Regional homogeneity as a marker of sensory cortex dysmaturity in preterm infants.

Atypical perinatal sensory experience in preterm infants is thought to increase their risk of neurodevelopmental disabilities by altering the development of the sensory cortices. Here, we used resting-state fMRI data from preterm and term-born infants scanned between 32 and 48 weeks post-menstrual age to assess the effect of early ex-utero exposure on sensory cortex development. Specifically, we utilized a measure of local correlated-ness called regional homogeneity (ReHo). First, we demonstrated that the brain-wide distribution of ReHo mirrors the known gradient of cortical maturation. Next, we showed that preterm birth differentially reduces ReHo across the primary sensory cortices. Finally, exploratory analyses showed that the reduction of ReHo in the primary auditory cortex of preterm infants is related to increased risk of autism at 18 months. In sum, we show that local connectivity within sensory cortices has different developmental trajectories, is differentially affected by preterm birth, and may be associated with later neurodevelopment.

Central Autonomic Network and heart rate variability in premature neonates.

INTRODUCTION: The Central Autonomic Network (CAN) is a hierarchy of brain structures that collectively influence cardiac autonomic input, mediating the majority of brain-heart interactions, but has never been studied in premature neonates. In this study, we use heart rate variability (HRV), which has been described as the "primary output" of the CAN, and resting state functional MRI to characterize brain-heart relationships in premature neonates. METHODS: We studied premature neonates who underwent resting state functional MRI (rsfMRI) at term, (37-weeks postmenstrual age [PMA] or above) and had HRV data recorded during the same week of their MRI. HRV was derived from continuous electrocardiogram data during the week of the rsfMRI scan. For rsfMRI, a seed-based approach was used to define regions of interest (ROI) pertinent to the CAN, and blood oxygen level-dependent signal was correlated between each ROI as a measure of functional connectivity. HRV was correlated with CAN connectivity (CANconn) for each region, and sub-group analysis was performed based on sex and clinical comorbidities. RESULTS: Forty-seven premature neonates were included in this study, with a mean gestational age at birth of 28.1 +/- 2.6 weeks. Term CANconn was found to be significantly correlated with HRV in approximately one-fifth of CAN connections. Two distinct patterns emerged among these HRV-CANconn relationships. In the first, increased HRV was associated with stronger CANconn of limbic regions. In the second pattern, stronger CANconn at the precuneus was associated with impaired HRV maturation. These patterns were especially pronounced in male premature neonates. CONCLUSION: We report for the first time evidence of brain-heart relationships in premature neonates and an emerging CAN, most striking in male neonates, suggesting that the brain-heart axis may be more vulnerable in male premature neonates. Signatures in the heart rate may eventually become an important non-invasive tool to identify premature males at highest risk for neurodevelopmental impairment.

Experience of early-life pain in premature infants is associated with atypical cerebellar development and later neurodevelopmental deficits.

BACKGROUND: Infants born very and extremely premature (V/EPT) are at a significantly elevated risk for neurodevelopmental disorders and delays even in the absence of structural brain injuries. These risks may be due to earlier-than-typical exposure to the extrauterine environment, and its bright lights, loud noises, and exposures to painful procedures. Given the relative underdeveloped pain modulatory responses in these infants, frequent pain exposures may confer risk for later deficits. METHODS: Resting-state fMRI scans were collected at term equivalent age from 148 (45% male) infants born V/EPT and 99 infants (56% male) born at term age. Functional connectivity analyses were performed between functional regions correlating connectivity to the number of painful skin break procedures in the NICU, including heel lances, venipunctures, and IV placements. Subsequently, preterm infants returned at 18 months, for neurodevelopmental follow-up and completed assessments for autism risk and general neurodevelopment. RESULTS: We observed that V/EPT infants exhibit pronounced hyperconnectivity within the cerebellum and between the cerebellum and both limbic and paralimbic regions correlating with the number of skin break procedures. Moreover, skin breaks were strongly associated with autism risk, motor, and language scores at 18 months. Subsample analyses revealed that the same cerebellar connections strongly correlating with breaks at term age were associated with language dysfunction at 18 months. CONCLUSIONS: These results have significant implications for the clinical care of preterm infants undergoing painful exposures during routine NICU care, which typically occurs without anesthesia. Repeated pain exposures appear to have an increasingly detrimental effect on brain development during a critical period, and effects continue to be seen even 18 months later.

