抗氧化对小儿缺血性心脑损害的防治研究
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摘要
围术期心脏停跳（CA）引起的小儿缺氧缺血（HI）性心脑损害是导致患儿急性死亡和慢性残障的主要原因,目前尚缺乏理想的综合预防和治疗手段。低温可降低细胞代谢、改善组织水肿，是体外循环（CPB）下小儿心脏手术心肌保护的重要措施，也是目前临床最具应用前景的CA后神经保护手段，但存在治疗时机和时间窗有限等问题。寻找能够在低温前有效扩大治疗时间窗的干预药物或措施，对协同低温发挥最佳心脑保护效果具有重要的临床价值和科学意义。
研究证实，CA及复跳期间，自由基引起的氧化应激在缺氧缺血性心脑损害中扮演重要角色。我们发现低温的心脑保护，与显著减轻组织蛋白和核酸的氧化、硝基化及羰基化损伤密切相关，而且复苏后早期抗氧化剂治疗可以提供部分神经保护作用。由此我们推测，在缺血早期，任何内源性或外源性，能够减轻氧化应激，或清除自由基的干预措施或药物，都极有可能为后期联合低温防治小儿缺血性心脑损害起到加强或协同的作用。电针刺激可模拟缺血预处理效应，减轻成年动物和人类心脑的缺血再灌注（I/R）损伤；而且，电针预处理具有明显增强抗氧化酶活性，减轻脂质过氧化，增加机体清除氧自由基的能力。然而，经皮穴位电刺激对小儿缺血性心脑损害是否具有同样的抗氧化和保护功效尚不清楚。
因此，本研究第一部分首先通过动物实验，在小猪缺氧缺血脑损伤模型基础上，探讨早期外源性使用抗氧化剂联合延迟开始的低温治疗是否具有协同的神经保护作用。第二部分再通过临床对照试验，观察术前给予经皮穴位电刺激，是否可通过内源性抗氧化机制对小儿CA下低温心内直视手术引起的缺血性心脑损伤起到预防作用，初步确定这些措施作为低温背景下联合防治围术期CA所致小儿缺氧缺血性心脑损害的有效性和可行性。
第一部分早期抗氧化剂联合延迟低温对小猪缺氧缺血性脑损伤的治疗作用
目的:确定复氧后早期，给予新型抗氧化剂EUK-134（锰超氧化物歧化酶及过氧化氢酶模拟物）抑制氧化损伤，联合复苏后延迟4小时开始，持续一天的全身低温治疗，是否对窒息性CA引起的小猪缺氧缺血性（HI）脑损伤具有协同的神经保护作用。
方法:选择1周大雄性小猪，采用缺氧40min (吸入氧浓度为10%)、窒息7min，然后人工心肺复苏的方法制备HI脑损伤模型。动物随机分为5组：假手术（Sham）组，HI常温（HI+NT+saline）组，HI低温（HI+HT+saline）组，HI+NT+EUK-134组，和HI+HT+EUK-134组，每组各10只。EUK-134在自主循环恢复（ROSC）后30min给予，首次剂量2.5mg/kg，iv.，然后以1.25mg/kg/h的速度持续泵注3.5h；低温在ROSC后4h开始，采用全身快速降温，目标体温34°C，低温持续20h。常温组维持正常体温（38.5°C）。所有动物在治疗期间采取全身麻醉，并行机械通气以防寒战可能引起的糖原消耗。通过比较5组新生猪恢复时期神经行为缺陷评分、脑纹状体及感觉运动皮层神经元病理形态学特征和存活密度，综合评价不同处理的脑复苏疗效。
结果：恢复期低温组体重增长明显慢于常温组和Sham组；在恢复第10天，HI+NT+saline组壳核神经元存活密度由正常对照Sham组的100±18%降至17±9%(P<0.01)。与HI+NT+saline组相比，HI+NT+EUK-134组壳核神经元存活密度为40±17%(P<0.05)；HI+HT+saline组壳核神经元存活密度为46±21%(P<0.05)；但与HI+NT+EUK-134组和HI+HT+saline组比，HI+HT+EUK-134组壳核神经元存活密度（47±25%）没有明显差异。尾核和感觉运动皮层损伤不及壳核严重，联合治疗对该区域神经元存活密度，同样没有明显较单独治疗结果有显著提升。HI各组动物存活第4天神经行为学评分差异没有统计学意义，表明尽管早期抗氧化剂EUK-134自身和延迟低温治疗均可提供部分神经保护作用，但早期抗氧化剂联合延迟低温治疗没有协同的保护效果。
结论：在小猪大脑对HI损伤高度敏感的基底神经节区，心肺复苏后30min抗氧化剂EUK-134治疗对延迟4h开始的低温神经保护缺乏有效协同的作用。联合治疗失败的原因，一方面可能是在抗氧化剂EUK-134治疗前，对HI高度敏感的神经元已经遭受了死亡信号的严重攻击，发生了不可逆的死亡；另一种可能是EUK-134和低温是经过同一条信号通路或相似的抗氧化损伤机制发挥的神经保护作用。
第二部分经皮穴位电刺激对小儿心脏手术心脑损害的影响---随机对照临床试验
目的：在小儿心脏直视手术患者中，验证经皮穴位电刺激（TEAS）预处理的心脑保护效应，并以氧化应激和炎症反应为切入点探讨其可能机制，为TEAS技术广泛用于临床，预防围术期心脑损伤提供科学依据。
