组织黏合剂治疗胃静脉曲张出血的基础和临床研究
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摘要
研究目的:食管胃静脉曲张出血(esophagogastric variceal bleeding,EGVB)是消化科的重危急症,如何控制其出血并防止再发出血,降低死亡率,是救治肝硬化患者生命、提高生活质量的重要问题。内镜下硬化剂治疗对制止食管静脉曲张急性出血以及预防再出血是一种有效的方法,已广泛被接受并应用于临床,但对胃静脉曲张出血的治疗还有争论。近年来,国内外许多临床研究已证实,经内镜注射组织粘合剂N-丁基-2-氰丙烯酸盐方法是控制胃静脉曲张出血的有效治疗方法。本课题从血管基础病理和临床治疗效果两个方面入手,旨在通过基础研究来探讨组织粘合剂在血管中的实际行为,分析影响其聚合的主要因素,找到发挥作用的最佳条件;并且观察注射入成兔血管后的组织病理学改变,阐明其止血机制及作用过程,更好的指导临床应用;通过临床研究组织粘合剂的用量和排胶规律,评价内镜下注射组织黏合剂治疗胃静脉曲张出血的远期疗效和安全性,从而明确其作为GV出血治疗首选方法的地位。
材料和方法:1、血液流变学研究:我们利用聚四氟乙烯管建立血流模型,分别研究血管直径、血流速度以及组织黏合剂配比浓度这三个因素对组织黏合剂聚合过程的影响。2、组织病理学研究:本部分采用2～3kg成兔作为研究对象,分别在其颈外静脉和股动脉内注入组织黏合剂(用量为0.1～0.2ml,顺血流方向),然后分别在注射后3天、7天、2周、3周和4周、2月和3月将注射部位及邻近血管周围组织切取成1cm的组织条,进行组织病理学研究。以不同的时间阶段分为7组,每组为6只新西兰白兔。取对侧正常血管作为对照。3、临床研究:在1年半内148例活动性或近期胃静脉曲张出血的患者行内镜下组织黏合剂注射治疗直到曲张静脉闭塞。组织黏合剂与碘油按1:1的混合比例快速注入曲张静脉内。25例为活动性出血,123例为近期出血。最常注射部位是胃底和贲门。根据上腹部平片和CT血管成像观察排胶规律。患者平均随访时间为13.1个月。
结果:组织黏合剂与碘油1:1配比混合物1.0ml快速注射至聚四氟乙烯
[Background and objective] Esophagogastric variceal bleeding(EGVB) is a serious and emergent disease of digestive system and how to control hemorrhage in order to decrease death rate is an important problem. Variceal bleeding results in considerable morbidity and mortality. Initial treatment is aimed at achiving hemostasis and preventing bleeding-related complications such as renal failure, infection, and hepatic decompensation. Although Endoscopic variceal sclerotherapy (EVS) is an effective solution for EV, while there is controversythe of the treatment for GV, which is one of the most important cause of death from hepatic cirrhosis and portal hypertension. Recently some studies reported that endoscopic injection of N-butyl-2-cyanoacrylate is an effective alternative for EGV therapy. In this study, we discussed the fact behavior of cyanoacrylate in vessels so as to find out the most vessel diameter and propriate time it blocked. In animal experiment we investigated the structure and pathological representation after injection. At the same time, the long-term efficacy and safety of the endoscopic injection of cyanoacrylate were evaluated to define its role as the initial treatment for bleeding gastric varices.[Methods and materials] 1. Basic study: we created a varix model. A volume of 0.5ml or 1.0ml of cyanoacrylate was injected into vinyl tubes of 0.4, 0.6 and 0.8cm in diameter, which were filled with still blood or flowing blood. We investigated the influence of the vesse diameter, the blood velocity and the match concentration of cyanoacrylate and lipiodol on the process of blood polymerization. 2. Animal experiment: The objections were 42 rabbits with 2~ 3kg. We injected 0.1~0.2ml mixtures of cyanoacrylate and lipiodol into cervical veins and femoral arteries of rabbits. And then, the animals were euthanized at various time intervals after injection. A lcm strip of tissue was resected for
histological evaluation. We divided into seven groups according to different time. There were six rabbits in each group. We compared the histological difference between arteries and veins. 3. Clinica study: 148 patients of liver cirrhosis with EGV at our hospital from June 2003 to December 2004 subjected to the injection. Cyanoacrylate was injected intravariceally as a 1:1 mixture with Lipiodal. In which 30 had isolate gastric varices, 38 had postoperative residual GV, 72 had dominant GV. 0.5~2.0ml of 1:1 mixture of cyanoacrylate and lipiodol was injected into each point. Each patient underwent scheduled or emergent endoscopic injection of cyanoacrylate and countercheck on the 7th day, lth month and 3th month after the first treatment respectively. The information of each patients' gender, age, complications, stage of gastric varices, number of trentment, dosage