抑肽酶对心脏外科术后结果的影响及氨甲环酸在心脏外科的初步研究
|
摘要
第一部分:成人心脏外科手术停用抑肽酶前、后围术期结果的比较
目的:比较心脏外科术中停用抑肽酶前、后的围术期结果,进一步探讨在心脏外科患者中抑肽酶的作用及安全性。
方法:回顾分析阜外心血管病医院停用抑肽酶前、后各6个月的患者资料,所有入选患者均在体外循环下进行心脏外科手术,且年龄均大于18岁。2007年6月19日至2007年12月18日的接受心脏手术且术中使用抑肽酶的患者定义为抑肽酶组;2007年12月19日至2008年06月18日的手术患者定义为对照组,入选患者在术中均未用抑肽酶。比较两组围术期结果,终点事件包括术后失血量、输血量、二次开胸发生率、住院死亡率及心、脑、肾、肺等重大并发症的发生率。为进一步减少组间选择性偏倚,同时进行多因素Logistic回归分析,明确抑肽酶是否为术后死亡及重大并发症发生的独立危险因素。
结果:共入选患者3924例,其中抑肽酶组1699例,对照组2225例。抑肽酶组术后24小时出血量(402.5±267.3ml vs 628.1±378.2ml P＜0.001)、血浆用量(317.0±746.0ml v.s 400.5±724.2ml P＜0.001)、红细胞用量(2.6±5.8u v.s 3.2±5.6p=0.002)及因出血二次开胸(2.0%v.s 3.7%p=0.002)均显著低于对照组。两组住院死亡率无显著差异(0.5%v.s 1.0%p=0.08)。两组间术后肾功能不全、肾衰需要透析治疗、低心排综合症、神经系统并发症、严重肺部感染、再次气管插管及总并发症的发生率均无显著差异。抑肽酶组延迟拔管发生率低于对照组(8.8%v.s10.7%p=0.04),呼吸机使用时间也低于对照组(18.9±45.0hrs v.s 22.2±53.6hrsp=0.04),动脉血气分析氧分压指数(PO2/FiO2)高于对照组(535.2±221.2mmHg v.s505.8±214.8mmHg p＜0.001)。应用多因素Logistic回归分析后,得到的结果与初步比较的结果一致,即术中应用抑肽酶是术后二次开胸及延迟拔管的保护性因素,而不是术后死亡及其它重大并发症的独立危险因素。
结论:心脏外科手术中使用抑肽酶可以明显降低术后出血量、输血量及因出血二次开胸的发生率,且对术后肺功能有一定的保护作用,但没有增加围术期死亡率和重大并发症的发生率。在国内乃至整个亚洲心脏外科患者中是否应该停用抑肽酶还需要进一步研究来确定。
第二部分:抑肽酶对冠状动脉旁路移植术后近、远期结果的影响
目的:评价国人冠状动脉旁路移植术中应用抑肽酶对术后近、远期结果的影响。
方法:回顾分析1999年1月～2005年12月在阜外心血管病医院接受单纯冠状动脉旁路移植手术(CABG)的患者的住院资料,根据术中是否应用抑肽酶分为两组,比较两组术后近、远期死亡率及心、脑、肾等重大并发症发生率。分别应用多因素Logistic回归和Cox回归对近期结果和远期结果进行分析,同时采用倾向性评分调整及组间配对的方法,进一步减少组间选择性偏倚。
结果:入选患者5103例,抑肽酶组4122例,非抑肽酶组981例。两组术后早期结果比较:抑肽酶组术后24小时出血量明显减少(462.4±251.7 vs 739.5±342.4p＜0.001)。ICU停留时间(78.45±101.45hrs vs 77.47±81.06hrs P=0.84)、呼吸机辅助通气时间(20.59±67.59hrs vs 19.02±44.81hrs P=0.62)无显著性差异。两组比较肾脏、心脏、脑血管并发症、总的并发症发生率及住院死亡率均未见显著差异。术后远期成功随访4893例患者,随访成功率97.0%,中位随访时间59.3个月。远期随访结果比较:两组远期死亡率、心肌梗死、冠脉再次血管化率、脑中风和主要不良心脑血管事件(MACCE)发生率均无显著性差异。应用多因素回归分析和倾向性评分调整及组间配对的方法,得到的结果与初步比较的结果一致,即术中应用抑肽酶不是术后近期死亡及心、脑、肾重大并发症的独立危险因素,也不是远期随访死亡及MACCE事件的独立危险因素。
结论:单纯冠状动脉旁路移植手术患者在手术中使用抑肽酶可以明显降低术后出血量,但没有增加术后近、远期死亡率和并发症的发生率。抑肽酶在国内CABG患者中的应用是安全有效的。
第三部分:氨甲环酸对非体外循环下冠状动脉旁路移植术后近期结果的影响
目的:观察氨甲环酸在非体外循环下冠状动脉旁路移植(OP-CABG)术中应用对术后结果的影响,初步探索氨甲环酸在国内心脏外科手术患者中的临床安全性及效果。
方法:前瞻性选择初次、择期非体外循环下冠状动脉旁路移植术患者,随机分为氨甲环酸试验组和对照组。试验组术中给予全量氨甲环酸,对照组不给予氨甲环酸或其它止血药物。收集患者术前、术中及术后资料并对两组围术期结果进行比较,终点事件包括术后出血量、输血量、二次开胸发生率、住院死亡率及心、脑、肾、肺等重大并发症的发生率。应用SPSS统计软件进行分析,P＜0.05认为有统计学显著性差异。
结果:共入选患者151例,其中氨甲环酸试验组75例,对照组76例。两组患者术前及术中基线资料进行比较,试验组平均体重(70.6±12.1 vs 75.0±9.8,p=0.02)、术前高血压比例(60.0%vs 76.3%,p=0.03)及术前吸烟患者比例(37.3%vs 57.9%,p=0.01)均低于对照组,其它基线资料比较均未见统计学显著差异。试验组术后各时间段出血量均显著低于对照组:术后6小时出血量(284.0±129.1ml vs 411.1±191.3mlp＜0.001),术后24小时出血量(701.1±269.5ml vs 915.9±310.1ml p＜0.001),术后48小时出血量(876.1±326.4ml vs 1120.0±454.6ml p＜0.001),术后总出血量(923.1±361.3ml vs 1215.8±651.1 p=0.001)。试验组血浆用量及红细胞用量均低于对照组,但未达到统计学显著差异。两组术后均无因出血二次开胸及住院期间死亡。两组间术后肾功能不全,脑部并发症,低心排综合症,再次气管插管,延迟拔管及总并发症的比较均未见统计学显著差异。两组间ICU停留时间,术后住院天数,术后呼吸机使用时间及术后24小时的动脉血气分析的氧分压指数(PaO2/FiO2)的比较也均无统计学显著差异。
结论:非体外循环下冠状动脉旁路移植术中应用全量氨甲环酸可明显减少术后出血量,但并未增加术后早期死亡率及重大并发症发生率,其应用是安全有效的。
Part one:
A comparison before and after aprotinin was suspended in cardiac surgery: Different results in real world from a single cardiac center of China.
Objective: Use of aprotinin has been suspended in cardiac surgery since recent studies reported its risks associated with mortality and other adverse events. This study was to investigate the safety and efficacy of aprotinin through a comparison before and after aprotinin was suspended in cardiac surgery.
Methods: We designed a case control study in two groups of patients who underwent cardiac surgery just before and after aprotinin was suspended in China. Aprotinin group (n=1699) was defined as operations from June 19,2007 to Dec 18,2007, when aprotinin was used in all the patients. Control group (n=2225) was defined as operations from Dec 19, 2007 to June 18, 2008, when aprotinin was not used. We compared early postoperative outcomes between the two groups.
Results: The aprotinin group had less postoperative blood loss, transfusion requirement and reoperation for bleeding. Application of aprotinin did not increase the risk of in-hospital mortality (0.5% vs. 1.0% p=0.08) and other major adverse outcome events, including renal, cardiac, neurological and pulmonary complications.
The aprotinin group had a shorter mechanical ventilation time (p=0.04), a lower rate of delayed mechanical ventilation time (p=0.04) and a higher PaO2/FiO2 in arterial blood gas analysis (p<0.001). Multivariable Logistic regression analysis confirmed findings from univariate analysis. After propensity adjustment for the baseline characteristics, we got similar results.
Conclusions: Use of aprotinin in cardiac surgery could reduce blood loss and transfusion requirement significantly, and showed a protective effect on the lungs, but did not increase the risk of mortality or major complications.
Part two:
Does Aprotinin Really Increase the Mortality and Complications after Coronary Surgery?—Different Short-term and Long-term Outcomes from Chinese Population.
Objective: Recent studies about aprotinin demonstrated that its use would increase the mortality and complications after coronary artery bypass grafting (CABG). This study was to investigate effect of aprotinin during isolated primary CABG on postoperative short-term and long-term outcomes in patients of Chinese population.
Methods: We studied 5103 consecutive Chinese patients who underwent isolated primary CABG at a single cardiac center from January 1, 1999 to December 31, 2005. Of all the patients, 4122 received aprotinin during operation (aprotinin grouop) and 981 received no aprotinin or other antifibrinolytic therapy (control group). Short-term complications and mortality after operation were analyzed with multivariable logistic regression analysis. Long-term mortality and major adverse cardiac and cerebrovascular events (MACCEs) were analyzed with Cox regression analysis. Propensity adjustment method was used to minimize the selection bias between the two groups, and propensity matching method was used to yield two well-matched groups for further comparison.
Results: Blood loss after operation was significantly reduced in aprotinin group as compared with that in the control group (462.4±251.7 vs 739.5±342.4 p<0.001). Application of aprotinin was not associated with the perioperative mortality (1.2% vs 1.0% p=0.57) and other main complications. Multivariable Logistic regression analysis confirmed the initial results. In the Cox regression analysis, use of aprotinin was not associated with the the long-term mortality (p=0.21 , relative risk, 1.26; 95% CI, 0.88 to 1.82) and MACCEs (p=0.82, relative risk, 0.98; 95% CI, 0.84 to 1.15). After propensity adjustment for the baseline characteristics, we got similar results. In addition, comparison between the two well-matched groups showed no significant difference either in baseline characteristics or in postoperative outcome events.
Conclusions: Application of aprotinin during isolated primary CABG could reduce the blood loss significantly, but was not associated with the short-term or long-term mortality and complications. Aprotinin during primary CABG in Chinese (Asian) population might be safe and effective.
Part 3:
Effects of tranexamic acid on postoperative outcomes in patients undergoing off-pump coronary artery bypass grafting.
Objective: Tranexamic acid is being used more and more in cardiac surgery after aprotinin was suspended for its safety concerns. This study was to investigate the safety and efficacy of tranexamic acid in patients undergoing off-pump coronary artery bypass grafting.
Methods: 151 selective patients undergoing off-pump coronary artery bypass grafting were randomly assigned to two groups: tranexamic acid group and control group. FuII-dose tranexamic acid was administered in tranexamic acid group but no tranexamic acid was used in control group. We compared early postoperative outcomes between the two groups, including blood loss, transfusion requirement, reoperation for bleeding, mortality and other major complications. All analyses were performed using SPSS statistical software (version 11.0). Statistical significance was set at P<0.05.
Results: There were 75 patients in the tranexamic acid group and 76 patients in the control group. The comparison of baseline characteristics showed no significant difference between two groups except weight, rate of hypertention and smoking. The tranexamic acid group had less postoperative blood loss: 6 hours (284.0+ 129. 1ml vs 411.1±191.3ml p<0.001), 24hours (701.1±269. 5ml vs 915. 9±310. 1ml p<0.001), 48 hours (876.1±326.4ml vs 1120.0±454. 6ml p<0.001), and total blood loss (923.1±361. 3ml vs 1215. 8±651.1 p=0.001) . Transfusion requirement in the tranexamic acid group was less than the control group, but did not reach statistically significant difference. There were no reoperation for bleeding and death after operation. Application of tranexamic acid did not increase the risk of other major adverse outcome events, including renal, cardiac, neurological and pulmonary complications. Furthermore, there were no significant difference in the length of ICU stay, length of in-hospital stay, total mechanical ventilation time, and PaO2/FiO2 in the blood gas analysis of 24 hours after operation.
Conclusions: Use of tranexamic acid in patients undergoing off-pump coronary artery bypass grafting could reduce blood loss significantly, but did not increase the risk of mortality or major complications.