方法：选择2-12岁，择期行先天性心脏缺陷修补手术的患儿，随机按1:1分为两组，TEAS组和对照组。TEAS组在手术当日进入手术室后，基础麻醉下给予双侧内关穴（P6）经皮电刺激（疏密波2/15Hz、强度以中指出现微颤动为止）30min。对照组除不给予刺激外，其余操作与TEAS组相同。分别在TEAS前、主动脉开放后30min、2h、8h和24h五个时间点抽取动脉血、离心提取血清，采用酶联免疫吸附试验（ELISA）进行生化指标检测。主要观察指标：主动脉开放后24小时内血清心肌肌钙蛋白I（cTnI）和脑损伤特异指标S100β浓度的组间差异。次要指标：临床预后包括术后气管带管时间、血管活性药物使用情况、ICU停留期间前24小时尿量、并发症、心脑不良事件、ICU停留时间、术后住院天数；其它生化指标包括血清肌红蛋白（Myo）、8-异构前列腺素F2α（8-iso PGF2α）以及白介素（IL）6、IL-10、肿瘤坏死因子（TNF-a）、超敏C-反应蛋白（hsCRP）浓度变化。
结果：纳入的74例患儿中70例全程完成试验，对照组36例和TEAS组34例。两组患儿术前平均年龄（3.45±2.1vs.3.95±2.4岁）及体重（14±3.9vs.15±3.1kg）组间没有明显差异。CPB转机时间及主动脉阻断时间组间差异也没有统计学意义。两组患儿术前血清cTnI浓度均处于较低水平（0.017ng/mL vs.0.021ng/mL）且组间没有明显差异；血清Myo基础水平组间也无明显差异(21.8±14.9μg/L vs.22.4±11.3μg/L)。所有患儿主动脉开放后，血清cTnI和Myo浓度显著上升并保持较高水平（与基础值相比，P<0.001）；与TEAS组相比，对照组恢复灌注后2h血清Myo浓度(432.7±146.4μg/L vs.287.1±125.2μg/L, P=0.037），以及8h和24h的血清cTnI浓度（分别为13.19±2.3ng/mL vs.9.21±2.0ng/mL, P=0.043和8.48±1.9ng/mLvs.5.68±1.7ng/mL, P=0.046)明显处于更高水平。所有患儿术前血清S100β水平均不超过0.02μg/L，主动脉开放后开始迅速显著升高，30min时升高值达最大（对照组1.44±0.67μg/L vs. TEAS组1.35±0.58μg/L），然后开始快速下降，2h时约降至30min时的一半（0.67±0.46μg/L vs.0.77±0.4μg/L）；8h时降至基础偏高水平，24h时基本恢复术前水平；各时间点血清S100β浓度升高程度，组间相比没有明显差异。与TEAS组患者相比，对照组术后机械通气时间和ICU停留持续时间明显延长（分别为10(8.5–20)h vs.6(5.5–10)h,P=0.004和46(24–50)h vs.41(23–47)h, P=0.032）。血清8-isoPGF2α在主动脉开放后明显升高，2h时出现峰值，但各时间点组间差异没有统计学意义。血清IL-6、IL-10浓度在主动脉开放后同样在2h达最高峰，随后平稳下降；而CRP和TNF-α浓度在主动脉开放后持续升高，术后24h血清浓度值最大。两组间相应各时间点血清IL-6、IL-10和TNF-α浓度变化差异没有统计学意义；然而，与对照组相比，TEAS组开放后8h的血清hsCRP浓度相对较低（2292±116pg/mL vs.1642±187pg/mL, P=0.039）。
结论：CPB结束后早期，血清心肌损伤标记物cTnI、Myo和脑损伤标记物S100β浓度明显升高，表明小儿先心术后存在一定程度的心脑损伤；主动脉开放后氧化应激指标8-isoPGF2、细胞促炎因子IL-6、TNF-α、hsCRP和抗炎因子IL-10血清水平的明显升高更加证实了这一点。术前给予患儿双侧内关穴30min的TEAS可明显降低开放后cTnI和Myo的释放，缩短术后辅助通气时间，具有一定的心肌保护作用。此作用可能部分与抑制急性缺血再灌注条件下hsCRP的释放有关。TEAS没有表现出明显的脑保护作用，可能与穴位的选择缺乏特异性或刺激时效不足有关。然而本研究结果表明，对小儿心脏直视手术患者，术前给予双侧内关穴TEAS是一项简单实用的心肌保护干预措施，具有良好的临床应用前景。
Background: Perioperative hypoxic-ischemia (HI) myocardial andneurologic damage caused by cardiac arrest (CA) is the leading cause of acutedeath and chronic disability in children. There is no comprehensive preventionand treatment to CA-induced pediatric HI damage. Hypothemia is an importantmanagement for myocardial protection during