重症脑出血应激性溃疡的胃电监测及相关机制研究
摘要
研究背景
应激性溃疡是重症脑出血常见并发症(可高达91%),其致死率可达80%以上。脑出血并发应激性溃疡是以脑出血为应激源,通过多种因素的综合作用,致使胃十二指肠粘膜发生急性糜烂或溃疡性损伤,病情轻者无临床表现,重者可发生上消化道出血,甚至出现大出血而危及患者生命。
及早诊断并正确处理脑出血后发生的应激性溃疡成为降低脑出血致死、致残率的关键因素之一。因为临床大样本循证对照研究发现,预防性用药并未减少应激性溃疡的发生,反而增加了患者的经济和身体负担,这就要求临床医生及时发现应激性溃疡的存在,并及时做出相应处理,同时掌握应激性溃疡的病情变化和药物疗效。
脑出血并发应激性溃疡的诊断方法及病情监测手段还是十分滞后的。应激性溃疡的诊断多根椐临床症状(呕血、黑便或持续输血补液血压仍持续下降)和胃液潜血化验结果来判定,这样使临床表现阴性的病例无法得到及时诊断,延误了治疗时机。胃窥镜可在直视下发现临床表现阴性的应激性溃疡病例,提高对应激性溃疡的诊断准确率和阳性率;但由于重症脑出血患者急性期多伴意识障碍或其他生命体征的改变,对麻醉药耐受力差,而且胃镜操作刺激产生的恶心呕吐诱发血压及颅内压增加,存在诱发再出血而加重病情的可能性,使得胃镜乃至无痛胃镜在脑出血急性期的应用受到限制;脑出血并发的应激性溃疡恰恰多发生在72h-14d脑出血急性期。找到一种无创、准确、并可时时监测脑出血后应激性溃疡发生及病情变化的方法是十分必要的。
胃电是胃平滑肌细胞电活动的表现,通过分析脑出血后胃电变化可能对应激性溃疡的诊断及病情变化提供有益的信息。体表胃电图可准确记录胃平滑肌活动的电信号,在临床上多用于诊断胃动力障碍性疾病。有研究表明原发性溃疡病人的胃电可表现为频率加快和波幅增大;脑出血后胃电节律也发生改变,但脑出血并发应激性溃疡的胃电变化还未见报道。脑出血并发应激性溃疡的发病机制还不是十分清楚,研究表明主要与神经内分泌失调、胃黏膜防御功能下降、胃黏膜损伤因素作用增强及植物神经功能失衡等因素有关。本研究通过临床实验观察脑出血并发应激性溃疡患者胃电活动改变,并通过动物实验了解脑出血并发应激性溃疡发生和胃电变化之间关系的病理生理机制,来探讨胃电做为监测脑出血后应激性溃疡发生和病情变化手段的可能性和临床应用价值。
目的
1.观察基底节区脑出血及并发应激性溃疡患者胃电的变化,通过对胃电各参数变化分析,判定脑出血后应激性溃疡存在与否。
2.监测基底节区脑出血及并发应激性溃疡患者颅内压的变化,探讨颅内压升高在应激性溃疡发生中的作用。
3.观察不同方法和不同干预剂量基底节区脑出血模型应激性溃疡发生情况,确立符合实验要求的脑出血并发应激性溃疡的实验动物模型。
4.观察脑出血及并发应激性溃疡大鼠胃电、颅内压、迷走神经传出放电、胃壁乙酰胆碱受体(M1、M2和M3)、胃液pH值、胃酸分泌总量、胃壁COX-2和幽门张力的改变,探讨基底节区脑出血胃电改变与应激性溃疡发生的关系及应激性溃疡发生病理生理机制。
方法
第一部分:临床实验
1.利用胃肠电图仪对重症脑出血患者行连续15d胃电检测,同时设正常健康对照组和原发性消化性溃疡对照组,分析胃电图各参数在脑出血组、脑出血并发应激性溃疡组、正常健康对照和原发性消化性溃疡对照组间的差别,并利用判别分析方法分析胃电变化对脑出血后应激性溃疡发生判定的准确性。
2.侧脑室置管监测重症脑出血患者颅内压,分析颅内压变化与脑出血后应激性溃疡发生的关系。
第二部分:动物实验
1.分别将50μl、100μl、150μl自体血和0.3U、0.6U、0.9U、1.2UⅦ胶原酶注入SD大鼠右侧脑基底节区,72h后行大鼠脑和胃壁HE染色、脑含水量和溃疡指数测定。
2.将符合要求健康SD大鼠随机分为假手术组(15只)、乙酸溃疡对照组(20只)和大脑基底节出血造模组,观察时间点为12h、1d、2d、3d、5d、7d和14d,每个时间点30只,大脑基底节出血造模后行迷走神经离断术,观察时间点12h和24h,每组30只。在上述各时间点记录各组大鼠胃电图、迷走神经传出放电、颅内压和幽门管压力,免疫组织化学法检测乙酰胆碱受体(M1、M2、M3)和COX-2在大鼠胃壁的表达,同时测定4h胃酸分泌量和胃液pH。
结果
第一部分:重症脑出血应激性溃疡患者的胃电动态变化及其与颅内压变化相互关系的实验研究(临床实验)
1.脑出血及并发应激性溃疡患者胃电变化
正常对照组胃电图原始波形为不规则的曲线,经滤波后可见较光滑的类正弦波形。原发消化性溃疡对照组Vpp增大(P<0.01),AF增加(P<0.01),DF和RA增加(P<0.01),DPR和NSW减小(P<0.01);脑出血未并发应激性溃疡组胃电波形变异较大,与正常对照组比较,Vpp增大(P<0.01),AF无变化(P>0.05),ARI增大,CVv增加(P<0.01),NSW减小(P<0.01),ICF和RA增加(P<0.01);脑出血并发应激性溃疡组的胃电图波形形态差异性更大,与脑出血未并发应激性溃疡患者相比,其Vpp增大(P<0.01),AF增加(P<0.01),ARI、CVv、CVf、DF、ICF和RA增加(P<0.05,P<0.01),DPR和NSW减小(P<0.05);与原发消化性溃疡对照组相比,Vpp增大(P<0.01),AF增加(P<0.05),ARI、CVv、CVf、DF、ICF和RA增加(P<0.01),NSW减小(P<0.05)。
2.胃电各参数对脑出血后应激性溃疡发生的判别
经判别分析后,得到对判别应激性溃疡发生有意义的胃电参数:Vpp、RA、ICF、NSW、AF、ARI和DPR,排除变量DF;并可得到胃电在正常健康人群、原发消化性溃疡患者、脑出血未并发和并发应激性溃疡患者的四个Fisher判别函数,其判别正确率可达87.9%。
3.脑出血患者颅内压变化情况及其与胃电变化的关系
脑出血后发生应激性溃疡患者的颅内压(5.69±0.53kPa)较无应激性溃疡发生者颅内压(4.22±1.14kPa)明显增高(P<0.01);随着颅内压升高,Vpp、DF、ARI、CVf、CVv、ICF和RA增大,NSW减小(P<0.05,P<0.01)。
第二部分:脑出血大鼠应激性溃疡发生与胃电变化及二者相关机制研究(动物实验)
实验一大鼠脑出血应激性溃疡模型制备
1.不同方法诱导基底节区出血的血肿体积变化
大鼠冠状位脑片HE染色测量血肿体积发现,50μl自体血组和0.3U胶原酶组血肿体积相似(P>0.05),100μl自体血组和0.6U胶原酶组血肿体积相似(P>0.05),随着注入自体血和胶原酶量的增加,右侧基底节区血肿体积增大。
2.不同剂量自体血和胶原酶脑出血模型应激性溃疡发生的比较
不同剂量自体血和胶原酶注入大鼠脑基底节区72h后,1.2U胶原酶组大鼠大部分死亡,脑血肿体积和脑含水量随注入剂量的增加而增大,同时溃疡发生率和溃疡指数增大;同等血肿体积胶原酶组所引起的溃疡发生率和溃疡指数大于自体血组。
实验二大鼠脑出血并发应激性溃疡与胃电变化相互关系机制研究
1.脑出血应激性溃疡大鼠的胃壁表现
