Cranial Point-of-Care Ultrasound for Neonatal Providers: A Feasibility Study.

OBJECTIVE: Despite strong evidence for its utility in clinical management and diagnosis of intracranial hemorrhage (ICH), the use of neonatal cranial point-of-care ultrasound (POCUS) has not been standardized in neonatal intensive care units (NICUs) in the United States. The primary aim of this study was to evaluate the feasibility of training NICU providers to perform cranial POCUS by tracking the quality of image acquisition following training. METHODS: Observational single-center cohort study of cranial POCUS images obtained by trained neonatal practitioners (attendings, fellows, and advanced practice providers) using a protocol developed by a radiologist and neonatologist. Exams were performed on infants born ≤1250 g and/or ≤30 weeks gestation within the first 3 days after birth. A survey to assess attitudes regarding cranial POCUS was given before each of three training sessions. Demographic and clinical data collection were portrayed with descriptive statistics. Metrics of image quality were assessed by a radiologist and sonographer independently. Analysis of trends in quality of POCUS images over time was performed using a multinomial Cochran-Armitage test. RESULTS: Eighty-two cranial POCUS scans were performed over a 2-year period. Infant median age at exam was 14 hours (IQR 7-22 hours). Metrics of image quality depicted quarterly demonstrated a significant improvement in depth (P = .01), gain (P = .048), and quality of anatomy images captured (P < .001) over time. Providers perceived increased utility and safety of cranial POCUS over time. CONCLUSION: Cranial POCUS image acquisition improved significantly following care team training, which may enable providers to diagnose ICH at the bedside.

Esophageal Versus Rectal Temperature Monitoring During Whole-Body Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy: Association with Short- and Long-Term Outcomes.

OBJECTIVE: To compare the short- and long-term outcomes of infants with hypoxic-ischemic encephalopathy (HIE) treated with whole-body therapeutic hypothermia (TH), monitored by esophageal vs rectal temperature. STUDY DESIGN: We conducted a secondary analysis of the multicenter High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial. All infants had moderate or severe HIE and were treated with whole-body TH. The primary outcome was death or neurodevelopmental impairment (NDI) at 22-36 months of age. Secondary outcomes included seizures, evidence of brain injury on magnetic resonance imaging, and complications of hypothermia. Logistic regression was used with adjustment for disease severity and site as clustering variable because cooling modality differed by site. RESULTS: Of the 500 infants who underwent TH, 294 (59%) and 206 (41%) had esophageal and rectal temperature monitoring, respectively. There were no differences in death or NDI, seizures, or evidence of injury on magnetic resonance imaging between the 2 groups. Infants treated with TH and rectal temperature monitoring had lower odds of overcooling (OR 0.52, 95% CI 0.34-0.80) and lower odds of hypotension (OR 0.57, 95% CI 0.39-0.84) compared with those with esophageal temperature monitoring. CONCLUSIONS: Although infants undergoing TH with esophageal monitoring were more likely to experience overcooling and hypotension, the rate of death or NDI was similar whether esophageal monitoring or rectal temperature monitoring was used. Further studies are needed to investigate whether esophageal temperature monitoring during TH is associated with an increased risk of overcooling and hypotension.

Contemporary definitions of infant growth failure and neurodevelopmental and behavioral outcomes in extremely premature infants at two years of age.

