Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities

Thayyil, Sudhin; Montaldo, Paolo; Krishnan, Vaisakh; Ivain, Phoebe; Pant, Stuti; Lally, Peter J.; Bandiya, Prathik; Benkappa, Naveen; Kamalaratnam, Chinnathambi N.; Chandramohan, Rema; Manerkar, Swati; Mondkar, Jayshree; Jahan, Ismat; Moni, Sadeka C.; Shahidullah, Mohammod; Rodrigo, Ranmali; Sumanasena, Samanmali; Sujatha, Radhika; Burgod, Constance; Garegrat, Reema; Mazlan, Munirah; Chettri, Ismita; Babu Peter, Sathyanathan; Joshi, Anagha R.; Swamy, Ravi; Chong, Kling; Pressler, Ronit R.; Bassett, Paul; Shankaran, Seetha

doi:10.1001/jamanetworkopen.2023.12152

Cited by 14 publications

(11 citation statements)

References 42 publications

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“…The administration of antipyretic steroids is another potential factor that has a substantial role in determining death rates. 23,24 CONCLUSION HT has not reduced, but may have increased, mortality in TBI patients in some high-quality studies. However, TBI patients with elevated ICP may benefit from hypothermia as therapy rather than as prophylaxis when initiated within 24 hours.…”

Section: Discussionmentioning

confidence: 98%

Role of Therapeutic Hypothermia in Improving Outcome After Traumatic Brain Injury : A Systematic Review

Roberto Pratama

2023

JARMHS

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Introduction: A nondegenerative and noncongenital brain injury caused by external mechanical forces can cause permanent or temporary harm to cognitive, physical, and psychosocial functions and change or diminish awareness. Traumatic brain injury can cause cerebral edema and ICP increase, worsening the lesion. Cellular death can occur minutes to hours after an injury, although negative effects can last 72 hours or more. Therapeutic hypothermia (HT) can lower ICP and protect neurons, improving patient prognosis and lowering mortality. The aim: This article showed role of therapeutic hypothermia in improving outcome after traumatic brain injury. Methods: This study demonstrated compliance with all requirements by comparing itself to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 standards. Therefore, the experts were able to ensure that the study was as current as feasible. For this search strategy, publications published between 2013 and 2023 were considered. Several online reference sources, including Pubmed and SagePub, were utilized for this purpose. It was determined not to consider review pieces, previously published works, or works that were only partially completed. Result: In the PubMed database, the results of our search brought up 112 articles, whereas the results of our search on SagePub brought up 107 articles. The results of the search conducted for the last year of 2013 yielded a total 59 articles for PubMed and 38 articles for SagePub. In the end, we compiled a total of 28 papers, 19 of which came from PubMed and nine of which came from SagePub. We included seven study that met the criteria. Conclusion: HT has not reduced, but may have increased, mortality in TBI patients in some high-quality studies. However, TBI patients with elevated ICP may benefit from hypothermia as therapy rather than as prophylaxis when initiated within 24 hours.

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Section: Discussionmentioning

confidence: 98%

Role of Therapeutic Hypothermia in Improving Outcome After Traumatic Brain Injury : A Systematic Review

Roberto Pratama

2023

JARMHS

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“…This might provide new insights for treating HIBD. Currently, hypothermia therapy is the only approved treatment method, but its high cost and uncertain prognostic effects remain a concern ( Ranjan and Gulati, 2023 ; Thayyil et al, 2023 ). Treatment starting within 6 h shows neuroprotective effects, posing a huge challenge for early diagnosis of HIBD.…”

Section: Discussionmentioning

confidence: 99%

GluN2B-containing NMDA receptor attenuated neuronal apoptosis in the mouse model of HIBD through inhibiting endoplasmic reticulum stress-activated PERK/eIF2α signaling pathway

Wu,

Xu,

et al. 2024

Front. Mol. Neurosci.

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IntroductionNeonatal hypoxic-ischemic brain damage (HIBD) refers to brain damage in newborns caused by hypoxia and reduced or even stopped cerebral blood flow during the perinatal period. Currently, there are no targeted treatments for neonatal ischemic hypoxic brain damage, primarily due to the incomplete understanding of its pathophysiological mechanisms. Especially, the role of NMDA receptors is less studied in HIBD. Therefore, this study explored the molecular mechanism of endogenous protection mediated by GluN2B-NMDAR in HIBD.MethodHypoxic ischemia was induced in mice aged 9-11 days. The brain damage was examined by Nissl staining and HE staining, while neuronal apoptosis was examined by Hoechst staining and TTC staining. And cognitive deficiency of mice was examined by various behavior tests including Barnes Maze, Three Chamber Social Interaction Test and Elevated Plus Maze. The activation of ER stress signaling pathways were evaluated by Western blot.ResultsWe found that after HIBD induction, the activation of GluN2B-NMDAR attenuated neuronal apoptosis and brain damage. Meanwhile, the ER stress PERK/eIF2α signaling pathway was activated in a time-dependent manner after HIBE. Furthermore, after selective inhibiting GluN2B-NMDAR in HIBD mice with ifenprodil, the PERK/eIF2α signaling pathway remains continuously activated, leading to neuronal apoptosis, morphological brain damage. and aggravating deficits in spatial memory, cognition, and social abilities in adult mice.DiscussionThe results of this study indicate that, unlike its role in adult brain damage, GluN2B in early development plays a neuroprotective role in HIBD by inhibiting excessive activation of the PERK/eIF2α signaling pathway. This study provides theoretical support for the clinical development of targeted drugs or treatment methods for HIBD.

