Cerebral Consequences of Hypothermic Circulatory Arrest in Adults

Despite widespread use of hypothermic circulatory arrest (HCA) in aneurysm surgery and for repair of congenital heart defects, there is continued concern about possible adverse cerebral sequelae. The search for ways to improve implementation of HCA has inspired retrospective clinical studies to try to identify risk factors for cerebral injury, and clinical and laboratory investigations to explore the physiology of HCA. At present, risk factors associated with less favorable cerebral outcome after HCA include: prolonged duration of HCA (usually greater than 60 min); advanced patient age; rapid cooling (less than 20 min); hyperglycemia either before HCA or during reperfusion; preoperative cyanosis or lack of adequate hemodilution; evidence of increased oxygen extraction before HCA or during reperfusion; and delayed reappearance of electroencephalogram (EEG) or marked EEG abnormality. Strategies advocated to increase safety of HCA include: pretreatment with barbiturates and steroids; use of alpha-stat pH regulation during cooling and rewarming; intraoperative monitoring of EEG; slow and adequate cooling, including packing of the head in ice; monitoring of jugular venous oxygen content; hemodilution; and avoidance of hyperglycemia. Current investigation focuses on delineating the relationship of cerebral blood flow (CBF) to cerebral oxygen consumption and glucose metabolism during cooling, HCA, rewarming, and later recovery, and identifying changes in acute intraoperative parameters, including the presence of intracerebral enzymes in cerebral spinal fluid, with cerebral outcome as assessed by neurological evaluation, quantitative EEG, and postmortem histology. Clinically, intraoperative monitoring of EEG and measurement of CBF by tracer washout or Doppler flows are contributing to better understanding of the physiology of HCA, and in the laboratory, nuclear magnetic resonance (NMR) spectroscopy has provided valuable insights into the kinetics of intracerebral energy metabolism. Promising strategies for the future include investigation of other pharmacological agents to increase cerebral protection, and use of "cerebroplegia" or intermittent perfusion between intervals of HCA to improve cerebral tolerance for longer durations of HCA.     

深低温停循环逆行性灌注脑保护

为评价上腔静脉逆行性灌注对脑保护的效果,对１０余年来的研究成果进行综述。上腔静脉逆行性灌注是深低温停循环环脑保护的辅助手段,已证明在低温状态下,它为脑部提供低流量血流,维持脑部低温状态;提供部分氧和营养物质,运走代谢产物;减少气栓及栓塞的发生,从而延长了深低温度循环脑保护的安全时限,而脑水肿的危险性限制了该方法在临床应用。在脑保护液中加入脑保护药物已取得一定进展,而上腔静脉逆行性灌注中束闭下腔静脉     

Cerebral Oxygenation during Pediatric Cardiac Surgery Using Deep Hypothermic Circulatory Arrest

Background: Deep hypothermic circulatory arrest is a widely used technique in pediatric cardiac surgery that carries a risk of neurologic injury. Previous work in neonates identified distinct changes in cerebral oxygenation during surgery. This study sought to determine whether the intraoperative changes in cerebral oxygenation vary between neonates, infants, and children and whether the oxygenation changes are associated with postoperative cerebral dysfunction.

Methods: The study included eight neonates, ten infants, and eight children without preexisting neurologic disease. Cerebrovascular hemoglobin oxygen saturation (ScO2), an index of brain oxygenation, was monitored intraoperatively by near-infrared spectroscopy. Body temperature was reduced to 15 degrees Celsius during cardiopulmonary bypass (CPB) before commencing circulatory arrest. Postoperative neurologic status was judged as normal or abnormal (seizures, stroke, coma).

Results: Relative to preoperative levels, the age groups experienced similar changes in ScO2 during surgery: Sco sub 2 increased 30 plus/minus 4% during deep hypothermic CPB, it decreased 62 plus/minus 5% by the end of arrest, and it increased 20 plus/minus 5% during CPB recirculation (all P < 0.001); after rewarming and removal of CPB, ScO2 returned to preoperative levels. During arrest, the half-life of ScO2 was 9 plus/minus 1 min in neonates, 6 plus/minus 1 min in infants, and 4 plus/minus 1 min in children (P < 0.001). Postoperative neurologic status was abnormal in three (12%) patients. The ScO2 increase during deep hypothermic CPB was less in these patients than in the remaining study population (3 plus/minus 2% versus 33 plus/minus 4%, P < 0.00l). There were no other significant ScO2 differences between outcome groups.     

