Dynamic PEEP Study: A Non-invasive Diagnostic Exam to Assess for Effective PEEP in Children with Severe BPD.

OBJECTIVE: Tracheobronchomalacia (TBM) is common in neonates with bronchopulmonary dysplasia (BPD) and is associated with higher morbidity. This study evaluates the value of a CT protocol to assess the degree of TBM and gauge the adequacy of prescribed PEEP. STUDY DESIGN: Four infants with severe BPD on invasive mechanical ventilation underwent a chest CT protocol, including limited reduced-dose expiratory scans with varying PEEP levels. RESULTS: Baseline PEEP was adjusted in all subjects after performing the Dynamic PEEP CT. In two infants, the PEEP was increased due to significant TBM and in the other two without signs of TBM PEEP was decreased. The clinical course improved in all patients after adjusting PEEP. CONCLUSION: A "Dynamic PEEP" study may be reliable and non-invasive imaging modality for the evaluation of adequate ventilator settings in infants with severe BPD who are not optimal candidates for bronchoscopy.

Longitudinal Trajectories of Regional Cerebral Blood Flow in Very Preterm Infants during Third Trimester Ex Utero Development Assessed with MRI.

Background The third trimester of gestation is a crucial phase of rapid brain development, but little has been reported on the trajectories of cerebral blood flow (CBF) in preterm infants in this period. Purpose To quantify regional CBF in very preterm infants longitudinally across the ex utero third trimester and to determine its relationship with clinical factors associated with brain injury and premature birth. Materials and Methods In this prospective study, very preterm infants were enrolled for three longitudinal MRI scans, and 22 healthy full-term infants were enrolled for one term MRI scan between November 2016 and February 2019. Global and regional CBF in the cortical gray matter, white matter, deep gray matter, and cerebellum were measured using arterial spin labeling with postlabeling delay of 2025 msec at 1.5 T and 3.0 T. Brain injury and clinical risk factors in preterm infants were investigated to determine associations with CBF. Generalized estimating equations were used to account for correlations between repeated measures in the same individual. Results A total of 75 preterm infants (mean postmenstrual age [PMA]: 29.5 weeks ± 2.3 [standard deviation], 34.9 weeks ± 0.8, and 39.3 weeks ± 2.0 for each scan; 43 male infants) and 22 full-term infants (mean PMA, 42.1 weeks ± 2.0; 13 male infants) were evaluated. In preterm infants, global CBF was 11.9 mL/100 g/min ± 0.2 (standard error). All regional CBF increased significantly with advancing PMA (P ≤ .02); the cerebellum demonstrated the most rapid CBF increase and the highest mean CBF. Lower CBF was associated with intraventricular hemorrhage in all regions (P ≤ .05) and with medically managed patent ductus arteriosus in the white matter and deep gray matter (P = .03). Mean CBF of preterm infants at term-equivalent age was significantly higher compared with full-term infants (P ≤ .02). Conclusion Regional cerebral blood flow increased significantly in preterm infants developing in an extrauterine environment across the third trimester and was associated with intraventricular hemorrhage and patent ductus arteriosus. © RSNA, 2021 Online supplemental material is available for this article.

Functional brain connectivity in ex utero premature infants compared to in utero fetuses.

Brain structural changes in premature infants appear before term age. Functional differences between premature infants and healthy fetuses during this period have yet to be explored. Here, we examined brain connectivity using resting state functional MRI in 25 very premature infants (VPT; gestational age at birth <32 weeks) and 25 healthy fetuses with structurally normal brain MRIs. Resting state data were evaluated using seed-based correlation analysis and network-based statistics using 23 regions of interest (ROIs) per hemisphere. Functional connectivity strength, the Pearson correlation between blood oxygenation level dependent signals over time across all ROIs, was compared between groups. In both cohorts, connectivity between homotopic ROIs showed a decreasing medial to lateral gradient. The cingulate cortex, medial temporal lobe and the basal ganglia shared the strongest connections. In premature infants, connections involving superior temporal, hippocampal, and occipital areas, among others, were stronger compared to fetuses. Premature infants showed stronger connectivity in sensory input and stress-related areas suggesting that extra-uterine environment exposure alters the development of select neural networks in the absence of structural brain injury.