of cyanoacrylate agent, outcome of GV, diameter of main portal tract, liver function, blood routine tests were collected. No marked side effects and complication were found.We described data with mean ±standard deviation( X ±SD), median(Md). [Results] 1. N-butyl-2-cyanoacrylate was similarly polymerized in the vinyl tubes and the animal veins. A volume of 1.0ml of the mixtures of cyanoacrylate and lipiodol (1:1) could block completely the blood stream with 15cm/s in velocity and 0.4cm in diameter or with lOcm/s in velocity and 0.6cm in diameter, respectively. With the increase of diameter and velocity, it can block vessel incompletely and we need more dosage of mixture. When the match concentration was changed, the effect decreased. Some polymer masses were fragmented. 2. When injected intravascularly, cyanoacrylate promptly solidifies, producing a cast of the vessel. Subtotal occlusion is immediate, and total occlusion occurs within hours. The results of animal experiment showed that we observed the acute inflammatory reaction at 3 days after injection, and then gradually developed into chronic granulomatous foreign body reaction. The elastic fibrin in arterial wall proliferated distinctly after three weeks resulted into the smallness of cavity. But there were little change in venous wall at fifferent time. 3. According to Sarin's category of GV, GOV- I detected in 68 (45.9%), GOV-II in 49 (33.1%), IGV- I in 30 (20.3%) and IGV-II in 1 (0.67%). The common cause of GOV was liver cirrhosis and IGV was segmental portal
材料和方法:1、血液流变学研究:我们利用聚四氟乙烯管建立血流模型,分别研究血管直径、血流速度以及组织黏合剂配比浓度这三个因素对组织黏合剂聚合过程的影响。2、组织病理学研究:本部分采用2～3kg成兔作为研究对象,分别在其颈外静脉和股动脉内注入组织黏合剂(用量为0.1～0.2ml,顺血流方向),然后分别在注射后3天、7天、2周、3周和4周、2月和3月将注射部位及邻近血管周围组织切取成1cm的组织条,进行组织病理学研究。以不同的时间阶段分为7组,每组为6只新西兰白兔。取对侧正常血管作为对照。3、临床研究:在1年半内148例活动性或近期胃静脉曲张出血的患者行内镜下组织黏合剂注射治疗直到曲张静脉闭塞。组织黏合剂与碘油按1:1的混合比例快速注入曲张静脉内。25例为活动性出血,123例为近期出血。最常注射部位是胃底和贲门。根据上腹部平片和CT血管成像观察排胶规律。患者平均随访时间为13.1个月。
结果:组织黏合剂与碘油1:1配比混合物1.0ml快速注射至聚四氟乙烯
[Background and objective] Esophagogastric variceal bleeding(EGVB) is a serious and emergent disease of digestive system and how to control hemorrhage in order to decrease death rate is an important problem. Variceal bleeding results in considerable morbidity and mortality. Initial treatment is aimed at achiving hemostasis and preventing bleeding-related complications such as renal failure, infection, and hepatic decompensation. Although Endoscopic variceal sclerotherapy (EVS) is an effective solution for EV, while there is controversythe of the treatment for GV, which is one of the most important cause of death from hepatic cirrhosis and portal hypertension. Recently some studies reported that endoscopic injection of N-butyl-2-cyanoacrylate is an effective alternative for EGV therapy. In this study, we discussed the fact behavior of cyanoacrylate in vessels so as to find out the most vessel diameter and propriate time it blocked. In animal experiment we investigated the structure and pathological representation after injection. At the same time, the long-term efficacy and safety of the endoscopic injection of cyanoacrylate were evaluated to define its role as the initial treatment for bleeding gastric varices.[Methods and materials] 1. Basic study: we created a varix model. A volume of 0.5ml or 1.0ml of cyanoacrylate was injected into vinyl tubes of 0.4, 0.6 and 0.8cm in diameter, which were filled with still blood or flowing blood. We investigated the influence of the vesse diameter, the blood velocity and the match concentration of cyanoacrylate and lipiodol on the process of blood polymerization. 2. Animal experiment: The objections were 42 rabbits with 2~ 3kg. We injected 0.1~0.2ml mixtures of cyanoacrylate and lipiodol into cervical veins and femoral arteries of rabbits. And then, the animals were euthanized at various time intervals after injection. A lcm strip of tissue was resected for