Impact of bronchopulmonary dysplasia on brain GABA concentrations in preterm infants: Prospective cohort study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with cognitive-behavioral deficits in very preterm (VPT) infants, often in the absence of structural brain injury. Advanced GABA-editing techniques like Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) can quantify in-vivo gamma-aminobutyric acid (GABA+, with macromolecules) and glutamate (Glx, with glutamine) concentrations to investigate for neurophysiologic perturbations in the developing brain of VPT infants. OBJECTIVE: To investigate the relationship between the severity of BPD and basal-ganglia GABA+ and Glx concentrations in VPT infants. METHODS: MRI studies were performed on a 3 T scanner in a cohort of VPT infants [born ≤32 weeks gestational age (GA)] without major structural brain injury and healthy-term infants (>37 weeks GA) at term-equivalent age. MEGA-PRESS (TE68ms, TR2000ms, 256averages) sequence was acquired from the right basal-ganglia voxel (∼3cm3) and metabolite concentrations were quantified in institutional units (i.u.). We stratified VPT infants into no/mild (grade 0/1) and moderate-severe (grade 2/3) BPD. RESULTS: Reliable MEGA-PRESS data was available from 63 subjects: 29 healthy-term and 34 VPT infants without major structural brain injury. VPT infants with moderate-severe BPD (n = 20) had the lowest right basal-ganglia GABA+ (median 1.88 vs. 2.28 vs. 2.12 i.u., p = 0.025) and GABA+/choline (0.73 vs. 0.99 vs. 0.88, p = 0.004) in comparison to infants with no/mild BPD and healthy-term infants. The GABA+/Glx ratio was lower (0.34 vs. 0.44, p = 0.034) in VPT infants with moderate-severe BPD than in infants with no/mild BPD. CONCLUSIONS: Reduced GABA+ and GABA+/Glx in VPT infants with moderate-severe BPD indicate neurophysiologic perturbations which could serve as early biomarkers of future cognitive deficits.

Ex-utero third trimester developmental changes in functional brain network organization in infants born very and extremely preterm.

Introduction: The latter half of gestation is a period of rapid brain development, including the formation of fundamental functional brain network architecture. Unlike in-utero fetuses, infants born very and extremely preterm undergo these critical maturational changes in the extrauterine environment, with growing evidence suggesting this may result in altered brain networks. To date, however, the development of functional brain architecture has been unexplored. Methods: From a prospective cohort of preterm infants, graph parameters were calculated for fMRI scans acquired prior to reaching term equivalent age. Eight graph properties were calculated, Clustering Coefficient (C), Characteristic Path Length (L), Modularity (Q), Local Efficiency (LE), Global Efficiency (GE), Normalized Clustering (λ), Normalized Path Length (γ), and Small-Worldness (σ). Properties were first compared to values generated from random and lattice networks and cost efficiency was evaluated. Subsequently, linear mixed effect models were used to assess relationship with postmenstrual age and infant sex. Results: A total of 111 fMRI scans were acquired from 85 preterm infants born at a mean GA 28.93 ± 2.8. Infants displayed robust small world properties as well as both locally and globally efficient networks. Regression models found that GE increased while L, Q, λ, γ, and σ decreased with increasing postmenstrual age following multiple comparison correction (r2Adj range 0.143-0.401, p < 0048), with C and LE exhibited trending increases with age. Discussion: This is the first direct investigation on the extra-uterine formation of functional brain architecture in preterm infants. Importantly, our results suggest that changes in functional architecture with increasing age exhibit a different trajectory relative to in utero fetus. Instead, they exhibit developmental changes more similar to the early postnatal period in term born infants.

Severity of prematurity and age impact early postnatal development of GABA and glutamate systems.

Gamma-aminobutyric acid (GABA) and glutamatergic system perturbations following premature birth may explain neurodevelopmental deficits in the absence of structural brain injury. Using GABA-edited spectroscopy (MEscher-GArwood Point Resolved Spectroscopy [MEGA-PRESS] on 3 T MRI), we have described in-vivo brain GABA+ (+macromolecules) and Glx (glutamate + glutamine) concentrations in term-born infants. We report previously unavailable comparative data on in-vivo GABA+ and Glx concentrations in the cerebellum, the right basal ganglia, and the right frontal lobe of preterm-born infants without structural brain injury. Seventy-five preterm-born (gestational age 27.8 ± 2.9 weeks) and 48 term-born (39.6 ± 0.9 weeks) infants yielded reliable MEGA-PRESS spectra acquired at post-menstrual age (PMA) of 40.2 ± 2.3 and 43.0 ± 2 weeks, respectively. GABA+ (median 2.44 institutional units [i.u.]) concentrations were highest in the cerebellum and Glx higher in the cerebellum (5.73 i.u.) and basal ganglia (5.16 i.u.), with lowest concentrations in the frontal lobe. Metabolite concentrations correlated positively with advancing PMA and postnatal age at MRI (Spearman's rho 0.2-0.6). Basal ganglia Glx and NAA, and frontal GABA+ and NAA concentrations were lower in preterm compared with term infants. Moderate preterm infants had lower metabolite concentrations than term and extreme preterm infants. Our findings emphasize the impact of premature extra-uterine stimuli on GABA-glutamate system development and may serve as early biomarkers of neurodevelopmental deficits.