Changes in Autonomic Tone in Premature Infants Developing Necrotizing Enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a complication of prematurity with a high mortality rate. Currently, there are no reliable biomarkers capable of identifying infants at risk for developing NEC. We sought to determine the autonomic nervous system antecedents of NEC in premature infants, using heart rate variability (HRV). MATERIALS AND METHODS: HRV was quantified by retrieving archived electrocardiogram (EKG) data from 30 premature infants from 4 days prior, through 4 days after, the clinical NEC diagnosis. HRV metrics were compared with those on the diagnosis day using the receiver operating characteristic (ROC) analysis. RESULTS: HRV metrics showed a depression of autonomic tone that preceded the clinical NEC diagnosis by 2 days, and which recovered to baseline by 2 days after diagnosis (area under the curve [AUC] < 0.7). The pattern of HRV change was significantly associated with the clinical severity of NEC (stage II vs. stage III). CONCLUSION: Our studies suggest that readily accessible metrics of autonomic depression might expedite the diagnosis of NEC and its severity in a clinically meaningful manner. Clearly, these studies need to be extended prospectively to determine the diagnostic utility of this approach.

In vitro and in vivo assessment of oxygenator blood volume for the prediction of clot formation in an ECMO circuit (theory and validation).

INTRODUCTION: Clotting is one of the major causes of mortality and morbidity during extracorporeal membrane oxygenation (ECMO). A large meta-analysis study suggests that 29% of patients require the oxygenator to be replaced during ECMO. As clots usually form in the oxygenator, the oxygenator blood volume (OXBV) decreases over time. The currently used pressure gradient as a predicator of clot formation is unreliable. OBJECTIVE: The aim of this study was to develop and validate ultrasound dilution technology in a quantitative assessment of clotting, using measurements of OXBV. METHODS: OXBV was measured using the ELSA monitor (Transonic Systems Inc., Ithaca, NY, USA) from the transit time of a saline bolus passing through the oxygenator as recorded by a sensor placed after the oxygenator. The accuracy and reproducibility (coefficient of variation [CV]) of OXBV measurement and its independence from ECMO flow was assessed in vitro in lambs and from a clinical data archive. RESULTS: The in vitro accuracy compared with volumetric measurements of OXBV of 22-134 ml at flows of 300-700 ml/min was -0.8±6.6%. For an OXBV of 355 ml at flows of 1020-7000 ml/min, accuracy was -0.4±1.6%. In 88 animal OXBV measurements, the CV was 1.49±1.12%. For an OXBV of 153 (range 42-387 ml), clinical measurements at flow ranged from 210-5960 ml/min, with a CV of 3.20±2.44 %. CONCLUSION: Dilution technology has the ability to accurately and reproducibly assess the clotting process in the oxygenator. Larger studies are needed to establish guidelines for the prediction of imminent clotting and may help to avoid unnecessary circuit changes.

Early Lipid Intake Improves Cerebellar Growth in Very Low-Birth-Weight Preterm Infants.

BACKGROUND: Despite recent advances in nutrition practice in the neonatal intensive care unit, infants remain at high risk for growth restriction following preterm birth. Additionally, optimal values for macronutrient administration, especially lipid intake, have yet to be established for preterm infants in the extrauterine environment. METHODS: We studied preterm infants born at very low-birth weight (VLBW, <1500 g) and ≤32 weeks' gestation. Cumulative macronutrient (carbohydrate, lipid, protein, energy) intake in the first 2 and 4 weeks of life was compared with total and regional brain volumes on magnetic resonance imaging (MRI) obtained at term-equivalent age. Preterm infants had no structural brain injury on conventional MRI. RESULTS: In a cohort of 67 VLBW infants, cumulative lipid intake in the first 2 weeks of life was positively associated with significantly greater cerebellar volume (ß = 95.8; P = .01) after adjusting for weight gain, gestational age at birth, and postmenstrual age at MRI. Cumulative lipid (ß = 36.1, P = .01) and energy (ß = 3.1; P = .02) intake in the first 4 weeks of life were both significantly associated with greater cerebellar volume. No relationship was seen between carbohydrate or protein intake in the first month of life and cerebral volume at term-equivalent age. CONCLUSION: Early cumulative lipid intake in the first month of life is associated with significantly greater cerebellar volume by term-equivalent age in very premature infants. Our findings emphasize the importance of early, aggressive nutrition interventions to optimize cerebellar development in VLBW infants.

