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Neonatal Hypoxic Ischemic Encephalopathy: Potential of Innovative NIRS to Optimize Hypothermia

Award Number: R01HD076258
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Neonatal Hypoxic Ischemic Encephalopathy: Potential of Innovative NIRS to Optimize Hypothermia - PROJECT SUMMARY/ABSTRACT Hypoxic ischemic encephalopathy (HIE), a major cause of perinatal mortality and long-term morbidity, affects 1- 5/1000 live births. Hypoxic ischemic insults (HII) lead to HIE through a cascade of neuronal injury that continues for hours to days. Therapeutic hypothermia (TH) proved that brain injury from HII can be avoided, revolutionizing treatment of HIE. Despite TH success, additional improvements are urgently needed as up to 63% of infants still die or have long term cognitive deficits. Also, guidelines for treatment are highly subjective, with no consensus on when to treat mild HIE. Our first premise is that adverse outcomes are due to ongoing neuronal injury after HII. As neurons are the primary consumer of oxygen, measures of cerebral oxygen metabolism (CMRO2) would provide a potential means to monitor neuronal health and the evolution of injury. Our second premise is that hemodynamic instability contributes to adverse outcomes through secondary neuronal injury. Secondary injury may be preventable with bedside measures of cerebral blood flow (CBF) to ensure the brain’s metabolic needs are met. In fact, direct CBF measures enable assessment of cerebral autoregulation (CA) and neurovascular coupling (NVC), which reflect hemodynamic stability. Bedside measures of CMRO2 and CBF could enable treatment optimization to prevent secondary injury and inform decisions on who to treat. In R01HD076258, our major achievement was performing >500 Frequency-Domain NIRS and Diffuse Correlation Spectroscopy (FDNIRS- DCS) measurements in >100 neonates with HIE, demonstrating that routine direct bedside measurement of CBF and CMRO2 are possible. Our major finding is that CMRO2 in the days after TH was the only early predictor of outcome, with higher CMRO2 strongly associated (r=0.62, P=0.002) with better 18-month cognitive scores of Bayley Scales of Infant Development 3rd edition (BSID-3). Our renewal goal is to perform early, continuous bedside monitoring of CMRO2 and CBF, demonstrating their potential as vital signs with three aims: Aim 1: Extend current infrastructure to enable continuous, real-time bedside monitoring of neonatal CBF and CMRO2 at 100Hz, integrated with data from other clinical monitors. Aim 2: In neonates with HIE, determine evolution of CMRO2, CA and NVC during TH and their association with post-TH CMRO2; validate that post-TH CMRO2 predicts 2-year outcome. Aim 3: In controls and neonates at risk for HIE but not meeting criteria for TH, determine CMRO2, CA and NVC during the first 24 hours; determine if day 1 CMRO2 predicts 2-year outcome. In the first grant, we demonstrated that bedside measures of CBF and CMRO2 are feasible and discovered that CMRO2 after TH predicts of outcome. In this renewal, we propose to turn CMRO2 and CBF into early, continuous, real-time, bedside vital signs. Our goal is to determine if there is evidence of neuronal injury (decreased CMRO2) mediated by cerebral hemodynamic instability (impaired CA and NVC). If successful, CMRO2 and CBF monitoring may improve neonatal outcomes by enabling medical optimization of hemodynamic stability during TH as well as to screen for neonates at risk for HIE who may benefit from TH.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $758,755 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	9	5/2/2025	NON-COMPETING CONTINUATION	$758,755
														Subtotal = $758,755

Issue Date FY: 2024 ( Subtotal = $751,613 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	8	5/22/2024	NON-COMPETING CONTINUATION	$751,613
														Subtotal = $751,613

Issue Date FY: 2023 ( Subtotal = $731,187 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	7	5/25/2023	NON-COMPETING CONTINUATION	$731,187
														Subtotal = $731,187

Issue Date FY: 2022 ( Subtotal = $600,151 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	6	6/1/2022	COMPETING CONTINUATION	$601,377
2022	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	5	10/28/2021	SUPPLEMENT FOR EXPANSION	-$1,226
														Subtotal = $600,151

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	5	8/7/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $743,915 )
2018	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	5	5/23/2018	NON-COMPETING CONTINUATION	$661,190
2018	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	5	9/5/2018	SUPPLEMENT FOR EXPANSION	$82,725
														Subtotal = $743,915

Issue Date FY: 2017 ( Subtotal = $703,158 )
2017	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	4	8/8/2017	NON-COMPETING CONTINUATION	$703,158
														Subtotal = $703,158

Issue Date FY: 2016 ( Subtotal = $711,134 )
2016	2016	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	3	6/2/2016	NON-COMPETING CONTINUATION	$711,134
														Subtotal = $711,134

Issue Date FY: 2015 ( Subtotal = $684,495 )
2015	2015	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	2	6/17/2015	NON-COMPETING CONTINUATION	$684,495
														Subtotal = $684,495

Issue Date FY: 2014 ( Subtotal = $714,129 )
2014	2014	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	1	5/26/2014	NEW	$714,129
														Subtotal = $714,129

Grand Total All Awards = $6,398,537

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Neonatal Hypoxic Ischemic Encephalopathy: Potential of Innovative NIRS to Optimize Hypothermia

Award Number: R01HD076258

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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