44 results on '"Sandra E Juul"'
Search Results
2. Prevalence of acute kidney injury (AKI) in extremely low gestational age neonates (ELGAN)
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Patrick D. Brophy, David J. Askenazi, Stuart L. Goldstein, Sandra E. Juul, Russell Griffin, Patrick J. Heagerty, Dennis E. Mayock, Robert H. Schmicker, and Sangeeta Hingorani
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Male ,Nephrology ,medicine.medical_specialty ,030232 urology & nephrology ,Gestational Age ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Intensive Care Units, Neonatal ,Internal medicine ,Prevalence ,Humans ,Medicine ,Creatinine ,biology ,business.industry ,Incidence (epidemiology) ,Infant, Newborn ,Acute kidney injury ,Gestational age ,Acute Kidney Injury ,medicine.disease ,chemistry ,Cystatin C ,Infant, Extremely Low Birth Weight ,Infant, Extremely Premature ,Pediatrics, Perinatology and Child Health ,Cohort ,biology.protein ,Female ,business ,Kidney disease - Abstract
BACKGROUND: To determine the prevalence and severity of acute kidney injury (AKI) at different time frames in relation to gestational age (GA) and birthweight (BW) in extremely low gestational age neonates (ELGAN). Our hypothesis is that ELGAN with lower GA and lower BW have higher AKI rates. METHODS: 923 ELGAN enrolled in the Preterm Erythropoietin Neuroprotection Trial were evaluated from birth until death or hospital discharge. AKI was defined according to kidney disease: improving global outcomes (KDIGO) definition from clinically-derived serum creatinine (SCr) measurements. Severe AKI was defined as stage 2 or higher. RESULTS: For the entire cohort, 351/923 (38.0%, CI = 34.8–41.3%) had at least one episode of stage 1 or higher AKI and 168/923 (18.2%, CI = 15.7–20.7%) had at least one episode of severe (stage 2 or higher) AKI. The prevalence of AKI stage 1 or higher for the entire cohort during the early (days 3–7), middle (days 8–14) and late follow-up period (after day 14) was 112/923 (12.1%, CI = 10.0–14.3%), 142/891 (15.9%, CI = 13.5–18.4%) and 249/875 (28.5%, CI = 25.4–31.5%), respectively. The rates of severe AKI during the hospital course were 27.8%, 21.9%, 13.6%, and 9.4% for the 24, 25, 26 and 27 week GA groups respectively. AKI rates were significantly higher with decreasing GA and decreasing BW for stated time trends (all p < 0.01 using tests for trend). CONCLUSIONS: AKI is relatively common in ELGAN during their initial hospital course, and is associated with lower GA and BW.
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- 2020
3. Utilization of Erythropoietin within the United States Neonatal Intensive Care Units from 2008 to 2017
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Sandra E. Juul, Robin K. Ohls, Kaashif A. Ahmad, Reese H. Clark, Veeral N. Tolia, and Monica Bennett
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Male ,Pediatrics ,medicine.medical_specialty ,Anemia ,Population ,Encephalopathy ,Gestational Age ,03 medical and health sciences ,0302 clinical medicine ,Intensive Care Units, Neonatal ,hemic and lymphatic diseases ,030225 pediatrics ,Intensive care ,medicine ,Humans ,In patient ,030212 general & internal medicine ,education ,Erythropoietin ,Retrospective Studies ,education.field_of_study ,Anemia, Neonatal ,business.industry ,Infant, Newborn ,Obstetrics and Gynecology ,Gestational age ,Retrospective cohort study ,medicine.disease ,Neuroprotection ,United States ,Hypoxia-Ischemia, Brain ,Infant, Small for Gestational Age ,Pediatrics, Perinatology and Child Health ,Drug Evaluation ,Female ,business ,medicine.drug - Abstract
Objective Little data are available regarding erythropoietin (Epo) utilization patterns within neonatal intensive care units (NICUs). We sought to describe the trends in Epo utilization across a large cohort of U.S. NICUs.Study Design This is a retrospective cohort study of infants discharged from 2008 to 2017 using the Pediatrix Clinical Data Warehouse.Results We identified 704,159 eligible infants from 358 sites, of whom 9,749 (1.4%) had Epo exposure. For extremely low gestational age newborns (ELGANs), Epo exposure ranged from 7.6 to 13.5%. We found significant site variability in Epo utilization in ELGANs. Among the 299 NICUs caring for ELGANs during the study period, 184 (61.5%) never used Epo for this population, whereas 21 (7%) utilized Epo in 50% or more of eligible infants. Epo was initiated at a median of 25 days in ELGANs. For infants with hypoxic–ischemic encephalopathy (HIE), Epo exposure remained ≤1% through 2014 then increased fourfold to 3.4% by 2017. The median day of Epo initiation was the day of birth for infants diagnosed with HIE.Conclusion Epo is utilized in ELGANs more commonly than for other NICU populations. Utilization patterns appear to indicate the treatment of established anemia for ELGANs and more recently for neuroprotection in patients diagnosed with HIE.
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- 2019
4. Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation
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Taeun Chang, Brenda Poindexter, Gregory M. Sokol, Patrick J Heagerty, Mark Smith, Jessica L Wisnowski, Amit M Mathur, Jeffrey Berman, Ping-Sun Keven Chen, James Dix, Trevor Flynn, Stanley Fricke, Seth D Friedman, Hayden W Head, Chang Y Ho, Beth Kline-Fath, Michael Oveson, Richard Patterson, Sumit Pruthi, Nancy Rollins, Yanerys M Ramos, John Rampton, Jerome Rusin, Dennis W Shaw, Jean Tkach, Shreyas Vasanawala, Arastoo Vossough, Matthew T Whitehead, Duan Xu, Kristen Yeom, Bryan Comstock, Sandra E Juul, Yvonne W Wu, Robert C McKinstry, Kaashif Ahmed, Mariana Beserga, Ellen Bendel-Stenzel, Lina Chalak, John Flibotte, Fernando Gonzalez, Andrea Lampland, Nathalie Maitre, Amit M. Mathur, Dennis Mayock, Ulrike Mietzsch, Rakesh Rao, David Riley, Krisa Van Meurs, Hendrik Weitkamp, Tai-Wei Wu, and Toby Yanowitz
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medicine.medical_specialty ,Encephalopathy ,Neuroimaging ,neonatology ,03 medical and health sciences ,Asphyxia ,0302 clinical medicine ,Clinical Trial Protocols as Topic ,medicine ,neonatal intensive & critical care ,Data monitoring committee ,neuroradiology ,Humans ,Multicenter Studies as Topic ,030212 general & internal medicine ,Intensive care medicine ,Erythropoietin ,Neuroradiology ,Protocol (science) ,business.industry ,Infant, Newborn ,Paediatrics ,General Medicine ,medicine.disease ,neurological injury ,Hypoxia-Ischemia, Brain ,Medicine ,developmental neurology & neurodisability ,paediatric radiology ,medicine.symptom ,Paediatric radiology ,business ,030217 neurology & neurosurgery ,Biomarkers ,medicine.drug - Abstract
Introduction MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms. Methods and analysis Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation—thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans. Ethics and dissemination IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor. Trial registration number NCT02811263; Pre-result.
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- 2021
5. Trends in reticulocyte hemoglobin equivalent values in critically ill neonates, stratified by gestational age
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Kendell R. German, Sandra E. Juul, Phuong T. Vu, and Jill D Irvine
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Pediatrics ,medicine.medical_specialty ,Reticulocytes ,Neonatal intensive care unit ,endocrine system diseases ,Anemia ,Critical Illness ,Iron ,Gestational Age ,Infant, Premature, Diseases ,Enteral administration ,Hemoglobins ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Intensive Care Units, Neonatal ,030225 pediatrics ,Humans ,Medicine ,030212 general & internal medicine ,Retrospective Studies ,Anemia, Iron-Deficiency ,business.industry ,Infant, Newborn ,Obstetrics and Gynecology ,Gestational age ,Retrospective cohort study ,Iron Deficiencies ,Iron deficiency ,medicine.disease ,Iron sulfate ,chemistry ,Dietary Supplements ,Pediatrics, Perinatology and Child Health ,Erythrocyte Count ,Hemoglobin ,business ,Biomarkers ,Infant, Premature - Abstract
The reticulocyte index reticulocyte hemoglobin equivalent (Ret-He) was evaluated as a marker of iron status. This is a retrospective cohort study of all infants admitted to the University of Washington Neonatal Intensive Care Unit, who received Ret-He measurements as part of routine care within the first 120 days of life. A total of 730 Ret-He measurements from 249 infants were analyzed (median gestational age at birth 32.1 weeks; 49 infants
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- 2019
6. Placental pathology and neonatal brain MRI in a randomized trial of erythropoietin for hypoxic–ischemic encephalopathy
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Amit M. Mathur, Dennis E. Mayock, Robert C. McKinstry, Krisa P. Van Meurs, Sandra E. Juul, Fernando F. Gonzalez, Amy M. Goodman, Sarah B. Mulkey, Yvonne W. Wu, Raymond W. Redline, and Taeun Chang
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medicine.medical_specialty ,Clinical pathology ,business.industry ,Encephalopathy ,Hypothermia ,medicine.disease ,Gastroenterology ,Hypoxic Ischemic Encephalopathy ,law.invention ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Erythropoietin ,law ,030225 pediatrics ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Abnormality ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Newborns with hypoxic–ischemic encephalopathy (HIE) may exhibit abnormalities on placental histology. In this phase II clinical trial ancillary study, we hypothesized that placental abnormalities correlate with MRI brain injury and with response to treatment. Fifty newborns with moderate/severe encephalopathy who received hypothermia were enrolled in a double-blind, placebo-controlled trial of erythropoietin for HIE. A study pathologist reviewed all available clinical pathology reports to determine the presence of chronic abnormalities and acute chorioamnionitis. Neonatal brain MRIs were scored using a validated HIE scoring system. Placental abnormalities in 19 of the 35 (54%) patients with available pathology reports included chronic changes (N = 13), acute chorioamnionitis (N = 9), or both (N = 3). MRI subcortical brain injury was less common in infants with a placental abnormality (26 vs. 69%, P = 0.02). Erythropoietin treatment was associated with a lower global brain injury score (median 2.0 vs. 11.5, P = 0.003) and lower rate of subcortical brain injury (33 vs. 90%, P = 0.01) among patients with no chronic placental abnormality but not in patients whose placentas harbored a chronic abnormality. Erythropoietin treatment was associated with less brain injury only in patients whose placentas exhibited no chronic histologic changes. Placentas may provide clues to treatment response in HIE.
