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BACKGROUND AND OBJECTIVES: Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal morbidity and mortality. Therapeutic hypothermia (TH), a proven treatment of moderate-severe HIE, was first used clinically after 2006. We describe trends in HIE diagnosis and use of TH over a 10-year period in California. METHODS: We identified 62 888 infants, ≥36 weeks gestation, who were cared for in California Perinatal Quality Care Collaborative-participating NICUs between 2010 and 2019, and linked them to birth certificate data. We evaluated trends in HIE diagnosis and use of TH. RESULTS: Over time, rates of HIE diagnosis increased from 0.6 to 1.7 per 1000 live births, and use of TH increased from 26.5 to 83.0 per 1000 infants. Rates of moderate HIE increased more than mild or severe, although use of TH for mild HIE increased more than for moderate. Of those with moderate-severe HIE, 25% remain untreated. Treatment varied by NICU level of care. CONCLUSIONS: The rates of HIE and TH increased steadily. Some infants with moderate-severe HIE remain untreated, suggesting a need for ongoing education. Further evaluation of systems of care is needed to assure all qualifying infants are treated. [ABSTRACT FROM AUTHOR]

Objective Describe the association between cardiac dysfunction and death or moderate-to-severe abnormalities on brain magnetic resonance imaging (MRI) in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE). Study Design Retrospective study in neonates with moderate or severe HIE undergoing therapeutic hypothermia between 2008 and 2017. Primary outcome was death or moderate-to-severe brain injury using the Barkovich score. Conventional and speckle-tracking echocardiography measures were extracted from available echocardiograms to quantify right (RV) and left (LV) ventricular functions. Results A total of 166 newborns underwent therapeutic hypothermia of which 53 (36.5%) had echocardiography performed. Ten (19%) died prior to hospital discharge, and 11 (26%) had moderate-to-severe brain injury. There was no difference in chronologic age at echocardiography between the normal and adverse outcome groups (22 [±19] vs. 28 [±21] hours, p = 0.35). Cardiac findings in newborns with abnormal outcome included lower systolic and diastolic blood pressure (BP) at echocardiography (p = 0.004) and decreased tricuspid annular plane systolic excursion (a marker of RV systolic function; p = 0.01), while the ratio of systolic pulmonary artery (PA) pressure to systolic BP indicated isosystemic pressures (>2/3 systemic) in both groups. A multilogistic regression analysis, adjusting for weight and seizure status, indicated an association between abnormal outcome and LV function by longitudinal strain, as well as by ejection fraction. Conclusion Newborns who died or had moderate–to-severe brain injury had a higher incidence of cardiac dysfunction but similar PA pressures when compared with those who survived with mild or no MRI abnormalities. Key Points Newborns with HIE with functional LV/RV dysfunction are at risk for death or brain injury. All neonates with HIE had elevated pulmonary pressure, but neonates with poor outcome had RV dysfunction. When evaluating newborns with HIE by echocardiography, beyond estimation of pulmonary pressure, it is important to assess biventricular function. [ABSTRACT FROM AUTHOR]

Background: Neonatal seizures are associated with death and neurological morbidity; however, little is known about how neonates with seizures die.Methods: This was a prospective, observational cohort study of neonates with seizures treated at seven sites of the Neonatal Seizure Registry. We characterized the mode of death, evaluated the association between infant characteristics and mode of death, and evaluated predictors of death or transfer to hospice.Results: We enrolled 611 consecutive neonates with seizures, and 90 neonates (15%) died before hospital discharge at a median age of 11 days (range: 1 to 163 days); 32 (36%) died in the first postnatal week. An additional 19 neonates (3%) were transferred to hospice. The most common mode of in-hospital death was death after extubation amidst concerns for poor neurological prognosis, in the absence of life-threatening physiologic instability (n = 43, 48%). Only one infant died while actively receiving cardiopulmonary resuscitation. In an adjusted analysis, premature birth (odds ratio: 3.06, 95% confidence interval 1.59 to 5.90) and high seizure burden (odds ratio: 4.33, 95% confidence interval 1.88 to 9.95) were associated with increased odds of death or transfer to hospice.Conclusion: In a cohort of neonates with seizures, death occurred predominantly after decisions to withdraw or withhold life-sustaining intervention(s). Future work should characterize how these decisions occur and develop optimized approaches to support families and clinicians caring for newborns with seizures. [ABSTRACT FROM AUTHOR]

Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, 2-center clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight, 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot liquid chromatography-tandem mass spectrometry assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling. The clearance of morphine and glucuronide metabolites was best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5-kg neonate, morphine clearance was 0.77 L/h (CV, 48%), and the steady-state volume of distribution was 8.0 L (CV, 49%). Compared with previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10 and 40 ng/mL. An optimized morphine loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h was predicted across birthweights. [ABSTRACT FROM AUTHOR]

The large randomized, controlled trials of therapeutic hypothermia for hypoxic-ischemic encephalopathy excluded neonates with congenital disorders. The objective of this study was to report our experience using hypothermia in neonates with signs of hypoxic-ischemic encephalopathy and a syndromic disorder or brain anomaly. Subjects were identified from a database of neonates admitted to the Neuro-Intensive Care Nursery at University of California, San Francisco. Of 169 patients fulfilling criteria for hypothermia, 8 (5%) had a syndromic disorder and were cooled per guidelines for nonsyndromic neonates. Perinatal characteristics of infants with and without syndromic disorder were not significantly different. Overall outcome was poor: 38% had evidence of acute hypoxic-ischemic injury, 3 subjects died, and 2 survivors had low developmental quotient (ie, 25). The risk versus benefit of therapeutic hypothermia for hypoxic-ischemic encephalopathy among neonates with congenital brain malformations or syndromic diagnoses is uncertain. [ABSTRACT FROM AUTHOR]

This cohort study examines medication use in term neonates with hypoxic-ischemic encephalopathy and seizures before and after implementation of a Neonatal Neurocritical Care Service (N = 108), which included increased seizure monitoring. Nearly all neonates received phenobarbital (96% pre– vs 95% post–Neonatal Neurocritical Care Service) and total loading dose did not vary among groups (33 [95% confidence interval 29-37] vs 30 [26-34] mg/kg). After adjustment for seizure burden, neonates managed during the Neonatal Neurocritical Care Service era, on average, received 30 mg/kg less cumulative phenobarbital (95% confidence interval 15-46 mg/kg) and were on maintenance 5 fewer days (95% confidence interval 3-8 days) than those who were treated prior to implementation of the service. In spite of the enhanced ability to detect seizures because of improved monitoring and increased vigilance by bedside practitioners, implementation of the Neonatal Neurocritical Care Service was associated with decreased use of potentially harmful phenobarbital treatment among neonates with hypoxic-ischemic encephalopathy. [ABSTRACT FROM AUTHOR]

Background: Erythropoietin is neuroprotective in animal models of neonatal hypoxic-ischemic encephalopathy. We previously reported a phase I safety and pharmacokinetic study of erythropoietin in neonates. This article presents the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial.Methods: We enrolled 24 newborns with hypoxic-ischemic encephalopathy in a dose-escalation study. Patients received up to six doses of erythropoietin in addition to hypothermia. All infants underwent neonatal brain magnetic resonance imaging (MRI) reviewed by a single neuroradiologist. Moderate-to-severe neurodevelopmental disability was defined as cerebral palsy with Gross Motor Function Classification System levels III-V or cognitive impairment based on Bayley Scales of Infant Development II mental developmental index or Bayley III cognitive composite score.Results: Outcomes were available for 22 of 24 infants, at mean age 22 months (range, 8-34 months). There were no deaths. Eight (36%) had moderate-to-severe brain injury on neonatal MRI. Moderate-to-severe disability occurred in one child (4.5%), in the setting of moderate-to-severe basal ganglia and/or thalamic injury. Seven infants with moderate-to-severe watershed injury exhibited the following outcomes: normal (three), mild language delay (two), mild hemiplegic cerebral palsy (one), and epilepsy (one). All 11 patients with a normal brain MRI had a normal outcome.Conclusions: This study is the first to describe neurodevelopmental outcomes in infants who received high doses of erythropoietin and hypothermia during the neonatal period. The findings suggest that future studies are warranted to assess the efficacy of this new potential neuroprotective therapy. [ABSTRACT FROM AUTHOR]

