铁在TBI后继发性脑损伤中的作用的实验研究及ICP、CPP、PbtO2监护在TBI救治中的临床应用研究
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摘要
第一部分铁在大鼠创伤性脑损伤(TBI)后继发脑损伤中的作用、机制及去铁胺的疗效研究
背景和目的
创伤性颅脑损伤(traumatic brain injury，TBI)是全球性最主要的健康和社会经济学问题之一，已经成为45岁以下年轻人的头号杀手，是首要的致残和致死原因。数十年来，虽然治疗措施、策略上不断改进，但TBI发病率和死亡率依然居高不下，而存活的TBI病例，虽然数月内神经功能往往可以得到快速恢复，但不少病例发现进行性神经功能损害(如认知功能障碍和记忆力下降)和脑萎缩在TBI后数年仍然存在，说明继发性脑损伤机制一直存在。实验采用药物阻断凋亡、阻断谷氨酸诱导的兴奋性神经毒性、抗炎症治疗以及减轻氧化应激以减少神经细胞的丢失来促进神经功能的恢复，然而，超过30种药物在动物实验中发现有效，在临床三期药物实验中均宣告失败，提示还持续存在其他因素导致继发性脑损害的发生。
文献报道脑组织铁离子过量具有神经毒性作用，参与慢性脑积水、脑出血(intracerebral hemorrhage,ICH)后神经损害以及神经退行性疾病等病理过程。在慢性脑积水、ICH和神经系统退行性疾病的研究中发现脑萎缩和神经功能损害存在，而铁离子在继发性脑损害中扮演重要角色。本课题组前期研究发现脑室内注射血液和FeCl3均可造成慢性脑积水，而采用铁离子螯合剂去铁胺(deferoxamine,DFO)治疗能显著降低脑积水的发生率。Xi等采用脑实质内注射Fe3+以及实验性ICH均发现过量铁离子具有神经毒性作用，予以DFO治疗能减轻脑萎缩和神经功能损害的程度。多数TBI也是一种脑出血性损伤(脑挫裂伤、脑内血肿)，红细胞分解同样会出现过量铁离子，我们推测TBI也存在铁离子过量造成的神经毒性作用。
本实验旨在认识TBI后是否存在过量铁离子造成的神经毒性作用，DFO治疗的实验性TBI的疗效、时效关系、量效关系以及安全性，以及相关的铁离子代谢蛋白的变化规律和自噬在TBI中扮演的角色，探索DFO是否可用于治疗TBI。
材料和方法
1、成年健康雄性SD大鼠104只，随机分为三组：假手术组、致伤组和DFO治疗组，其中DFO治疗组又分为早期治疗组(E50mg/Kg, E100mg/Kg, E150mg/Kg)和延期治疗组(D50mg/Kg, D100mg/Kg, D150mg/Kg)。早期DFO治疗组伤后2h给药，按照不同剂量分别给药50mg/Kg、100mg/Kg、150mg/Kg，每12h腹腔注射给药1次，持续28d，延期治疗组前2天注射生理盐水，3d后给药同早期DFO治疗组。假手术组和致伤组予以生理盐水作为对照；
2、实验28d完成Morris水迷宫实验，将平台搜索时间和平台搜索策略纳入观察内容，以评估实验动物的空间学习记忆力；
3、用4%多聚甲醛灌注后开颅取大脑，将大脑完整取下后，测量各组实验动物的大脑缺损的长宽高，采用多田公式计算大脑缺损体积；
4、取致伤灶周围脑组织匀浆，离心后取上清液采用原子分光光度计测量铁离子含量；
5、取4%多聚甲醛固定的大鼠致伤灶周围脑组织、股骨、胸骨、脾脏、肝脏，制成石蜡切片(其中股骨、胸骨需要脱钙处理)，完成Perl’s染色、HE染色和Nissl染色(脑组织)。
6、采用免疫荧光技术检测脑组织铁蛋白轻链(ferritin light chain，FL)、铁蛋白重链(ferritin heavy chain，FH)、转铁蛋白(transferrin，Tf)、TRPC6在神经元、星形胶质细胞和少突胶质细胞上的表达情况；
7、采用免疫组化技术检测Beclin1的分布和表达情况；
8、采用Western Blot技术，定量检测FL、FH、Tf和TRPC6表达情况。
结果
1、TBI后28d，致伤组可以观察到损伤区域直径较打击杆直径显著扩大，大脑缺损体积达到(209.99±16.7)mm3，早期(2h)予以DFO(100mg/Kg)治疗能显著缩小大脑缺损体积至(115.35±13.7)mm3(P＜0.05)，其余治疗组无显著改善；
2、与假手术组(搜索时间为14.52±1.86s，搜索策略为3.63±0.52)比较，致伤组Morris水迷宫实验结果提示，平台搜索时间(110±47.34s)明显延长(P＜0.05)，搜索策略(2.13±0.64)明显降低(P＜0.05)，早期(2h)予以DFO(100mg/Kg)治疗能显著改善大鼠Morris水迷宫实验结果，缩短平台搜索时间(36.15±26.63s，P＜0.05)，提高平台搜索策略(3.13±0.35，P＜0.05)；
3、致伤组致伤灶周围脑组织铁离子含量较假手术组显著升高(P＜0.01)，予以DFO治疗后，各组脑组织铁离子含量均无显著降低(P＞0.05)；
4、本课题将各组实验动物性别、肛温、血糖、血红蛋白进行了比较，无显著差异；
5、TBI后FL、FH、Tf和TRPC6表达均显著上调(P＜0.05)，早期(2h)予以DFO(100mg/Kg)治疗能显著下调其表达(P＜0.05)，双标结果提示TBI后难以见到完整的致伤灶周围脑组织神经元、星形胶质细胞，而E100组虽然细胞皱缩变形，但能见到完整的神经元、星形胶质细胞，与TRPC6共表达均增强；
6、免疫组化和Western Blot结果提示致伤组可见致伤灶周围脑组织Beclin1表达均明显增强(P＜0.05)，早期(2h)予以DFO(100mg/Kg)治疗能显著下调其表达(P＜0.05)；
7、DFO治疗TBI具有时效关系和量效关系，在时效关系上，只有早期(2h)治疗疗效比较显著，延期(3d)治疗基本无效；在量效关系上，最佳治疗剂量为100mg/Kg，早期50mg/Kg治疗，只有部分有效；
8、本实验观察了死亡率和主要脏器的铁离子代谢情况，未发现DFO治疗会增加死亡率，也未发现对血红蛋白和铁离子代谢有明显影响。
结论
1、实验性TBI后28d，存在脑铁过量造成的神经毒性作用；
2、DFO治疗实验性TBI有效，能显著减少大脑缺损体积，能显著改善实验动物的空间学习记忆能力；
3、从时效关系上讲，DFO治疗TBI的最佳时间是伤后2h，从量效关系上讲，最佳的剂量是100mg/Kg；
4、TBI后致伤灶周围脑组织难以见到完整的神经元、星形胶质细胞，早期(2h)予以DFO100mg/Kg治疗后，可见较多形态完整的神经元、星形胶质细胞，尽管细胞皱缩变形，从细胞水平上证实了DFO对“半暗带”神经元和星形胶质细胞的保护作用，而TRPC6可能在其中扮演重要角色；
5、TBI后致伤灶周围脑组织自噬标记物Beclin1表达显著上调，予以DFO治疗后显著下调其表达，提示TBI后存在自噬损伤，DFO治疗能减轻自噬损伤的作用，铁可能扮演重要角色；
6、本课题延长了DFO治疗TBI的时间至28d，增大DFO剂量至150mg/Kg，结果发现实验动物死亡率、血红蛋白和铁离子代谢并未受到显著影响，提示DFO治疗TBI是安全的。
第二部分ICP、CPP、Pb_tO_2监护技术在颅脑创伤救治中的临床应用研究
研究背景
创伤性脑损伤(TBI)目前仍然存在发病率、致残率和死亡率高的特点。数十年来，重型TBI的致残率、死亡率并没有显著下降，尤其是严重脑挫裂伤的TBI病例目前尚无临床救治指南，其手术时机、手术方式等仍存在较大的争议，神经外科医生只能根据自身有限的经验进行救治。因此有必要进行颅内压(ICP)、脑灌注压(CPP)以及脑组织氧分压(Pb_tO_2)等多参数重症监护，以期获得一些临床资料，对制定严重脑挫裂伤的救治指南提供重要佐证，为临床上严重脑挫裂伤、急性硬膜下血肿病例的救治提供依据，实验因此而展开。
资料与方法
1、入选标准
各种原因导致的颅脑损伤病例,从中选择广泛脑挫裂伤或/和硬膜下血肿病例，中～重型颅脑外伤，GCS评分为3～12分，并且头颅CT检查提示颅内广泛脑挫裂伤(单侧或双侧)，或/和广泛硬膜下血肿。
2、排除标准
