubated premature infants are deficient in active surfactant, in part due to increased intra-alveolar metabolism, low SP-B content, and protein inhibition, and that the severity of this deficit is predictive of BPD. Late surfactant treatment at the frequency used did not provide a sustained increase in airway surfactant.
To evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the ...contribution of socioeconomic, environmental, and biological factors on this relationship.
We assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis.
Of 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively.
Among former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences.
ClinicalTrials.gov: NCT01022580.
Arguably one of the most important advances in critical care medicine in recent years has been the understanding that mechanical ventilators can impart harm and that lung-protective ventilation ...strategies can save lives. High-frequency oscillatory ventilation appears ideally suited for lung protection at first glance. Two camps of opinion exist, however, even in neonates where this modality has been most extensively studied. In the present debate, the prevailing arguments from each of those camps are made available for the reader to decide.
IMPORTANCE: Practice variability exists in the use of corticosteroids to treat or prevent bronchopulmonary dysplasia in extremely preterm infants, but there is limited information on longer-term ...impacts. OBJECTIVE: To describe the use of corticosteroids in extremely preterm infants and evaluate the association with neurodevelopmental outcomes. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) randomized clinical trial, conducted at 19 participating sites and 30 neonatal intensive care units (NICUs) in the US. Inborn infants born between 24 0/7 and 27 6/7 weeks gestational age between December 2013 and September 2016 were included in analysis. Data analysis was conducted between February 2021 and January 2022. EXPOSURES: Cumulative dose of dexamethasone and duration of therapy for dexamethasone and prednisolone or methyl prednisolone were evaluated. MAIN OUTCOMES AND MEASURES: Demographic and clinical characteristics were described in infants who did or did not receive corticosteroids of interest and survived to discharge. Neurodevelopmental outcomes at 2 years of age were evaluated using the Bayley Scales of Infant Development–Third Edition (BSID-III) at corrected age 2 years. RESULTS: A total of 828 extremely preterm infants (403 49% girls; median IQR gestational age, 26 25-27 weeks) born at 19 sites who survived to discharge were included in this analysis, and 312 infants (38%) were exposed to at least 1 corticosteroid of interest during their NICU stay, including 279 exposed to dexamethasone, 137 exposed to prednisolone or methylprednisolone, and 79 exposed to both. Exposed infants, compared with nonexposed infants, had a lower birth weight (mean SD, 718 168 g vs 868 180 g) and were born earlier (mean SD gestational age, 25 1 weeks vs 26 1 weeks). The median (IQR) start day was 29 (20-44) days for dexamethasone and 53 (30-90) days for prednisolone or methylprednisolone. The median (IQR) total days of exposure was 10 (5-15) days for dexamethasone and 13 (6-25) days for prednisolone or methylprednisolone. The median (IQR) cumulative dose of dexamethasone was 1.3 (0.9-2.8) mg/kg. After adjusting for potential confounders, treatment with dexamethasone for longer than 14 days was associated with worse neurodevelopmental outcomes, with mean scores in BSID-III 7.4 (95% CI, –12.3 to –2.5) points lower in the motor domain (P = .003) and 5.8 (95% CI, –10.9 to –0.6) points lower in the language domain (P = .03), compared with unexposed infants. CONCLUSIONS AND RELEVANCE: These findings suggest that long duration and higher cumulative dose of dexamethasone were associated with worse neurodevelopmental scores at corrected age 2 years. Potential unmeasured differences in the clinical conditions of exposed vs unexposed infants may contribute to these findings. Improved standardization of treatment and documentation of indications would facilitate replication studies.