cardiopulmonary bypass (CPB)cardiac surgery, it is also the only effective way for post-resuscitation treatmentthrough reduces the metabolism and attenuates tissue edema in children. But thetime window and clinical efficacy of hypothermia in pediatric CA is limited.Therefore, a clinical need remains for finding agents or intervention that can beadministered easily and that can provide an added benefit with delayedhypothermia in protecting the heart and brain from HI.
Oxidant stress is considered a major contributing factor to CA–induced HIdamage in immature heart and brain. In our previous studies demonstrated thathypothermia-mediated myocardial/neurologic protection is related to increased formation of protein carbonyl groups, nitration of proteins and nucleic acids, andhydroxylation of nucleic acids. And early antioxidant therapy can provide partialneuroprotection after resuscitation. Therefore, we presume that interventions or agentswith an antioxidant capacity would provide additive cardio/neuroprotection fordelayed hypothermia. Acupuncture mimics pretreatment that exertsneuroprotective and cardioprotective effects through increasing activity ofantioxidant enzyme and enhancing ability of free radical scavenging in animalmodels and in adult patients underwent cardiac surgery; however, data in effect oftranscutaneous electrical acupoint stimulation on pediatric ischemiccardio/cerebral damage from cardiac arrest are unavailable.
In this study part I, we tested the hypothesis that treatment with thesuperoxide dismutase-catalase mimetic EUK-134at30minutes of recoveryprovides additive neuronal protection when combined with one day of wholebody hypothermia implemented4hours after resuscitation. In Part II, through aclinical controlled trial, we investigated that the effects of transcutaneouselectrical acupoint stimulation on the hypoxic ischemia heart and brain damagecaused by CA with hypothermia in the pediatric open heart surgery，to determinewhether these measures can be used as an alternative prevention to reduce heartand brain damage from perioperative CA in children.
