细胞素在体外循环所致炎症反应中的作用及干预性治疗的实验与临床研究
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摘要
目的：探索细胞素（白细胞介素-6，8，10和肿瘤坏死因子-α）在体外循环所致的
炎症反应中的发生发展规律及它们在干预性治疗下的发生发展规律；并在相同时
点同时观察每组患者体外循环炎症反应临床表现的变化规律。方法：随机选取30
例6-12岁的“先天性心脏病：膜部室间隔缺损”患者，分成3组（根据：年龄、
性别、体重、手术中有无阻断升主动脉和有无室缺补片等因素采用：“积分之和
最小”原则均衡3组患者），其中：A组（抑肽酶组，Aprotinin）、M组（甲基强
的松龙组，Methylprednisolone）和C组（对照组，Control），每组10例。A组
患者在体外循环机器的预冲液中加入抑肽酶2,500,000KIU（500,000KIU/支×5
支）；M组患者在体外循环机器的预冲液中加入甲基强的松龙200mg（40mg/支×
5支）；C组患者的体外循环机器的预冲液中不加入其它的药物而作为对照。并在：
麻醉诱导插管后手术前、体外循环开始后10分钟的即刻、体外循环停机后30分
钟的即刻、术后第1天（早晨7时，后同）、术后第3天和术后第7天6个时点
采集患者的血液标本，每次2ml，立即注入含有EDTA的抗凝管中，离心分离的
血浆立即置-30℃冰箱中冷藏。第一部分，实验研究：采用ELISA法测定这6个
时段患者血浆中的白细胞介素-6，8，10和肿瘤坏死因子-α的值（pg/ml），并进行
各组的数值分析和比较；第二部分，临床研究：同时在以上采血的6个时点观察
记录：各项临床指标（包括：反映呼吸和循环系统功能指标及其它各项指标），
安徽医科大学硕士学位论文
并作各组数值的分析和比较。结果：实验部分：凡贞：在停CPB的30分，A组
与C组相卜较（A：叩厂8土16．19晗ml，C：135．巧比6．97晗m1Z卜0刀004），M组与C
组相卜较（M：56＊7士24．24Pg／ITll，C：135．45土86．97pg／ITll；2－0＊025），差异均有非常
显著性；u上丑：在停＊＊B的3O分，A组与C组相卜较（A：82．34土23．42帕加乙C：
134．61士41．93pg加1；P一0＊017），差异有非常显著性，而M组与C组相卜较（M：
106．12幻2．57晗M，C：门4石1H1．93阳／ml；卜0刀68O），差异无显著性。在术后第1
天，A组与C组十比较（A：21．81坊．37略二1，C：30．98土11．47pg／ttil；卜0刀引0），差
异有显著性，而M组与C组相比较（M：21．79士8．46pg／ffil，C：30．98到1．47Pg／ml；
P－0刀305），差异有显著性。在术后第3天，A组与C组相卜较（A：41．86士14．35p＊ml，
C：75．39土＊斗3阻加1；卜0＊08O），差异有非常显著性，而M组与C组相卜较（M：
63．83129．38pg／ml，C：75．39土刀．43pg／ml；P二0．3322），差异己无显著性；thin：在
＊PB开始后10 分，A组与C组相卜较（A：106＊2士30．5＊咖1，C：57．83士32．70p＊ml；
＊－0＊026），差异有非常显著性，而M组与C组相卜较（M：93．30幻5．38＊加1，C：
57．83土32．70pg／ffil；P＝0＊232），差异有显著性。在停 CPB的 30分，A组与 C组相
卜较（A：刀0．33土127石2晗二1，C：旧9．叩幻8．57pg／ffil；P一0刀001），差异有非常显著
性，而M组与C组相卜较（M：525．16士149．47pg／thl，C：189．46土58．57p咖IZ
P－0＊00），差异有非常显著性，而A组与M组相b较（A：720．33土127＊Zp＊二1，M：
525．16ti49．47pg／ml；P－0＊010），差异也有非常显著性。在术后第 1天，A组与 C
组相卜较（A：106．47士SO．11p咖＊C：45．46士28＊7pg加1；P－0＊016），差异有非常显
著性，而M组与C组相 卜较（M：69．80士4．46＊＊m卜C：45．＊士28＊7＊ml二
P司．1723人 差异己无显著性。】囚L土 在 CPB开始后 10分，A组与 C组相比
较（A：106＊2130．56Pg／ml，C：312．13＝I＝306．18Pg／gi；P－0＊087），差异有非常显著性，
而M组与C组相卜较（M：54．31土4O．36 pg／ffil，C：3 12．13土306．18pg／ttil；P一0＊041），
差异也有非常显著性。在停＊PB的3O分，A组与C组相L较（A：558．95土197．79p以ml，
C：956刀0f248．35pg／ttil；P一0刀006），差异有非常显著性，而 M组与 C组相卜较（M：
68．7时24．52 p令二1，C：956＊0土248．35pg／ffil；P－0＊129），差异有显著性。在术后
第1天卫A组与C组相卜较（A：516．41幻66．85p咖1多C：991．21幻63．11赂二1；
4
安徽医科大学硕士学位论文
卜O刀067），差异有非常显著性，而M组与
Objective: To try to find out laws of cytokines (including IL-6, IL-8, IL-10 and TNF-
a) occuring and developing both during inflammatory response to cardiopulmonary
bypass and under intervention treatments, while to observe the every patient抯 clinical
manifestations of inflammatory response to cardiopulmonary bypass at the same time.