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“… 6 Nonetheless, hypothermia was not neuroprotective, regardless of the duration of birth depression or birth acidosis 7 and place of birth. 6 It is not known whether the differential response to whole-body hypothermia between HICs and South Asia is associated with the underlying disease mechanisms. Whole-blood gene expression profile is increasingly used to characterize host responses in various infectious diseases, 8 , 9 , 10 , 11 including neonatal cytomegalovirus infections, 12 and in HIE wherein the gene profiles are different for healthy neonates vs those with sepsis.…”

Section: Introductionmentioning

confidence: 97%

“…However, the Hypothermia for Encephalopathy in Low-Income and Middle-Income Countries (HELIX) trial, the largest clinical trial of hypothermia in the world that was conducted in South Asia, reported that hypothermia did not reduce brain injury but increased mortality. Whole-body hypothermia was administered using servocontrolled devices in the HELIX trial, and attainment of the target temperature was earlier than in hypothermia trials in HICs . Nonetheless, hypothermia was not neuroprotective, regardless of the duration of birth depression or birth acidosis and place of birth .…”

Section: Introductionmentioning

confidence: 99%

“…Whole-body hypothermia was administered using servocontrolled devices in the HELIX trial, and attainment of the target temperature was earlier than in hypothermia trials in HICs . Nonetheless, hypothermia was not neuroprotective, regardless of the duration of birth depression or birth acidosis and place of birth . It is not known whether the differential response to whole-body hypothermia between HICs and South Asia is associated with the underlying disease mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Whole-Blood Gene Expression Profile After Hypoxic-Ischemic Encephalopathy

Montaldo,

Burgod,

Herberg

et al. 2024

JAMA Netw Open

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ImportanceInduced hypothermia, the standard treatment for hypoxic-ischemic encephalopathy (HIE) in high-income countries (HICs), is less effective in the low-income populations in South Asia, who have the highest disease burden.ObjectiveTo investigate the differences in blood genome expression profiles of neonates with HIE from an HIC vs neonates with HIE from South Asia.Design, Setting, and ParticipantsThis case-control study analyzed data from (1) a prospective observational study involving neonates with moderate or severe HIE who underwent whole-body hypothermia between January 2017 and June 2019 and age-matched term healthy controls in Italy and (2) a randomized clinical trial involving neonates with moderate or severe HIE in India, Sri Lanka, and Bangladesh recruited between August 2015 and February 2019. Data were analyzed between October 2020 and August 2023.ExposureWhole-blood RNA that underwent next-generation sequencing.Main Outcome and MeasuresThe primary outcomes were whole-blood genome expression profile at birth associated with adverse outcome (death or disability at 18 months) after HIE in the HIC and South Asia cohorts and changes in whole-genome expression profile during the first 72 hours after birth in neonates with HIE and healthy controls from the HIC cohort. Blood samples for RNA extraction were collected before whole-body hypothermia at 4 time points (6, 24, 48, and 72 hours after birth) for the HIC cohort. Only 1 blood sample was drawn within 6 hours after birth for the South Asia cohort.ResultsThe HIC cohort was composed of 35 neonates (21 females [60.0%]) with a median (IQR) birth weight of 3.3 (3.0-3.6) kg and gestational age of 40.0 (39.0-40.6) weeks. The South Asia cohort consisted of 99 neonates (57 males [57.6%]) with a median (IQR) birth weight of 2.9 (2.7-3.3) kg and gestational age of 39.0 (38.0-40.0) weeks. Healthy controls included 14 neonates (9 females [64.3%]) with a median (IQR) birth weight of 3.4 (3.2-3.7) kg and gestational age of 39.2 (38.9-40.4) weeks. A total of 1793 significant genes in the HIC cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate &lt;0.05). Only 11 of these genes were in common, and all had opposite direction in fold change. The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signaling in the HIC cohort (z score = −4.56; P &lt; .001) and aldosterone signaling in epithelial cells in the South Asia cohort (z score = null; P &lt; .001). The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours, and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14).Conclusions and RelevanceThis case-control study found that disease mechanisms underlying HIE were primarily associated with acute hypoxia in the HIC cohort and nonacute hypoxia in the South Asia cohort. This finding might explain the lack of hypothermic neuroprotection.

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Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities

Cited by 14 publications

References 42 publications

Role of Therapeutic Hypothermia in Improving Outcome After Traumatic Brain Injury : A Systematic Review

Role of Therapeutic Hypothermia in Improving Outcome After Traumatic Brain Injury : A Systematic Review

GluN2B-containing NMDA receptor attenuated neuronal apoptosis in the mouse model of HIBD through inhibiting endoplasmic reticulum stress-activated PERK/eIF2α signaling pathway

Whole-Blood Gene Expression Profile After Hypoxic-Ischemic Encephalopathy

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