Carbon dioxide and retinopathy of prematurity in extremely low birth weight infants.

Objective: To evaluate the relationship between partial pressure of carbon dioxide (PCO2) during the first 3 days of life and retinopathy of prematurity (ROP) in extremely low birthweight (ELBW) infants.Patients and methods: A retrospective evaluation of data on ELBW infants were collected over a period of 4 years. Data during the first 72 hours of life was divided into six, 12-hour epochs. The average highest and overall means of PCO2, PO2, FiO2, and glucose were calculated for each epoch. Logistic regression analysis was used to determine the association between PCO2 and ROP after controlling for covariables.Results: A total of 78 neonates were included: birth weight (BW) (703 ± 157 g) and gestational age (25 ± 1.4 weeks). A total of 45 out of 78 had ROP: stage 1 (N = 8), stage 2 (N = 26), stage 3 (N = 14), and plus (N = 4). The overall mean PCO2 correlated with ROP in the first 72 hours of life (R = 0.31, p = .0069). This correlation was significant in epochs 2 (p = .049), 4 (p = .008) and 6 (p = .038). The average of the highest PCO2 also correlated with ROP in the first 72 hours of life (R = 0.38, p = .0007). This correlation was significant in epochs 2 (p = .0115), 4 (p = .0011), 5 (p = .028) and 6 (p = .037). The correlation between the stage of ROP and PCO2 was significant after controlling for PO2 and glucose concentrations. Other variables that correlated with ROP were the overall means of FiO2 (R = 0.23, p = .04), PO2 (R = 0.39, p = .0005) and glucose (R = 0.39, p = .0004) as well as the average highest concentrations of FiO2 (R = 0.26, p = .025), PO2 (R = 0.38, p = .0008) and glucose (R = 0.34, p = .007).Conclusion: After controlling for confounding variables, ROP correlated with the overall means and average highest PCO2. ROP also correlated with FiO2, PO2 and glucose concentrations. Further studies are needed to define the safe PCO2 range and the effect of PCO2 on the normal development of the retina.

Validation of a new predictive model to improve risk stratification in bronchopulmonary dysplasia.

We need a better risk stratification system for the increasing number of survivors of extreme prematurity suffering the most severe forms of bronchopulmonary dysplasia (BPD). However, there is still a paucity of studies providing scientific evidence to guide future updates of BPD severity definitions. Our goal was to validate a new predictive model for BPD severity that incorporates respiratory assessments beyond 36 weeks postmenstrual age (PMA). We hypothesized that this approach improves BPD risk assessment, particularly in extremely premature infants. This is a longitudinal cohort of premature infants (≤32 weeks PMA, n = 188; Washington D.C). We performed receiver operating characteristic analysis to define optimal BPD severity levels using the duration of supplementary O2 as predictor and respiratory hospitalization after discharge as outcome. Internal validation included lung X-ray imaging and phenotypical characterization of BPD severity levels. External validation was conducted in an independent longitudinal cohort of premature infants (≤36 weeks PMA, n = 130; Bogota). We found that incorporating the total number of days requiring O2 (without restricting at 36 weeks PMA) improved the prediction of respiratory outcomes according to BPD severity. In addition, we defined a new severity category (level IV) with prolonged exposure to supplemental O2 (≥120 days) that has the highest risk of respiratory hospitalizations after discharge. We confirmed these findings in our validation cohort using ambulatory determination of O2 requirements. In conclusion, a new predictive model for BPD severity that incorporates respiratory assessments beyond 36 weeks improves risk stratification and should be considered when updating current BPD severity definitions.

Age and Sex Influences Gamma-aminobutyric Acid Concentrations in the Developing Brain of Very Premature Infants.