Part I Effect of Combined Early Antioxidant Treatmentand Delayed Hypothermia on Neuroprotection afterHypoxic-Ischemia in Piglet
Objective: To test the hypothesis that treatment with the superoxidedismutase-catalase mimetic EUK-134at30minutes of recovery provides additive neuronal protection when combined with one day of whole body hypothermiaimplemented4hours after resuscitation in a piglet model of hypoxic-ischmia(HI).
Methods: Anesthetized piglets were subjected to40minutes of hypoxia(10%inspired oxygen) followed by7minutes of airway occlusion andresuscitation. EUK-134was administrated with a bolus dose2.5mg/kg at30minutes of recovery, plus1.25mg/kg/h intravenous infusion until4hours ofrecovery. Body temperature was maintained at38.5°C in normothermic groupsand at34°C in hypothermic groups. All groups were mechanically ventilated,sedated, and received muscle relaxants during the first day of recovery.
Results: At10days of recovery, neuronal viability in putamen of anormothermic group treated with saline vehicle was reduced to17±9%(±SD) ofthe value in a sham-operated control group (100±18%). Intravenous infusion ofEUK-134with normothermic recovery resulted in40±17%viable neurons inputamen. Treatment with saline vehicle followed by delayed hypothermiaresulted in partial protection (46±21%). Combining early EUK-134treatmentwith delayed hypothermia did not produce additional protection in putamen(47±25%). Furthermore, no additive neuroprotection was detected in caudatenucleus or parasagittal neocortex, where neuronal loss was less severe.
Conclusions: We conclude that early treatment with this antioxidant doesnot extend the therapeutic benefit of hypothermia in protecting highly vulnerableneurons in ischemic-ischemia (HI)-insulted pediatrics, possibly because basalganglia neurons are already undergoing irreversible cell death signaling by thetime EUK-134is administered or because this compound and hypothermiaattenuate similar mechanisms of injury.
Part II Myocardial/Neurologic Protection of TEAS in thePediatric Cardiac Patients: A Randomized Controlled Trial
Objective: To investigate the effects of transcutaneous electric acupointstimulation (TEAS) on acute myocardial/neurologic injury from pediatricopen-heart surgery.
Methods: Children, aged2–12years, with congenital heart defectsscheduled for surgical repair were enrolled. They were randomized to TEAS(administrated at bilateral P6acupoint for30min after basal anesthesia) andcontrol (an electrode was placed on the arm without stimulus) groups. Theduration of cardiopulmonary bypass and aortic cross-clamp time was recorded.The primary end point was serum cardiac troponin I (cTnI) and S100βlevelover24h after aortic unclamping. Furthermore, clinical outcome, and serummyohemoglobin (Myo), interleukin (IL-8, IL-10), tumor necrosis factor (TNF-α),C-reactive protein (CRP) and8-isoprostane (8-iso PGF2α) concentrations wereevaluated pre-and postoperatively.
Results: Seventy eligible children were analyzed,36in controls and34inTEAS group. Compared with controls, the mean serum Myo concentration wassignificantly lower in TEAS group at2h (P=0.037); the mean cTnI levels weresignificantly lower in TEAS group at8h (P=0.043) and24h (P=0.046) afteraortic unclamping. After aortic unclamping, S100βlevel significantly increasedand rearched a peak at30min (control group1.44±0.67ug/L vs. TEAS group1.35±0.58ug/L), thereafter, declined rapidly; the serum concentration of S100βdecreased to a half of peak values by2h (0.67±0.46ug/L vs.0.77±0.4ug/L),then recovered to preoperative level at24h; there is no significant differences of serum S100β elevated level in each time point between groups. The duration ofventilation (P=0.004) and length of ICU stay (P=0.032) was significantly longerin controls than in TEAS group. There was a significant difference in the releaseof C-reactive protein at8h (P=0.039) between two groups, whereas the valuesfor8-iso PGF2α and cytokines were not significant.