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- 2019
7. Prevalence of iron deficiency in first trimester, nonanemic pregnant women
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Sandra E. Juul, Jessica Abernathy, Vanessa L. Short, Michael Auerbach, and Richard J. Derman
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medicine.medical_specialty ,030204 cardiovascular system & hematology ,Hemoglobins ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Prevalence ,medicine ,Humans ,030219 obstetrics & reproductive medicine ,Anemia, Iron-Deficiency ,business.industry ,Task force ,Obstetrics ,Infant, Newborn ,Infant ,Obstetrics and Gynecology ,Iron deficiency ,medicine.disease ,United Kingdom ,Pregnancy Trimester, First ,First trimester ,Pediatrics, Perinatology and Child Health ,Female ,Pregnant Women ,business - Abstract
Despite a high frequency of iron deficiency in pregnancy, the United States Preventative Services Task Force (USPSTF) stated: "there is inconclusive evidence routine supplementation for iron deficiency anemia improves maternal or infant clinical health outcomes." In contradistinction, high-quality epidemiologic studies report long lasting deficits in infants diagnosed with iron deficiency in the first 6 months of life compared with infants who were not, with specific deficits in cognition, memory, executive function and electrophysiology documented up to 19 years of age. Infants are not routinely screened for iron deficiency. United Kingdom guidelines differ and recommend screening high-risk infants who are preterm, of diabetic, underweight, obese, or vegetarian mothers, those born to anemic or iron deficient mothers, of smokers, those with inflammatory bowel disease or abnormal uterine bleeding, and from pregnancies in which the intergravid period is6 months. Iron parameters are not routinely drawn unless anemia is present and in some cases only if microcytic. In that iron deficiency precedes the development of anemia, and waiting for its development misses a large number of overtly iron deficient gravidas. Iron parameters were measured in 102 consecutive, nonselected, nonanemic, first trimester women presenting to their obstetricians. Using standard cutoffs of percent transferrin saturation and/or serum ferritin, 42% were observed to be iron deficient. Given the lack of harm of testing for iron deficiency, it appears prudent to err on the side of caution and screen all presenting pregnant mothers until properly powered outcome data become available. The current recommendations of the USPSTF may need to be revisited.
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- 2019
8. Perinatal Iron Deficiency: Implications for Mothers and Infants
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Sandra E. Juul, Michael Auerbach, and Richard J. Derman
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medicine.medical_specialty ,Pediatrics ,Anemia ,Gestational Age ,Severe anemia ,Hemoglobins ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,hemic and lymphatic diseases ,030225 pediatrics ,Epidemiology ,Prevalence ,medicine ,Humans ,030212 general & internal medicine ,Fetal Death ,Fetus ,Anemia, Iron-Deficiency ,business.industry ,Infant, Newborn ,Iron Deficiencies ,Iron deficiency ,Fetal Blood ,medicine.disease ,Iron-deficiency anemia ,Pediatrics, Perinatology and Child Health ,Treatment strategy ,Female ,business ,Developmental Biology - Abstract
Iron deficiency, with or without anemia, is common in pregnant women. In fact, nearly 30% of reproductive-age women are anemic worldwide, and anemia in pregnancy has an estimated global prevalence of 38%. Severe anemia can substantially increase the risk of maternal mortality, and can adversely affect fetal development. In this review, we examine the available data regarding epidemiology and consequences of iron deficiency in mothers and infants, current treatment strategies, and make recommendations for screening and treatment of iron deficiency anemia in gravidas and neonates.
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- 2019
9. Severe Acute Kidney Injury and Mortality in Extremely Low Gestational Age Neonates
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Robert H. Schmicker, Patrick J. Heagerty, Sangeeta Hingorani, Penut Investigators, Sandra E. Juul, Patrick D. Brophy, David J. Askenazi, and Stuart L. Goldstein
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Male ,medicine.medical_specialty ,Epidemiology ,Gestational Age ,Critical Care and Intensive Care Medicine ,urologic and male genital diseases ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,030225 pediatrics ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Prospective Studies ,Erythropoietin ,Cause of death ,Transplantation ,business.industry ,Proportional hazards model ,Hazard ratio ,Acute kidney injury ,Infant, Newborn ,Gestational age ,Acute Kidney Injury ,medicine.disease ,Confidence interval ,female genital diseases and pregnancy complications ,Recombinant Proteins ,Intraventricular hemorrhage ,Nephrology ,Infant, Extremely Premature ,Female ,Original Article ,business ,Kidney disease - Abstract
BACKGROUND AND OBJECTIVES: AKI is associated with poor short- and long-term outcomes. Questions remain about the frequency and timing of AKI, and whether AKI is a cause of death in extremely low gestational age neonates. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Recombinant Erythropoietin for Protection of Infant Kidney Disease Study examines the kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo Neuroprotection study, a randomized, placebo-controlled trial of recombinant human erythropoietin. We included 900 of 941 patients enrolled in Preterm Epo Neuroprotection. Baseline characteristics were compared by primary exposure (severe AKI versus none/stage 1 AKI) using unadjusted logistic regression models. Cox regression models estimated the relationship between severe AKI and death after adjustment for potential confounders. Time-dependent AKI was modeled as a binary outcome and a categorical variable by stage of AKI. We fit Cox models using time-dependent AKI status lagged by
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- 2020
10. Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia
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Raymand Pang, Nicola J. Robertson, Tatenda Mutshiya, Xavier Golay, Kathryn A. Martinello, Qin Yang, Christopher Meehan, F. J. Torrealdea, Mariya Hristova, Alan Bainbridge, Adnan Avdic-Belltheus, Sandra E. Juul, and Magdalena Sokolska
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melatonin ,therapeutic hypothermia ,Pharmacology ,Neuroprotection ,Melatonin ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Bolus (medicine) ,030225 pediatrics ,Medicine ,Biological Psychiatry ,AcademicSubjects/SCI01870 ,business.industry ,Neonatal encephalopathy ,neonatal encephalopathy ,Hypoxia (medical) ,Hypothermia ,medicine.disease ,Perinatal asphyxia ,Psychiatry and Mental health ,Neurology ,Erythropoietin ,Original Article ,AcademicSubjects/MED00310 ,neuroprotection ,erythropoietin ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
As therapeutic hypothermia is only partially protective for neonatal encephalopathy, safe and effective adjunct therapies are urgently needed. Melatonin and erythropoietin show promise as safe and effective neuroprotective therapies. We hypothesized that melatonin and erythropoietin individually augment 12-h hypothermia (double therapies) and hypothermia + melatonin + erythropoietin (triple therapy) leads to optimal brain protection. Following carotid artery occlusion and hypoxia, 49 male piglets (, As therapeutic hypothermia is partially protective in neonatal encephalopathy, adjunct therapies are required. In a piglet model of perinatal asphyxia, Pang et al. report that melatonin and erythropoietin are safe and individually augment cooling through different mechanisms. Staggered rather than concomitant dosing may be optimal for brain protection., Graphical Abstract Graphical Abstract
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- 2020
11. Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial
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Dennis E. Mayock, Nishant Srinivasan, Ivan D. Frantz, Kaashif A. Ahmad, Nancy Fahim, L. Corbin Downey, Maureen M. Gilmore, Michael O'Shea, Janine Y. Khan, Bryan A. Comstock, Tonya W Robinson, Robin K. Ohls, Andrea L. Lampland, Raghavendra Rao, Michael D. Weiss, Sherry E. Courtney, Ellen M. Bendel-Stenzel, Jorge E. Perez, Mariana Baserga, Victor J. McKay, Rajan Wadhawan, Edmund F. LaGamma, Sandra E. Juul, Phuong T. Vu, and Patrick J. Heagerty
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Blood transfusion ,medicine.medical_treatment ,Population ,Gestational Age ,Infant, Premature, Diseases ,Hematocrit ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,030225 pediatrics ,Intensive care ,medicine ,Humans ,Blood Transfusion ,030212 general & internal medicine ,education ,Erythropoietin ,education.field_of_study ,medicine.diagnostic_test ,Dose-Response Relationship, Drug ,business.industry ,Postmenstrual Age ,Infant, Newborn ,Gestational age ,Correction ,Infant, Low Birth Weight ,Low birth weight ,Pediatrics, Perinatology and Child Health ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure.To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions.The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019.In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks.Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein.A total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P .001).These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants.ClinicalTrials.gov Identifier: NCT01378273.
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- 2020
12. Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial
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Dennis E. Mayock, Phuong T. Vu, Robin K. Ohls, Patrick J. Heagerty, Kendell R. German, Sandra E. Juul, and Bryan A. Comstock
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Adult ,Central Nervous System ,Pediatrics ,medicine.medical_specialty ,Population ,Placebo ,law.invention ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Randomized controlled trial ,law ,Pregnancy ,030225 pediatrics ,Post-hoc analysis ,Medicine ,Humans ,education ,Erythropoietin ,education.field_of_study ,Clinical Research Article ,business.industry ,Postmenstrual Age ,Infant, Newborn ,Gestational age ,Neuroprotective Agents ,Treatment Outcome ,Infant, Extremely Low Birth Weight ,Pediatrics, Perinatology and Child Health ,Gestation ,Female ,business ,Erythrocyte Transfusion ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population. Methods This is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions. Results Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of [-1.34, -0.57]), a decrease in mean motor score of 1.51 (-1.91, -1.12), and a decrease in mean language score of 1.10 (-1.54, -0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group. Conclusions Transfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes. Impact Transfusion number, volume, and donor exposure in the neonatal period are associated with worse neurodevelopmental (ND) outcome at 2 years of age, as assessed by the Bayley Infant Scales of Development, Third Edition (BSID-III). The impact of neonatal packed red blood cell transfusions on the neurodevelopmental outcome of preterm infants is unknown. We speculate that strategies to minimize the need for transfusions may improve neurodevelopmental outcomes.
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- 2020
13. High-Dose Erythropoietin in Extremely Low Gestational Age Neonates Does Not Alter Risk of Retinopathy of Prematurity
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Bryan A. Comstock, Zimeng Xie, Sandra E. Juul, Dennis E. Mayock, and Patrick J. Heagerty
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Male ,Pediatrics ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Birth weight ,Gestational Age ,Placebo ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Risk Factors ,030225 pediatrics ,Medicine ,Humans ,Retinopathy of Prematurity ,030212 general & internal medicine ,Erythropoietin ,business.industry ,Incidence (epidemiology) ,Infant, Newborn ,Gestational age ,Infant ,Retinopathy of prematurity ,Infant, Low Birth Weight ,medicine.disease ,eye diseases ,Pediatrics, Perinatology and Child Health ,Gestation ,Female ,business ,Infant, Premature ,Developmental Biology ,medicine.drug - Abstract
Introduction: The Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial sought to determine the safety and efficacy of early high-dose Epo as a potential neuroprotective treatment. We hypothesized that Epo would not increase the incidence or severity of retinopathy of prematurity (ROP). Methods: A total of 941 infants born between 24–0/7 and 27–6/7 weeks’ gestation were randomized to 1,000 U/kg Epo or placebo intravenously for 6 doses, followed by subcutaneous or sham injections of 400 U/kg Epo 3 times a week through 32 weeks post-menstrual age. In this secondary analysis of PENUT trial data, survivors were evaluated for ROP. A modified intention-to-treat approach was used to compare treatment groups. In addition, risk factors for ROP were evaluated using regression methods that account for multiples and allow for adjustment for treatment and gestational age at birth. Results: Of 845 subjects who underwent ROP examination, 503 were diagnosed with ROP with similar incidence and severity between treatment groups. Gestational age at birth, birth weight, prenatal magnesium sulfate, maternal antibiotic exposure, and presence of heart murmur at 2 weeks predicted the development of any ROP, while being on high-frequency oscillator or high-frequency jet ventilation (HFOV/HFJV) at 2 weeks predicted severe ROP. Conclusion: Early high-dose Epo followed by maintenance dosing through 32 weeks does not increase the risk of any or severe ROP in extremely low gestational age neonates. Gestational age, birth weight, maternal treatment with magnesium sulfate, antibiotic use during pregnancy, and presence of a heart murmur at 2 weeks were associated with increased risk of any ROP. Treatment with HFOV/HFJV was associated with an increased risk of severe ROP.