Methods: 30 patients having diagnosed as Cl-ID VSD ( congenital heart disease,
membranous ventricular septal defect ) were randomized into A (Aprotinin, 10 cases),
M ( Methylprednisolone, 10 cases) and C (Control, 10 cases) group. They all were
balanced into 3 groups according to 憄rinciple of the least fractions adding up?by age,
sex, body weight, using aortic cross-clamp or not and VSD needing patching or not
during operations. In group A, Aprotinin (2,500,000KW ) were added to extracorporeal
circulation machine and in group M, Methylprednisolone ( 200mg ) were also given
into the heart-lung machine, while in group C, only the standard anaesthetic techniques
and operative procedures were to be used. In each group, blood samples were taken
from the radial artery at the following times: after induction of anaesthesia, 10 minutes
after the start of CPB, and the 1st, 3rd and 7th day of post-operation ( 7AM ). Blood
( 2ml every time ) was drawn into EDTA ( ethylene-diamine-tetraacetic-acid ) tubes.
8
After centrifugation for 10 minutes ( 2000g at 400), plasma samples were frozen
immediately in aliquots at ~300C and were thawed only before testing. The first part,
experiment investigation, cytokines levels determined by enzyme-linked
immunosorbent assay ( commercial test kits of YES BLOTECH LABORATORIES
LTD, Canada ). All values were measured twice, extinction rate was determined at a
wave length of 405 nm. The second part, clinical study, all clinical markers, involving
functions of breath and circulatory system and others, were be recorded at the same
times. All data were given as mean + standard. For a comparison between the groups,
analysis of variance (Repeated Design ANOVA, SAS 6.12 ) was performed. A P value
of less than 0.05 was considered to indicate statistical significance. Resu1ts:.1b.e....fir~
part experiment investigation IL~ There are statistical significances between group A
and C (A: 40.78+16.l9pg/ml, C: 135.45+86.97pg/ml; P0.0004) and group M and C (M:
56.67+24.24pg/ml, C: 135.45+86.97pgIml; P0.0025) at 30 mm after the end of CPB.
JL~8 There are statistical significances between group A and C (A: 82.34?3.42pg/ml,
C: 134.61+41.93pg/ml; P0.00l7) and there are no statistical significances between
group M and C (M: 106.12+32.57pg/ml, C: 134.61+41.93pglml; P0.0680) at 30 mm
after the end of CPB. There are statistical significances between group A and C (A:
21.81+6.37pg/ml, C: 30.98?1.47pg/ml; P==0.0310) and group M and C (M:
21.79+8.46pg/ml, C: 30.98+11.47pg/ml; P0.0305) at the 1st day of post-operation.