Conclusion: Transcutaneous electric acupoint stimulation on the bilateral P6acupoint is effective for attenuation myocardial injury in children undergoingcardiac surgery. The beneficial effects may be partially associated with reductionin cTnI and C-reactive protein level in the early postoperative period.
研究证实，CA及复跳期间，自由基引起的氧化应激在缺氧缺血性心脑损害中扮演重要角色。我们发现低温的心脑保护，与显著减轻组织蛋白和核酸的氧化、硝基化及羰基化损伤密切相关，而且复苏后早期抗氧化剂治疗可以提供部分神经保护作用。由此我们推测，在缺血早期，任何内源性或外源性，能够减轻氧化应激，或清除自由基的干预措施或药物，都极有可能为后期联合低温防治小儿缺血性心脑损害起到加强或协同的作用。电针刺激可模拟缺血预处理效应，减轻成年动物和人类心脑的缺血再灌注（I/R）损伤；而且，电针预处理具有明显增强抗氧化酶活性，减轻脂质过氧化，增加机体清除氧自由基的能力。然而，经皮穴位电刺激对小儿缺血性心脑损害是否具有同样的抗氧化和保护功效尚不清楚。
因此，本研究第一部分首先通过动物实验，在小猪缺氧缺血脑损伤模型基础上，探讨早期外源性使用抗氧化剂联合延迟开始的低温治疗是否具有协同的神经保护作用。第二部分再通过临床对照试验，观察术前给予经皮穴位电刺激，是否可通过内源性抗氧化机制对小儿CA下低温心内直视手术引起的缺血性心脑损伤起到预防作用，初步确定这些措施作为低温背景下联合防治围术期CA所致小儿缺氧缺血性心脑损害的有效性和可行性。
第一部分早期抗氧化剂联合延迟低温对小猪缺氧缺血性脑损伤的治疗作用
目的:确定复氧后早期，给予新型抗氧化剂EUK-134（锰超氧化物歧化酶及过氧化氢酶模拟物）抑制氧化损伤，联合复苏后延迟4小时开始，持续一天的全身低温治疗，是否对窒息性CA引起的小猪缺氧缺血性（HI）脑损伤具有协同的神经保护作用。
方法:选择1周大雄性小猪，采用缺氧40min (吸入氧浓度为10%)、窒息7min，然后人工心肺复苏的方法制备HI脑损伤模型。动物随机分为5组：假手术（Sham）组，HI常温（HI+NT+saline）组，HI低温（HI+HT+saline）组，HI+NT+EUK-134组，和HI+HT+EUK-134组，每组各10只。EUK-134在自主循环恢复（ROSC）后30min给予，首次剂量2.5mg/kg，iv.，然后以1.25mg/kg/h的速度持续泵注3.5h；低温在ROSC后4h开始，采用全身快速降温，目标体温34°C，低温持续20h。常温组维持正常体温（38.5°C）。所有动物在治疗期间采取全身麻醉，并行机械通气以防寒战可能引起的糖原消耗。通过比较5组新生猪恢复时期神经行为缺陷评分、脑纹状体及感觉运动皮层神经元病理形态学特征和存活密度，综合评价不同处理的脑复苏疗效。
结果：恢复期低温组体重增长明显慢于常温组和Sham组；在恢复第10天，HI+NT+saline组壳核神经元存活密度由正常对照Sham组的100±18%降至17±9%(P<0.01)。与HI+NT+saline组相比，HI+NT+EUK-134组壳核神经元存活密度为40±17%(P<0.05)；HI+HT+saline组壳核神经元存活密度为46±21%(P<0.05)；但与HI+NT+EUK-134组和HI+HT+saline组比，HI+HT+EUK-134组壳核神经元存活密度（47±25%）没有明显差异。尾核和感觉运动皮层损伤不及壳核严重，联合治疗对该区域神经元存活密度，同样没有明显较单独治疗结果有显著提升。HI各组动物存活第4天神经行为学评分差异没有统计学意义，表明尽管早期抗氧化剂EUK-134自身和延迟低温治疗均可提供部分神经保护作用，但早期抗氧化剂联合延迟低温治疗没有协同的保护效果。
结论：在小猪大脑对HI损伤高度敏感的基底神经节区，心肺复苏后30min抗氧化剂EUK-134治疗对延迟4h开始的低温神经保护缺乏有效协同的作用。联合治疗失败的原因，一方面可能是在抗氧化剂EUK-134治疗前，对HI高度敏感的神经元已经遭受了死亡信号的严重攻击，发生了不可逆的死亡；另一种可能是EUK-134和低温是经过同一条信号通路或相似的抗氧化损伤机制发挥的神经保护作用。
第二部分经皮穴位电刺激对小儿心脏手术心脑损害的影响---随机对照临床试验
目的：在小儿心脏直视手术患者中，验证经皮穴位电刺激（TEAS）预处理的心脑保护效应，并以氧化应激和炎症反应为切入点探讨其可能机制，为TEAS技术广泛用于临床，预防围术期心脑损伤提供科学依据。