histological evaluation. We divided into seven groups according to different time. There were six rabbits in each group. We compared the histological difference between arteries and veins. 3. Clinica study: 148 patients of liver cirrhosis with EGV at our hospital from June 2003 to December 2004 subjected to the injection. Cyanoacrylate was injected intravariceally as a 1:1 mixture with Lipiodal. In which 30 had isolate gastric varices, 38 had postoperative residual GV, 72 had dominant GV. 0.5~2.0ml of 1:1 mixture of cyanoacrylate and lipiodol was injected into each point. Each patient underwent scheduled or emergent endoscopic injection of cyanoacrylate and countercheck on the 7th day, lth month and 3th month after the first treatment respectively. The information of each patients' gender, age, complications, stage of gastric varices, number of trentment, dosage of cyanoacrylate agent, outcome of GV, diameter of main portal tract, liver function, blood routine tests were collected. No marked side effects and complication were found.We described data with mean ±standard deviation( X ±SD), median(Md). [Results] 1. N-butyl-2-cyanoacrylate was similarly polymerized in the vinyl tubes and the animal veins. A volume of 1.0ml of the mixtures of cyanoacrylate and lipiodol (1:1) could block completely the blood stream with 15cm/s in velocity and 0.4cm in diameter or with lOcm/s in velocity and 0.6cm in diameter, respectively. With the increase of diameter and velocity, it can block vessel incompletely and we need more dosage of mixture. When the match concentration was changed, the effect decreased. Some polymer masses were fragmented. 2. When injected intravascularly, cyanoacrylate promptly solidifies, producing a cast of the vessel. Subtotal occlusion is immediate, and total occlusion occurs within hours. The results of animal experiment showed that we observed the acute inflammatory reaction at 3 days after injection, and then gradually developed into chronic granulomatous foreign body reaction. The elastic fibrin in arterial wall proliferated distinctly after three weeks resulted into the smallness of cavity. But there were little change in venous wall at fifferent time. 3. According to Sarin's category of GV, GOV- I detected in 68 (45.9%), GOV-II in 49 (33.1%), IGV- I in 30 (20.3%) and IGV-II in 1 (0.67%). The common cause of GOV was liver cirrhosis and IGV was segmental portal
引文
1 Jan L, Petr H, Tomas V. Management of acute variceal bleeding. Dig Dis 2003; 21: 6-15
2 Jaime B, Juan G. Management of gastrointestinal bleeding in patients with cirrgosis of the liver. Semin Hematol 2004; 41(1): 8-12
3 Masahiro A, Takao M, Kunio O. Pathomorphology of esophageal and gastric varices. Seminars in Liver Disease 2002; 22(1): 73-82
4 Abraldes JG, Tarantino I, Turnes J, et al. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology 2003; 37: 902-908
5 Kapoor D, Sarin SK. Pathophysiology of portal hypertension. Journal of Gastroenterology and Hepatology 2002; 17: S482-S487
6 Abraldes JG, Dell'Era A, Bosch J. Medical management of variceal bleeding in patients with cirrhosis. Can J Gastroenterol 2004 Feb; 18(2): 109-113
7 Goth JP, Zimmermann P. Une nouvelle technique de traitement endoscopique des varices oesophagiennes: l'obliteration. 1984; 7: 10-12
8 Akahoshi T, Hashizume M, Shimabukuro R, et al. Long-term results of endoscopic Histoacryl injection sclerotherapy for gastric variceal bleeding: a 10-year experience. Surgery 2002; 131(1 Suppl): S171-175
9 程留芳,王志强,令狐恩强等.经内镜注射组织胶治疗食管胃静脉曲张.中华消化内镜杂志,1999:16(2):88-90.