为保证实验更具有可靠性，本实验将一些可能影响预后判断的病例予以排除，包括⑴生命体征不稳定，脑干功能衰竭，频死状态者；⑵受伤前患者有出血素质或凝血功能障碍；⑶合并严重重要脏器慢性疾病或不能耐受手术者；⑷合并其他重要脏器严重并发伤者；⑸CT扫描提示单纯硬膜外血肿和弥漫性轴索损伤病例除外。
3、临床资料
将2009年5月～2011年3月在我院、涪陵中心医院、万州三峡中心医院、巴南区人民医院完成的ICP、Pb_tO_2监测的中重型TBI病例43例纳入研究对象。本组病例年龄分布为14～76岁，平均年龄50.9岁，其中男31例，女12例，男：女=2.58:1。按入院时GCS评分分：12分4例，9分3例，8分14例，7分1例，6分5例，5分6例，4分2例，3分8例。按出院时GOS评分分，5分19例，4分9例，3分1例，2分4例，1分10例。本组病例预后良好率(GOS评分为4分和5分)为65.1%，出院时死亡率为23.3%，6m随访死亡率30.2%。
结果
1、预后不良组与预后良好组血糖无论是术前还是术后均升高，而预后不良组血糖升高更为严重。与预后良好组比较，预后不良组血糖水平术前和术后5d均显著升高，统计学差异显著(P＜0.01)，术后1d有统计学差异(P＜0.05)；
2、预后不良组出血量往往较大，100ml以上4例，70～100m l6例，预后良好组大部分分布在30～50ml水平；
3、预后不良组术前ICP升高程度更明显，术后ICP有所下降，但仍然显著高于正常水平，之后又逐步升高，而预后良好组术前ICP也显著升高，手术减压后ICP即显著下降，虽然3d有所升高，但总的趋势是逐步下降至正常范围内。与预后不良组比较，预后良好组ICP均显著降低，经统计学处理，发现术前、1d和5d统计学差异显著(P＜0.01)，术后3d有统计学差异(P＜0.05)；
4、预后良好组，术前CPP略低于正常，减压术后，CPP迅速升高，恢复正常。预后不良组则CPP显著下降，减压术后改善也不明显。与预后不良组比较，预后良好组CPP无论是术前还是术后，均有显著统计学差异(P＜0.01)；
5、术前预后良好组Pb_tO_2略低于正常，术后Pb_tO_2即逐步恢复正常，而预后不良组为Pb_tO_2显著低于正常状态，手术并未改善Pb_tO_2。与预后不良组比较，预后良好组各时间点均显著升高，其中3d有统计学差异(P＜0.05)，术前、术后1d和5d差异显著(P＜0.01)；
6、标准大骨瓣在降低手术前后ICP的作用是十分显著的，预后良好组和预后不良组分别为(31.22±2.73)mmHg和(29.45±3.30)mmHg，然而在提高Pb_tO_2和CPP水平方面，预后不良组大骨瓣减压作用非常有限，而预后良好组大骨瓣减压作用则非常显著。与预后不良组比较，大骨瓣减压能显著提高预后良好组Pb_tO_2和CPP(P＜0.05)，而两组在降低ICP方面没有统计学差异。
结论
1、中重型TBI病例监测ICP、CPP是非常必要的，不但能早期确定病例是否需要手术，还能早期判断术后是否继发出血、预后等情况；
2、Pb_tO_2是一个安全有效的现代神经外科监测措施，较ICP、CPP监测更为敏感而特异，能较ICP、CPP更早预警病情变化，对伤后是否存在早期脑缺氧、供氧自动调节机能及脑的能量代谢状态进行连续性的监测起着至关重要的作用，还能早期判断病例预后；
3、现代神经外科监护应该结合ICP、CPP和Pb_tO_2等进行多参数监测，这样不但可以为神经外科医生早期判断病情，并及时处理提供更为详细可靠的信息，还能指导临床用药、早期判断病例预后；
4、在TBI病例救治中，就减压效果而言，本试验支持标准大骨瓣减压是治疗中重型TBI的首选方法，不但可以显著降低ICP，也能显著提高CPP和Pb_tO_2，改善病例预后。
Part ⅠEffects and mechanisms of brain iron on secondary brain injury afterexperimental traumatic brain injury (TBI), and the protective effects of deferoxamine
Background
Traumatic brain injury (TBI) is one of the critical problems affected the health andeconomics in the world. TBI is the first killer of the people younger than45years-old, andthe first reason of disability and mortality. Although the methods of treatment for TBI haveimproved greatly within several decades, the mobility and mortality are still very high.Usually, some of the neurological functions of patients suffered from TBI recovered quicklywithin months, but some impairment, such as the deteriorations of congnition and memory,and the brain atrophy would last for several years. It was indicated there would be somelasting mechanisms of secondary brain injury after TBI. However, some medicines, such asagents for anti-apoptosis, obstructing glutamate-induced neurotoxicity, anti-inflammation,and inhibiting oxidative stress were failed to take advantages for the recovery ofneurological functions. There were more than30drugs which were proved useful for TBI inanimals but were failed in the Ⅲ stage clinical trials. There would other factors whichinduced the secondary brain injury.
It was reported that iron over-loading would induce neurotoxicity in experimentalintracerebral hemorrhage (ICH), neurodegenerative diseases and experimental chronichydrocephalus. The abnormal iron accumulation played critical roles on the brain atrophyand neurological injuries in ICH and neurodegenerative diseases. In experimental ICH,administration of deferoxamine (DFO) could reduce the brain atrophy and neurologicalinjuries. In our previous study, injection of FeCl3to the ventricle could induce chronic hydrocephalus, and administration of DFO would decrease the the morbility of chronichydrocephalus. Which suggested that iron over-loading would induce neurotoxicity, andadministration of DFO can lower the possibility of brain atrophy and the neurologicalinjuries. Hemorrhage is also one of the most frequent pathological changes in TBI，especially in contusion and laceration of brain and intracerebral hematoma. Theneurotoxicity caused by iron over-loading might be happened in TBI.