Animal studies suggest that hypothermia decreases seizure burden, whereas limited human data are inconclusive. This retrospective cohort study examines the relationship between therapeutic hypothermia and seizure in neonates with hypoxic-ischemic encephalopathy. Our center admitted 224 neonates from July 2004 to December 2011 who met institutional cooling criteria. Seventy-three neonates were born during the pre-cooling era, prior to November 2007, and 151 were born during the cooling era. Among neonates with moderate encephalopathy, the incidence of seizure in cooled infants was less than half the incidence in those not cooled (26% cooling, 61% pre-cooling era; risk ratio = 0.43, 95% confidence interval = 0.30-0.61). Among neonates with severe encephalopathy, there was no difference in the incidence (83% vs 87%; risk ratio = 1.05, 95% confidence interval = 0.78-1.39). These results support animal data and suggest a mechanism by which neonates with moderate encephalopathy can benefit more from cooling than neonates with severe encephalopathy. [ABSTRACT FROM PUBLISHER]

Advances in the care of high-risk newborn babies have contributed to reduced mortality rates for premature and term births, but the surviving neonates often have increased neurological morbidity. Therapies aimed at reducing the neurological sequelae of birth asphyxia at term have brought hypothermia treatment into the realm of standard care. However, this therapy does not provide complete protection from neurological complications and a need to develop adjunctive therapies for improved neurological outcomes remains. In addition, the care of neurologically impaired neonates, regardless of their gestational age, clearly requires a focused approach to avoid further injury to the brain and to optimize the neurodevelopmental status of the newborn baby at discharge from hospital. This focused approach includes, but is not limited to, monitoring of the patient's brain with amplitude-integrated and continuous video EEG, prevention of infection, developmentally appropriate care, and family support. Provision of dedicated neurocritical care to newborn babies requires a collaborative effort between neonatologists and neurologists, training in neonatal neurology for nurses and future generations of care providers, and the recognition that common neonatal medical problems and intensive care have an effect on the developing brain. [ABSTRACT FROM AUTHOR]

To describe the concept, implementation, patient characteristics, and preliminary outcomes of a Neonatal Neurocritical Care Service (NNCS) recently established at the University of California, San Francisco. The NNCS was developed to better address the special needs of neonates at risk for neurological injury. The service combines dedicated neurological care, specialized neonatal medical and nursing expertise, neuromonitoring, neuroimaging, neurodevelopmental care, and long-term follow up. Newborns evaluated by the NNCS between July 2008 and June 2009 were included in the analysis. Demographic data (gestational age at birth, sex, admission diagnosis, and reason for consult), outcome (mortality, length of stay), and neurophysiology and imaging resources were extracted from patient charts. Over the 12-month period, 155 newborns were evaluated (approximately 25% of all admissions); of these, 51 were preterm (<36 weeks gestation) and 104 were term. Approximately half were admitted for primary medical diagnoses, such as preterm birth, congenital malformations or apnea/apparent life-threatening event (ALTE), with the remainder admitted for primary neurological problems, including perinatal asphyxia, seizures/possible seizures, or congenital cerebral malformation. The most common neurological diagnoses were hypoxic-ischemic encephalopathy (38%) and seizure (35%). Among preterm newborns, intraventricular hemorrhage grade III and periventricular hemorrhagic infarction were most common. Mortality was approximately 20% in both preterm and term populations. While specialized neurocritical care has improved outcomes in adult populations, longitudinal studies are needed to determine whether specialized neurocritical care services will also result in improved neurodevelopmental outcomes for newborns. [ABSTRACT FROM AUTHOR]