深低温停循环重力脑逆行灌注在主动脉瘤手术中的脑保护作用

目的 探讨深低温停循环重力脑逆行性灌注技术在主动脉夹层动脉瘤手术中对脑和脊髓的保护作用。方法 建立体外循环后，开始降温。肛温17℃时，患者深度头低位（deep trendelenburg position)。控制股静脉回流，股动脉流量降至1．5L／min，升高和维持中心静脉压在20－23cmH2O(1kPa=10.2cmH2O)，即可完成脑逆行性灌注。结果 本组2例患者停循环脑逆行性灌注时间分别为50分钟和116分钟，术后未发生神经系统并发症。结论 深低温停循环重力脑逆行性灌注技术操作简单，能够充分暴露术野，对脑和脊髓有很好的保护作用。     

Neuronal Nitric Oxide Synthase Inhibition Reduces Neuronal Apoptosis After Hypothermic Circulatory Arrest

Background. Neurologic injury, including choreoathetosis and learning and memory deficits, occurs after prolonged hypothermic circulatory arrest (HCA). Apoptosis, or programmed cell death, is a possible cause of the neurologic injury seen after HCA. However, the mechanism of apoptosis is unknown. Hypothermic circulatory arrest causes glutamate excitotoxicity, resulting in increased nitric oxide production. We therefore hypothesized that nitric oxide mediates apoptosis. The purpose of this study was to determine if neuronal nitric oxide synthase inhibition reduces neuronal apoptosis in an established canine model of HCA.

Methods. Fourteen male hound dogs (weight, 20 to 27 kg) were placed on closed-chest cardiopulmonary bypass, subjected to 2 hours of HCA at 18°C, rewarmed to normothermia, and sacrificed 8 hours after HCA. Group 1 (n = 7) dogs were treated with the neuronal nitric oxide inhibitor 7-nitroindazole, 25 mg/kg intraperitoneally, before arrest and every 2 hours until sacrifice. Group 2 (n = 7) dogs received vehicle only. The brains were analyzed histopathologically. Apoptosis, identified by hematoxylin-eosin staining, was confirmed by DNA terminal deoxynucleotidyltransferase–mediated dUTP-biotin nick end-labeling assay and electron microscopy. Apoptosis was scored by a blinded neuropathologist from 0 (normal) to 100 (severe injury).

Results. Apoptosis occurred early after HCA in select neuronal populations, including the hippocampus, stria terminalis, neocortex, and entorhinal cortex. Apoptotic neurons showed a characteristic shrunken cytoplasm and nuclear chromatin condensation. 7-Nitroindazole significantly inhibited apoptosis (group 1 versus 2: 19.17 ± 14.39 versus 61.11 ± 5.41; p < .001).

Conclusions. Our results provide evidence that apoptosis is associated with the neurologic injury that occurs after HCA and that nitric oxide mediates the apoptosis that occurs after HCA. Strategies for cerebral protection during HCA may include the inhibition of neuronal nitric oxide synthase.     

Hypothermic Asanguineous Circulatory Arrest in Adult Dogs

A new technique for the institution of hypothermic asanguineous circulatory arrest (HACA) is described and evaluated. It employs rapid cooling and hemodilution at high flow rates. Survival and protection of neurologic and other organ function were obtained using asanguineous circulatory arrest, and the method appears to be an improvement over circulatory arrest using conventional methods for cooling. The total duration of extracorporeal circulation is much shorter than with currently used methods of circulatory arrest. Applications of this technique in general and transplantation surgery as well as cardiac surgery are discussed.     

深低温停循环联合顺行性脑灌注对患者认知功能的影响

目的探讨急性StanfordA型主动脉夹层采用深低温停循环联合顺行性脑灌注对患者认知功能的影响。方法2009年1月至2012年3月南京医科大学附属南京医院48例急性StanfordA型主动脉夹层采用孙氏手术（主动脉弓部置换加支架象鼻手术）,其中男40例,女8例,年龄（51．3±13．6）岁。手术均采用深低温停循环、顺行胜脑灌注技术。记录术中停循环时间、术后苏醒时间,根据简易智力状态检查量表（mini．mentalstatesexamination,MMSE）评价患者术前、术后的认知功能。结果48例患者体外循环时间（237．3±58．5）rain,术中停循环时间（37．3±6．9）min。手术死亡4例,死亡原因：肺部感染、多脏器功能衰竭、心肌梗死和急性呼吸窘迫综合征。4l例患者术后24h内苏醒,苏醒时间（1513±6．5）h。MMSE评分术前为（28．6±1．1）分,术后1周时为（23．6±4．5）分。随访3l例,随访率70．45％,随访时间6个月。术后6个月时31例患者MMSE评分为（27．6±2．1）分,较术后MMSE评分大幅度提高（户〈0．05）,但与术前MMSE比较,差异无统计学意义（P〉0．05）。结论治疗急性StanfordA型主动脉夹层采用深低温停循环联合顺行性脑灌注技术,可以取得满意的脑保护效果,但短期内对认知功能可能存在负面影响;只要头颅CT排除梗塞或出血病灶,这种负面影响在半年内基本可以自行消除。     