Polymyxin flushes for endotracheal tube suction catheters in extremely low birth-weight infants: Any benefit in preventing ventilator-associated events?

We report that receipt of polymyxin B endotracheal tube suction catheter flushes did not reduce the incidence of pediatric ventilator-associated events (PedVAE) in infants weighing <1,000 g in this retrospective study. Incidence of PedVAE in our group of extremely low birth-weight infants was 6 per 1,000 ventilator days.

Automatic brain segmentation in preterm infants with post-hemorrhagic hydrocephalus using 3D Bayesian U-Net.

Post-hemorrhagic hydrocephalus (PHH) is a severe complication of intraventricular hemorrhage (IVH) in very preterm infants. PHH monitoring and treatment decisions rely heavily on manual and subjective two-dimensional measurements of the ventricles. Automatic and reliable three-dimensional (3D) measurements of the ventricles may provide a more accurate assessment of PHH, and lead to improved monitoring and treatment decisions. To accurately and efficiently obtain these 3D measurements, automatic segmentation of the ventricles can be explored. However, this segmentation is challenging due to the large ventricular anatomical shape variability in preterm infants diagnosed with PHH. This study aims to (a) propose a Bayesian U-Net method using 3D spatial concrete dropout for automatic brain segmentation (with uncertainty assessment) of preterm infants with PHH; and (b) compare the Bayesian method to three reference methods: DenseNet, U-Net, and ensemble learning using DenseNets and U-Nets. A total of 41 T2 -weighted MRIs from 27 preterm infants were manually segmented into lateral ventricles, external CSF, white and cortical gray matter, brainstem, and cerebellum. These segmentations were used as ground truth for model evaluation. All methods were trained and evaluated using 4-fold cross-validation and segmentation endpoints, with additional uncertainty endpoints for the Bayesian method. In the lateral ventricles, segmentation endpoint values for the DenseNet, U-Net, ensemble learning, and Bayesian U-Net methods were mean Dice score = 0.814 ± 0.213, 0.944 ± 0.041, 0.942 ± 0.042, and 0.948 ± 0.034 respectively. Uncertainty endpoint values for the Bayesian U-Net were mean recall = 0.953 ± 0.037, mean  negative predictive value = 0.998 ± 0.005, mean accuracy = 0.906 ± 0.032, and mean AUC = 0.949 ± 0.031. To conclude, the Bayesian U-Net showed the best segmentation results across all methods and provided accurate uncertainty maps. This method may be used in clinical practice for automatic brain segmentation of preterm infants with PHH, and lead to better PHH monitoring and more informed treatment decisions.

GABA and glutamate in the preterm neonatal brain: In-vivo measurement by magnetic resonance spectroscopy.

Cognitive and behavioral disabilities in preterm infants, even without obvious brain injury on conventional neuroimaging, underscores a critical need to identify the subtle underlying microstructural and biochemical derangements. The gamma-aminobutyric acid (GABA) and glutamatergic neurotransmitter systems undergo rapid maturation during the crucial late gestation and early postnatal life, and are at-risk of disruption after preterm birth. Animal and human autopsy studies provide the bulk of current understanding since non-invasive specialized proton magnetic resonance spectroscopy (1H-MRS) to measure GABA and glutamate are not routinely available for this vulnerable population due to logistical and technical challenges. We review the specialized 1H-MRS techniques including MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS), special challenges and considerations needed for interpretation of acquired data from the developing brain of preterm infants. We summarize the limited in-vivo preterm data, highlight the gaps in knowledge, and discuss future directions for optimal integration of available in-vivo approaches to understand the influence of GABA and glutamate on neurodevelopmental outcomes after preterm birth.

The Application of Neurodiagnostic Studies to Inform the Acute Management of a Newborn Presenting With Sarbamoyl Shosphate Synthetase 1 Deficiency.

Neonatal-onset urea cycle disorders (UCDs) may result in hyperammonemic (HA) encephalopathy presenting with several neurologic sequelae including seizures, coma, and death. However, no recommendations are given in how and when neurodiagnostic studies should be used to screen or assess for these neurologic complications. We present a case of carbamoyl phosphate synthetase 1 (CPS1) deficiency in a newborn female in which electroencephalogram monitoring to assess encephalopathy and seizures, and magnetic resonance imaging measurements of brain metabolites were used to guide care during her hyperammonemic crisis. Her neurologic course and response to treatment characterizes the significant neurologic impact of HA encephalopathy. Our group herein proposes a clinical neurodiagnostic pathway for managing acute HA encephalopathy.

