TY - JOUR
T1 - Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy
T2 - A Report from the HEAL Trial
AU - The HEAL Consortium
AU - Wisnowski, Jessica L.
AU - Monsell, Sarah E.
AU - Bluml, Stefan
AU - Goodman, Amy M.
AU - Li, Yi
AU - Comstock, Bryan A.
AU - Heagerty, Patrick J.
AU - Juul, Sandra E.
AU - Wu, Yvonne W.
AU - Mckinstry, Robert C.
AU - Mathur, Amit M.
AU - Ahmed, Kaashif
AU - Chen, Ping Sun Keven
AU - Dix, James
AU - Bendel-Stenzel, Ellen
AU - Lampland, Andrea
AU - Patterson, Richard
AU - Ramos, Yanerys M.
AU - Chang, Taeun
AU - Fricke, Stanley
AU - Whitehead, Matthew
AU - Wu, Tai Wei
AU - Yanowitz, Toby
AU - Panigrahy, Ashok
AU - Flibotte, John
AU - Berman, Jeff
AU - Vossough, Arastoo
AU - Poindexter, Brenda
AU - Tkach, Jean
AU - KlineFath, Beth
AU - Riley, David
AU - Head, Hayden W.
AU - Maitre, Nathalie
AU - Smith, Mark
AU - Rusin, Jerome
AU - Beserga, Mariana
AU - Oveson, Michael
AU - Rampton, John
AU - Mietzsch, Ulrike
AU - Sokol, Gregory M.
AU - Ho, Chang Y.
AU - Mayock, Dennis
AU - Friedman, Seth
AU - Shaw, Dennis
AU - Van Meurs, Krisa
AU - Vasanawala, Shreyas
AU - Yeom, Kristen
AU - Gonzalez, Fernando
AU - Wu, Yvonne
AU - Flynn, Trevor
AU - Xu, Duan
AU - Weitkamp, Joern Hendrik
AU - Pruthi, Sumit
AU - Chalak, Lina
AU - Rollins, Nancy
AU - Rao, Rakesh
AU - Vesoulis, Zachary
N1 - Publisher Copyright:
© 2023 The Author(s). Published by S. Karger AG, Base.
PY - 2024/10/1
Y1 - 2024/10/1
N2 - Introduction: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. Methods: This study was a secondary analysis of neuroimaging data from the Highdose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 to 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks' gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1,000 U/kg/ dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern, and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. Results: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR: 4.5-5.8). The incidence of injury to the deep gray nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n = 414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. Conclusion: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.
AB - Introduction: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. Methods: This study was a secondary analysis of neuroimaging data from the Highdose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 to 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks' gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1,000 U/kg/ dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern, and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. Results: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR: 4.5-5.8). The incidence of injury to the deep gray nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n = 414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. Conclusion: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.
KW - Erythropoietin
KW - Lactate
KW - MRI
KW - Neonatal
KW - Neuroprotection
UR - http://www.scopus.com/inward/record.url?scp=85178648161&partnerID=8YFLogxK
U2 - 10.1159/000534618
DO - 10.1159/000534618
M3 - Article
C2 - 37906983
AN - SCOPUS:85178648161
SN - 0378-5866
VL - 46
SP - 285
EP - 296
JO - Developmental Neuroscience
JF - Developmental Neuroscience
IS - 5
ER -