The purpose of this study was to disclose the effects of iron over-loading on TBI andthe therapeutic effects and the safety of DFO. Furthermore, the roles of iron metabolismproteins in the TBI were demonstrated.
Materials and methods
1. One hundred and four healthy adult male SD rats were divided randomly intothree groups: sham group, injury group, and DFO-treated group. and the last group dividedinto Early DFO-treated subgroups: E50subgroup (50mg/Kg), E100subgroup (100mg/Kg),E150subgroup (150mg/Kg), and Delayed DFO-treated subgroups: D50subgroup(50mg/Kg), D100subgroup (100mg/Kg), and D150subgroup (150mg/Kg). EarlyDFO-treated subgroups were administrated DFO2h after TBI，12h interval for28days,and delayed DFO-treated subgroups were administrated DFO3days after TBI，12h intervalfor25days. The sham group and injury group were administrated saline.
2. Morris water maze was done at the endpoint of the experiment. The time andstrategy of searching platform were calculated to evaluate the ability of learning andmemory.
3. The volume of brain lose was calculated by Coniglobus formula after the animalswere perfused by4%Paraformaldehyde and the brains were taken.
4. The content of the peri-injury brain iron was calculated by spectrophotometer.
5. The perl’s staining、HE staining and Nissl staining(brain tissue) were performed inthe tissues of peri-injury brain, femur, sternum, spleen, and liver.
6. The expression of ferritin light chain (FL), ferritin heavy chain (FH), transferring(Tf) and TRPC6in the neurons, astrocytes, and oligodendroglias were detected withimmunofluorescence.
7. The expression of Beclin1was detected with the immunohistochemisty.
8. The expressions of FL, FH, Tf and TRPC6were also detected by western blot.
Results
1. The volume of brain lose was (209.99±16.7mm~3). And it could be decreasedsignificantly (115.35±13.7mm~3，P＜0.05) by early100mg/Kg DFO-treated.
2. Time of platform searching was14.52±1.86s, and strategy of platform searchingwas3.63±0.52with Morris water maze in nomal rats. While time of platform searchingextended to110±47.34s (P＜0.05), and strategy of platform searching lowered to2.13±0.64(P＜0.05) in injury group. The early (2h) DFO administration (100mg/Kg) coulddecrease the time of platform searching to36.15±26.63s (P＜0.05), and improve thestrategy of platform searching to3.13±0.35(P＜0.05).
3. Compared with sham group, the content of brain iron in injury group increasesgreatly (P＜0.01). However, the administration of DFO failed to decrease the brain iron (P＞0.05).
4. There were no statistical differences of sexuality, rectal temperature, glucose andhemoglobin in each group.
5. Compared with sham group, the expressions of FL, FH, Tf and TRPC6wereup-regulated (P＜0.05) after TBI and could be down-regulated by early (2h after TBI)administration of100mg/Kg DFO. In injury group, there were no neurons and astrocytes inthe peri-injury zones after TBI, while many shrinkage neurons and astrocytes with TRPC6expressing were detected in group with early (2h after TBI) administration of100mg/KgDFO.