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- 2020
14. The Impact of Erythropoietin on Short- and Long-Term Kidney-Related Outcomes in Neonates of Extremely Low Gestational Age. Results of a Multicenter, Double-Blind, Placebo-Controlled Randomized Clinical Trial
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David J. Askenazi, Patrick J. Heagerty, Robert H. Schmicker, Patrick Brophy, Sandra E. Juul, Stuart L. Goldstein, Sangeeta Hingorani, Bryan A. Comstock, Rajan Wadhawan, Dennis E. Mayock, Sherry E. Courtney, Tonya Robinson, Kaashif A. Ahmad, Ellen Bendel-Stenzel, Mariana Baserga, Edmund F. LaGamma, L. Corbin Downey, Raghavendra Rao, Nancy Fahim, Andrea Lampland, Ivan D. Frantz, Janine Y. Khan, Michael Weiss, Maureen M. Gilmore, Robin Ohls, Nishant Srinivasan, Jorge E. Perez, Victor McKay, Phuong T. Vu, Billy Thomas, Nahed Elhassan, Sarah Mulkey, Philip Dydynski, Vivek K. Vijayamadhavan, Neil Mulrooney, Bradley Yoder, Jordan S. Kase, Jennifer Check, Semsa Gogcu, Erin Osterholm, Sara Ramel, Catherine Bendel, Cheryl Gale, Thomas George, Michael Georgieff, Tate Gisslen, Sixto Guiang, Anne Hall, Dana Johnson, Katie Pfister, Heather Podgorski, Kari Roberts, Erin Stepka, Melissa Engel, Heidi Kamrath, Johannah Scheurer, Angela Hanson, Katherine Satrom, Susan Pfister, Ann Simones, Erin Plummer, Elizabeth Zorn, Camilia R. Martin, Deirdre O'Reilly, Nicolas Porta, Catalina Bazacliu, Jonathan Williams, Dhanashree Rajderkar, Frances Northington, Raul Chavez Valdez, Sandra Beauman, Patel Saurabhkumar, Magaly Diaz-Barbosa, Arturo Serize, Jorge Jordan, Debbie Ott, Ariana Franco Mora, Pamela Hedrick, Vicki Flynn, Amy Silvia, Bailey Clopp, John B. Feltner, Isabella Esposito, Stephanie Hauge, Samantha Nikirk, Andrea Purnell, Emilie Loy, Natalie Sikes, Melanie Mason, Jana McConnell, Tiffany Brown, Henry Harrison, Denise Pearson, Tammy Drake, Jocelyn Wright, Debra Walden, Annette Guy, Jennifer Nason, Morgan Talbot, Kristen Lee, Sarah Penny, Terri Boles, Melanie Drummond, Katy Kohlleppel, Charmaine Kathen, Brian Kaletka, Shania Gonzales, Cathy Worwa, Molly Fisher, Tyler Richter, Alexander Ginder, Brixen Reich, Carrie Rau, Manndi Loertscher, Laura Bledsoe, Kandace McGrath, Kimberlee Weaver Lewis, Jill Burnett, Susan Schaefer, Karie Bird, Clare Giblin, Rita Daly, Kristi Lanier, Kelly Warden, Jenna Wassenaar, Jensina Ericksen, Bridget Davern, Mary Pat Osborne, Brittany Gregorich, Neha Talele, Evelyn Obregon, Tiglath Ziyeh, Molly Clarke, Rachel E. Wegner, Palak Patel, Molly Schau, Annamarie Russow, Kelly Curry, Susan Sinnamon, Lisa Barnhart, Charlamaine Parkinson, Mary Hanson, Elizabeth Kuan, Conra Backstrom Lacy, Edshelee M. Galvis, Susana Bombino, Denise Martinez, Suzi Bell, Corrie Long, Cathy Longa, Michael Westerveld, Stacy McConkey, Anne Hay, Niranjana Natarajan, Shari Gaudette, Sarah Cobb, Gregory Sharp, Elizabeth Schumacher, Leslie Schuschke, Charlotte Frey, Mario Fierro, Lois Gilmore, Pamela Lundequam, Ronald Hoekstra, Anastasia Ketko, Nina Perdue, Sean Cunningham, Kelly Stout, Becky Hall, Galina Morshedzadeh, Betsy Ostrander, Sarah Winter, Lauren Cox, Matthew A. Rainaldi, Sarah Hensley, Melissa Morris, Dia Roberts, Melissa Tuttle, Christopher Boys, Solveig Hultgren, Elizabeth I. Pierpont, Tom George, Kelly E. King, Katherine Bataglia, Cathy Neis, Mark Bergeron, Cristina Miller, Cara Accomando, Jennifer Anne Gavin, Elizabeth Maczek, Susan Marakovitz, Aimee Knorr, Vincent C. Smith, Jane E. Stewart, Marie Weissbourd, Raye-Ann deRegnier, Nana Matoba, Shelly C. Heaton, Erika M. Cascio, Janet Brady, Suman Ghosh, Jessica Ditto, Mary Leppert, Jean Lowe, Janell Fuller, Tara DuPont, Pamela Kloska, Saurabh Patel, Lauren Carbonell, Anna Maria Patino-Fernandez, Carmen de Lerma, Kelly McDonough, Maiana De Cortada, Lacy Chavis, Jane Shannon, Mark A. Konodi, Christopher Nefcy, Karl C.K. Kuban, Jean R. Lowe, T. Michael O'Shea, Manjiri Dighe, Todd Richards, Dennis W.W. Shaw, Colin Studholme, Christopher M. Traudt, Roberta Ballard, Adam Hartman, Scott Janis, T. Robin Ohls, Michael O'Shea, Ronnie Guillet, M. Bethany Ball, Hannah Glass, Ben Saville, and Michael Schreiber
- Subjects
Male ,medicine.medical_specialty ,Renal function ,Gestational Age ,Infant, Premature, Diseases ,Placebo ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,030225 pediatrics ,Internal medicine ,medicine ,Albuminuria ,Humans ,030212 general & internal medicine ,Renal Insufficiency, Chronic ,Erythropoietin ,business.industry ,Acute kidney injury ,Infant, Newborn ,Gestational age ,Acute Kidney Injury ,medicine.disease ,Recombinant Proteins ,Blood pressure ,Infant, Extremely Premature ,Pediatrics, Perinatology and Child Health ,Hypertension ,Female ,medicine.symptom ,business ,medicine.drug ,Glomerular Filtration Rate - Abstract
OBJECTIVE: To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22–26 months corrected gestational age (cGA) compared with those randomized to placebo. STUDY DESIGN: We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs. RESULTS: The prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs. placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine [SCr]/ cystatin C values at days 0, 7, 9 and 14). At 22–26 months cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) 30 mg/g, 23% had a systolic blood pressure (SBP) >95(th) percentile for age, and 40% had a diastolic blood pressure (DBP) >95(th) percentile for age. SBP >90(th) percentile occurred less often among recipients of erythropoietin (p95(th) percentile or DBP >90(th) or >95(th) percentiles. CONCLUSIONS: ELGANs have high rates of in-hospital AKI and kidney-related problems at 22–26 months cGA. Recombinant erythropoietin (rhEpo) may protect ELGANs against long-term elevated SBP, but does not appear to protect from AKI, low eGFR, albuminuria or elevated DBP at 22–26 months cGA.
- Published
- 2020
15. A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants
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Sandra E. Juul, Dennis E. Mayock, Andrea L. Lampland, Mariana Baserga, Kaashif A. Ahmad, Ivan D. Frantz, Robin K. Ohls, Jorge E. Perez, Rajan Wadhawan, Edmund F. LaGamma, Tonya W Robinson, T. Michael O'Shea, Nancy Fahim, Karl C.K. Kuban, Maureen M. Gilmore, Phuong T. Vu, Janine Y. Khan, Patrick J. Heagerty, Victor J. McKay, Nishant Srinivasan, L. Corbin Downey, Jean R. Lowe, Adam L. Hartman, Bryan A. Comstock, Raghavendra Rao, Michael D. Weiss, Sherry E. Courtney, and Ellen M. Bendel-Stenzel
- Subjects
Oncology ,medicine.medical_specialty ,Extremely premature ,business.industry ,Follow up studies ,General Medicine ,030204 cardiovascular system & hematology ,Neuroprotection ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Multicenter study ,Erythropoietin ,law ,Internal medicine ,Neonatal brain ,Medicine ,030212 general & internal medicine ,Ultrasonography ,business ,medicine.drug - Abstract
BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.)
- Published
- 2020
16. Association between newborn screening analytes and hypoxic ischemic encephalopathy
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Pranesh Chakraborty, Julian Little, Malia S.Q. Murphy, Steven Hawken, Lindsay A. Wilson, Thierry Lacaze-Masmonteil, Kumanan Wilson, Deshayne B. Fell, Sandra E. Juul, C. Wong, Mark Walker, and Beth K. Potter
- Subjects
Male ,medicine.medical_specialty ,Population ,Encephalopathy ,lcsh:Medicine ,Logistic regression ,Article ,Hypoxic Ischemic Encephalopathy ,03 medical and health sciences ,Medical research ,Neonatal Screening ,0302 clinical medicine ,Risk Factors ,030225 pediatrics ,Internal medicine ,Humans ,Medicine ,Registries ,lcsh:Science ,education ,Ontario ,education.field_of_study ,Pregnancy ,Newborn screening ,Multidisciplinary ,business.industry ,lcsh:R ,Infant, Newborn ,medicine.disease ,Cord blood ,Hypoxia-Ischemia, Brain ,Gestation ,Female ,lcsh:Q ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Hypoxic ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. Our study sought to examine whether patterns of newborn screening analytes differed between infants with and without neonatal HIE in order to identify opportunities for potential use of these analytes for diagnosis in routine clinical practice. We linked a population-based newborn screening registry with health databases to identify cases of HIE among term infants (≥37 weeks’ gestation) in Ontario from 2010–2015. Correlations between HIE and screening analytes were examined using multivariable logistic regression models containing clinical factors and individual screening analytes (acyl-carnitines, amino acids, fetal-to-adult hemoglobin ratio, endocrine markers, and enzymes). Among 731,841 term infants, 3,010 were diagnosed with HIE during the neonatal period. Multivariable models indicated that clinical variables alone or in combination with hemoglobin values were not associated with HIE diagnosis. Although the model was improved after adding acyl-carnitines and amino acids, the ability of the model to identify infants with HIE was moderate. Our findings indicate that analytes associated with catabolic stress were altered in infants with HIE; however, future research is required to determine whether amino acid and acyl-carnitine profiles could hold clinical utility in the early diagnosis or clinical management of HIE. In particular, further research should examine whether cord blood analyses can be used to identify HIE within a clinically useful timeframe or to guide treatment and predict long-term health outcomes.