Gamma-aminobutyric acid (GABA) and glutamate are principal neurotransmitters essential for late gestational brain development and may play an important role in prematurity-related brain injury. In vivo investigation of GABA in the preterm infant with standard proton magnetic resonance spectroscopy (1H-MRS) has been limited due to its low concentrations in the developing brain, and overlap in the spectrum by other dominant metabolites. We describe early postnatal profiles of in vivo GABA and glutamate concentrations in the developing preterm brain measured by using the J-difference editing technique, Mescher-Garwood point resolved spectroscopy. We prospectively enrolled very preterm infants born ≤32 weeks gestational age and non-sedated 1H-MRS (echo time 68 ms, relaxation time 2000 ms, 256 signal averages) was acquired on a 3 Tesla magnetic resonance imaging scanner from a right frontal lobe voxel. Concentrations of GABA + (with macromolecules) was measured from the J-difference spectra; whereas glutamate and composite glutamate + glutamine (Glx) were measured from the unedited (OFF) spectra and reported in institutional units. We acquired 42 reliable spectra from 38 preterm infants without structural brain injury [median gestational age at birth of 28.0 (IQR 26.0, 28.9) weeks; 19 males (50%)] at a median postmenstrual age of 38.4 (range 33.4 to 46.4) weeks. With advancing post-menstrual age, the concentrations of glutamate OFF increased significantly, adjusted for co-variates (generalized estimating equation ß = 0.22, p = 0.02). Advancing postnatal weeks of life at the time of imaging positively correlated with GABA + (ß = 0.06, p = 0.02), glutamate OFF (ß = 0.11, p = 0.02) and Glx OFF (ß = 0.12, p = 0.04). Male infants had higher GABA + (1.66 ± 0.07 vs. 1.33 ± 0.11, p = 0.01) concentrations compared with female infants. For the first time, we report the early ex-utero developmental profile of in vivo GABA and glutamate stratified by age and sex in the developing brain of very preterm infants. This data may provide novel insights into the pathophysiology of neurodevelopmental disabilities reported in preterm infants even in the absence of structural brain injury.

Are Immune Modulating Single Nucleotide Polymorphisms Associated with Necrotizing Enterocolitis?

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency. The purpose of this study is to determine if functional single nucleotide polymorphisms (SNPs) in immune-modulating genes pre-dispose infants to NEC. After Institutional Review Board approval and parental consent, buccal swabs were collected for DNA extraction. TaqMan allelic discrimination assays and BglII endonuclease digestion were used to genotype specific inflammatory cytokines and TRIM21. Statistical analysis was completed using logistic regression. 184 neonates were analyzed in the study. Caucasian neonates with IL-6 (rs1800795) were over 6 times more likely to have NEC (p = 0.013; OR = 6.61, 95% CI 1.48-29.39), and over 7 times more likely to have Stage III disease (p = 0.011; OR = 7.13, (95% CI 1.56-32.52). Neonates with TGFß-1 (rs2241712) had a decreased incidence of NEC-related perforation (p = 0.044; OR = 0.28, 95% CI: 0.08-0.97) and an increased incidence of mortality (p = 0.049; OR = 2.99, 95% CI: 1.01 - 8.86). TRIM21 (rs660) was associated with NEC-related intestinal perforation (p = 0.038; OR = 4.65, 95% CI 1.09-19.78). In premature Caucasian neonates, the functional SNP IL-6 (rs1800795) is associated with both the development and increased severity of NEC. TRIM21 (rs660) and TGFß-1 (rs2241712) were associated with NEC- related perforation in all neonates in the cohort. These findings suggest a possible genetic role in the development of NEC.

Genomics in premature infants: a non-invasive strategy to obtain high-quality DNA.

We used a cost-effective, non-invasive method to obtain high-quality DNA from buccal epithelial-cells (BEC) of premature infants for genomic analysis. DNAs from BEC were obtained from premature infants with gestational age ≤ 36 weeks. Short terminal repeats (STRs) were performed simultaneously on DNA obtained from the buccal swabs and blood from the same patient. The STR profiles demonstrated that the samples originated from the same individual and exclude any contamination by external DNAs. Whole exome sequencing was performed on DNAs obtained from BEC on premature infants with and without necrotizing enterocolitis, and successfully provided a total number of reads and variants corroborating with those obtained from healthy blood donors. We provide a proof of concept that BEC is a reliable and preferable source of DNA for high-throughput sequencing in premature infants.