目的:比较心脏外科术中停用抑肽酶前、后的围术期结果,进一步探讨在心脏外科患者中抑肽酶的作用及安全性。
方法:回顾分析阜外心血管病医院停用抑肽酶前、后各6个月的患者资料,所有入选患者均在体外循环下进行心脏外科手术,且年龄均大于18岁。2007年6月19日至2007年12月18日的接受心脏手术且术中使用抑肽酶的患者定义为抑肽酶组;2007年12月19日至2008年06月18日的手术患者定义为对照组,入选患者在术中均未用抑肽酶。比较两组围术期结果,终点事件包括术后失血量、输血量、二次开胸发生率、住院死亡率及心、脑、肾、肺等重大并发症的发生率。为进一步减少组间选择性偏倚,同时进行多因素Logistic回归分析,明确抑肽酶是否为术后死亡及重大并发症发生的独立危险因素。
结果:共入选患者3924例,其中抑肽酶组1699例,对照组2225例。抑肽酶组术后24小时出血量(402.5±267.3ml vs 628.1±378.2ml P＜0.001)、血浆用量(317.0±746.0ml v.s 400.5±724.2ml P＜0.001)、红细胞用量(2.6±5.8u v.s 3.2±5.6p=0.002)及因出血二次开胸(2.0%v.s 3.7%p=0.002)均显著低于对照组。两组住院死亡率无显著差异(0.5%v.s 1.0%p=0.08)。两组间术后肾功能不全、肾衰需要透析治疗、低心排综合症、神经系统并发症、严重肺部感染、再次气管插管及总并发症的发生率均无显著差异。抑肽酶组延迟拔管发生率低于对照组(8.8%v.s10.7%p=0.04),呼吸机使用时间也低于对照组(18.9±45.0hrs v.s 22.2±53.6hrsp=0.04),动脉血气分析氧分压指数(PO2/FiO2)高于对照组(535.2±221.2mmHg v.s505.8±214.8mmHg p＜0.001)。应用多因素Logistic回归分析后,得到的结果与初步比较的结果一致,即术中应用抑肽酶是术后二次开胸及延迟拔管的保护性因素,而不是术后死亡及其它重大并发症的独立危险因素。
结论:心脏外科手术中使用抑肽酶可以明显降低术后出血量、输血量及因出血二次开胸的发生率,且对术后肺功能有一定的保护作用,但没有增加围术期死亡率和重大并发症的发生率。在国内乃至整个亚洲心脏外科患者中是否应该停用抑肽酶还需要进一步研究来确定。
第二部分:抑肽酶对冠状动脉旁路移植术后近、远期结果的影响
目的:评价国人冠状动脉旁路移植术中应用抑肽酶对术后近、远期结果的影响。
方法:回顾分析1999年1月～2005年12月在阜外心血管病医院接受单纯冠状动脉旁路移植手术(CABG)的患者的住院资料,根据术中是否应用抑肽酶分为两组,比较两组术后近、远期死亡率及心、脑、肾等重大并发症发生率。分别应用多因素Logistic回归和Cox回归对近期结果和远期结果进行分析,同时采用倾向性评分调整及组间配对的方法,进一步减少组间选择性偏倚。
结果:入选患者5103例,抑肽酶组4122例,非抑肽酶组981例。两组术后早期结果比较:抑肽酶组术后24小时出血量明显减少(462.4±251.7 vs 739.5±342.4p＜0.001)。ICU停留时间(78.45±101.45hrs vs 77.47±81.06hrs P=0.84)、呼吸机辅助通气时间(20.59±67.59hrs vs 19.02±44.81hrs P=0.62)无显著性差异。两组比较肾脏、心脏、脑血管并发症、总的并发症发生率及住院死亡率均未见显著差异。术后远期成功随访4893例患者,随访成功率97.0%,中位随访时间59.3个月。远期随访结果比较:两组远期死亡率、心肌梗死、冠脉再次血管化率、脑中风和主要不良心脑血管事件(MACCE)发生率均无显著性差异。应用多因素回归分析和倾向性评分调整及组间配对的方法,得到的结果与初步比较的结果一致,即术中应用抑肽酶不是术后近期死亡及心、脑、肾重大并发症的独立危险因素,也不是远期随访死亡及MACCE事件的独立危险因素。
结论:单纯冠状动脉旁路移植手术患者在手术中使用抑肽酶可以明显降低术后出血量,但没有增加术后近、远期死亡率和并发症的发生率。抑肽酶在国内CABG患者中的应用是安全有效的。
第三部分:氨甲环酸对非体外循环下冠状动脉旁路移植术后近期结果的影响
目的:观察氨甲环酸在非体外循环下冠状动脉旁路移植(OP-CABG)术中应用对术后结果的影响,初步探索氨甲环酸在国内心脏外科手术患者中的临床安全性及效果。
方法:前瞻性选择初次、择期非体外循环下冠状动脉旁路移植术患者,随机分为氨甲环酸试验组和对照组。试验组术中给予全量氨甲环酸,对照组不给予氨甲环酸或其它止血药物。收集患者术前、术中及术后资料并对两组围术期结果进行比较,终点事件包括术后出血量、输血量、二次开胸发生率、住院死亡率及心、脑、肾、肺等重大并发症的发生率。应用SPSS统计软件进行分析,P＜0.05认为有统计学显著性差异。
结果:共入选患者151例,其中氨甲环酸试验组75例,对照组76例。两组患者术前及术中基线资料进行比较,试验组平均体重(70.6±12.1 vs 75.0±9.8,p=0.02)、术前高血压比例(60.0%vs 76.3%,p=0.03)及术前吸烟患者比例(37.3%vs 57.9%,p=0.01)均低于对照组,其它基线资料比较均未见统计学显著差异。试验组术后各时间段出血量均显著低于对照组:术后6小时出血量(284.0±129.1ml vs 411.1±191.3mlp＜0.001),术后24小时出血量(701.1±269.5ml vs 915.9±310.1ml p＜0.001),术后48小时出血量(876.1±326.4ml vs 1120.0±454.6ml p＜0.001),术后总出血量(923.1±361.3ml vs 1215.8±651.1 p=0.001)。试验组血浆用量及红细胞用量均低于对照组,但未达到统计学显著差异。两组术后均无因出血二次开胸及住院期间死亡。两组间术后肾功能不全,脑部并发症,低心排综合症,再次气管插管,延迟拔管及总并发症的比较均未见统计学显著差异。两组间ICU停留时间,术后住院天数,术后呼吸机使用时间及术后24小时的动脉血气分析的氧分压指数(PaO2/FiO2)的比较也均无统计学显著差异。
结论:非体外循环下冠状动脉旁路移植术中应用全量氨甲环酸可明显减少术后出血量,但并未增加术后早期死亡率及重大并发症发生率,其应用是安全有效的。
Part one:
A comparison before and after aprotinin was suspended in cardiac surgery: Different results in real world from a single cardiac center of China.
Objective: Use of aprotinin has been suspended in cardiac surgery since recent studies reported its risks associated with mortality and other adverse events. This study was to investigate the safety and efficacy of aprotinin through a comparison before and after aprotinin was suspended in cardiac surgery.
Methods: We designed a case control study in two groups of patients who underwent cardiac surgery just before and after aprotinin was suspended in China. Aprotinin group (n=1699) was defined as operations from June 19,2007 to Dec 18,2007, when aprotinin was used in all the patients. Control group (n=2225) was defined as operations from Dec 19, 2007 to June 18, 2008, when aprotinin was not used. We compared early postoperative outcomes between the two groups.
Results: The aprotinin group had less postoperative blood loss, transfusion requirement and reoperation for bleeding. Application of aprotinin did not increase the risk of in-hospital mortality (0.5% vs. 1.0% p=0.08) and other major adverse outcome events, including renal, cardiac, neurological and pulmonary complications.
The aprotinin group had a shorter mechanical ventilation time (p=0.04), a lower rate of delayed mechanical ventilation time (p=0.04) and a higher PaO2/FiO2 in arterial blood gas analysis (p<0.001). Multivariable Logistic regression analysis confirmed findings from univariate analysis. After propensity adjustment for the baseline characteristics, we got similar results.
Conclusions: Use of aprotinin in cardiac surgery could reduce blood loss and transfusion requirement significantly, and showed a protective effect on the lungs, but did not increase the risk of mortality or major complications.
Part two:
Does Aprotinin Really Increase the Mortality and Complications after Coronary Surgery?—Different Short-term and Long-term Outcomes from Chinese Population.
Objective: Recent studies about aprotinin demonstrated that its use would increase the mortality and complications after coronary artery bypass grafting (CABG). This study was to investigate effect of aprotinin during isolated primary CABG on postoperative short-term and long-term outcomes in patients of Chinese population.
Methods: We studied 5103 consecutive Chinese patients who underwent isolated primary CABG at a single cardiac center from January 1, 1999 to December 31, 2005. Of all the patients, 4122 received aprotinin during operation (aprotinin grouop) and 981 received no aprotinin or other antifibrinolytic therapy (control group). Short-term complications and mortality after operation were analyzed with multivariable logistic regression analysis. Long-term mortality and major adverse cardiac and cerebrovascular events (MACCEs) were analyzed with Cox regression analysis. Propensity adjustment method was used to minimize the selection bias between the two groups, and propensity matching method was used to yield two well-matched groups for further comparison.
Results: Blood loss after operation was significantly reduced in aprotinin group as compared with that in the control group (462.4±251.7 vs 739.5±342.4 p<0.001). Application of aprotinin was not associated with the perioperative mortality (1.2% vs 1.0% p=0.57) and other main complications. Multivariable Logistic regression analysis confirmed the initial results. In the Cox regression analysis, use of aprotinin was not associated with the the long-term mortality (p=0.21 , relative risk, 1.26; 95% CI, 0.88 to 1.82) and MACCEs (p=0.82, relative risk, 0.98; 95% CI, 0.84 to 1.15). After propensity adjustment for the baseline characteristics, we got similar results. In addition, comparison between the two well-matched groups showed no significant difference either in baseline characteristics or in postoperative outcome events.
Conclusions: Application of aprotinin during isolated primary CABG could reduce the blood loss significantly, but was not associated with the short-term or long-term mortality and complications. Aprotinin during primary CABG in Chinese (Asian) population might be safe and effective.
Part 3:
Effects of tranexamic acid on postoperative outcomes in patients undergoing off-pump coronary artery bypass grafting.
Objective: Tranexamic acid is being used more and more in cardiac surgery after aprotinin was suspended for its safety concerns. This study was to investigate the safety and efficacy of tranexamic acid in patients undergoing off-pump coronary artery bypass grafting.
Methods: 151 selective patients undergoing off-pump coronary artery bypass grafting were randomly assigned to two groups: tranexamic acid group and control group. FuII-dose tranexamic acid was administered in tranexamic acid group but no tranexamic acid was used in control group. We compared early postoperative outcomes between the two groups, including blood loss, transfusion requirement, reoperation for bleeding, mortality and other major complications. All analyses were performed using SPSS statistical software (version 11.0). Statistical significance was set at P<0.05.
Results: There were 75 patients in the tranexamic acid group and 76 patients in the control group. The comparison of baseline characteristics showed no significant difference between two groups except weight, rate of hypertention and smoking. The tranexamic acid group had less postoperative blood loss: 6 hours (284.0+ 129. 1ml vs 411.1±191.3ml p<0.001), 24hours (701.1±269. 5ml vs 915. 9±310. 1ml p<0.001), 48 hours (876.1±326.4ml vs 1120.0±454. 6ml p<0.001), and total blood loss (923.1±361. 3ml vs 1215. 8±651.1 p=0.001) . Transfusion requirement in the tranexamic acid group was less than the control group, but did not reach statistically significant difference. There were no reoperation for bleeding and death after operation. Application of tranexamic acid did not increase the risk of other major adverse outcome events, including renal, cardiac, neurological and pulmonary complications. Furthermore, there were no significant difference in the length of ICU stay, length of in-hospital stay, total mechanical ventilation time, and PaO2/FiO2 in the blood gas analysis of 24 hours after operation.
Conclusions: Use of tranexamic acid in patients undergoing off-pump coronary artery bypass grafting could reduce blood loss significantly, but did not increase the risk of mortality or major complications.
引文
[1] Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-91
[2] Michael Havel, Florian Grabenwoger, Johannes Schneider. Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg 1994;107:807-810.
[3] Hayashida N, Isomura T, Sato T, Maruyama H, Kosuga K, Aoyagi S. Effects of minimal-dose aprotinin on coronary artery bypass grafting. J Thorac Cardiovasc Surg 1997;114(2):261-9.
[4] Murkin JM. Attenuation of neurologic injury during cardiac surgery. Ann Thorac Surg 2001; 72(5): S1838-44.
[5] Sedrakyan A, Treasure T, Elefteriades JA. Efect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004;128: 442—448
[6] Poston RS, White C, Gu J. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting. Ann Thorac Surg 2006; 81 (1): 104-10.
[7] Royston D, Levy JH, Fitch J. Full-dose aprotinin use in coronary artery bypass graft surgery: an analysis of perioperative pharmacotherapy and patient outcomes. Anesth Analg 2006; 103(5): 1082-8
[8] Ronald A, Dunning J. Does use of aprotinin decrease the incidence of stroke and neurological complications in adult patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 2006;5(6):767-73.
[9] Mangano DT, Tudor IC, Dietzel C, et al. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353—365.
[10] Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007;297(5):471-9.
[11] Kertai MD, Varga KS, Royston D, London MJ, Szabolcs Z, Grebenik CR, et al. Aprotinin and perioperative complications in cardiac surgery. J Cardiovasc Surg (Torino). 2007 Dec; 48(6): 761-72.
[12] Mouton R, Finch D, Davies I, Binks A, Zacharowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet. 2008 Feb 9;371(9611):475-82.
[13] Koster A, Buz S, Krabatsch T, Dehmel F, Kuppe H, Hetzer R, et al. High-dose aprotinin effectively reduces blood loss during on-pump coronary artery bypass grafting with bivalirudin anticoagulation. J Thorac Cardiovasc Surg. 2008 Mar;135(3):685-7.
[14] Pagano D, Howell NJ, Freemantle N, Cunningham D, Bonser RS, Graham TR, et al. Bleeding in cardiac surgery: the use of aprotinin does not affect survival. J Thorac Cardiovasc Surg. 2008 Mar;135(3):495-502.
[15] Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 2008;358:771-83.
[16] Shaw AD, Stafford-Smith M, White WD, Philips-Bute B, Swaminathan M, Milano C, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358:784-93.
[17] Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358:2319-31.
[18] Kain K, Catto AJ, Grant PJ. Impaired fibrinolysis and increased fibrinogen levels in South Asian subjects. Atherosclerosis 2001; 156(2):457-61
[19] Forouhi NG, Rumley A, Lowe GD. Specific elevation in plasma tissue plasminogen activator antigen concentrations in South Asians relative to Europeans. Blood Coagul Fibrinolysis 2003;14(8):755-60
[20] El Rouby S, Mestres CA, LaDuca FM, Zucker ML. Racial and ethnic differences in warfarin response. J Heart Valve Dis 2004; 13(1):15-21.