Although the utility of magnetic resonance imaging (MRI) as a universal screening tool in preterminfants has been contested, it is increasingly used to investigate neonatal seizures. The authors evaluated 236 infants <34 weeks' gestationat birth. Seizures were documented according to the clinical standard of care. Infants underwent MRI and head ultrasound during the neonatal period, and a neuroradiologist and ultrasonologist performed detailed reviews of the images. During the hospital course, 9 infants (3.8%) had clinical suspicion of seizures. Magnetic resonance imaging was abnormal in each case. Periventricular hemorrhagic infarct was more common in infants with seizures. Infants with seizures were more likely to have white matter injury, though the difference was not significant. Head ultrasound failed to detect the extent of brain abnormality in 8 (89%) of the infants. In this large cohort, infants with clinical suspicion of seizures had a high rate of MRI abnormalities that were not as well characterized by head ultrasound. Magnetic resonance imaging may be the study of choice for evaluating preterm infants with seizures. [ABSTRACT FROM AUTHOR]

Background: Neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia (HIE + TH) are at risk for acute kidney injury (AKI). The standardized Kidney Disease Improving Global Outcomes (KDIGO) criteria identifies AKI based on a rise in serum creatinine (SCr) or reduced urine output. This definition is challenging to apply in neonates given the physiologic decline in SCr during the first week of life. Gupta et al. proposed alternative neonatal criteria centered on rate of SCr decline. This study aimed to compare the rate of AKI based on KDIGO and Gupta in neonates with HIE and to examine associations with mortality and morbidity. Methods: A retrospective review was performed of neonates with moderate to severe HIE + TH from 2008 to 2020 at a single center. AKI was assessed in the first 7 days after birth by KDIGO and Gupta criteria. Mortality, brain MRI severity of injury, length of stay, and duration of respiratory support were compared between AKI groups. Results: Among 225 neonates, 64 (28%) met KDIGO, 69 (31%) neonates met Gupta but not KDIGO, and 92 (41%) did not meet either definition. Both KDIGO-AKI and GuptaOnly-AKI groups had an increased risk of the composite mortality and/or moderate/severe brain MRI injury along with longer length of stay and prolonged duration of respiratory support compared to those without AKI. Conclusions: AKI in neonates with HIE + TH was common and varied by definition. The Gupta definition based on rate of SCr decline identified additional neonates not captured by KDIGO criteria who are at increased risk for adverse outcomes. Incorporating the rate of SCr decline into the neonatal AKI definition may increase identification of clinically relevant kidney injury in neonates with HIE + TH. [ABSTRACT FROM AUTHOR]

This study aimed to characterize the circumstances of death in encephalopathic neonates treated with therapeutic hypothermia. Patients who died after or during treatment with therapeutic hypothermia between 2007-2014 were identified. Patient circumstance of death was characterized using an established paradigm. Thirty-one of 229 patients died (14%) at a median of 3 days of life. Most who died were severely encephalopathic on examination (90%) and had severely abnormal electroencephalographic (EEG) findings (87%). All those who had magnetic resonance images (n = 13) had evidence of moderate-severe brain injury; 6 had near-total brain injury. Cooling was discontinued prematurely in 61% of patients. Most patients (90%) were physiologically stable at the time of death; 81% died following elective extubation for quality of life considerations. Three patients (10%) died following withholding or removal of artificial hydration and nutrition. Characterization of death in additional cohorts is needed to identify differences in decision making practices over time and between centers. [ABSTRACT FROM AUTHOR]

The total seizure burden (p = 0.003, Kruskal-Wallis test) and maximum hourly seizure burden (p = 0.007, Kruskal-Wallis test) were both significantly associated with outcome so that the deceased neonates and those who developed epilepsy had a higher total seizure burden and maximum hourly seizure burden than those with a favorable outcome. B RESULTS: b The statistical tests indicated that graph metrics derived from different FCMs for pre-seizure and seizure segments significantly differed for both EEG montages (p < 0.001), with global efficiency having the largest variations between pre-seizure and seizure segments for both montages and all functional networks, and mean clustering coefficient having the smallest differences (Fig. These data support the use of screening cvEEG to detect seizures in preterm infants with ICH, as about one-third of high-risk preterm neonates with encephalopathy/abnormal imaging had EEG-seizures despite a lack of clinically-suspected seizures. Feeding during therapeutic hypothermia is safe and may improve outcomes in newborns with peri... B Alburaki W b SP a,b sp , Scringer-Wilkes M SP c sp , Dawoud F SP c sp , Oliver N SP c sp , Lind J SP c sp , Zein H SP c,d sp , Leijser L SP c,d sp , Esser M SP c,d sp , Mohammad K SP c,d sp I SP a sp Horizon Health Network, Saint John, Canada i I SP b sp Dalhousie and Memorial Universities, Saint John, Canada i I SP c sp Alberta Health Services, Calgary, Canada i I SP d sp University of Calgary, Calgary, Canada i B OBJECTIVE: b We assessed the impact of early enteral feeding introduction during therapeutic hypothermia on time to reach full enteral feeding (FEF) and other feeding related outcomes in infants born at =35 weeks gestational age and diagnosed with moderate to severe Hypoxic-Ischemic Encephalopathy. [Extracted from the article]

