Sterz F, Leonov Y, Safar P, Radovsky A, Stezoski S W, Reich H, Shearman G T, Greber T F
Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh, Pennsylvania.
Anesthesiology. 1989 Dec;71(6):907-18. doi: 10.1097/00000542-198912000-00014.
Excitatory amino acids accumulating in the brain during ischemia may cause selective neuronal damage postischemia. This hypothesis was tested in a series of studies using MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in a reproducible outcome model of prolonged cardiac arrest in dogs. After normothermic ventricular fibrillation cardiac arrest, the dogs were resuscitated with closed-chest femoral veno-arterial cardiopulmonary bypass. At 4 h they were separated from bypass, ventilation was controlled for 20 h, and intensive care was continued to 96 h. In Study I, ventricular fibrilation cardiac arrest (no-flow) was 17 min; starting immediately with reperfusion, MK-801 1200 mg/kg (n = 5) or an equal volume of placebo (n = 5) was infused over 12 h in blinded, randomized fashion. In Study II, the duration of the no-flow period was reduced to 15 min, and MK-801 2400 mg.kg-1 (n = 4) or placebo (n = 4) was infused. In Study III, no-flow lasted for 15 min, and MK-801 2400 mg/kg was started 30 min before ventricular fibrillation (n = 4); comparison was with Study II controls. In all three studies, MK-801 plasma concentrations peaked at greater than 50 ng/ml and were 15-30 ng/ml over 12 h. All 22 dogs of experiments within protocol survived with severe brain damage. MK-801 delayed return of pupillary reactivity, EEG activity, consciousness, and respiration, necessitating longer periods of controlled ventilation. Neurologic deficit scores, overall performance categories, and brain and heart morphologic damage scores at 96 h did not differ between placebo and MK-801 pretreatment or post-treatment groups. These negative outcome results after prolonged cardiac arrest do not negate the hyperexcitability hypothesis of selective vulnerability, but suggest the existance of additional mechanisms of secondary brain damage.
缺血期间在大脑中积累的兴奋性氨基酸可能会导致缺血后选择性神经元损伤。在一系列研究中，使用N-甲基-D-天冬氨酸（NMDA）受体阻滞剂MK-801，在犬类可重现的长时间心脏骤停结局模型中对这一假设进行了验证。在常温下发生室颤性心脏骤停后，犬类通过闭胸股静脉-动脉体外循环进行复苏。4小时后停止体外循环，控制通气20小时，并继续重症监护至96小时。在研究I中，室颤性心脏骤停（无血流）时间为17分钟；再灌注一开始，以盲法、随机方式在12小时内输注1200 mg/kg的MK-801（n = 5）或等体积的安慰剂（n = 5）。在研究II中，无血流期时长减至15分钟，并输注2400 mg·kg-1的MK-801（n = 4）或安慰剂（n = 4）。在研究III中，无血流持续15分钟，在室颤前30分钟开始输注2400 mg/kg的MK-801（n = 4）；与研究II中的对照组进行比较。在所有三项研究中，MK-801的血浆浓度在大于50 ng/ml时达到峰值，并在12小时内维持在15 - 30 ng/ml。方案内实验的所有22只犬均存活，但伴有严重脑损伤。MK-801延迟了瞳孔反应性、脑电图活动、意识和呼吸的恢复，需要更长时间的控制通气。安慰剂组与MK-801预处理或后处理组在96小时时的神经功能缺损评分、总体表现类别以及脑和心脏形态学损伤评分并无差异。长时间心脏骤停后的这些阴性结果并未否定选择性易损性的过度兴奋假说，但提示存在继发性脑损伤的其他机制。