Positive fluid balance is associated with death and severity of brain injury in neonates with hypoxic-ischemic encephalopathy.

OBJECTIVE: To investigate the association between fluid balance during therapeutic hypothermia (TH) and severity of brain injury on magnetic resonance imaging (MRI) in neonates with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: This is a secondary analysis of data from a prospective observational study in neonates with HIE. Daily net positive fluid balance during TH was investigated for association with the adverse primary outcome of death or moderate-to-severe brain injury on MRI using multivariable logistic regression. RESULTS: Of the 150 neonates included, 50 suffered adverse outcome and had significantly higher net positive fluid balance (53 vs. 19 ml/kg/day, p < 0.01) during first 24 hours of TH. Neonates with a net positive fluid balance (>25 ml/kg/day) at 24 hours of TH had 3.4 (95% CI 1.3-9) times higher odds of adverse outcome. CONCLUSIONS: Positive fluid balance during TH in neonates with HIE is independently associated with death or moderate-to-severe brain injury on MRI.

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.

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.

Reducing Vancomycin Use in a Level IV NICU.

BACKGROUND AND OBJECTIVES: Vancomycin remains one of the most commonly prescribed antibiotics in NICUs despite recommendations to limit its use for known resistant infections. Baseline data revealing substantially higher vancomycin use in our NICU compared to peer institutions informed our quality improvement initiative. Our aim was to reduce the vancomycin prescribing rate in neonates hospitalized in our NICU by 50% within 1 year and sustain for 1 year. METHODS: In the 60-bed level IV NICU of an academic referral center, we used a quality improvement framework to develop key drivers and interventions including (1) physician education with benchmarking antibiotic prescribing rates; (2) pharmacy-initiated 48-hour antibiotic time-outs on rounds; (3) development of clinical pathways to standardize empirical antibiotic choices for early-onset sepsis, late-onset sepsis, and necrotizing enterocolitis; coupled with (4) daily prospective audit with feedback from the antimicrobial stewardship program. RESULTS: We used statistical process u-charts to show vancomycin use declined from 112 to 38 days of therapy per 1000 patient-days. After education, pharmacy-initiated 48-hour time-outs, and development of clinical pathways, vancomycin use declined by 29%, and by an additional 52% after implementation of prospective audit with feedback. Vancomycin-associated acute kidney injury also declined from 1.4 to 0.1 events per 1000 patient-days. CONCLUSIONS: Through a sequential implementation approach of education, standardization of care with clinical pathways, pharmacist-initiated 48-hour time-outs, and prospective audit with feedback, vancomycin days of therapy declined by 66% over a 1-year period and has been sustained for 1 year.

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.

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.

Third Trimester Cerebellar Metabolite Concentrations are Decreased in Very Premature Infants with Structural Brain Injury.

Advanced neuroimaging techniques have improved our understanding of microstructural changes in the preterm supratentorial brain as well as the cerebellum and its association with impaired neurodevelopmental outcomes. However, the metabolic interrogation of the developing cerebellum during the early postnatal period after preterm birth remains largely unknown. Our study investigates the relationship between cerebellar neurometabolites measured by proton magnetic spectroscopy (1H-MRS) in preterm infants with advancing post-menstrual age (PMA) and brain injury during ex-utero third trimester prior to term equivalent age (TEA). We prospectively enrolled and acquired high quality 1H-MRS at median 33.0 (IQR 31.6-35.2) weeks PMA from a voxel placed in the cerebellum of 53 premature infants born at a median gestational age of 27.0 (IQR 25.0-29.0) weeks. 1H-MRS data were processed using LCModel software to calculate absolute metabolite concentrations of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr). We noted positive correlations of cerebellar concentrations of NAA, Cho and Cr (Spearman correlations of 0.59, 0.64 and 0.52, respectively, p value < 0.0001) and negative correlation of Cho/Cr ratio (R -0.5, p value 0.0002) with advancing PMA. Moderate-to-severe cerebellar injury was noted on conventional magnetic resonance imaging (MRI) in 14 (26.4%) of the infants and were noted to have lower cerebellar NAA, Cho and Cr concentrations compared with those without injury (p value < 0.001). Several clinical complications of prematurity including necrotizing enterocolitis, systemic infections and bronchopulmonary dysplasia were associated with altered metabolite concentrations in the developing cerebellum. We report for the first time that ex-utero third trimester cerebellar metabolite concentrations are decreased in very preterm infants with moderate-to-severe structural cerebellar injury. We report increasing temporal trends of metabolite concentrations in the cerebellum with advancing PMA, which was impaired in infants with brain injury on MRI and may have early diagnostic and prognostic value in predicting neurodevelopmental outcomes in very preterm infants.

