Mujsce D J, Towfighi J, Heitjan D F, Vannucci R C
Department of Pediatrics, Pennsylvania State University School of Medicine, Milton S. Hershey Medical Center, Hershey 17033.
Stroke. 1994 Jul;25(7):1433-41; discussion 1442. doi: 10.1161/01.str.25.7.1433.
Hypothermia to core temperatures ranging from 16 degrees C to 24 degrees C has become an established procedure to extend the "safe" interval of cardiac arrest during open heart surgery in human infants. The present experiment was designed to ascertain whether differences in core (rectal) temperature during hypothermic circulatory arrest influence the presence and extent of ischemic brain damage in newborn dogs.
Newborn dogs (postnatal age, 3 to 5 days) were anesthetized with halothane (4% induction; 0.5% maintenance), intubated, paralyzed, and artificially ventilated with 70% nitrous oxide/30% oxygen. Thereafter, the dogs were surface cooled with ice packs to either 16 degrees C (n = 6), 20 degrees C (n = 8), or 24 degrees C (n = 6). The dogs then were subjected to circulatory arrest for 1.75 hours by the intravenous injection of KCl, following which they were resuscitated with intravenous NaHCO3 and epinephrine, artificial ventilation, and closed chest cardiac massage. Those dogs that survived for 8 hours of recovery (n = 16) underwent neurobehavioral examination followed by perfusion-fixation of their brains for pathological analysis.
All newborn dogs were successfully resuscitated after 1.75 hours of cardiac arrest, rewarmed to 37 degrees C, and ultimately weaned from anesthesia and ventilatory support. Four dogs sustained secondary systemic complications with death at 4 to 7 hours. All surviving dogs remained stable, with systemic blood pressure, heart rate, arterial oxygen, and acid-base balance within the normal, normothermic range. Of the 16 surviving dogs, all except 1 showed histological evidence of brain damage at 8 hours of recovery. Morphometric analysis of the number of necrotic neurons in the vulnerable gray matter structures showed the greatest damage to cerebral cortex at 24 degrees C and the least damage to this structure at 16 degrees C by either regression analysis (r = .62; P = .01) or a repeated-measures model (P = .008). The extent of damage to the caudate nucleus was similar in the three temperature groups, while damage to the amygdaloid nucleus was greater at 24 degrees C compared with 20 degrees C but with no difference in the severity of damage between 20 degrees C and 16 degrees C. A close correlation existed between neurobehavioral deficits in the surviving dogs and the severity of damage to the cerebral cortex (r = .72; P = .001).
The findings indicate that differences in intraischemic core temperature during deep hypothermic circulatory arrest influence the severity of damage to the cerebral cortex of newborn dogs. Specifically, the lower the temperature below 24 degrees C, the more protected the structure from ischemic injury. Furthermore, the greater the cortical damage, the more severe the neurobehavioral deficits. Such was not the case for the amygdaloid nucleus and especially for the caudate nucleus. Accordingly, differences in core temperature, even at very low levels, appear critical for optimal protection of the newborn brain during hypothermic circulatory arrest.
将核心体温降至16摄氏度至24摄氏度已成为在人类婴儿心脏直视手术中延长心脏骤停“安全”间隔时间的既定程序。本实验旨在确定低温循环骤停期间核心（直肠）温度的差异是否会影响新生犬缺血性脑损伤的存在及程度。
新生犬（出生后3至5天）用氟烷麻醉（诱导浓度4%；维持浓度0.5%），插管、麻痹，并用70%氧化亚氮/30%氧气进行人工通气。此后，用冰袋将犬体表冷却至16摄氏度（n = 6）、20摄氏度（n = 8）或24摄氏度（n = 6）。然后通过静脉注射氯化钾使犬循环骤停1.75小时，之后用静脉注射碳酸氢钠和肾上腺素、人工通气及胸外心脏按压进行复苏。存活8小时恢复的犬（n = 16）接受神经行为检查，随后对其大脑进行灌注固定以进行病理分析。
所有新生犬在心脏骤停1.75小时后均成功复苏，复温至37摄氏度，最终停用麻醉和通气支持。4只犬出现继发性全身并发症，在4至7小时死亡。所有存活犬均保持稳定，全身血压、心率、动脉血氧和酸碱平衡处于正常、正常体温范围内。在16只存活犬中，除1只外，其余在恢复8小时时均有脑损伤的组织学证据。对易损灰质结构中坏死神经元数量的形态计量分析表明，通过回归分析（r = 0.62；P = 0.01）或重复测量模型（P = 0.008），24摄氏度时大脑皮质损伤最严重，16摄氏度时该结构损伤最轻。三个温度组尾状核的损伤程度相似，而24摄氏度时杏仁核的损伤比20摄氏度时更严重，但20摄氏度和16摄氏度时损伤严重程度无差异。存活犬的神经行为缺陷与大脑皮质损伤严重程度之间存在密切相关性（r = 0.72；P = 0.001）。
研究结果表明，深度低温循环骤停期间缺血核心温度的差异会影响新生犬大脑皮质的损伤严重程度。具体而言，低于24摄氏度的温度越低，该结构受缺血损伤的保护越好。此外，皮质损伤越严重，神经行为缺陷越严重。杏仁核尤其是尾状核并非如此。因此，即使在非常低的水平，核心温度的差异对于低温循环骤停期间新生脑的最佳保护似乎也至关重要。