6. The up-regulation of Beclin1was detected after injury. And the expression wasinhibited by early (2h after TBI) administration of100mg/Kg DFO.
7. The best therapeutic effect of DFO was appeared in the group which the DFO wasadministrated in2hours after TBI with dosage of100mg/Kg.
8. There were no affects of motality, hemoglobin and iron metabolism caused by DFOadministration after TBI.
Conclusions
1. Over-load brain iron plays the role of neurotoxicity at28thday after experimental TBI.
2. DFO is the effective drug in experimental TBI, which can significantly reduce thevolume of brain defect, and significantly improve the ability of spatial learning and memoryin experimental animals.
3. Taken the time-effect relationship into account, the best treatment time of DFO is2h after TBI, and as the dose-effect relationship, the optical dose is100mg/Kg.
4. There is few intact neurons and astrocytes peri-injury after TBI,while DFOadministered at2h after TBI, more neurons and astrocytes are detected though the cellshrinkage, which suggests that the protective effect of neurons and astrocytes in“penumbra” at the cell level, and TRPC6may play important role in the procedure.
5. The expression of Beclin1，the marker of autophagy, upregulates significantlyperi-injury after TBI,and down regulation after DFO administered, which suggests thatautophagy injury exists after TBI, and DFO administered can reduce autophagy, and ironmay play important role..
6. In this experiment, the time of DFO administered extends to28d, and the doseincreases to150mg/Kg, which has no significant changes in mortality, hemoglobin and ironmetabolisms. In other words, DFO is a safe drug of TBI treatment.
Part Ⅱ The application of ICP,CPP and P_(bt)O_2monitoring in moderate andsevere traumatic brain injury
Background
The characteristics of traumatic brain injury (TBI) are high morbility, disability andmortality. The rate of disability and mortality caused by TBI were not decreasedsignificantly for decades. Lacking of guidelines and controversies on the strategies of thetreatment of contusion and laceration of brain limited the treatment based on theexperiences of the individual neurosurgeons. So ICP, CPP and P_(bt)O_2monitoring mightprovide more evidence for guiding the treatment of TBI.
Materials and methods
Selected standard
Patients of moderate and severe traumatic brain injuries with contusion and lacerationof brain and/or subdural hematoma, GCS from3to12were selected.
Exclusion criteria
Some cases were eliminated from the experiment in order to keep the reliability,including (1) patients with instability vital signs and exhaustion of brainstem functions;(2)hemorrhagic diathesis or hemorrhagic diathesis before TBI;(3) combining with chronicdisease of important organ or fail to tolerance operation;(4) pure epidural hematoma anddiffuse axonal injury with CT scan.
Clinical data
From May2009to Mar2011,43moderate to severe TBI cases from our hospital,Fuling center hospital, Sanxia center hospital and people’s hospital of Banan district wereperformed ICP and P_(bt)O_2monitoring. Within the43patients, there were31male and12female, aged from14to76years old.There were4cases with GCS12,3cases with GCS9,14cases with GCS8,1case with GCS7,5cases with GCS6,6cases with GCS5,2caseswith GCS4, and8cases with GCS3.When discharged from hospital, there were19caseswith GOS5,9cases with GOS4,1case with GOS3,4cases with GOS2, and10caseswith GOS1.The ratio of good outcome (GOS from4to5) was65.1%, the motality was23.3%as discharged, and30.2%after6months.
Results
1. The blood glucose increased in both the group of good outcome and the group ofbad outcome. Compared with the patients with good outcome, the concentration of bloodglucose was higher in patients with bad outcome at pre-operation,1day and5days afteroperation.
2. The volumes of hemorrhage were usually huge in the bad outcome group,4casesabove100ml,6from70ml to100ml. While in the good outcome group, there were mostfrom30ml to50ml.
3. The values of ICP were detected pre-operation in the bad outcome group higher thanthese in the good group, and decreased after operation, but still increased significant abovethe normal level, and then increased quickly. While the values of ICP were still detectedincreasing pre-operation, but decreased significant after operation, lower to normal lever, though certain increased at3d.Compared with the bad outcome group, the values of ICPdecreasing were significant at pre-operation,1d and5d(P＜0.01),even at3d(P＜0.05).
4. The values of CPP were little lower compared with the normal lever in the goodoutcome group and increased soon after operation. These were decreased in the badoutcome group. Compared with in the bad outcome group, those in the good outcome groupincreased significantly (P＜0.01).
5. The values of P_(bt)O_2were little lower compared with the normal lever in the goodoutcome group and then recovered to normal after operation. However, these in the badgroup lowered significantly pre-operation. Eventhough, this condition couldn’t be improvedafter operation. Compared with the bad outcome group, the levers increased significantly atpre-operation,1d,5d(P＜0.01) amd3d(P＜0.05).
6. Standard large trauma craniotomy was performed in the experiment, the lever of ICPdecreased significantly both in the bad outcome group (29.45±3.30mmHg) and the goodoutcome group (31.22±2.73mmHg). However, it failed to improve the lever of CPP andP_(bt)O_2in the bad outcome group, while it did in the good outcome group. Compared with thebad outcome group, Standard large trauma craniotomy was performed to improve CPP andP_(bt)O_2(P＜0.05), but there was no difference in decreasing ICP in both groups.
Conclusions
1. It is very necessary to monitor ICP and CPP after moderate to severe TBI, which candecide the case to operate or not early, and the secondary hemorrhage and outcome can bealso judged early.
2. The monitoring of P_(bt)O_2is a safe and effective method in neurosurgery intensivecare unit, and more sensitive and specific than the monitoring of ICP and CPP, which isearlier in reflecting the changes of patient’s condition than the later. It is important tohypoxia, homeostasis and energy metabolism of brain with monitoring of P_(bt)O_2, and theoutcome also can be judged early.
3. Multi-monitoring of ICP,CPP and P_(bt)O_2should be performed in neurosurgeryintensive care unit, which can provide more information to neurosurgeon early, and makethe treatment reliable, and can be as the guideline for the clinical medication and outcome.