BACKGROUND: Associations of 2-year neurodevelopmental and behavioral outcomes with growth trajectories of preterm infants are unknown. METHODS: This secondary analysis of a preterm cohort examined in-hospital and discharge to 2-year changes in anthropometric z-scores. Two-year follow-up included Bayley Scales of Infant Development (BSID-III) and Child Behavior Checklist. RESULTS: Among 590 infants, adjusted in-hospital growth was not associated with any BSID-III subscale. Occipitofrontal circumference (OFC) growth failure (GF) in-hospital was associated with increased adjusted odds of attention problems (aOR 1.65 [1.03, 2.65]), aggressive behavior (aOR 2.34 [1.12, 4.89]), and attention-deficit-hyperactivity symptoms (aOR 1.86 [1.05, 3.30]). Infants with OFC GF at 2 years had lower adjusted BSID-III language scores (-4.0 [-8.0, -0.1]), increased odds of attention problems (aOR 2.29 [1.11, 4.74]), aggressive behavior (aOR 3.09 [1.00, 9.56]), and externalizing problems (aOR 3.01 [1.07, 8.45]) compared to normal OFC growth cohort. CONCLUSION: Infants with OFC GF are at risk for neurodevelopmental and behavioral impairment. CLINICAL TRIAL REGISTRATION: This study is a secondary analysis of pre-existing data from the PENUT Trial Registration: NCT01378273.

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm.

Importance: Infants born extremely preterm receive transfusions at higher platelet count thresholds than older children and adults due to concerns for intracranial hemorrhage. A recent randomized trial comparing 2 platelet transfusion thresholds showed the higher threshold was associated with increased risk of long-term adverse neurodevelopmental outcomes. Objective: To evaluate the association of platelet transfusion exposure with death and severe neurodevelopmental impairment (NDI) at 2 years' corrected age in a cohort of infants born extremely preterm. Design, Setting, and Participants: An observational cohort study and secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, a randomized, placebo-controlled clinical trial of erythropoietin neuroprotection in neonates born extremely preterm, was conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 819 infants born extremely preterm at 24 to 27 completed weeks of gestation who had a documented outcome (death or neurodevelopmental assessment). Analysis was performed in April 2023. Exposures: Any platelet transfusion during neonatal intensive care unit hospitalization. Main Outcomes and Measures: The primary composite outcome was death or severe NDI evaluated at 2 years' corrected age using the Bayley Scales of Infant Development-Third Edition (BSID-III) and the Gross Motor Function Classification System and was defined as the presence of severe cerebral palsy or a BSID-III composite motor or cognitive score 2 SDs below the mean. Confounding by indication for platelet transfusion was addressed with covariate adjustment and propensity score methods. Results: Of the 819 infants included in the analysis (429 [52.4%] male; mean [SD] gestational age, 25.5 [1.1] weeks), 245 (30.0%) received at least 1 platelet transfusion during their initial hospitalization. The primary outcome occurred in 46.5% (114 of 245) of infants exposed to a platelet transfusion and 13.9% (80 of 574) of nonexposed infants with a corresponding odds ratio of 2.43 (95% CI, 1.24-4.76), adjusted for propensity score, gestational age at birth, and trial treatment group. The individual components of death and severe NDI were directionally consistent with the overall composite outcome. Conclusions and Relevance: The findings of this study suggest that platelet transfusion in infants born extremely preterm may be associated with an increased risk of death or severe NDI at 2 years' corrected age, although the possibility of residual confounding by indication cannot be excluded.

Time to regain birthweight and association with neurodevelopmental outcomes among extremely preterm newborns.

OBJECTIVE: Determine association between time to regain birthweight and 2-year neurodevelopment among extremely preterm (EP) newborns. STUDY DESIGN: Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial evaluating time to regain birthweight, time from birth to weight nadir, time from nadir to regain birthweight, and cumulative weight loss with 2-year corrected Bayley Scales of Infant and Toddler Development 3rd edition. RESULTS: Among n = 654 EP neonates, those with shorter nadir-to-regain had lower cognitive scores (≤1 day versus ≥8 days: -5.0 points, [CI -9.5, -0.6]) and lower motor scores (≤1 day versus ≥8 days: -4.6 points [CI -9.2, -0.03]) in adjusted stepwise forward regression modeling. Increasingly cumulative weight loss was associated with lower cognitive scores (≤-50 percent-days: -5.6, [CI -9.4, -1.8]), motor scores (≤-50 percent-days: -4.2, [CI -8.2, -0.2]); and language scores (≤-50 percent-days: -6.0, [CI -10.1, -1.9]). CONCLUSION: Faster nadir-to-regain and excessive cumulative weight loss are associated with adverse 2-year neurodevelopmental outcomes. TRIAL REGISTRATION: PENUT Trial Registration: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 . CLINICAL TRIAL REGISTRATION: This study is a post-hoc secondary analysis of pre-existing data from the PENUT Trial (NCT #01378273).