There are statistical significances between group A and C (A: 4l.86+14.35pg/ml, C:
75.39+31 .43pg/ml; P0.0080) and there are no statistical significances between group
M and C (M: 63.83+29.38pg/ml, C: 75.39?1.43pg/ml; P0.3322) at the 3rd day of
post-operation. J.L4Q There are statistical significances between group A and C (A:
106.62+30.56pg/ml, C: 57.83+32.7Opg/ml; P=0.0026) and group M and C (M:
93.30?5.38pg/ml, C: 57.83+32.7OpgIml; P0.0232) at 10 minutes after the start of
CPB . There are statistical significances between group A a
炎症反应中的发生发展规律及它们在干预性治疗下的发生发展规律；并在相同时
点同时观察每组患者体外循环炎症反应临床表现的变化规律。方法：随机选取30
例6-12岁的“先天性心脏病：膜部室间隔缺损”患者，分成3组（根据：年龄、
性别、体重、手术中有无阻断升主动脉和有无室缺补片等因素采用：“积分之和
最小”原则均衡3组患者），其中：A组（抑肽酶组，Aprotinin）、M组（甲基强
的松龙组，Methylprednisolone）和C组（对照组，Control），每组10例。A组
患者在体外循环机器的预冲液中加入抑肽酶2,500,000KIU（500,000KIU/支×5
支）；M组患者在体外循环机器的预冲液中加入甲基强的松龙200mg（40mg/支×
5支）；C组患者的体外循环机器的预冲液中不加入其它的药物而作为对照。并在：
麻醉诱导插管后手术前、体外循环开始后10分钟的即刻、体外循环停机后30分
钟的即刻、术后第1天（早晨7时，后同）、术后第3天和术后第7天6个时点
采集患者的血液标本，每次2ml，立即注入含有EDTA的抗凝管中，离心分离的
血浆立即置-30℃冰箱中冷藏。第一部分，实验研究：采用ELISA法测定这6个
时段患者血浆中的白细胞介素-6，8，10和肿瘤坏死因子-α的值（pg/ml），并进行
各组的数值分析和比较；第二部分，临床研究：同时在以上采血的6个时点观察
记录：各项临床指标（包括：反映呼吸和循环系统功能指标及其它各项指标），
安徽医科大学硕士学位论文
并作各组数值的分析和比较。结果：实验部分：凡贞：在停CPB的30分，A组
与C组相卜较（A：叩厂8土16．19晗ml，C：135．巧比6．97晗m1Z卜0刀004），M组与C
组相卜较（M：56＊7士24．24Pg／ITll，C：135．45土86．97pg／ITll；2－0＊025），差异均有非常
显著性；u上丑：在停＊＊B的3O分，A组与C组相卜较（A：82．34土23．42帕加乙C：
134．61士41．93pg加1；P一0＊017），差异有非常显著性，而M组与C组相卜较（M：
106．12幻2．57晗M，C：门4石1H1．93阳／ml；卜0刀68O），差异无显著性。在术后第1
天，A组与C组十比较（A：21．81坊．37略二1，C：30．98土11．47pg／ttil；卜0刀引0），差
异有显著性，而M组与C组相比较（M：21．79士8．46pg／ffil，C：30．98到1．47Pg／ml；
P－0刀305），差异有显著性。在术后第3天，A组与C组相卜较（A：41．86士14．35p＊ml，
C：75．39土＊斗3阻加1；卜0＊08O），差异有非常显著性，而M组与C组相卜较（M：
63．83129．38pg／ml，C：75．39土刀．43pg／ml；P二0．3322），差异己无显著性；thin：在
＊PB开始后10 分，A组与C组相卜较（A：106＊2士30．5＊咖1，C：57．83士32．70p＊ml；
＊－0＊026），差异有非常显著性，而M组与C组相卜较（M：93．30幻5．38＊加1，C：
57．83土32．70pg／ffil；P＝0＊232），差异有显著性。在停 CPB的 30分，A组与 C组相
卜较（A：刀0．33土127石2晗二1，C：旧9．叩幻8．57pg／ffil；P一0刀001），差异有非常显著
性，而M组与C组相卜较（M：525．16士149．47pg／thl，C：189．46土58．57p咖IZ
P－0＊00），差异有非常显著性，而A组与M组相b较（A：720．33土127＊Zp＊二1，M：
525．16ti49．47pg／ml；P－0＊010），差异也有非常显著性。在术后第 1天，A组与 C
组相卜较（A：106．47士SO．11p咖＊C：45．46士28＊7pg加1；P－0＊016），差异有非常显
著性，而M组与C组相 卜较（M：69．80士4．46＊＊m卜C：45．＊士28＊7＊ml二
P司．1723人 差异己无显著性。】囚L土 在 CPB开始后 10分，A组与 C组相比
较（A：106＊2130．56Pg／ml，C：312．13＝I＝306．18Pg／gi；P－0＊087），差异有非常显著性，
而M组与C组相卜较（M：54．31土4O．36 pg／ffil，C：3 12．13土306．18pg／ttil；P一0＊041），
差异也有非常显著性。在停＊PB的3O分，A组与C组相L较（A：558．95土197．79p以ml，
C：956刀0f248．35pg／ttil；P一0刀006），差异有非常显著性，而 M组与 C组相卜较（M：
68．7时24．52 p令二1，C：956＊0土248．35pg／ffil；P－0＊129），差异有显著性。在术后
第1天卫A组与C组相卜较（A：516．41幻66．85p咖1多C：991．21幻63．11赂二1；
4
安徽医科大学硕士学位论文
卜O刀067），差异有非常显著性，而M组与
Objective: To try to find out laws of cytokines (including IL-6, IL-8, IL-10 and TNF-
a) occuring and developing both during inflammatory response to cardiopulmonary
