DOES THE TIMING OF INITIATION OF THERAPEUTIC HYPOTHERMIA INFLUENCE MRI FINDINGS AND OUTCOMES IN ENCEPHALOPATHIC BABIES?

Abstract BACKGROUND Therapeutic hypothermia (TH), initiated < 6h of life, is the standard treatment for infants with moderate to severe hypoxic ischemic encephalopathy (HIE). While preclinical studies show that TH is more effective when started early, little clinical data exists. OBJECTIVES The objectives of our study are to examine the effect of early vs. late TH on the severity and pattern of brain injury on MRI and on the neurodevelopmental outcomes. DESIGN/METHODS This retrospective cohort included infants with HIE treated with TH at a level three neonatal intensive care unit between 2009 and 2016. Babies were grouped into: early cooling (TH started ≤ 180 minutes of life) or late cooling (TH started > 180 minutes of life). Two radiologists evaluated the severity and pattern of brain injury on MRI using both NICHD and Barkovich scoring system. Neurodevelopmental outcomes were evaluated at 4, 10, 18 and 48 months. RESULTS Ninety-four patients (median gestational age 39 weeks; median birth weight 3.3 kg) were included in the study, 55 in the early cooling and 39 in the late cooling group. The early cooling group included more patients with severe HIE (32.7% vs 10.3%, p=0.01). No difference was observed between the 2 groups in regard to the pattern and severity of brain injury. In the late cooling group, there was a trend toward more severe watershed (WS) injury (WS score ≥3) (30.6% vs 17%, p=0.19) and more moderate to severe brain injury (33.3% vs 23.4%, p=0.33). There was no difference in the neurodevelopmental outcomes between the 2 groups. CONCLUSION TH initiated early (before 180 minutes of life) was neither associated with a difference in brain injury on MRI nor better neurodevelopmental outcomes. Despite having more infants with severe HIE in the early cooling group, there was a trend toward less significant brain injury in this group.

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Influence of timing of initiation of therapeutic hypothermia on brain MRI and neurodevelopment at 18 months in infants with HIE: a retrospective cohort study

BMJ Paediatrics Open ◽

10.1136/bmjpo-2019-000442 ◽

2019 ◽

Vol 3 (1) ◽

pp. e000442 ◽

Cited By ~ 2

Author(s):

Mireille Guillot ◽

Marissa Philippe ◽

Elka Miller ◽

Jorge Davila ◽

Nicholas James Barrowman ◽

...

Keyword(s):

Cohort Study ◽

Brain Injury ◽

Therapeutic Hypothermia ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Neonatal Intensive Care ◽

Brain Mri ◽

Whole Body ◽

Neurodevelopmental Outcomes ◽

Timing Of Initiation

ObjectiveTo examine the influence of timing of initiation of therapeutic hypothermia (TH) on brain injury on MRI and on neurodevelopmental outcomes at 18 months.DesignRetrospective cohort study.SettingTertiary neonatal intensive care unit in Ontario, Canada.PatientsNinety-one patients with hypoxic ischaemic encephalopathy (HIE) were included, 54 in the early TH group and 37 in the late TH group.InterventionWhole-body hypothermia administered for 72 hours, initiated either before 3 hours of life (early TH) or between 3 and 6 hours of life (late TH).Main outcome measuresBrain injury on MRI after TH (assessed by two neuroradiologists), and neurodevelopmental outcomes at 18 months old.ResultsTH was initiated at a median time of 1.4 hours (early TH) and 4.4 hours (late TH). Sixty-four neonates (early TH=36, late TH=28) survived and completed neurodevelopmental assessment at 18 months. Neonates in the early TH group received more extensive resuscitation than neonates in the late TH group (p=0.0008). No difference was observed between the two groups in the pattern or severity of brain injury on MRI, or in the neurodevelopmental outcomes at 18 months. The non-survivors (n=16) had lower Apgar scores at 10 min, more extensive resuscitation, suffered from more severe HIE and had significantly more abnormal cerebral function monitoring.ConclusionIn this retrospective cohort study, TH initiated early was associated neither with a difference in brain injury on MRI nor better neurodevelopmental outcomes at 18 months.

