抑肽酶联合控制性降压在脊柱手术中的应用

目的 探讨抑肽酶联合控制性降压在脊柱手术中应用的血液保护效应.方法 45例择期行脊柱手术患者,随机均分为抑肽酶联合控制性降压组(联合组)、单纯控制性降压组(降压组)和对照组.分别在术前、术毕、术后24 h抽血检测血常规和凝血功能.比较三组患者手术失血量、输血量和凝血功能变化.结果 联合组与降压组手术失血量、输血量、术后24 h切口引流量均较对照组明显下降(P<0.01),联合组上述指标低于降压组(P<0.05).与对照组和降压组比较,联合组术后部分凝血活酶时间(APTT)延长(P<0.01),纤维蛋白原(Fib)值偏高(P<0.05).结论 抑肽酶联合控制性降压可明显减少脊柱手术的失血量和异体血的输入量.     

Does perioperative use of aprotinin reduce the rejection rate in heart transplant recipients?

Objective: Allograft rejection continues to be one of the most common causes of mortality after heart transplantation. We investigated if perioperative use of antifibrinolytics such as aprotinin and tranexamic acid can decrease the rate of rejection after heart transplant and their effect on transfusion. Methods: A retrospective analysis was conducted on the data from patients who received a first heart transplant at Papworth Hospital between 2000 and 2005. Transplant registry and audit data were used for the study. Rejection biopsy results and treatment were used to designate rejection episodes as mild (grades 1A, 1B or 2 untreated) or severe (grades 2 treated, grades 3 and 4). The relationship between antifibrinolytics and rejection episodes was assessed using univariate and multiple Poisson regression. Kaplan–Meier methods and Kruskal–Wallis tests, respectively, were used to analyse survival/time to first rejection and transfusion. Results: There were 225 patients who underwent a first heart transplant between January 2000 and December 2005. Of these, 101 patients (44.9%) had received aprotinin, 63 (28.0%) tranexamic acid, 2 (0.9%) both (aprotinin and tranexamic acid) and 59 (26.2%) no antifibrinolytics. There was no difference in time to first rejection by antifibrinolytic treatment (p = 0.20). There was no difference in the rate of treated rejection per 100 patient-days between aprotinin and tranexamic acid groups between 0 and 3 months post-transplant, (0.6 in both), but aprotinin had a small clinical effect when compared to no treatment (0.6 vs 0.8, p = 0.54). Between 4 and 6 months, the treated and severe rejection rates were lower in the patients receiving aprotinin as compared to those receiving tranexamic acid, but these differences again did not reach statistical significance (0.1 vs 0.3, p = 0.14, 0.2 vs 0.4, p = 0.18). Aprotinin was associated with higher postoperative blood loss and transfusion requirements in the subgroup of patients that had a ventricular assist device, prior sternotomy or anticoagulant therapy. Conclusions: The use of aprotinin in heart transplant surgery may be associated with a small decrease in the incidence of treated/severe rejection within 6 months of transplantation. The perioperative use of antifibrinolytics did not influence time to first rejection or reduce blood transfusion.     

抑肽酶对小儿体外循环术后细胞因子的影响

目的：观察小儿体外循环术中，术后细胞因子肿瘤坏死因子（TNF）－α，白细胞介素（IL）－6，IL－8的变化，评价抑肽酶对体外循环炎 反应的抑制作用。方法：19例在体外循环下行心内直视手术的先天性心脏病病儿，随机分为2组，试验组10例，于转机过程中加入凶肽酶4－5万KIU／kg；对照组9例，未用抑肽酶，分别于麻醉后，升主动脉阻断后10min，停机后10min，停机后24h共4个时点采取动脉血，酶标免疫放射法分别测定IL－6，IL－8，TNF－α。结果：对照组IL－6，IL－8，TNF－α于体外循环开始后升高，IL－8，TNF－α于术后24h恢复至基础值，试验组TNF－α各时间点升高不明显，IL－6，IL－8升高幅度低于对照组（P＜0．01，0．05），结论：抑肽酶可能降低体外循环术后IL－6，IL－8，TNF－α等细胞因子水平，从而减轻炎性反应。     

Effects of aprotinin on hemorrhagic complications in ARDS patients during prolonged extracorporeal CO2 removal

The effects of aprotinin, a broad-based proteinase inhibitor, in the management of hemorrhagic complications during prolonged venovenous extracorporeal CO₂ removal in patients with adult respiratory distress syndrome are not evaluated. In two patients, aprotinin infusion was added to heparin to treat bleeding, occurring after few days of bypass and responsible for respiratory and hemodynamic deterioration. After aprotinin infusion (loading dose of 2×10⁶ kIU followed by a continuous infusion of 5×10⁵ kIU/h) combined with heparin, bleeding vanished until the end of bypass.     