方法：选择2-12岁，择期行先天性心脏缺陷修补手术的患儿，随机按1:1分为两组，TEAS组和对照组。TEAS组在手术当日进入手术室后，基础麻醉下给予双侧内关穴（P6）经皮电刺激（疏密波2/15Hz、强度以中指出现微颤动为止）30min。对照组除不给予刺激外，其余操作与TEAS组相同。分别在TEAS前、主动脉开放后30min、2h、8h和24h五个时间点抽取动脉血、离心提取血清，采用酶联免疫吸附试验（ELISA）进行生化指标检测。主要观察指标：主动脉开放后24小时内血清心肌肌钙蛋白I（cTnI）和脑损伤特异指标S100β浓度的组间差异。次要指标：临床预后包括术后气管带管时间、血管活性药物使用情况、ICU停留期间前24小时尿量、并发症、心脑不良事件、ICU停留时间、术后住院天数；其它生化指标包括血清肌红蛋白（Myo）、8-异构前列腺素F2α（8-iso PGF2α）以及白介素（IL）6、IL-10、肿瘤坏死因子（TNF-a）、超敏C-反应蛋白（hsCRP）浓度变化。
结果：纳入的74例患儿中70例全程完成试验，对照组36例和TEAS组34例。两组患儿术前平均年龄（3.45±2.1vs.3.95±2.4岁）及体重（14±3.9vs.15±3.1kg）组间没有明显差异。CPB转机时间及主动脉阻断时间组间差异也没有统计学意义。两组患儿术前血清cTnI浓度均处于较低水平（0.017ng/mL vs.0.021ng/mL）且组间没有明显差异；血清Myo基础水平组间也无明显差异(21.8±14.9μg/L vs.22.4±11.3μg/L)。所有患儿主动脉开放后，血清cTnI和Myo浓度显著上升并保持较高水平（与基础值相比，P<0.001）；与TEAS组相比，对照组恢复灌注后2h血清Myo浓度(432.7±146.4μg/L vs.287.1±125.2μg/L, P=0.037），以及8h和24h的血清cTnI浓度（分别为13.19±2.3ng/mL vs.9.21±2.0ng/mL, P=0.043和8.48±1.9ng/mLvs.5.68±1.7ng/mL, P=0.046)明显处于更高水平。所有患儿术前血清S100β水平均不超过0.02μg/L，主动脉开放后开始迅速显著升高，30min时升高值达最大（对照组1.44±0.67μg/L vs. TEAS组1.35±0.58μg/L），然后开始快速下降，2h时约降至30min时的一半（0.67±0.46μg/L vs.0.77±0.4μg/L）；8h时降至基础偏高水平，24h时基本恢复术前水平；各时间点血清S100β浓度升高程度，组间相比没有明显差异。与TEAS组患者相比，对照组术后机械通气时间和ICU停留持续时间明显延长（分别为10(8.5–20)h vs.6(5.5–10)h,P=0.004和46(24–50)h vs.41(23–47)h, P=0.032）。血清8-isoPGF2α在主动脉开放后明显升高，2h时出现峰值，但各时间点组间差异没有统计学意义。血清IL-6、IL-10浓度在主动脉开放后同样在2h达最高峰，随后平稳下降；而CRP和TNF-α浓度在主动脉开放后持续升高，术后24h血清浓度值最大。两组间相应各时间点血清IL-6、IL-10和TNF-α浓度变化差异没有统计学意义；然而，与对照组相比，TEAS组开放后8h的血清hsCRP浓度相对较低（2292±116pg/mL vs.1642±187pg/mL, P=0.039）。
结论：CPB结束后早期，血清心肌损伤标记物cTnI、Myo和脑损伤标记物S100β浓度明显升高，表明小儿先心术后存在一定程度的心脑损伤；主动脉开放后氧化应激指标8-isoPGF2、细胞促炎因子IL-6、TNF-α、hsCRP和抗炎因子IL-10血清水平的明显升高更加证实了这一点。术前给予患儿双侧内关穴30min的TEAS可明显降低开放后cTnI和Myo的释放，缩短术后辅助通气时间，具有一定的心肌保护作用。此作用可能部分与抑制急性缺血再灌注条件下hsCRP的释放有关。TEAS没有表现出明显的脑保护作用，可能与穴位的选择缺乏特异性或刺激时效不足有关。然而本研究结果表明，对小儿心脏直视手术患者，术前给予双侧内关穴TEAS是一项简单实用的心肌保护干预措施，具有良好的临床应用前景。
Background: Perioperative hypoxic-ischemia (HI) myocardial andneurologic damage caused by cardiac arrest (CA) is the leading cause of acutedeath and chronic disability in children. There is no comprehensive preventionand treatment to CA-induced pediatric HI damage. Hypothemia is an importantmanagement for myocardial protection during