肉眼可见应激性溃疡大鼠溃疡多发生于前、后胃交界胃小弯处,与迷走神经分布密集区相同。胃黏膜表现为单一或散在的出血点或是大小不一的溃疡面,深度可达肌层,甚至穿孔。HE染色镜下可见溃疡呈火山口样,累及粘膜至粘膜下层,部分累及肌层和浆膜层;在溃疡边缘有浓染的炎性细胞聚集、血管闭塞及出血,典型溃疡表现多发生在造模后2d和3d。
2.实验大鼠胃电记录与溃疡指数评定及相关性分析
正常组大鼠胃电图慢波多数呈正弦波形,少数有切迹呈双峰型。与假手术组比较,溃疡对照组Amp在12h、1d、2d、3d、5d时增大(P<0.01),脑出血无应激性溃疡组在12h、1d、2d时胃电图Amp增大(P<0.05,P<0.01);与假手术组、乙酸溃疡对照组、脑出血无应激性溃疡组相比,在所有实验时间点脑出血应激性溃疡组Amp增大(P<0.05,P<0.01)。与假手术组比,乙酸溃疡对照组F在12h、1d、2d、3d时增大(P<0.05,P<0.01),脑出血无应激性溃疡组在12h、1d、2d、3d、5d、7d时胃电图F增大(P<0.01),与假手术组、乙酸溃疡对照组、脑出血无应激性溃疡组相比,在所有实验时间点脑出血应激性溃疡组F增大(P<0.05,P<0.01)。ARI和CV在各时间点乙酸溃疡对照组与假手术组无差异;除脑出血无应激性溃疡组14d外,所有脑出血造模组ARI和CV在各时间点均高于假手术组(P<0.01);脑出血溃疡组ARI和CV大于无溃疡组(P<0.05,P<0.01)。
在不同时间点对脑出血后发生应激溃疡的实验大鼠在解剖显微下进行溃疡指数计数,溃疡指数在1d和2d时较小,3d时达到高峰,随后溃疡指数下降,经相关性分析可见胃电各参数与溃疡指数相关(P<0.01)。
3.实验大鼠颅内压记录及其与相关参数相关性分析
大鼠脑出血造模后12h时颅内压明显增高,2d达高峰,7d基本恢复正常;造模组的颅内压在12h、1d、2d、3d和5d明显高于假手术组(P<0.01),脑出血造模组发生应激性溃疡的大鼠颅内压在上述五个时间点也明显高于未发生溃疡大鼠的颅内压(P<0.01);脑出血造模后大鼠颅内压水平与溃疡指数呈正相关(P<0.01,R=0.732);脑出血模型大鼠胃电的F、Amp、ARI和CV四项参数均与颅内压存在相关性(P<0.01)。
4.实验大鼠颅内压增高对下丘脑及脑干组织细胞损伤和细胞凋亡的影响
颅内压增高时,大鼠下丘脑和脑干HE染色可见坏死和出血改变;Tunel染色凋亡阳性细胞在下丘脑和脑干中线结构分布增多。
5.实验大鼠迷走神经传出放电记录及其与相关参数相关性分析
大鼠脑出血造模后12h、1d、2d、3d时迷走神经传出放电的VF和VA高于假手术组(P<0.05,P<0.01);脑出血造模组中出现溃疡者高于无溃疡者(P<0.05,P<0.01)。PCV在所有时间点脑出血造模组高于假手术组,脑出血造模组中有溃疡者高于无溃疡者(P<0.01);大鼠脑出血造模后颅内压和迷走神经传出放电呈正相关(P<0.01);迷走神经传出放电的VF、VA和PCV与胃电的F、Amp、ARI和CV相关(P<0.01);迷走神经传出放电VF、VA和PCV与溃疡指数相关(P<0.01);脑出血模型大鼠迷走神经离断后与离断术前比较,胃电F下降,Amp降低,CV减少。
6.实验大鼠胃壁M1受体表达、胃酸分泌量和胃液pH值变化及其与相关参数的相关性分析
在12h、1d、2d和3d时间点,脑出血造模后大鼠胃壁M1受体的IOD值高于假手术组(P<0.01),脑出血造模中有溃疡者高于无溃疡者(P<0.01)。4h胃酸分泌量测定可见,脑出血大鼠无溃疡发生者12h较假手术组胃酸分泌明显增高(P<0.01),其他时间点未见差异(P>0.05);在12h、1d、2d、3d时发生溃疡者高于无溃疡发生者(P<0.01)。大鼠脑出血后,胃液pH值低于假手术组(P<0.05,P<0.01),这种表现在14d时不明显(P>0.05),造模组中有溃疡发生者pH值低于无溃疡发生者(P<0.05,P<0.01)。脑出血造模大鼠迷走神经传出放电与M1表达呈正相关,与pH值呈负相关;M1表达与溃疡指数呈正相关;pH值与溃疡指数表达呈负相关。大鼠脑出血行迷走神经切断与未离断前相比,12h M1受体表达下降、胃酸分泌减少和胃液pH值升高(P<0.05)。
7.实验大鼠胃壁M2、M3受体表达及其与相关参数相关性分析
在脑出血造模后12h即出现M2和M3受体表达的上调(P<0.01),24h达高峰,峰值状态一直持续到5d,7d时二者表达有所下降(P<0.05);脑出血中有溃疡发生者在各时间点的M2、M3受体表达均高于无溃疡发生者(P<0.01,P<0.05),胃壁M2和M3受体在大鼠脑出血后表达变化与迷走神经传出放电和胃电各参数有较好的相关性(P<0.01)。
8.实验大鼠胃壁COX-2表达和幽门张力的变化
大鼠脑出血12h时COX-2表达增加,其IOD值明显高于假手术组(P<0.01),2d达到高峰,14d与假手术组无差异(P>0.05);在脑出血造模组内,有溃疡发生者高于无溃疡者(P<0.01)。脑出血大鼠幽门收缩的频率减慢、幅度下降,在造模后12h、1d、和2d变化明显(P<0.01),脑出血造模组溃疡发生者比无溃疡发生者这种变化表现更明显(P<0.01)。
9.实验大鼠胃电变化对大鼠脑出血并发应激性溃疡的判别分析将胃电四个参数F、Amp、ARI和CV在大鼠脑出血溃疡组和无溃疡组、乙酸诱发溃疡组和假手术组行判别分析可得Fisher判别函数,其正确判断率可达到90.8%。
结论
胃电对脑出血后是否并发应激性溃疡有诊断价值,并可做为应激性溃疡病情变化的一种可靠监测指标;胃电对应激性溃疡的指示作用可能机制之一是脑出血所致颅内压升高影响自主神经中枢,使自主神经发生功能紊乱,迷走神经传出冲动增加,胃酸分泌增加,pH值下降,发生急性胃粘膜受伤,同时迷走神经传出冲动增加也参与胃运动调节,从而使胃电发生变化。
Background
Stress ulcer (SU) is a common complication of severe cerebral hemorrhage (up to 91%) and the death rate can reach to 80%. Cerebral hemorrhage(CH)as a stress source results in acute erosive or ulcerative injury of gastroduodenal mucosal through complex action which many factors participated, so stress ulcer occurred afetr CH. Those mild cases have no apparent clinical manifestations whereas upper gastrointestinal bleeding even with life-threatening bleeding might happen within severe cases.