不同剂量国产抑肽酶对体外循环中血小板的保护作用

目的：观察体外循环中应用抑肽酶对血小板数及功能的影响。方法：２９例心内直视手术患者，分为Ｉ观察组（ｎ＝１０）预充液中一次性加入国产抑肽酶５万单位／ｋｇ，Ｉ观察组（ｎ＝１０）一次性加入抑肽酶８～１０万单位／ｋｇ，对照组（ｎ＝９）常规预充。３组均观察血小板计数、血小板聚集功能、术后２４小时胸腔引流量和血红蛋白及输血量。结果：术后血小板计数在Ｉ观察组为（１２３．０±３．０）×１０９／Ｌ，显著高于对照组的（９１．５±４．０）×１０９／Ｌ（Ｐ＜０．０５）。血小板聚集功能体外循环中较体外循环前降低，在Ｉ观察组降低不明显与Ｉ观察组和对照组相比较差异显著（Ｐ＜０．０５），术后２４小时胸腔引流量及输血量在ＩＩ观察组较对照组分别减少４２．７％（Ｐ＜０．０５）和４８．１％（Ｐ＜０．０５）。结论：体外循环中应用大剂量国产抑肽酶对术后血小板数及功能均有良好的保护作用，明显减少术后出血及库血的应用。     

乌司他丁和抑肽酶对心血管手术患者血液的保护作用

目的观察乌司他丁和抑肽酶对体外循环(CPB)心脏手术的血液保护功能。方法选择90例风湿性心脏病瓣膜置换术的患者,随机分成3组。乌司他丁组(30例):给予乌司他丁12000U/kg,于麻醉诱导后至CPB开始前缓慢静注半量,另半量加入预充液中随转机进入体内;抑肽酶组(30例):于CPB中一次性给予抑肽酶5000000U;对照组(30例):给予等量生理盐水。结果与对照组相比,乌司他丁组术后24h胸腔积液量减少33.3%(P<0.05),抑肽酶组术后24h胸腔积液量减少39.8%(P<0.05),乌司他丁组和抑肽酶组相比差异无统计学意义。抑肽酶组有2例发生严重过敏。结论乌司他丁和抑肽酶均具有维持纤溶活性稳定,保护血小板功能,从而减少术中及术后出血量。     

Aprotinin application has no negative effect on osseous implant integration: a biomechanical and histomorphometric investigation in a rat model

Intraoperative blood loss requiring allogenic blood transfusion (ABT) is a common problem in major orthopedic surgery. Since transfusion related side effects up to fatal consequences due to blood type incompatibility cannot be excluded completely, it is desirable to reduce the amount of blood loss and transfusions to a minimum. Encouraging results in the application of aprotinin, a natural protease-inhibitor with antifibrinolytic, bleeding-reducing properties, in thoracic-, heart- and abdominal surgery led to the use of aprotinin also in orthopedic surgery. One important safety issue in the use of aprotinin in orthopedic surgery is a possible negative effect on the osseous integration of an implant due to the multiple interactions of aprotinin with several enzymatic systems. In this study, we therefore investigated the influence of aprotinin on the osseous ingrowth of a titanium-implant in a rat model. Forty female Sprague–Dawley rats underwent unilateral retrograde nailing of the femur. Animals were divided in two groups, one receiving i.v. aprotinin intraoperatively, the other group receiving the same amount as saline solution. After 56 days animals were killed and from each group half of the femora were prepared for biomechanical testing, the other half for histological examination. The push-out experiment revealed no significant difference between the aprotinin-group and the control-group, both showing comparable shear stresses. In addition, the histomorphometrical analysis showed comparable implant integration between both groups. The results demonstrate that perioperative aprotinin application has no negative effect on osseous implant integration in a rat model. An erratum to this article can be found at     

Aprotinin in cardiac surgery patients: is the risk worth the benefit?