cardiopulmonary bypass (CPB)cardiac surgery, it is also the only effective way for post-resuscitation treatmentthrough reduces the metabolism and attenuates tissue edema in children. But thetime window and clinical efficacy of hypothermia in pediatric CA is limited.Therefore, a clinical need remains for finding agents or intervention that can beadministered easily and that can provide an added benefit with delayedhypothermia in protecting the heart and brain from HI.
Oxidant stress is considered a major contributing factor to CA–induced HIdamage in immature heart and brain. In our previous studies demonstrated thathypothermia-mediated myocardial/neurologic protection is related to increased formation of protein carbonyl groups, nitration of proteins and nucleic acids, andhydroxylation of nucleic acids. And early antioxidant therapy can provide partialneuroprotection after resuscitation. Therefore, we presume that interventions or agentswith an antioxidant capacity would provide additive cardio/neuroprotection fordelayed hypothermia. Acupuncture mimics pretreatment that exertsneuroprotective and cardioprotective effects through increasing activity ofantioxidant enzyme and enhancing ability of free radical scavenging in animalmodels and in adult patients underwent cardiac surgery; however, data in effect oftranscutaneous electrical acupoint stimulation on pediatric ischemiccardio/cerebral damage from cardiac arrest are unavailable.
In this study part I, we tested the hypothesis that treatment with thesuperoxide dismutase-catalase mimetic EUK-134at30minutes of recoveryprovides additive neuronal protection when combined with one day of wholebody hypothermia implemented4hours after resuscitation. In Part II, through aclinical controlled trial, we investigated that the effects of transcutaneouselectrical acupoint stimulation on the hypoxic ischemia heart and brain damagecaused by CA with hypothermia in the pediatric open heart surgery，to determinewhether these measures can be used as an alternative prevention to reduce heartand brain damage from perioperative CA in children.