Early diagnosis and proper treatment to intracerebral hemorrhage with stress ulcer cut down mortality and disability of CH. Through the large sample evidence-based controlled study, prophylactic medication cann’t reduce the incidence of stress ulcer, but increase the economic and physical burden on patients. This requires clinicians to detect the presence of stress ulcer, and take appropriate action in time, as well as monitor changes in stress ulcer and drug efficacy of treatment.
Diagnosis and monitoring of cerebral hemorrhage stress ulcer are very sluggish. To diagnose stress ulcer complicated with hemorrhage is based on clinical symptoms including hematemesis, black stools, persistent blood pressure being decreased while continuous infusion or blood and positive results of gastric occult blood test. So that the cases with negative clinical manifestations can not receive timely treatment and the treatment time is delayed. The SU cases with negative clinical manifestations can be diagnosed by gastroscope which improve the diagnosis rate and accuracy of SU. However, the anesthetic tolerance is poor in acute phase of severe intracerebral hemorrhage following disturbance of consciousness or other changes in vital signs, furthermore gastroscopy operation can induce nausea and vomiting which increase the possibility of re-bleeding. Endoscopy in the acute phase of cerebral hemorrhage limited and even painless gastroscopy. Stress ulcer be complicated by cerebral hemorrhage in r mostly occurs in 72h-14d Acute stage. To find a non-invasive, accurate, and constantly monitoring way is essential for estimating the development of stress ulcer after intracerebral hemorrhage.
Gastric electrical activities response electrical activities of gastric smooth muscle cells. Through the analysis of EGG after cerebral hemorrhage stress ulcer might be diagnosed and useful information might be provided. EGG records the activities of gastric smooth muscle signals accurately being used for clinical diagnosis of gastric motility disorders. Some studies showed that the frequency was faster and the amplitude was higher in ulcer patients. It also showed that change of gastric electrical rhythm after intracerebral hemorrhage. But gastric electrical change has not been reported about the stress ulcer after intracerebral hemorrhage. The pathogenesis of stress ulcer is not clear. Studies showed that neuroendocrine disorders, defense function of gastric mucosal being decreased, injury factors of gastric mucosal being strengthened and imbalance of autonomic function and so on. This study was to observe gastric electrical activity changes in stress ulcer complicated by cerebral hemorrhage of clinical patients and to understand pathology between stress ulcer complicated by cerebral hemorrhage and gastric electrical changes by animal experiments. To explore clinical application of EGG monitoring happen and development of stress ulcer complicated by cerebral hemorrhage .
Purpose
1. Observing the gastric electrical changes of cerebral hemorrhage in patients with stress ulcer, the presence or absence of stress ulcer was determined by analyzing the parameters of EGG.
2. Monitoring intracranial pressure of intracerebral hemorrhage patients with stress ulcer to explore the role of intracranial pressure in stress ulcer.
3. Observing the incidence of stress ulcer at different intracerebral hemorrhage model, to establish intracerebral hemorrhage animal model with stress ulcer.
4. Through observing EGG, intracranial pressure, efferent discharge of vagus nerve, expression of acetylcholine receptor (M1, M2 and M3) and COX-2 in stomach mucosa, pH of gastric fluid, gastric acid secretion volume and tension of pylorus changes of intracerebral hemorrhage, to explore relationship between changes of EGG and stress ulcer and pathogenesis of stress ulcer after cerebral hemorrhage.
Methods
Part I: clinical trials
1. The parameters of EGG were analyzed in the normal group , primary ulcer group, SU after CH group and CH group through monitoring the gastric electrical activity 15 days. The accuracy to judge the occuring of SU after CH was analyzed by discriminant analysis.
2. The relationship between the genesis of stress ulcer and the level of ICP was analyzed by monitoring intracranial pressure in patients with severe cerebral hemorrhage through lateral ventricle catheter .
Part II: animal experiments
1. 150μl, 100μl, 150μl of autologous blood and 0.3U, 0.6U, 0.9U, 1.2UⅦcollagenase were injected into the right side basal ganglia of SD rat brain respectively. HE staining of brain and stomach, brain water content and ulcer index were undergone at 72h after CH.
2. The healthy SD rats meeting with the requirements were randomly divided into normal control group (15), acetic acid ulcer control group (20) and brain basal ganglia hemorrhage model group, being setted up time for the 12h, 1d, 2d, 3d, 5d, 7d , 14d, 30 rats at each time point. The vagus nerves of 60 rats were transected at 12h and 24h after the brain basal ganglia hemorrhage. EGG, vagus nerve efferent discharge, intracranial pressure and pyloric pressure were recorded, acetylcholine receptor (M1, M2, M3) and COX-2 in gastric mucosa were measured by immunohistochemical method at each time in each group. Gastric acid secretion in 4h and gastric pH were measured at same time.
Results
Part I: Dynamic changes of EGG of Severe cerebral hemorrhage patients with stress ulcer and relationship between intracranial pressure and stress ulcer (clinical trials)
1. EGG of intracerebral hemorrhage patients with stress ulcer
EGG showed smooth sine wave transferred from the irregular curve of the original wave form through the filter in normal control group. In ulcer control group, Vpp, AF, DF, RA increased (P<0.01), DPR and the NSW decreased (P<0.01). In intracerebral hemorrhage with no complication of stress ulcer group, the wave type varied greatly, Vpp, ARI, CVf, ICF and RA increased (P< 0.01), AF remained unchanged (P> 0.05), NSW decreased (P<0.01) being compared with the normal control group. Differences in waveform morphology were more in cerebral hemorrhage complicated stress ulcer group. Compared the EGG between intracerebral hemorrhage with stress ulcer group and CH without stress ulcer group, Vpp, ARI, DF, CVv, CVf, ICF, AF and RA increased (P<0.05, P<0.01), DPR and NSW decreased (P<0.05). while compared with ulcer control group, Vpp, AF, ARI, CVv, DF, CVf, ICF and RA increased (P<0.05, P<0.01), NSW decreased (P<0.05).
2. Discriminant analysis of EGG parameters
The significant parameters of EGG were achieved through discriminant analysis to diagnose SU, including Vpp, RA, ICF, NSW, AF, ARI and the DPR. Fisher discriminant function was setted up which EGG was applied to discriminate normal healthy people, patients with ulcer, patients with CH, patients with CH complicated with SU. The discriminant accuracy rate was 87.9%.
3. The relationship between Intracranial pressure and EGG of patients with intracerebral hemorrhage
Intracranial pressure(5.69±0.53kPa) was higher in intracerebral hemorrhage with stress ulcer than that of those without stress ulcer (4.22±1.14kPa, P<0.01). Along with increased intracranial pressure, Vpp, DF, ARI, CVf, CVv, ICF, and RA increased, NSW and C decreased (P<0.05, P<0.01).
Part II: Rearch to cerebral hemorrhage with stress ulcer in rats and related mechanism (animal experiments)
Experiment one Construction of cerebral hemorrhage stress ulcer models in rats
1. Hematoma volume changes in different basal ganglia hemorrhage models
Hematoma volume of 50μl autologous blood group was similar to 0.3U collagenase group by HE stainning measurement of brain slices (P>0.05), so as to 100μl autologous blood group and 0.6U collagenase group(P>0.05). With the dose of autologous blood and collagenase increased, the hematoma volume of right basal ganglia was enlarged.