Rectal temperature after hypoxia-ischemia predicts white matter and cortical pathology in the near-term ferret.

BACKGROUND: Neonatal encephalopathy (NE) remains a common cause of infant morbidity and mortality. Neuropathological corollaries of NE associated with acute hypoxia-ischemia include a central injury pattern involving the basal ganglia and thalamus, which may interfere with thermoregulatory circuits. Spontaneous hypothermia (SH) occurs in both preclinical models and clinical hypoxic-ischemic NE and may provide an early biomarker of injury severity. To determine whether SH predicts the degree of injury in a ferret model of hypoxic-ischemic NE, we investigated whether rectal temperature (RT) 1 h after insult correlated with long-term outcomes. METHODS: Postnatal day (P)17 ferrets were presensitized with Escherichia coli lipopolysaccharide before undergoing hypoxia-ischemia/hyperoxia (HIH): bilateral carotid artery ligation, hypoxia-hyperoxia-hypoxia, and right ligation reversal. One hour later, nesting RTs were measured. RESULTS: Animals exposed to HIH were separated into normothermic (NT; ≥34.4 °C) or spontaneously hypothermic (SH; <34.4 °C) groups. At P42, cortical development, ex vivo MRI, and neuropathology were quantitated. Whole-brain volume and fractional anisotropy in SH brains were significantly decreased compared to control and NT animals. SH brains also had significantly altered gyrification, greater cortical pathology, and increased corpus callosum GFAP staining relative to NT and control brains. CONCLUSION: In near-term-equivalent ferrets, nesting RT 1 h after HIH may predict long-term neuropathological outcomes. IMPACT: High-throughput methods to determine injury severity prior to treatment in animal studies of neonatal brain injury are lacking. In a gyrified animal model of neonatal inflammation-sensitized hypoxic-ischemic brain injury in the ferret, rectal temperature 1 h after hypoxia predicts animals who will have increased cortical pathology and white matter changes on MRI. These changes parallel similar responses in rodents and humans but have not previously been correlated with long-term neuropathological outcomes in gyrified animal models. Endogenous thermoregulatory responses to injury may provide a translational marker of injury severity to help stratify animals to treatment groups or predict outcome in preclinical studies.

Time to Reaching Target Cooling Temperature and 2-year Outcomes in Infants with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To determine if time to reaching target temperature (TT) is associated with death or neurodevelopmental impairment (NDI) at 2 years of age in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Newborn infants ≥36 weeks of gestation diagnosed with moderate or severe HIE and treated with therapeutic hypothermia were stratified based on time at which TT was reached, defined as early (ie, ≤4 hours of age) or late (>4 hours of age). Primary outcomes were death or NDI. Secondary outcomes included neurodevelopmental assessment with Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at age 2. RESULTS: Among 500 infants, the median time to reaching TT was 4.3 hours (IWR, 3.2-5.7 hours). Infants in early TT group (n = 211 [42%]) compared with the late TT group (n = 289 [58%]) were more likely to be inborn (23% vs 13%; P < .001) and have severe HIE (28% vs 19%; P = .03). The early and late TT groups did not differ in the primary outcome of death or any NDI (adjusted RR, 1.05; 95% CI, 0.85-0.30; P = .62). Among survivors, neurodevelopmental outcomes did not differ significantly in the 2 groups (adjusted mean difference in Bayley Scales of Infant Development-III scores: cognitive, -2.8 [95% CI, -6.1 to 0.5], language -3.3 [95% CI, -7.4 to 0.8], and motor -3.5 [95% CI, -7.3 to 0.3]). CONCLUSIONS: In infants with HIE, time to reach TT is not independently associated with risk of death or NDI at age 2 years. Among survivors, developmental outcomes are similar between those who reached TT at <4 and ≥4 hours of age. TRIAL REGISTRATION: High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL); NCT02811263; https://beta. CLINICALTRIALS: gov/study/NCT02811263.

