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HYPOTHERMIC CIRCULATORY ARREST

低温循环骤停

基本信息

批准号：
6272282
负责人：
ROBERT C. VANNUCCI
金额：
$ 12.04万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 1999-06-30
项目状态：
已结题

项目摘要

This experimental protocol, to be conducted in newborn dogs, was designed to elucidate the manner and extent to which the immature brain is protected from ischemic damage during hypothermic circulatory arrest. The rationale for this line of research relates to the well-established approach to the surgical repair of congenital cardiac defects. Specific aims include: 1) to characterize the early evolution of ischemic brain damage which results from prolonged hypothermic circulatory arrest in newborn dogs and to determine whether or not a delayed neuronal necrosis occurs; 2) to investigate underlying mechanisms which protect the perinatal ischemic brain from injury during hypothermic circulatory arrest other than or in addition to a suppression of oxidative metabolism; 3) to compare the extent to which incomplete versus complete cerebral ischemia is protective (or deleterious) to newborn dog brain during hypothermia; 4) to ascertain the beneficial or deleterious effect of hyperglycemia on the brain damage which results from hypothermic circulatory arrest in newborn dogs; and 5) to determine the protective influence of specific therapeutic modalities on ischemic brain damage resulting from hypothermic circulatory arrest in newborn dogs. Experimental procedures will involve the induction of hypothermia by surface cooling in anesthetized, paralyzed and artifically ventilated newborn dogs to 20degreesC followed by cardiac arrest for up to 120 minutes. Thereafter, the animals will be resuscitated, following which they will undergo neuropathologic analysis at specific intervals of recovery. Regional oxidative and energy metabolism will be determined during and following hypothermic circulatory arrest by the in situ analysis of concentrations of selected glycolytic and Krebs cycle intermediates and high-energy phosphate compounds, using enzymatic, fluorometric techniques. 31P MR spectroscopy also will be used to measure sequentially cerebral high-energy phosphate reserves and intracellular pH (pHi) during and following hypothermic circulatory arrest. Extracellular concentrations of excitatory and inhibitory neurotransmitters also will be measured using a microdialysis technique. Lastly, the regional accumulation of calcium in brain during and following hypothermic circulatory arrest will be accomplished using [45Ca]-autoradiography. Therapeutic interventions to potentially reduce the extent of brain damage during hypothermic circulatory arrest will include thiopental sodium, the xanthine oxidase inhibitor, oxypurinol, and the calcium channel blocker, nimodipine. Additional experimental protocols include the induction of a 'low flow' rather that a 'no flow' state and the determination of the effect of hyperglycemia on hypothermic ischemic brain damage. It is anticipated that these investigations will provide insight into the physiochemical mechanism(s) and duration of the protective influence of hypothermia on circulatory arrest.

该实验方案将在新生狗中进行，其设计目的是阐明大脑不成熟的方式和程度在低温停循环期间免受缺血性损伤。这一研究方向的基本原理与公认的先天性心脏缺陷的外科修复方法。具体的目标包括：1）表征缺血性大脑的早期演化长时间低温停循环造成的损害新生犬并确定是否有迟发性神经元坏死发生； 2）研究保护的潜在机制低温循环过程中损伤造成的围产期脑缺血除了抑制氧化之外或除了抑制氧化之外的逮捕代谢; 3）比较不完整与完整的程度脑缺血对新生狗的大脑有保护作用（或有害）体温过低时； 4）确定有益或有害的影响高血糖对低温引起的脑损伤的影响新生犬的循环停止； 5) 确定保护措施特定治疗方式对缺血性脑损伤的影响新生犬体温过低导致停循环。实验程序将涉及通过以下方式诱导低温麻醉、瘫痪和人工通气时的表面冷却新生狗温度升至 20 摄氏度后心脏骤停最多 120 秒分钟。此后，动物将被复苏，随后他们将在特定的时间间隔进行神经病理学分析恢复。区域氧化和能量代谢将被确定在原位低温停循环期间和之后分析选定的糖酵解和克雷布斯循环的浓度中间体和高能磷酸化合物，使用酶促，荧光测定技术。 31P MR 光谱也将用于依次测量大脑高能磷酸盐储备和低温循环期间和之后的细胞内 pH (pHi) 逮捕。细胞外兴奋性和抑制性浓度神经递质也将使用微透析技术进行测量。最后，在期间和期间大脑中钙的局部积累低温停循环后将使用 [45Ca]-放射自显影。治疗干预措施可能会减少低温停循环期间脑损伤的程度包括硫喷妥钠、黄嘌呤氧化酶抑制剂、奥昔嘌呤醇、和钙通道阻滞剂尼莫地平。附加实验协议包括诱导“低流量”而不是“无流量” 状态和高血糖对低温影响的测定缺血性脑损伤。预计这些调查将提供对物理化学机制和持续时间的深入了解低温对停循环的保护性影响。