bypass and under intervention treatments, while to observe the every patient抯 clinical
manifestations of inflammatory response to cardiopulmonary bypass at the same time.
Methods: 30 patients having diagnosed as Cl-ID VSD ( congenital heart disease,
membranous ventricular septal defect ) were randomized into A (Aprotinin, 10 cases),
M ( Methylprednisolone, 10 cases) and C (Control, 10 cases) group. They all were
balanced into 3 groups according to 憄rinciple of the least fractions adding up?by age,
sex, body weight, using aortic cross-clamp or not and VSD needing patching or not
during operations. In group A, Aprotinin (2,500,000KW ) were added to extracorporeal
circulation machine and in group M, Methylprednisolone ( 200mg ) were also given
into the heart-lung machine, while in group C, only the standard anaesthetic techniques
and operative procedures were to be used. In each group, blood samples were taken
from the radial artery at the following times: after induction of anaesthesia, 10 minutes
after the start of CPB, and the 1st, 3rd and 7th day of post-operation ( 7AM ). Blood
( 2ml every time ) was drawn into EDTA ( ethylene-diamine-tetraacetic-acid ) tubes.
8
After centrifugation for 10 minutes ( 2000g at 400), plasma samples were frozen
immediately in aliquots at ~300C and were thawed only before testing. The first part,
experiment investigation, cytokines levels determined by enzyme-linked
immunosorbent assay ( commercial test kits of YES BLOTECH LABORATORIES
LTD, Canada ). All values were measured twice, extinction rate was determined at a
wave length of 405 nm. The second part, clinical study, all clinical markers, involving
functions of breath and circulatory system and others, were be recorded at the same
times. All data were given as mean + standard. For a comparison between the groups,
analysis of variance (Repeated Design ANOVA, SAS 6.12 ) was performed. A P value
of less than 0.05 was considered to indicate statistical significance. Resu1ts:.1b.e....fir~
part experiment investigation IL~ There are statistical significances between group A
and C (A: 40.78+16.l9pg/ml, C: 135.45+86.97pg/ml; P0.0004) and group M and C (M:
56.67+24.24pg/ml, C: 135.45+86.97pgIml; P0.0025) at 30 mm after the end of CPB.
JL~8 There are statistical significances between group A and C (A: 82.34?3.42pg/ml,
C: 134.61+41.93pg/ml; P0.00l7) and there are no statistical significances between
group M and C (M: 106.12+32.57pg/ml, C: 134.61+41.93pglml; P0.0680) at 30 mm
after the end of CPB. There are statistical significances between group A and C (A:
21.81+6.37pg/ml, C: 30.98?1.47pg/ml; P==0.0310) and group M and C (M:
21.79+8.46pg/ml, C: 30.98+11.47pg/ml; P0.0305) at the 1st day of post-operation.