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Cardiac Dysfunction in Neonatal HIE Is Associated with Increased Mortality and Brain Injury by MRI

American Journal of Perinatology ◽

10.1055/s-0041-1735618 ◽

2021 ◽

Author(s):

Gabriel Altit ◽

Sonia L. Bonifacio ◽

Carolina V. Guimaraes ◽

Shazia Bhombal ◽

Ganesh Sivakumar ◽

...

Keyword(s):

Brain Injury ◽

Therapeutic Hypothermia ◽

Cardiac Dysfunction ◽

Systolic Function ◽

Brain Magnetic Resonance Imaging ◽

Lv Function ◽

Severe Brain Injury ◽

Key Points ◽

Magnetic Resonance Imaging Mri ◽

Ischemic Encephalopathy

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

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Wavelet Autoregulation Monitoring Identifies Blood Pressures Associated With Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy

Frontiers in Neurology ◽

10.3389/fneur.2021.662839 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiuyun Liu ◽

Aylin Tekes ◽

Jamie Perin ◽

May W. Chen ◽

Bruno P. Soares ◽

...

Keyword(s):

Blood Pressure ◽

Brain Injury ◽

Therapeutic Hypothermia ◽

Near Infrared ◽

Brain Regions ◽

Hypoxic Ischemic Encephalopathy ◽

Volume Index ◽

Arterial Blood ◽

Blood Pressures ◽

Ischemic Encephalopathy

Dysfunctional cerebrovascular autoregulation may contribute to neurologic injury in neonatal hypoxic-ischemic encephalopathy (HIE). Identifying the optimal mean arterial blood pressure (MAPopt) that best supports autoregulation could help identify hemodynamic goals that support neurologic recovery. In neonates who received therapeutic hypothermia for HIE, we hypothesized that the wavelet hemoglobin volume index (wHVx) would identify MAPopt and that blood pressures closer to MAPopt would be associated with less brain injury on MRI. We also tested a correlation-derived hemoglobin volume index (HVx) and single- and multi-window data processing methodology. Autoregulation was monitored in consecutive 3-h periods using near infrared spectroscopy in an observational study. The neonates had a mean MAP of 54 mmHg (standard deviation: 9) during hypothermia. Greater blood pressure above the MAPopt from single-window wHVx was associated with less injury in the paracentral gyri (p = 0.044; n = 63), basal ganglia (p = 0.015), thalamus (p = 0.013), and brainstem (p = 0.041) after adjustments for sex, vasopressor use, seizures, arterial carbon dioxide level, and a perinatal insult score. Blood pressure exceeding MAPopt from the multi-window, correlation HVx was associated with less injury in the brainstem (p = 0.021) but not in other brain regions. We conclude that applying wavelet methodology to short autoregulation monitoring periods may improve the identification of MAPopt values that are associated with brain injury. Having blood pressure above MAPopt with an upper MAP of ~50–60 mmHg may reduce the risk of brain injury during therapeutic hypothermia. Though a cause-and-effect relationship cannot be inferred, the data support the need for randomized studies of autoregulation and brain injury in neonates with HIE.

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Altered plasma-type gelsolin and amyloid-β in neonates with hypoxic-ischaemic encephalopathy under therapeutic hypothermia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18757419 ◽

2018 ◽

Vol 39 (7) ◽

pp. 1349-1354

Author(s):

Isabel Benavente-Fernandez ◽

Juan J Ramos-Rodriguez ◽

Carmen Infante-Garcia ◽

Gema Jimenez-Gomez ◽

Alfonso Lechuga-Sancho ◽

...

Keyword(s):