STUDY OBJECTIVE To evaluate the pharmacokinetics of gentamicin in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia and to identify an empiric gentamicin dosing strategy in this population that optimizes achievement of target peak and trough concentrations. DESIGN Population pharmacokinetic study using retrospective medical record data. SETTING Tertiary neonatal intensive care unit. PATIENTS A total of 29 full-term neonates diagnosed with HIE treated with hypothermia who received gentamicin and underwent therapeutic drug monitoring. MEASUREMENT AND MAIN RESULTS Patient demographics and gentamicin concentration data were retrospectively collected over a 2-year period. A population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). Using the developed model, Monte Carlo simulations were performed to evaluate the probability of achieving target peak (> 6 mg/L) and trough (< 2 mg/L) gentamicin concentrations for various potential dosing regimens. A one-compartment model best described the available gentamicin concentration data. Birthweight and serum creatinine significantly influenced gentamicin clearance. For the typical study neonate (birthweight 3.3 kg, serum creatinine 0.9 mg/dl), clearance was 0.034 L/hour/kg and volume was 0.52 L/kg. At a 24-hour dosing interval, Monte Carlo simulations predicted target gentamicin peak and trough concentrations could not be reliably achieved at any dose. At a 36-hour dosing interval, a dose of 4-5 mg/kg is predicted to achieve target gentamicin peak and trough concentrations in more than 90% of neonates. CONCLUSIONS Gentamicin clearance is decreased in neonates with HIE treated with hypothermia compared with previous reports in nonasphyxiated normothermic full-term neonates. A prolonged 36-hour dosing interval will be needed to achieve target gentamicin trough concentrations in this population. Further prospective evaluation of this dosing recommendation is needed. [ABSTRACT FROM AUTHOR]

Abstract: Neonatal seizures are common clinical conditions in both term and preterm neonates, yet no clinical management guidelines for direct care exist. We surveyed 193 international neurologists, neonatologists, and specialists in neonatal neurology or neonatal neurocritical care to assess management practices for seizures in preterm and term neonates. We found high reported rates of electroencephalogram and amplitude-integrated electroencephalogram (aEEG) monitoring to detect neonatal seizures, prevalent use of older anticonvulsant agents, and high rates of neuroimaging. Overall, responses were similar for term and preterm neonates. However, term neonates were likelier to be more heavily investigated, with higher use of magnetic resonance imaging and of electroencephalogram and aEEG monitoring of at-risk neonates. Continuous monitoring and cranial imaging of neonatal seizures now comprise the standard of care in many centers, although management practices vary widely. Early recognition and management of neonatal seizures and possible underlying injury may lead to increased opportunities for stopping seizures, protecting the brain, and improving developmental outcomes in at-risk neonates. The need for collaboration among neonatologists and neurologists is urgent, to address gaps in knowledge regarding management of neonatal seizures in term and preterm neonates. [Copyright &y& Elsevier]