There are statistical significances between group A and C (A: 4l.86+14.35pg/ml, C:
75.39+31 .43pg/ml; P0.0080) and there are no statistical significances between group
M and C (M: 63.83+29.38pg/ml, C: 75.39?1.43pg/ml; P0.3322) at the 3rd day of
post-operation. J.L4Q There are statistical significances between group A and C (A:
106.62+30.56pg/ml, C: 57.83+32.7Opg/ml; P=0.0026) and group M and C (M:
93.30?5.38pg/ml, C: 57.83+32.7OpgIml; P0.0232) at 10 minutes after the start of
CPB . There are statistical significances between group A a
引文
1 Kirklin JK, Westaby S, Blackstone EH, et al. Complement and damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 183;86:845-857
2 Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552-559
3 Steinberg JB, Kapelanski DP, Olson JD, et al. Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 106:1008-1016
4 Casey LC. Role of cytokines in the pathogenesis of cardiopulmonary-induced multisystem organ failure. Ann Thorac Surg 1993;56:92-96
5 Schluter B, Konig B, Bergmann U, et al. Interleukin-6-A potential mediator of lethal sepsis after major thermal trauma: evidence for increased IL-6 production by peripheral blood mononuclear cells. J Trauma 1991;31:1663-1670
6 Cremer J, Haverich A, Borst HG, et al. Systemic inflammatory response after cardiac operations. Ann Thorac Surg 1996;61:1714-1720
7 Boyle Jr EM, Pohlman TH, Johson MC, et al. The systemic Inflammatory Response. Ann Thorac Surg 1997;64:31-37
8 Hennein HA, Ebba H, Rodriguez JR, et al. Relationship of the pro inflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg 1994; 108:626-635
9 Kalfin RE, Engelman RM, Rousou JA, et al. Induction of interleukin-8 expression during cardiopulmonary bypass. Circuation 1993;88:401-406
10 Dehoux M, Durand G. Early production of interleukin-10 during normothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995; 110:286287
11 Haring F, Hohenstein B, von der Emde J, et al. Immunomonitoring during and after
CPB for analysis of cytokine secretion patterns and developing of a preventive strategy of SIRS after cardiac surgery. Thorac Cardiovasc Surg 1997;45(Suppl. 1) :138
12 Hill GE, Diego RP, Stammers AH, et al. Aprotinin enhances the endogenous release of interleukin-10 after cardiac operations. Ann Thorac Surg 1998;65:66-69
13 Bruda NL, Hurlbert BJ, Hill GE. Aprotinin reduces nitric oxide production in vitro and in vivo in a dose-dependent manner. Clin Sci (Colch) 1998;94:505-509
14 Wan S, DeSmet JM, Barvais L, et al. Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996;112:806-811
15 Wan S, LeClerc JL, Schmartz D, et al. Hepatic release of interleukin-10 during cardiopulmonary bypass in steroid-pretreated patients. Am Heart J 1997; 133:335-339
16 Royston D, Bidstrup BP, Taylor KM, et al. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-1293
17 Bidstruyp BP, Royston D, McGuinessc KM. Aprotinin in aspirin-pretreated patients. Perfusion 1990;5(Suppl):77-83
18 Cosgrove DM 3d, Heric B, Lytte BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992;54:1031-1038
19 Tatar H, Cicek S, Demirkilic B, et al. Topical use of aprotinin in open heart operations. Ann Thorac Surg 1993;55:659-665
20 黄惠民，丁文祥，苏肇伉，等．抑肽酶在体外循环时小儿先心病手术中的应 用．中华胸心血管外科杂志，1994；10：205-207
21 华东平，朱洪生，俞美娟，等．抑肽酶在体外循环心脏外科的临床应用．中 华胸心血管外科杂志，1995；11：25-27
22 吴熹，马游，顾懋栋，等．体外循环时小剂量抑肽酶对纤溶系统和血小 板的影响．中华胸心血管外科杂志，1996；12：146-148
23 曹彬，房士琦，李清泉，等．抑肽酶抑制体外循环期间血小板激活反应．中 华胸心血管外科杂志，1997；13：25-27
24 Seghaye MC, Duchateau J, Grabitz RG, et al. Influence of low-dose aprotinin on the inflammatory reaction due to cardiopulmonary bypass in children. Ann Thorac Surg 1996;61:1205-1211