2. Incidence of SU after different doses of autologous blood and the collagenase intracerebral hemorrhage model
Most of the rats in 1.2U collagenase group died at 72h after different dose autologous blood and collagnase injected into the cerebral basal ganglia. Hematoma volume and brain water content increased with the dose increase of blood and collagnanse being injected, so as to the incidence of SU and ulcer index. The incidence of SU was greater in collagenase group than in autologous blood group at the equal hematoma volume.
Experiment two EGG changes of cerebral hemorrhage stress ulcer and mechanism of the relationship between EGG and stress ulcer
1. Gastric wall of rats with SU
The gastric ulcer mostly occured in arcus minor ventriculi at the junction of proventriculus and stomach in which the vagus nerve distributed. Gastric mucosa showed a single or sporadic bleeding or ulcers of different sizes, depth up to muscle, or even perforation. HE staining showed crater-like ulcer, involving the mucosa to the submucosa, partial to muscularis and serosa. It could be seen that accumulation of inflammatory cells, vascular occlusion and bleeding in the ulcer margin. Typical ulceration was more ofen occurred at 2d and 3d.
2. EGG recording, evaluation of ulcer index and relationship between them
Slow wave of EGG showed sine wave, in which some had notch and bimodal in normal group. Compared to the sham-operated group, Amp increased at 12h, 1d, 2d, 3d, 5d in acetic acid ulcer control group (P<0.01). Amp became larger at 12h, 1d, 2d in intracerebral hemorrhage without stress ulcer group (P<0.05, P<0.01). Amp was higher than all other groups in intracerebral hemorrhage with SU(P<0.05, P<0.01). Compared with the sham-operated group, F increased at 12h, 1d, 2d, 3d in acetic acid ulcer control group (P<0.05, P<0.01), at 12h, 1d, 2d, 3d, 5d, 7d in intracerebral hemorrhage without stress ulcer group(P<0.01). F was faster than all other groups in intracerebral hemorrhage with SU (P<0.05, P<0.01). ARI and CV had no difference between the acetic acid ulcers control group and sham-operated group at each time point. Except for intracerebral hemorrhage without SU group at 14d, ARI and CV were higher than sham-operated group in all intracerebral hemorrhage group at each time points (P<0.01); in which ARI and CV were higher in intracerebral hemorrhage with SU than that of CH with non-ulcer group (P<0.05, P<0.01).
At experimental different time points, under a dissecting microscope counted UI of occurred ulcers in rats, UI is small at 24h and 48h, to 72h the peak reached, then reduced. All EGG parameters associated with UI by the correlation analysis (P<0.01).
3. Intracranial pressure recording and correlation with other parameters in experimental rats
Intracranial pressure elevated significantly at 12h, then to the peak at 2d and returned to nomal at 7d after intracerebral hemorrhage in rats. Intracranial pressure of intracerebral hemorrhage modules was higher significantly than sham-operated group at 12h, 1d, 2d, 3d and 5d (P<0.01). At same time, intracranial pressure was higher in CH with SU group than those without ulcers groups (P<0.01). The level of intracranial pressure correlated positively with ulcer index (P<0.01, R=0.732). F, Amp, ARI and CV of EGG parameters correlated with intracranial pressure (P<0.01).
4. Intracranial hypertension effects to cell apoptosis and tissue injury of hypothalamus and brainstem in experimental rats
Necrosis and hemorrhage could be seen in the hypothalamus and brainstem of CH rats through HE staining. Tunnel positive staining apoptotic cells were located in the hypothalamus and midline structures of brainstem.
5. Vagus nerve efferent discharge records and correlation with other parameters in experimental rats
VF and VA of vagus nerve efferent discharge was higher in basal ganglia hemorrhage rats than sham-operated group at 12h, 1d, 2d, 3d (P<0.05, P<0.01). Within CH groups, VF and VA were higher in CH with SU group than those without ulcer group(P<0.05, P<0.01). PCV in the CH group was higher than that of sham-operated group at each time point. Within CH groups, PCV was higher in CH with SU group than those without ulcer group(P<0.05, P<0.01). There was positive relationship between intracranial pressure and efferent discharge of vagus nerve after CH (P<0.01). VF, VA and PCV of vagus nerve efferent discharge were related to F, Amp, ARI and CV of EGG (P<0.01). VF, VA, and PCV of vagus nerve efferent discharge related to the ulcer index (P<0.01). F, Amp, CV decreased after vagus nerve being transected in CH rats compared with before(P<0.01).
6. Changes of the expression of M1 receptors in gastric muscoa, volume of gastric acid secretion and pH value of gastric wall and their correlation with other parameters
IOD value of the expression of M1 receptors was higher at 12h, 1d, 2d and 3d in CH groups compared with the sham-operated group (P<0.01). Within which IOD value of the CH with SU was higher than those without SU (P<0.01). 4h volume of gastric acid secretion was greater at 12h in CH groups than that of sham-operated group (P<0.01), while there has no difference at the other times(P<0.05). Within CH groups which SU occurred, the volume of gastric acid secretion was higher at 12h, 1d, 2d,3d than that of those with no SU (P<0.01). pH value of gastric wall descended at each time after basal ganglia hemorrhage in rats (P<0.05, P<0.01)except for 14d(P>0.05). It was lower in CH with SU groups compared with the CH with no SU group(P<0.05, P<0.01). The vagus nerve efferent discharge had positive relationship with the expression of M1 receptor in gastric muscoa and acid secretion, negative correlated with the pH value. The expressions of M1 receptor and ulcer index were positively related. pH value and the ulcer index was negatively correlated. The expression of M1 receptor was decreased and gastric acid secretion reduced and pH value increased after the vagotomy at 12h in CH rats(P<0.05).
7. Expressions of M2, M3 receptor in gastric muscoa and their correlation with other parameters in experimental rats
Expressions of M2, M3 receptor in gastric muscoa was up-regulation at 12h after CH (P<0.01), up to peak level at 24h, being stated until 5d and decreased at 7d (P<0.05). It was expressed intensivly in CH with SU rats than that of the CH rats which SU not occurred (P<0.01, P<0.05). M2 and M3 receptors in the stomach wall in rats the expression of basal ganglia hemorrhage and vagus nerve efferent discharge has a good correlation (P<0.01). The expression of M2, M3 receptor had relationship with EGG and the efferent discharge of vagus nerve.
8. Expression of COX-2 in gastric muscoa and changes of pyloric tension in experimental rats
The IOD of COX-2 expression was significantly higher at 12h in basal ganglia hemorrhage groups than sham-operated group (P<0.01), up to peak at 2d, there was no significant difference at 14d compared with the sham-operated group (P>0.05). It was higher in CH with SU group than that of CH without SU (P<0.01). The frequency of pyloric contraction slowed and its amplitude decreased at 12h, 1d, and 2d after CH significantly (P<0.01), This change was more obvious in the CH rats which SU occured(P<0.01).
9. Discriminant analysis of EGG judge the experimental basal ganglia intracerebral hemorrhage compicated with stress ulcer in rats
The discriminat function was achieved about the four parameters of EGG including F, Amp, ARI and CV. Its accuracy rate was 90.8% to discriminate the CH complicated with SU rats and no SU, rats with ulcer induced by acetic acid and noamal rats.
Conclusions
EGG had diagnostic value to stress ulcer after intracerebral hemorrhage and could be a reliable method to monitor the pathogenetic condition mobility. EGG instructions on the role of stress ulcer is one possible mechanism of cerebral hemorrhage due to increased intracranial pressure effects on the autonomic nerve center, so that autonomic dysfunction occurs, vagus nerve efferent impulses and gastric acid secretion increase, pH value decreases. Acute gastric mucosa is injuried while increased vagal efferent impulses are also involved in regulating gastric motility and affect changes of EGG.