1 Mercy Children's Hospital at St. Vincent Mercy
Medical Center, and 2 Department of Pediatrics,
Medical College of Ohio, Toledo, Ohio 43608; and
3 Department of Pediatrics, Cooper Hospital and
...Robert Wood Johnson Medical School, Camden, New Jersey 08103
We compared the
harmonic content of tidal flows measured simultaneously at the mouth
and chest wall in spontaneously breathing very low birth weight infants
( n = 16, 1,114 ± 230 g, gestation age:
28 ± 2 wk). Airway opening flows were measured via face
mask-pneumotachograph (P-tach), whereas chest wall flows were derived
from respiratory inductance plethysmography (RIP) excursions. Next, for
each, we computed two spectral shape indexes: 1 ) harmonic
distortion ( k d ; k d,P-tach
and k d,RIP , respectively) defines the extent to
which flows deviated from a single sine wave, and 2 ) the
exponent of the power law ( s ; s P-tach
and s RIP , respectively), describing the
spectral energy vs. frequency. P-tach and RIP flow spectra exhibited
similar power law functional forms consistently in all infants. Also,
mouth s P-tach = 3.73 ± 0.23% (95%
confidence interval), k d,P-tach = 38.8 ± 4.6% and chest wall ( s RIP = 3.51 ± 0.30%, k d,RIP = 42.8 ± 4.8%)
indexes were similar and highly correlated ( s RIP = 1.17 × s P-tach + 0.85;
r 2 = 0.81;
k d,RIP = 0.90 × k d,P-tach + 8.0;
r 2 = 0.76). The corresponding time to peak
tidal expiratory flow-to-expiratory time ratio (0.62 ± 0.08) was
higher than reported in older infants. The obtained s and
k d values are similar to those reported in older
and/or larger chronic lung disease infants, yet appreciably lower than
for 1-mo-old healthy infants of closer age and/or size; this indicated
increased complexity of tidal flows in very low birth weight
babies. Importantly, we found equivalent flow spectral data
from mouth and chest wall tidal flows. The latter are desirable because
they avoid face mask artificial effects, including leaks around it,
they do not interfere with ventilatory support delivery, and they may
facilitate longer measurements that are useful in control of breathing assessment.
harmonic distortion; control of breathing; power law; respiratory
mechanics; respiratory inductance plethysmography
Infants born extremely preterm (<28 weeks’ gestation) are at high risk of neurodevelopmental impairment (NDI) with 50% of survivors showing moderate or severe NDI when at 2 years of age. We sought to ...develop novel models by which to predict neurodevelopmental outcomes, hypothesizing that combining baseline characteristics at birth with medical care and environmental exposures would produce the most accurate model.
Using a prospective database of 692 infants from the Preterm Epo Neuroprotection (PENUT) Trial, which was carried out between December 2013 and September 2016, we developed three predictive algorithms of increasing complexity using a Bayesian Additive Regression Trees (BART) machine learning approach to predict both NDI and continuous Bayley Scales of Infant and Toddler Development 3rd ed subscales at 2 year follow-up using: 1) the 5 variables used in the National Institute of Child Health and Human Development (NICHD) Extremely Preterm Birth Outcomes Tool, 2) 21 variables associated with outcomes in extremely preterm (EP) infants, and 3) a hypothesis-free approach using 133 potential variables available for infants in the PENUT database.
The NICHD 5-variable model predicted 3–4% of the variance in the Bayley subscale scores, and predicted NDI with an area under the receiver operator curve (AUROC, 95% CI) of 0.62 (0.56–0.69). Accuracy increased to 12–20% of variance explained and an AUROC of 0.77 (0.72–0.83) when using the 21 pre-selected clinical variables. Hypothesis-free variable selection using BART resulted in models that explained 20–31% of Bayley subscale scores and AUROC of 0.87 (0.83–0.91) for severe NDI, with good calibration across the range of outcome predictions. However, even with the most accurate models, the average prediction error for the Bayley subscale predictions was around 14–15 points, leading to wide prediction intervals. Higher total transfusion volume was the most important predictor of severe NDI and lower Bayley scores across all subscales.
While the machine learning BART approach meaningfully improved predictive accuracy above a widely used prediction tool (NICHD) as well as a model utilizing NDI-associated clinical characteristics, the average error remained approximately 1 standard deviation on either side of the true value. Although dichotomous NDI prediction using BART was more accurate than has been previously reported, and certain clinical variables such as transfusion exposure were meaningfully predictive of outcomes, our results emphasize the fact that the field is still not able to accurately predict the results of complex long-term assessments such as Bayley subscales in infants born EP even when using rich datasets and advanced analytic methods. This highlights the ongoing need for long-term follow-up of all EP infants.
Supported by the National Institute of Neurological Disorders and StrokeU01NS077953 and U01NS077955.
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