Early Glycemic State and Outcomes of Neonates With Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: In infants with hypoxic-ischemic encephalopathy (HIE), conflicting information on the association between early glucose homeostasis and outcome exists. We characterized glycemic profiles in the first 12 hours after birth and their association with death and neurodevelopmental impairment (NDI) in neonates with moderate or severe HIE undergoing therapeutic hypothermia. METHODS: This post hoc analysis of the High-dose Erythropoietin for Asphyxia and Encephalopathy trial included n = 491 neonates who had blood glucose (BG) values recorded within 12 hours of birth. Newborns were categorized based on their most extreme BG value. BG >200 mg/dL was defined as hyperglycemia, BG <50 mg/dL as hypoglycemia, and 50 to 200 mg/dL as euglycemia. Primary outcome was defined as death or any NDI at 22 to 36 months. We calculated odds ratios for death or NDI adjusted for factors influencing glycemic state (aOR). RESULTS: Euglycemia was more common in neonates with moderate compared with severe HIE (63.6% vs 36.6%; P < .001). Although hypoglycemia occurred at similar rates in severe and moderate HIE (21.4% vs 19.5%; P = .67), hyperglycemia was more common in severe HIE (42.3% vs 16.9%; P < .001). Compared with euglycemic neonates, both, hypo- and hyperglycemic neonates had an increased aOR (95% confidence interval) for death or NDI (2.62; 1.47-4.67 and 1.77; 1.03-3.03) compared to those with euglycemia. Hypoglycemic neonates had an increased aOR for both death (2.85; 1.09-7.43) and NDI (2.50; 1.09-7.43), whereas hyperglycemic neonates had increased aOR of 2.52 (1.10-5.77) for death, but not NDI. CONCLUSIONS: Glycemic profile differs between neonates with moderate and severe HIE, and initial glycemic state is associated death or NDI at 22 to 36 months.

Reducing Severe Intraventricular Hemorrhage in Preterm Infants With Improved Care Bundle Adherence.

BACKGROUND AND OBJECTIVES: Intraventricular hemorrhage prevention bundles (IVHPBs) can decrease the incidence of intraventricular hemorrhage (IVH) in premature infants. Our center had a high rate of severe (grade III/IV) IVH (9.8%), and poor adherence (24%) to an IVHPB in neonates born ≤1250 g or ≤30 gestational weeks. Improvement initiatives were planned to decrease the incidence of severe IVH by 30% over 2 years. METHODS: A multidisciplinary team undertook interventions including in-service training, prompt initiation of IVHPB, revision of guidelines, and process standardization. Baseline data were collected from May 2016 to June 2018, with interventions occurring from July 2018 to May 2020. Adherence to the IVHPB was the primary process measure, and incidence of severe IVH the primary outcome measure. Control charts were used to analyze the effect of interventions on outcome. Balancing measures included use of breast milk at discharge, use of mechanical ventilation after initial resuscitation, and bronchopulmonary dysplasia. RESULTS: A total of 240 infants were assessed preintervention, and 185 during interventions. Adherence to the IVHPB improved from 24% to 88%. During this period, the incidence of severe IVH decreased from 9.8% to 2.4%, a 76% reduction from baseline. A higher adherence score was associated with reduced odds of IVH (odds ratio 0.30; 95% confidence interval 0.10-0.90, P = .03). CONCLUSIONS: Interventions focused on enhancing adherence to an IVHPB were associated with a reduced rate of severe IVH in high-risk neonates, highlighting the importance of assessing adherence to clinical guidelines.