10 Sarin SK, Jain AK, Jain M, Gupta R. A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol 2002; 97(4): 1010-1015
11 Bruce DG, Stephen HC, Elizabeth E, et al. N-2-Butyl-Cyanoacrylate for bleeding gastric varices: a United States pilot study and cost analysis. Am J Gastroenterol 2003; 98: 1982-1988
12 Ishii H, Matsutani S, Mizumono H, et al. Portal hemodynamics in patients with fundic gastric varices: analysis of percutaneous transhepatic portography and Doppler ultrasonography. (In Japanese with English abstract). Acta Hepatol Jpn 1994; 35: 645-651
13 Ohnishi K, Nakata H, Terabayashi H, et al. The effects of endoscopic sclerotherapy combined with transhepatic variceal obliteration on portal hemodynamics. Am J Gastroenterol 1987; 82: 1138-1142
14 T Suga, T Akamatsu, Y Kawamura, et al. Actual behaviour of N-butyl-2-cyanoacrylate (Histoacryl) in a blood vessel: a modal of the varix. Endoscopy 2002; 34(1): 73-77
15 Lo GH, Lai KH, Cheng JS et al. A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices. Hepatology 2001; 33: 1060-1064
16 Tissue adhesives and fibrin glues. Technology Status Evaluation Report. Gastrointest Endosc 2004; 60 (3): 327-332
17 O Levrier, C Mekkaoui, K Murphy, et al. Efficacy and low vascular toxicity of embolization with radical versus anionic polymerization of N-butyl-2-cyanoacrylate(组织黏合剂). J Neuroradiol. 2003; 30: 95-102
18 渡边恒彦,岩垂司,武石询主编:组织标本制作的基本技术,北京:日中交流促进会出版,1985;38-39
19 Behan N, Birkinshaw C, Clarke N. Poly n-butyl cyanoacrylate nanoparticles: a mechanistic study of polymerization and particle formation. Biomaterials 2001; 22: 1335-1344
20 Behan N, Birkinshaw C. The mechanism of polymerization of butyl cyanoacrylate in aqueous dispersions. Colloid and polymer science 2000; 21: 884-886
21 Halil I, Ibrahim V, Emin M, et al. Tissue response to N-butyl-2-cyanoacrylate after percutaneous injection into cutaneous vascular lesions. Ann Plast Surg 2002; 49(5): 520-526
22 Calvo WJ, Lieber BB, Hopkins N, et al. Europium fluorescence to visualize N-butyl-2-cyanoacrylate in embolized vessels of an arteriovenous malformation swine model. Am J Neuroradiol 2001; 22: 691-697
23 Duffner F, Ritz R, Bornemann A, et al. Combined therapy of cerebral arteriovenous malformations: histological differences between a non-adhesive liquid embolic agent and N-butyl-2-cyanoacrylate (NBCA). Clinical Neuropathology 2002; 21: 13-17
24 Rossle M. When endoscopic therapy or pharmacotherapy fails to control variceal bleeding: what should be done? Immediate control of bleeding by TIPS?: Langenbecks Arch Surg. 2003 Jul; 388 (3): 155-62. Epub 2003 May 01