25 Hill GE, Springall DR, Robbins RA. Aprotinin is associated with a decrease in nitric oxide production during cardiopulmonary bypass. Surgery 1997;121:449-455
26 Davies MJ, Allen A, Kort H, et al. Prospective, randomized, double-blind study of high-dose aprotinin in pediatric cardiac operations. Ann Thorac Surg 1997;63:497-503
27 Ashraf S, Tian Y, Cowan D, et al. "Low-dose" aprotinin modifies hemostasis but not proinflammatory cytokine release. Ann Thorac Surg 1997;63:68-73
28 Shirasawa B, Hamano K, Gohra H, et al. Dose the administration of low-dose aprotinin conyribute to an anti-inflammatory effect in coronary artery bypass grafting? Kyobu Geka 1999;52:943-945
29 Harig F, Feyrer R, Mahmoud FO, et al. Reducing the post-pump syndrome by using heparin-coated circuits, steroids, or aprotinin. Thorac Cardiovasc Surg 1999;47:111-118
30 Denizot Y, Feiss P, Nathan N. Are lipid mediators implicated in the production of pro-and anti-inflammatory cytokines during cardiopulmonary bypass graft with extracorporeal circulation? Cytokine 1999; 11:301-304
31 Tassani P, Richter JA, Barankay A, et al. Dose high-dose methylprednisolone in aprotinin-treated patients attenuate the systemic inflammatory response during coronary artery bypass grafting procedures? J Cardiothorac Vasc Anesth 1999;13:165-172
32 Parolari A, Alamanni F, Gherli T, er al. 'High dose' aprotinin and heparin-coated circuits: clinical efficacy and inflammatory response. Cardiovasc Surg 1999;7:117-127
33 Osaka M, Fukuda I, Ohuchi H. Aprotinin and recombinant human erythropoietin reduce the need for homologous blood transfusion in cardiac surgery. JPN J Thorac Cardiovasc Surg 1998;46:846-853
34 王强，刘迎龙，朱晓东，等．含抑肽酶低温灌注液减轻体外循环肺损伤．中 华胸心血管外科杂志，1999；15：177-179
35 曹心来，胡小琴，李韶然．抑肽酶剂量对体外循环炎性反应的作用及影响．中 华胸心血管外科杂志，2001；17：25-26
36 夏家红，肖诗亮，李伦明，等．白介素-10 在心脏移植排斥反应中的表达及机 制．中华胸心血管外科杂志，2001；17：32-34
37 院存珍，唐进，王子林．大剂量抑肽酶对心肌缺血再灌注损伤的保护作用．中 华胸心血管外科杂志，2001；17：35-37
38 Homles AFA. The disulphide linkages in kallekrein inactivator of bovine iung. J Biol Chem 1966;241:1568-1663
39 Snudt TM 3d, Kouchoukos NT, Saffiftz JE, et al. Renal dysfunction and intravascular coagulation with aprtinin and hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418-1426
40 Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993;55:1033-1039
41 Gillinov MA, Redmond M, Zehr KJ. Inhibition of neutrophil adhesion during cardiopulmonary bypass. 1994;57:126-133
42 Boldt J, Knothe C, Zickmann B, rt al. Platelet function in cardiac surgery: influence of temperature and aprotinin. Ann Thorac Surg 1993;55:652-659
43 Lavee J, Raviv Z, Smolinsky A, et al. Platelet protection by low-dose aprotinin in cardiopulmonary bypass: electron microscopic study. Ann Thorac Surg 1993;55:114-117
44 Wenger RK, Lukasiewicz H, Mikuta BC, et al. Loss of piatelet fibrinogen receptors during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989;97:235-239
45 Van Oevreen W, Harder MP, Roozendaal KJ, et al. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99;788-794
46 Kawasuji M, Ueyama K, Sakakibara N, et al. Effect of low-dose aprotinin on coagulation and fibrinolysis in cardiopulmonary bypass. Ann Thorac Surg
1993;55:1205-1209
47 Heimark RL, Kurachi K, Fujikawa K, et al. Surface activation of blood coagulation, fibrinolysis and kinin formation. Nature 1980;286:456-461
48 Horder MP, Eijsman L, Wildevuur CRH, et al. Increased anticoagulation during cardiopulmonary bypass by aprotinin. J Thorac Cardiovasc Surg 1990; 100:52-59
