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.
Neonates with congenital cardiac diseases undergoing surgery requiring cardiopulmonary bypass using deep hypothermic circulatory arrest (DHCA) are at high risk for impaired neurodevelopmental progression due to time-related ischemia and exposure to toxic levels of brain metabolites. We will use 1H magnetic resonance spectroscopy to determine the real time metabolic changes occurring in the brain during DHCA and, importantly, during the alternative clinical strategy of antegrade cerebral perfusion (ACP) that provides oxygenated blood to the brain. The proposed studies will document continuous time-related changes in brain metabolites and correlate altered levels of these metabolites with alterations in cognitive development following DHCA and ACP bypass procedures.