[21] Yu HY, Liu CH, Chen YS, Wang SS, Chu SH, Lin FY. Relationship of international normalized ratio to bleeding and thromboembolism rates in Taiwanese patients receiving vitamin K antagonist after mechanical valve replacement. J Formos Med Assoc 2005; 104(4):236-43.
[22] McEvoy MD, Reeves ST, Reves JG, Spinale FG. Aprotinin in cardiac surgery: a review of conventional and novel mechanisms of action. Anesth Analg 2007; 105:949-62.
[23] Khan TA, Bianchi C, Voisine P. Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest. J Thorac Cardiovasc Surg 2004; 128(4): 602-8.
[24] Lazar HL, Bao Y, Tanzillo L, O'Gara P, Reardon D, Price D, et al. Aprotinin decreases ischemic damage during coronary revascularization. J Card Surg . 2005 Nov-Dec;20(6):519-23.
[25]Kunt AS,Darcin OT,Aydin S,Demir D,Selli C,Andac MH.Mini-dose pump-prime aprotinin inhibited enhanced fibrinolytic activity and reduced blood loss and transfusion requirements after coronary artery bypass surgery.J Thromb Thrombolysis.2005 Jun;19(3):197-200.
[26]Erdogan M,Kalaycioglu S,Iriz E.Protective effect of aprotinin against lung damage in patients undergoing CABG surgery.Acta Cardiol.2005 Aug;60(4
[1]Sundt TM Ⅲ,Kouchoukos NT,Saffitz JE,Murphy SF,Wareing TH,Stahl DJ.Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest.Ann Thorac Surg 1993;55:1418-24.
[2]Feindt PR,Walcher S,Volkmer I,et al.Effects of high dose aprotinin on renal function in aortocoronary bypass grafting.Ann Thorac Surg 1995;60:1076-80.
[3]Alderman EL,Levy JH,Rich JB.Analyses of coronary graft patency after aprotinin use.J Thorac Cardiovasc Surg.1998;116:716-730.
[4]Michael Havel,MD,Florian Grabenw(o|¨)ger,MD,Johannes Schneider;MD.Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood.J Thorac Cardiovasc Surg 1994;107:807-810.
[5]Hayashida N,Isomura T,Sato T,Effects of minimal-dose aprotinin on coronary artery bypass grafting.J Thorac Cardiovasc Surg 1997;114(2):261-9.
[6]Murkin JM.Attenuation of neurologic injury during cardiac surgery.Ann Thorac Surg 2001;72(5):S1838-44.
[7]Sedrakyan A,Treasure T,Elefteriades JA.Efect of aprotinin on clinical outcomes in coronary artery bypass graft surgery:a systematic review and meta-analysis of randomized clinical trials.J Thorac Cardiovasc Surg 2004;128:442-448
[8]Poston RS,White C,Gu J.Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting.Ann Thorac Surg 2006;81(1):104-10.
[9]Royston D,Levy JH,Fitch J.Full-dose aprotinin use in coronary artery bypass graft surgery:an analysis of perioperative pharmacotherapy and patient outcomes.Anesth Analg 2006;103(5):1082-8
[10]Ronald A,Dunning J.Does use of aprotinin decrease the incidence of stroke and neurological complications in adult patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 2006;5(6):767-73.
[11]Mangano DT,Tudor IC,Dietzel C,Tudor IC,Juneja R,Filipescu D,Hoeft A,Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353—365.
[12] Mangano DT, Miao Y, Vuylsteke A. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007;297(5):471-9.
[13] Shaw AD, Stafford-Smith M, White WD, Philips-Bute B, Swaminathan M, Milano C, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358:784-93.
[14] Sebastian Schneeweiss, M.D., Sc.D., John D. Seeger, Pharm.D., Dr.P.H., Joan Landon, M.P.H., and Alexander M. Walker, M.D., Dr.P.H. Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death. N Engl J Med 2008; 358:771-783.
[15] Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358:2319-31.
[16] Meade TW, Brozovic M, Chakrabarti R, Haines AP, North WR, Stirling Y. Ethnic group comparisons of variables associated with ischaemic heart disease. Br Heart J 1978 ;40(7):789-95
[17] Shephard RJ. The influences of race and environment on ischemic heart disease. Can Med Assoc J 1974 ;111(12):1336-40.
[18] Alter M. Black-white differences in stroke frequency: challenges for research. Neuroepidemiology 1994;13(6):301-7
[19] Frey JL, Jahnke HK, Bulfinch EW. Differences in stroke between white, Hispanic, and Native American patients: the Barrow Neurological Institute stroke database. Stroke 1998;29(1):29-33.
[20] Kain K, Catto AJ, Grant PJ. Impaired fibrinolysis and increased fibrinogen levels in South Asian subjects. Atherosclerosis 2001;156(2):457-61
[21] Forouhi NG, Rumley A, Lowe GD, Specific elevation in plasma tissue plasminogen activator antigen concentrations in South Asians relative to Europeans. Blood Coagul Fibrinolysis 2003;14(8):755-60
[22] El Rouby S, Mestres CA, LaDuca FM, Zucker ML. Racial and ethnic differences in warfarin response. J Heart Valve Dis 2004;13(1):15-21.
[23] Yu HY, Liu CH, Chen YS, Wang SS, Chu SH, Lin FY. Relationship of international normalized ratio to bleeding and thromboembolism rates in Taiwanese patients receiving vitamin K antagonist after mechanical valve replacement. J Formos Med Assoc 2005;104(4):236-43.
[1]Mangano DT,Tudor IC,Dietzel C,Tudor IC,Juneja R,Filipescu D,Hoefl A,Fontes ML,Hillel Z,Ott E,Titov T,Dietzel C,Levin J.The risk associated with aprotinin in cardiac surgery.N Engl J Med 2006;354:353-365.
[2]Mangano DT,Miao Y,Vuylsteke A.Mortality associated with aprotinin during 5years following coronary artery bypass graft surgery.JAMA 2007;297(5):471-9.
[3]Shaw AD,Stafford-Smith M,White WD,Phllips-Bute B,Swaminathan M,Milano C,et al.The effect of aprotinin on outcome after coronary-artery bypass grafting.N Engl J Med 2008;358:784-93.
[4]Sebastian Schneeweiss,M.D.,Sc.D.,John D.Seeger,Pharm.D.,Dr.P.H.,Joan Landon,M.P.H.,and Alexander M.Walker,M.D.,Dr.P.H.Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death.N Engl J Med 2008;358:771-783.
[5]Fergusson DA,Hebert PC,Mazer CD,Fremes S,MacAdams C,Murkin JM,et al.A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.N Engl J Med 2008;358:2319-31.
[6].Ruel MA,Wang F,Bouker ME,et al:Is tranexamic acid safe in patients undergoing coronary endarterectomy? Ann Thorac Surg 71:1508-1511,2001
[7]Kareski J,Djaiani G,Carroll J,et al:Tranexamic acid and early saphenous vein graft patency in conventional coronary artery bypass graft surgery:A prospective randomized controlled clinical trial.J Thorac Cardiovasc Surg 130:309-314,2005
[8].Levi M,Cromheecke ME,de Jonge E,et al:Pharmacological strategies to decrease excessive blood loss in cardiac surgery:A metaanalysis of clinically relevant endpoints.Lancet 354:1940-1947,1999
[9].Biglioli P,Cannata A,Alamanni F,et al:Biological effects of off-pump vs.on-pump coronary artery surgery:Focus on inflammation,hemostasis and oxidative stress.Eur J Cardiothorac Surg 24:260-269,2003
[10]. Hekmat K, Zimmermann T, Kampe S, et al: Impact of tranexamic acid vs. aprotinin on blood loss and transfusion requirements after cardiopulmonary bypass: A prospective, randomized, double-blind trial. Curr Med Res Opin 20:121-126, 2004
[11]. Iaco AL, Contini M, Teodori G, et al: Off or on bypass: What is the safety threshold? Ann Thorac Surg 68:1468-1469,1999
[12]. Cartier R, Brann S, Dagenais F, et al: Systematic off-pump coronary artery revascularization multivessel disease: Experience of three hundred cases. J Thorac Cardiovasc Surg 119:221-229, 2000
[13]. Nader ND, Reich NT, Khadra WZ, et al: Blood product use in cardiac revascularization: comparison of on- and off-pump techniques. Ann Thorac Surg 68:1640-1643,1999
[14]. Wei M, Jian K, Guo Z, et al: Tranexamic acid reduces postoperative bleeding in off-pump coronary artery bypass grafting. Scand Cardiovasc J 40:105-190, 2006
[15]. Casati V, Gerli Ch, Franco A, et al: Tranexamic acid in offpump coronary surgery: A preliminary, randomized, double-blind, placebo- controlled study. Ann Thorac Surg 72:470-475,2001
[16]. Vanek T, Jares M, Fajt R, et al: Fibrinolytic inhibitors in off-pump coronary surgery: A prospective, randomized, double-blind TAP study. Eur J Cardiothorac 28:563-568, 2005
[17]. Jares M, Vanek T, Straka Z, et al: Tranexamic acid reduces bleeding after off-pump coronary artery bypass grafting. J Cardiovasc Surg (Torino) 44:205-208, 2003
[18]. Casati V, Delia Valle P, Benussi S, et al: Effects of tranexamic acid in postoperative bleeding and related hematological variables in coronary surgery: Comparison between on-pump and off-pump techniques. J Thorac Cardiovasc Surg 128:83-91, 2004
[19] Thiagarajamurthy S, Levine A, Dunning J. Does prophylactic tranexamic acid safely reduce bleeding without increasing thrombotic complications in patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 2004;(3):489—94.
[20] Ovrum E, Am HE, Abdelnoor M, Oystese R, Ringdal ML. Tranexamic acid (Cyklokapron) is not necessary to reduce blood loss after coronary artery bypass operations. J Thorac Cardiovasc Surg 1993;105(1):78—83.