A systematic review and meta-regression of exogenous ketone infusion rates and resulting ketosis-A tool for clinicians and researchers.

Introduction: Ketone bodies such as beta-hydroxybutyrate (BHB) have pleiotropic functional benefits as fuel and signaling metabolites and may have multiple clinical applications. An alternative to inducing ketosis by dietary modification is intravenous delivery of exogenous sources of ketones. It is unknown whether there is a strong relationship between BHB infusion rate and blood BHB concentrations in the published literature; this information is vital for clinical studies investigating therapeutic effects of ketosis. This systematic review aimed to aggregate available data and address this gap. Methods: The PubMed and EMBASE databases were searched, and data were extracted from 23 manuscripts where BHB was infused and maximum and/or steady state BHB levels assessed. Infusion rate was adjusted when racemic BHB was infused but only D-BHB was measured. Results: Using a random effects meta-regression, strong linear relationships between BHB infusion rate and maximal (y = 0.060 + 0.870x, R 2 = 87.2%, p < 0.0001) and steady state (y = -0.022 + 0.849x, R 2 = 86.9%, p < 0.0001) blood BHB concentrations were found. Sensitivity analysis found this relationship was stronger when studies in non-healthy populations were excluded (y = 0.059 + 0.831x, R 2 = 96.3%, p < 0.0001). Conclusion: There is a strong relationship between BHB infusion rate and blood BHB concentrations; the regressions described here can be used by clinicians or researchers to determine ketone delivery required for a target blood concentration.

Characteristics, Genetic Testing, and Diagnoses of Infants with Neonatal Encephalopathy Not Due to Hypoxic Ischemic Encephalopathy: A Cohort Study.

OBJECTIVE: To characterize the presentation and evaluation of infants with neonatal encephalopathy (NE) not due to hypoxic-ischemic encephalopathy (non-HIE NE) and to describe the genetic abnormalities identified. STUDY DESIGN: Retrospective cohort study of 193 non-HIE NE neonates admitted to a level IV NICU from 2015 through 2019. For changes in testing over time, Cochrane-Armitage test for trend was used with a Bonferroni-corrected P-value, and comparison between groups was performed using Fisher exact test. RESULT: The most common symptom of non-HIE NE was abnormal tone in 47% (90/193). Ten percent (19/193) died prior to discharge, and 48% of survivors (83/174) required medical equipment at discharge. Forty percent (77/193) underwent genetic testing as an inpatient. Of 52 chromosomal studies, 54 targeted tests, and 16 exome sequences, 10%, 41%, and 69% were diagnostic, respectively, with no difference in diagnostic rates between infants with and without an associated congenital anomaly and/or dysmorphic feature. Twenty-eight genetic diagnoses were identified. CONCLUSIONS: Neonates with non-HIE NE have high rates of morbidity and mortality and may benefit from early genetic testing, even in the absence of other exam findings. This study broadens our knowledge of genetic conditions underlying non-HIE NE, which may enable families and care teams to anticipate the needs of the individual, allow early initiation of targeted therapies, and facilitate decisions surrounding goals of care.

Preterm infants variability in cerebral near-infrared spectroscopy measurements in the first 72-h after birth.