- Published
- 2019
17. The fetus at the tipping point: modifying the outcome of fetal asphyxia
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Simerdeep K Dhillon, Joanne O. Davidson, Guido Wassink, Alistair J. Gunn, Nicola J. Robertson, Christopher A. Lear, Sandra E. Juul, Robert Galinsky, and Laura Bennet
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Fetus ,medicine.medical_specialty ,Physiology ,business.industry ,Obstetrics ,Fetal asphyxia ,Inflammation ,Hypoxia (medical) ,medicine.disease ,Perinatal asphyxia ,Cerebral palsy ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Diabetes mellitus ,medicine ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Glucocorticoid ,medicine.drug - Abstract
Brain injury around birth is associated with nearly half of all cases of cerebral palsy. Although brain injury is multifactorial, particularly after preterm birth, acute hypoxia-ischaemia is a major contributor to injury. It is now well established that the severity of injury after hypoxia-ischaemia is determined by a dynamic balance between injurious and protective processes. In addition, mothers who are at risk of premature delivery have high rates of diabetes and antepartum infection/inflammation and are almost universally given treatments such as antenatal glucocorticoids and magnesium sulphate to reduce the risk of death and complications after preterm birth. We review evidence that these common factors affect responses to fetal asphyxia, often in unexpected ways. For example, glucocorticoid exposure dramatically increases delayed cell loss after acute hypoxia-ischaemia, largely through secondary hyperglycaemia. This critical new information is important to understand the effects of clinical treatments of women whose fetuses are at risk of perinatal asphyxia.
- Published
- 2018
18. Curcumin-loaded polymeric nanoparticles for neuroprotection in neonatal rats with hypoxic-ischemic encephalopathy
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Chih-Chung Chen, Elizabeth Nance, Pratik Parikh, Thomas R. Wood, Andrea Joseph, Sandra E. Juul, Jessica M. Snyder, and Kylie Corry
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0301 basic medicine ,business.industry ,Encephalopathy ,technology, industry, and agriculture ,Drug delivery to the brain ,Pharmacology ,Condensed Matter Physics ,medicine.disease ,Neuroprotection ,Atomic and Molecular Physics, and Optics ,Hypoxic Ischemic Encephalopathy ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,In vivo ,Drug delivery ,Curcumin ,Medicine ,General Materials Science ,Electrical and Electronic Engineering ,business ,030217 neurology & neurosurgery ,Drug metabolism - Abstract
Hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Inflammatory processes play a key role in the progression of this disease and may be amenable to a targeted pharmaceutical intervention. Curcumin is a dietary compound with potent anti-inflammatory, antioxidant, and antiapoptotic properties but is limited in therapeutic applications due to its low aqueous solubility, low bioavailability, and rapid first-pass hepatic metabolism. To address these limitations, loading curcumin into poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles may increase relevant pharmacokinetic parameters and allow for effective drug delivery to the brain. Using the Vannucci model of unilateral hypoxic-ischemic brain injury in neonatal rats, we studied the in vivo effect of curcumin-loaded PLGA-PEG nanoparticles on brain uptake and diffusion of curcumin and on neuroprotection. The curcumin-loaded nanoparticles were able to overcome the impaired blood–brain barrier, diffuse effectively through the brain parenchyma, localize in regions of injury, and deliver a protective effect in the injured neonatal brain. The application of curcumin and PLGA-PEG nanoparticle-mediated delivery to a clinically relevant model of neonatal brain injury provides greater opportunities for clinical translation of targeted therapies for hypoxic-ischemic encephalopathy.
- Published
- 2018
19. Informed consent for a neonatal clinical trial: parental experiences and perspectives
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Sherry E. Courtney, Robin K. Ohls, Sandra E. Juul, Ivan D. Frantz, Patrick J. Heagerty, Charmaine M. Kathen, Anita Shah, Amy Silvia, Kaashif A. Ahmad, Semsa Gogcu, Christine E. Bishop, Benjamin S. Wilfond, Kerry Hancuch, and David E Woodrum
- Subjects
Male ,Parents ,medicine.medical_specialty ,Cross-sectional study ,Study Personnel ,Decision Making ,MEDLINE ,Decisional conflict ,0603 philosophy, ethics and religion ,03 medical and health sciences ,0302 clinical medicine ,Informed consent ,Surveys and Questionnaires ,030225 pediatrics ,medicine ,Humans ,Randomized Controlled Trials as Topic ,Retrospective Studies ,Chi-Square Distribution ,Informed Consent ,business.industry ,Patient Selection ,Infant, Newborn ,Obstetrics and Gynecology ,Flexibility (personality) ,Retrospective cohort study ,06 humanities and the arts ,United States ,Clinical trial ,Cross-Sectional Studies ,Family medicine ,Pediatrics, Perinatology and Child Health ,Female ,060301 applied ethics ,business - Abstract
There is a variability regarding timing of consent and personnel used in patient recruitment for neonatal research. We explored the associations between the study personnel and timing of consent with parents’ decisional conflict and ultimately their decision to enroll. This was a multi-site, cross-sectional survey conducted between August 2015 and October 2017. Participants were parents approached to enroll their 24–28-week infant in a clinical trial. Parents completed an interviewer-administered 61-item questionnaire. Overall, 163 surveys were completed; 105 by parents of enrolled infants and 58 by parents of non-enrolled infants (54.5% participation rate). Neither the individual requesting nor timing of consent was associated with parents’ knowledge score, decisional conflict, or decision to enroll. Parents preferred to be approached prenatally and by their infant’s doctor. Study designers and IRBs may allow flexibility in personnel and timing of consent as it is respectful of parents and may enhance trial enrollment.
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- 2018
20. A working model for hypothermic neuroprotection
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Alistair J. Gunn, Joanne O. Davidson, Frances J. Northington, Christopher A. Lear, Laura Bennet, Sandra E. Juul, and Guido Wassink
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Programmed cell death ,Physiology ,business.industry ,Growth factor ,medicine.medical_treatment ,Cell ,Stem-cell therapy ,Hypothermia ,Bioinformatics ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Erythropoietin ,030225 pediatrics ,medicine ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Intracellular ,medicine.drug - Abstract
Therapeutic hypothermia significantly improves survival without disability in near-term and full-term newborns with moderate to severe hypoxic-ischaemic encephalopathy. However, hypothermic neuroprotection is incomplete. The challenge now is to find ways to further improve outcomes. One major limitation to progress is that the specific mechanisms of hypothermia are only partly understood. Evidence supports the concept that therapeutic cooling suppresses multiple extracellular death signals, including intracellular pathways of apoptotic and necrotic cell death and inappropriate microglial activation. Thus, the optimal depth of induced hypothermia is that which effectively suppresses the cell death pathways after hypoxia-ischaemia, but without inhibiting recovery of the cellular environment. Thus mild hypothermia needs to be continued until the cell environment has recovered until it can actively support cell survival. This review highlights that key survival cues likely include the inter-related restoration of neuronal activity and growth factor release. This working model suggests that interventions that target overlapping mechanisms, such as anticonvulsants, are unlikely to materially augment hypothermic neuroprotection. We suggest that further improvements are most likely to be achieved with late interventions that maximise restoration of the normal cell environment after therapeutic hypothermia, such as recombinant human erythropoietin or stem cell therapy.
- Published
- 2018
21. Ontogeny of white matter, toll‐like receptor expression, and motor skills in the neonatal ferret
- Author
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Daniel H. Moralejo, Sandra E. Juul, Kylie Corry, Jessica M. Snyder, Pratik Parikh, and Thomas R. Wood
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Inflammation ,Infant, Premature, Diseases ,Article ,White matter ,03 medical and health sciences ,0302 clinical medicine ,Developmental Neuroscience ,Internal medicine ,Reflex ,medicine ,Animals ,Humans ,Gait ,Postural Balance ,Neuroinflammation ,Hyperoxia ,biology ,Toll-Like Receptors ,Ferrets ,Infant, Newborn ,Hypoxia (medical) ,White Matter ,Toll-Like Receptor 3 ,Myelin basic protein ,Toll-Like Receptor 4 ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Animals, Newborn ,Motor Skills ,biology.protein ,TLR4 ,medicine.symptom ,030217 neurology & neurosurgery ,Immunostaining ,Developmental Biology - Abstract
Inflammation caused by perinatal infection, superimposed with hypoxia and/or hyperoxia, appears to be important in the pathogenesis of preterm neonatal encephalopathy, with white matter particularly vulnerable during the third trimester. The associated inflammatory response is at least partly mediated through Toll-like receptor (TLR)-dependent mechanisms. Immunohistochemistry, gene expression, and behavioral studies were used to characterize white matter development and determine TLR3 and TLR4 expression and accumulation in the neonatal ferret brain. Expression of markers of white matter development increased significantly between postnatal day (P)1 and P10 (NG2, PDGFRα) or P15 (Olig2), and either remained elevated (NG2), or decreased again at P40 (PDGFRα, Olig2). Olig2 immunostaining within the internal capsule was also greatest at P15. Myelin basic protein (MBP) immunostaining and mRNA expression increased markedly from P15 to P40 and into adulthood, which correlated with increasing performance on behavioral tests (negative geotaxis, cliff aversion, righting reflex, and catwalk gait analysis). TLR4 and TLR3 positive staining was low at all ages, but TLR3 and TLR4 mRNA expression both increased significantly from P1 to P40. Following lipopolysaccharide (LPS) and hypoxia/hyperoxia exposure at P10, meningeal and parenchymal inflammation was seen, including an increase in TLR4 positive cells. These data suggest that the neuroinflammation associated with prematurity could be modeled in the newborn ferret.