[1]. Dietrich W. Cardiac surgery and the coagulation system. Curr Opin Anesth 2000;13:27-34
[2]. Laffey J, Boylan J, Cheng D. The systemic inflammatory response to cardiac surgery. Implications for the anesthesiologist. Anesthesiology 2002;97:215-52
[3]. Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 2003;75:S715-20
[4]. Gravlee GP. Update on cardiopulmonary bypass. Curr Opin Anesth 2001;14:11-16
[5]. Mangano DT. Cardiovascular morbidity and CABG surgery—a perspective: epidemiology, costs, and potential therapeutic solutions. J Card Surg 1995;10:366-8
[6]. Edmunds LH Jr. Why cardiopulmonary bypass makes people sick: strategies to control the blood-synthetic interface. In: Karp RB, Laks H, Wechsler AS, eds. Advances in cardiac surgery. Vol 6. Chicago, IL: Mosby-Year Book, 1995:131-67
[7]. Shernan SK. Perioperative myocardial ischemia reperfusion injury. Anesthesiol Clin North America 2003;21:465-85
[8]. Alston TA. Aprotinin. Int Anesthesiol Clin 2004;42:81-91
[9] Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552-9
[10]. de Mendonca-Filho HT, Pereira KC, Fontes M, Vieira DA, de Mendonca ML, Campos LA, Castro-Faria-Neto HC. Circulating inflammatory mediators and organ dysfunction after cardiovascular surgery with cardiopulmonary bypass: a prospective observational study. Crit Care 2006;10:R46
[11]. Bolli R, Becker L, Gross G, Mentzer R, Balshaw D, Lathrop DA. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 2004;95:125-34
[12]. Levy J. Overview of clinical efficacy and safety of pharmacologic strategies for blood conservation. Am J Health Syst Pharm 2005;62:S15-18
[13]. Englberger L, Kipfer B, Berdat PA, Nydegger UE, Carrel TP. Aprotinin in coronary operation with cardiopulmonary bypass: does "low-dose" aprotinin inhibit the inflammatory response? Ann Thorac Surg 2002;73:1897-1904
[14]. Koster A, Huebler S, Merkle F, Hentschel T, Grundel M, Krabatsch T, Tambeur L, Praus M, Habazettl H, Kuebler WM, Kuppe H. Heparin-level-based anticoagulation management during cardiopulmonary bypass: a pilot investigation on the effects of a half-dose aprotinin protocol on postoperative blood loss and hemostatic activation and inflammatory response. Anesth Analg 2004;98:285-90
[15]. Greilich PE, Brouse CF, Rinder CS, Smith BR, Sandoval BA, Rinder HM, Eberhart RC, Jessen ME. Effects of -aminocaproic acid and aprotinin on leukocyte-platelet adhesion in patients undergoing cardiac surgery. Anesthesiology 2004;100:225-33
[16]. Despotis GJ, Avidan MS, Hogue CW. Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001;72:S1821-31
[17]. Pruefer D, Buerke U, Khalil M, Dahm M, Darius H, Oelert H, Buerke M. Cardioprotective effects of the serine protease inhibitor aprotinin after regional ischemia and reperfusion on the beating heart. J Thorac Cardiovasc Surg 2002; 124:942-9
[18]. Hill GE, Diego RP, Stammers AH, Huffman SM, Pohorecki R. Aprotinin enhances the endogenous release of interleukin-10 after cardiac operations. Ann Thorac Surg 1998;65:66-9
[19]. Rahman A, Ustunda B, Burma O, Ozercan IH, Cekirdekci A, Bayar MK. Does aprotinin reduce lung perfusion after cardiopulmonary bypass? Eur J Cardiothorac Surg 2000;18:583-8
[20]. Kuepper F, Dangas G, Mueller-Chorus A, Kulka PM, Zenz M, Wiebalck A. Fibrinolytic activity and bleeding after cardiac surgery with cardiopulmonary bypass and low-dose aprotinin therapy. Blood Coagul Fibrinolysis 2003; 14:147-53
[21]. Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. Anesth Analg 1997; 85:1258-67
[22]. Levy JH, Pifarre R, Schaff HV, Horrow J, Albus R, Spiess B, Rosengart TK, Murray J, Clark RE, Smith P. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995;92:2236-44
[23]. Landis RC, Asimakopoulos G, Poullis M, Haskard DO, Taylor KM. The antithrombotic and antiinflammatory mechanisms of action of aprotinin. Ann Thorac Surg 2001;72:2169-75
[24]. Frumento RJ, O'Malley CMN, Bennett-Guerrero E. Stroke after cardiac surgery: a retrospective analysis of the effect of aprotinin dosing regimens. Ann Thorac Surg 2003;75:479-84
[25]. Forestier F, Belisle S, Robitaille D, Martineau R, Perrault LP, Hardy JF. Low-dose aprotinin is ineffective to treat excessive bleeding after cardiopulmonary bypass. Ann Thorac Surg 2000;69:452-6
[26]. Taggart DP, Djapardy V, Naik M, Davies A. A randomized trial of aprotinin (Trasylol) on blood loss, blood product requirement, and myocardial injury in total arterial grafting. J Thorac Cardiovasc Surg 2003;126:1084-94
[27]. Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in a coronary arterty bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004;128:442-8
[28]. Lemmer JH, Dilling EW, Morton JR, Rich JB, Robicsek F, Bricker D, Hantler C, Copeland J, Ochsner J, Daily P, Whitten C, Noon G, Maddi R. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 1996;62:1659-68
[29]. Gott JP, Cooper WA, Schmidt FE, Brown WM III, Wright CE, Merlino JD, Fortenberry JD, Clark WS, Guyton RA. Modifying risk for extracorporeal circulation: trial of four anti-inflammatory strategies. Ann Thorac Surg 1998;66:747-54
[30]. Hill GE, Pohorecki R, Alonso A, Rennard S, Robbins R. Aprotinin reduces interleukin-8 production and lung neutrophil accumulation after cardiopulmonary bypass. Anesth Analg 1996;83:696-700
[31]. Greilich PE, Okada K, Latham P, Kumar RR, Jessen ME. Aprotinin but not _-aminocaproic acid decreases interleukin-10 after cardiac surgery with extracorporeal circulation. Circulation 2004;104:1265-9
[32]. Bull D, Connors R, Albanil A, Reid BB, Neumayer LA, Nelson R, Stringham JC, Karwande SV. Cardiopulmonary support and physiology. Aprotinin preserves myocardial biochemical function during cold storage through suppression of tumor necrosis factor. J Thorac Cardiovasc Surg 2000;119:242-50
[33]. Bull D, Maurer J. Aprotinin and preservation of myocardial function after ischemia-reperfusion injury. Ann Thorac Surg 2003;75:S735-9
[34]. McCarthy RJ, Tuman K, O'Connor C, Ivankovish AD. Aprotinin pretreatment diminished postichemic myocardial contractile dysfunction in dogs. Anesth Analg 1999;89:1096-1101
[35]. Peters DC, Noble S. Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery. Drugs 1999;57:233-60
[36]. Waxier B, Rabito S. Aprotinin: a serine protease inhibitor with therapeutic actions: its interaction with ace inhibitors. Curr Pharm Design 2003;9:777-87
[37]. Engles L. Review and application of serine protease inhibition in coronary artery bypass graft surgery. Am J Health Syst Pharm 2005;62:S9-14
[38]. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-65
[39]. Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A, Wijeysundera DN, Fedorko L, Yau TM. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006;46:327-38
[40]. Dietrich W, Busley R, Kriner M. High-dose aprotinin in cardiac surgery: is high-dose high enough? An analysis of 8281 cardiac surgical patients treated with aprotinin. Anesth Analg 2006; 103:1074-81
[41]. Royston D, Levy JH, Fitch J, Dietrich W, Body SC, Murkin JM, Spiess BD, Nadel A. Full-dose aprotinin use in coronary artery bypass graft surgery: an analysis of perioperative pharmacotherapy and patient outcomes. Anesth Analg 2006;103:1082-8
[42]. Hogue CW, London MJ. Aprotinin use during cardiac surgery: a new or continuing controversy? Anesth Analg 2006;103:1067-70
[43]. Body SC, Mazer CD. Pro: aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth Analg 2006;103:1354-9
[44]. Beattie WS, Karkouti K. Con: aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth Analg 2006;103:1360-4
[45]. Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, Hoeft A, Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J. Mortality associated with aprotinin during 5 years after coronary artery bypass graft surgery. JAMA 2007;297:471-9
[46]. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-91
[47]. Wildevuur CR, Eijsman L, Roozendaal KJ, Harder MP, Chang M, van Oeveren W. Platelet preservation during cardiopulmonary bypass with aprotinin. Eur J Cardiothorac Surg 1989;3:533-7
[48]. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Reduced blood loss following open heart surgery with aprotinin (Trasylol) is associated with an increase in intraoperative activated clotting time (ACT). J Cardiothorac Anesth 1989;3:80
[49]. Alajmo F, Calamai G, Perna AM, Melissano G, Pretelli P, Palmarini MF, Carbonetto F, Noferi D, Boddi V, Palminiello A. High-dose aprotinin: hemostatic effects in open heart operations. Ann Thorac Surg 1989;48:536-9
[50]. Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354:1940-7
[51]. Fraedrich G, Weber C, Bernard C, Hettwer A, Schlosser V. Reduction of blood transfusion requirement in open heart surgery by administration of high doses of aprotininpreliminary results. Thorac Cardiovasc Surg 1989;37:89—91
[52]. Dietrich W, Henze R, Barankay A, Niekau E, Sebening F, Richter JA. High-dose aprotinin application reduces homologous blood requirement in cardiac surgery. J Cardiothorac Anesth 1989;3:79
[53]. Dietrich W, Barankay A, Dilthey G, Henze R, Niekau E, Sebening F, Richter JA. Reduction of homologous blood requirement in cardiac surgery by intraoperative aprotinin application—clinical experience in 152 cardiac surgical patients. Thorac Cardiovasc Surg 1989;37:92-8
[54]. Royston D. The serine antiprotease aprotinin (Trasylol): a novel approach to reducing postoperative bleeding. Blood Coagul Fibrinolysis 1990;1:55-69
[55]. Niimi KS. Aprotinin dosing: how much is enough? J Extra Corpor Technol 2004;36:384-90
[56]. Smith PK, Datta SK, Muhlbaier LH, Samsa G, Nadel A, Lipscomb J. Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials. Ann Thorac Surg 2004;77:635-42
[57]. Royston D. High-dose aprotinin therapy: a review of the first five years' experience. J Cardiothorac Vasc Anesth 1992;6: 76-100
[58]. Royston D, Cardigan R, Gippner-Steppert C, Jochum M. Is perioperative plasma aprotinin concentration more predictable and constant after a weight-related dose regimen? Anesth Analg 2001;92:830-6
[59]. Bennett-Guerrero E, Sorohan JG, Howell ST, Ayuso L, Cardigan RA, Newman MF, Mackie IJ, Reves JG, Mythen MG. Maintenance of therapeutic plasma aprotinin levels during prolonged cardiopulmonary bypass using a large-dose regimen. Anesth Analg 1996;83:1189-92
[60]. Beath SM, Nuttall GA, Fass DN, Oliver WC Jr, Ereth MH, Oyen LJ. Plasma aprotinin concentrations during cardiac surgery: full- versus half-dose regimens. Anesth Analg 2000;91:257-64
[61]. Levy JH, Bailey JM, Salmenpera M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 1994;80:1013-18
[62]. Wegner J. Biochemistry of serine protease inhibitors and their mechanisms of action: a review. J Extra Corpor Technol 2003;35:326-38
[63]. Khan MH, Gikakis N, Miyamoto S, Rao AK, Cooper SL, Edmunds LH Jr, Colman RW. Aprotinin inhibits thrombin formation and monocyte tissue factor in simulated cardiopulmonary bypass. Ann Thorac Surg 1999;68:473-8
[64]. Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheikh S, Hunt B, Smith KJ. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993;82:3350-7
[65]. Taby O, Chabbat J, Steinbuch M. Inhibition of activated protein C by aprotinin and the use of the insolublized inhibitor for its purification. Thromb Res 1990;59:27-35
[66]. Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost 1997;77:522-5
[67]. Khalil PN, Ismail M, Kalmar P, von Knobelsdorff G, Marx G. Activation of fibrinolysis in the pericardial cavity after cardiopulmonary bypass. Thromb Haemost 2004;92:568-74
[68]. Kang HM, Kalnoski MH, Frederick M, Chandler WL. The kinetics of plasmin inhibition by aprotinin in vivo. Thromb Res 2005; 115:327-40
[69]. Day JR, Punjabi PP, Randi AM, Haskard DO, Landis RC, Taylor KM. Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery. Circulation 2004; 110:2597-600
[70]. Ferraris VA, Ferraris SP, Singh A, Fuhr W, Koppel D, McKenna D, Rodriguez E, Reich H. The platelet thrombin receptor and postoperative bleeding. Ann Thorac Surg 1998;65:352-8
[71]. Day JR, Taylor KM, Lidington EA, Mason JC, Haskard DO, Randi AM, Landis RC. Aprotinin inhibits proinflammatory activation of endothelial cells by thrombin through the protease-activated receptor 1. J Thorac Cardiovasc Surg 2006;131:21-7
[72]. Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittelforschung 1983;33:479-94
[73]. Dietrich W, Spannagl M, Jochum M, Wendt P, Schramm W, Barankay A, Sebening F, Richter JA. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119-26
[74]. Speekenbrink RG, Wildevuur CR, Sturk A, Eijsman L. Lowdose and high-dose aprotinin improve hemostasis in coronary operations. J Thorac Cardiovasc Surg 1996;112:523-30
[75]. Li S, Ji H, Lin J, Lenehan E, Ji B, Liu J, Liu J, Long C, Crane TA. Combination of acute preoperative plateletpheresis, cell salvage, and aprotinin minimizes blood loss and requirement during cardiac surgery. J Extra Corpor Technol 2005;37:9 -14
[76]. Harmon D, Lan W, Shorten G. The effect of aprotinin on hypoxia-reoxygenation-induced changes in neutrophil and endothelial function. Eur J Anaesthesiol 2004;21:973-9
[77]. Mojcik CF, Levy JH. Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. Ann Thorac Surg 2001;71:745-54
[78]. Asimakopoulos G, Thompson R, Nourshargh S, Lidington EA, Mason JC, Ratnatunga CP, Haskard DO, Taylor KM, Landis RC. An anti-inflammatory property of aprotinin detected at the level of leukocyte extravasation. J Thorac Cardiovasc Surg 2000;120:361-9
[79]. Wachtfogel YT, Kucich U, Hack CE, Gluszko P, Niewiarowski S, Colman RW, Edmunds LH Jr. Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993;106: 1-9
[80]. Ulker S, Cinar MG, Bayraktutan U, Evinc A. Aprotinin impairs endothelium-dependent relaxation in rat aorta and inhibits nitric oxide release from rat coronary endothelial cells. Cardiovasc Res 2001;50:589-96
[81]. Ulker S, McKeown PP, Bayraktutan U. Aprotinin impairs coronary endothelial function and down-regulates endothelial NOS in rat coronary microvascular endothelial cells. Cardiovasc Res 2002;55:830-7
[82]. Fischer JH, Steinhoff M. Effects of aprotinin on endotheliumdependent relaxation of large coronary arteries. Eur J Cardiothorac Surg 2005;28:801-4
[83]. Pandey R, Deshpande SB. Protective effects of aprotinin on respiratory and cardiac abnormalities induced by Mesobunthus tamulus venom in adult rats. Toxicon 2004;44:201-5