BACKGROUND: Cerebral near-infrared spectroscopy is a non-invasive tool used to measure regional cerebral tissue oxygenation (rScO2) initially validated in adult and pediatric populations. Preterm neonates, vulnerable to neurologic injury, are attractive candidates for NIRS monitoring; however, normative data and the brain regions measured by the current technology have not yet been established for this population. METHODS: This study's aim was to analyze continuous rScO2 readings within the first 6-72 h after birth in 60 neonates without intracerebral hemorrhage born at ≤1250 g and/or ≤30 weeks' gestational age (GA) to better understand the role of head circumference (HC) and brain regions measured. RESULTS: Using a standardized brain MRI atlas, we determined that rScO2 in infants with smaller HCs likely measures the ventricular spaces. GA is linearly correlated, and HC is non-linearly correlated, with rScO2 readings. For HC, we infer that rScO2 is lower in infants with smaller HCs due to measuring the ventricular spaces, with values increasing in the smallest HCs as the deep cerebral structures are reached. CONCLUSION: Clinicians should be aware that in preterm infants with small HCs, rScO2 displayed may reflect readings from the ventricular spaces and deep cerebral tissue. IMPACT: Clinicians should be aware that in preterm infants with small head circumferences, cerebral near-infrared spectroscopy readings of rScO2 displayed may reflect readings from the ventricular spaces and deep cerebral tissue. This highlights the importance of rigorously re-validating technologies before extrapolating them to different populations. Standard rScO2 trajectories should only be established after determining whether the mathematical models used in NIRS equipment are appropriate in premature infants and the brain region(s) NIRS sensors captures in this population, including the influence of both gestational age and head circumference.

Increasing Sodium Variability in the First 96 Hours after Birth is Associated with Adverse In-Hospital Outcomes of Preterm Newborns.

Background: Neonatal intraventricular hemorrhage prevention bundles for preterm infants commonly defer daily weighing for the first 72 h, with reweighing occurring on day 4. Clinicians rely on maintaining stable sodium values as a proxy of fluid status to inform fluid management decisions over the first 96 h after birth. Yet, there exists a paucity of research evaluating whether serum sodium or osmolality are appropriate proxies for weight loss and whether increasing variability in sodium or osmolality during this early transitional period is associated with adverse in-hospital outcomes. Objectives: To evaluate whether serum sodium or osmolality change in the first 96 h after birth was associated with percent weight change from birth weight, and to assess potential associations between serum sodium and osmolality variability with in-hospital outcomes. Methods: This retrospective, cross-sectional study included neonates born at ≤30 gestational weeks or ≤1250 g. We evaluated associations between serum sodium coefficient of variation (CoV), osmolality CoV, and maximal weight loss percentage in the first 96 h after birth with in-hospital neonatal outcomes. Results: Among 205 infants, serum sodium and osmolality were poorly correlated with percent weight change in individual 24-h increments (R2 = 0.01-0.14). For every 1% increase in sodium CoV, there was an associated 2-fold increased odds of surgical necrotizing enterocolitis and 2-fold increased odds of in-hospital mortality (odds ratio, 2.07; 95% CI: 1.02, 4.54; odds ratio, 1.95; 95% CI: 1.10, 3.64, respectively). Sodium CoV was more strongly associated with outcomes than absolute sodium maximal change. Conclusions: In the first 96 h, serum sodium and osmolality are poor proxies for assessing percent weight change. Increasing variability of serum sodium is associated with later development of surgical necrotizing enterocolitis and all-cause in-hospital mortality. Prospective research is needed to evaluate whether reducing sodium variability in the first 96 h after birth, as assessed by CoV, improves newborn health outcomes.

Patterns of Infections among Extremely Preterm Infants.