应激性溃疡是重症脑出血常见并发症(可高达91%),其致死率可达80%以上。脑出血并发应激性溃疡是以脑出血为应激源,通过多种因素的综合作用,致使胃十二指肠粘膜发生急性糜烂或溃疡性损伤,病情轻者无临床表现,重者可发生上消化道出血,甚至出现大出血而危及患者生命。
及早诊断并正确处理脑出血后发生的应激性溃疡成为降低脑出血致死、致残率的关键因素之一。因为临床大样本循证对照研究发现,预防性用药并未减少应激性溃疡的发生,反而增加了患者的经济和身体负担,这就要求临床医生及时发现应激性溃疡的存在,并及时做出相应处理,同时掌握应激性溃疡的病情变化和药物疗效。
脑出血并发应激性溃疡的诊断方法及病情监测手段还是十分滞后的。应激性溃疡的诊断多根椐临床症状(呕血、黑便或持续输血补液血压仍持续下降)和胃液潜血化验结果来判定,这样使临床表现阴性的病例无法得到及时诊断,延误了治疗时机。胃窥镜可在直视下发现临床表现阴性的应激性溃疡病例,提高对应激性溃疡的诊断准确率和阳性率;但由于重症脑出血患者急性期多伴意识障碍或其他生命体征的改变,对麻醉药耐受力差,而且胃镜操作刺激产生的恶心呕吐诱发血压及颅内压增加,存在诱发再出血而加重病情的可能性,使得胃镜乃至无痛胃镜在脑出血急性期的应用受到限制;脑出血并发的应激性溃疡恰恰多发生在72h-14d脑出血急性期。找到一种无创、准确、并可时时监测脑出血后应激性溃疡发生及病情变化的方法是十分必要的。
胃电是胃平滑肌细胞电活动的表现,通过分析脑出血后胃电变化可能对应激性溃疡的诊断及病情变化提供有益的信息。体表胃电图可准确记录胃平滑肌活动的电信号,在临床上多用于诊断胃动力障碍性疾病。有研究表明原发性溃疡病人的胃电可表现为频率加快和波幅增大;脑出血后胃电节律也发生改变,但脑出血并发应激性溃疡的胃电变化还未见报道。脑出血并发应激性溃疡的发病机制还不是十分清楚,研究表明主要与神经内分泌失调、胃黏膜防御功能下降、胃黏膜损伤因素作用增强及植物神经功能失衡等因素有关。本研究通过临床实验观察脑出血并发应激性溃疡患者胃电活动改变,并通过动物实验了解脑出血并发应激性溃疡发生和胃电变化之间关系的病理生理机制,来探讨胃电做为监测脑出血后应激性溃疡发生和病情变化手段的可能性和临床应用价值。
目的
1.观察基底节区脑出血及并发应激性溃疡患者胃电的变化,通过对胃电各参数变化分析,判定脑出血后应激性溃疡存在与否。
2.监测基底节区脑出血及并发应激性溃疡患者颅内压的变化,探讨颅内压升高在应激性溃疡发生中的作用。
3.观察不同方法和不同干预剂量基底节区脑出血模型应激性溃疡发生情况,确立符合实验要求的脑出血并发应激性溃疡的实验动物模型。
4.观察脑出血及并发应激性溃疡大鼠胃电、颅内压、迷走神经传出放电、胃壁乙酰胆碱受体(M1、M2和M3)、胃液pH值、胃酸分泌总量、胃壁COX-2和幽门张力的改变,探讨基底节区脑出血胃电改变与应激性溃疡发生的关系及应激性溃疡发生病理生理机制。
方法
第一部分:临床实验
1.利用胃肠电图仪对重症脑出血患者行连续15d胃电检测,同时设正常健康对照组和原发性消化性溃疡对照组,分析胃电图各参数在脑出血组、脑出血并发应激性溃疡组、正常健康对照和原发性消化性溃疡对照组间的差别,并利用判别分析方法分析胃电变化对脑出血后应激性溃疡发生判定的准确性。
2.侧脑室置管监测重症脑出血患者颅内压,分析颅内压变化与脑出血后应激性溃疡发生的关系。
第二部分:动物实验
1.分别将50μl、100μl、150μl自体血和0.3U、0.6U、0.9U、1.2UⅦ胶原酶注入SD大鼠右侧脑基底节区,72h后行大鼠脑和胃壁HE染色、脑含水量和溃疡指数测定。
2.将符合要求健康SD大鼠随机分为假手术组(15只)、乙酸溃疡对照组(20只)和大脑基底节出血造模组,观察时间点为12h、1d、2d、3d、5d、7d和14d,每个时间点30只,大脑基底节出血造模后行迷走神经离断术,观察时间点12h和24h,每组30只。在上述各时间点记录各组大鼠胃电图、迷走神经传出放电、颅内压和幽门管压力,免疫组织化学法检测乙酰胆碱受体(M1、M2、M3)和COX-2在大鼠胃壁的表达,同时测定4h胃酸分泌量和胃液pH。
结果
第一部分:重症脑出血应激性溃疡患者的胃电动态变化及其与颅内压变化相互关系的实验研究(临床实验)
1.脑出血及并发应激性溃疡患者胃电变化
正常对照组胃电图原始波形为不规则的曲线,经滤波后可见较光滑的类正弦波形。原发消化性溃疡对照组Vpp增大(P<0.01),AF增加(P<0.01),DF和RA增加(P<0.01),DPR和NSW减小(P<0.01);脑出血未并发应激性溃疡组胃电波形变异较大,与正常对照组比较,Vpp增大(P<0.01),AF无变化(P>0.05),ARI增大,CVv增加(P<0.01),NSW减小(P<0.01),ICF和RA增加(P<0.01);脑出血并发应激性溃疡组的胃电图波形形态差异性更大,与脑出血未并发应激性溃疡患者相比,其Vpp增大(P<0.01),AF增加(P<0.01),ARI、CVv、CVf、DF、ICF和RA增加(P<0.05,P<0.01),DPR和NSW减小(P<0.05);与原发消化性溃疡对照组相比,Vpp增大(P<0.01),AF增加(P<0.05),ARI、CVv、CVf、DF、ICF和RA增加(P<0.01),NSW减小(P<0.05)。
2.胃电各参数对脑出血后应激性溃疡发生的判别
经判别分析后,得到对判别应激性溃疡发生有意义的胃电参数:Vpp、RA、ICF、NSW、AF、ARI和DPR,排除变量DF;并可得到胃电在正常健康人群、原发消化性溃疡患者、脑出血未并发和并发应激性溃疡患者的四个Fisher判别函数,其判别正确率可达87.9%。
3.脑出血患者颅内压变化情况及其与胃电变化的关系
脑出血后发生应激性溃疡患者的颅内压(5.69±0.53kPa)较无应激性溃疡发生者颅内压(4.22±1.14kPa)明显增高(P<0.01);随着颅内压升高,Vpp、DF、ARI、CVf、CVv、ICF和RA增大,NSW减小(P<0.05,P<0.01)。
第二部分:脑出血大鼠应激性溃疡发生与胃电变化及二者相关机制研究(动物实验)
实验一大鼠脑出血应激性溃疡模型制备
1.不同方法诱导基底节区出血的血肿体积变化
大鼠冠状位脑片HE染色测量血肿体积发现,50μl自体血组和0.3U胶原酶组血肿体积相似(P>0.05),100μl自体血组和0.6U胶原酶组血肿体积相似(P>0.05),随着注入自体血和胶原酶量的增加,右侧基底节区血肿体积增大。
2.不同剂量自体血和胶原酶脑出血模型应激性溃疡发生的比较
不同剂量自体血和胶原酶注入大鼠脑基底节区72h后,1.2U胶原酶组大鼠大部分死亡,脑血肿体积和脑含水量随注入剂量的增加而增大,同时溃疡发生率和溃疡指数增大;同等血肿体积胶原酶组所引起的溃疡发生率和溃疡指数大于自体血组。
实验二大鼠脑出血并发应激性溃疡与胃电变化相互关系机制研究
1.脑出血应激性溃疡大鼠的胃壁表现