Therapeutic Hypothermia ◽

Amyloid Beta ◽

Brain Injuries ◽

Standard Treatment ◽

Amyloid Β ◽

Neonatal Deaths ◽

Neonatal Complication ◽

Learning Impairment ◽

Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication responsible for ∼23% of all neonatal deaths. Also, 30–70% of these patients will suffer lifetime disabilities, including learning impairment, epilepsy or cerebral palsy. However, biomarkers for HIE screening, or monitoring disease progression are limited. Herein, we sought to evaluate the clinical usefulness of plasma-type gelsolin (pGSN) and amyloid-beta (Aβ) 40 and 42 as prognostic biomarkers for HIE. pGSN has been previously suggested as a feasible marker in other brain injuries and amyloid-beta 40 and 42 are classically assessed in neurodegenerative diseases. However, to our knowledge, they have not been previously assessed in HIE patients. We have analyzed plasma pGSN and Aβ 40 and 42 levels in 55 newborns (16 controls, 16 mild and 23 moderate-severe HIE) at birth, during 72 h of therapeutic hypothermia, a gold-standard treatment for HIE, and 24 h after hypothermia. Aβ levels were lower in HIE patients, and pGSN levels were progressively reduced in mild and moderate-severe HIE patients. The fact that pGSN reductions could predict the severity of HIE and significantly correlated with the time to undergo hypothermia supports the prognostic value of plasmatic pGSN. Further studies are warranted to investigate the role of pGSN in neonatal HIE.

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Correlation Between White Matter Injury Identified by Neonatal Diffusion Tensor Imaging and Neurodevelopmental Outcomes Following Term Neonatal Asphyxia and Therapeutic Hypothermia: An Exploratory Pilot Study

Journal of Child Neurology ◽

10.1177/0883073819841717 ◽

2019 ◽

Vol 34 (10) ◽

pp. 556-566 ◽

Cited By ~ 4

Author(s):

Gwendolyn J. Gerner ◽

Eric I. Newman ◽

V. Joanna Burton ◽

Brenton Roman ◽

Elizabeth A. Cristofalo ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Pilot Study ◽

Therapeutic Hypothermia ◽

Diffusion Tensor ◽

White Matter Injury ◽

Hypoxic Ischemic Encephalopathy ◽

Group Differences ◽

Neurodevelopmental Outcomes ◽

Ischemic Encephalopathy

Aim: Hypoxic-ischemic encephalopathy is associated with damage to deep gray matter; however, white matter involvement has become recognized. This study explored differences between patients and clinical controls on diffusion tensor imaging, and relationships between diffusion tensor imaging and neurodevelopmental outcomes. Method: Diffusion tensor imaging was obtained for 31 neonates after hypoxic-ischemic encephalopathy treated with therapeutic hypothermia and 10 clinical controls. A subgroup of patients with hypoxic-ischemic encephalopathy (n = 14) had neurodevelopmental outcomes correlated with diffusion tensor imaging scalars. Results: Group differences in diffusion tensor imaging scalars were observed in the putamen, anterior and posterior centrum semiovale, and the splenium of the corpus callosum. Differences in these regions of interest were correlated with neurodevelopmental outcomes between ages 20 and 32 months. Conclusion: Therapeutic hypothermia may not be a complete intervention for hypoxic-ischemic encephalopathy, as neonatal white matter changes may continue to be evident, but further research is warranted. Patterns of white matter change on neonatal diffusion tensor imaging correlated with neurodevelopmental outcomes in this exploratory pilot study.

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Pontine and cerebellar injury in neonatal hypoxic-ischemic encephalopathy: MRI features and clinical outcomes

Acta Radiologica ◽

10.1177/0284185119900442 ◽

2020 ◽

Vol 61 (10) ◽

pp. 1398-1405

Author(s):

Katsumi Hayakawa ◽

Koichi Tanda ◽

Sachiko Koshino ◽

Akira Nishimura ◽

Zenro Kizaki ◽

...

Keyword(s):