4. Only taken effect of decompression into account, the standard large trauma craniotomy is supported to be the preference approach in our experiment, which not onlycan decrease ICP significantly, but also improve CPP and P_(bt)O_2.
背景和目的
创伤性颅脑损伤(traumatic brain injury，TBI)是全球性最主要的健康和社会经济学问题之一，已经成为45岁以下年轻人的头号杀手，是首要的致残和致死原因。数十年来，虽然治疗措施、策略上不断改进，但TBI发病率和死亡率依然居高不下，而存活的TBI病例，虽然数月内神经功能往往可以得到快速恢复，但不少病例发现进行性神经功能损害(如认知功能障碍和记忆力下降)和脑萎缩在TBI后数年仍然存在，说明继发性脑损伤机制一直存在。实验采用药物阻断凋亡、阻断谷氨酸诱导的兴奋性神经毒性、抗炎症治疗以及减轻氧化应激以减少神经细胞的丢失来促进神经功能的恢复，然而，超过30种药物在动物实验中发现有效，在临床三期药物实验中均宣告失败，提示还持续存在其他因素导致继发性脑损害的发生。
文献报道脑组织铁离子过量具有神经毒性作用，参与慢性脑积水、脑出血(intracerebral hemorrhage,ICH)后神经损害以及神经退行性疾病等病理过程。在慢性脑积水、ICH和神经系统退行性疾病的研究中发现脑萎缩和神经功能损害存在，而铁离子在继发性脑损害中扮演重要角色。本课题组前期研究发现脑室内注射血液和FeCl3均可造成慢性脑积水，而采用铁离子螯合剂去铁胺(deferoxamine,DFO)治疗能显著降低脑积水的发生率。Xi等采用脑实质内注射Fe3+以及实验性ICH均发现过量铁离子具有神经毒性作用，予以DFO治疗能减轻脑萎缩和神经功能损害的程度。多数TBI也是一种脑出血性损伤(脑挫裂伤、脑内血肿)，红细胞分解同样会出现过量铁离子，我们推测TBI也存在铁离子过量造成的神经毒性作用。
本实验旨在认识TBI后是否存在过量铁离子造成的神经毒性作用，DFO治疗的实验性TBI的疗效、时效关系、量效关系以及安全性，以及相关的铁离子代谢蛋白的变化规律和自噬在TBI中扮演的角色，探索DFO是否可用于治疗TBI。
材料和方法
1、成年健康雄性SD大鼠104只，随机分为三组：假手术组、致伤组和DFO治疗组，其中DFO治疗组又分为早期治疗组(E50mg/Kg, E100mg/Kg, E150mg/Kg)和延期治疗组(D50mg/Kg, D100mg/Kg, D150mg/Kg)。早期DFO治疗组伤后2h给药，按照不同剂量分别给药50mg/Kg、100mg/Kg、150mg/Kg，每12h腹腔注射给药1次，持续28d，延期治疗组前2天注射生理盐水，3d后给药同早期DFO治疗组。假手术组和致伤组予以生理盐水作为对照；
2、实验28d完成Morris水迷宫实验，将平台搜索时间和平台搜索策略纳入观察内容，以评估实验动物的空间学习记忆力；
3、用4%多聚甲醛灌注后开颅取大脑，将大脑完整取下后，测量各组实验动物的大脑缺损的长宽高，采用多田公式计算大脑缺损体积；
4、取致伤灶周围脑组织匀浆，离心后取上清液采用原子分光光度计测量铁离子含量；
5、取4%多聚甲醛固定的大鼠致伤灶周围脑组织、股骨、胸骨、脾脏、肝脏，制成石蜡切片(其中股骨、胸骨需要脱钙处理)，完成Perl’s染色、HE染色和Nissl染色(脑组织)。
6、采用免疫荧光技术检测脑组织铁蛋白轻链(ferritin light chain，FL)、铁蛋白重链(ferritin heavy chain，FH)、转铁蛋白(transferrin，Tf)、TRPC6在神经元、星形胶质细胞和少突胶质细胞上的表达情况；
7、采用免疫组化技术检测Beclin1的分布和表达情况；
8、采用Western Blot技术，定量检测FL、FH、Tf和TRPC6表达情况。
结果
1、TBI后28d，致伤组可以观察到损伤区域直径较打击杆直径显著扩大，大脑缺损体积达到(209.99±16.7)mm3，早期(2h)予以DFO(100mg/Kg)治疗能显著缩小大脑缺损体积至(115.35±13.7)mm3(P＜0.05)，其余治疗组无显著改善；
2、与假手术组(搜索时间为14.52±1.86s，搜索策略为3.63±0.52)比较，致伤组Morris水迷宫实验结果提示，平台搜索时间(110±47.34s)明显延长(P＜0.05)，搜索策略(2.13±0.64)明显降低(P＜0.05)，早期(2h)予以DFO(100mg/Kg)治疗能显著改善大鼠Morris水迷宫实验结果，缩短平台搜索时间(36.15±26.63s，P＜0.05)，提高平台搜索策略(3.13±0.35，P＜0.05)；
3、致伤组致伤灶周围脑组织铁离子含量较假手术组显著升高(P＜0.01)，予以DFO治疗后，各组脑组织铁离子含量均无显著降低(P＞0.05)；
4、本课题将各组实验动物性别、肛温、血糖、血红蛋白进行了比较，无显著差异；
5、TBI后FL、FH、Tf和TRPC6表达均显著上调(P＜0.05)，早期(2h)予以DFO(100mg/Kg)治疗能显著下调其表达(P＜0.05)，双标结果提示TBI后难以见到完整的致伤灶周围脑组织神经元、星形胶质细胞，而E100组虽然细胞皱缩变形，但能见到完整的神经元、星形胶质细胞，与TRPC6共表达均增强；
6、免疫组化和Western Blot结果提示致伤组可见致伤灶周围脑组织Beclin1表达均明显增强(P＜0.05)，早期(2h)予以DFO(100mg/Kg)治疗能显著下调其表达(P＜0.05)；
7、DFO治疗TBI具有时效关系和量效关系，在时效关系上，只有早期(2h)治疗疗效比较显著，延期(3d)治疗基本无效；在量效关系上，最佳治疗剂量为100mg/Kg，早期50mg/Kg治疗，只有部分有效；
8、本实验观察了死亡率和主要脏器的铁离子代谢情况，未发现DFO治疗会增加死亡率，也未发现对血红蛋白和铁离子代谢有明显影响。
结论
1、实验性TBI后28d，存在脑铁过量造成的神经毒性作用；
2、DFO治疗实验性TBI有效，能显著减少大脑缺损体积，能显著改善实验动物的空间学习记忆能力；
3、从时效关系上讲，DFO治疗TBI的最佳时间是伤后2h，从量效关系上讲，最佳的剂量是100mg/Kg；
4、TBI后致伤灶周围脑组织难以见到完整的神经元、星形胶质细胞，早期(2h)予以DFO100mg/Kg治疗后，可见较多形态完整的神经元、星形胶质细胞，尽管细胞皱缩变形，从细胞水平上证实了DFO对“半暗带”神经元和星形胶质细胞的保护作用，而TRPC6可能在其中扮演重要角色；
5、TBI后致伤灶周围脑组织自噬标记物Beclin1表达显著上调，予以DFO治疗后显著下调其表达，提示TBI后存在自噬损伤，DFO治疗能减轻自噬损伤的作用，铁可能扮演重要角色；
6、本课题延长了DFO治疗TBI的时间至28d，增大DFO剂量至150mg/Kg，结果发现实验动物死亡率、血红蛋白和铁离子代谢并未受到显著影响，提示DFO治疗TBI是安全的。
第二部分ICP、CPP、Pb_tO_2监护技术在颅脑创伤救治中的临床应用研究
研究背景
创伤性脑损伤(TBI)目前仍然存在发病率、致残率和死亡率高的特点。数十年来，重型TBI的致残率、死亡率并没有显著下降，尤其是严重脑挫裂伤的TBI病例目前尚无临床救治指南，其手术时机、手术方式等仍存在较大的争议，神经外科医生只能根据自身有限的经验进行救治。因此有必要进行颅内压(ICP)、脑灌注压(CPP)以及脑组织氧分压(Pb_tO_2)等多参数重症监护，以期获得一些临床资料，对制定严重脑挫裂伤的救治指南提供重要佐证，为临床上严重脑挫裂伤、急性硬膜下血肿病例的救治提供依据，实验因此而展开。
资料与方法
1、入选标准
各种原因导致的颅脑损伤病例,从中选择广泛脑挫裂伤或/和硬膜下血肿病例，中～重型颅脑外伤，GCS评分为3～12分，并且头颅CT检查提示颅内广泛脑挫裂伤(单侧或双侧)，或/和广泛硬膜下血肿。
2、排除标准