25 Bhasin D.K, Siyad I. Variceal bleeding and portal hypertension: new lights on old horizon. Endoscopy 2004; 36: 120-129
26 Lunderquist A, Borjesson B, Owman T, et al. Isobutyl 2-cyanoacrylate(bucrylate) in obliteration of gastric coronary vein and esophageal varices. Am J Roentgenol 1978; 130: 1-6
27 Soehendra N, Nam VC, Grimm H, Kempeneers I. Endoscopic obliteration of large esophagogastric varices with bucrylate. Endoscopy 1986; 18: 25-26
28 《实用内科学》编委会 陈灏珠主编.实用内科学.人民卫生出版社 2002年4月第11版:1856
29 李兆申.门静脉曲张的治疗.胃肠病学和肝病学杂志,2001;10(1):92-96
30 De Franchis R. Updating consensus in portal hypertension: report of the Baveno Ⅲ Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol. 2000 Nov; 33(5): 846-52
31 Ryan BM, Stockbrugger RW, Ryan JM. A pathophysiologic, gastroenterologic and radiologic approach to the management of gastric varices. Gastroenterology 2004; 126: 1175-1189
32 Seewald S, Sriram PVJ, Nagra M, et al. The expert approach: cyanoacrylate glue in gastric variceal bleeding. Endoscopy 2002; 34: 926-32
33 Shiha G, EI-sayed SS. Gastric variceal ligation: a new technique. Gastrointest Endosc 1999; 49: 437-441
34 Sarin SK, Jain AK, Jain M, Gupta R. A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol 2002; 97(4): 1010-1015
35 Kind R, Guglielmi A, Rodella L et al. Bucrylate treatment of bleeding gastric varices: 12 years'experience. Endoscopy 2000; 32: 512-519
36 Nguyen AJ, Baron TH, Burgart LJ, et al. 2-Octyl-cyanoacrylate
2 Jaime B, Juan G. Management of gastrointestinal bleeding in patients with cirrgosis of the liver. Semin Hematol 2004; 41(1): 8-12
3 Masahiro A, Takao M, Kunio O. Pathomorphology of esophageal and gastric varices. Seminars in Liver Disease 2002; 22(1): 73-82
4 Abraldes JG, Tarantino I, Turnes J, et al. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology 2003; 37: 902-908
5 Kapoor D, Sarin SK. Pathophysiology of portal hypertension. Journal of Gastroenterology and Hepatology 2002; 17: S482-S487
6 Abraldes JG, Dell'Era A, Bosch J. Medical management of variceal bleeding in patients with cirrhosis. Can J Gastroenterol 2004 Feb; 18(2): 109-113
7 Goth JP, Zimmermann P. Une nouvelle technique de traitement endoscopique des varices oesophagiennes: l'obliteration. 1984; 7: 10-12
8 Akahoshi T, Hashizume M, Shimabukuro R, et al. Long-term results of endoscopic Histoacryl injection sclerotherapy for gastric variceal bleeding: a 10-year experience. Surgery 2002; 131(1 Suppl): S171-175
9 程留芳,王志强,令狐恩强等.经内镜注射组织胶治疗食管胃静脉曲张.中华消化内镜杂志,1999:16(2):88-90.
