Brain Oxygen and Metabolism in Cardiopulmonary Bypass

描述（由申请人提供）：心脏和循环系统的出生缺陷比任何其他类型的出生缺陷对婴儿的影响都要大。在每年出生的所有婴儿中，大约每115人中就有1人患有心脏和/或循环系统缺陷，其中大多数人需要进行体外循环手术。尽管外科手术取得了显著进步，但这些患者中有相当一部分表现出神经和发育异常。新生儿大脑中与DHCA相关的神经损伤的细胞和分子机制尚不清楚。在拟议的研究中，我们实验室开发的一种测量氧气的无创光学方法——氧依赖性磷光猝灭，将用于测量新生仔猪大脑微血管中的氧气。该方法允许首次连续评估组织氧合DHCA状态和骤停后恢复。氧气直方图将与血流量、脑代谢状态和脑损伤程度的测量相结合。我们的研究将确定纹状体内神经元损伤的多巴胺依赖机制。我们还将评估一些有希望的方法来保护大脑免受DHCA引起的神经元损伤。

DESCRIPTION (provided by applicant): Birth defects of the heart and circulatory system affect more infants than any other type of birth defect. Of all infants born each year, approximately 1 in 115 has heart and/or circulatory defects and most of them require cardiopulmonary bypass surgery. Despite remarkable advances in surgery, a substantial fraction of these patients manifest neurological and developmental abnormalities. The cellular and molecular mechanisms of neurologic injury in the newborn brain, associated with DHCA, are poorly understood. In proposed studies, oxygen dependent quenching of phosphorescence, a noninvasive optical method for measuring oxygen developed in our laboratory, will be used to measure the oxygen in the microvasculature of the brain of newborn piglets. This method allows for the first time continuous evaluation of the status of tissue oxygenation DHCA and post-arrest recovery. The oxygen histograms will be coupled with measurements of the blood flow, status of brain metabolism and the extent of brain injury. Our study will determine the dopamine dependent mechanisms of neuronal injury within the striatum. We will also evaluate some promising approaches in the protection of the brain from neuronal injury caused by DHCA. This proposal has two major goals: (a) To determine the role of dopamine and dopamine dependent biochemical and molecular alterations on striatal injury following circulatory arrest. (b) To identify potential strategies for neural protection, particularly in striatum, following circulatory arrest. To achieve these goals, we will test the following specific aims: 1. Hypoxia induced increase in extracellular levels of dopamine in the striatum during DHCA is a major contributor of neuronal injury in the striatum of newborn piglets. 2. Dopamine exerts a neurotoxic effect in striatum of newborn piglets by increasing production of free radicals during post-arrest period. 3. Increased extracellular dopamine in the striatum, acting through the D1 and D2 receptors, alters a cascade of key regulatory processes that contribute substantially to neuronal injury induced by DHCA. 4. During DHCA, brain oxygen deficiency results in a massive increase in extracellular dopamine and brain injury, and this can be prevented by selective cerebral perfusion (SCP). 5. Dopamine dependent striatal injury from prolonged periods of DHCA can be decreased with intermittent brief rescue periods of LFCPB.