Brain Injury ◽

Clinical Outcomes ◽

Dentate Nucleus ◽

Injury Pattern ◽

Severe Brain Injury ◽

Mri Features ◽

Dorsal Portion ◽

Cerebellar Injury ◽

Cerebellar Involvement ◽

Ischemic Encephalopathy

Background Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of death and disability in infants. Magnetic resonance imaging (MRI) is valuable for predicting the outcome in high-risk neonates. The relationship of pontine and cerebellar injury to outcome has not been explored sufficiently. Purpose To characterize MRI features of pontine and cerebellar injury and to assess the clinical outcomes of these neonates. Material and Methods The retrospective study included 59 term neonates (25 girls) examined by MRI using 1.5-T scanner in the first two weeks of life between 2008 and 2017. Involvement of the pons and cerebellum was judged as a high signal intensity on diffusion-weighted image (DWI) and a restricted diffusion on an apparent diffusion coefficient (ADC) map. Results Pontine involvement was observed in the dorsal portion of pons in eight neonates and cerebellar involvement was observed in dentate nucleus (n = 8), cerebellar vermis (n = 3), and hemisphere (n = 1) in 11 neonates. Combined pontine and cerebellar involvement was observed in eight neonates and only cerebellar involvement in three. The pontine and cerebellar injuries were always associated with very severe brain injury including a basal ganglia/thalamus injury pattern and a total brain injury pattern. In terms of clinical outcome, all but four lost to follow-up, had severe cerebral palsy. Conclusion Pontine and cerebellar involvement occurred in the dorsal portion of pons and mostly dentate nucleus and was always associated with a more severe brain injury pattern as well as being predictive of major disability.

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Conventional MRI scan and DTI imaging show more severe brain injury in neonates with hypoxic-ischemic encephalopathy and seizures

Early Human Development ◽

10.1016/j.earlhumdev.2018.05.008 ◽

2018 ◽

Vol 122 ◽

pp. 8-14 ◽

Cited By ~ 7

Author(s):

Beth M. Kline-Fath ◽

Paul S. Horn ◽

Weihong Yuan ◽

Stephanie Merhar ◽

Charu Venkatesan ◽

...

Keyword(s):

Brain Injury ◽

Hypoxic Ischemic Encephalopathy ◽

Severe Brain Injury ◽

Mri Scan ◽

Conventional Mri ◽

Ischemic Encephalopathy

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Outcomes of Infants with Mild Hypoxic Ischemic Encephalopathy Who Did Not Receive Therapeutic Hypothermia

Biomedicine Hub ◽

10.1159/000502936 ◽

2019 ◽

Vol 4 (3) ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Jonathan Reiss ◽

Mridu Sinha ◽

Jeffrey Gold ◽

Julie Bykowski ◽

Shelley M. Lawrence

Keyword(s):

Therapeutic Hypothermia ◽

Severe Disease ◽

Significant Risk ◽

Brain Magnetic Resonance Imaging ◽

Adverse Outcomes ◽

Hypoxic Ischemic Encephalopathy ◽

Neurodevelopmental Outcomes ◽

Specific Patient ◽

Increased Risk ◽

Ischemic Encephalopathy

Introduction: Accurately diagnosing and treating infants with mild forms of hypoxic ischemic encephalopathy (HIE) is important, as the majority of neonates with signs and symptoms of HIE after birth do not meet clinical criteria for moderate or severe disease. Emerging evidence, however, suggests that infants with mild HIE (mHIE) have an increased risk for neurodevelopmental impairment (NDI). Methods: This retrospective descriptive study examined all inborn infants ≥35 week’s gestational age at a single, level III neonatal intensive care unit (NICU) in California between January 1, 2012, and December 31, 2015. International Classification of Diseases codes were used as a proxy to identify neonates with mHIE but who did not receive therapeutic hypothermia (TH). Short- and long-term neurodevelopmental outcomes were documented, including abnormal (1) brain magnetic resonance imaging within 10 days of birth suggestive of HIE, (2) electroencephalogram with electrographic seizures, (3) neurologic discharge examination, or (4) NDI following NICU discharge. Results: Over the 4-year study period, 25 infants met inclusion criteria. Eight of 25 (32%) infants demonstrated neurologic impairment, defined by an abnormality in at least one of the four categories. The remaining 17 infants were without documented evidence for adverse outcomes. Conclusion: Our results indicate that children with mHIE are at significant risk for neurologic injury and may benefit from more aggressive interventions. Further prospective studies should be completed to determine the efficacy of TH in this specific patient population.

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Is Erythropoietin Combining with Therapeutic Hypothermia an Efficient and Safe Therapy in Neonatal Hypoxic Ischemic Encephalopathy: A Prospective and Randomized Clinical Trial

10.21203/rs.3.rs-26962/v1 ◽

2020 ◽

Author(s):

Liang-yan Zou ◽

Bing-xue Huang ◽

Peng Zhang ◽

Guo-qiang Cheng ◽

Chun-mei Lu ◽

...