为保证实验更具有可靠性，本实验将一些可能影响预后判断的病例予以排除，包括⑴生命体征不稳定，脑干功能衰竭，频死状态者；⑵受伤前患者有出血素质或凝血功能障碍；⑶合并严重重要脏器慢性疾病或不能耐受手术者；⑷合并其他重要脏器严重并发伤者；⑸CT扫描提示单纯硬膜外血肿和弥漫性轴索损伤病例除外。
3、临床资料
将2009年5月～2011年3月在我院、涪陵中心医院、万州三峡中心医院、巴南区人民医院完成的ICP、Pb_tO_2监测的中重型TBI病例43例纳入研究对象。本组病例年龄分布为14～76岁，平均年龄50.9岁，其中男31例，女12例，男：女=2.58:1。按入院时GCS评分分：12分4例，9分3例，8分14例，7分1例，6分5例，5分6例，4分2例，3分8例。按出院时GOS评分分，5分19例，4分9例，3分1例，2分4例，1分10例。本组病例预后良好率(GOS评分为4分和5分)为65.1%，出院时死亡率为23.3%，6m随访死亡率30.2%。
结果
1、预后不良组与预后良好组血糖无论是术前还是术后均升高，而预后不良组血糖升高更为严重。与预后良好组比较，预后不良组血糖水平术前和术后5d均显著升高，统计学差异显著(P＜0.01)，术后1d有统计学差异(P＜0.05)；
2、预后不良组出血量往往较大，100ml以上4例，70～100m l6例，预后良好组大部分分布在30～50ml水平；
3、预后不良组术前ICP升高程度更明显，术后ICP有所下降，但仍然显著高于正常水平，之后又逐步升高，而预后良好组术前ICP也显著升高，手术减压后ICP即显著下降，虽然3d有所升高，但总的趋势是逐步下降至正常范围内。与预后不良组比较，预后良好组ICP均显著降低，经统计学处理，发现术前、1d和5d统计学差异显著(P＜0.01)，术后3d有统计学差异(P＜0.05)；
4、预后良好组，术前CPP略低于正常，减压术后，CPP迅速升高，恢复正常。预后不良组则CPP显著下降，减压术后改善也不明显。与预后不良组比较，预后良好组CPP无论是术前还是术后，均有显著统计学差异(P＜0.01)；
5、术前预后良好组Pb_tO_2略低于正常，术后Pb_tO_2即逐步恢复正常，而预后不良组为Pb_tO_2显著低于正常状态，手术并未改善Pb_tO_2。与预后不良组比较，预后良好组各时间点均显著升高，其中3d有统计学差异(P＜0.05)，术前、术后1d和5d差异显著(P＜0.01)；
6、标准大骨瓣在降低手术前后ICP的作用是十分显著的，预后良好组和预后不良组分别为(31.22±2.73)mmHg和(29.45±3.30)mmHg，然而在提高Pb_tO_2和CPP水平方面，预后不良组大骨瓣减压作用非常有限，而预后良好组大骨瓣减压作用则非常显著。与预后不良组比较，大骨瓣减压能显著提高预后良好组Pb_tO_2和CPP(P＜0.05)，而两组在降低ICP方面没有统计学差异。
结论
1、中重型TBI病例监测ICP、CPP是非常必要的，不但能早期确定病例是否需要手术，还能早期判断术后是否继发出血、预后等情况；
2、Pb_tO_2是一个安全有效的现代神经外科监测措施，较ICP、CPP监测更为敏感而特异，能较ICP、CPP更早预警病情变化，对伤后是否存在早期脑缺氧、供氧自动调节机能及脑的能量代谢状态进行连续性的监测起着至关重要的作用，还能早期判断病例预后；
3、现代神经外科监护应该结合ICP、CPP和Pb_tO_2等进行多参数监测，这样不但可以为神经外科医生早期判断病情，并及时处理提供更为详细可靠的信息，还能指导临床用药、早期判断病例预后；
4、在TBI病例救治中，就减压效果而言，本试验支持标准大骨瓣减压是治疗中重型TBI的首选方法，不但可以显著降低ICP，也能显著提高CPP和Pb_tO_2，改善病例预后。
Part ⅠEffects and mechanisms of brain iron on secondary brain injury afterexperimental traumatic brain injury (TBI), and the protective effects of deferoxamine
Background
Traumatic brain injury (TBI) is one of the critical problems affected the health andeconomics in the world. TBI is the first killer of the people younger than45years-old, andthe first reason of disability and mortality. Although the methods of treatment for TBI haveimproved greatly within several decades, the mobility and mortality are still very high.Usually, some of the neurological functions of patients suffered from TBI recovered quicklywithin months, but some impairment, such as the deteriorations of congnition and memory,and the brain atrophy would last for several years. It was indicated there would be somelasting mechanisms of secondary brain injury after TBI. However, some medicines, such asagents for anti-apoptosis, obstructing glutamate-induced neurotoxicity, anti-inflammation,and inhibiting oxidative stress were failed to take advantages for the recovery ofneurological functions. There were more than30drugs which were proved useful for TBI inanimals but were failed in the Ⅲ stage clinical trials. There would other factors whichinduced the secondary brain injury.
It was reported that iron over-loading would induce neurotoxicity in experimentalintracerebral hemorrhage (ICH), neurodegenerative diseases and experimental chronichydrocephalus. The abnormal iron accumulation played critical roles on the brain atrophyand neurological injuries in ICH and neurodegenerative diseases. In experimental ICH,administration of deferoxamine (DFO) could reduce the brain atrophy and neurologicalinjuries. In our previous study, injection of FeCl3to the ventricle could induce chronic hydrocephalus, and administration of DFO would decrease the the morbility of chronichydrocephalus. Which suggested that iron over-loading would induce neurotoxicity, andadministration of DFO can lower the possibility of brain atrophy and the neurologicalinjuries. Hemorrhage is also one of the most frequent pathological changes in TBI，especially in contusion and laceration of brain and intracerebral hematoma. Theneurotoxicity caused by iron over-loading might be happened in TBI.