- Published
- 2018
22. Neuroprotective Strategies in Neonatal Brain Injury
- Author
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Pratik Parikh and Sandra E. Juul
- Subjects
business.industry ,Pharmacology ,Neuroprotection ,Hypoxic Ischemic Encephalopathy ,03 medical and health sciences ,0302 clinical medicine ,Erythropoietin ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,Neonatal brain ,Medicine ,business ,030217 neurology & neurosurgery ,medicine.drug - Published
- 2018
23. Comparison of two markers of iron sufficiency and neurodevelopmental outcomes
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Kendell R. German, Sandra E. Juul, Sara Neches, and Phuong T. Vu
- Subjects
medicine.medical_specialty ,Iron ,Birth weight ,Gestational Age ,Heme ,Nervous System ,Bayley Scales of Infant Development ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,Statistical significance ,medicine ,Humans ,Retrospective Studies ,biology ,business.industry ,Infant, Newborn ,Obstetrics and Gynecology ,Gestational age ,Retrospective cohort study ,Iron deficiency ,medicine.disease ,Optimal management ,Ferritin ,Ferritins ,Pediatrics, Perinatology and Child Health ,biology.protein ,business ,030217 neurology & neurosurgery - Abstract
Background Iron deficiency during critical windows of brain development is associated with suboptimal neurodevelopmental outcomes. Identifying markers of neonatal iron status that best correlate with neurodevelopmental outcome is critical for optimal management of iron supplementation of neonates. Aims We aimed to evaluate two markers of iron sufficiency, ferritin and zinc protoporphyrin-to-heme ratios (ZnPP/H), with neurodevelopmental outcomes. Study design This is a retrospective cohort study. Subjects All infants with concurrent ferritin and ZnPP/H measurements obtained between October 2014 and April 2017 and Bayley Scales of Infant Development, 3rd Edition (BSID-III) evaluated at 24 months corrected age were included. Outcome measures Associations between iron markers (minimum, maximum and median ferritin and ZnPP/H) and BSID-III score at 24 months were assessed. Results 223 lab measurements from 62 infants were assessed. Mean gestational age was 28.1 weeks (SD = 2.6) with a mean birth weight of 1.1 kg (SD = 0.4). Significant associations between maximum and median ZnPP/H and motor score, and between median ZnPP/H and cognitive score were observed. Trends were also seen with higher minimum, median and maximum ZnPP/H associated with lower BSID-III scores, but did not reach statistical significance (p > 0.05). The associations between ferritin values and BSID scores were less consistent. Conclusions A positive association was seen between ZnPP/H values and BSID-III scores. Trends between ferritin and BSID values were less consistent, potentially because ferritin is more affected by inflammation. Consideration should be given to using ZnPP/H preferentially to adjust iron supplementation in the NICU to improve neurodevelopmental outcomes.
- Published
- 2021
24. Evaluating a Targeted Bedside Measure of Cerebral Perfusion in a Nonhuman Primate Model of Neonatal Hypoxic-Ischemic Encephalopathy
- Author
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Sandra E. Juul, C.K. Ezeokeke, Pierre D. Mourad, and Eric S. Peeples
- Subjects
education.field_of_study ,Radiological and Ultrasound Technology ,business.industry ,Thalamus ,Population ,Hypothermia ,medicine.disease ,Umbilical cord ,Cerebral palsy ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030225 pediatrics ,medicine.artery ,Anesthesia ,medicine ,Anterior cerebral artery ,Radiology, Nuclear Medicine and imaging ,Umbilical Cord Occlusion ,medicine.symptom ,Cerebral perfusion pressure ,business ,education ,030217 neurology & neurosurgery - Abstract
Objectives To compare ultrasound-derived resistive indices (RIs) obtained at the level of the thalamus via fast Doppler ultrasound with traditional anterior cerebral artery measures in a model of neonatal hypoxic-ischemic encephalopathy and to correlate each with clinical outcomes. Methods Nine nonhuman primate neonates underwent no umbilical cord occlusion (n = 3), umbilical cord occlusion without hypothermia (n = 3), or umbilical cord occlusion with hypothermia (n = 3). The RI was measured in the anterior cerebral artery and thalamus on days 0, 1, and 4 of life. Magnetic resonance imaging with spectroscopy was performed on day 4. Results Mean thalamus and anterior cerebral artery RI values in the first 36 hours of life were statistically different in neonates who died (+0.13; P = .019) or developed cerebral palsy (−0.08; P = .003). Thalamic RI values showed stronger associations with serum and spectroscopic lactate values than those in the anterior cerebral artery. The umbilical cord occlusion-with-hypothermia group showed a significant increase in the RI in the thalamus but not the anterior cerebral artery. Conclusions Resistive index measurements in the thalamus may eventually supplement other bedside measures for predicting outcomes in the HIE population, but further studies need to differentiate the effect of hypothermia from illness severity on thalamic perfusion.
- Published
- 2017
25. Impact of processing methods on urinary biomarkers analysis in neonates
- Author
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Zahra Afsharinejad, Dennis E. Mayock, Stuart L. Goldstein, Sandra E. Juul, James W. MacDonald, David J. Askenazi, Theo K. Bammler, Patrick D. Brophy, Michelle C. Starr, and Sangeeta Hingorani
- Subjects
Male ,medicine.medical_specialty ,Neonatal intensive care unit ,Urinary system ,Coefficient of variation ,Population ,030232 urology & nephrology ,Urine ,Article ,Specimen Handling ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Biomarker Analysis ,education ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Infant ,Electrochemical Techniques ,Acute Kidney Injury ,Nephrology ,Immunoassay ,Pediatrics, Perinatology and Child Health ,Immunology ,Biomarker (medicine) ,Female ,business ,Biomarkers - Abstract
In neonates, the validation of urinary biomarkers to diagnose acute kidney injury is a rapidly evolving field. The neonatal population poses unique challenges when assessing the collection, storage, and processing of urinary samples for biomarker analysis. Given this, establishing optimal and consistent sample processing in this population for meaningful use in ongoing clinical trials is important. Urine from a cohort of 19 hospitalized neonatal intensive care unit patients enrolled in the Preterm Erythropoietin Neuroprotection Trial (Clinical Trial NCT01378273) was collected for biomarker analysis by indirect techniques using Fisher-brand cotton balls placed in the diapers. Fourteen urinary biomarkers were measured using commercially available kits via electrochemiluminescence on multiarray plates and compared between paired samples processed with centrifugation prior to storage versus prior to analysis. None of the biomarker concentrations differed between samples undergoing centrifugation prior to storage versus prior to analysis. The difference between samples was within 2% of the estimated concentration for the protein in 12 of 14 biomarkers (86%), and all paired biomarker concentrations were within 4%. The percentage error analysis did not show a difference between paired samples, with biomarker percentage errors smaller than the stated immunoassay coefficient of variance. The urinary concentrations of biomarkers were comparable between paired samples, demonstrating that indirectly collected neonatal urine samples do not require centrifugation after collection and before storage. The ability to use routine urine collection and storage methods to obtain samples for subsequent quantitative immunoassay analysis should facilitate studies of newborns and young children.
- Published
- 2017
26. Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy
- Author
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Bobbi Fleiss, Robin L. Haynes, Niranjana Natarajan, Leslie Schwendimann, Jessica M. Snyder, Sandra E. Juul, Pierre Gressens, Ryan M. McAdams, and Christopher M. Traudt
- Subjects
Pediatrics ,medicine.medical_specialty ,Cerebellum ,Central nervous system ,Article ,Hypothermia induced ,Hypoxic Ischemic Encephalopathy ,Cerebral palsy ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Developmental Neuroscience ,Hypothermia, Induced ,030225 pediatrics ,Journal Article ,medicine ,Animals ,Erythropoietin ,Random allocation ,Asphyxia Neonatorum ,business.industry ,Cerebral Palsy ,medicine.disease ,Nonhuman primate ,Disease Models, Animal ,medicine.anatomical_structure ,Animals, Newborn ,Neurology ,Anesthesia ,Hypoxia-Ischemia, Brain ,Macaca nemestrina ,business ,030217 neurology & neurosurgery ,Motor disability - Abstract
Background: Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited. Methodology: Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed. Results: All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP. Conclusions/Significance: In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.
- Published
- 2017
27. High-Dose Erythropoietin Population Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia
- Author
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Adam Frymoyer, Sandra E. Juul, Yvonne W. Wu, An N. Massaro, and Theo K. Bammler
- Subjects
Population ,Hypothermia ,Pediatrics ,Hypoxic Ischemic Encephalopathy ,Article ,Dose-Response Relationship ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Hypothermia, Induced ,030225 pediatrics ,Hypoxia-Ischemia ,medicine ,Humans ,Dosing ,education ,Erythropoietin ,Volume of distribution ,education.field_of_study ,Dose-Response Relationship, Drug ,business.industry ,Induced ,Area under the curve ,Infant, Newborn ,Brain ,Infant ,Newborn ,3. Good health ,Anesthesia ,Area Under Curve ,Pediatrics, Perinatology and Child Health ,Hypoxia-Ischemia, Brain ,Public Health and Health Services ,medicine.symptom ,Drug ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background High-dose erythropoietin (Epo) is a promising neuroprotective treatment in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of high-dose Epo in this population to inform future dosing strategies. Methods We performed a population pharmacokinetic analysis of 47 neonates with HIE treated with hypothermia who received up to 6 doses of Epo in two previous clinical trials. We compared the ability of different dosing regimens to achieve the target neuroprotective Epo exposure levels determined from animal models of hypoxic-ischemia (i.e., area under the curve during the first 48 hours of treatment [AUC48h] 140,000 mU*h/ml). Results Birth weight scaled via allometry was a significant predictor of Epo clearance and volume of distribution (p
- Published
- 2017
28. Active cooling temperature required to achieve therapeutic hypothermia correlates with short-term outcome in neonatal hypoxic-ischaemic encephalopathy
- Author
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Frances A. Boyle, Rupa Radhakrishnan, Thomas R. Wood, Sandra E. Juul, and Ulrike Mietzsch
- Subjects
0301 basic medicine ,Physiology ,Encephalopathy ,Grey matter ,Outcome (game theory) ,Hypoxic Ischemic Encephalopathy ,03 medical and health sciences ,0302 clinical medicine ,Hypothermia, Induced ,medicine ,Humans ,Child ,Cause of death ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Temperature ,Infant ,Magnetic resonance imaging ,Hypothermia ,medicine.disease ,Magnetic Resonance Imaging ,030104 developmental biology ,medicine.anatomical_structure ,Anesthesia ,Hypoxia-Ischemia, Brain ,Biomarker (medicine) ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
KEY POINTS Hypoxic-ischaemic encephalopathy (HIE) affects 2-4/1000 live term births. Treatment with therapeutic hypothermia (TH) improves the long-term neurodevelopmental outcome of neonates with moderate to severe HIE. However, early prediction of outcome still remains challenging, and no reliable and easily obtainable biomarker has been identified to date. Neonates with HIE display impaired thermoregulation, resulting in spontaneous hypothermia. The degree of cooling required to achieve TH may therefore act as a biomarker of injury severity. The present study demonstrates a correlation between servo-controlled mattress temperature during TH and short-term outcome. Neonates with an unfavourable outcome require less cooling to maintain a core temperature between 33 and 34°C during TH compared to neonates with a favourable outcome. The degree of impaired temperature regulation was strongly associated with a high magnetic resonance imaging injury score and death. Cooling device output temperature is a potential and easily obtainable early physiological biomarker of outcome in infants with HIE undergoing TH. ABSTRACT Neonatal hypoxic-ischaemic encephalopathy (HIE) is a leading cause of death and disability in children. Therapeutic hypothermia (TH) at 33.5°C for 72 h is the only therapy to date shown to improve outcome in moderate to severe HIE; however, assessment of severity and prediction of outcome remains challenging. Infants with HIE display significant physiological perturbations, including spontaneous hypothermia. We hypothesized that neonates with more severe brain injury on magnetic resonance imaging (MRI) would exhibit a greater degree of spontaneous hypothermia, and thus require less active cooling to attain TH. Twenty-eight neonates with moderate or severe HIE treated with TH were included in the present study. MRI images obtained on day of life 4-7 were scored according to standardized injury criteria. Unfavourable outcome was defined as death or significant grey matter injury on MRI according to a previously validated scoring system. A significantly higher cooling device output temperature was seen in infants with an unfavourable outcome. All neonates who required the mattress to provide a temperature ≥32°C to maintain their core body temperature at 33.5°C had a high likelihood of unfavourable outcome (likelihood ratio = 14.4). By contrast, infants who never required a device output temperature ≥32°C had a low likelihood of an unfavourable outcome (likelihood ratio = 0.07, P
- Published
- 2019
29. Neuroprotection strategies in preterm encephalopathy
- Author
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Sandra E. Juul and Pratik Parikh
- Subjects
medicine.medical_specialty ,Pediatrics ,Population ,Encephalopathy ,Neuroprotection ,Article ,Cerebral palsy ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,030225 pediatrics ,medicine ,Animals ,Humans ,Neonatology ,education ,Intracerebral hemorrhage ,education.field_of_study ,Brain Diseases ,business.industry ,Infant, Newborn ,Brain ,medicine.disease ,Fetal Diseases ,Infant, Extremely Premature ,Pediatrics, Perinatology and Child Health ,Gestation ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Advances in neonatology have led to unprecedented improvements in neonatal survival such that those born as early as 22 weeks of gestation now have some chance of survival, and over 70% of those born at 24 weeks of gestation survive. Up to 50% of infants born extremely preterm develop poor outcomes involving long-term neurodevelopmental impairments affecting cognition and learning, or motor problems such as cerebral palsy. Poor outcomes arise because the preterm brain is vulnerable both to direct injury (by events such as intracerebral hemorrhage, infection, and/or hypoxia), or indirect injury due to disruption of normal development. This neonatal brain injury and/or dysmaturation is called "encephalopathy of prematurity". Current and future strategies to improve outcomes in this population include prevention of preterm birth, and pre-, peri-, and postnatal approaches to protect the developing brain. This review will describe mechanisms of preterm brain injury, and current and upcoming therapies in the antepartum and postnatal period to improve preterm encephalopathy.