[84]. Venturini G, Colasanti M, Ascenzi P. Aprotinin, the first competitive protein inhibitor of NOS activity. Biochem Biophys Res Commun 1998;249:263-5
[85]. Pruefer D, Makowski J, Dahm M, Guth S, Oelert H, Darius H, Buerke M. Aprotinin inhibits leukocyte-endothelial cell interactions after hemorrhage and reperfusion. Ann Thorac Surg 2003;75:210-15
[86]. McEvoy MD, Taylor AB, Zavadzkas JA, Mains IM, Jeffords LB, Ford RL, Beck C, Stroud RE, Reeves ST, Spinale FG. Aprotinin causes dose-dependent and differential effects on myocardial contractility, cytokine release and oxidative stress with ischemia-reperfusion. Circulation 2006;114:A2529
[87]. Mossinger H, Dietrich W, Braun SL, Jochum M, Meisner H, Richter JA. High-dose aprotinin reduces activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation in pediatric cardiac surgery. Ann Thorac Surg 2003;75:430-7
[88]. Governa M, Fenoglio I, Amati M, Valentino M, Bolognini L, Coloccini S, Volpe AR, Carmignani M, Fubini B. Cleavage of the fifth component of human complement and release of a split product with C5a-like activity by crystalline silica through free radical generation and kallikrein activation. Toxicol Appl Pharmacol 2002;179:129-36
[89]. Himmelfarb J, Holbrook D, McMonagle E. Effects of aprotinin on complement and granulocyte activation during ex vivo hemodialysis. Am J Kidney Dis 1994;24:901-6
[90]. Olivencia-Yurvati AH, Wallace WE, Wallace N, Dimitrijevich D, Knust JK, Haas L, Raven PB. Intraoperative treatment strategy to reduce the incidence of postcardiopulmonary bypass atrial fibrillation. Perfusion 2002;17(suppl):35-9
[91]. Sedrakyan A, Wu A, Sedrakyan G, Diener-West M, Tranquilli M, Elefteriades J. Aprotinin use in thoracic aortic surgery: safety and outcomes. J Thorac Cardiovasc Surg 2006; 132:909-17
[92]. Khan TA, Bianchi C, Voisine P, Feng J, Baker J, Hart M, Takahashi M, Stahl G, Sellke FW. Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest. J Thorac Cardiovasc Surg 2004;128:602-8
[93]. Lazar HL, Bao Y, Tanzillo L, O'Gara P, Reardon D, Price D, Crowley R, Cabral HJ. Aprotinin decreases ischemic damage during coronary revascularization. J Card Surg 2005;20:519-23
[94]. Sirieix D, Clinquart F, Delayance S, Massonnet-Castel S, Paris M, Baron JF. Does aprotinin modify the effects of ischaemiareperfusion on the myocardial performance of a blood perfused isolated rabbit heart? Eur J Anaesthesiol 1999;16:712-18
[95]. Khan TA, Bianchi C, Araujo E, Voisine P, Xu SH, Feng J, Li J, Sellke FW. Aprotinin preserves cellular junctions and reduces myocardial edema after regional ischemia and cardioplegic arrest. Circulation 2005;112:I196-201
[96]. Hendrikx M, Rega F, Jamaer L, Valkenborgh T, Gutermann H, Mees U. Na(+)/H(+)-exchange inhibition and aprotinin administration: promising tools for myocardial protection during minimally invasive CABG. Eur J Cardiothorac Surg 2001;19: 633-9
[97]. Fra¨_dorf J, Ebel D, Weber NC, Preckel B, Schlack W. Sevoflurane induced preconditioning is blocked by aprotinin in rat hearts in vivo. Anesthesiology 2006; 105:A1086
[98]. Zhang X, Liu B. Effects of aprotinin on extravascular lung water in patients undergoing mitral valve replacement. Anesthesiology 2006;105:A1227
[99]. Mathias MA, Tribble CG, Dietz JF, Nguyen RP, Shockey KS, Kern JA, Kron IL. Aprotinin improves pulmonary function during reperfusion in an isolated lung model. Ann Thorac Surg 2000;70:1671-4
[100]. Yun TJ, Rho JR. Aprotinin attenuates the elevation of pulmonary vascular resistance after cardiopulmonary bypass. J Korean Med Sci 2006;21:25-9
[101]. Eren S, Esme H, Balci AE, Cakir O, Buyukbayram H, Eren MN, Erdinc L, Satici O. The effect of aprotinin on ischemiareperfusion injury in an in situ normothermic ischemic lung model. Eur J Cardiothorac Surg 2003;23:60-5
[102]. Ege T, Arar C, Canbaz S, Cikirikcioglu M, Sunar H, Yuksel V, Duran E. The importance of aprotinin and pentoxifylline in preventing leukocyte sequestration and lung injury caused by protamine at the end of cardiopulmonary bypass surgery. Thorac Cardiovasc Surg 2004;52:10-15
[103]. Koksal C, Bozkurt AK, Ustundag N, Konukoglu D, Musellim B, Sirin G, Cortelekoglu T, Sayin AG. Attenuation of acute lung injury following lower limb ischemia/reperfusion: the pharmacological approach. J Cardiovasc Surg 2006;47:445-9
[104]. Erdogan M, Kalaycioglu S, Iriz E. Protective effect of aprotinin against lung damage in patients undergoing CABG surgery. Acta Cardiol 2005;60:367-72
[105]. Nader ND, Davidson BA, Tait AR, Holm BA, Knight PR. Serine antiproteinase administration preserves innate superoxide dismutase levels after acid aspiration and hyperoxia but does not decrease lung injury. Anesth Analg 2005;101:213-19
[106]. Schweizer A, Hohn L, Morel DR, Kalangos A, Licker M. Aprotinin does not impair renal haemodynamics and function after cardiac surgery. Br J Anaesth 2000;84:16-22
[107]. Fauli A, Gomar C, Campistol JM, Alvarez L, Manig AM, Matute P. Kidney-specific proteins in patients receiving aprotinin at high- and low-dose regimens during coronary artery bypass graft with cardiopulmonary bypass. Eur J Anaesthesiol 2005;22:666-71
[108]. Wagener G, Jan M, Kim M, Mori K, Barasch JM, Sladen R, Lee HT. Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006;105:485-91
[109]. Wagener G, Gubitosa G, Jalbout M, Sladen R, Lee HT. Aprotinin increases urinary NGAL, a marker for renal tubular injury after cardiac surgery. Anesthesiology 2006;105:A1732
[110]. Kher A, Meldrum KK, Hile KL, Wang M, Tsai BM, Turrentine MW, Brown JW, Meldrum DR. Aprotinin improves kidney function and decreases tubular cell apoptosis and proapoptotic signaling after renal ischemia-reperfusion. J Thorac Cardiovasc Surg 2005;130:662-9
[111]. Ozer Z, Sucu N, Dusmez D, Tamer L, Altunkan AA, DIkmengII M, Oral U. The effect of aprotinin on ischemiareperfusion injury in the rabbit kidney. Pharmacol Res 2001;44:455-60
[112]. Ramlawi B, Rudolph JL, Mieno S, Khabbaz K, Sodha NR, Boodhwani M, Levkoff SE, Marcantonio ER, Sellke FW. Serologic markers of brain injury and cognitive function after cardiopulmonary bypass. Ann Surg 2006;244:593-601
[113]. Harmon DC, Ghori KG, Eustace NP, O'Callaghan SJ, O'Donnell AP, Shorten GD. Aprotinin decreases the incidence of cognitive deficit following CABG and cardiopulmonary bypass: a pilot randomized controlled study. Can J Anaesth 2004;51:1002-9
[114]. Grocott HP, Sheng H, Miura Y, Sarraf-Yazdi S, Mackensen GB, Pearlstein RD, Warner DS. The effects of aprotinin on outcome from cerebral ischemia in the rat. Anesth Analg 1999;88:l-7
[115]. Takahashi H, Nagai N, Urano T. Role of tissue plasminogen activator/plasmin cascade in delayed neuronal death after transient forebrain ischemia. Neurosci Lett 2005;381:189-93
[116]. Ranby M, Bergsdorf N, Nilsson T. Enzymatic properties of the one- and two-chain forms of tissue plasminogen activator. Thromb Res 1982;27:175-83
[117]. Durgut K, Hosgor K, Gormus N, Ozergin U, Solak H. The cerebroprotective effects of pentoxifylline and aprotinin during cardiopulmonary bypass in dogs. Perfusion 2004;19:101-6
[118]. Anttila V, Hagino I, Iwata Y, Mettler BA, Lidov HG, Zurakowski D, Jonas RA. Aprotinin improves cerebral protection: evidence from a survival porcine model. J Thorac Cardiovasc Surg 2006; 132:948-53
[119]. McEvoy MD, Taylor AB, Zavadzkas JA, McLean JE, Reeves ST, Spinale FG. Dose-dependent effects of aprotinin on systolic performance in a mouse model of ischemia-reperfusion. Anesth Analg 2007;104:S37
[120]. Kaminski KA, Bonda TA, Korecki J, Musial WJ. Oxidative stress and neutrophil activation—the two keystones of ischemia/reperfusion injury. Int J Cardiol 2002;86:41-59
[121]. Li JM, Shah AM. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 2004;287:R1014-30
[122]. Bruda NL, Hurlbert BJ, Hill GE. Aprotinin reduces nitric oxide production in vitro and in vivo in a dose-dependent manner. Clin Sci (Lond) 1998;94:505-9
[123]. Buerke M, Sankat D, Schlitt A, Buerke U. Serine protease inhibitor aprotinin exerts cardio protective effects by inhibition of gene activation following myocardial ischemia and reperfusion in rats. Circulation 2006;114:A2528
[124]. Wippermann CF, Schmid FX, Eberle B, Huth RG, Kampmann C, Schranz D, Oelert H. Reduced inotropic support after aprotinin therapy during pediatric cardiac operations. Ann Thorac Surg 1999;67:173-6
[125]. Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chairman B, Nadel A. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998;116:716-30
[126]. Yang Z, Eton D, Zheng F, Livingstone AS, Yu H. Effect of tissue plasminogen activator on vascular smooth muscle cells. J Vasc Surg 2005;42:532-8
[127]. Mukherjee R, Herron AR, Lowry AS, Stroud RE, Stroud MR, Wharton JM, Ikonomidis JS, Crumbley AJ III, Spinale FG, Gold MR. Selective induction of matrix metalloproteinases and tissue inhibitor of metalloproteinases in atrial and ventricular myocardium in patients with atrial fibrillation. Am J Cardiol 2006;97:532-7
[128]. Koch CG, Li L, Van Wagoner DR, Duncan AI, Gillinov AM, Blackstone EH. Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg 2006;82:1747-56
[129]. Tselentakis EV, Woodford E, Chandy J, Gaudette GR, Saltman AE. Inflammation effects on the electrical properties of atrial tissue and inducibility of postoperative atrial fibrillation. J Surg Res 2006;135:68-75
[130]. Roberts RF, Nishanian GP, Carey JN, Darbinian SH, Kim JD, Sakamaki Y, Chang JY, Starnes VA, Barr ML. Addition of aprotinin to organ preservation solutions decreases lung reperfusion injury. Ann Thorac Surg 1998;66:225-30
[131]. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med 1998;128: 194-203
[132]. Augoustides JG, Pochettino A, Ochroch EA, Cowie D, Weiner J, Gambone AJ, Pinchasik D, Bavaria JE, Jobes DR. Renal dysfunction after thoracic aortic surgery requiring deep hypothermic circulatory arrest: definition, incidence, and clinical predictors. J Cardiothorac Vasc Anesth 2006;20:673-7
[133]. Lemmer JH Jr, Stanford W, Bonney SL, Chomka EV, Karp RB, Laub GW, Rumberger JA, Schaff HV. Aprotinin for coronary artery bypass grafting: effect on postoperative renal function. Ann Thorac Surg 1995;59:132-6
[134]. D'Ambra MN, Akins CW, Blackstone EH, Bonney SL, Cohn LH, Cosgrove DM, Levy JH, Lynch KE, Maddi R. Aprotinin in primary valve replacement and reconstruction: a multicenter, double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg 1996;112:1081-9
[135]. Furnary AP, Hiratzka LF, Wu Y, Grunkemeier GL, Page SU. Does aprotinin increase the risk of renal failure in cardiac surgery patients? Circulation 2006;114:A3347
[136]. Baran D, Tenstad O, Aukland K. Aprotinin uptake in the proximal tubules in the rat kidney. II. Uptake site relative to glomerulus. J Struct Biol 2003;142:409-15
[137]. Baran D, Tenstad O, Aukland K. Aprotinin uptake in the proximal tubules in the rat kidney. I. Length of proximal tubular uptake segment. J Struct Biol 2003; 142:402-8
[138]. Mantur M, Kemona H, Dabrowska M, Dabrowska J, Sobolewski S, Prokopowicz J. Alphal-microglobulin as a marker of proximal tubular damage in urinary tract infection in children. Clin Nephrol 2000;53:283-87
[139]. Schmidt-Ott KM, Mori K, Kalandadze A, Li JY, Paragas N, Nicholas T, Devarajan P, Barasch J. Neutrophil gelatinaseassociated lipocalin-mediated iron traffic in kidney epithelia. Curr Opin Nephrol Hypertens 2006;15:442-9
[140]. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P. Identification of neutrophil gelatinaseassociated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003;14:2534-43
[141]. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231-8
[142]. Murkin JM. Attenuation of neurologic injury during cardiac surgery. Ann Thorac Surg 2001;72:S1838-44
[143]. Lee R, Tsuji K, Lee SR, Lo EH. Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci 2004;24:671-8
[144]. Seto S, Akahoshi M, Kusano S, Kitamura S, Hashiba K. Central effect of aprotinin, a serine protease inhibitor, on blood pressure in spontaneously hypertensive and Wistar-Kyoto rats. Adv Exp Med Biol 1989;247:49-54
[145]. Bessler H, Gilgal R, Djaldetti M, Zahavi I. Effect of pentoxifylline on the phagocytic activity, cAMP levels, and superoxide anion production by monocytes and polymorphonuclear cells.J Leukoc Biol 1986;40:747-54
[146].Jonsson H,Johnsson P,Hoglund P,Ailing C,Blomquist S.Elimination of S100B and renal function after cardiac surgery.J Cardiothorac Vasc Anesth 2000;14:698-701
[147].Rainer TH,Wong KS,Lam W,Lam NY,Graham CA,Lo YM.Comparison of plasma beta-globin DNA and S-100 protein concentrations in acute stroke.Clin Chim Acta 2007;376:190 - 6
[2] Michael Havel, Florian Grabenwoger, Johannes Schneider. Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg 1994;107:807-810.
[3] Hayashida N, Isomura T, Sato T, Maruyama H, Kosuga K, Aoyagi S. Effects of minimal-dose aprotinin on coronary artery bypass grafting. J Thorac Cardiovasc Surg 1997;114(2):261-9.
[4] Murkin JM. Attenuation of neurologic injury during cardiac surgery. Ann Thorac Surg 2001; 72(5): S1838-44.
[5] Sedrakyan A, Treasure T, Elefteriades JA. Efect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004;128: 442—448
[6] Poston RS, White C, Gu J. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting. Ann Thorac Surg 2006; 81 (1): 104-10.
[7] Royston D, Levy JH, Fitch J. Full-dose aprotinin use in coronary artery bypass graft surgery: an analysis of perioperative pharmacotherapy and patient outcomes. Anesth Analg 2006; 103(5): 1082-8
[8] Ronald A, Dunning J. Does use of aprotinin decrease the incidence of stroke and neurological complications in adult patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 2006;5(6):767-73.
[9] Mangano DT, Tudor IC, Dietzel C, et al. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353—365.
[10] Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007;297(5):471-9.
[11] Kertai MD, Varga KS, Royston D, London MJ, Szabolcs Z, Grebenik CR, et al. Aprotinin and perioperative complications in cardiac surgery. J Cardiovasc Surg (Torino). 2007 Dec; 48(6): 761-72.
[12] Mouton R, Finch D, Davies I, Binks A, Zacharowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet. 2008 Feb 9;371(9611):475-82.