Infections remain a leading cause of neonatal death, especially among the extremely preterm infants. To evaluate the incidence, pathogenesis, and in-hospital outcomes associated with sepsis among hospitalized extremely preterm infants born at 24-0/7 to 27-6/7 weeks of gestation, we designed a post hoc analysis of data collected prospectively during the Preterm Epo Neuroprotection (PENUT) Trial, NCT #01378273. We analyzed culture positive infection data, as well as type and duration of antibiotic course and described their association with in-hospital morbidities and mortality. Of 936 included infants, 229 (24%) had at least one positive blood culture during their hospitalization. Early onset sepsis (EOS, ≤3 days after birth) occurred in 6% of the infants, with Coagulase negative Staphylococci (CoNS) and Escherichia Coli the most frequent pathogens. Late onset sepsis (LOS, >day 3) occurred in 20% of the infants. Nearly all infants were treated with antibiotics for presumed sepsis at least once during their hospitalization. The risk of confirmed or presumed EOS was lower with increasing birthweight. Confirmed EOS had no significant association with in-hospital outcomes or death while LOS was associated with increased risk of necrotizing enterocolitis and death. Extremely premature infants with presumed sepsis as compared to culture positive sepsis had lower rates of morbidities. In conclusion, the use of antibiotics for presumed sepsis remains much higher than confirmed infection rates. Ongoing work exploring antibiotic stewardship and presumed, culture-negative sepsis in extremely preterm infants is needed.

Temperature dysregulation during therapeutic hypothermia predicts long-term outcome in neonates with HIE.

Few reliable or easily obtainable biomarkers to predict long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) have been identified. We previously showed that mattress temperature (MT), as proxy for disturbed temperature regulation during therapeutic hypothermia (TH), predicts injury on early MRI and holds promise as physiologic biomarker. To determine whether MT in neonates treated with TH for moderate-severe HIE is associated with long-term outcome at 18-22 months, we performed a secondary analysis of the Optimizing Cooling trial using MT data from 167 infants treated at a core temperature of 33.5°C. Median MTs from four time-epochs (0-6 h, 6-24 h, 24-48 h, and 48-72 h of TH) were used to predict death or moderate-severe neurodevelopmental impairment (NDI), using epoch-specific derived and validated MT cutoffs. Median MT of infants who died or survived with NDI was consistently 1.5-3.0°C higher throughout TH. Infants requiring a median MT above the derived cut-offs had a significantly increased odds of death or NDI, most notably at 0-6 h (aOR 17.0, 95%CI 4.3-67.4). By contrast, infants who remained below cut-offs across all epochs had 100% NDI-free survival. MTs in neonates with moderate-severe HIE during TH are highly predictive of long-term outcome and can be used as physiologic biomarker.

Predicting 2-year neurodevelopmental outcomes in extremely preterm infants using graphical network and machine learning approaches.

Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: Supported by the National Institute of Neurological Disorders and StrokeU01NS077953 and U01NS077955.

Restraint stress during neonatal hypoxia-ischemia alters brain injury following normothermia and hypothermia.

Rodent models of neonatal hypoxic-ischemic (HI) injury require a subset of animals to be immobilized for continuous temperature monitoring during the insult and subsequent treatment. Restrained animals are discarded from the analysis due to the effect of restraint on the brain injury as first demonstrated by Thoresen et al 1996. However, the effects of restraint on responses to hypothermic (HT) post-insult therapy are not well described. We examine the effects of restraint associated with different probe placements on HI brain injury. We have conducted a meta-analysis of 23 experiments comparing probe rats (skin n = 42, rectal n = 35) and free-moving matched non-probe controls (n = 80) that underwent HI injury (left common carotid artery ligation and 90 min 8% O2 ) at postnatal day 7 (P7), followed by 5 h of NT (37°C) or HT (32°C). On P14, brain regions were analyzed for injury (by neuropathology and area loss), microglial reactivity and brain-derived neurotrophic factor (BDNF). HI injury was mitigated in NT skin and rectal probe rats, with greater neuroprotection among the rectal probe rats. Following HT, the skin probe rats maintained the restraint-associated neuroprotection, while brain injury was significantly exacerbated among the rectal probe rats. Microglial reactivity strongly correlated with the acquired injury, with no detectable difference between the groups. Likewise, we observed no differences in BDNF signal intensity. Our findings suggest a biphasic neuroprotection from restraint stress, which becomes detrimental in combination with HT and the presumed discomfort from the rectal probe. This finding is useful in highlighting unforeseen effects of common experimental designs or routine clinical management.