Summary: In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic‐ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to characterize seizures among preterm neonates enrolled in the Neonatal Seizure Registry, a prospective cohort of consecutive neonates with seizures at seven pediatric centers that follow the American Clinical Neurophysiology Society's neonatal electroencephalography monitoring guideline.Study Design: Of 611 enrolled neonates with seizures, 92 (15%) were born preterm. Seizure characteristics were evaluated by gestational age at birth for extremely preterm (<28 weeks, N = 18), very preterm (28 to <32 weeks, N = 18), and moderate to late preterm (32 to <37 weeks, N = 56) and compared with term neonates.Results: Hypoxic-ischemic encephalopathy (33%) and intracranial hemorrhage (27%) accounted for the etiology in more than half of preterm neonates. Hypothermia therapy was utilized in 15 moderate to late preterm subjects with encephalopathy. The presence of subclinical seizures, monotherapy treatment failure, and distribution of seizure burden (including status epilepticus) was similar in preterm and term neonates. However, exclusively subclinical seizures occurred more often in preterm than term neonates (24% vs 14%). Phenobarbital was the most common initial medication for all gestational age groups, and failure to respond to an initial loading dose was 63% in both preterm and term neonates. Mortality was similar among the three preterm gestational age groups; however, preterm mortality was more than twice that of term infants (35% vs 15%).Conclusions: Subclinical seizures were more common and mortality was higher for preterm than term neonates. These data underscore the importance of electroencephalographic monitoring and the potential for improved management in preterm neonates. [ABSTRACT FROM AUTHOR]

Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the safety and pharmacokinetics of eryth- ropoietin (Epo) given in conjunction with hypothermia for hypoxic- ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10 000 U/L; area under the curve = 117 000-140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit > 12), 10-minute Apgar score 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (A/= 6), 1000 (A/= 7), or 2500 U/kg per dose (A/= 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500,1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the safety and pharmacokinetics of eryth- ropoietin (Epo) given in conjunction with hypothermia for hypoxic- ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10 000 U/L; area under the curve = 117 000-140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit > 12), 10-minute Apgar score ^ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (A/= 6), 1000 (A/= 7), or 2500 U/kg per dose (A/= 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500,1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE. [ABSTRACT FROM AUTHOR]

Defining the structural and functional connectivity of the human brain (the human "connectome") is a basic challenge in neuroscience. Recently, techniques for noninvasively characterizing structural connectivity networks in the adult brain have been developed using diffusion and high-resolution anatomic MRI. The purpose of this study was to establish a framework for assessing structural connectivity in the newborn brain at any stage of development and to show how network properties can be derived in a clinical cohort of six-month old infants sustaining perinatal hypoxic ischemic encephalopathy (HIE). Two different anatomically unconstrained parcellation schemes were proposed and the resulting network metrics were correlated with neurological outcome at 6 months. Elimination and correction of unreliable data, automated parcellation of the cortical surface, and assembling the large-scale baby connectome allowed an unbiased study of the network properties of the newborn brain using graph theoretic analysis. In the application to infants with HIE, a trend to declining brain network integration and segregation was observed with increasing neuromotor deficit scores. [ABSTRACT FROM AUTHOR]

Within a single-center prospective cohort study of neonatal encephalopathy involving 315 subjects, 15 neonates were found to have a focal stroke on magnetic resonance imaging. These 15 patients were matched on the basis of gender and degree of encephalopathy to 30 neonates without stroke from the same cohort. On Bayley Scales of Infant Development, the stroke group had Mental Development Index scores that were 1.7 standard deviations lower compared with controls (P = .007). This association was no longer seen after adjustment for the presence of neonatal seizures (P = .11). Of the 15 patients with stroke, 5 had been treated with hypothermia. None of these 5 had seizures in the neonatal period, compared with 7 of the untreated 10. This is the first human study to demonstrate a potential treatment effect of therapeutic hypothermia on perinatal stroke. It was also shown that seizures are associated with worse cognitive outcomes for stroke that presents with encephalopathy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy. METHODS: In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n - 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar <5, pH <7.00 or base deficit ≥15, or resuscitation at 10 minutes); and received hypothermia. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale and Warner Initial Developmental Evaluation. Two independent observers rated MRI brain injury severity by using an established scoring system. RESULTS: The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo-treated [n = 21) versus placebo-treated (n - 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P=.05). CONCLUSIONS: High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function. [ABSTRACT FROM AUTHOR]