The purpose of this study was to disclose the effects of iron over-loading on TBI andthe therapeutic effects and the safety of DFO. Furthermore, the roles of iron metabolismproteins in the TBI were demonstrated.
Materials and methods
1. One hundred and four healthy adult male SD rats were divided randomly intothree groups: sham group, injury group, and DFO-treated group. and the last group dividedinto Early DFO-treated subgroups: E50subgroup (50mg/Kg), E100subgroup (100mg/Kg),E150subgroup (150mg/Kg), and Delayed DFO-treated subgroups: D50subgroup(50mg/Kg), D100subgroup (100mg/Kg), and D150subgroup (150mg/Kg). EarlyDFO-treated subgroups were administrated DFO2h after TBI，12h interval for28days,and delayed DFO-treated subgroups were administrated DFO3days after TBI，12h intervalfor25days. The sham group and injury group were administrated saline.
2. Morris water maze was done at the endpoint of the experiment. The time andstrategy of searching platform were calculated to evaluate the ability of learning andmemory.
3. The volume of brain lose was calculated by Coniglobus formula after the animalswere perfused by4%Paraformaldehyde and the brains were taken.
4. The content of the peri-injury brain iron was calculated by spectrophotometer.
5. The perl’s staining、HE staining and Nissl staining(brain tissue) were performed inthe tissues of peri-injury brain, femur, sternum, spleen, and liver.
6. The expression of ferritin light chain (FL), ferritin heavy chain (FH), transferring(Tf) and TRPC6in the neurons, astrocytes, and oligodendroglias were detected withimmunofluorescence.
7. The expression of Beclin1was detected with the immunohistochemisty.
8. The expressions of FL, FH, Tf and TRPC6were also detected by western blot.
Results
1. The volume of brain lose was (209.99±16.7mm~3). And it could be decreasedsignificantly (115.35±13.7mm~3，P＜0.05) by early100mg/Kg DFO-treated.
2. Time of platform searching was14.52±1.86s, and strategy of platform searchingwas3.63±0.52with Morris water maze in nomal rats. While time of platform searchingextended to110±47.34s (P＜0.05), and strategy of platform searching lowered to2.13±0.64(P＜0.05) in injury group. The early (2h) DFO administration (100mg/Kg) coulddecrease the time of platform searching to36.15±26.63s (P＜0.05), and improve thestrategy of platform searching to3.13±0.35(P＜0.05).
3. Compared with sham group, the content of brain iron in injury group increasesgreatly (P＜0.01). However, the administration of DFO failed to decrease the brain iron (P＞0.05).
4. There were no statistical differences of sexuality, rectal temperature, glucose andhemoglobin in each group.
5. Compared with sham group, the expressions of FL, FH, Tf and TRPC6wereup-regulated (P＜0.05) after TBI and could be down-regulated by early (2h after TBI)administration of100mg/Kg DFO. In injury group, there were no neurons and astrocytes inthe peri-injury zones after TBI, while many shrinkage neurons and astrocytes with TRPC6expressing were detected in group with early (2h after TBI) administration of100mg/KgDFO.
6. The up-regulation of Beclin1was detected after injury. And the expression wasinhibited by early (2h after TBI) administration of100mg/Kg DFO.