肉眼可见应激性溃疡大鼠溃疡多发生于前、后胃交界胃小弯处,与迷走神经分布密集区相同。胃黏膜表现为单一或散在的出血点或是大小不一的溃疡面,深度可达肌层,甚至穿孔。HE染色镜下可见溃疡呈火山口样,累及粘膜至粘膜下层,部分累及肌层和浆膜层;在溃疡边缘有浓染的炎性细胞聚集、血管闭塞及出血,典型溃疡表现多发生在造模后2d和3d。
2.实验大鼠胃电记录与溃疡指数评定及相关性分析
正常组大鼠胃电图慢波多数呈正弦波形,少数有切迹呈双峰型。与假手术组比较,溃疡对照组Amp在12h、1d、2d、3d、5d时增大(P<0.01),脑出血无应激性溃疡组在12h、1d、2d时胃电图Amp增大(P<0.05,P<0.01);与假手术组、乙酸溃疡对照组、脑出血无应激性溃疡组相比,在所有实验时间点脑出血应激性溃疡组Amp增大(P<0.05,P<0.01)。与假手术组比,乙酸溃疡对照组F在12h、1d、2d、3d时增大(P<0.05,P<0.01),脑出血无应激性溃疡组在12h、1d、2d、3d、5d、7d时胃电图F增大(P<0.01),与假手术组、乙酸溃疡对照组、脑出血无应激性溃疡组相比,在所有实验时间点脑出血应激性溃疡组F增大(P<0.05,P<0.01)。ARI和CV在各时间点乙酸溃疡对照组与假手术组无差异;除脑出血无应激性溃疡组14d外,所有脑出血造模组ARI和CV在各时间点均高于假手术组(P<0.01);脑出血溃疡组ARI和CV大于无溃疡组(P<0.05,P<0.01)。
在不同时间点对脑出血后发生应激溃疡的实验大鼠在解剖显微下进行溃疡指数计数,溃疡指数在1d和2d时较小,3d时达到高峰,随后溃疡指数下降,经相关性分析可见胃电各参数与溃疡指数相关(P<0.01)。
3.实验大鼠颅内压记录及其与相关参数相关性分析
大鼠脑出血造模后12h时颅内压明显增高,2d达高峰,7d基本恢复正常;造模组的颅内压在12h、1d、2d、3d和5d明显高于假手术组(P<0.01),脑出血造模组发生应激性溃疡的大鼠颅内压在上述五个时间点也明显高于未发生溃疡大鼠的颅内压(P<0.01);脑出血造模后大鼠颅内压水平与溃疡指数呈正相关(P<0.01,R=0.732);脑出血模型大鼠胃电的F、Amp、ARI和CV四项参数均与颅内压存在相关性(P<0.01)。
4.实验大鼠颅内压增高对下丘脑及脑干组织细胞损伤和细胞凋亡的影响
颅内压增高时,大鼠下丘脑和脑干HE染色可见坏死和出血改变;Tunel染色凋亡阳性细胞在下丘脑和脑干中线结构分布增多。
5.实验大鼠迷走神经传出放电记录及其与相关参数相关性分析
大鼠脑出血造模后12h、1d、2d、3d时迷走神经传出放电的VF和VA高于假手术组(P<0.05,P<0.01);脑出血造模组中出现溃疡者高于无溃疡者(P<0.05,P<0.01)。PCV在所有时间点脑出血造模组高于假手术组,脑出血造模组中有溃疡者高于无溃疡者(P<0.01);大鼠脑出血造模后颅内压和迷走神经传出放电呈正相关(P<0.01);迷走神经传出放电的VF、VA和PCV与胃电的F、Amp、ARI和CV相关(P<0.01);迷走神经传出放电VF、VA和PCV与溃疡指数相关(P<0.01);脑出血模型大鼠迷走神经离断后与离断术前比较,胃电F下降,Amp降低,CV减少。
6.实验大鼠胃壁M1受体表达、胃酸分泌量和胃液pH值变化及其与相关参数的相关性分析
在12h、1d、2d和3d时间点,脑出血造模后大鼠胃壁M1受体的IOD值高于假手术组(P<0.01),脑出血造模中有溃疡者高于无溃疡者(P<0.01)。4h胃酸分泌量测定可见,脑出血大鼠无溃疡发生者12h较假手术组胃酸分泌明显增高(P<0.01),其他时间点未见差异(P>0.05);在12h、1d、2d、3d时发生溃疡者高于无溃疡发生者(P<0.01)。大鼠脑出血后,胃液pH值低于假手术组(P<0.05,P<0.01),这种表现在14d时不明显(P>0.05),造模组中有溃疡发生者pH值低于无溃疡发生者(P<0.05,P<0.01)。脑出血造模大鼠迷走神经传出放电与M1表达呈正相关,与pH值呈负相关;M1表达与溃疡指数呈正相关;pH值与溃疡指数表达呈负相关。大鼠脑出血行迷走神经切断与未离断前相比,12h M1受体表达下降、胃酸分泌减少和胃液pH值升高(P<0.05)。
7.实验大鼠胃壁M2、M3受体表达及其与相关参数相关性分析
在脑出血造模后12h即出现M2和M3受体表达的上调(P<0.01),24h达高峰,峰值状态一直持续到5d,7d时二者表达有所下降(P<0.05);脑出血中有溃疡发生者在各时间点的M2、M3受体表达均高于无溃疡发生者(P<0.01,P<0.05),胃壁M2和M3受体在大鼠脑出血后表达变化与迷走神经传出放电和胃电各参数有较好的相关性(P<0.01)。
8.实验大鼠胃壁COX-2表达和幽门张力的变化
大鼠脑出血12h时COX-2表达增加,其IOD值明显高于假手术组(P<0.01),2d达到高峰,14d与假手术组无差异(P>0.05);在脑出血造模组内,有溃疡发生者高于无溃疡者(P<0.01)。脑出血大鼠幽门收缩的频率减慢、幅度下降,在造模后12h、1d、和2d变化明显(P<0.01),脑出血造模组溃疡发生者比无溃疡发生者这种变化表现更明显(P<0.01)。
9.实验大鼠胃电变化对大鼠脑出血并发应激性溃疡的判别分析将胃电四个参数F、Amp、ARI和CV在大鼠脑出血溃疡组和无溃疡组、乙酸诱发溃疡组和假手术组行判别分析可得Fisher判别函数,其正确判断率可达到90.8%。
结论
胃电对脑出血后是否并发应激性溃疡有诊断价值,并可做为应激性溃疡病情变化的一种可靠监测指标;胃电对应激性溃疡的指示作用可能机制之一是脑出血所致颅内压升高影响自主神经中枢,使自主神经发生功能紊乱,迷走神经传出冲动增加,胃酸分泌增加,pH值下降,发生急性胃粘膜受伤,同时迷走神经传出冲动增加也参与胃运动调节,从而使胃电发生变化。
Background
Stress ulcer (SU) is a common complication of severe cerebral hemorrhage (up to 91%) and the death rate can reach to 80%. Cerebral hemorrhage(CH)as a stress source results in acute erosive or ulcerative injury of gastroduodenal mucosal through complex action which many factors participated, so stress ulcer occurred afetr CH. Those mild cases have no apparent clinical manifestations whereas upper gastrointestinal bleeding even with life-threatening bleeding might happen within severe cases.
