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

【作者】 王现强；

【导师】 胡盛寿； 王巍； 郑哲； 敖虎山；

【作者基本信息】 中国协和医科大学 ， 心脏外科， 2009， 博士

【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。更多还原

【Abstract】 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.更多还原