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Neurometabolic Outcomes of Different Cardiopulmonary Bypass Strategies

Award Number: R01HL152757
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Neurometabolic Outcomes of Different Cardiopulmonary Bypass Strategies - Project Description Patients with congenital cardiac diseases undergoing surgery requiring cardiopulmonary bypass (CPB) are at risk for impaired neurodevelopmental progression due to time-related ischemia and exposure to toxic levels of brain metabolites. Two competing CPB methodologies are currently practiced for certain commonly occurring cardiac defects: 1) Deep Hypothermic Circulatory Arrest (DHCA), in which the pump is turned off to provide a bloodless surgical field at the expense of no cerebral perfusion, and 2) Antegrade Cerebral Perfusion (ACP), whereby selective perfusion of the brain is maintained throughout surgery. Importantly, DHCA in cardiac surgery is strongly associated with long-term neurocognitive deficits in a manner proportional to length of the circulatory arrest time. The alternative use of ACP for CPB, designed as a strategy to protect the cerebral cortex, has become a common approach, though the value of ACP over DHCA remains hotly debated, with well-designed and objective comparative studies lacking. Here we propose preclinical studies of a piglet model using MRI and dynamic proton magnetic resonance spectroscopy (MRS) which measures metabolite activity in real time, to quantify alterations in the brain’s metabolic state continuously over time during all phases of these CPB strategies. Preliminary data reveal that DHCA causes marked alterations in brain energy metabolism, (e.g., a > 10-fold buildup in brain lactate and a reduction in glucose), while no such derangement is seen with ACP. Importantly, post- surgery quantitative spatial learning assessments will be used to identify metabolic markers most strongly associated with poor clinical outcomes. Success of this project will demonstrate for the first time the advantages of ACP over DHCA in preventing brain cellular injury-inducing metabolite derangements that may hinder normal cognitive development. The real time continuous measurements used in this study will also provide insights into underlying causes of the correlation between DHCA duration and neurological injury. Data from these studies are expected to establish a benchmark for safety when DHCA or ACP is required in the clinical setting. We anticipate that the results of this objective study in the piglet will be directly and rapidly translatable to clinical practice. The Specific Aims are: 1) Using a CPB piglet model we will image the brain metabolic state continuously in real time using MRS. The CPB model will utilize the two commonly used forms of CPB, DHCA and ACP. Both DHCA and ACP will be performed under varying conditions of temperature, flow and time, to determine the most effective methodology to preserve a healthy brain metabolic state., and 2) To evaluate neurocognitive outcomes and correlate with observed alterations in brain metabolism.


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: 2024 ( Subtotal = $676,868 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	4	6/21/2024	NON-COMPETING CONTINUATION	$55,255
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	4	1/11/2024	NON-COMPETING CONTINUATION	$621,613
														Subtotal = $676,868

Issue Date FY: 2023 ( Subtotal = $730,627 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	3	2/1/2023	NON-COMPETING CONTINUATION	$730,627
														Subtotal = $730,627

Issue Date FY: 2022 ( Subtotal = $714,427 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	2	6/17/2022	NON-COMPETING CONTINUATION	$71,446
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	2/28/2022	NON-COMPETING CONTINUATION	$642,981
														Subtotal = $714,427

Issue Date FY: 2021 ( Subtotal = $789,481 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	1	6/23/2021	NEW	$77,465
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	2/12/2021	NEW	$712,016
														Subtotal = $789,481

Grand Total All Awards = $2,911,403

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Neurometabolic Outcomes of Different Cardiopulmonary Bypass Strategies

Award Number: R01HL152757

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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