Keyword(s):

Brain Injury ◽

Adverse Events ◽

Therapeutic Hypothermia ◽

Brain Mri ◽

Adverse Outcomes ◽

Hypoxic Ischemic Encephalopathy ◽

Control Group ◽

Term Infants ◽

Basal Nuclei ◽

Ischemic Encephalopathy

Abstract BackgroundTo evaluate the efficacy and safety of erythropoietin (Epo) combined with therapeutic hypothermia (TH) in neonatal hypoxic-ischemic encephalopathy (HIE).MethodsA total of 78 term infants with HIE were assigned randomly to receive Epo (n = 40) or placebo (n = 38). All infants received TH. Blood samples before TH, after TH and after Epo/placebo were collected for measuring TH associated adverse events, Epo associated factors and potential neural biomarkers. Basal ganglia/ watershed (BG/W) scoring system was used to assess brain injury in MRI. Neurodevelopmental evaluations were performed at 18 months by using BayleyScales of Infant Development II (Bayley II).ResultsEpo-treated group tend to have lower serum creatine kinase (CK) concentration (114 vs 202, P = .04) and higher serum K+, Mg2+ concentration (5.0 vs 4.5, P = .03; 1.0 vs 0.9, P = .02) than control group after intervention. Brain MRI was performed in 65 (83%) neonatal. Totally brain injury score was in even distribution between two groups (median, 0 vs 0, P = .61), but injury region in cortex plus basal nuclei comparing with in basal nuclei solely was less common in the Epo than in the control group (21% vs 31%, P = .046). Only forty patients (40/78, 51%) succeeded in achieving 18-month follow up data. The totally adverse outcomes were trend to decline in the Epo group (35% vs 60%, P = .21). No adverse events were ascribed to Epo treatment.ConclusionsThe combination of Epo and TH is proved to be feasible, safe and potential effective.Trial registration: ChiCTR-TRC-14004532, date of registration: April 18th, 2014.

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Early Troponin I Levels in Newborns Undergoing Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy and Residual Encephalopathy at Discharge

American Journal of Perinatology ◽

10.1055/s-0040-1721497 ◽

2020 ◽

Author(s):

Upender K. Munshi ◽

Meredith Monaco Brown ◽

Kate A. Tauber ◽

Michael J. Horgan

Keyword(s):

Therapeutic Hypothermia ◽

Predictive Value ◽

Troponin I ◽

Retrospective Chart Review ◽

Hypoxic Ischemic Encephalopathy ◽

Mri Findings ◽

Group 3 ◽

Group 2 ◽

Ischemic Encephalopathy ◽

Group 1

Objective Elevation of serum troponin I has been reported in newborns with hypoxic ischemic encephalopathy (HIE), but it is diagnostic and prognostic utility for newborn under 6 hours is not clear. Study the predictive value of early serum troponin I levels in newborns with HIE undergoing therapeutic hypothermia (TH) for persistent residual encephalopathy (RE) at discharge. Study Design Retrospective chart review of newborns admitted with diagnosis of HIE to neonatal intensive care unit (NICU) for TH over a period of 3 years. Troponin levels were drawn with the initial set of admission laboratories while initiating TH. Newborns were followed up during hospital course and stratified into three groups based on predischarge examination and their electrical encephalography and cranial MRI findings: Group 1: no RE, Group 2: mild-to-moderate RE, and Group 3: severe RE or needing assisted medical technology or death. Demographic and clinical characteristics including troponin I levels were compared in each group. Results Out of 104 newborns who underwent TH, 65 infants were in Group 1, 26 infants in Group 2, and 13 newborns in Group 3. All groups were comparable in demographic characteristics. There was a significant elevation of serum troponin in group 2 (mild-to-moderate RE) and group 3 (severe RE) as compared with group 1 (no RE). Receiver operator curve analysis for any RE (groups 2 and 3) compared with group 1 (no RE as control) had 0.88 (0.81–0.95) area under curve, p < 0.001. A cut-off level of troponin I ≥0.12 µg/L had a sensitivity of 77% and specificity of 78% for diagnosis of any RE, positive predictive value of 68%, and a negative predictive value of 84%. Conclusion In newborns undergoing TH for HIE, the elevation of troponin within 6 hours of age predicts high risk of having RE at discharge. Key Points

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