49 Butler J, Chong GL, Baigrie RJ, et al. Cytokine responses to cardiopulmonary bypass with membrane and bubble oxygention. Ann Thorac Surg 1992;53:833-836
50 Espana F, Estelles A, Griffin JH, et al. Aprotinin (trasylol) is a campetitive inhibitor of activated protein C. Thromb Res 1989;56:751-757
2 Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552-559
3 Steinberg JB, Kapelanski DP, Olson JD, et al. Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 106:1008-1016
4 Casey LC. Role of cytokines in the pathogenesis of cardiopulmonary-induced multisystem organ failure. Ann Thorac Surg 1993;56:92-96
5 Schluter B, Konig B, Bergmann U, et al. Interleukin-6-A potential mediator of lethal sepsis after major thermal trauma: evidence for increased IL-6 production by peripheral blood mononuclear cells. J Trauma 1991;31:1663-1670
6 Cremer J, Haverich A, Borst HG, et al. Systemic inflammatory response after cardiac operations. Ann Thorac Surg 1996;61:1714-1720
7 Boyle Jr EM, Pohlman TH, Johson MC, et al. The systemic Inflammatory Response. Ann Thorac Surg 1997;64:31-37
8 Hennein HA, Ebba H, Rodriguez JR, et al. Relationship of the pro inflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg 1994; 108:626-635
9 Kalfin RE, Engelman RM, Rousou JA, et al. Induction of interleukin-8 expression during cardiopulmonary bypass. Circuation 1993;88:401-406
10 Dehoux M, Durand G. Early production of interleukin-10 during normothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995; 110:286287
11 Haring F, Hohenstein B, von der Emde J, et al. Immunomonitoring during and after
CPB for analysis of cytokine secretion patterns and developing of a preventive strategy of SIRS after cardiac surgery. Thorac Cardiovasc Surg 1997;45(Suppl. 1) :138
12 Hill GE, Diego RP, Stammers AH, et al. Aprotinin enhances the endogenous release of interleukin-10 after cardiac operations. Ann Thorac Surg 1998;65:66-69
13 Bruda NL, Hurlbert BJ, Hill GE. Aprotinin reduces nitric oxide production in vitro and in vivo in a dose-dependent manner. Clin Sci (Colch) 1998;94:505-509
14 Wan S, DeSmet JM, Barvais L, et al. Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996;112:806-811
15 Wan S, LeClerc JL, Schmartz D, et al. Hepatic release of interleukin-10 during cardiopulmonary bypass in steroid-pretreated patients. Am Heart J 1997; 133:335-339
16 Royston D, Bidstrup BP, Taylor KM, et al. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-1293
17 Bidstruyp BP, Royston D, McGuinessc KM. Aprotinin in aspirin-pretreated patients. Perfusion 1990;5(Suppl):77-83
18 Cosgrove DM 3d, Heric B, Lytte BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992;54:1031-1038
19 Tatar H, Cicek S, Demirkilic B, et al. Topical use of aprotinin in open heart operations. Ann Thorac Surg 1993;55:659-665
20 黄惠民，丁文祥，苏肇伉，等．抑肽酶在体外循环时小儿先心病手术中的应 用．中华胸心血管外科杂志，1994；10：205-207
21 华东平，朱洪生，俞美娟，等．抑肽酶在体外循环心脏外科的临床应用．中 华胸心血管外科杂志，1995；11：25-27
22 吴熹，马游，顾懋栋，等．体外循环时小剂量抑肽酶对纤溶系统和血小 板的影响．中华胸心血管外科杂志，1996；12：146-148
23 曹彬，房士琦，李清泉，等．抑肽酶抑制体外循环期间血小板激活反应．中 华胸心血管外科杂志，1997；13：25-27
24 Seghaye MC, Duchateau J, Grabitz RG, et al. Influence of low-dose aprotinin on the inflammatory reaction due to cardiopulmonary bypass in children. Ann Thorac Surg 1996;61:1205-1211
25 Hill GE, Springall DR, Robbins RA. Aprotinin is associated with a decrease in nitric oxide production during cardiopulmonary bypass. Surgery 1997;121:449-455
26 Davies MJ, Allen A, Kort H, et al. Prospective, randomized, double-blind study of high-dose aprotinin in pediatric cardiac operations. Ann Thorac Surg 1997;63:497-503