- Published
- 2019
30. Infants with evolving bronchopulmonary dysplasia demonstrate monocyte-specific expression of IL-1 in tracheal aspirates
- Author
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Rane S. Creasy, Dennis E. Mayock, Steven F. Ziegler, Sandra E. Juul, Laurie C. Eldredge, Jason S. Debley, and Scott R. Presnell
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Male ,Pathology ,medicine.medical_specialty ,Physiology ,Interleukin-1beta ,Lipopolysaccharide Receptors ,Gestational Age ,Pilot Projects ,Lung injury ,GPI-Linked Proteins ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Physiology (medical) ,Interleukin-1alpha ,mental disorders ,medicine ,Humans ,Prospective Studies ,RNA, Messenger ,Respiratory system ,Bronchopulmonary Dysplasia ,business.industry ,Sequence Analysis, RNA ,Monocyte ,Receptors, IgG ,Infant, Newborn ,Infant ,Cell Biology ,medicine.disease ,Trachea ,Interleukin 1 Receptor Antagonist Protein ,030104 developmental biology ,medicine.anatomical_structure ,Bronchopulmonary dysplasia ,Gene Expression Regulation ,Female ,business ,Bronchoalveolar Lavage Fluid ,Infant, Premature ,Signal Transduction - Abstract
Bronchopulmonary dysplasia (BPD) remains a devastating consequence of prematurity. Repeated inflammatory insults worsen lung injury, but there are no predictors for BPD-related respiratory outcomes or targeted therapies. We sought to understand inflammatory mechanisms in evolving BPD through molecular characterization of monocytes in tracheal aspirates from infants at risk for developing BPD. We performed flow cytometry targeting myeloid cell populations on prospectively collected tracheal aspirates from intubated patients born before 29 wk of gestation and +CD16+ (double-positive) and CD14+CD16− (single-positive) monocytes and characterized their gene expression profiles by RNA sequencing and quantitative PCR. We further analyzed differential gene expression between time points to evaluate changes in monocyte function over the first weeks of life. Expression of IL-1A, IL-1B, and IL-1 receptor antagonist mRNA was increased in monocytes collected at day of life ( DOL) 7, DOL 14, and DOL 28 compared with those collected at DOL 3. This study suggests that early changes in monocyte-specific IL-1 cytokine pathways may be associated with evolving BPD.
- Published
- 2019
31. A Ferret Model of Encephalopathy of Prematurity
- Author
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Christopher M. Traudt, Kylie Corry, Elizabeth Nance, Jessica M. Snyder, Chad Curtis, Pratik Parikh, Thomas R. Wood, Daniel H. Moralejo, and Sandra E. Juul
- Subjects
medicine.diagnostic_test ,business.industry ,Encephalopathy ,Physiology ,Magnetic resonance imaging ,Human brain ,medicine.disease ,Hyperintensity ,Article ,OLIG2 ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Developmental Neuroscience ,Neurology ,030225 pediatrics ,medicine ,Reflex ,Gestation ,business ,030217 neurology & neurosurgery ,Ex vivo - Abstract
There is an ongoing need for relevant animal models in which to test therapeutic interventions for infants with neurological sequelae of prematurity. The ferret is an attractive model species as it has a gyrified brain with a white-to-gray matter ratio similar to that in the human brain. A model of encephalopathy of prematurity was developed in postnatal day 10 (P10) ferret kits, considered to be developmentally equivalent to infants of 24–26 weeks’ gestation. Cross-fostered P10 ferret kits received 5 mg/kg of lipopolysaccharide (LPS) before undergoing consecutive hypoxia-hyperoxia-hypoxia (60 min at 9%, 120 min at 60%, and 30 min at 9%). Control animals received saline vehicle followed by normoxia. The development of basic reflexes (negative geotaxis, cliff aversion, and righting) as well as gait coordination on an automated catwalk were assessed between P28 and P70, followed by ex vivo magnetic resonance imaging (MRI) and immunohistochemical analysis. Compared to controls, injured animals had slower overall reflex development between P28 and P40, as well as smaller hind-paw areas consistent with “toe walking” at P42. Injured animals also displayed significantly greater lateral movement during CatWalk assessment as a result of reduced gait coordination. Ex vivo MRI showed widespread white-matter hyperintensity on T2-weighted imaging as well as altered connectivity patterns. This coincided with white-matter dysmaturation characterized by increased intensity of myelin basic protein staining, white-matter thinning, and loss of oligodendrocyte transcription factor 2 (OLIG2)-positive cells. These results suggest both pathological and motor deficits consistent with premature white-matter injury. This newborn ferret model can therefore provide an additional platform to assess potential therapies before translation to human clinical trials.
- Published
- 2018
32. Exogenous Ketone Bodies as Promising Neuroprotective Agents for Developmental Brain Injury
- Author
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Sandra E. Juul, Thomas R. Wood, and Brianna J. Stubbs
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Ketone ,business.industry ,Inflammation ,Metabolism ,Pharmacology ,medicine.disease ,medicine.disease_cause ,Neuroprotection ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Developmental Neuroscience ,Neurology ,chemistry ,Neurotrophic factors ,Ketone bodies ,Medicine ,Ketosis ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Ketone bodies are a promising area of neuroprotection research that may be ideally suited to the injured newborn. During normal development, the human infant is in significant ketosis for at least the first week of life. Ketone uptake and metabolism is upregulated in the both the fetus and neonate, with ketone bodies providing at least 10% of cerebral metabolic energy requirements, as well as being the preferred precursors for the synthesis of fatty acids and cholesterol. At the same time, ketone bodies have been shown to have multiple neuroprotective effects, including being anticonvulsant, decreasing oxidative stress and inflammation, and epigenetically upregulating the production of neurotrophic factors. While ketogenic diets and exogenous ketosis are largely being investigated in the setting of adult brain injury, the adaptation of the neonate to ketosis suggests that developmental brain injury may be the area most suited to the use of ketones for neuroprotection. Here, we describe the mechanisms by which ketone bodies exert their neuroprotective effects, and how these may translate to benefits within each of the phases of neonatal asphyxial brain injury.
- Published
- 2018
33. Cytokine and chemokine responses to injury and treatment in a nonhuman primate model of hypoxic-ischemic encephalopathy treated with hypothermia and erythropoietin
- Author
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Sandra E. Juul, Janessa B Law, Thomas R. Wood, Theo K. Bammler, Dennis E. Mayock, Phuong T. Vu, Patrick J. Heagerty, Thomas M. Burbacher, and Bryan A. Comstock
- Subjects
Chemokine ,medicine.medical_treatment ,Encephalopathy ,Severity of Illness Index ,Hypoxic Ischemic Encephalopathy ,03 medical and health sciences ,0302 clinical medicine ,Hypothermia, Induced ,Pregnancy ,030225 pediatrics ,medicine ,Animals ,Erythropoietin ,Asphyxia ,biology ,business.industry ,Original Articles ,Hypothermia ,medicine.disease ,Nonhuman primate ,Monocyte Chemoattractant Proteins ,Disease Models, Animal ,Cytokine ,Animals, Newborn ,ROC Curve ,Neurology ,Area Under Curve ,Hypoxia-Ischemia, Brain ,Immunology ,biology.protein ,Cytokines ,Intercellular Signaling Peptides and Proteins ,Female ,Neurology (clinical) ,Chemokines ,Macaca nemestrina ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) remains an ongoing clinical challenge. We investigated plasma biomarkers and their association with 6-month outcomes in a nonhuman primate model of HIE with or without therapeutic hypothermia (TH) and erythropoietin (Epo). Twenty-nine Macaca nemestrina were randomized to control cesarean section (n = 7) or 20 min of umbilical cord occlusion (UCO, n = 22) with either no treatment (n = 11) or TH/Epo (n = 11). Initial injury severity was scored using 30-min arterial pH, base deficit, and 10-min Apgar score. Twenty-four plasma cytokines, chemokines, and growth factors were measured 3, 6, 24, 72, and 96 h after UCO. Interleukin 17 (IL-17) and macrophage-derived chemokine (MDC) differentiated the normal/mild from moderate/severe injury groups. Treatment with TH/Epo was associated with increased monocyte chemotactic protein-4 (MCP-4) at 3 h–6h, and significantly lower MCP-4 and MDC at 24 h–72h, respectively. IL-12p40 was lower at 24 h–72h in animals with death/cerebral palsy (CP) compared to survivors without CP. Baseline injury severity was the single best predictor of death/CP, and predictions did not improve with the addition of biomarker data. Circulating chemokines associated with the peripheral monocyte cell lineage are associated with severity of injury and response to therapy, but do not improve ability to predict outcomes.
