HYPOTHERMIC CIRCULATORY ARREST

低温循环骤停

• 批准号: 6241224
• 负责人: ROBERT C. VANNUCCI
• 金额: $ 11.69万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6241224
• 关键词: aerobiosis; allopurinol; bioenergetics; brain injury; brain metabolism; calcium; calcium channel blockers; cerebral ischemia /hypoxia; chemoprevention; divalent cations; dogs; free radical scavengers; glutamates; glycolysis; heart surgery; histopathology; hyperglycemia; induced hypothermia; microdialysis; neuroprotectants; newborn animals; nuclear magnetic resonance spectroscopy; perinatal; thiopental

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.

本实验方案在新生犬中进行， 来阐明未成熟的大脑 在低温停循环期间免受缺血性损伤。 这一系列研究的基本原理与公认的 先天性心脏缺损的外科修复方法。 具体 目的包括：1）表征缺血性脑的早期演变 长时间低温停循环造成的损害， 新生狗，并确定是否有迟发性神经元坏死 发生; 2）调查保护的潜在机制， 围生期脑缺血与低温循环损伤 除了抑制氧化抑制之外的抑制 3）比较不完全与完全代谢的程度， 脑缺血对新生犬脑有保护作用（或有害作用） 在低温期间; 4）确定有益或有害的影响 高血糖对脑损伤的影响， 新生犬循环停止; 5）确定保护性 特异性治疗方法对缺血性脑损伤的影响 新生狗的低温循环停止引起的 实验程序将涉及通过以下方法诱导体温降低： 麻醉、麻痹和人工通气下的表面冷却 新生狗在20 ℃下心脏骤停达120 分钟 之后，动物将复苏， 他们将在特定的时间间隔进行神经病理学分析， 复苏 将确定区域氧化和能量代谢 原位低温停循环期间和之后 选择的糖酵解和克雷布斯循环的浓度分析 中间体和高能磷酸盐化合物，使用酶， 荧光技术。 31 P MR光谱也将用于 连续测量大脑高能磷酸盐储备， 低温循环过程中和之后细胞内pH（pHi） 逮捕了 兴奋性和抑制性的细胞外浓度 还将使用微透析技术测量神经递质。 最后，脑内钙的区域性积聚， 在低温停循环后，将使用 [45 Ca]-放射自显影。 治疗性干预措施， 低温停循环过程中脑损伤的程度 包括硫喷妥钠、黄嘌呤氧化酶抑制剂、羟嘌呤醇 和钙通道阻滞剂尼莫地平 另外的实验 方案包括诱导“低流量”而不是“无流量” 状态和高血糖对低体温影响的测定 缺血性脑损伤 预计这些调查将 提供对生理化学机制和持续时间的深入了解， 低温对循环停止的保护作用。