Background: Aprotinin is the only Food and Drug Administration-approved agent to reduce haemorrhage related to cardiac surgery and its safety and efficacy has been extensively studied. Our study sought to compare the efficacy, early and late mortality and major morbidity associated with aprotinin compared with e-aminocaproic acid (EACA) in cardiac surgery operations. Methods: Between January 2002 and December 2006, 2101 patients underwent coronary artery bypass grafting (CABG), valve surgery or CABG and valve surgery in our institution with the use of aprotinin (1898 patients) or EACA (203 patients). Logistic regression and propensity score analysis were used to adjust for imbalances in the patients’ preoperative characteristics. The propensity score-adjusted sample included 570 patients who received aprotinin and 114 who received EACA (1–5 matching). Results: Operative mortality was higher in the aprotinin group in univariate (aprotinin 4.3% vs EACA 1%, p = 0.023) but not propensity score-adjusted multivariate analysis (4% vs 0.9%, p = 0.16). In propensity score-adjusted analysis, aprotinin was also associated with a lower rate of blood transfusion (38.8% vs 50%, p = 0.04), a lower rate of haemorrhage-related re-exploration (3.7% vs 7.9%, p = 0.04) and a higher risk of in-hospital cardiac arrest (3.7% vs 0%, p = 0.03) and a marginally but not statistically significantly higher risk of acute renal failure (6.8% vs 2.6%, p = 0.09). In Cox proportional hazards regression analysis, the risk of late death was higher in the aprotinin compared to EACA group (hazard ratio = 4.33, 95% confidence interval (CI) = 1.60–11.67, p = 0.004). Conclusion: Aprotinin decreases the rate of postoperative blood transfusion and haemorrhage-related re-exploration, but increases the risk of in-hospital cardiac arrest and late mortality after cardiac surgery when compared to EACA. Cumulative evidence suggests that the risk associated with aprotinin may not be worth the haemostatic benefit.     

Use of aprotinin in cardiac surgery: effectiveness and safety in a population-based study

Objective: The effectiveness and safety of aprotinin use in cardiac surgery have been questioned. More data reflecting everyday clinical practice from large-scale, unselected populations are needed. We compared the effectiveness and safety of aprotinin in cardiac surgery with those of tranexamic acid in a follow-up study using the population-based Danish health-care databases. Methods: We identified a total of 3535 patients who underwent cardiac surgery at the Aarhus University Hospital, Skejby, between 1 January 2003 and 31 December 2006; of these, 635 patients were treated with aprotinin and 2900 with tranexamic acid. We used propensity score matching to match aprotinin-treated patients with tranexamic-acid-treated patients in a 1:1 ratio, followed by Poisson regression analysis to compute relative risks (RRs). Results: Patients treated with aprotinin had more severe preoperative risk profiles than the tranexamic-acid-treated patients. The rates of postoperative drainage and transfusion of red blood cells were similar in the two groups, whereas the aprotinin group received plasma (adjusted RR = 1.39; 95% confidence interval (CI): 1.15–1.68) and platelets (adjusted RR = 1.47; 95% CI: 1.19–1.81) more frequently than the tranexamic acid group. There were no statistically significant differences in risks of re-operation due to bleeding (adjusted RR = 1.22; 95% CI: 0.84–1.78), 30-day mortality (adjusted RR = 1.03; 95% CI: 0.69–1.54), acute myocardial infarction (adjusted RR = 1.06; 95% CI: 0.69–1.64), stroke (adjusted RR = 1.36; 95% CI: 0.75–2.44) or composite major event (adjusted RR = 1.14; 95% CI: 0.87–1.50) between the two groups. However, patients who received aprotinin had an increased risk of postoperative dialysis (adjusted RR = 1.76; 95% CI: 1.15–2.70). Conclusions: Aprotinin treatment was associated with an increased use of plasma and platelet transfusion and an increased risk for postoperative dialysis, but not with other adverse outcomes, including short-term mortality.     

Heme Oxygenase-1 Induced by Aprotinin Inhibits Vascular Smooth Muscle Cell Proliferation Through Cell Cycle Arrest in Hypertensive Rats

Spontaneous hypertensive rats (SHR) are an established model of genetic hypertension. Vascular smooth muscle cells (VSMC) from SHR proliferate faster than those of control rats (Wistar-Kyoto rats; WKY). We tested the hypothesis that induction of heme oxygenase (HO)-1 induced by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats. Aprotinin treatment inhibited VSMC proliferation in SHR more than in normotensive rats. These inhibitory effects were associated with cell cycle arrest in the G1 phase. Tin protoporphyrin IX (SnPPIX) reversed the anti-proliferative effect of aprotinin in VSMC from SHR. The level of cyclin D was higher in VSMC of SHR than those of WKY. Aprotinin treatment downregulated the cell cycle regulator, cyclin D, but upregulated the cyclin-dependent kinase inhibitor, p21, in VSMC of SHR. Aprotinin induced HO-1 in VSMC of SHR, but not in those of control rats. Furthermore, aprotinin-induced HO-1 inhibited VSMC proliferation of SHR. Consistently, VSMC proliferation in SHR was significantly inhibited by transfection with the HO-1 gene. These results indicate that induction of HO-1 by aprotinin inhibits VSMC proliferation through cell cycle arrest in hypertensive rats.