Carotid Artery Doppler Flow Pattern After Deep Hypothermic Circulatory Arrest in Neonatal Piglets

The mechanisms of cerebral injury after cardiac surgery in neonates are not clear. The aim of the study was the analysis of flow changes in the carotid artery of neonatal piglets after deep hypothermic circulatory arrest (DHCA). Eight neonatal piglets were connected to cardiopulmonary bypass (CPB) and underwent (i) cooling to 18°C core temperature within 30 min, (ii) DHCA for 90 min, and finally (iii) rewarming to 37°C after cross‐clamp release (60 min of reperfusion). The blood flow was measured in the left carotid artery by an ultrasonic flow probe before CPB (baseline; T₀), immediately after termination of reperfusion on CPB (T₁), 30 min later (T₂), and 60 min later (T₃). Additionally, the pulsatility index and the resistance index were calculated and compared. Finally, the relationship between the carotid artery flow and the corresponding pressure at each time‐point was compared. After termination of CPB (T₁), the mean carotid artery flow was reduced from 45.26 ± 2.58 mL/min at baseline to 23.29 ± 2.58 mL/min (P < 0.001) and remained reduced 30 and 60 min later (P < 0.001 vs. baseline). Both the pulsatility index and the resistance index were increased after termination of reperfusion, with the maximum occurring 30 min after CPB end. In conclusion, the carotid artery Doppler flow in neonatal piglets was reduced after DHCA, while the indices of pulsatility and resistance increased.     

Ischemic Preconditioning Improves Islet Recovery After Pancreas Cold Preservation

Increasing evidence supports the beneficial effects of ischemic preconditioning (IPC) of organs on subsequent ischemia. The aim of this study was to assess the effects of IPC of the pancreas on islet cell recovery after cold preservation using a rat model. The pancreas was deprived of perfusion (celiac artery and superior mesenteric artery occlusion) for 10 minutes followed by 10 minutes of reperfusion. Islet isolation was performed after 18 hours of cold ischemia. Glands undergoing IPC yielded significantly greater numbers of islets than controls. Following overnight culture, a significantly greater proportion of islets was recovered from IPC-treated pancreata. Microarray genomic analysis of pancreatic tissue revealed a significant differential expression of ∼600 unique mRNA strands within IPC pancreata compared to only <100 unique mRNA strands within non-IPC pancreata (>2-fold change; P < .05). Proteomic analysis revealed significant differential expression of at least 5 proteins >1.5-fold change; P < .05) within the IPC vs control group. Our data indicated that IPC of the pancreas prior to cold preservation was associated with improved islet cell recovery after cold ischemia. IPC of the pancreas may represent a viable therapeutic intervention to increase islet transplantation success from a single donor and to maximize organ utilization.     

L-精氨酸对乳猪深低温停循环脑代谢与结构的影响

目的　通过深低温停循环 ( DHCA)转流模型 ,研究左旋精氨酸 ( L- arg)在低温缺血时对脑代谢和结构的影响。　方法　采用上海种白猪 ,3～ 4周龄 ,随机均分成 4组 :L- arg组 ,左旋硝基精氨酸甲酯 ( L- NAME)组 ,L- arg L-NAME组和对照组 ,每组 10只。按临床方法行心肺转流术 ,于转流前、降温末、复温末和转流结束等分别测定颈内静脉一氧化氮 ( NO)、脑皮质三磷酸腺苷 ( ATP)和颈内静脉乳酸含量。并行脑组织学和超微结构观察。　结果　降温末 L-NAME组和对照组 NO含量较其它两组明显下降 ( P<0 .0 1)。复温末 ,除 L- NAME组外 ,其余 3组均恢复至转流前水平( P<0 .0 1) ,L- arg组 NO水平在复温末较转流前高 ( P<0 .0 1)。转流开始后大脑皮质 ATP即有明显下降 ,L- arg组下降幅度最小 ,且在复温末已接近转流前水平 ;L- NAME组下降幅度最大 ( P<0 .0 1)。转流开始后颈内静脉乳酸含量即升高 ,L- arg组和 L- arg L- NAME组上升幅度较小 ;降温末和转流结束乳酸含量较其它两组低 ( P<0 .0 1)。大脑皮质组织学和超微结构检查显示 ,大脑皮质细胞结构变化 L- arg组和 L- arg L- NAME组较对照组和L- NAME组轻。　结论　深低温停循环手术时 ,应用 L- arg具有较好的脑保护作用 ,而 L- NAME有脑损害作用。 L- arg可部分