10 Sarin SK, Jain AK, Jain M, Gupta R. A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol 2002; 97(4): 1010-1015
11 Bruce DG, Stephen HC, Elizabeth E, et al. N-2-Butyl-Cyanoacrylate for bleeding gastric varices: a United States pilot study and cost analysis. Am J Gastroenterol 2003; 98: 1982-1988
12 Ishii H, Matsutani S, Mizumono H, et al. Portal hemodynamics in patients with fundic gastric varices: analysis of percutaneous transhepatic portography and Doppler ultrasonography. (In Japanese with English abstract). Acta Hepatol Jpn 1994; 35: 645-651
13 Ohnishi K, Nakata H, Terabayashi H, et al. The effects of endoscopic sclerotherapy combined with transhepatic variceal obliteration on portal hemodynamics. Am J Gastroenterol 1987; 82: 1138-1142
14 T Suga, T Akamatsu, Y Kawamura, et al. Actual behaviour of N-butyl-2-cyanoacrylate (Histoacryl) in a blood vessel: a modal of the varix. Endoscopy 2002; 34(1): 73-77
15 Lo GH, Lai KH, Cheng JS et al. A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices. Hepatology 2001; 33: 1060-1064
16 Tissue adhesives and fibrin glues. Technology Status Evaluation Report. Gastrointest Endosc 2004; 60 (3): 327-332
17 O Levrier, C Mekkaoui, K Murphy, et al. Efficacy and low vascular toxicity of embolization with radical versus anionic polymerization of N-butyl-2-cyanoacrylate(组织黏合剂). J Neuroradiol. 2003; 30: 95-102
18 渡边恒彦,岩垂司,武石询主编:组织标本制作的基本技术,北京:日中交流促进会出版,1985;38-39
19 Behan N, Birkinshaw C, Clarke N. Poly n-butyl cyanoacrylate nanoparticles: a mechanistic study of polymerization and particle formation. Biomaterials 2001; 22: 1335-1344
20 Behan N, Birkinshaw C. The mechanism of polymerization of butyl cyanoacrylate in aqueous dispersions. Colloid and polymer science 2000; 21: 884-886
21 Halil I, Ibrahim V, Emin M, et al. Tissue response to N-butyl-2-cyanoacrylate after percutaneous injection into cutaneous vascular lesions. Ann Plast Surg 2002; 49(5): 520-526
22 Calvo WJ, Lieber BB, Hopkins N, et al. Europium fluorescence to visualize N-butyl-2-cyanoacrylate in embolized vessels of an arteriovenous malformation swine model. Am J Neuroradiol 2001; 22: 691-697
23 Duffner F, Ritz R, Bornemann A, et al. Combined therapy of cerebral arteriovenous malformations: histological differences between a non-adhesive liquid embolic agent and N-butyl-2-cyanoacrylate (NBCA). Clinical Neuropathology 2002; 21: 13-17
24 Rossle M. When endoscopic therapy or pharmacotherapy fails to control variceal bleeding: what should be done? Immediate control of bleeding by TIPS?: Langenbecks Arch Surg. 2003 Jul; 388 (3): 155-62. Epub 2003 May 01
25 Bhasin D.K, Siyad I. Variceal bleeding and portal hypertension: new lights on old horizon. Endoscopy 2004; 36: 120-129
26 Lunderquist A, Borjesson B, Owman T, et al. Isobutyl 2-cyanoacrylate(bucrylate) in obliteration of gastric coronary vein and esophageal varices. Am J Roentgenol 1978; 130: 1-6
27 Soehendra N, Nam VC, Grimm H, Kempeneers I. Endoscopic obliteration of large esophagogastric varices with bucrylate. Endoscopy 1986; 18: 25-26
28 《实用内科学》编委会 陈灏珠主编.实用内科学.人民卫生出版社 2002年4月第11版:1856
29 李兆申.门静脉曲张的治疗.胃肠病学和肝病学杂志,2001;10(1):92-96
30 De Franchis R. Updating consensus in portal hypertension: report of the Baveno Ⅲ Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol. 2000 Nov; 33(5): 846-52
31 Ryan BM, Stockbrugger RW, Ryan JM. A pathophysiologic, gastroenterologic and radiologic approach to the management of gastric varices. Gastroenterology 2004; 126: 1175-1189
32 Seewald S, Sriram PVJ, Nagra M, et al. The expert approach: cyanoacrylate glue in gastric variceal bleeding. Endoscopy 2002; 34: 926-32
33 Shiha G, EI-sayed SS. Gastric variceal ligation: a new technique. Gastrointest Endosc 1999; 49: 437-441
34 Sarin SK, Jain AK, Jain M, Gupta R. A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol 2002; 97(4): 1010-1015
35 Kind R, Guglielmi A, Rodella L et al. Bucrylate treatment of bleeding gastric varices: 12 years'experience. Endoscopy 2000; 32: 512-519
36 Nguyen AJ, Baron TH, Burgart LJ, et al. 2-Octyl-cyanoacrylate