[13] Koster A, Buz S, Krabatsch T, Dehmel F, Kuppe H, Hetzer R, et al. High-dose aprotinin effectively reduces blood loss during on-pump coronary artery bypass grafting with bivalirudin anticoagulation. J Thorac Cardiovasc Surg. 2008 Mar;135(3):685-7.
[14] Pagano D, Howell NJ, Freemantle N, Cunningham D, Bonser RS, Graham TR, et al. Bleeding in cardiac surgery: the use of aprotinin does not affect survival. J Thorac Cardiovasc Surg. 2008 Mar;135(3):495-502.
[15] Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 2008;358:771-83.
[16] Shaw AD, Stafford-Smith M, White WD, Philips-Bute B, Swaminathan M, Milano C, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358:784-93.
[17] Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358:2319-31.
[18] Kain K, Catto AJ, Grant PJ. Impaired fibrinolysis and increased fibrinogen levels in South Asian subjects. Atherosclerosis 2001; 156(2):457-61
[19] Forouhi NG, Rumley A, Lowe GD. Specific elevation in plasma tissue plasminogen activator antigen concentrations in South Asians relative to Europeans. Blood Coagul Fibrinolysis 2003;14(8):755-60
[20] El Rouby S, Mestres CA, LaDuca FM, Zucker ML. Racial and ethnic differences in warfarin response. J Heart Valve Dis 2004; 13(1):15-21.
[21] Yu HY, Liu CH, Chen YS, Wang SS, Chu SH, Lin FY. Relationship of international normalized ratio to bleeding and thromboembolism rates in Taiwanese patients receiving vitamin K antagonist after mechanical valve replacement. J Formos Med Assoc 2005; 104(4):236-43.
[22] McEvoy MD, Reeves ST, Reves JG, Spinale FG. Aprotinin in cardiac surgery: a review of conventional and novel mechanisms of action. Anesth Analg 2007; 105:949-62.
[23] Khan TA, Bianchi C, Voisine P. Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest. J Thorac Cardiovasc Surg 2004; 128(4): 602-8.
[24] Lazar HL, Bao Y, Tanzillo L, O'Gara P, Reardon D, Price D, et al. Aprotinin decreases ischemic damage during coronary revascularization. J Card Surg . 2005 Nov-Dec;20(6):519-23.
[25]Kunt AS,Darcin OT,Aydin S,Demir D,Selli C,Andac MH.Mini-dose pump-prime aprotinin inhibited enhanced fibrinolytic activity and reduced blood loss and transfusion requirements after coronary artery bypass surgery.J Thromb Thrombolysis.2005 Jun;19(3):197-200.
[26]Erdogan M,Kalaycioglu S,Iriz E.Protective effect of aprotinin against lung damage in patients undergoing CABG surgery.Acta Cardiol.2005 Aug;60(4
[1]Sundt TM Ⅲ,Kouchoukos NT,Saffitz JE,Murphy SF,Wareing TH,Stahl DJ.Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest.Ann Thorac Surg 1993;55:1418-24.
[2]Feindt PR,Walcher S,Volkmer I,et al.Effects of high dose aprotinin on renal function in aortocoronary bypass grafting.Ann Thorac Surg 1995;60:1076-80.
[3]Alderman EL,Levy JH,Rich JB.Analyses of coronary graft patency after aprotinin use.J Thorac Cardiovasc Surg.1998;116:716-730.
[4]Michael Havel,MD,Florian Grabenw(o|¨)ger,MD,Johannes Schneider;MD.Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood.J Thorac Cardiovasc Surg 1994;107:807-810.
[5]Hayashida N,Isomura T,Sato T,Effects of minimal-dose aprotinin on coronary artery bypass grafting.J Thorac Cardiovasc Surg 1997;114(2):261-9.
[6]Murkin JM.Attenuation of neurologic injury during cardiac surgery.Ann Thorac Surg 2001;72(5):S1838-44.
[7]Sedrakyan A,Treasure T,Elefteriades JA.Efect of aprotinin on clinical outcomes in coronary artery bypass graft surgery:a systematic review and meta-analysis of randomized clinical trials.J Thorac Cardiovasc Surg 2004;128:442-448
[8]Poston RS,White C,Gu J.Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery bypass grafting.Ann Thorac Surg 2006;81(1):104-10.
[9]Royston D,Levy JH,Fitch J.Full-dose aprotinin use in coronary artery bypass graft surgery:an analysis of perioperative pharmacotherapy and patient outcomes.Anesth Analg 2006;103(5):1082-8
[10]Ronald A,Dunning J.Does use of aprotinin decrease the incidence of stroke and neurological complications in adult patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 2006;5(6):767-73.
[11]Mangano DT,Tudor IC,Dietzel C,Tudor IC,Juneja R,Filipescu D,Hoeft A,Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353—365.
[12] Mangano DT, Miao Y, Vuylsteke A. Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007;297(5):471-9.
[13] Shaw AD, Stafford-Smith M, White WD, Philips-Bute B, Swaminathan M, Milano C, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358:784-93.
[14] Sebastian Schneeweiss, M.D., Sc.D., John D. Seeger, Pharm.D., Dr.P.H., Joan Landon, M.P.H., and Alexander M. Walker, M.D., Dr.P.H. Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death. N Engl J Med 2008; 358:771-783.
[15] Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358:2319-31.
[16] Meade TW, Brozovic M, Chakrabarti R, Haines AP, North WR, Stirling Y. Ethnic group comparisons of variables associated with ischaemic heart disease. Br Heart J 1978 ;40(7):789-95
[17] Shephard RJ. The influences of race and environment on ischemic heart disease. Can Med Assoc J 1974 ;111(12):1336-40.
[18] Alter M. Black-white differences in stroke frequency: challenges for research. Neuroepidemiology 1994;13(6):301-7
[19] Frey JL, Jahnke HK, Bulfinch EW. Differences in stroke between white, Hispanic, and Native American patients: the Barrow Neurological Institute stroke database. Stroke 1998;29(1):29-33.
[20] Kain K, Catto AJ, Grant PJ. Impaired fibrinolysis and increased fibrinogen levels in South Asian subjects. Atherosclerosis 2001;156(2):457-61
[21] Forouhi NG, Rumley A, Lowe GD, Specific elevation in plasma tissue plasminogen activator antigen concentrations in South Asians relative to Europeans. Blood Coagul Fibrinolysis 2003;14(8):755-60
[22] El Rouby S, Mestres CA, LaDuca FM, Zucker ML. Racial and ethnic differences in warfarin response. J Heart Valve Dis 2004;13(1):15-21.
[23] Yu HY, Liu CH, Chen YS, Wang SS, Chu SH, Lin FY. Relationship of international normalized ratio to bleeding and thromboembolism rates in Taiwanese patients receiving vitamin K antagonist after mechanical valve replacement. J Formos Med Assoc 2005;104(4):236-43.
[1]Mangano DT,Tudor IC,Dietzel C,Tudor IC,Juneja R,Filipescu D,Hoefl A,Fontes ML,Hillel Z,Ott E,Titov T,Dietzel C,Levin J.The risk associated with aprotinin in cardiac surgery.N Engl J Med 2006;354:353-365.
[2]Mangano DT,Miao Y,Vuylsteke A.Mortality associated with aprotinin during 5years following coronary artery bypass graft surgery.JAMA 2007;297(5):471-9.
[3]Shaw AD,Stafford-Smith M,White WD,Phllips-Bute B,Swaminathan M,Milano C,et al.The effect of aprotinin on outcome after coronary-artery bypass grafting.N Engl J Med 2008;358:784-93.
[4]Sebastian Schneeweiss,M.D.,Sc.D.,John D.Seeger,Pharm.D.,Dr.P.H.,Joan Landon,M.P.H.,and Alexander M.Walker,M.D.,Dr.P.H.Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death.N Engl J Med 2008;358:771-783.
[5]Fergusson DA,Hebert PC,Mazer CD,Fremes S,MacAdams C,Murkin JM,et al.A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.N Engl J Med 2008;358:2319-31.
[6].Ruel MA,Wang F,Bouker ME,et al:Is tranexamic acid safe in patients undergoing coronary endarterectomy? Ann Thorac Surg 71:1508-1511,2001
[7]Kareski J,Djaiani G,Carroll J,et al:Tranexamic acid and early saphenous vein graft patency in conventional coronary artery bypass graft surgery:A prospective randomized controlled clinical trial.J Thorac Cardiovasc Surg 130:309-314,2005
[8].Levi M,Cromheecke ME,de Jonge E,et al:Pharmacological strategies to decrease excessive blood loss in cardiac surgery:A metaanalysis of clinically relevant endpoints.Lancet 354:1940-1947,1999
[9].Biglioli P,Cannata A,Alamanni F,et al:Biological effects of off-pump vs.on-pump coronary artery surgery:Focus on inflammation,hemostasis and oxidative stress.Eur J Cardiothorac Surg 24:260-269,2003
[10]. Hekmat K, Zimmermann T, Kampe S, et al: Impact of tranexamic acid vs. aprotinin on blood loss and transfusion requirements after cardiopulmonary bypass: A prospective, randomized, double-blind trial. Curr Med Res Opin 20:121-126, 2004
[11]. Iaco AL, Contini M, Teodori G, et al: Off or on bypass: What is the safety threshold? Ann Thorac Surg 68:1468-1469,1999
[12]. Cartier R, Brann S, Dagenais F, et al: Systematic off-pump coronary artery revascularization multivessel disease: Experience of three hundred cases. J Thorac Cardiovasc Surg 119:221-229, 2000
[13]. Nader ND, Reich NT, Khadra WZ, et al: Blood product use in cardiac revascularization: comparison of on- and off-pump techniques. Ann Thorac Surg 68:1640-1643,1999
[14]. Wei M, Jian K, Guo Z, et al: Tranexamic acid reduces postoperative bleeding in off-pump coronary artery bypass grafting. Scand Cardiovasc J 40:105-190, 2006
[15]. Casati V, Gerli Ch, Franco A, et al: Tranexamic acid in offpump coronary surgery: A preliminary, randomized, double-blind, placebo- controlled study. Ann Thorac Surg 72:470-475,2001
[16]. Vanek T, Jares M, Fajt R, et al: Fibrinolytic inhibitors in off-pump coronary surgery: A prospective, randomized, double-blind TAP study. Eur J Cardiothorac 28:563-568, 2005
[17]. Jares M, Vanek T, Straka Z, et al: Tranexamic acid reduces bleeding after off-pump coronary artery bypass grafting. J Cardiovasc Surg (Torino) 44:205-208, 2003
[18]. Casati V, Delia Valle P, Benussi S, et al: Effects of tranexamic acid in postoperative bleeding and related hematological variables in coronary surgery: Comparison between on-pump and off-pump techniques. J Thorac Cardiovasc Surg 128:83-91, 2004
[19] Thiagarajamurthy S, Levine A, Dunning J. Does prophylactic tranexamic acid safely reduce bleeding without increasing thrombotic complications in patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 2004;(3):489—94.
[20] Ovrum E, Am HE, Abdelnoor M, Oystese R, Ringdal ML. Tranexamic acid (Cyklokapron) is not necessary to reduce blood loss after coronary artery bypass operations. J Thorac Cardiovasc Surg 1993;105(1):78—83.