7. The best therapeutic effect of DFO was appeared in the group which the DFO wasadministrated in2hours after TBI with dosage of100mg/Kg.
8. There were no affects of motality, hemoglobin and iron metabolism caused by DFOadministration after TBI.
Conclusions
1. Over-load brain iron plays the role of neurotoxicity at28thday after experimental TBI.
2. DFO is the effective drug in experimental TBI, which can significantly reduce thevolume of brain defect, and significantly improve the ability of spatial learning and memoryin experimental animals.
3. Taken the time-effect relationship into account, the best treatment time of DFO is2h after TBI, and as the dose-effect relationship, the optical dose is100mg/Kg.
4. There is few intact neurons and astrocytes peri-injury after TBI,while DFOadministered at2h after TBI, more neurons and astrocytes are detected though the cellshrinkage, which suggests that the protective effect of neurons and astrocytes in“penumbra” at the cell level, and TRPC6may play important role in the procedure.
5. The expression of Beclin1，the marker of autophagy, upregulates significantlyperi-injury after TBI,and down regulation after DFO administered, which suggests thatautophagy injury exists after TBI, and DFO administered can reduce autophagy, and ironmay play important role..
6. In this experiment, the time of DFO administered extends to28d, and the doseincreases to150mg/Kg, which has no significant changes in mortality, hemoglobin and ironmetabolisms. In other words, DFO is a safe drug of TBI treatment.
Part Ⅱ The application of ICP,CPP and P_(bt)O_2monitoring in moderate andsevere traumatic brain injury
Background
The characteristics of traumatic brain injury (TBI) are high morbility, disability andmortality. The rate of disability and mortality caused by TBI were not decreasedsignificantly for decades. Lacking of guidelines and controversies on the strategies of thetreatment of contusion and laceration of brain limited the treatment based on theexperiences of the individual neurosurgeons. So ICP, CPP and P_(bt)O_2monitoring mightprovide more evidence for guiding the treatment of TBI.
Materials and methods
Selected standard
Patients of moderate and severe traumatic brain injuries with contusion and lacerationof brain and/or subdural hematoma, GCS from3to12were selected.
Exclusion criteria
Some cases were eliminated from the experiment in order to keep the reliability,including (1) patients with instability vital signs and exhaustion of brainstem functions;(2)hemorrhagic diathesis or hemorrhagic diathesis before TBI;(3) combining with chronicdisease of important organ or fail to tolerance operation;(4) pure epidural hematoma anddiffuse axonal injury with CT scan.
Clinical data
From May2009to Mar2011,43moderate to severe TBI cases from our hospital,Fuling center hospital, Sanxia center hospital and people’s hospital of Banan district wereperformed ICP and P_(bt)O_2monitoring. Within the43patients, there were31male and12female, aged from14to76years old.There were4cases with GCS12,3cases with GCS9,14cases with GCS8,1case with GCS7,5cases with GCS6,6cases with GCS5,2caseswith GCS4, and8cases with GCS3.When discharged from hospital, there were19caseswith GOS5,9cases with GOS4,1case with GOS3,4cases with GOS2, and10caseswith GOS1.The ratio of good outcome (GOS from4to5) was65.1%, the motality was23.3%as discharged, and30.2%after6months.
Results
1. The blood glucose increased in both the group of good outcome and the group ofbad outcome. Compared with the patients with good outcome, the concentration of bloodglucose was higher in patients with bad outcome at pre-operation,1day and5days afteroperation.
2. The volumes of hemorrhage were usually huge in the bad outcome group,4casesabove100ml,6from70ml to100ml. While in the good outcome group, there were mostfrom30ml to50ml.
3. The values of ICP were detected pre-operation in the bad outcome group higher thanthese in the good group, and decreased after operation, but still increased significant abovethe normal level, and then increased quickly. While the values of ICP were still detectedincreasing pre-operation, but decreased significant after operation, lower to normal lever, though certain increased at3d.Compared with the bad outcome group, the values of ICPdecreasing were significant at pre-operation,1d and5d(P＜0.01),even at3d(P＜0.05).
4. The values of CPP were little lower compared with the normal lever in the goodoutcome group and increased soon after operation. These were decreased in the badoutcome group. Compared with in the bad outcome group, those in the good outcome groupincreased significantly (P＜0.01).
5. The values of P_(bt)O_2were little lower compared with the normal lever in the goodoutcome group and then recovered to normal after operation. However, these in the badgroup lowered significantly pre-operation. Eventhough, this condition couldn’t be improvedafter operation. Compared with the bad outcome group, the levers increased significantly atpre-operation,1d,5d(P＜0.01) amd3d(P＜0.05).
6. Standard large trauma craniotomy was performed in the experiment, the lever of ICPdecreased significantly both in the bad outcome group (29.45±3.30mmHg) and the goodoutcome group (31.22±2.73mmHg). However, it failed to improve the lever of CPP andP_(bt)O_2in the bad outcome group, while it did in the good outcome group. Compared with thebad outcome group, Standard large trauma craniotomy was performed to improve CPP andP_(bt)O_2(P＜0.05), but there was no difference in decreasing ICP in both groups.
Conclusions
1. It is very necessary to monitor ICP and CPP after moderate to severe TBI, which candecide the case to operate or not early, and the secondary hemorrhage and outcome can bealso judged early.
2. The monitoring of P_(bt)O_2is a safe and effective method in neurosurgery intensivecare unit, and more sensitive and specific than the monitoring of ICP and CPP, which isearlier in reflecting the changes of patient’s condition than the later. It is important tohypoxia, homeostasis and energy metabolism of brain with monitoring of P_(bt)O_2, and theoutcome also can be judged early.
3. Multi-monitoring of ICP,CPP and P_(bt)O_2should be performed in neurosurgeryintensive care unit, which can provide more information to neurosurgeon early, and makethe treatment reliable, and can be as the guideline for the clinical medication and outcome.
4. Only taken effect of decompression into account, the standard large trauma craniotomy is supported to be the preference approach in our experiment, which not onlycan decrease ICP significantly, but also improve CPP and P_(bt)O_2.
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