- Published
- 2021
34. Neonatal Encephalopathy
- Author
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Ryan M. McAdams and Sandra E. Juul
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Neonatal encephalopathy ,Standard treatment ,Encephalopathy ,Obstetrics and Gynecology ,Hypothermia ,medicine.disease ,Cerebral palsy ,03 medical and health sciences ,0302 clinical medicine ,Erythropoietin ,030225 pediatrics ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Medicine ,Gestation ,Dexmedetomidine ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Neonatal encephalopathy (NE) is a major cause of neonatal mortality and morbidity. Therapeutic hypothermia (TH) is standard treatment for newborns at 36 weeks of gestation or greater with intrapartum hypoxia-related NE. Term and late preterm infants with moderate to severe encephalopathy show improved survival and neurodevelopmental outcomes at 18 months of age after TH. TH can increase survival without increasing major disability, rates of an IQ less than 70, or cerebral palsy. Neonates with severe NE remain at risk of death or severe neurodevelopmental impairment. This review discusses the evidence supporting TH for term or near term neonates with NE.
- Published
- 2016
35. Evaluating an Association between Ampicillin and Intraventricular Hemorrhage in Preterm Infants
- Author
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Sandra E. Juul, Thomas P. Strandjord, and Eric S. Peeples
- Subjects
Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Population ,Gestational Age ,030105 genetics & heredity ,Cerebral Ventricles ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Ampicillin ,Humans ,Medicine ,Platelet activation ,education ,Cerebral Hemorrhage ,Retrospective Studies ,education.field_of_study ,business.industry ,Infant, Newborn ,Case-control study ,Gestational age ,Retrospective cohort study ,General Medicine ,Odds ratio ,medicine.disease ,Anti-Bacterial Agents ,Logistic Models ,Intraventricular hemorrhage ,Case-Control Studies ,Infant, Extremely Premature ,Multivariate Analysis ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,business ,Infant, Premature ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Intraventricular hemorrhage (IVH) is a common and potentially devastating adverse outcome affecting up to 30% of preterm infants. β-Lactam antibiotics affect platelet activation through interaction with platelet surface receptors. The objective of this study was to evaluate an association between ampicillin use and the development of IVH in preterm infants. This was a single-center and a retrospective case-control study of preterm low-birth-weight infants diagnosed with IVH and matched controls without IVH. Conditional logistic regression was performed on 10 clinical features from the first week of life to evaluate the association with IVH. Data were obtained for 174 subjects with no significant differences between groups in demographic factors and level of illness indicators. Earlier administration of the first dose of ampicillin was associated with increased odds of developing IVH (odds ratio [OR]: 0.95, p = 0.028) when controlling for other common associations. Longer courses of ampicillin were not significantly associated with the development of IVH (OR: 1.13, p = 0.089). The odds of developing IVH in our population increased with earlier, but not longer initial courses of ampicillin. Further research into the associations with IVH should include the assessment of ampicillin dose, timing, and duration.
- Published
- 2016
36. Fast Doppler as a novel bedside measure of cerebral perfusion in preterm infants
- Author
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Sandra E. Juul, Edin Mehic, Eric S. Peeples, and Pierre D. Mourad
- Subjects
Pediatrics ,medicine.medical_specialty ,Ultrasonography, Doppler, Transcranial ,Blood Pressure ,Gestational Age ,Pilot Projects ,Doppler imaging ,03 medical and health sciences ,0302 clinical medicine ,Heart Rate ,Predictive Value of Tests ,030225 pediatrics ,Internal medicine ,Heart rate ,medicine ,Homeostasis ,Humans ,Autoregulation ,Prospective Studies ,Ultrasonography, Doppler, Color ,Cerebral perfusion pressure ,business.industry ,Infant, Newborn ,Reproducibility of Results ,Gestational age ,Blood flow ,Blood pressure ,Cerebral blood flow ,Point-of-Care Testing ,Cerebrovascular Circulation ,Infant, Extremely Premature ,Pediatrics, Perinatology and Child Health ,Linear Models ,Cardiology ,business ,Blood Flow Velocity ,030217 neurology & neurosurgery - Abstract
Altered cerebral perfusion from impaired autoregulation may contribute to the morbidity and mortality associated with premature birth. We hypothesized that fast Doppler imaging could provide a reproducible bedside estimation of cerebral perfusion and autoregulation in preterm infants. This is a prospective pilot study using fast Doppler ultrasound to assess blood flow velocity in the basal ganglia of 19 subjects born at 26–32 wk gestation. Intraclass correlation provided a measure of test–retest reliability, and linear regression of cerebral blood flow velocity and heart rate or blood pressure allowed for estimations of autoregulatory ability. The intraclass correlation when imaging in the first 48 h of life was 0.634. We found significant and independent correlations between the systolic blood flow velocity and both systolic blood pressure and heart rate (P = 0.015 and 0.012 respectively) only in the 26–28 wk gestational age infants in the first 48 h of life. Our results suggest that fast Doppler provides reliable bedside measurements of cerebral blood flow velocity at the tissue level in premature infants, acting as a proxy for cerebral tissue perfusion. Additionally, autoregulation appears to be impaired in the extremely preterm infants, even within a normal range of blood pressures.
- Published
- 2015
37. High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL): A Randomized Controlled Trial - Background, Aims, and Study Protocol
- Author
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Bryan A. Comstock, Patrick J. Heagerty, Sandra E. Juul, Yvonne W. Wu, Dennis E. Mayock, Stephanie Hauge, Fernando F. Gonzalez, and Amy M. Goodman
- Subjects
Male ,Pediatrics ,Hypothermia ,Reproductive health and childbirth ,Neurodegenerative ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,Hypothermia, Induced ,law ,Infant Mortality ,Multicenter Studies as Topic ,Therapeutic hypothermia ,Randomized Controlled Trials as Topic ,Pediatric ,Brain ,Hematology ,Neuroprotection ,Phase III as Topic ,Neuroprotective Agents ,6.1 Pharmaceuticals ,Hypoxia-Ischemia, Brain ,Female ,medicine.symptom ,medicine.drug ,medicine.medical_specialty ,Physical Injury - Accidents and Adverse Effects ,Intellectual and Developmental Disabilities (IDD) ,Encephalopathy ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Neonatal encephalopathy ,Article ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Asphyxia ,Double-Blind Method ,Clinical Research ,030225 pediatrics ,Multicenter trial ,Hypoxia-Ischemia ,medicine ,Humans ,Clinical Trials ,Erythropoietin ,business.industry ,Cerebral Palsy ,Induced ,Infant, Newborn ,Neurosciences ,Infant ,Evaluation of treatments and therapeutic interventions ,Perinatal Period - Conditions Originating in Perinatal Period ,medicine.disease ,Newborn ,Brain Disorders ,Logistic Models ,Clinical Trials, Phase III as Topic ,Pediatrics, Perinatology and Child Health ,business ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Background: Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection. Objectives: The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia. Methods: This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria. Results and Conclusions: Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.
- Published
- 2018
38. Zinc Protoporphyrin-to-Heme Ratio and Ferritin as Measures of Iron Sufficiency in the Neonatal Intensive Care Unit
- Author
-
Kimberly N. Grelli, Kendell R. German, Sandra E. Juul, Phuong T. Vu, Gina Lee, and Christopher C Denton
- Subjects
Male ,medicine.medical_specialty ,Blood transfusion ,medicine.medical_treatment ,Iron ,Population ,Protoporphyrins ,Heme ,Gastroenterology ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,Intensive Care Units, Neonatal ,medicine ,Humans ,030212 general & internal medicine ,education ,Erythropoietin ,Retrospective Studies ,education.field_of_study ,biology ,business.industry ,Zinc protoporphyrin ,Infant, Newborn ,Gestational age ,Infant ,Iron deficiency ,medicine.disease ,Ferritin ,Hospitalization ,chemistry ,Pediatrics, Perinatology and Child Health ,Ferritins ,biology.protein ,Protoporphyrin ,Female ,business ,Erythrocyte Transfusion ,Biomarkers ,Infant, Premature - Abstract
To evaluate ferritin and zinc protoporphyrin-to-heme (ZnPP/H) ratios as biomarkers of iron status in neonates, determine how specific clinical events affected these measures, and assess how iron status changed during hospitalization.We performed a retrospective study of all infants with paired ferritin and ZnPP/H measurements between October 2014 and May 2016. Concordance of these measurements, effects of sepsis, red blood cell transfusion, erythropoietin treatment, and iron supplementation were assessed. Iron status was measured over time.A total of 228 patients (mean birth weight 1.3 kg, median gestational age 29 weeks) were evaluated. Mean log ZnPP/H values in infants with and without sepsis were not significantly different (4.98 µmol/mol vs 4.97 µmol/mol, adjusted P = .103), whereas log-transformed ferritin values increased significantly during infection (5.23 ng/mL vs 4.04 ng/mL, adjusted P .001). Ferritin also increased more significantly than ZnPP/H following red blood cell transfusion (ferritin: mean 5.03 ng/mL vs 4.0 ng/mL, P .001; ZnPP/H: mean 4.85 µmol/mol vs 4.98 µmol/mol, P .001). The mean iron supplementations at 30, 60, and 90 days were 5.4, 6.9, and 7.4 mg/kg/day, respectively. Ferritin values decreased with advancing postnatal age (adjusted P .001), with 66% of ferritin values less than 76 ng/mL. Treatment with erythropoietin increased ZnPP/H, but not ferritin levels.Ferritin is more significantly affected by inflammatory events such as sepsis and transfusion than ZnPP/H, thus, ZnPP/H may be a more reliable marker of iron status in this population. Infants showed worsening iron sufficiency over time despite supplementation above American Academy of Pediatrics guidelines.
- Published
- 2017
39. Erythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy: Volume of Acute Brain Injury and 1-Year Neurodevelopmental Outcome
- Author
-
Amit M. Mathur, Shasha Bai, Chunqiao Luo, Dennis E. Mayock, Taeun Chang, Yvonne W. Wu, Raghu H. Ramakrishnaiah, Sandra E. Juul, Robert C. McKinstry, G. Bradley Schaefer, Krisa P. Van Meurs, and Sarah B. Mulkey
- Subjects
Male ,Time Factors ,Encephalopathy ,Neuroprotection ,Hypoxic Ischemic Encephalopathy ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,030225 pediatrics ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Erythropoietin ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Infant ,Magnetic resonance imaging ,Hypothermia ,medicine.disease ,Magnetic Resonance Imaging ,United States ,Neuroprotective Agents ,Treatment Outcome ,Anesthesia ,Brain Injuries ,Pediatrics, Perinatology and Child Health ,Hypoxia-Ischemia, Brain ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug ,Diffusion MRI - Abstract
In the Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes study, 9/20 erythropoietin-treated vs 12/24 placebo-treated infants with hypoxic-ischemic encephalopathy had acute brain injury. Among infants with acute brain injury, the injury volume was lower in the erythropoietin than the placebo group (P = .004). Higher injury volume correlated with lower 12-month neurodevelopmental scores. Trial registration ClinicalTrials.gov : NCT01913340 .