[1]. Dietrich W. Cardiac surgery and the coagulation system. Curr Opin Anesth 2000;13:27-34
[2]. Laffey J, Boylan J, Cheng D. The systemic inflammatory response to cardiac surgery. Implications for the anesthesiologist. Anesthesiology 2002;97:215-52
[3]. Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 2003;75:S715-20
[4]. Gravlee GP. Update on cardiopulmonary bypass. Curr Opin Anesth 2001;14:11-16
[5]. Mangano DT. Cardiovascular morbidity and CABG surgery—a perspective: epidemiology, costs, and potential therapeutic solutions. J Card Surg 1995;10:366-8
[6]. Edmunds LH Jr. Why cardiopulmonary bypass makes people sick: strategies to control the blood-synthetic interface. In: Karp RB, Laks H, Wechsler AS, eds. Advances in cardiac surgery. Vol 6. Chicago, IL: Mosby-Year Book, 1995:131-67
[7]. Shernan SK. Perioperative myocardial ischemia reperfusion injury. Anesthesiol Clin North America 2003;21:465-85
[8]. Alston TA. Aprotinin. Int Anesthesiol Clin 2004;42:81-91
[9] Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993;55:552-9
[10]. de Mendonca-Filho HT, Pereira KC, Fontes M, Vieira DA, de Mendonca ML, Campos LA, Castro-Faria-Neto HC. Circulating inflammatory mediators and organ dysfunction after cardiovascular surgery with cardiopulmonary bypass: a prospective observational study. Crit Care 2006;10:R46
[11]. Bolli R, Becker L, Gross G, Mentzer R, Balshaw D, Lathrop DA. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 2004;95:125-34
[12]. Levy J. Overview of clinical efficacy and safety of pharmacologic strategies for blood conservation. Am J Health Syst Pharm 2005;62:S15-18
[13]. Englberger L, Kipfer B, Berdat PA, Nydegger UE, Carrel TP. Aprotinin in coronary operation with cardiopulmonary bypass: does "low-dose" aprotinin inhibit the inflammatory response? Ann Thorac Surg 2002;73:1897-1904
[14]. Koster A, Huebler S, Merkle F, Hentschel T, Grundel M, Krabatsch T, Tambeur L, Praus M, Habazettl H, Kuebler WM, Kuppe H. Heparin-level-based anticoagulation management during cardiopulmonary bypass: a pilot investigation on the effects of a half-dose aprotinin protocol on postoperative blood loss and hemostatic activation and inflammatory response. Anesth Analg 2004;98:285-90
[15]. Greilich PE, Brouse CF, Rinder CS, Smith BR, Sandoval BA, Rinder HM, Eberhart RC, Jessen ME. Effects of -aminocaproic acid and aprotinin on leukocyte-platelet adhesion in patients undergoing cardiac surgery. Anesthesiology 2004;100:225-33
[16]. Despotis GJ, Avidan MS, Hogue CW. Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg 2001;72:S1821-31
[17]. Pruefer D, Buerke U, Khalil M, Dahm M, Darius H, Oelert H, Buerke M. Cardioprotective effects of the serine protease inhibitor aprotinin after regional ischemia and reperfusion on the beating heart. J Thorac Cardiovasc Surg 2002; 124:942-9
[18]. Hill GE, Diego RP, Stammers AH, Huffman SM, Pohorecki R. Aprotinin enhances the endogenous release of interleukin-10 after cardiac operations. Ann Thorac Surg 1998;65:66-9
[19]. Rahman A, Ustunda B, Burma O, Ozercan IH, Cekirdekci A, Bayar MK. Does aprotinin reduce lung perfusion after cardiopulmonary bypass? Eur J Cardiothorac Surg 2000;18:583-8
[20]. Kuepper F, Dangas G, Mueller-Chorus A, Kulka PM, Zenz M, Wiebalck A. Fibrinolytic activity and bleeding after cardiac surgery with cardiopulmonary bypass and low-dose aprotinin therapy. Blood Coagul Fibrinolysis 2003; 14:147-53
[21]. Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. Anesth Analg 1997; 85:1258-67
[22]. Levy JH, Pifarre R, Schaff HV, Horrow J, Albus R, Spiess B, Rosengart TK, Murray J, Clark RE, Smith P. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995;92:2236-44
[23]. Landis RC, Asimakopoulos G, Poullis M, Haskard DO, Taylor KM. The antithrombotic and antiinflammatory mechanisms of action of aprotinin. Ann Thorac Surg 2001;72:2169-75
[24]. Frumento RJ, O'Malley CMN, Bennett-Guerrero E. Stroke after cardiac surgery: a retrospective analysis of the effect of aprotinin dosing regimens. Ann Thorac Surg 2003;75:479-84
[25]. Forestier F, Belisle S, Robitaille D, Martineau R, Perrault LP, Hardy JF. Low-dose aprotinin is ineffective to treat excessive bleeding after cardiopulmonary bypass. Ann Thorac Surg 2000;69:452-6
[26]. Taggart DP, Djapardy V, Naik M, Davies A. A randomized trial of aprotinin (Trasylol) on blood loss, blood product requirement, and myocardial injury in total arterial grafting. J Thorac Cardiovasc Surg 2003;126:1084-94
[27]. Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in a coronary arterty bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004;128:442-8
[28]. Lemmer JH, Dilling EW, Morton JR, Rich JB, Robicsek F, Bricker D, Hantler C, Copeland J, Ochsner J, Daily P, Whitten C, Noon G, Maddi R. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 1996;62:1659-68
[29]. Gott JP, Cooper WA, Schmidt FE, Brown WM III, Wright CE, Merlino JD, Fortenberry JD, Clark WS, Guyton RA. Modifying risk for extracorporeal circulation: trial of four anti-inflammatory strategies. Ann Thorac Surg 1998;66:747-54
[30]. Hill GE, Pohorecki R, Alonso A, Rennard S, Robbins R. Aprotinin reduces interleukin-8 production and lung neutrophil accumulation after cardiopulmonary bypass. Anesth Analg 1996;83:696-700
[31]. Greilich PE, Okada K, Latham P, Kumar RR, Jessen ME. Aprotinin but not _-aminocaproic acid decreases interleukin-10 after cardiac surgery with extracorporeal circulation. Circulation 2004;104:1265-9
[32]. Bull D, Connors R, Albanil A, Reid BB, Neumayer LA, Nelson R, Stringham JC, Karwande SV. Cardiopulmonary support and physiology. Aprotinin preserves myocardial biochemical function during cold storage through suppression of tumor necrosis factor. J Thorac Cardiovasc Surg 2000;119:242-50
[33]. Bull D, Maurer J. Aprotinin and preservation of myocardial function after ischemia-reperfusion injury. Ann Thorac Surg 2003;75:S735-9
[34]. McCarthy RJ, Tuman K, O'Connor C, Ivankovish AD. Aprotinin pretreatment diminished postichemic myocardial contractile dysfunction in dogs. Anesth Analg 1999;89:1096-1101
[35]. Peters DC, Noble S. Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery. Drugs 1999;57:233-60
[36]. Waxier B, Rabito S. Aprotinin: a serine protease inhibitor with therapeutic actions: its interaction with ace inhibitors. Curr Pharm Design 2003;9:777-87
[37]. Engles L. Review and application of serine protease inhibition in coronary artery bypass graft surgery. Am J Health Syst Pharm 2005;62:S9-14
[38]. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-65
[39]. Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A, Wijeysundera DN, Fedorko L, Yau TM. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006;46:327-38
[40]. Dietrich W, Busley R, Kriner M. High-dose aprotinin in cardiac surgery: is high-dose high enough? An analysis of 8281 cardiac surgical patients treated with aprotinin. Anesth Analg 2006; 103:1074-81
[41]. Royston D, Levy JH, Fitch J, Dietrich W, Body SC, Murkin JM, Spiess BD, Nadel A. Full-dose aprotinin use in coronary artery bypass graft surgery: an analysis of perioperative pharmacotherapy and patient outcomes. Anesth Analg 2006;103:1082-8
[42]. Hogue CW, London MJ. Aprotinin use during cardiac surgery: a new or continuing controversy? Anesth Analg 2006;103:1067-70
[43]. Body SC, Mazer CD. Pro: aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth Analg 2006;103:1354-9
[44]. Beattie WS, Karkouti K. Con: aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth Analg 2006;103:1360-4
[45]. Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, Hoeft A, Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J. Mortality associated with aprotinin during 5 years after coronary artery bypass graft surgery. JAMA 2007;297:471-9
[46]. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-91
[47]. Wildevuur CR, Eijsman L, Roozendaal KJ, Harder MP, Chang M, van Oeveren W. Platelet preservation during cardiopulmonary bypass with aprotinin. Eur J Cardiothorac Surg 1989;3:533-7
[48]. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Reduced blood loss following open heart surgery with aprotinin (Trasylol) is associated with an increase in intraoperative activated clotting time (ACT). J Cardiothorac Anesth 1989;3:80
[49]. Alajmo F, Calamai G, Perna AM, Melissano G, Pretelli P, Palmarini MF, Carbonetto F, Noferi D, Boddi V, Palminiello A. High-dose aprotinin: hemostatic effects in open heart operations. Ann Thorac Surg 1989;48:536-9
[50]. Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354:1940-7
[51]. Fraedrich G, Weber C, Bernard C, Hettwer A, Schlosser V. Reduction of blood transfusion requirement in open heart surgery by administration of high doses of aprotininpreliminary results. Thorac Cardiovasc Surg 1989;37:89—91
[52]. Dietrich W, Henze R, Barankay A, Niekau E, Sebening F, Richter JA. High-dose aprotinin application reduces homologous blood requirement in cardiac surgery. J Cardiothorac Anesth 1989;3:79
[53]. Dietrich W, Barankay A, Dilthey G, Henze R, Niekau E, Sebening F, Richter JA. Reduction of homologous blood requirement in cardiac surgery by intraoperative aprotinin application—clinical experience in 152 cardiac surgical patients. Thorac Cardiovasc Surg 1989;37:92-8
[54]. Royston D. The serine antiprotease aprotinin (Trasylol): a novel approach to reducing postoperative bleeding. Blood Coagul Fibrinolysis 1990;1:55-69
[55]. Niimi KS. Aprotinin dosing: how much is enough? J Extra Corpor Technol 2004;36:384-90
[56]. Smith PK, Datta SK, Muhlbaier LH, Samsa G, Nadel A, Lipscomb J. Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials. Ann Thorac Surg 2004;77:635-42
[57]. Royston D. High-dose aprotinin therapy: a review of the first five years' experience. J Cardiothorac Vasc Anesth 1992;6: 76-100
[58]. Royston D, Cardigan R, Gippner-Steppert C, Jochum M. Is perioperative plasma aprotinin concentration more predictable and constant after a weight-related dose regimen? Anesth Analg 2001;92:830-6
[59]. Bennett-Guerrero E, Sorohan JG, Howell ST, Ayuso L, Cardigan RA, Newman MF, Mackie IJ, Reves JG, Mythen MG. Maintenance of therapeutic plasma aprotinin levels during prolonged cardiopulmonary bypass using a large-dose regimen. Anesth Analg 1996;83:1189-92
[60]. Beath SM, Nuttall GA, Fass DN, Oliver WC Jr, Ereth MH, Oyen LJ. Plasma aprotinin concentrations during cardiac surgery: full- versus half-dose regimens. Anesth Analg 2000;91:257-64
[61]. Levy JH, Bailey JM, Salmenpera M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 1994;80:1013-18
[62]. Wegner J. Biochemistry of serine protease inhibitors and their mechanisms of action: a review. J Extra Corpor Technol 2003;35:326-38
[63]. Khan MH, Gikakis N, Miyamoto S, Rao AK, Cooper SL, Edmunds LH Jr, Colman RW. Aprotinin inhibits thrombin formation and monocyte tissue factor in simulated cardiopulmonary bypass. Ann Thorac Surg 1999;68:473-8
[64]. Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheikh S, Hunt B, Smith KJ. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993;82:3350-7
[65]. Taby O, Chabbat J, Steinbuch M. Inhibition of activated protein C by aprotinin and the use of the insolublized inhibitor for its purification. Thromb Res 1990;59:27-35
[66]. Brown NJ, Nadeau JH, Vaughan DE. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin. Thromb Haemost 1997;77:522-5
[67]. Khalil PN, Ismail M, Kalmar P, von Knobelsdorff G, Marx G. Activation of fibrinolysis in the pericardial cavity after cardiopulmonary bypass. Thromb Haemost 2004;92:568-74
[68]. Kang HM, Kalnoski MH, Frederick M, Chandler WL. The kinetics of plasmin inhibition by aprotinin in vivo. Thromb Res 2005; 115:327-40
[69]. Day JR, Punjabi PP, Randi AM, Haskard DO, Landis RC, Taylor KM. Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery. Circulation 2004; 110:2597-600
[70]. Ferraris VA, Ferraris SP, Singh A, Fuhr W, Koppel D, McKenna D, Rodriguez E, Reich H. The platelet thrombin receptor and postoperative bleeding. Ann Thorac Surg 1998;65:352-8
[71]. Day JR, Taylor KM, Lidington EA, Mason JC, Haskard DO, Randi AM, Landis RC. Aprotinin inhibits proinflammatory activation of endothelial cells by thrombin through the protease-activated receptor 1. J Thorac Cardiovasc Surg 2006;131:21-7
[72]. Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittelforschung 1983;33:479-94
[73]. Dietrich W, Spannagl M, Jochum M, Wendt P, Schramm W, Barankay A, Sebening F, Richter JA. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119-26
[74]. Speekenbrink RG, Wildevuur CR, Sturk A, Eijsman L. Lowdose and high-dose aprotinin improve hemostasis in coronary operations. J Thorac Cardiovasc Surg 1996;112:523-30
[75]. Li S, Ji H, Lin J, Lenehan E, Ji B, Liu J, Liu J, Long C, Crane TA. Combination of acute preoperative plateletpheresis, cell salvage, and aprotinin minimizes blood loss and requirement during cardiac surgery. J Extra Corpor Technol 2005;37:9 -14
[76]. Harmon D, Lan W, Shorten G. The effect of aprotinin on hypoxia-reoxygenation-induced changes in neutrophil and endothelial function. Eur J Anaesthesiol 2004;21:973-9
[77]. Mojcik CF, Levy JH. Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. Ann Thorac Surg 2001;71:745-54
[78]. Asimakopoulos G, Thompson R, Nourshargh S, Lidington EA, Mason JC, Ratnatunga CP, Haskard DO, Taylor KM, Landis RC. An anti-inflammatory property of aprotinin detected at the level of leukocyte extravasation. J Thorac Cardiovasc Surg 2000;120:361-9