Part I Effect of Combined Early Antioxidant Treatmentand Delayed Hypothermia on Neuroprotection afterHypoxic-Ischemia in Piglet
Objective: To test the hypothesis that treatment with the superoxidedismutase-catalase mimetic EUK-134at30minutes of recovery provides additive neuronal protection when combined with one day of whole body hypothermiaimplemented4hours after resuscitation in a piglet model of hypoxic-ischmia(HI).
Methods: Anesthetized piglets were subjected to40minutes of hypoxia(10%inspired oxygen) followed by7minutes of airway occlusion andresuscitation. EUK-134was administrated with a bolus dose2.5mg/kg at30minutes of recovery, plus1.25mg/kg/h intravenous infusion until4hours ofrecovery. Body temperature was maintained at38.5°C in normothermic groupsand at34°C in hypothermic groups. All groups were mechanically ventilated,sedated, and received muscle relaxants during the first day of recovery.
Results: At10days of recovery, neuronal viability in putamen of anormothermic group treated with saline vehicle was reduced to17±9%(±SD) ofthe value in a sham-operated control group (100±18%). Intravenous infusion ofEUK-134with normothermic recovery resulted in40±17%viable neurons inputamen. Treatment with saline vehicle followed by delayed hypothermiaresulted in partial protection (46±21%). Combining early EUK-134treatmentwith delayed hypothermia did not produce additional protection in putamen(47±25%). Furthermore, no additive neuroprotection was detected in caudatenucleus or parasagittal neocortex, where neuronal loss was less severe.
Conclusions: We conclude that early treatment with this antioxidant doesnot extend the therapeutic benefit of hypothermia in protecting highly vulnerableneurons in ischemic-ischemia (HI)-insulted pediatrics, possibly because basalganglia neurons are already undergoing irreversible cell death signaling by thetime EUK-134is administered or because this compound and hypothermiaattenuate similar mechanisms of injury.
Part II Myocardial/Neurologic Protection of TEAS in thePediatric Cardiac Patients: A Randomized Controlled Trial
Objective: To investigate the effects of transcutaneous electric acupointstimulation (TEAS) on acute myocardial/neurologic injury from pediatricopen-heart surgery.
Methods: Children, aged2–12years, with congenital heart defectsscheduled for surgical repair were enrolled. They were randomized to TEAS(administrated at bilateral P6acupoint for30min after basal anesthesia) andcontrol (an electrode was placed on the arm without stimulus) groups. Theduration of cardiopulmonary bypass and aortic cross-clamp time was recorded.The primary end point was serum cardiac troponin I (cTnI) and S100βlevelover24h after aortic unclamping. Furthermore, clinical outcome, and serummyohemoglobin (Myo), interleukin (IL-8, IL-10), tumor necrosis factor (TNF-α),C-reactive protein (CRP) and8-isoprostane (8-iso PGF2α) concentrations wereevaluated pre-and postoperatively.
Results: Seventy eligible children were analyzed,36in controls and34inTEAS group. Compared with controls, the mean serum Myo concentration wassignificantly lower in TEAS group at2h (P=0.037); the mean cTnI levels weresignificantly lower in TEAS group at8h (P=0.043) and24h (P=0.046) afteraortic unclamping. After aortic unclamping, S100βlevel significantly increasedand rearched a peak at30min (control group1.44±0.67ug/L vs. TEAS group1.35±0.58ug/L), thereafter, declined rapidly; the serum concentration of S100βdecreased to a half of peak values by2h (0.67±0.46ug/L vs.0.77±0.4ug/L),then recovered to preoperative level at24h; there is no significant differences of serum S100β elevated level in each time point between groups. The duration ofventilation (P=0.004) and length of ICU stay (P=0.032) was significantly longerin controls than in TEAS group. There was a significant difference in the releaseof C-reactive protein at8h (P=0.039) between two groups, whereas the valuesfor8-iso PGF2α and cytokines were not significant.
Conclusion: Transcutaneous electric acupoint stimulation on the bilateral P6acupoint is effective for attenuation myocardial injury in children undergoingcardiac surgery. The beneficial effects may be partially associated with reductionin cTnI and C-reactive protein level in the early postoperative period.
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