Early diagnosis and proper treatment to intracerebral hemorrhage with stress ulcer cut down mortality and disability of CH. Through the large sample evidence-based controlled study, prophylactic medication cann’t reduce the incidence of stress ulcer, but increase the economic and physical burden on patients. This requires clinicians to detect the presence of stress ulcer, and take appropriate action in time, as well as monitor changes in stress ulcer and drug efficacy of treatment.
Diagnosis and monitoring of cerebral hemorrhage stress ulcer are very sluggish. To diagnose stress ulcer complicated with hemorrhage is based on clinical symptoms including hematemesis, black stools, persistent blood pressure being decreased while continuous infusion or blood and positive results of gastric occult blood test. So that the cases with negative clinical manifestations can not receive timely treatment and the treatment time is delayed. The SU cases with negative clinical manifestations can be diagnosed by gastroscope which improve the diagnosis rate and accuracy of SU. However, the anesthetic tolerance is poor in acute phase of severe intracerebral hemorrhage following disturbance of consciousness or other changes in vital signs, furthermore gastroscopy operation can induce nausea and vomiting which increase the possibility of re-bleeding. Endoscopy in the acute phase of cerebral hemorrhage limited and even painless gastroscopy. Stress ulcer be complicated by cerebral hemorrhage in r mostly occurs in 72h-14d Acute stage. To find a non-invasive, accurate, and constantly monitoring way is essential for estimating the development of stress ulcer after intracerebral hemorrhage.
Gastric electrical activities response electrical activities of gastric smooth muscle cells. Through the analysis of EGG after cerebral hemorrhage stress ulcer might be diagnosed and useful information might be provided. EGG records the activities of gastric smooth muscle signals accurately being used for clinical diagnosis of gastric motility disorders. Some studies showed that the frequency was faster and the amplitude was higher in ulcer patients. It also showed that change of gastric electrical rhythm after intracerebral hemorrhage. But gastric electrical change has not been reported about the stress ulcer after intracerebral hemorrhage. The pathogenesis of stress ulcer is not clear. Studies showed that neuroendocrine disorders, defense function of gastric mucosal being decreased, injury factors of gastric mucosal being strengthened and imbalance of autonomic function and so on. This study was to observe gastric electrical activity changes in stress ulcer complicated by cerebral hemorrhage of clinical patients and to understand pathology between stress ulcer complicated by cerebral hemorrhage and gastric electrical changes by animal experiments. To explore clinical application of EGG monitoring happen and development of stress ulcer complicated by cerebral hemorrhage .
Purpose
1. Observing the gastric electrical changes of cerebral hemorrhage in patients with stress ulcer, the presence or absence of stress ulcer was determined by analyzing the parameters of EGG.
2. Monitoring intracranial pressure of intracerebral hemorrhage patients with stress ulcer to explore the role of intracranial pressure in stress ulcer.
3. Observing the incidence of stress ulcer at different intracerebral hemorrhage model, to establish intracerebral hemorrhage animal model with stress ulcer.
4. Through observing EGG, intracranial pressure, efferent discharge of vagus nerve, expression of acetylcholine receptor (M1, M2 and M3) and COX-2 in stomach mucosa, pH of gastric fluid, gastric acid secretion volume and tension of pylorus changes of intracerebral hemorrhage, to explore relationship between changes of EGG and stress ulcer and pathogenesis of stress ulcer after cerebral hemorrhage.
Methods
Part I: clinical trials
1. The parameters of EGG were analyzed in the normal group , primary ulcer group, SU after CH group and CH group through monitoring the gastric electrical activity 15 days. The accuracy to judge the occuring of SU after CH was analyzed by discriminant analysis.
2. The relationship between the genesis of stress ulcer and the level of ICP was analyzed by monitoring intracranial pressure in patients with severe cerebral hemorrhage through lateral ventricle catheter .
Part II: animal experiments
1. 150μl, 100μl, 150μl of autologous blood and 0.3U, 0.6U, 0.9U, 1.2UⅦcollagenase were injected into the right side basal ganglia of SD rat brain respectively. HE staining of brain and stomach, brain water content and ulcer index were undergone at 72h after CH.
2. The healthy SD rats meeting with the requirements were randomly divided into normal control group (15), acetic acid ulcer control group (20) and brain basal ganglia hemorrhage model group, being setted up time for the 12h, 1d, 2d, 3d, 5d, 7d , 14d, 30 rats at each time point. The vagus nerves of 60 rats were transected at 12h and 24h after the brain basal ganglia hemorrhage. EGG, vagus nerve efferent discharge, intracranial pressure and pyloric pressure were recorded, acetylcholine receptor (M1, M2, M3) and COX-2 in gastric mucosa were measured by immunohistochemical method at each time in each group. Gastric acid secretion in 4h and gastric pH were measured at same time.
Results
Part I: Dynamic changes of EGG of Severe cerebral hemorrhage patients with stress ulcer and relationship between intracranial pressure and stress ulcer (clinical trials)
1. EGG of intracerebral hemorrhage patients with stress ulcer
EGG showed smooth sine wave transferred from the irregular curve of the original wave form through the filter in normal control group. In ulcer control group, Vpp, AF, DF, RA increased (P<0.01), DPR and the NSW decreased (P<0.01). In intracerebral hemorrhage with no complication of stress ulcer group, the wave type varied greatly, Vpp, ARI, CVf, ICF and RA increased (P< 0.01), AF remained unchanged (P> 0.05), NSW decreased (P<0.01) being compared with the normal control group. Differences in waveform morphology were more in cerebral hemorrhage complicated stress ulcer group. Compared the EGG between intracerebral hemorrhage with stress ulcer group and CH without stress ulcer group, Vpp, ARI, DF, CVv, CVf, ICF, AF and RA increased (P<0.05, P<0.01), DPR and NSW decreased (P<0.05). while compared with ulcer control group, Vpp, AF, ARI, CVv, DF, CVf, ICF and RA increased (P<0.05, P<0.01), NSW decreased (P<0.05).
2. Discriminant analysis of EGG parameters
The significant parameters of EGG were achieved through discriminant analysis to diagnose SU, including Vpp, RA, ICF, NSW, AF, ARI and the DPR. Fisher discriminant function was setted up which EGG was applied to discriminate normal healthy people, patients with ulcer, patients with CH, patients with CH complicated with SU. The discriminant accuracy rate was 87.9%.
3. The relationship between Intracranial pressure and EGG of patients with intracerebral hemorrhage
Intracranial pressure(5.69±0.53kPa) was higher in intracerebral hemorrhage with stress ulcer than that of those without stress ulcer (4.22±1.14kPa, P<0.01). Along with increased intracranial pressure, Vpp, DF, ARI, CVf, CVv, ICF, and RA increased, NSW and C decreased (P<0.05, P<0.01).
Part II: Rearch to cerebral hemorrhage with stress ulcer in rats and related mechanism (animal experiments)
Experiment one Construction of cerebral hemorrhage stress ulcer models in rats
1. Hematoma volume changes in different basal ganglia hemorrhage models
Hematoma volume of 50μl autologous blood group was similar to 0.3U collagenase group by HE stainning measurement of brain slices (P>0.05), so as to 100μl autologous blood group and 0.6U collagenase group(P>0.05). With the dose of autologous blood and collagenase increased, the hematoma volume of right basal ganglia was enlarged.