Early Glycemic Profile Is Associated with Brain Injury Patterns on Magnetic Resonance Imaging in Hypoxic Ischemic Encephalopathy.

OBJECTIVE: To investigate whether the early glycemic profile in infants with hypoxic ischemic encephalopathy is associated with distinct patterns of brain injury on magnetic resonance imaging (MRI). STUDY DESIGN: We performed a secondary analysis of 178 prospectively enrolled infants who received therapeutic hypothermia for hypoxic ischemic encephalopathy. Glycemic profiles were identified by glucose concentrations within 24 hours after birth: normoglycemia (all glucose concentrations of >47 to ≤150 mg/dL; n = 62); hypoglycemia (≥1 concentration ≤47 mg/dL; n = 17); hyperglycemia (≥1 concentration >150 mg/dL; n = 76); and labile glucose (both hypoglycemia and hyperglycemia; n = 23). Patterns of brain injury were identified for 151 infants based on Barkovich scores from the postrewarming brain MRIs at a median age of 9 days. RESULTS: A normal brain MRI was reported in 37 of 62 infants (60%) with normal blood glucose values compared with 37 of 116 infants (32%) with an abnormal glucose profile (adjusted for Sarnat stage of encephalopathy and Apgar score at 5 minutes; P = .02). The distribution of MRI patterns of brain injury differed among the glycemic groups (P = .03). The odds of predominant watershed or focal-multifocal injury was higher in infants with hypoglycemia (aOR, 6; 95% CI, 1.5-24.2) and labile glucose (6.6; 95% CI, 1.6-27) compared with infants with normoglycemia. Infants with labile glucose had higher odds (5.6; 95% CI, 1.1-29.3) of predominant basal ganglia or global injury compared with infants with normal blood glucose values. CONCLUSIONS: The early glycemic profile in infants with hypoxic ischemic encephalopathy is associated with specific patterns of brain injury on MRI. Further investigation is needed to explore its prognostic significance and role as a phenotype biomarker.

Hyperglycaemia in infants with hypoxic-ischaemic encephalopathy is associated with improved outcomes after therapeutic hypothermia: a post hoc analysis of the CoolCap Study.

OBJECTIVE: To investigate whether glycaemic profile is associated with multiorgan dysfunction and with response to hypothermia after perinatal hypoxic-ischaemic encephalopathy (HIE). DESIGN: Post hoc analysis of the CoolCap Study. SETTING: 25 perinatal centres in UK, USA and New Zealand during 1999-2002. PATIENTS: 194/234 (83%) infants of ≥36 weeks' gestation with moderate-to-severe HIE enrolled in the CoolCap Study with documented plasma glucose levels and follow-up outcome. INTERVENTION: Infants were randomised to head cooling for 72 hours starting within 6 hours of birth or standard care. Plasma glucose levels were measured at predetermined time intervals after randomisation. MAIN OUTCOME MEASURE: Unfavourable primary outcome was defined as death and/or severe neurodevelopmental disability at 18 months. Glycaemic profile (hypoglycaemia (≤40 mg/dL, ≤2.2 mmol/L), hyperglycaemia (>150 mg/dL, >8.3 mmol/L) and normoglycaemia) during 12 hours after randomisation was investigated for association with multiorgan dysfunction or risk reduction of primary outcome after hypothermia treatment. RESULTS: Hypoglycaemia but not hyperglycaemia was associated with more deranged multiorgan function parameters (mean pH 7.23 (SD 0.16) vs 7.36 (0.13), p<0.001; aspartate transaminase 2101 (2450) vs 318 (516) IU/L, p=0.002; creatinine 1.95 (0.59) vs 1.26 (0.5) mg/dL, p<0.001) compared with normoglycaemia. After adjusting for Sarnat stage and 5 min Apgar score, only hyperglycaemic infants randomised to hypothermia had reduced risk of unfavourable outcome (adjusted risk ratio: 0.80, 95% CI 0.66 to 0.99), whereas hypoglycaemic and normoglycaemic infants did not. CONCLUSIONS: Early glycaemic profile in infants with moderate-to-severe HIE may help to identify risk of multiorgan dysfunction and response to therapeutic hypothermia. TRIAL REGISTRATION NUMBER: NCT00383305.