- Published
- 2016
40. Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates
- Author
-
Ryan M. McAdams, Raj P. Kapur, Ronald J. McPherson, and Sandra E. Juul
- Subjects
Encephalopathy ,Hypoxic Ischemic Encephalopathy ,Article ,03 medical and health sciences ,0302 clinical medicine ,Developmental Neuroscience ,030225 pediatrics ,medicine ,Animals ,Asphyxia ,Fetus ,Asphyxia Neonatorum ,business.industry ,Putamen ,medicine.disease ,Perinatal asphyxia ,Disease Models, Animal ,Neurology ,Gliosis ,Animals, Newborn ,In utero ,Anesthesia ,Hypoxia-Ischemia, Brain ,medicine.symptom ,Macaca nemestrina ,business ,030217 neurology & neurosurgery - Abstract
Worldwide, hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. To better understand the mechanisms contributing to brain injury and improve outcomes in neonates with HIE, better preclinical animal models that mimic the clinical situation following birth asphyxia in term newborns are needed. In an effort to achieve this goal, we modified our nonhuman primate model of HIE induced by in utero umbilical cord occlusion (UCO) to include postnatal hypoxic episodes, in order to simulate apneic events in human neonates with HIE. We describe a cohort of 4 near-term fetal Macaca nemestrina that underwent 18 min of in utero UCO, followed by cesarean section delivery, resuscitation, and subsequent postnatal mechanical ventilation, with exposure to intermittent daily hypoxia (3 min, 8% O2 3-8 times daily for 3 days). After delivery, all animals demonstrated severe metabolic acidosis (pH 7 ± 0.12; mean ± SD) and low APGAR scores (
- Published
- 2016
41. High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial
- Author
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Sandra E. Juul, Elizabeth E. Rogers, Amit M. Mathur, Katherine W. Tan, Sonia L. Bonifacio, Robert C. McKinstry, Yvonne W. Wu, Taeun Chang, Patrick J. Heagerty, Michael E. Msall, Roberta A. Ballard, Dennis E. Mayock, Lawrence Dong, Fernando F. Gonzalez, An N. Massaro, Krisa P. Van Meurs, Sarah B. Mulkey, Bryan A. Comstock, and Hannah C. Glass
- Subjects
Male ,Phases of clinical research ,Reproductive health and childbirth ,Hypothermia ,Neurodegenerative ,Neuropsychological Tests ,Pediatrics ,Medical and Health Sciences ,Severity of Illness Index ,Hypoxic Ischemic Encephalopathy ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,Infant Mortality ,Pediatric ,Brain ,Magnetic Resonance Imaging ,Motor Skills Disorders ,6.1 Pharmaceuticals ,Anesthesia ,Neurological ,Hypoxia-Ischemia, Brain ,Injections, Intravenous ,Biomedical Imaging ,Female ,medicine.symptom ,Intravenous ,medicine.drug ,Physical Injury - Accidents and Adverse Effects ,Clinical Trials and Supportive Activities ,Encephalopathy ,Placebo ,Drug Administration Schedule ,Injections ,03 medical and health sciences ,Double-Blind Method ,Clinical Research ,030225 pediatrics ,Hypoxia-Ischemia ,Severity of illness ,medicine ,Humans ,Erythropoietin ,business.industry ,Psychology and Cognitive Sciences ,Neurosciences ,Infant, Newborn ,Evaluation of treatments and therapeutic interventions ,Infant ,Perinatal Period - Conditions Originating in Perinatal Period ,Newborn ,medicine.disease ,Brain Disorders ,Neurodevelopmental Disorders ,Brain Injuries ,Pediatrics, Perinatology and Child Health ,business ,030217 neurology & neurosurgery - Abstract
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 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.
- Published
- 2016
42. Plasma Biomarkers of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy
- Author
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Sarah B. Mulkey, Sandra E. Juul, Bryan A. Comstock, Robert C. McKinstry, Amit M. Mathur, Yvonne W. Wu, Dennis E. Mayock, Krisa P. Van Meurs, Theo K. Bammler, An N. Massaro, and Taeun Chang
- Subjects
Oncology ,medicine.medical_specialty ,Encephalopathy ,Tau protein ,tau Proteins ,Context (language use) ,Neuroprotection ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,030225 pediatrics ,Internal medicine ,medicine ,Humans ,Erythropoietin ,Brain-derived neurotrophic factor ,biology ,business.industry ,Brain-Derived Neurotrophic Factor ,Infant, Newborn ,Hypothermia ,medicine.disease ,Magnetic Resonance Imaging ,Brain Injuries ,Hypoxia-Ischemia, Brain ,Pediatrics, Perinatology and Child Health ,biology.protein ,Cytokines ,medicine.symptom ,business ,Biomarkers ,030217 neurology & neurosurgery ,medicine.drug - Abstract
To evaluate plasma brain specific proteins and cytokines as biomarkers of brain injury in newborns with hypoxic-ischemic encephalopathy (HIE) and, secondarily, to assess the effect of erythropoietin (Epo) treatment on the relationship between biomarkers and outcomes.A study of candidate brain injury biomarkers was conducted in the context of a phase II multicenter randomized trial evaluating Epo for neuroprotection in HIE. Plasma was collected at baseline (24 hours) and on day 5. Brain injury was assessed by magnetic resonance imaging (MRI) and neurodevelopmental assessments at 1 year. The relationships between Epo, brain-specific proteins (S100B, ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], total Tau, neuron specific enolase), cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, IL-12P70, IL-13, interferon-gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], brain-derived neurotrophic factor [BDNF], monocyte chemoattractant protein-1), and brain injury were assessed.In 50 newborns with encephalopathy, elevated baseline S100B, Tau, UCH-L1, IL-1β, IL-6, IL-8, IL-10, IL-13, TNF-α, and IFN-γ levels were associated with increasing brain injury severity by MRI. Higher baseline Tau and lower day 5 BDNF were associated with worse 1 year outcomes. No statistically significant evidence of Epo treatment modification on biomarkers was detected in this small cohort.Elevated plasma brain-specific proteins and cytokine levels in the first 24 hours of life are associated with worse brain injury by MRI in newborns with HIE. Only Tau and BDNF levels were found to be related to neurodevelopmental outcomes. The effect of Epo treatment on the relationships between biomarkers and brain injury in HIE requires further study.ClinicalTrials.gov: 01913340.
- Published
- 2018
43. Absorption of enteral recombinant human erythropoietin by neonates
- Author
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Sandra E. Juul and Robert D. Christensen
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Amniotic fluid ,030204 cardiovascular system & hematology ,Pharmacology ,Placebo ,030226 pharmacology & pharmacy ,Enteral administration ,03 medical and health sciences ,0302 clinical medicine ,Enteral Nutrition ,Pregnancy ,medicine ,Humans ,Pharmacology (medical) ,Prospective Studies ,Erythropoietin ,Analysis of Variance ,Cross-Over Studies ,Milk, Human ,business.industry ,Infant, Newborn ,Gestational age ,Crossover study ,Recombinant Proteins ,Intestinal Absorption ,Immunology ,Erythropoiesis ,Colostrum ,Female ,Infant Food ,business ,medicine.drug - Abstract
BACKGROUND: Erythropoietin (EPO) is present in amniotic fluid, colostrum, and human milk. One possible function of ingested EPO might be to stimulate erythropoiesis. However, it is unclear whether human neonates absorb recombinant human erythropoietin (rhEPO) after oral administration. OBJECTIVE: To determine whether circulating EPO concentrations increase following enteral administration of rhEPO to neonates. METHODS: The study was designed as a 2-center prospective, blinded, randomized, 2 times 2 crossover study, with each infant receiving 1 dose of rhEPO 1000 units/kg and 1 dose of placebo. Serum EPO concentrations were measured at baseline, 2, and 4 hours following study drug administration. The rhEPO and placebo dosing were separated by a mean of 72 hours. Analysis was stratified by gestational age (≤35 wk, >35 wk) and feeding type (human milk, infant formula). RESULTS: No significant change in serum EPO concentration was identified at 2 or 4 hours following enteral administration of rhEPO. CONCLUSIONS: Enteral administration of a large dose of rhEPO to neonates
- Published
- 2003
44. Immunohistochemical localization of erythropoietin and its receptor in the developing human brain
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Amyn M. Rojiani, Robert D. Christensen, Sandra E. Juul, and Anthony T. Yachnis
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Adult ,Pathology ,medicine.medical_specialty ,Central nervous system ,Subventricular zone ,Biology ,Pathology and Forensic Medicine ,03 medical and health sciences ,Embryonic and Fetal Development ,0302 clinical medicine ,Pregnancy ,hemic and lymphatic diseases ,medicine ,Receptors, Erythropoietin ,Humans ,Erythropoietin ,Neurons ,Fetus ,030219 obstetrics & reproductive medicine ,Brain ,General Medicine ,Human brain ,Immunohistochemistry ,Erythropoietin receptor ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Astrocytes ,Pediatrics, Perinatology and Child Health ,Immunology ,Female ,Neuron ,Neuroglia ,Astrocyte ,medicine.drug - Abstract
We have previously shown erythropoietin (Epo) and its receptor (Epo-R) to be present in the fetal human central nervous system (CNS), and Epo to be present in the spinal fluid of normal preterm and term infants. To investigate the cellular specificities and developmental patterns of expression of these polypeptides in the human brain—areas that have not been well researched—we designed the following study. Human brains ranging in maturity from 5 weeks post-conception to adult were preserved at the time of elective abortion, surgical removal (tubal pregnancy, or removal for temporal lobe epilepsy), or autopsy. Immunohistochemistry was used to localize Epo and Epo-R reactivity in brains of different stages of development. Astrocytes, neurons, and microglia were identified in sequential tissue sections by specific antibodies. At 5 to 6 weeks post-conception, both Epo and Epo-R localized to cells in the periventricular germinal zone. At 10 weeks post-conception, Epo immunoreactivity was present throughout the cortical wall, with the most intense immunoreactivity present in the ventricular and subventricular zones. Epo-R, in contrast, was localized primarily to the subventricular zone, with little staining evident in the ventricular zone. In late fetal brains, Epo-R reactivity was most prominent in astrocytic cells, although modest reactivity was observed in certain neuron populations. In contrast, Epo staining localized primarily to neurons in fetal brains, although a subpopulation of astrocytes was also immunoreactive. In postnatal brains, both astrocyte and neuron populations were immunoreactive with antibodies to Epo-R and Epo. From these results it is clear that Epo and its receptor are present in the developing human brain as early as 5 weeks post-conception, and each protein shows a specific distribution that changes with development. We speculate that Epo is important in neurodevelopment, and that it also plays a role in brain homeostasis later in life, functioning in an autocrine or paracrine manner.
- Published
- 1999
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