2. Incidence of SU after different doses of autologous blood and the collagenase intracerebral hemorrhage model
Most of the rats in 1.2U collagenase group died at 72h after different dose autologous blood and collagnase injected into the cerebral basal ganglia. Hematoma volume and brain water content increased with the dose increase of blood and collagnanse being injected, so as to the incidence of SU and ulcer index. The incidence of SU was greater in collagenase group than in autologous blood group at the equal hematoma volume.
Experiment two EGG changes of cerebral hemorrhage stress ulcer and mechanism of the relationship between EGG and stress ulcer
1. Gastric wall of rats with SU
The gastric ulcer mostly occured in arcus minor ventriculi at the junction of proventriculus and stomach in which the vagus nerve distributed. Gastric mucosa showed a single or sporadic bleeding or ulcers of different sizes, depth up to muscle, or even perforation. HE staining showed crater-like ulcer, involving the mucosa to the submucosa, partial to muscularis and serosa. It could be seen that accumulation of inflammatory cells, vascular occlusion and bleeding in the ulcer margin. Typical ulceration was more ofen occurred at 2d and 3d.
2. EGG recording, evaluation of ulcer index and relationship between them
Slow wave of EGG showed sine wave, in which some had notch and bimodal in normal group. Compared to the sham-operated group, Amp increased at 12h, 1d, 2d, 3d, 5d in acetic acid ulcer control group (P<0.01). Amp became larger at 12h, 1d, 2d in intracerebral hemorrhage without stress ulcer group (P<0.05, P<0.01). Amp was higher than all other groups in intracerebral hemorrhage with SU(P<0.05, P<0.01). Compared with the sham-operated group, F increased at 12h, 1d, 2d, 3d in acetic acid ulcer control group (P<0.05, P<0.01), at 12h, 1d, 2d, 3d, 5d, 7d in intracerebral hemorrhage without stress ulcer group(P<0.01). F was faster than all other groups in intracerebral hemorrhage with SU (P<0.05, P<0.01). ARI and CV had no difference between the acetic acid ulcers control group and sham-operated group at each time point. Except for intracerebral hemorrhage without SU group at 14d, ARI and CV were higher than sham-operated group in all intracerebral hemorrhage group at each time points (P<0.01); in which ARI and CV were higher in intracerebral hemorrhage with SU than that of CH with non-ulcer group (P<0.05, P<0.01).
At experimental different time points, under a dissecting microscope counted UI of occurred ulcers in rats, UI is small at 24h and 48h, to 72h the peak reached, then reduced. All EGG parameters associated with UI by the correlation analysis (P<0.01).
3. Intracranial pressure recording and correlation with other parameters in experimental rats
Intracranial pressure elevated significantly at 12h, then to the peak at 2d and returned to nomal at 7d after intracerebral hemorrhage in rats. Intracranial pressure of intracerebral hemorrhage modules was higher significantly than sham-operated group at 12h, 1d, 2d, 3d and 5d (P<0.01). At same time, intracranial pressure was higher in CH with SU group than those without ulcers groups (P<0.01). The level of intracranial pressure correlated positively with ulcer index (P<0.01, R=0.732). F, Amp, ARI and CV of EGG parameters correlated with intracranial pressure (P<0.01).
4. Intracranial hypertension effects to cell apoptosis and tissue injury of hypothalamus and brainstem in experimental rats
Necrosis and hemorrhage could be seen in the hypothalamus and brainstem of CH rats through HE staining. Tunnel positive staining apoptotic cells were located in the hypothalamus and midline structures of brainstem.
5. Vagus nerve efferent discharge records and correlation with other parameters in experimental rats
VF and VA of vagus nerve efferent discharge was higher in basal ganglia hemorrhage rats than sham-operated group at 12h, 1d, 2d, 3d (P<0.05, P<0.01). Within CH groups, VF and VA were higher in CH with SU group than those without ulcer group(P<0.05, P<0.01). PCV in the CH group was higher than that of sham-operated group at each time point. Within CH groups, PCV was higher in CH with SU group than those without ulcer group(P<0.05, P<0.01). There was positive relationship between intracranial pressure and efferent discharge of vagus nerve after CH (P<0.01). VF, VA and PCV of vagus nerve efferent discharge were related to F, Amp, ARI and CV of EGG (P<0.01). VF, VA, and PCV of vagus nerve efferent discharge related to the ulcer index (P<0.01). F, Amp, CV decreased after vagus nerve being transected in CH rats compared with before(P<0.01).
6. Changes of the expression of M1 receptors in gastric muscoa, volume of gastric acid secretion and pH value of gastric wall and their correlation with other parameters
IOD value of the expression of M1 receptors was higher at 12h, 1d, 2d and 3d in CH groups compared with the sham-operated group (P<0.01). Within which IOD value of the CH with SU was higher than those without SU (P<0.01). 4h volume of gastric acid secretion was greater at 12h in CH groups than that of sham-operated group (P<0.01), while there has no difference at the other times(P<0.05). Within CH groups which SU occurred, the volume of gastric acid secretion was higher at 12h, 1d, 2d,3d than that of those with no SU (P<0.01). pH value of gastric wall descended at each time after basal ganglia hemorrhage in rats (P<0.05, P<0.01)except for 14d(P>0.05). It was lower in CH with SU groups compared with the CH with no SU group(P<0.05, P<0.01). The vagus nerve efferent discharge had positive relationship with the expression of M1 receptor in gastric muscoa and acid secretion, negative correlated with the pH value. The expressions of M1 receptor and ulcer index were positively related. pH value and the ulcer index was negatively correlated. The expression of M1 receptor was decreased and gastric acid secretion reduced and pH value increased after the vagotomy at 12h in CH rats(P<0.05).
7. Expressions of M2, M3 receptor in gastric muscoa and their correlation with other parameters in experimental rats
Expressions of M2, M3 receptor in gastric muscoa was up-regulation at 12h after CH (P<0.01), up to peak level at 24h, being stated until 5d and decreased at 7d (P<0.05). It was expressed intensivly in CH with SU rats than that of the CH rats which SU not occurred (P<0.01, P<0.05). M2 and M3 receptors in the stomach wall in rats the expression of basal ganglia hemorrhage and vagus nerve efferent discharge has a good correlation (P<0.01). The expression of M2, M3 receptor had relationship with EGG and the efferent discharge of vagus nerve.
8. Expression of COX-2 in gastric muscoa and changes of pyloric tension in experimental rats
The IOD of COX-2 expression was significantly higher at 12h in basal ganglia hemorrhage groups than sham-operated group (P<0.01), up to peak at 2d, there was no significant difference at 14d compared with the sham-operated group (P>0.05). It was higher in CH with SU group than that of CH without SU (P<0.01). The frequency of pyloric contraction slowed and its amplitude decreased at 12h, 1d, and 2d after CH significantly (P<0.01), This change was more obvious in the CH rats which SU occured(P<0.01).
9. Discriminant analysis of EGG judge the experimental basal ganglia intracerebral hemorrhage compicated with stress ulcer in rats
The discriminat function was achieved about the four parameters of EGG including F, Amp, ARI and CV. Its accuracy rate was 90.8% to discriminate the CH complicated with SU rats and no SU, rats with ulcer induced by acetic acid and noamal rats.
Conclusions
EGG had diagnostic value to stress ulcer after intracerebral hemorrhage and could be a reliable method to monitor the pathogenetic condition mobility. EGG instructions on the role of stress ulcer is one possible mechanism of cerebral hemorrhage due to increased intracranial pressure effects on the autonomic nerve center, so that autonomic dysfunction occurs, vagus nerve efferent impulses and gastric acid secretion increase, pH value decreases. Acute gastric mucosa is injuried while increased vagal efferent impulses are also involved in regulating gastric motility and affect changes of EGG.
引文
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