27 Ashraf S, Tian Y, Cowan D, et al. "Low-dose" aprotinin modifies hemostasis but not proinflammatory cytokine release. Ann Thorac Surg 1997;63:68-73
28 Shirasawa B, Hamano K, Gohra H, et al. Dose the administration of low-dose aprotinin conyribute to an anti-inflammatory effect in coronary artery bypass grafting? Kyobu Geka 1999;52:943-945
29 Harig F, Feyrer R, Mahmoud FO, et al. Reducing the post-pump syndrome by using heparin-coated circuits, steroids, or aprotinin. Thorac Cardiovasc Surg 1999;47:111-118
30 Denizot Y, Feiss P, Nathan N. Are lipid mediators implicated in the production of pro-and anti-inflammatory cytokines during cardiopulmonary bypass graft with extracorporeal circulation? Cytokine 1999; 11:301-304
31 Tassani P, Richter JA, Barankay A, et al. Dose high-dose methylprednisolone in aprotinin-treated patients attenuate the systemic inflammatory response during coronary artery bypass grafting procedures? J Cardiothorac Vasc Anesth 1999;13:165-172
32 Parolari A, Alamanni F, Gherli T, er al. 'High dose' aprotinin and heparin-coated circuits: clinical efficacy and inflammatory response. Cardiovasc Surg 1999;7:117-127
33 Osaka M, Fukuda I, Ohuchi H. Aprotinin and recombinant human erythropoietin reduce the need for homologous blood transfusion in cardiac surgery. JPN J Thorac Cardiovasc Surg 1998;46:846-853
34 王强，刘迎龙，朱晓东，等．含抑肽酶低温灌注液减轻体外循环肺损伤．中 华胸心血管外科杂志，1999；15：177-179
35 曹心来，胡小琴，李韶然．抑肽酶剂量对体外循环炎性反应的作用及影响．中 华胸心血管外科杂志，2001；17：25-26
36 夏家红，肖诗亮，李伦明，等．白介素-10 在心脏移植排斥反应中的表达及机 制．中华胸心血管外科杂志，2001；17：32-34
37 院存珍，唐进，王子林．大剂量抑肽酶对心肌缺血再灌注损伤的保护作用．中 华胸心血管外科杂志，2001；17：35-37
38 Homles AFA. The disulphide linkages in kallekrein inactivator of bovine iung. J Biol Chem 1966;241:1568-1663
39 Snudt TM 3d, Kouchoukos NT, Saffiftz JE, et al. Renal dysfunction and intravascular coagulation with aprtinin and hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418-1426
40 Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993;55:1033-1039
41 Gillinov MA, Redmond M, Zehr KJ. Inhibition of neutrophil adhesion during cardiopulmonary bypass. 1994;57:126-133
42 Boldt J, Knothe C, Zickmann B, rt al. Platelet function in cardiac surgery: influence of temperature and aprotinin. Ann Thorac Surg 1993;55:652-659
43 Lavee J, Raviv Z, Smolinsky A, et al. Platelet protection by low-dose aprotinin in cardiopulmonary bypass: electron microscopic study. Ann Thorac Surg 1993;55:114-117
44 Wenger RK, Lukasiewicz H, Mikuta BC, et al. Loss of piatelet fibrinogen receptors during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989;97:235-239
45 Van Oevreen W, Harder MP, Roozendaal KJ, et al. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99;788-794
46 Kawasuji M, Ueyama K, Sakakibara N, et al. Effect of low-dose aprotinin on coagulation and fibrinolysis in cardiopulmonary bypass. Ann Thorac Surg
1993;55:1205-1209
47 Heimark RL, Kurachi K, Fujikawa K, et al. Surface activation of blood coagulation, fibrinolysis and kinin formation. Nature 1980;286:456-461
48 Horder MP, Eijsman L, Wildevuur CRH, et al. Increased anticoagulation during cardiopulmonary bypass by aprotinin. J Thorac Cardiovasc Surg 1990; 100:52-59
49 Butler J, Chong GL, Baigrie RJ, et al. Cytokine responses to cardiopulmonary bypass with membrane and bubble oxygention. Ann Thorac Surg 1992;53:833-836
50 Espana F, Estelles A, Griffin JH, et al. Aprotinin (trasylol) is a campetitive inhibitor of activated protein C. Thromb Res 1989;56:751-757