[79]. Wachtfogel YT, Kucich U, Hack CE, Gluszko P, Niewiarowski S, Colman RW, Edmunds LH Jr. Aprotinin inhibits the contact, neutrophil, and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993;106: 1-9
[80]. Ulker S, Cinar MG, Bayraktutan U, Evinc A. Aprotinin impairs endothelium-dependent relaxation in rat aorta and inhibits nitric oxide release from rat coronary endothelial cells. Cardiovasc Res 2001;50:589-96
[81]. Ulker S, McKeown PP, Bayraktutan U. Aprotinin impairs coronary endothelial function and down-regulates endothelial NOS in rat coronary microvascular endothelial cells. Cardiovasc Res 2002;55:830-7
[82]. Fischer JH, Steinhoff M. Effects of aprotinin on endotheliumdependent relaxation of large coronary arteries. Eur J Cardiothorac Surg 2005;28:801-4
[83]. Pandey R, Deshpande SB. Protective effects of aprotinin on respiratory and cardiac abnormalities induced by Mesobunthus tamulus venom in adult rats. Toxicon 2004;44:201-5
[84]. Venturini G, Colasanti M, Ascenzi P. Aprotinin, the first competitive protein inhibitor of NOS activity. Biochem Biophys Res Commun 1998;249:263-5
[85]. Pruefer D, Makowski J, Dahm M, Guth S, Oelert H, Darius H, Buerke M. Aprotinin inhibits leukocyte-endothelial cell interactions after hemorrhage and reperfusion. Ann Thorac Surg 2003;75:210-15
[86]. McEvoy MD, Taylor AB, Zavadzkas JA, Mains IM, Jeffords LB, Ford RL, Beck C, Stroud RE, Reeves ST, Spinale FG. Aprotinin causes dose-dependent and differential effects on myocardial contractility, cytokine release and oxidative stress with ischemia-reperfusion. Circulation 2006;114:A2529
[87]. Mossinger H, Dietrich W, Braun SL, Jochum M, Meisner H, Richter JA. High-dose aprotinin reduces activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation in pediatric cardiac surgery. Ann Thorac Surg 2003;75:430-7
[88]. Governa M, Fenoglio I, Amati M, Valentino M, Bolognini L, Coloccini S, Volpe AR, Carmignani M, Fubini B. Cleavage of the fifth component of human complement and release of a split product with C5a-like activity by crystalline silica through free radical generation and kallikrein activation. Toxicol Appl Pharmacol 2002;179:129-36
[89]. Himmelfarb J, Holbrook D, McMonagle E. Effects of aprotinin on complement and granulocyte activation during ex vivo hemodialysis. Am J Kidney Dis 1994;24:901-6
[90]. Olivencia-Yurvati AH, Wallace WE, Wallace N, Dimitrijevich D, Knust JK, Haas L, Raven PB. Intraoperative treatment strategy to reduce the incidence of postcardiopulmonary bypass atrial fibrillation. Perfusion 2002;17(suppl):35-9
[91]. Sedrakyan A, Wu A, Sedrakyan G, Diener-West M, Tranquilli M, Elefteriades J. Aprotinin use in thoracic aortic surgery: safety and outcomes. J Thorac Cardiovasc Surg 2006; 132:909-17
[92]. Khan TA, Bianchi C, Voisine P, Feng J, Baker J, Hart M, Takahashi M, Stahl G, Sellke FW. Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest. J Thorac Cardiovasc Surg 2004;128:602-8
[93]. Lazar HL, Bao Y, Tanzillo L, O'Gara P, Reardon D, Price D, Crowley R, Cabral HJ. Aprotinin decreases ischemic damage during coronary revascularization. J Card Surg 2005;20:519-23
[94]. Sirieix D, Clinquart F, Delayance S, Massonnet-Castel S, Paris M, Baron JF. Does aprotinin modify the effects of ischaemiareperfusion on the myocardial performance of a blood perfused isolated rabbit heart? Eur J Anaesthesiol 1999;16:712-18
[95]. Khan TA, Bianchi C, Araujo E, Voisine P, Xu SH, Feng J, Li J, Sellke FW. Aprotinin preserves cellular junctions and reduces myocardial edema after regional ischemia and cardioplegic arrest. Circulation 2005;112:I196-201
[96]. Hendrikx M, Rega F, Jamaer L, Valkenborgh T, Gutermann H, Mees U. Na(+)/H(+)-exchange inhibition and aprotinin administration: promising tools for myocardial protection during minimally invasive CABG. Eur J Cardiothorac Surg 2001;19: 633-9
[97]. Fra¨_dorf J, Ebel D, Weber NC, Preckel B, Schlack W. Sevoflurane induced preconditioning is blocked by aprotinin in rat hearts in vivo. Anesthesiology 2006; 105:A1086
[98]. Zhang X, Liu B. Effects of aprotinin on extravascular lung water in patients undergoing mitral valve replacement. Anesthesiology 2006;105:A1227
[99]. Mathias MA, Tribble CG, Dietz JF, Nguyen RP, Shockey KS, Kern JA, Kron IL. Aprotinin improves pulmonary function during reperfusion in an isolated lung model. Ann Thorac Surg 2000;70:1671-4
[100]. Yun TJ, Rho JR. Aprotinin attenuates the elevation of pulmonary vascular resistance after cardiopulmonary bypass. J Korean Med Sci 2006;21:25-9
[101]. Eren S, Esme H, Balci AE, Cakir O, Buyukbayram H, Eren MN, Erdinc L, Satici O. The effect of aprotinin on ischemiareperfusion injury in an in situ normothermic ischemic lung model. Eur J Cardiothorac Surg 2003;23:60-5
[102]. Ege T, Arar C, Canbaz S, Cikirikcioglu M, Sunar H, Yuksel V, Duran E. The importance of aprotinin and pentoxifylline in preventing leukocyte sequestration and lung injury caused by protamine at the end of cardiopulmonary bypass surgery. Thorac Cardiovasc Surg 2004;52:10-15
[103]. Koksal C, Bozkurt AK, Ustundag N, Konukoglu D, Musellim B, Sirin G, Cortelekoglu T, Sayin AG. Attenuation of acute lung injury following lower limb ischemia/reperfusion: the pharmacological approach. J Cardiovasc Surg 2006;47:445-9
[104]. Erdogan M, Kalaycioglu S, Iriz E. Protective effect of aprotinin against lung damage in patients undergoing CABG surgery. Acta Cardiol 2005;60:367-72
[105]. Nader ND, Davidson BA, Tait AR, Holm BA, Knight PR. Serine antiproteinase administration preserves innate superoxide dismutase levels after acid aspiration and hyperoxia but does not decrease lung injury. Anesth Analg 2005;101:213-19
[106]. Schweizer A, Hohn L, Morel DR, Kalangos A, Licker M. Aprotinin does not impair renal haemodynamics and function after cardiac surgery. Br J Anaesth 2000;84:16-22
[107]. Fauli A, Gomar C, Campistol JM, Alvarez L, Manig AM, Matute P. Kidney-specific proteins in patients receiving aprotinin at high- and low-dose regimens during coronary artery bypass graft with cardiopulmonary bypass. Eur J Anaesthesiol 2005;22:666-71
[108]. Wagener G, Jan M, Kim M, Mori K, Barasch JM, Sladen R, Lee HT. Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006;105:485-91
[109]. Wagener G, Gubitosa G, Jalbout M, Sladen R, Lee HT. Aprotinin increases urinary NGAL, a marker for renal tubular injury after cardiac surgery. Anesthesiology 2006;105:A1732
[110]. Kher A, Meldrum KK, Hile KL, Wang M, Tsai BM, Turrentine MW, Brown JW, Meldrum DR. Aprotinin improves kidney function and decreases tubular cell apoptosis and proapoptotic signaling after renal ischemia-reperfusion. J Thorac Cardiovasc Surg 2005;130:662-9
[111]. Ozer Z, Sucu N, Dusmez D, Tamer L, Altunkan AA, DIkmengII M, Oral U. The effect of aprotinin on ischemiareperfusion injury in the rabbit kidney. Pharmacol Res 2001;44:455-60
[112]. Ramlawi B, Rudolph JL, Mieno S, Khabbaz K, Sodha NR, Boodhwani M, Levkoff SE, Marcantonio ER, Sellke FW. Serologic markers of brain injury and cognitive function after cardiopulmonary bypass. Ann Surg 2006;244:593-601
[113]. Harmon DC, Ghori KG, Eustace NP, O'Callaghan SJ, O'Donnell AP, Shorten GD. Aprotinin decreases the incidence of cognitive deficit following CABG and cardiopulmonary bypass: a pilot randomized controlled study. Can J Anaesth 2004;51:1002-9
[114]. Grocott HP, Sheng H, Miura Y, Sarraf-Yazdi S, Mackensen GB, Pearlstein RD, Warner DS. The effects of aprotinin on outcome from cerebral ischemia in the rat. Anesth Analg 1999;88:l-7
[115]. Takahashi H, Nagai N, Urano T. Role of tissue plasminogen activator/plasmin cascade in delayed neuronal death after transient forebrain ischemia. Neurosci Lett 2005;381:189-93
[116]. Ranby M, Bergsdorf N, Nilsson T. Enzymatic properties of the one- and two-chain forms of tissue plasminogen activator. Thromb Res 1982;27:175-83
[117]. Durgut K, Hosgor K, Gormus N, Ozergin U, Solak H. The cerebroprotective effects of pentoxifylline and aprotinin during cardiopulmonary bypass in dogs. Perfusion 2004;19:101-6
[118]. Anttila V, Hagino I, Iwata Y, Mettler BA, Lidov HG, Zurakowski D, Jonas RA. Aprotinin improves cerebral protection: evidence from a survival porcine model. J Thorac Cardiovasc Surg 2006; 132:948-53
[119]. McEvoy MD, Taylor AB, Zavadzkas JA, McLean JE, Reeves ST, Spinale FG. Dose-dependent effects of aprotinin on systolic performance in a mouse model of ischemia-reperfusion. Anesth Analg 2007;104:S37
[120]. Kaminski KA, Bonda TA, Korecki J, Musial WJ. Oxidative stress and neutrophil activation—the two keystones of ischemia/reperfusion injury. Int J Cardiol 2002;86:41-59
[121]. Li JM, Shah AM. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 2004;287:R1014-30
[122]. Bruda NL, Hurlbert BJ, Hill GE. Aprotinin reduces nitric oxide production in vitro and in vivo in a dose-dependent manner. Clin Sci (Lond) 1998;94:505-9
[123]. Buerke M, Sankat D, Schlitt A, Buerke U. Serine protease inhibitor aprotinin exerts cardio protective effects by inhibition of gene activation following myocardial ischemia and reperfusion in rats. Circulation 2006;114:A2528
[124]. Wippermann CF, Schmid FX, Eberle B, Huth RG, Kampmann C, Schranz D, Oelert H. Reduced inotropic support after aprotinin therapy during pediatric cardiac operations. Ann Thorac Surg 1999;67:173-6
[125]. Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chairman B, Nadel A. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998;116:716-30
[126]. Yang Z, Eton D, Zheng F, Livingstone AS, Yu H. Effect of tissue plasminogen activator on vascular smooth muscle cells. J Vasc Surg 2005;42:532-8
[127]. Mukherjee R, Herron AR, Lowry AS, Stroud RE, Stroud MR, Wharton JM, Ikonomidis JS, Crumbley AJ III, Spinale FG, Gold MR. Selective induction of matrix metalloproteinases and tissue inhibitor of metalloproteinases in atrial and ventricular myocardium in patients with atrial fibrillation. Am J Cardiol 2006;97:532-7
[128]. Koch CG, Li L, Van Wagoner DR, Duncan AI, Gillinov AM, Blackstone EH. Red cell transfusion is associated with an increased risk for postoperative atrial fibrillation. Ann Thorac Surg 2006;82:1747-56
[129]. Tselentakis EV, Woodford E, Chandy J, Gaudette GR, Saltman AE. Inflammation effects on the electrical properties of atrial tissue and inducibility of postoperative atrial fibrillation. J Surg Res 2006;135:68-75
[130]. Roberts RF, Nishanian GP, Carey JN, Darbinian SH, Kim JD, Sakamaki Y, Chang JY, Starnes VA, Barr ML. Addition of aprotinin to organ preservation solutions decreases lung reperfusion injury. Ann Thorac Surg 1998;66:225-30
[131]. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med 1998;128: 194-203
[132]. Augoustides JG, Pochettino A, Ochroch EA, Cowie D, Weiner J, Gambone AJ, Pinchasik D, Bavaria JE, Jobes DR. Renal dysfunction after thoracic aortic surgery requiring deep hypothermic circulatory arrest: definition, incidence, and clinical predictors. J Cardiothorac Vasc Anesth 2006;20:673-7
[133]. Lemmer JH Jr, Stanford W, Bonney SL, Chomka EV, Karp RB, Laub GW, Rumberger JA, Schaff HV. Aprotinin for coronary artery bypass grafting: effect on postoperative renal function. Ann Thorac Surg 1995;59:132-6
[134]. D'Ambra MN, Akins CW, Blackstone EH, Bonney SL, Cohn LH, Cosgrove DM, Levy JH, Lynch KE, Maddi R. Aprotinin in primary valve replacement and reconstruction: a multicenter, double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg 1996;112:1081-9
[135]. Furnary AP, Hiratzka LF, Wu Y, Grunkemeier GL, Page SU. Does aprotinin increase the risk of renal failure in cardiac surgery patients? Circulation 2006;114:A3347
[136]. Baran D, Tenstad O, Aukland K. Aprotinin uptake in the proximal tubules in the rat kidney. II. Uptake site relative to glomerulus. J Struct Biol 2003;142:409-15
[137]. Baran D, Tenstad O, Aukland K. Aprotinin uptake in the proximal tubules in the rat kidney. I. Length of proximal tubular uptake segment. J Struct Biol 2003; 142:402-8
[138]. Mantur M, Kemona H, Dabrowska M, Dabrowska J, Sobolewski S, Prokopowicz J. Alphal-microglobulin as a marker of proximal tubular damage in urinary tract infection in children. Clin Nephrol 2000;53:283-87
[139]. Schmidt-Ott KM, Mori K, Kalandadze A, Li JY, Paragas N, Nicholas T, Devarajan P, Barasch J. Neutrophil gelatinaseassociated lipocalin-mediated iron traffic in kidney epithelia. Curr Opin Nephrol Hypertens 2006;15:442-9
[140]. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P. Identification of neutrophil gelatinaseassociated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003;14:2534-43
[141]. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231-8
[142]. Murkin JM. Attenuation of neurologic injury during cardiac surgery. Ann Thorac Surg 2001;72:S1838-44
[143]. Lee R, Tsuji K, Lee SR, Lo EH. Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci 2004;24:671-8
[144]. Seto S, Akahoshi M, Kusano S, Kitamura S, Hashiba K. Central effect of aprotinin, a serine protease inhibitor, on blood pressure in spontaneously hypertensive and Wistar-Kyoto rats. Adv Exp Med Biol 1989;247:49-54
[145]. Bessler H, Gilgal R, Djaldetti M, Zahavi I. Effect of pentoxifylline on the phagocytic activity, cAMP levels, and superoxide anion production by monocytes and polymorphonuclear cells.J Leukoc Biol 1986;40:747-54
[146].Jonsson H,Johnsson P,Hoglund P,Ailing C,Blomquist S.Elimination of S100B and renal function after cardiac surgery.J Cardiothorac Vasc Anesth 2000;14:698-701
[147].Rainer TH,Wong KS,Lam W,Lam NY,Graham CA,Lo YM.Comparison of plasma beta-globin DNA and S-100 protein concentrations in acute stroke.Clin Chim Acta 2007;376:190 - 6